Original Article

Improving medication safety and diabetes management in Hong Kong: a multidisciplinary approach

Hong Kong Med J 2017 Apr;23(2):158–67 | Epub 17 Mar 2017

DOI: 10.12809/hkmj165014

ORIGINAL ARTICLE CME

Improving medication safety and diabetes management in Hong Kong: a multidisciplinary approach

Agnes YS Chung, BPharm¹; Shweta Anand, BDS¹; Ian CK Wong, PhD²; Kathryn CB Tan, MD, MBBCH³; Christine FF Wong, PharmD⁴; William CM Chui, MSc⁴; Esther W Chan, PhD¹

¹ Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

² Research Department of Practice and Policy, School of Pharmacy, University College London, United Kingdom

³ Department of Medicine, Queen Mary Hospital, Pokfulam, Hong Kong

⁴ Department of Pharmacy, Queen Mary Hospital, Pokfulam, Hong Kong

Corresponding author: Dr Esther W Chan (ewchan@hku.hk)

Full paper in PDF

Abstract

Introduction: Patients with diabetes often require complex medication regimens. The positive impact of pharmacists on improving diabetes management or its co-morbidities has been recognised worldwide. This study aimed to characterise drug-related problems among diabetic patients in Hong Kong and their clinical significance, and to explore the role of pharmacists in the multidisciplinary diabetes management team by evaluating the outcome of their clinical interventions.

Methods: An observational study was conducted at the Diabetes Clinic of a public hospital in Hong Kong from October 2012 to March 2014. Following weekly screening, and prior to the doctor’s consultation, selected high-risk patients were interviewed by a pharmacist for medication reconciliation and review. Drug-related problems were identified and documented by the pharmacist who presented clinical recommendations to doctors to optimise a patient’s drug regimen and resolve or prevent potential drug-related problems.

Results: A total of 522 patients were analysed and 417 drug-related problems were identified. The incidence of patients with drug-related problems was 62.8% with a mean of 0.9 (standard deviation, 0.6) drug-related problems per patient. The most common categories of drug-related problems were associated with dosing (43.9%), drug choice (17.3%), and non-allergic adverse reactions (15.6%). Drugs most frequently involved targeted the endocrine or cardiovascular system. The majority (71.9%) of drug-related problems were of moderate clinical significance and 28.1% were considered minor problems. Drug-related problems were totally solved (50.1%) and partially solved (11.0%) by doctors’ acceptance of pharmacist recommendations, or received acknowledgement from doctors (5.5%).

Conclusions: Pharmacists, in collaboration with the multidisciplinary team, demonstrated a positive impact by identifying, resolving, and preventing drug-related problems in patients with diabetes. Further plans for sustaining pharmacy service in the Diabetes Clinic would enable further studies to explore the long-term impact of pharmacists in improving patients’ clinical outcomes in diabetes management.

New knowledge added by this study

Pharmacists make an important contribution to the identification, resolution, and prevention of drug-related problems by medication reconciliation and review. Most problems were related to dosing with moderate clinical significance according to Dean and Barber’s validated scale for scoring medication errors. Over half of the clinical interventions initiated by pharmacists were accepted or acknowledged by doctors to improve medication management.

Implications for clinical practice or policy

Collaboration between pharmacists and other health care professionals is valuable for the improvement of medication safety in the management of diabetes.

[Abstract in Chinese]

Introduction

Diabetes mellitus is a chronic disease that is prevalent worldwide.1 Patients with diabetes often require complex medication regimens and are likely to develop multiple irreversible complications that significantly worsen their quality of life.2 Effective diabetes management requires collaboration among health care professionals in a multidisciplinary diabetes management team (DMT). Pharmacists, as a part of the DMT, are well positioned to optimise pharmacological treatment, educate patients about diabetes management, and promote medication compliance.3

The major role of a pharmacist in a DMT is to conduct medication reconciliation (MR) and medication review—MR is the process of comparing a patient’s prescriptions with all their usual medications and identifying the most complete and updated medication history4; whereas medication review aims to review a patient’s medical and drug history, assess their current prescriptions, and ascertain their drug knowledge and compliance.5 This enables pharmacists to identify drug-related problems (DRPs) that can actually or potentially interfere with optimum health outcomes in specific patients.6 7 Polypharmacy (concurrent use of multiple medications) is commonly seen in people with chronic diseases which could lead to potential DRPs.8 9 These DRPs might be overlooked by prescribers and interfere with diabetes management. In several overseas studies, pharmacists have implemented timely interventions to resolve or prevent DRPs by offering recommendations to prescribers, with an acceptance rate of over 60%.10 11 12 13

The positive impact of pharmacists in improving diabetes management or its co-morbidities has also been recognised by interventional and controlled observational studies worldwide.14 Greater overall improvement in glycosylated haemoglobin, fasting plasma glucose, blood pressure, cholesterol levels, renal outcomes, and medication adherence has been demonstrated in patients who received pharmacist-led diabetes services compared with the standard care.12 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Few studies, however, have been conducted in Hong Kong.17 29 In view of inadequate available data and potential for expansion of local pharmacy services, more studies are required to investigate the future development of a sustainable diabetes service provided by pharmacists.

This study aimed to characterise DRPs among Chinese diabetic out-patients, and to define the clinical significance and outcome of pharmacist interventions; thereby highlighting their contribution to the detection, resolution, and prevention of DRPs to improve medication safety and diabetes management.

Methods

Study design and setting

An observational study was conducted weekly in the Diabetes Clinic at Queen Mary Hospital (QMH) from October 2012 to March 2014. The study protocol was approved by the Institutional Review Board of the University of Hong Kong (HKU)/Hospital Authority (HA) Hong Kong West Cluster. Informed consent was not required for the study.

Inclusion and exclusion criteria

Patients were included if they were at ‘high risk’ due to their multiple disease state and complex drug regimen and if they fulfilled the following criteria:

Aged ≥65 years (elderly patients are considered having high risk for DRPs since they usually take more drugs than younger patients)
Taking five or more medications including all routes of administration, or over-the-counter medications (regular or as needed)
Taking medications that have a low therapeutic index or require monitoring
Attending multiple specialist clinics

Nursing home residents were excluded due to their relatively low risk for non-compliance, compared with community-dwelling elderly patients.

Procedure and materials

The day before the scheduled weekly clinic consultation, two researchers screened the medical history, previous consultation notes, current medications, and latest laboratory results of Chinese elderly patients with diabetes to select high-risk patients. Selected patient records were printed and prepared for quick reference during the medication interview. To facilitate data collection, a memo was attached to the patient’s records to indicate patient selection.

Two pharmacists from QMH and one from the HKU attended the clinic on alternate Wednesdays to compile a thorough medication history from selected patients and conduct an independent medication review prior to the medical consultation. During the review, pharmacists also recorded medications not shown in the Clinical Management System (CMS), such as drugs prescribed by general practitioners (GPs), over-the-counter products, vitamins, and herbal supplements.

A MR form (Appendix 1) was then completed by pharmacists, documenting the identified DRPs and formulating an intervention proposal. The MR forms were collected following medical consultation, either on the same day or within the next few days.

Appendix 1. Medication reconciliation form

Pharmacist intervention

For the selected high-risk patients, pharmacists reviewed the patient’s drug regimen and made recommendations to doctors for adjustment, provided doctors with an updated drug list after MR, suggested a need to further investigate a patient’s condition, provided drug education to patients and caregivers, reinforced the importance of drug compliance to patients, and suggested lifestyle modifications such as dietary control.

Drug-related problems were identified from the completed MR forms, and pharmacist recommendations were collected for analysis. The CMS was checked for outcome of intervention.

Data collection

Demographic data—for example, age, gender, drug allergy status, number of regular medications obtained from the HA clinics, and the most current laboratory results, including glycosylated haemoglobin, fasting plasma glucose, and lipids (Appendix 2)—were retrieved from the CMS. Additional information in terms of medication, drug storage methods, smoking status, drinking habits, vaccination record, and latest readings from self-monitoring of blood glucose (SMBG) was also collected.

Appendix 2. Form for patient’s laboratory values

Data analysis

Demographic data were tabulated as frequency and percentage using Microsoft Excel 2010. Primary outcomes included the frequency and categories of DRPs, drug classes involved, clinical significance of DRPs, and outcome of pharmacist interventions. The incidence of DRPs was also calculated as the percentage of patients with at least one DRP.

Definition and classification of drug-related problems

Using the Pharmaceutical Care Network Europe (PCNE) classification system for DRPs V5.01, DRPs were categorised as ‘adverse reactions’, ‘drug choice problem’, ‘dosing problem’, ‘drug use problem’, ‘interactions’, or ‘others’.7 This is an established system that has been revised several times with tested validity and reproducibility11 31 and has been used in many studies.9 32 33 When a single drug was associated with more than one possible DRP category, the one that best described the clinical scenario was chosen. Drugs involved in DRPs were categorised according to their British National Formulary classification.34

The clinical significance of DRPs was assessed to determine their actual or potential consequence for patient health outcomes. Using a validated scale,35 four independent reviewers (two pharmacists and two doctors) scored the severity of each DRP from 0 (without potential effects on the patient) to 10 (lead to a fatal event). A mean score of <3 indicated a minor problem (very unlikely to cause adverse effects), 3 to 7 indicated a moderate problem (likely to cause some adverse effects or interfere with therapeutic goals), and >7 indicated a severe DRP that could likely cause death or lasting impairment.

To evaluate prescribers’ acceptance level, the outcome of pharmacist interventions was categorised as ‘not known’, ‘solved’, ‘partially solved’, or ‘not solved’ according to PCNE classification V5.01.7

Results

Patient demographics and characteristics

During the study period, a total of 652 patients were included based on the selection criteria; 526 (80.7%) were interviewed, of whom 522 (99.2%) were analysed (Fig).

Figure. Selection of study patients

The mean (± standard deviation) age of the 522 patients was 75.2 ± 5.4 years (range, 65-91 years). The number of prescribed regular HA medications ranged from 5 to 17 with a mean of 9 ± 2. The demographics and characteristics of patients are shown in Table 1.

Table 1. Demographics and characteristics of patients

Categories of drug-related problems

A total of 417 DRPs were identified. Among the 522 patients analysed, 328 (62.8%) had at least one DRP and the mean number of DRPs per patient was 0.9 ± 0.6. The most prevalent DRP category was related to dosing (n=183, 43.9%), followed by drug choice (n=72, 17.3%) and non-allergic adverse reaction (n=65, 15.6%). The subcategories of each of them are listed in Table 2.

Table 2. Categories of drug-related problems

Classes of medications involved in drug-related problems

The most common classes of medication involved were those targeting the endocrine system with 190 (45.6%) DRPs, followed by cardiovascular system with 159 (38.1%) DRPs (Table 3).

Table 3. Classes of medications involved in drug-related problems

Clinical significance of drug-related problems

The mean clinical severity scores assigned to DRPs ranged from 0.50 to 7.00. The majority of DRPs (n=300, 71.9%) were classified as moderate with the remainder (n=117, 28.1%) considered minor. No clinically severe DRP was identified (Table 4).

Table 4. Clinical severity scores assigned to drug-related problems

Outcome of pharmacist interventions

As Table 5 shows, modifying drug regimens or reinforcing compliance by doctors or referral to pharmacists solved 209 (50.1%) DRPs. On the other hand, 46 (11.0%) DRPs were partially resolved by doctors adjusting prescriptions, although not according to pharmacist recommendations; 62 (14.9%) DRPs were not resolved due to patient reluctance to change prescriptions, resolution considered unnecessary, or for unknown reasons; 23 (5.5%) DRPs had an unknown outcome because these were non-compliance issues not acknowledged by doctors.

Table 5. Outcome of pharmacist interventions

Discussion

The incidence of patients with DRPs (62.8%) and the mean number of DRPs per patient analysed (0.9) in this study were comparable to a Norwegian study (59.2% and 1.2, respectively)10 but considerably lower than those identified in four overseas studies (incidence of 80.7%-90.5%, and mean number of DRPs per patient between 1.9 ± 1.2 and 4.6 ± 1.7).9 11 12 36 Such discrepancies might be attributed to variations in patient selection criteria, data collection methods, pharmacists’ clinical experience, as well as study duration and setting.9 36 37

The majority of DRPs were dosing problems (43.9%), with “drug dose too low or dosage regimen insufficient” as the largest subcategory. In contrast to the lower percentage (5.9%-21.6%) in five overseas studies,9 10 11 12 36 our high prevalence of dosing problems was in line with a local study of medication incidents among hospital in-patients,38 mostly arising from self-adjustment of dosage or frequency, confusion about previous dose changes and dosage modification by GPs or doctors overseas. These highlight the pivotal role of local pharmacists in conducting MR, reviewing drug dosages to ensure safety and efficacy, monitoring patients’ metabolic control regularly as well as reminding patients and/or their caregivers to maintain an updated medication list and follow the latest drug label instructions.

Drug choice problem was the second most common DRP; 17.3% of DRPs related to this category, which is comparable to the findings of two overseas studies (9.1%, 23%)9 36 but deviating from others (31.8%-30.2%).10 11 The most common subcategory was “no drug prescribed but clear indication”, such as the omission of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB) in patients with microalbuminuria or patient’s reluctance to use insulin. Hence, pharmacists have a role in advising doctors to adhere to the latest treatment guidelines and educate patients about the treatment benefits of each drug class.39 Other causes of problems surrounding drug choice included drug duplication and changes to drug choices by GPs to prevent side-effects. This suggests that some DRPs might have arisen due to the lack of a common platform between the public and private health care sector for sharing patient information. Pharmacists can make a valuable contribution by establishing a patient’s drug history by MR and by liaison with different health care sectors.

Adverse reactions were the third most common DRP (15.6%). The major types of “side-effects suffered (non-allergic)” were insulin-induced hypoglycaemia, gastrointestinal disturbances, and dizziness caused by antidiabetic drugs, for which pharmacists recommended changes in drug choice or dosage. Adverse reactions could lead to other DRP categories,7 such as drug choice and drug use problems. This reflects the pharmacist’s pivotal role in reviewing prescribed doses, suggesting dosage adjustments to doctors, monitoring adverse effects, and providing information about prevention of side-effects (such as performing SMBG regularly to prevent hypoglycaemia).39

Drug use issues were the fourth most common category with comparable prevalence (12.0%) with a Malaysian study9 although this ranges widely among other studies (3.8%-54.2%).10 11 36 Reasons for the subcategory of “drug not taken/administered at all” included inability to purchase a self-financed item due to cost, ignorance of the indications, concern about side-effects, and confusion about previous regimen changes.40 In our study, pharmacists mainly intervened by direct patient counselling, recommending reinforcement of patient compliance to doctors or suggesting changes to drug regimens. Pharmacists could also work closely with other DMT members to educate patients about their disease and the most updated regimen, address drug cost concerns or side-effects, and encourage patients to update their medication list and use dose administration aids such as pill boxes.41

The low prevalence of drug interactions (1.0%) was similar to that (0.6%) in a Danish study,36 although much higher percentages were found in three other studies (8.0%-16.3%),9 10 11 possibly ascribed to differences in prescribing practice, references used to define drug interactions,9 and also because CMS could already detect a range of clinically significant interactions when doctors issued prescriptions. Nonetheless system checking and prompts cannot replace clinical judgement or recommendations of alternative regimens. Other categories of DRPs included “insufficient awareness of health and diseases” (such as poor dietary control) and “inappropriate timing of administration”, but this category could also encompass therapy failure and inappropriate lifestyle choices, resulting in greater variation of prevalence from overseas studies (6.8%-46.6%).9 10 11 36 Pharmacists are ideally positioned to advise patients about the importance of diet, smoking cessation, regular exercise, and SMBG.22

The drug classes most implicated in DRPs were for the endocrine system (45.6%) followed by cardiovascular system (38.1%). These findings were not surprising as insulins, oral antidiabetic drugs, antihypertensive, antihyperlipidaemic, antiplatelet agents, and ACEI/ARB are most commonly prescribed to manage diabetes, its co-morbidities and complications.11 39

The majority of DRPs were classified as moderate. Among similar overseas studies, only one analysed the clinical significance of DRPs, in which 87% had high or medium clinical/practical relevance.10 These findings could not be readily compared with the present study because of different assessment scales, potential variations in reviewers’ clinical experience,35 and unknown relative proportions of cases with medium and high relevance.

Over half of the DRPs were totally solved as doctors implemented pharmacist recommendations. The acceptance rate was somewhat similar to that observed in two overseas studies (60.2%-62.7%).12 13 The physicians acknowledged the provision of service by pharmacists and were more aware of the written recommendations provided by pharmacists. In particular, the value of verbal communication between different health care professionals in resolving or preventing DRPs has been recognised in earlier studies,10 42 43 44 45 suggesting potential improvement in the acceptance rate if pharmacists had more time to hand over DRPs by speaking with doctors.

The outcome of pharmacist interventions could also be influenced by doctors’ clinical experience and familiarity with the new service. Doctors’ acceptance level could have been underestimated since some of them might have neglected or missed written information from pharmacists. This highlights the importance of promoting the role of pharmacists to doctors and keeping all participating doctors well-informed.

Difficulties and limitations

This pilot study allowed for an opportunity to assess the proportion of patients who might be seen by clinical pharmacists in a busy specialist out-patient clinic at a teaching hospital. Approximately 10% of patients were chosen each week and not all eligible patients could be selected owing to time restrictions. The number of patients interviewed was further limited due to time constraints, patient absence or refusal. Local figures from the QMH Diabetes Clinic indicate that approximately 7% to 8% of all patients who attend the clinic are deemed ‘high risk’, based on ongoing work and prioritisation of those taking five or more regular medications. Limited work space was another consideration. A designated area is required to conduct patient interviews. Further arrangements could be made with the medical and nursing staff in the Diabetes Clinic to access better space.

This study only described the current situation of DRPs. It did not assess the implementation of interventions and their impact on patient health outcome. As the majority of patients did not bring their drugs to the clinic and had no medication list available, the MR process was not always comprehensive or effective. Only a minority of patients could name their regular drugs. The majority relied on pharmacist investigation and prompts about the colour, shape, package, or indication of each drug. Due to the potential for misinterpretation, DRP prevalence may be underestimated. One possible solution might be to show patients samples of commonly prescribed medications. Alternatively, selected patients could be telephoned in advance and asked to bring along their medications, although this measure may not be sustainable. A multifaceted promotional campaign could be introduced to encourage patients to bring their regular medications to clinic. This has been shown to be effective in an emergency setting.46

Although completed MR forms were presented to doctors after the interviews, some written information might have been missed with a consequent lack of response to certain DRPs. Pharmacists should ideally have informed doctors about every DRP in person, but this was not always possible due to time constraints and the great volume of patients. In the long run, pharmacists should document DRPs and their recommendations in the CMS. This would enhance visibility and allow doctors to input their response electronically and facilitate organised documentation and easy data retrieval.

Future directions

Upon completion of this study, pharmacists have been continuing to provide MR and medication review services in QMH Diabetes Clinic. They have also been collecting data about DRPs to plan for a sustainable service. Following a longer study period, patient and staff satisfaction surveys could be introduced and also control groups added to enable comparison of the effectiveness of pharmacist intervention. This would further support the extension of hours of service and potentially the setup of similar pharmacy services to other hospitals and diabetes clinics in Hong Kong.

Conclusions

Approximately two thirds of patients at the Diabetes Clinic had at least one DRP. The most frequent categories of DRPs were related to dosing, drug choice, and non-allergic adverse reaction. Drugs targeting the endocrine and cardiovascular systems were most commonly involved. The majority of DRPs were of moderate clinical significance. Pharmacist interventions for over half the DRPs were accepted or acknowledged by prescribers. Through effective communication and collaboration within the multidisciplinary health care team, pharmacists had a positive impact on identifying, resolving, and preventing DRPs. Future plans to sustain the diabetes service will enable more local research to enhance medication safety and optimise patients’ medication regimens in diabetes management.

Acknowledgements

We would like to acknowledge Ms Cyan Chan for her assistance in patient screening and data collection, and pharmacists Ms Phoebe Chan (HKU); Ms Amy Chan, Ms Dominique Yeung, Ms Katie Chan, and Mr Ric Fung (QMH); Prof Karen Lam (QMH); nursing and medical staff in S6 Diabetes Clinic, QMH for their advice and contributions to service provision in the study. We would also like to thank Mr Michael Ling and Ms Elaine Lo (Kwong Wah Hospital); Dr Michael Mok (Geelong Hospital, Victoria, Australia); Dr Vickie Tse (HKU) contributing to the independent assessment of clinical severity of DRPs; and Dr Anthony Tam (HKU) and Sharon Law (HKU) for proofreading the manuscript.

References

1. International Diabetes Federation International diabetes atlas. 6th ed. Available from: http://www.diabetesatlas.org/resources/previous-editions.html. Accessed Mar 2014.

2. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes 2008;26:77-82. Crossref

3. Tapp H, Phillips SE, Waxman D, Alexander M, Brown R, Hall M. Multidisciplinary team approach to improved chronic care management for diabetic patients in an urban safety net ambulatory care clinic. J Am Board Fam Med 2012;25:245-6. Crossref

4. Hellström LM, Bondesson Å, Höglund P, Eriksson T. Errors in medication history at hospital admission: prevalence and predicting factors. BMC Clin Pharmacol 2012;12:9. Crossref

5. Krska J, Cromarty JA, Arris F, et al. Pharmacist-led medication review in patients over 65: a randomized, controlled trial in primary care. Age Ageing 2001;30:205-11. Crossref

6. Draft statement on pharmaceutical care. ASHP Council on Professional affairs. American Society of Hospital Pharmacists. Am J Hosp Pharm 1993;50:126-8.

7. Pharmaceutical Care Network Europe. The PCNE Classification V 5.01. 2006. Available from: http://www.pcne.org/upload/files/16_PCNE_classification_V5.01.pdf. Accessed 22 Oct 2013.

8. Viktil KK, Blix HS, Moger TA, Reikvam A. Polypharmacy as commonly defined is an indicator of limited value in the assessment of drug-related problems. Br J Clin Pharmacol 2007;63:187-95. Crossref

9. Zaman Huri H, Fun Wee H. Drug related problems in type 2 diabetes patients with hypertension: a cross-sectional retrospective study. BMC Endocr Disord 2013;13:2. Crossref

10. Granas AG, Berg C, Hjellvik V, et al. Evaluating categorisation and clinical relevance of drug-related problems in medication reviews. Pharm World Sci 2010;32:394-403. Crossref

11. van Roozendaal BW, Krass I. Development of an evidence-based checklist for the detection of drug related problems in type 2 diabetes. Pharm World Sci 2009;31:580-95. Crossref

12. Borges AP, Guidoni CM, Ferreira LD, de Freitas O, Pereira LR. The pharmaceutical care of patients with type 2 diabetes mellitus. Pharm World Sci 2010;32:730-6. Crossref

13. DeName B, Divine H, Nicholas A, Steinke DT, Johnson CL. Identification of medication-related problems and health care provider acceptance of pharmacist recommendations in the DiabetesCARE program. J Am Pharm Assoc 2008;48:731-6. Crossref

14. Kiel PJ, McCord AD. Pharmacist impact on clinical outcomes in a diabetes disease management program via collaborative practice. Ann Pharmacother 2005;39:1828-32. Crossref

15. Wubben DP, Vivian EM. Effects of pharmacist outpatient interventions on adults with diabetes mellitus: a systematic review. Pharmacotherapy 2008;28:421-36. Crossref

16. Evans CD, Watson E, Eurich DT, et al. Diabetes and cardiovascular disease interventions by community pharmacists: a systematic review. Ann Pharmacother 2011;45:615-28. Crossref

17. Chan CW, Siu SC, Wong CK, Lee VW. A pharmacist care program: positive impact on cardiac risk in patients with type 2 diabetes. J Cardiovasc Pharmacol Ther 2012;17:57-64. Crossref

18. Pepper MJ, Mallory N, Coker TN, Chaki A, Sando KR. Pharmacists’ impact on improving outcomes in patients with type 2 diabetes mellitus. Diabetes Educ 2012;38:409-16. Crossref

19. Jarab AS, Alqudah SG, Mukattash TL, Shattat G, Al-Qirim T. Randomized controlled trial of clinical pharmacy management of patients with type 2 diabetes in an outpatient diabetes clinic in Jordan. J Manag Care Pharm 2012;18:516-26. Crossref

20. Jacobs M, Sherry PS, Taylor LM, Amato M, Tataronis GR, Cushing G. Pharmacist Assisted Medication Program Enhancing the Regulation of Diabetes (PAMPERED) study. J Am Pharm Assoc 2012;52:613-21. Crossref

21. Ali M, Schifano F, Robinson P, et al. Impact of community pharmacy diabetes monitoring and education programme on diabetes management: a randomized controlled study. Diabet Med 2012;29:e326-33. Crossref

22. Al Mazroui NR, Kamal MM, Ghabash NM, Yacout TA, Kole PL, McElnay JC. Influence of pharmaceutical care on health outcomes in patients with type 2 diabetes mellitus. Br J Clin Pharmacol 2009;67:547-57. Crossref

23. Mehuys E, Van Bortel L, De Bolle L, et al. Effectiveness of a community pharmacist intervention in diabetes care: a randomized controlled trial. J Clin Pharm Ther 2011;36:602-13. Crossref

24. Shah M, Norwood CA, Farias S, Ibrahim S, Chong PH, Fogelfeld L. Diabetes transitional care from inpatient to outpatient setting: pharmacist discharge counseling. J Pharm Pract 2013;26:120-4. Crossref

25. Heisler M, Hofer TP, Schmittdiel JA, et al. Improving blood pressure control through a clinical pharmacist outreach program in patients with diabetes mellitus in 2 high-performing health systems: the adherence and intensification of medications cluster randomized, controlled pragmatic trial. Circulation 2012;125:2863-72. Crossref

26. Dobesh PP. Managing hypertension in patients with type 2 diabetes mellitus. Am J Health Syst Pharm 2006;63:1140-9. Crossref

27. Planas LG, Crosby KM, Mitchell KD, Farmer KC. Evaluation of a hypertension medication therapy management program in patients with diabetes. J Am Pharm Assoc 2009;49:164-70. Crossref

28. Leal S, Soto M. Chronic kidney disease risk reduction in a Hispanic population through pharmacist-based disease-state management. Adv Chronic Kidney Dis 2008;15:162-7. Crossref

29. Leung WY, So WY, Tong PC, Chan NN, Chan JC. Effects of structured care by a pharmacist-diabetes specialist team in patients with type 2 diabetic nephropathy. Am J Med 2005;118:1414. Crossref

30. American Pharmacists Association. DOTx. MED: Pharmacist-delivered interventions to improve care for patients with diabetes. J Am Pharm Assoc 2012;52:25-33. Crossref

31. Björkman IK, Sanner MA, Bernsten CB. Comparing 4 classification systems for drug-related problems: processes and functions. Res Social Adm Pharm 2008;4:320-31. Crossref

32. Eichenberger PM, Lampert ML, Kahmann IV, van Mil JW, Hersberger KE. Classification of drug-related problems with new prescriptions using a modified PCNE classification system. Pharm World Sci 2010;32:362-72. Crossref

33. Hohmann C, Eickhoff C, Klotz JM, Schulz M, Radziwill R. Development of a classification system for drug-related problems in the hospital setting (APS-Doc) and assessment of the inter-rater reliability. J Clin Pharm Ther 2012;37:276-81. Crossref

34. British Medical Association, Royal Pharmaceutical Society of Great Britain. British National Formulary 71. London: British Medical Association, Royal Pharmaceutical Society; 2016.

35. Dean BS, Barber ND. A validated, reliable method of scoring the severity of medication errors. Am J Health Syst Pharm 1999;56:57-62.

36. Haugbølle LS, Sørensen EW. Drug-related problems in patients with angina pectoris, type 2 diabetes and asthma—interviewing patients at home. Pharm World Sci 2006;28:239-47. Crossref

37. Westerlund T, Almarsdottir AB, Melander A. Factors influencing the detection rate of drug-related problems in community pharmacy. Pharm World Sci 1999;21:245-50. Crossref

38. Song L, Chui WC, Lau CP, Cheung BM. A 3-year study of medication incidents in an acute general hospital. J Clin Pharm Ther 2008;33:109-14. Crossref

39. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care 2013;36 Suppl 1:S11-66. Crossref

40. Odegard PS, Gray SL. Barriers to medication adherence in poorly controlled diabetes mellitus. Diabetes Educ 2008;34:692-7. Crossref

41. Morello CM, Chynoweth M, Kim H, Singh RF, Hirsch JD. Strategies to improve medication adherence reported by diabetes patients and caregivers: results of a taking control of your diabetes survey. Ann Pharmacother 2011;45:145-53. Crossref

42. Perera PN, Guy MC, Sweaney AM, Boesen KP. Evaluation of prescriber responses to pharmacist recommendations communicated by fax in a medication therapy management program (MTMP). J Manag Care Pharm 2011;17:345-54. Crossref

43. Doucette WR, McDonough RP, Klepser D, McCarthy R. Comprehensive medication therapy management: identifying and resolving drug-related issues in a community pharmacy. Clin Ther 2005;27:1104-11. Crossref

44. Chrischilles EA, Carter BL, Lund BC, et al. Evaluation of the Iowa Medicaid pharmaceutical case management program. J Am Pharm Assoc 2004;44:337-49. Crossref

45. Galt KA. Cost avoidance, acceptance, and outcomes associated with a pharmacotherapy consult clinic in a Veterans Affairs Medical Center. Pharmacotherapy 1998;18:1103-11.

46. Chan EW, Taylor SE, Marriott JL, Barger B. Bringing patients’ own medications into an emergency department by ambulance: effect on prescribing accuracy when these patients are admitted to hospital. Med J Aust 2009;191:374-7.

Mothers’ attitude to the use of a combined oral contraceptive pill by their daughters for menstrual disorders or contraception

Hong Kong Med J 2017 Apr;23(2):150–7 | Epub 24 Feb 2017

DOI: 10.12809/hkmj164993

ORIGINAL ARTICLE

Mothers’ attitude to the use of a combined oral contraceptive pill by their daughters for menstrual disorders or contraception

KW Yiu, MRCOG, FHKAM (Obstetrics and Gynaecology); Symphorosa SC Chan, FRCOG, FHKAM (Obstetrics and Gynaecology); Tony KH Chung, FRANZCOG, FRCOG

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong

Corresponding author: Dr Symphorosa SC Chan (symphorosa@cuhk.edu.hk)

Full paper in PDF

Abstract

Introduction: Mothers’ attitude may affect use of combined oral contraceptive pills by their daughters. We explored Chinese mothers’ knowledge of and attitudes towards the use of combined oral contraceptive pills by their daughters for menstrual disorders or contraception, and evaluate the factors affecting their attitude.

Methods: This survey was conducted from October 2012 to March 2013, and recruited Chinese women who attended a gynaecology clinic or accompanied their daughter to a gynaecology clinic, and who had one or more daughters aged 10 to 18 years. They completed a 41-item questionnaire to assess their knowledge of and attitude towards use of the combined oral contraceptive pills by their daughters. The demographic data of the mothers and their personal experience in using the pills were also collected.

Results: A total of 300 women with a mean age of 45.2 (standard deviation, 5.0) years completed the questionnaire. Only 58.3% of women reported that they had knowledge about the combined oral contraceptive pills; among them, a majority (63.3%) reported that their source of knowledge came from medical professionals. Of a total possible score of 22, their mean knowledge score for risk, side-effects, benefits, and contra-indications to use of combined oral contraceptive pills was only 5.0 (standard deviation, 4.7). If the medical recommendation to use an oral contraceptive was to manage their daughter’s dysmenorrhoea, menorrhagia, acne, or contraception needs, 32.0%, 39.3%, 21.0% and 29.7%, respectively would accept this advice. Women who were an ever-user of combined oral contraceptive pills or who were more knowledgeable about combined oral contraceptives had a higher acceptance rate.

Conclusions: Chinese women had a low acceptance level of using combined oral contraceptive pills as a legitimate treatment for their daughters. This was associated with lack of knowledge or a high degree of uncertainty about their risks and benefits. It is important that health caregivers provide up-to-date information about combined oral contraceptive pills to women and their daughters.

New knowledge added by this study

Chinese women had a low acceptance level of combined oral contraceptive (COC) pills as a legitimate treatment for their daughters. This was associated with lack of knowledge or a high degree of uncertainty about the risks and benefits of COC use.

Implications for clinical practice or policy

Health caregivers should provide up-to-date information to potential COC users.

[Abstract in Chinese]

Introduction

The combined oral contraceptive (COC) pill is an effective contraception. It has a very low-risk profile documented over several decades and its protective effect on endometrial and ovarian carcinoma has been well established.1 It is also an effective treatment for menstrual problems and polycystic ovarian syndrome,2 3 which are common in adolescents.4 5 6 7 The prevalences of menorrhagia, dysmenorrhoea, and menstrual symptoms in adolescent girls have been reported to be 17.9%, 68.7%, and 37.7%, respectively.4 The prevalence of polycystic ovarian syndrome in adolescent girls has been reported to be 16% in those who attended a local paediatric and adolescent gynaecology clinic.5 Nonetheless, the use of COC pills in Chinese women has remained low; only 1% of women of reproductive age (20-49 years) in China used the pills in 2010.8 There are some obstacles to access although family planning is a relatively well-funded area of health care in China and has been implemented for decades. In Hong Kong, the situation is slightly less unusual. From an online survey conducted in Hong Kong, 12.6% of women had used an oral contraceptive in the year prior to the survey, but many of them had stopped using it.9 According to the annual report of the Family Planning Association of Hong Kong in 2014-2015, 22% of the 48 363 clients who practised birth control, including women who were both married and unmarried, used an oral contraceptive.10 Only 6% of teenage girls who attended the youth health care centres used COC pills for contraception.11

Although sex education has been integrated into the primary and secondary educational curriculum for many years, efforts to provide quality sex education have been limited.12 According to a survey conducted by the Hong Kong SAR Government, sex education at the junior secondary school level is limited to an average of 3 to 4 school hours only.13 Sometimes concepts emphasised included protection of self and avoidance of sex, especially prior to marriage.14 The median age of marriage in Hong Kong is now close to 30 years. It is notable that Hong Kong has a high rate of therapeutic abortion that is underestimated by official statistics because an indeterminate proportion is performed in mainland China due to cost considerations. In women attending for their antenatal visit, a high proportion of 36.5% reported a previous therapeutic abortion (unpublished data from our institute). This suggests that women of reproductive age may not have been educated about contraception. There is little published information on the use of COC pills for the management of menstrual problems in Hong Kong but it is likely to be low. Misconceptions and myths about COC pills are likely to be the main obstacles to use. Although extensive high-quality information about use of COC is currently available from various sources, many women remain unaware of the non-contraceptive benefits of COC. They also have little awareness of the risks of COC.15 For female adolescents, their decision about whether to use COC is likely to be influenced by their parents, especially their mothers, who may be giving advice to their daughters based on little or erroneous knowledge. This may lead mothers to make decisions that are not in their daughter’s best interests.

Focused education about COC may lead to a more balanced view, both in adolescents and their mothers. In a study of Korean and Japanese university students, significant correlation between knowledge of and positive attitude towards COC pills was reported.16 Mothers in Asia are also often involved in their teenage daughters’ decision to begin sexual relationships, the use of contraceptives, and even vaccination.17 18 Since the mothers’ attitude may affect use of COC by their daughters, we explored Chinese mothers’ knowledge of and attitudes towards such use. Mothers’ knowledge about the COC pills and factors affecting their attitude were also evaluated.

Methods

The study was conducted from October 2012 to March 2013 in the gynaecology clinic of a tertiary teaching hospital in Hong Kong. Women who attended the clinic or accompanied a daughter to the clinic, and who had one or more daughters aged 10 to 18 years were recruited. Women who did not speak or read Chinese were excluded. The participants completed a 41-item questionnaire to assess their knowledge of and attitude towards use of COC pills by their daughters. Firstly, they were asked to self-assess their own knowledge of the COC pill. The knowledge domain consisted of 19 items testing their knowledge of the non-contraceptive health benefits and side-effects of COC pills, and three items on contra-indications to use of COC pills. For each item, participants were asked to respond “yes”, “no”, or “don’t know”. They were then asked about their attitudes to the use of COC pills by their daughters aged 10 to 18 years for the management of dysmenorrhoea, menorrhagia, acne, or as a contraceptive. They were asked to respond from “strongly agree”, “agree”, “disagree”, to “strongly disagree”. Reasons for agreeing or disagreeing with the use of COC pills and the appropriate age or life-events for using COC pills by their daughters were also asked. Finally, demographic data and their personal experience in using COC pills were collected. Knowledge score and uncertainty score were calculated for the participants based on their response15 16—knowledge score was defined as the score of correct answers with 1 score given for each correct answer (ie range from 0-22); a “don’t know” reply would create the uncertainty score. The participants provided written informed consent, and approval was obtained from the local ethics committee (CRE-2012.186).

Statistical analyses

Descriptive statistics were used to summarise participants’ demographic information. Association between participant characteristics and overall attitude was explored using Chi squared and independent-samples t test. A P value of <0.05 was considered statistically significant. All statistical analyses were conducted using the SPSS (Windows version 18.0; SPSS Inc, Chicago [IL], United States). Assuming that 50% of the women accepted the use of COC pills by their daughters with an accepted error of 0.05%, 278 women were required. An additional 10% was recruited to prepare for an incomplete questionnaire.

Results

Apart from 150 women who were excluded because they did not have a daughter aged 10 to 18 years, a total of 317 women were invited to participate; 302 agreed and 300 (94.6%) completed the questionnaire. Demographic characteristics of the participants are shown in Table 1. Their mean age was 45.2 years (range, 28-58 years). The median number of daughters was one and most participants (88.3%) were married. Most (>70%) had high school education. In all, 125 (41.7%) were ever-users of COC pills, including both current and ex-users. Overall, 175 (58.3%) reported that they had knowledge about the COC pills, while 125 (41.7%) reported no knowledge.

Table 1. Demographics of the participants

The rates of giving correct answers about the COC pill and the comparison between ever- and never-users of COC pills are shown in Table 2. Of a total possible score of 22, the mean (± standard deviation) knowledge score of all the participants was 5.0 ± 4.7. Of all the participants, only approximately 20% of the mothers correctly answered that COC pills would not cause carcinoma of ovary and corpus; 26.0%, 29.7%, and 30.3% respectively correctly answered that COC pills did not have proven teratogenicity, cause pelvic inflammatory disease and infertility; 10.3% knew that COC pills would not cause weight gain and 25.7% answered that COC pills would not lead to a depressive mood. In all, 43.3%, 33.0%, and 25.3% knew that COC pills had the benefits of regulating the menstrual cycle, decreasing menstrual flow, and helping to relieve dysmenorrhoea, respectively. Moreover only 20% knew that the COC pills are not contra-indicated in people with a family history of breast cancer but is contra-indicated in thromboembolism. The knowledge score of the 175 women who responded to have knowledge of the COC pills was significantly higher than those who reported lack of knowledge (8.0 ± 4.4 vs 3.0 ± 3.7; P<0.001). Among those who declared they had knowledge about the use of COC pills, their sources of knowledge were from medical professional (63.3%), media (30.3%), friends (24.6%), family members (6.9%), school (2.9%), and others (1%).

Table 2. Rates of giving correct answers about COC and comparison between ever- and never-users of COC pills

The rate of responding “uncertain” to the health benefit, side-effects, or contra-indications of COC use ranged from 43.7% to 71.0% for each item. The mean uncertainty score among all participants was 13.0 ± 7.6. The uncertainty score was significantly higher in participants who reported to have lack of knowledge when compared with those reported to have knowledge about COC pills (15.6 ± 7.1 vs 9.1 ± 6.7; P<0.001).

Among the ever-users, 43 (34%), five (4%), and 96 (77%) women reported that COC pills had been used to manage their own menstrual problems, acne problems, and as contraception, respectively. Table 3 lists the participants’ acceptance rate of COC use by their daughters in different gynaecological conditions and the comparison between ever- and never-users of COC pills. More ever-users than never-users accepted the use of COC for their daughter’s gynaecological indications. Participants who accepted their daughter’s use of COC also had a higher knowledge score and lower uncertainty score (Table 4). Table 5 shows the participants’ reasons for accepting use of COC pills by their daughters. Recommendation by medical professionals was the major reason, followed by the knowledge that COC pills provided effective contraception.

Table 3. Participants’ acceptance of COC use by their daughters for different gynaecological conditions and comparison between ever- and never-users of COC pills

Table 4. Comparison of the knowledge score and uncertainty score in participants who agreed or disagreed with the use of COC pills by their daughters under different gynaecological conditions

Table 5. Participants’ reasons for accepting use of COC pills by their daughters for menstrual problems

Age, education level, and whether they had previous experience of side-effects of COC pills were not associated with participants’ acceptance of COC use by their daughters. Among the 125 ever-users of COC pills, 65 (52.0%) reported they had experienced side-effects, including weight gain (n=45), fluid retention (n=25), headache (n=12), increase in appetite (n=8), mode disturbance (n=8), and acne (n=4). Table 6 lists the reasons for disagreement with the use of COC pills by their daughters for menstrual problems. Finally, only 71 (23.6%) participants thought that the use of COC pills was appropriate in girls aged 12 to 18 years.

Table 6. Participants’ reasons for disagreement with the use of COC pills by their daughters for menstrual problems

Discussion

Our study highlights a notable lack of knowledge about the use of COC pills in many Hong Kong Chinese mothers. Many were uncertain or had erroneous beliefs about the use of COC pills. They believed that such usage would lead to cancers, fetal deformity, and cause infertility and pelvic inflammatory disease. These misconceptions and uncertainties may further reinforce their non-acceptance of the COC pills as an appropriate medication for their daughters. This inevitably often leads to suboptimal treatment for their daughters.

Fear of increased risk of cancer is an important reason for low acceptance of COC pills and only 22% of our participants thought it did not increase the risk for carcinoma of ovary or uterus. More than 60% of the participants were uncertain about the risk of cancer with the use of COC pills (results not shown). Research has shown that contraceptives have a significantly protective effect on carcinoma of ovary and corpus uteri.19 20 In fact, a collaborative re-analysis of individual data from 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies revealed that while women were taking COC pills and in the 10 years after stopping, there was a small increase in the relative risk of breast cancer.21 There was, however, no significant excess risk of having breast cancer diagnosed ≥10 years after stopping use of COC pills. The breast cancer incidence rises steeply with age. The estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use. The estimated excess number of breast cancers diagnosed up to 10 years after stopping use from the age of 16 to 19 years among 10 000 women has been reported to be 0.5 (95% confidence interval, 0.3-0.7) only.21 The Nurses’ Health Study with 121 701 participants followed up for 36 years revealed that longer duration of COC use was strongly associated with premature mortality due to breast cancer.22 Another highlight was that only 20.7% of our participants knew that a family history of breast cancer was not a contra-indication to use of COC pills.

Another common misconception is that the use of COC pills can lead to future subfertility. The COC pill preserves fertility by diminishing the risk of ectopic pregnancy.23 According to a review, 1-year pregnancy rates after discontinuation of COC ranged from 79% to 96%, similar to those reported following discontinuation of barrier methods or no contraception.24 Moreover, the progestogen effect of COC pills results in production of thick, tenacious cervical mucus that resists penetration by bacteria and spermatozoa and reduces the risk of upper genital tract infection. Use of COC pills was also quoted to be protective against symptomatic pelvic inflammatory disease, with a 50% reduction in rate of hospitalisation for the disease, with itself being a risk factor for subfertility.25 The COC pill does not protect against sexually transmitted infections. On the other hand, there is no evidence to support the notion that the use of COC pills is associated with high-risk sexual behaviour in adolescents, which is a very common fear among Hong Kong mothers.

Primary dysmenorrhoea is prevalent during adolescence. Approximately 6.4% of adolescents or 29% of those reporting severe dysmenorrhoea seek help from a physician.4 A review and meta-analysis of five trials of the use of COC pills concluded that it was more effective than placebo in managing dysmenorrhoea.2 One of the most common problems reported by adolescents is irregular and/or profuse menstruation. The COC pill is also effective in treating and preventing heavy menstrual bleeding. In our study, only 25% to 43% of the participants knew that it is an appropriate treatment for menstrual problems and 50% were uncertain.

The fear of side-effects often leads to reluctance to using new treatments.18 In many cases, such fears are often unfounded. In our study, participants believed that weight gain and depressive mood were side-effects of COC pills, although pooled analysis of a placebo-controlled trial showed no difference in weight gain.26 Furthermore, depressive symptoms are common in adolescence.27 In a randomised controlled study, there was no difference in mood changes throughout the menstrual cycle between COC users and non-users.28 In a prospective study of 43 adolescents, subjects anticipated more side-effects than they actually experienced after 6 months of taking COC pills.29

It is important to provide correct information to women and their teenage daughters if they are contemplating the use of COC pills. In our study, 40% of participants indicated that recommendation from a medical professional was a critical factor in their acceptance of the use of COC pills by their daughters.

Only 19% of participants were aware that thromboembolism is a contra-indication to COC use. Venous thromboembolism in Asians has been reported to be low.30 A recent case-control study confirmed that current exposure to any COC poses a 3-times higher risk of venous thromboembolism compared with no exposure in the previous year.31 The risk is higher with COC pills containing desogestrel (odds ratio, 4.3), gestodene (3.6), drospirenone (4.1), and cyproterone (4.3) than the second-generation COC pills with levonorgestrel (2.4) and norgestimate (2.5).31 The risk of venous thromboembolism is also increased for COC users with a family history of venous thromboembolism.32 Clinicians should assess the woman’s personal and family history of thromboembolism, and provide information about the warning symptoms of venous thromboembolism before prescribing a new generation pill. As recommended by the World Health Organization, the COC pill is not contra-indicated in smokers <35 years old33; approximately 30% of our participants answered this correctly.

This study has several limitations. First, there may be selection bias as subjects were women who presented to the gynaecology clinic or accompanied their daughter to a gynaecology clinic for a gynaecological problem. The results may not be generalised to the whole population of Hong Kong. Second, the questionnaire was not validated and the questions did not include all aspects of the use of COC pills. Third, we relied on women’s self-reported use of COC pills and could not verify the information. Despite these, the questionnaire included the most widely studied aspects of non-contraceptive benefits and risks of the COC pill and knowledge score or uncertainty score have been used in previous literature.15 16 Although this study was conducted in only one centre and in Chinese women only, it helps clinicians to understand the low levels of acceptance of and compliance with prescribed COC pills.

The degree of misconception among Hong Kong mothers about COC use is of concern. Hong Kong has a well-developed education system with many highly regarded universities. The reported limited sex education in schools may be responsible for this knowledge gap of Hong Kong mothers.13 This may in turn have an impact on the advice they give their daughters, who are usually compliant with their mother’s wishes. Specific training in communication and counselling skills should be provided to health care professionals when promoting sexual health to women and adolescents.34

Conclusions

Our study found that the Hong Kong Chinese women who attended a gynaecology clinic of a tertiary centre had a low acceptance rate of the use of COC pills by their daughters. This low acceptance was associated with a lack of knowledge and misconception of the risks and benefits of the COC pills. Such ignorance will exert an adverse influence on the choice of treatment for many gynaecological problems in teenage daughters.

Declaration

All authors have disclosed no conflicts of interest.

References

1. Vessey M, Painter R. Oral contraceptive use and cancer. Findings in a large cohort study, 1968-2004. Br J Cancer 2006;95:385-9. Crossref

2. Proctor ML, Roberts H, Farquhar CM. Combined oral contraceptive pill (OCP) as treatment for primary dysmenorrhoea. Cochrane Database Syst Rev 2001;(4):CD002120.

3. Nader S, Diamanti-Kandarakis E. Polycystic ovary syndrome, oral contraceptives and metabolic issues: new perspectives and a unifying hypothesis. Hum Reprod 2007;22:317-22. Crossref

4. Chan SS, Yiu KW, Yuen PM, Sahota DS, Chung TK. Menstrual problems and health-seeking behaviour in Hong Kong Chinese girls. Hong Kong Med J 2009;15:18-23.

5. Chung PW, Chan SS, Yiu KW, Lao TT, Chung TK. Menstrual disorders in a Paediatric and Adolescent Gynaecology Clinic: patient presentations and longitudinal outcomes. Hong Kong Med J 2011;17:391-7.

6. Esmaelizadeh S, Delavar MA, Amiri M, Khafri S, Pasha NG. Polycystic ovary syndrome in Iranian adolescents. Int J Adolesc Med Health 2014;26:559-65. Crossref

7. Christensen SB, Black MH, Smith N, et al. Prevalence of polycystic ovary syndrome in adolescents. Fertil Steril 2013;100:470-7. Crossref

8. Wang C. Trends in contraceptive use and determinants of choice in China: 1980-2010. Contraception 2012;85:570-9. Crossref

9. Lo SS, Fan SY. Acceptability of the combined oral contraceptive pill among Hong Kong women. Hong Kong Med J 2016;22:231-6.

10. The Family Planning Association of Hong Kong. 2014-2015 Annual report. Available from: http://www.famplan.org.hk/fpahk/en/template1.asp?style=template1.asp&content=about/annualreport.asp. Accessed 28 Apr 2016.

11. The Family Planning Association of Hong Kong. Youth sexuality in Hong Kong secondary school survey. Available from: http://www.famplan.org.hk/fpahk/en/template1.asp?content=info/research.asp. Accessed 28 Apr 2016.

12. Che FS. A study of the implementation of sex education in Hong Kong secondary schools. Sex Educ 2005;5:281-94. Crossref

13. Survey of life skills-based education on HIV/AIDS at junior level of secondary schools in Hong Kong. Red Ribbon Centre, Department of Health, Hong Kong SAR Government; 2014.

14. Wong WC, Lee A, Tsang KK, Lynn H. The impact of AIDS/sex education by schools or family doctors on Hong Kong Chinese adolescents. Psychol Health Med 2006;11:108-16. Crossref

15. Voqt C, Schaefer M. Disparities in knowledge and interest about benefits and risks of combined oral contraceptives. Eur J Contracept Reprod Health Care 2011;16:183-93. Crossref

16. Lim HJ, Lee MS, Cho YH, Kazumi U. A comparative study of knowledge about and attitudes toward the combined oral contraceptives among Korean and Japanese university students. Pharmacoepidemiol Drug Saf 2004;13:741-7. Crossref

17. Bachar R, Yogev Y, Fisher M, Geva A, Blumberg G, Kaplan B. Attitudes of mothers toward their daughters’ use of contraceptives in Israel. Contraception 2002;66:117-20. Crossref

18. Chan SS, Cheung TH, Lo WK, Chung TK. Women’s attitudes on human papillomavirus vaccination to their daughters. J Adolesc Health 2007;41:204-7. Crossref

19. Cibula D, Gompel A, Mueck AO, et al. Hormonal contraception and risk of cancer. Hum Reprod Update 2010;16:631-50. Crossref

20. Bitzer J. Oral contraceptives in adolescent women. Best Pract Res Clin Endocrinol Metab 2013;27:77-89. Crossref

21. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713-27. Crossref

22. Charlton BM, Rich-Edwards JW, Colditz GA, et al. Oral contraceptive use and mortality after 36 years of follow-up in the Nurses’ Health Study: prospective cohort study. BMJ 2014;349:g6356. Crossref

23. Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 2004;190 (4 Suppl):S5-22. Crossref

24. Mansour D, Gemzell-Dianielsson K, Inki P, Jensen JT. Fertility after discontinuation of contraception: a comprehensive review of the literature. Contraception 2011;84:465-77. Crossref

25. Guillebaud J, MacGregor A. Contraception: your questions answered. 6th ed. London: Churchill Livingstone; 2013.

26. Gallo MF, Lopez LM, Grimes DA, Carayon F, Schulz KF, Helmerhorst FM. Combination contraceptives: effects on weight. Cochrane Database Syst Rev 2014;(1):CD003987. Crossref

27. Saluja G, Iachan R, Scheidt PC, Overpeck MD, Sun W, Giedd JN. Prevalence of and risk factors for depressive symptoms among young adolescents. Arch Pediatr Adolesc Med 2004;158:760-5. Crossref

28. Walker A, Bancroft J. Relationship between premenstrual symptoms and oral contraceptive use: a controlled study. Psychosom Med 1990;52:86-96. Crossref

29. Rosenthal SL, Cotton S, Ready JN, Potter LS, Succop PA. Adolescents’ attitudes and experiences regarding levonorgestrel 100 mcg/ethinyl estradiol 20 mcg. J Pediatr Adolesc Gynecol 2002;15:301-5. Crossref

30. Lee WS, Kim KI, Lee HJ, Kyung HS, Seo SS. The incidence of pulmonary embolism and deep vein thrombosis after knee arthroplasty in Asians remains low: a meta-analysis. Clin Orthop Relat Res 2013;471:1523-32. Crossref

31. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015;350:h2135. Crossref

32. Zöller B, Ohlsson H, Sundquist J, Sundquist K. Family history of venous thromboembolism is a risk factor for venous thromboembolism in combined oral contraceptive users: a nationwide case-control study. Thromb J 2015;13:34. Crossref

33. Medical eligibility criteria for contraceptive use. 5th ed. Geneva: World Health Organization; 2015.

34. Yip BH, Sheng XT, Chan VW, Wong LH, Lee SW, Abraham AA. ‘Let’s talk about sex’—a knowledge, attitudes and practice study among paediatric nurses about teen sexual health in Hong Kong. J Clin Nurs 2015;24:2591-600. Crossref

A hospital-wide screening programme to control an outbreak of vancomycin-resistant enterococci in a large tertiary hospital in Hong Kong

Hong Kong Med J 2017 Apr;23(2):140–9 | Epub 24 Feb 2017

DOI: 10.12809/hkmj164939

ORIGINAL ARTICLE

A hospital-wide screening programme to control an outbreak of vancomycin-resistant enterococci in a large tertiary hospital in Hong Kong

Christopher KC Lai, MB, ChB, FHKCPath^1,2; Stephenie YN Wong, MB, BS, FHKCPath^1,2; Shirley SY Lee, BSc (Nursing), MSC (Nursing)²; HK Siu, BSc (Statistics), MPhil (Social Medicine)³; CY Chiu, BSc (Biomedical Sciences), MSc (Medical Laboratory Sciences)⁴; Dominic NC Tsang, MB, BS, FHKCPath^1,2,3; Margaret PY Ip, FRCP, FRCPath⁴; CT Hung, FANZCA, FHKAM (Anaesthesiology)⁵

¹ Department of Pathology, Queen Elizabeth Hospital, Hong Kong

² Infection Control Team, Queen Elizabeth Hospital, Hong Kong

³ Chief Infection Control Officer’s Office, Hospital Authority, Hong Kong

⁴ Department of Microbiology, The Chinese University of Hong Kong, Hong Kong

⁵ Queen Elizabeth Hospital, Hong Kong

Corresponding authors: Dr Christopher KC Lai (laikcc@ha.org.hk)

Full paper in PDF

Abstract

Introduction: Apart from individual small-scale outbreaks, infections with vancomycin-resistant enterococci are uncommon in Hong Kong. A major outbreak of vancomycin-resistant enterococci, however, occurred at a large tertiary hospital in 2013. We describe the successful control of this outbreak and share the lessons learned.

Methods: In 2013, there was an abnormal increase in the incidence of vancomycin-resistant enterococci carriage compared with baseline in multiple clinical departments at Queen Elizabeth Hospital. A multipronged approach was adopted that included a 10-week hospital-wide active screening programme, which aimed to identify and isolate hidden vancomycin-resistant enterococci carriers among all in-patients. The identified carriers were completely segregated in designated wards where applicable. Other critical infection control measures included directly observed hand hygiene and environmental hygiene. A transparent and open disclosure approach was adopted throughout the outbreak.

Results: The infection control measures were successfully implemented. The active screening of vancomycin-resistant enterococci was conducted between 30 September and 10 November 2013. A total of 7053 rectal swabs were collected from patients in 46 hospital wards from 11 departments. The overall carriage rate of vancomycin-resistant enterococci was 2.8% (201/7053). Pulsed-field gel electrophoresis showed a predominant outbreak clone. We curbed the outbreak and kept the colonisation of vancomycin-resistant enterococci among patients at a pre-upsurge low level.

Conclusions: We report the largest cohesive effort to control spread of vancomycin-resistant enterococci in Hong Kong. Coupled with other infection control measures, we successfully controlled vancomycin-resistant enterococci to the pre-outbreak level. We have demonstrated that the monumental tasks can be achieved with meticulous planning, and thorough communication and understanding between all stakeholders.

New knowledge added by this study

This is the largest vancomycin-resistant enterococci control study ever conducted in Hong Kong.
We have demonstrated the infection control measures required in controlling a large outbreak in a Hong Kong public hospital setting.
The key infection control measures are active case finding followed by case-cohorting, directly observed hand hygiene, and equipment and environmental hygiene.

Implications for clinical practice or policy

Control of large infectious disease outbreaks and effective implementation of infection control measures can be achieved with meticulous planning, thorough communication, and understanding between all stakeholders.

[Abstract in Chinese]

Introduction

Vancomycin-resistant enterococci (VRE) is an important cause of health care–associated infection and is known to prolong hospital stay, increase treatment cost, and patient morbidity and mortality.1 2 3 4 5 A VRE carrier was defined as any patient with VRE isolated from a clinical or surveillance specimen. The first case of VRE in Hong Kong was identified at Queen Elizabeth Hospital (QEH) in 1997.6 In 2010, VRE constituted 0.4% of all Enterococcus isolates. Apart from individual small-scale outbreaks,7 8 VRE had not gained a foothold in Hong Kong. Queen Elizabeth Hospital is the largest public acute general tertiary hospital under the administration of the Hospital Authority (HA) with 1800 beds. There are more than 160 000 admissions with 104 000 in-patients treated annually. A major VRE outbreak occurred in QEH in 2013. There was an abnormal increase in the incidence of VRE carriage in multiple clinical departments compared with baseline. Prior to this outbreak, VRE control measures were stipulated by the HA Guideline on Control of VRE. Active screening was not mandatory but was usually performed in contact investigations after VRE was recovered from clinical specimens. The baseline incidence of VRE never exceeded five per week prior to December 2012. Nonetheless, the incidence crept up and by March 2013, a total of 34 VRE carriers were identified in week 13 alone. This study aimed to describe in detail the approach to rapidly control VRE in our hospital.

Methods

Multipronged infection control measures for vancomycin-resistant enterococci

The hospital’s control measures can be divided into two phases based on the intensity of measures with the triggering event of the constitution of QEH VRE Task Group.

Emerging phase (1 January 2012 to 13 May 2013)

(1) Find and confine—active case finding by admission screening in high prevalence wards with additional weekly screening for outbreak wards. Carriers of VRE were cohorted in either a single room or designated cubicles with a mobile curtain as segregation. Signage for contact precautions was posted at the entrance to the cohort area and at the patients’ bedside. Gloves and gowns were worn when in contact with the patient or patient environment. All VRE cases and their contacts were tagged in the corporate electronic Clinical Management System.
(2) Hand hygiene—chlorhexidine-alcohol hand rub was used in clinical areas with high VRE prevalence. Only two visitors were allowed per VRE patient with their hand hygiene compliance monitored.
(3) Nursing care—all patients in Intensive Care Unit were bathed with chlorhexidine daily. Wards were advised that excreta and tube feeding should be handled by separate teams.
(4) Equipment and environment—we introduced colour-coding to all clinical wards. Two-in-one disinfectants and disposable wipes were provided to clinical wards to improve two-step cleaning. Dedicated non-critical patient care equipment was provided for all VRE cases. Hydrogen peroxide vaporisation sessions were used to disinfect non-critical patient care equipment. Cleaners were coached by infection control nurses and their performance was gauged by environmental sampling and fluorescence markers.
(5) Open disclosure—all outbreaks were disclosed through press release.

Intensive control phase (13 May 2013 to 10 November 2013)

(1) Command and control—a VRE Task Group was formed with clear administrative mandates from the Hospital Chief Executive, head of nursing, and head of administrative services. The Task Group included senior representatives from clinical departments, human resources, laboratories, and infection control teams. Weekly meetings were held. Local experts from HA Head Office, Centre for Health Protection, and a local university were also invited to jointly devise an intensive VRE control programme.
(2) Active screening—the pan-hospital VRE screening was the hallmark of this period; it exemplified the determination of the hospital administration. Rectal swabs were collected to identify VRE carriers in different stages. Each ward performed a point prevalence screening followed by 2 weeks of admission and discharge screening. The screening of 46 hospital wards from 11 departments was to be completed within 10 weeks.

Carriage of VRE is associated with additional length of stay.1 A sudden surge in VRE cases would result in blockage of admissions, resulting in redirection of emergency admissions to other hospitals. Based on prevalence figures from contact investigations in previous localised VRE outbreaks (range, 0%-20%), bed status and occupancy rates, 126 VRE cases would be identified on the first day of screening alone, 566 cases would be identified at the end of the screening, assuming 10% of our in-patients were VRE carriers. To avoid overwhelming the hospital services due to inadequate isolation facilities, a modified risk-based pan-hospital screening was adopted with consideration of the following parameters: daily number of specimens, daily number of VRE carriers identified, consequent additional length of stay, and designated cohort ward capacity. The final schedule had exacted the number of specimens to be taken by ward and date over a 10-week period and was agreed by all stakeholders.

To segregate VRE carriers, a VRE ward was created to avert cross-transmission. Bed capacity was ‘created’ by rescheduling elective procedures from both medical and surgical teams.

To avoid inadvertently overloading the hospital’s capacity during active screening, two ‘brake points’ were set, namely number of patients waiting at the emergency department at 7 am each morning for emergency hospital admission should not exceed 30, and total VRE cases identified should not exceed 25 per day. When these points were met, screening on that particular day would stop. A real-time close monitoring communication group using instant messaging (WhatsApp) was formed to connect all key stakeholders on a 24/7 basis.

Other additional measures included:

Hand hygiene—audit results of hand hygiene compliance were reported to department and hospital administration on a weekly basis. Alcoholic hand rub dispensers were installed in patient toilets. Hand hygiene before meals and medications in all conscious hospitalised patients were directly observed.
Nursing care—disposable disinfection wipes were provided to optimise disinfection of commodes, bedpans, and urinals. On-site coaching was provided by infection control nurses about contamination-prone procedures, particularly napkin change and care for nasogastric tube.
Equipment and environment—we increased cleaning staff manpower by recruiting additional external cleaning staff and instigating an overtime allowance for existing staff. The frequency of changing privacy curtains was shortened from monthly to biweekly for all VRE carriers. Cleaning efficacy was monitored by regular environmental sampling using Polywipe (Medical Wire & Equipment/Wiltshire, United Kingdom) in wards where the outbreak was detected.
Staff engagement, education, and communication—staff forums were organised so all parties would understand the importance of VRE and their role as health care workers, with dedicated sessions in Cantonese for supporting staff.
Open disclosure—the result from the pan-hospital screening was released to hospital administration and HA head office on a daily basis.

Laboratory protocol

Rectal swabs and stool specimens were inoculated onto chromID VRE agar (bioMérieux, France) and incubated at 35°C ± 2°C according to the manufacturer’s recommendations. The agar plates were examined daily for 2 days. Suspected colonies were identified to be Enterococcus species by both MALDI-TOF (Vitek-MS, bioMérieux) and conventional microbiological methods of Gram stain and biochemical reactions. Vancomycin resistance was confirmed by E-test (bioMérieux, France) according to Clinical Laboratory Standards Institute breakpoints.9 Detection of vancomycin resistance genes was performed by the local reference laboratory. Strains were typed by pulsed-field gel electrophoresis (PFGE) and patterns of SmaI-restricted chromosomal DNA analysed by unweighted pair group method with arithmetic mean (UPGMA) using the BioNumerics software (Applied Maths).10

Hand hygiene compliance audit

We adopted the World Health Organization (WHO) hand hygiene observation tools by directly observing compliance with the WHO five moments. The observation was conducted by infection control nurses using a WHO standardised audit form. Nurses, supporting staff, doctors, and allied health personnel were included for observation.

Antibiotics consumption data

The consumption of vancomycin, ceftazidime, and ceftriaxone in QEH between week 1 of 2012 and week 39 of 2015 was retrieved from the Clinical Data Analysis and Reporting System. Consumption data were presented in defined daily dose.

Statistical analysis

The relationship between VRE carriage, a binary dependent variable, and five independent variables related to patients’ demographic background and hospitalisation history were analysed by univariate methods (Chi squared test supplemented with measurement of the association [odds ratio for binary variables and Spearman’s correlation for ordinal variables]) and the significant independent variables were included in the subsequent multiple logistic regression model. The 30-day mortality between groups was analysed by Chi squared test.

In multiple logistic regression, one category of each independent variable was selected as ‘reference category’ to compare with other categories in the variable and the odds ratio calculated. Likelihood ratio test was used to compare the final model with null model and Hosmer-Lemeshow test was used to evaluate the goodness-of-fit of the final model. The Statistical Package for the Social Sciences (SPSS Windows version 21.0; IBM Corp, Armonk [NY], United States) was used for data analysis.

Results

Our multipronged infection control measures successfully brought down VRE to pre-outbreak level. Prior to screening, 150 non-emergency procedures were rescheduled. The screening was conducted between 30 September and 10 November 2013. A total of 7053 specimens from 4966 patients were collected—1422 from point prevalence, 4225 from admission, and 1406 on discharge (Table 1). We managed to complete the screening schedule without meeting the brake points.

Table 1. Results of the pan-hospital screening of VRE based on clinical departments

The baseline incidence of VRE never exceeded five per week prior to the current outbreak. After December 2012, it crept up and peaked at week 13 of 2013 with 34 new VRE cases identified. After the pan-hospital screening, the incidence dropped to no more than five cases per week after March 2015 (Fig 1).

Figure 1. VRE epidemiology in Queen Elizabeth Hospital from January 2012 to September 2015

Of all the specimens screened, 2.8% (201/7053) were positive for VRE—65.7% (132/201) of VRE came from the specialty of medicine, 19.9% (40/201) from the surgical stream (all surgical subspecialties except neurosurgery and orthopaedics). The point prevalence of VRE was 5.8% (83/1422), admission prevalence was 1.8% (75/4225), and discharge prevalence was 3.1% (43/1406). Risk factors for VRE carriage included male gender, residence in a home for the elderly, older age, longer hospital stay, and more hospitalisation episodes in the previous 90 days prior to screening (Table 2). From logistic regression results compared with the reference group, there was a progressive increase in the risk of VRE carriage with increasing age, and increase in days of hospitalisation in the previous 90 days prior to screening, but not with increasing episodes of hospitalisation in the previous 90 days prior to screening (Table 3).

Table 2. Demographic data for VRE-positive patients

Table 3. Logistic regression results (outcome: patient ever has VRE-positive result = yes)

Infection control measures

A total of 28 588 hand hygiene observations were made in 2013. The compliance rate improved from 37% in the first quarter of 2013 to 73% in the fourth quarter of 2013. The improvement was seen across all departments and all staff groups. A total of 30 sessions of on-site education about napkin change, nasogastric tube care, and environmental cleaning were provided with 88 napkin care procedures observed in 28 wards. Furthermore, 37 hydrogen peroxide vapour sessions were offered to disinfect non-critical equipment; and 15 staff forums dedicated to VRE control were held with a total of 1339 attendances.

Microbiology

During the screening period, 105 VRE isolates recovered from the pan-hospital screening were all vanA gene carrying Enterococcus faecalis. They were analysed with eight unrelated archived VRE strains. The PFGE patterns of SmaI-restricted chromosomal DNA of 113 VRE isolates are shown in Figure 2. Dendrogram of PFGE patterns was obtained by UPGMA method. A predominant cluster A was classified using a cut-off at 90% similarity, as calculated by Dice coefficient with 1% position tolerance and 2% band optimisation. Cluster A comprised 49 strains from the current pan-hospital screening and one unrelated archived strain from another hospital.

Figure 2. PFGE patterns of SmaI-restricted chromosomal DNA of 113 VRE isolates

Carriage of vancomycin-resistant enterococci and 30-day mortality

During the pan-hospital screening period, the 30-day all-cause mortality of all VRE carriers identified in the pan-hospital screening and non-VRE carriers were 20.5% and 6.1%, respectively. The odds ratio was 3.93 (95% confidence interval, 2.68-5.78). When compared with previously known VRE carriers but with negative VRE screening results in the same period (13.6%), the 30-day all-cause mortality were 20.5% and 13.6%, respectively. The odds ratio was 1.64 (95% confidence interval, 0.71-3.76).

Antibiotic consumption

There was no significant change in consumption of vancomycin or ceftazidime during the emerging phase or during and beyond the intensive control phase. There was an apparent increase in consumption of ceftriaxone noted after the intensive phase in the first half of 2014 (Fig 1).

Discussion

Identification of VRE carriers, segregation of primary sources, hand hygiene, and environmental hygiene are the critical success factors in controlling the VRE outbreak. The territory-wide effort to control the emergence of VRE in public hospitals in Hong Kong has been discussed elsewhere.11 Our study revealed the critical elements involved in controlling a multi-sourced VRE outbreak in a major tertiary hospital. We believe our failure to contain VRE in the emerging phase was in part due to the lack of perceived need of staff for VRE control as well as skepticism about the effectiveness of infection control measures. Senior clinicians may be ambivalent towards our approach due to perceived loss of autonomy. Frontline staff rebuffed the screening programme as they sensed extra work and doubted its effectiveness. Overseas experience has shown that once VRE becomes hospital endemic, eradication is difficult despite the best efforts.12 13 14

We faced an additional challenge of an absence of facilities to completely segregate VRE carriers. Our hospital faces overcrowding on a daily basis with bed occupancy often exceeding 100%, and reaching as high as 130% during influenza seasons. Studies have shown that bed occupancy, isolation room availability, and staffing have a direct impact on ease of VRE control.15 16 Our difficulties were compounded by lack of inter-bed spacing and limited toilet facilities as the hospital was designed more than 60 years ago, and the need to keep the hospital functioning at all times.

In the intensive control phase, commitment from hospital administration became visible as a result of the pan-hospital screening. Close liaison between departments, careful and extensive planning with input from the frontline at every step, effective communication, and staff engagement were also key to our success. Some researchers have questioned the effectiveness of active surveillance cultures in reducing VRE transmission.17 Others have suggested that VRE will not be successfully controlled if the policy excludes asymptomatic VRE colonisation.18 19 20 21 We believed it was necessary to take drastic action and perform active screening of the whole hospital.

Our planning took reference from similar overseas experiences. Christiansen et al18 successfully controlled VRE by screening 19 658 patients and found 169 patients from 23 wards to be colonised with vanB-containing Enterococcus faecium in 6 months. Their experience was different from ours as they had fewer cases. Moretti et al19 reported their extensive active surveillance with enhanced infection control measures in a Brazilian teaching hospital. They performed 8692 rectal swabs for VRE (mean, 300 swabs/month), with an overall positive rate of 3.7%. In their 2.5-year intervention, their VRE positive rate decreased from 7.2% in 2007 to 1.5% in 2009. Kurup et al20 reported their experience in a large Singaporean hospital. They performed a large-scale screening of 4924 patients over 2 months and successfully reduced the positive rate from 11.4% at the peak of the outbreak to 4.2% at the end of screening. We did not observe a decline over the pan-hospital screening period as in the Singaporean experience. It was because we deliberately spaced out the departments with a high VRE prevalence throughout the 10-week period to avoid overwhelming the hospital’s facilities.

Rapid laboratory turnaround time is another key element.22 It was soon evident that the hospital laboratory could not handle the additional specimens alone. Assistance from three HA microbiology laboratories was sought. A huge amount of liaison work with extensive communication between laboratory directors, senior medical technologists, and scientific officers followed to ensure the smooth running of this unprecedented inter-laboratory cooperation. A unified set of logistics was established, governing the tiniest details. Procurement of key reagents like chromogenic agar was coordinated centrally with support from the HA head office.

Hygiene management has been shown to be important in controlling VRE in endemic areas.16 23 24 Contamination of the hospital environment by VRE, and occurrence of cross-contamination, either through the hands of health care workers, equipment, or surfaces is well known.25 26 27 The association of environmental contamination and the occurrence of an outbreak has also been well established.18 28 29 30

The improvement in hand hygiene compliance from approximately 37% to 73% was remarkable. Several explanations are postulated: (1) the VRE Task Group escalated the need for urgent improvement. The weekly reporting of hand hygiene compliance rate via the VRE workgroup created a driving force at an administrative level; (2) we implemented directly observed hand hygiene before meals and when taking medications in all conscious hospitalised patients; (3) we actively engaged infection control link nurses, creating a collective learning opportunity that has facilitated collaboration and system thinking; and (4) making the hand hygiene compliance data visible (and comparing with other wards/departments) might change the behaviour of many.31

All the VRE recovered in the pan-hospital screening was vanA-containing Enterococcus faecium. The PFGE patterns showed 49 out of the 105 pan-hospital screening isolates belonged to a single cluster (cluster A), signifying the possibility of clonal spread of a dominant strain, with co-circulation of various less dominant strains. Some clones may have developed de novo. Further analysis of these strains will allow a more thorough understanding of the transmission dynamics within the hospital, and whether the outbreak clone has a survival advantage over other clones.

We identified residents of homes for the elderly, advanced age, and prolonged hospitalisation as risk factors for VRE carriage. This is most likely due to their associated co-morbidities rather than the individual factors per se. It is unknown why men were at a higher risk than women. It might have been a chance finding since more outbreaks occurred in male wards before and during the study period than female wards.

Antibiotics, especially vancomycin and third-generation cephalosporins like ceftazidime and ceftriaxone, were known to be a risk for VRE colonisation. We did not observe significant changes in the consumption of vancomycin or ceftazidime throughout the study period. Nonetheless, an increase in consumption of ceftriaxone was observed in the first half of 2014. We hypothesise the increase might be a squeeze-the-balloon effect by actively avoiding big gun antibiotics, or an artefact due to irregularities in returning ward antibiotic stock to the hospital pharmacy.

We observed a significant increase in 30-day mortality in VRE carriers identified in the pan-hospital screening when compared with those who tested negative for VRE during the same period. However, when we compared the VRE carriers identified in pan-hospital screening with those who tested VRE negative but were known to have had previous VRE carriage, they were not significantly different. Confounding factors like length of hospitalisation and co-morbidities are likely causes of this observation. Further analysis of these factors is required to give a more definitive answer.

The pan-hospital screening was immediately followed by the 10-week HA-wide targeted surveillance screening. Any patient with a history of admission to any one of the hospitals in Hong Kong within 3 months, or on haemodialysis, were actively screened for VRE on admission. The VRE level continues to be maintained at a low level, 3 years after the intensive period that ended in 2013. This is important because a one-time effort is often difficult and does not always result in a lasting effect unless a system and culture change has been brought about.

A limitation of this study was that the analysis was performed retrospectively. We retrospectively studied the odds ratio after both the exposure and the outcomes had already occurred. It is in contrast to prospective cohort studies where participants are enrolled and then followed over time to identify the occurrence of VRE carriage. In addition, sustained control of VRE is multifactorial and not dependent on any one isolated intervention. Although there were no large-scale outbreaks or VRE control programmes in other hospitals, interdependence among hospitals and other health care facilities are well described.

Conclusions

We have successfully controlled a multiple-sourced hospital-wide VRE outbreak in a tertiary hospital with multipronged infection control measures. The need to establish a close working relation between all stakeholders in the hospital cannot be overemphasised. Our experience is useful to other hospitals challenged by VRE or other multidrug-resistant bacteria.

Acknowledgements

We are grateful to all the medical, nursing, and supporting staff in Queen Elizabeth Hospital who assisted in VRE control. We thank the microbiology laboratories of Princess Margaret Hospital, United Christian Hospital, and Queen Mary Hospital for their excellent support in handling VRE specimens during pan-hospital screening.

Declaration

We would like to acknowledge the Food and Health Bureau, Hong Kong SAR for supporting the typing of the VRE strains under Health and Medical Research Fund (Commissioned HMRF Project No. CU-15-B5).

References

1. Cheah AL, Spelman T, Liew D, et al. Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization. Clin Microbiol Infect 2013;19:E181-9. Crossref

2. Vergis EN, Hayden MK, Chow JW, et al. Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia: A prospective multicenter study. Ann Intern Med 2001;135:484-92. Crossref

3. Lloyd-Smith P, Younger J, Lloyd-Smith E, Green H, Leung V, Romney MG. Economic analysis of vancomycin-resistant enterococci at a Canadian hospital: assessing attributable cost and length of stay. J Hosp Infect 2013;85:54-9. Crossref

4. Carmeli Y, Eliopoulos G, Mozaffari E, Samore M. Health and economic outcomes of vancomycin-resistant enterococci. Arch Intern Med 2002;162:2223-8. Crossref

5. Muto CA, Giannetta ET, Durbin LJ, Simonton BM, Farr BM. Cost-effectiveness of perirectal surveillance cultures for controlling vancomycin-resistant Enterococcus. Infect Control Hosp Epidemiol 2002;23:429-35. Crossref

6. Chuang VW, Tsang DN, Lam JK, Lam RK, Ng WH. An active surveillance study of vancomycin-resistant Enterococcus in Queen Elizabeth Hospital, Hong Kong. Hong Kong Med J 2005;11:463-71.

7. Cheng VC, Tai JW, Ng ML, et al. Extensive contact tracing and screening to control the spread of vancomycin-resistant Enterococcus faecium ST414 in Hong Kong. Chin Med J 2012;125:3450-7.

8. Cheng VC, Chan JF, Tai JW, et al. Successful control of vancomycin-resistant Enterococcus faecium outbreak in a neurosurgical unit at non-endemic region. Emerg Health Threats J 2009;2:e9. Crossref

9. Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing: twenty-third informational supplement M100-S23. Wayne, PA: CLSI; 2013.

10. Miranda AG, Singh KV, Murray BE. DNA fingerprinting of Enterococcus faecium by pulsed-field gel electrophoresis may be a useful epidemiologic tool. J Clin Microbiol 1991;29:2752-7.

11. Cheng VC, Tai JW, Chau PH, et al. Successful control of emerging vancomycin-resistant enterococci by territory-wide implementation of directly observed hand hygiene in patients in Hong Kong. Am J Infect Control 2016;44:1168-71. Crossref

12. Willems RJ, Top J, van Santen M, et al. Global spread of vancomycin-resistant Enterococcus faecium from distinct nosocomial genetic complex. Emerg Infect Dis 2005;11:821-8. CrossRef

13. Arias CA, Murray BE. The rise of the Enterococcus: beyond vancomycin resistance. Nat Rev Microbiol 2012;10:266-78. Crossref

14. Werner G, Coque TM, Hammerum AM, et al. Emergence and spread of vancomycin resistance among enterococci in Europe. Euro Surveill 2008;13.pii:19046.

15. Arias CA, Mendes RE, Stilwell MG, Jones RN, Murray BE. Unmet needs and prospects for oritavancin in the management of vancomycin-resistant enterococcal infections. Clin Infect Dis 2012;54 Suppl 3:S233-8. Crossref

16. Aumeran C, Baud O, Lesens O, Delmas J, Souweine B, Traoré O. Successful control of a hospital-wide vancomycin-resistant Enterococcus faecium outbreak in France. Eur J Clin Microbiol Infect Dis 2008;27:1061-4. Crossref

17. Huskins WC, Huckabee CM, O’Grady NP, et al. Intervention to reduce transmission of resistant bacteria in intensive care. N Engl J Med 2011;364:1407-18. Crossref

18. Christiansen KJ, Tibbett PA, Beresford W, et al. Eradication of a large outbreak of a single strain of vanB vancomycin-resistant Enterococcus faecium at a major Australian teaching hospital. Infect Control Hosp Epidemiol 2004;25:384-90. Crossref

19. Moretti ML, de Oliveira Cardoso LG, Levy CE, et al. Controlling a vancomycin-resistant enterococci outbreak in a Brazilian teaching hospital. Eur J Clin Microbiol Infect Dis 2011;30:369-74. Crossref

20. Kurup A, Chlebicki MP, Ling ML, et al. Control of a hospital-wide vancomycin-resistant Enterococci outbreak. Am J Infect Control 2008;36:206-11. Crossref

21. Lee SC, Wu MS, Shih HJ, et al. Identification of vancomycin-resistant enterococci clones and inter-hospital spread during an outbreak in Taiwan. BMC Infect Dis 2013;13:163. Crossref

22. Delmas J, Robin F, Schweitzer C, Lesens O, Bonnet R. Evaluation of a new chromogenic medium, ChromID VRE, for detection of vancomycin-resistant Enterococci in stool samples and rectal swabs. J Clin Microbiol 2007;45:2731-3. Crossref

23. Nolan SM, Gerber JS, Zaoutis T, et al. Outbreak of vancomycin-resistant enterococcus colonization among pediatric oncology patients. Infect Control Hosp Epidemiol 2009;30:338-45. Crossref

24. Morris-Downes M, Smyth EG, Moore J, et al. Surveillance and endemic vancomycin-resistant enterococci: some success in control is possible. J Hosp Infect 2010;75:228-33. Crossref

25. Ramsey AM, Zilberberg MD. Secular trends of hospitalization with vancomycin-resistant enterococcus infection in the United States, 2000-2006. Infect Control Hosp Epidemiol 2009;30:184-6. Crossref

26. Muto CA, Jernigan JA, Ostrowsky BE, et al. SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains of Staphylococcus aureus and enterococcus. Infect Control Hosp Epidemiol 2003;24:362-86.

27. Morris JG Jr, Shay DK, Hebden JN, et al. Enterococci resistant to multiple antimicrobial agents, including vancomycin. Establishment of endemicity in a university medical center. Ann Intern Med 1995;123:250-9. Crossref

28. Rossini FA, Fagnani R, Leichsenring ML, et al. Successful prevention of the transmission of vancomycin-resistant enterococci in a Brazilian public teaching hospital. Rev Soc Bras Med Trop 2012;45:184-8. Crossref

29. Boyce JM. Environmental contamination makes an important contribution to hospital infection. J Hosp Infect 2007;65 Suppl 2:50-4. Crossref

30. Harris AD. How important is the environment in the emergence of nosocomial antimicrobial-resistant bacteria? Clin Infect Dis 2008;46:686-8. Crossref

31. Kirkland KB, Homa KA, Lasky RA, Ptak JA, Taylor EA, Splaine ME. Impact of a hospital-wide hand hygiene initiative on healthcare-associated infections: results of an interrupted time series. BMJ Qual Saf 2012;21:1019-26. Crossref

Ten-year review of survival and management of malignant glioma in Hong Kong

Hong Kong Med J 2017 Apr;23(2):134–9 | Epub 2 Dec 2016

DOI: 10.12809/hkmj164879

ORIGINAL ARTICLE

Ten-year review of survival and management of malignant glioma in Hong Kong

Danny TM Chan, FRCS, FHKAM (Surgery); Sonia YP Hsieh, MB, BS, MSc; Claire KY Lau, MSc; Michael KM Kam, FRCR, FHKAM (Radiology); Herbert HF Loong, MB, BS, MRCP (UK); WK Tsang, FRCR, FHKAM (Radiology); Darren MC Poon, FRCR, FHKAM (Radiology); WS Poon, FRCS, FHKAM (Surgery)

CUHK Otto Wong Brain Tumour Centre, 1/F, Sir Yue-kong Pao Centre for Cancer, Prince of Wales Hospital, Shatin, Hong Kong

Corresponding author: Dr Danny TM Chan (tmdanny@surgery.cuhk.edu.hk)

Full paper in PDF

Abstract

Introduction: Surgical resection used to be the mainstay of treatment for glioma. In the last decade, however, opinion has changed about the goal of surgical resection in treating glioma. Ample evidence shows that maximum safe resection in glioblastoma improves survival. Neurosurgeons have therefore revised their objective of surgery from diagnostic biopsy or limited debulking to maximum safe resection. Given these changes in the management of glioma, we compared the survival of local Chinese patients with glioblastoma multiforme over a period of 10 years.

Methods: We retrospectively reviewed the data of the brain tumour registry of the CUHK Otto Wong Brain Tumour Centre in Hong Kong. Data of patients with glioblastoma multiforme were reviewed for two periods, during 1 January 2003 to 31 December 2005 and 1 January 2010 to 31 December 2012. Overall survival during these two periods of time was assessed by Kaplan-Meier survival estimates. Risk factors including age, type and extent of resection, use of chemotherapy, and methylation status of O⁶-methylguanine-DNA methyltransferase were also assessed.

Results: There were 26 patients with glioblastoma multiforme with a mean age of 52.2 years during 2003 to 2005, and 42 patients with a mean age of 55.1 years during 2010 to 2012. The mean overall survival during these two periods was 7.4 months and 12.7 months, respectively (P<0.001). The proportion of patients who underwent surgical resection was similar: 69.2% in 2003 to 2005 versus 78.6% in 2010 to 2012 (P=0.404). There was a higher proportion of patients in whom surgery achieved total removal in 2010 to 2012 than in 2003 to 2005 (35.7% and 7.7%, respectively; P=0.015). During 2010 to 2012, patients who were given concomitant chemoradiotherapy showed definitively longer survival than those who were not (17.9 months vs 4.5 months; P=0.001). The proportion of patients who survived 2 years after surgery increased from 11.5% in 2003 to 2005 to 21.4% in 2010 to 2012.

Conclusions: Hong Kong has made substantial improvements in the management of glioblastoma multiforme over the last decade with corresponding improved survival outcomes. The combination of an aggressive surgical strategy and concomitant chemoradiotherapy are probably the driving force for the improvement.

New knowledge added by this study

Maximum safe resection of glioblastoma multiforme (GBM) is feasible and has improved survival of patients over the last decade.
Concomitant chemoradiotherapy has been shown to improve overall survival of patients with GBM.

Implications for clinical practice or policy

A combined multidisciplinary approach with surgery, radiotherapy, and chemotherapy should be adopted for treatment of GBM.

[Abstract in Chinese]

Introduction

Glioblastoma multiforme (GBM) is a malignant primary brain tumour with an incidence of 1 to 2 per 100 000 population in Hong Kong.1 The survival of patients with GBM remains dismal, mainly due to its inevitable progression and recurrence. Little progress was made until the last decade. The establishment of concomitant chemoradiotherapy (CCRT) with temozolomide (TMZ) and the discovery of O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation in association with significantly better outcome were the two major and inspiring breakthroughs.2 3 Before these developments, the treatment for GBM was homogeneous but desperate, and comprised surgery and irradiation only.

In 2001, TMZ was first used in the treatment of recurrent high-grade glioma in Hong Kong. Its favourable anti-tumour activity and acceptable safety profile were proven in a local study.4 In 2005, TMZ was the first chemotherapy to show objective survival benefit as a primary treatment when used together with radiotherapy as part of CCRT in GBM.2 Since then, CCRT for GBM has become the norm in Hong Kong.

In the last decade, opinion has changed about the goal of surgical resection in treating glioma. Ample evidence has shown that maximum safe resection in GBM improves survival. Neurosurgeons have therefore revised their objective of surgery from a diagnostic biopsy or limited debulking to a maximum safe resection. Knowing the infiltrative nature of the tumour, surgeons have a demanding job of balancing maximum resection and safe surgery. Awake craniotomy and mapping technique are two essential surgical techniques that enable safe resection.5 The goal of maximum resection can be achieved with a fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA).6

Given these changes to the management of GBM, we therefore analysed the changes in overall survival of GBM over the past 10 years in Hong Kong.

Methods

Data were retrieved from the Chinese University of Hong Kong Otto Wong Brain Tumour Centre brain tumour registry. The registry has been collecting data from all histology-proven glioma patients in the institute since January 2003. Patients aged 18 years or above with histologically proven glioma diagnosed in the institute were included in the registry. Patients with histologically confirmed World Health Organization grade IV GBM during January 2003 to December 2005 and January 2010 to December 2012 were recruited and grouped. Patients treated between 2006 and 2009 were excluded because the surgical policy was evolving and the availability of chemotherapy was variable during the period. Therefore this would be a heterogeneous group of patients with various treatments due to availability or affordability. Patients with an unstable neurological condition or who were considered a poor medical risk after surgery resulting in Karnofsky Performance Scale score of below 70 were excluded, as were those who received initial chemotherapeutics other than TMZ, ie procarbazine, lomustine, vincristine, or bevacizumab. Data on type of surgery, extent of resection, tumour histology, irradiation and chemotherapy parameters were collected as well as information about patient’s age and gender. The registry defined the death date according to the electronic patient record in the Hospital Authority Clinical Management System. For patients who defaulted from clinical follow-up, telephone follow-up ascertained death date. The study end date was 30 June 2015.

During 2003 to 2005, all patients were treated with surgical resection and adjuvant radiotherapy; TMZ was only used in patients with recurrent disease. Ability to pay for chemotherapy was the key determinant of its application and utility. In our hospital, TMZ was prescribed at a dose of 200 mg/m² once per day for 5 days in a 28-day cycle.

With regard to the contouring methodology of irradiation, either European Organisation for Research and Treatment of Cancer or Radiation Therapy Oncology Group protocol was chosen according to the serial assessment of both pre- and post-operative magnetic resonance imaging (MRI) scans. A total dose of 60 Gy irradiation was delivered to the tumour bed and its adjacent tissue in 30 fractions, with 2 Gy each.

Since 2009, neuroradiologists have been responsible for assessing the extent of resection by MRI on postoperative day 1. Total resection was defined as no remaining contrast enhancement on MRI T1-weighted and subtraction scans of T1 plain with T1 plus contrast. For patients in whom the enhancing lesion was still noticeable, the resection was categorised as debulking.

In the 2010-2012 cohorts, TMZ was recommended to all patients. The dosage was 75 mg/m²/day concomitant with radiotherapy, then 150-200 mg/m²/day on the first 5 days every 4 weeks for 6 cycles, in accordance with the regimen described by Stupp et al.2 Methylation status of the MGMT was detected using methylation-specific polymerase chain reaction at our institution. The method has been explained in detail in one of our earlier studies.7 Survival was calculated from the date of surgery for brain tumour to death. Kaplan-Meier survival curves were used to compare different groups of biopsy versus surgical resection and chemoradiotherapy versus radiotherapy alone.

This audit review was done in accordance with the principles outlined in the Declaration of Helsinki.

Results

Demographics, management, and survival of patients are shown in the Table.

Table. Demographics, management, and survival of patients

During the period 1 January 2003 to 31 December 2005, 26 patients with a mean age of 52.2 years were eligible for study. Two patients below the age of 18 years were excluded from the registry. The median overall survival for this cohort was 7.4 months (Fig 1). Eight (30.7%) patients underwent biopsy only, with a non-inferior median overall survival compared with the remaining 18 patients who underwent resection (7.2 months vs 7.4 months, P=0.988, log-rank test; Fig 2). Total removal could be achieved in only two patients, with overall survival of 14.7 and 28.8 months, respectively. For the remaining 16 patients who underwent debulking surgery, the median overall survival was 7.2 months.

Figure 1. Kaplan-Meier curves for overall survival of patients during the two periods
2003-2005 (n=26): 7.4 months; 2010-2012 (n=42): 12.7 months

Figure 2. Kaplan-Meier curves for overall survival of the biopsy group and surgical resection group during 2003 to 2005
Biopsy (n=8): 7.2 months; resection (n=18): 7.4 months

During the period 1 January 2010 to 31 December 2012, 42 patients with a mean age of 55.1 years were identified. One patient was excluded because he declined CCRT after surgery and opted for alternative medicine. The median overall survival was markedly prolonged to 12.7 months (P<0.001, log-rank test; Fig 1). The proportion of patients who had biopsy (9/42, 21.4%) during 2010 to 2012 remained similar to 10 years ago (8/26, 30.8%). Patients with resection performed was not significantly different between the two periods (P=0.404, Chi squared test). Overall survival of the surgical resection group was distinctly longer than that for the biopsy group (15.2 months and 4.5 months, respectively; P=0.026, log-rank test; Fig 3). A higher proportion of patients achieved total surgical removal in 2010-2012 than in 2003-2005, being 35.7% (15/42) and 7.7% (2/26), respectively (P=0.015, Chi squared test). The difference between debulking and total resection remained undefined in the 2010-2012 arm (13.0 months vs 16.0 months; P=0.966, log-rank test) by the time of analysis.

Figure 3. Kaplan-Meier curves for overall survival of the biopsy group and surgical resection group during 2010 to 2012
Biopsy (n=9): 4.5 months; resection (n=33): 15.2 months

Of the 42 patients with GBM during 2010-2012, CCRT was initiated in 23, accompanied by a meaningful longer median survival of 17.9 months compared with only 4.5 months for those given radiotherapy only (P=0.001, log-rank test; Fig 4). Data for MGMT were available in 33 patients. The overall survival of 19 patients with methylated MGMT promoter was longer than that of 14 patients with unmethylated MGMT promoter, being 28.4 months and 6.3 months, respectively (P<0.001, log-rank test).

Figure 4. Kaplan-Meier curves for overall survival of the surgery plus concomitant chemoradiotherapy (CCRT) group and surgery plus radiotherapy (RT) group during 2010 to 2012
Surgery + CCRT (n=23): 17.9 months versus surgery + RT (n=19): 4.5 months

Improvement in 2-year survival was also evident, from 11.5% in the earlier cohort, to 21.4% in the later one.

Discussion

Glioma has attracted international research interest over the last 20 years in both clinical and laboratory setting. The determination to fight the disease yielded with proven survival benefit of TMZ in recurrent high-grade glioma in 2000.8 A 6-month event-free survival of 21% in TMZ compared favourably with 9% for procarbazine.8 The full effect of TMZ was reported in a randomised trial as primary treatment for GBM in 2005.2 The regimen included two phases of TMZ, starting with a concomitant phase of daily low-dose TMZ during the course of radiotherapy, followed by the adjuvant phase of a high-dose TMZ for 5 days during each 28-day cycle for 6 cycles.2 The results of the study benchmarked a standard for chemotherapy in the treatment of GBM. The median survival of 14.6 months in the CCRT arm compared favourably with the 12.1 months of the control radiotherapy-alone arm.2

In Hong Kong, TMZ was first introduced in 2001. Its safety and effect had been tested and reported in a small series of recurrent high-grade glioma.4 The use of CCRT in Hong Kong was also reported with favourable results.9 The overall survival was much improved in these 10 years from 7.4 months in 2003-2005 to 12.7 months in 2010-2012. Among the cohorts in 2010-2012, however, only 54.8% (23/42) received CCRT. This can be attributed to the fact that in 2010, TMZ, whilst already incorporated into the Hospital Authority Drug Formulary, was listed as a self-financed item only. The financial burden on patients was the major cause of low usage during the time.

In 2011, TMZ was granted conditional funding through the Samaritan Fund scheme. Approval of funding was based on the financial situation of the patient and the tumour’s MGMT methylation status, with approval only granted to patients with tumours with MGMT methylation. This may have been a cost-effectiveness consideration because the largest survival benefit would be in MGMT-methylated GBM. Local data showed that only 43% of local GBM were methylated in MGMT status,9 thus essentially limiting the possibility of funding for less than half of the patients with GBM. Thus, within the 2010-2012 cohort, only patients diagnosed from 2011 onwards with tumours of methylated MGMT status (accounting for roughly a further half of the patient population) would have benefited from the scheme. This may account for the relatively low number of patients treated with CCRT. Then the policy of restricting funding based on MGMT status was re-addressed and such criterion was removed in 2013. Currently, support of Samaritan Fund for TMZ is available for eligible patients with GBM based on their financial situation, and regardless of their tumour MGMT status.

The treatment of CCRT had made an impact not only on clinical outcomes, but also on the working dynamics between different professional disciplines involved in the management of patients with GBM. The need for timely arrangement and administration of radiotherapy and chemotherapy within a short postoperative window has encouraged a multidisciplinary team approach. This continues to be the current treatment delivery model for patients with GBM in many hospitals in Hong Kong. Better clinical outcomes encouraged professional enthusiasm. In this atmosphere, a local group of clinicians got together and founded the Hong Kong Neuro-Oncology Society in 2011.

The reasons for longer survival of GBM in recent years are likely to be multifactorial. The extent of surgical resection has been intensely studied over the last two decades. Nonetheless, since a prospective randomised surgical study would be unethical, evidence to support maximum safe resection must be gleaned retrospectively. Despite this, neurosurgical professionals were convinced that surgical resection was the first and major treatment for GBM. Surgical conservatism was abandoned and the demand for maximum safe resection was set out by neurosurgeons. This change was reflected in the decrease in surgical biopsy rate from 30.8% in 2003-2005 to 21.4% in 2010-2012. The ability of total surgical removal of the contrast-enhancing tumour was also increased from 7.7% in 2003-2005 to 35.7% in 2010-2012. Local neurosurgeons have been equipped with two surgical techniques to achieve maximum safe resection in the last 10 years—the technique of cortical mapping and awake surgery was brought to all local neurosurgeons in two workshops of commissioned training organised by the Hospital Authority in 2003 and 2010. This technique allows safer resection of the tumour at or near the eloquent area of the brain. A tumour fluorescent technique (5-ALA) was introduced in 2009 that facilitated detection of residual tumour for maximum resection. In 2003-2005, the survival of the surgical resection group and biopsy group was similar but in 2010-2012, those in the surgical resection group survived longer. The difference was probably due to both aggressive surgical resection and CCRT in the latter group.

The major limitation of this study was the presence of potential confounding factors during the 10-year study period. Such factors included incomplete data of MGMT methylation status and extent of resection in the 2003-2005 group. There was no MGMT methylation testing or day-1 MRI scan after resection in 2003-2005. The interval between surgery and commencement of radiotherapy has been controlled to within 4 weeks since 2009 but this was not the case in 2003-2005. All these confounding factors made valid comparison of the effect of surgical resection or chemotherapy during these two time periods difficult. Moreover, the registry included only surgical patients who had undergone biopsy or resection, and excluded a small group of patients, who were usually elderly (age >70 years) or with poor co-morbidities, who may have received radiotherapy or chemotherapy alone.

Conclusions

Hong Kong has made substantial improvements in the management of GBM with improved survival over the last decade. The combination of aggressive surgical strategy and CCRT are probably the driving force for the improvement.

Declaration

None of the authors has disclosed any conflicts of interest.

References

1. Pu JK, Ng GK, Leung GK, Wong CK. One-year review of the incidence of brain tumours in Hong Kong Chinese patients as part of the Hong Kong Brain and Spinal Tumours Registry. Surg Pract 2012;16:133-6. Crossref

2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. Crossref

3. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997-1003. Crossref

4. Chan DT, Poon WS, Chan YL, Ng HK. Temozolomide in the treatment of recurrent malignant glioma in Chinese patients. Hong Kong Med J 2005;11:452-6.

5. Chan DT, Kan PK, Lam JM, et al. Cerebral motor cortical mapping: awake procedure is preferable to general anaesthesia. Surg Pract 2010;14:12-8. Crossref

6. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006;7:392-401. Crossref

7. Dong SM, Pang JC, Poon WS, et al. Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors. J Neuropathol Exp Neurol 2001;60:808-16. Crossref

8. Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000;83:588-93. Crossref

9. Chan DT, Kam MK, Ma BB, et al. Association of molecular marker O⁶Methylguanine DNA methyltransferase and concomitant chemoradiotherapy with survival in Southern Chinese glioblastoma patients. Hong Kong Med J 2011;17:184-8.

Preimplantation genetic diagnosis and screening by array comparative genomic hybridisation: experience of more than 100 cases in a single centre

Hong Kong Med J 2017 Apr;23(2):129–33 | Epub 17 Feb 2017

DOI: 10.12809/hkmj164883

ORIGINAL ARTICLE

Preimplantation genetic diagnosis and screening by array comparative genomic hybridisation: experience of more than 100 cases in a single centre

Judy FC Chow, MPhil¹; William SB Yeung, PhD¹; Vivian CY Lee, FHKAM (Obstetrics and Gynaecology)²; Estella YL Lau, PhD²; PC Ho, FRCOG, FHKAM (Obstetrics and Gynaecology)¹; Ernest HY Ng, FRCOG, FHKAM (Obstetrics and Gynaecology)¹;

¹ Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong

² Department of Obstetrics and Gynaecology, Queen Mary Hospital, Hong Kong

Corresponding author: Dr William SB Yeung (wsbyeung@hku.hk)

Full paper in PDF

Abstract

Introduction: Preimplantation genetic screening has been proposed to improve the in-vitro fertilisation outcome by screening for aneuploid embryos or blastocysts. This study aimed to report the outcome of 133 cycles of preimplantation genetic diagnosis and screening by array comparative genomic hybridisation.

Methods: This study of case series was conducted in a tertiary assisted reproductive centre in Hong Kong. Patients who underwent preimplantation genetic diagnosis for chromosomal abnormalities or preimplantation genetic screening between 1 April 2012 and 30 June 2015 were included. They underwent in-vitro fertilisation and intracytoplasmic sperm injection. An embryo biopsy was performed on day-3 embryos and the blastomere was subject to array comparative genomic hybridisation. Embryos with normal copy numbers were replaced. The ongoing pregnancy rate, implantation rate, and miscarriage rate were studied.

Results: During the study period, 133 cycles of preimplantation genetic diagnosis for chromosomal abnormalities or preimplantation genetic screening were initiated in 94 patients. Overall, 112 cycles proceeded to embryo biopsy and 65 cycles had embryo transfer. The ongoing pregnancy rate per transfer cycle after preimplantation genetic screening was 50.0% and that after preimplantation genetic diagnosis was 34.9%. The implantation rates after preimplantation genetic screening and diagnosis were 45.7% and 41.1%, respectively and the miscarriage rates were 8.3% and 28.6%, respectively. There were 26 frozen-thawed embryo transfer cycles, in which vitrified and biopsied genetically transferrable embryos were replaced, resulting in an ongoing pregnancy rate of 36.4% in the screening group and 60.0% in the diagnosis group.

Conclusions: The clinical outcomes of preimplantation genetic diagnosis and screening using comparative genomic hybridisation in our unit were comparable to those reported internationally. Genetically transferrable embryos replaced in a natural cycle may improve the ongoing pregnancy rate and implantation rate when compared with transfer in a stimulated cycle.

New knowledge added by this study

Array comparative genomic hybridisation is a reliable method for preimplantation genetic diagnosis for translocation/inversion carriers, and for patients with mosaic sex chromosome aneuploidy. Replacement of vitrified embryos after warming in a natural cycle may improve the ongoing pregnancy rate and implantation rate.

Implications for clinical practice or policy

Preimplantation genetic diagnosis by array comparative genomic hybridisation shall be offered as an alternative to prenatal diagnosis for translocation/inversion carriers, and for patients with mosaic sex chromosome aneuploidy. The results of this local case series provide information, such as the anticipated percentage of genetically transferrable embryos and the expected ongoing pregnancy rate, which is useful for patient counselling before preimplantation genetic diagnosis or screening.

[Abstract in Chinese]

Introduction

Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis for detection of chromosomal abnormalities in translocation or inversion carrier couples. In the past 13 years, more than 6000 cycles of PGD for chromosomal abnormalities have been performed.1 Fluorescence in-situ hybridisation (FISH) was first used in PGD for translocation carriers.2 Due to its technical limitations however,3 4 5 it has been replaced by array comparative genomic hybridisation (aCGH) in many centres. In our centre, we have previously shown that the use of aCGH for PGD in translocation carriers results in a significantly higher rate of ongoing pregnancy than PGD by FISH.6

Aneuploidy is the most common abnormality found in embryos derived from in-vitro fertilisation (IVF), and leads to poor outcomes.7 8 9 10 11 12 13 Morphological assessment of embryos or blastocysts alone, however, cannot negate the potential risk of replacing aneuploid embryos or blastocysts.14 Preimplantation genetic screening (PGS) has been proposed to improve the IVF outcomes by screening for aneuploid embryos or blastocysts. More than 26 000 PGS cycles have been performed worldwide.1 The aCGH technique enables us to screen all 24 chromosomes within 24 hours and makes fresh transfer possible after blastomere biopsy or trophectoderm biopsy.15 A randomised study has shown that PGS by aCGH plus selection by morphology of blastocysts can significantly improve the ongoing pregnancy rate in patients with good prognosis when compared with selection of blastocysts by morphology alone.16 Another randomised study also showed an improvement in the implantation rate after PGS by aCGH in addition to morphological assessment of embryos.17 We report here the clinical outcome of 133 cycles of PGD/PGS by aCGH in a local unit.

Methods

Study population

Data from all treatment cycles performed for PGD and PGS in the Department of Obstetrics and Gynaecology, Queen Mary Hospital/The University of Hong Kong from 1 April 2012 to 30 June 2015 were retrieved. This study was done in accordance with the principles outlined in the Declaration of Helsinki. Patient consent has been obtained. Data were stored in a database and coded for indication. Indications for PGS were defined as: (1) advanced maternal age (AMA) group for patients aged >38 years; (2) recurrent miscarriage (RM) group with patients having at least two clinical miscarriages and negative investigations for RM; (3) repeated implantation failure group (RIF) with those who failed to get pregnant after three embryo transfer cycles with at least six good-quality embryos replaced; and (4) optional PGS group included those with normal karyotype but who had experienced a previous pregnancy with abnormal karyotype, and those who opted for PGS when performing PGD for monogenetic disease.

Indications for PGD by aCGH were divided as follows: (1) mosaic were those with mosaic sex chromosome abnormalities on karyotyping, including mosaic Klinefelter’s or mosaic Turner’s syndromes; (2) Robertsonian translocation; (3) reciprocal translocation; (4) inversion; and (5) double translocations.

Treatment regimen

The details of the ovarian stimulation regimen, gamete handling, and frozen-thawed embryo transfer (FET) have been previously described.18 Surplus good-quality blastocysts with no aneuploidy/unbalanced chromosome detected were vitrified by the CVM Vitrification System (CryoLogic, Victoria, Australia). If the patient did not get pregnant in the stimulated cycle, the vitrified blastocysts were warmed and replaced in subsequent FET cycles. The details of biopsy and PGD/ PGS by aCGH have been described elsewhere.6 19 In brief, a single blastomere was removed from good-quality day-3 embryos (6-to-8 cell stage) and the blastomere underwent whole-genome amplification (SurePlex; BlueGnome, Cambridge, United Kingdom). Array CGH was performed using 24sure+ (BlueGnome) on reciprocal translocation and inversion cases while other cases were tested by 24sure V3 (BlueGnome) according to the manufacturer’s protocol. All results were interpreted independently by two laboratory staff, usually with a high concordant rate (>95%). Discrepancies were resolved through consensus.

Results

Between 1 April 2012 and 30 June 2015, 94 couples underwent 133 cycles of ovarian stimulation for PGD for chromosomal abnormalities, or PGS with indications listed in Table 1. The most frequent indication for PGD/PGS was reciprocal translocation (35.3%) followed by RM (27.1%) and Robertsonian translocation (16.5%). The median age of the women was 36.5 (range, 25-44) years. Embryo biopsy was performed in 112 cycles. The mean number of embryos biopsied per retrieval cycle was 5.6 (740/133), with 99.2% of biopsies resulting in a conclusive diagnosis, of which only 25.8% (191/740) were genetically transferrable. The whole-genome amplification failed in all the samples with inconclusive diagnosis.

Table 1. Indications for PGD and PGS

Overall, PGD/PGS was cancelled in 21 (15.8%) cycles after ovarian stimulation due to poor response (19 cycles), failed fertilisation (1 cycle), or no sperm found in the testicular biopsy (1 cycle). In case of poor response (<4 good-quality embryos on day 3), cleavage-stage embryos were frozen/vitrified, subsequently thawed/warmed, and pooled with fresh embryos from the following stimulation cycle for diagnosis. Fresh embryo transfer was cancelled in 47 (42.0%) cycles after biopsy due to unavailability of genetically transferrable embryo (31 cycles), high serum progesterone level on the day of human chorionic gonadotropin (>5 nmol/L; 10 cycles), risk of ovarian hyperstimulation (2 cycles), delayed assay (3 cycles), or patient request (1 cycle). Overall, 65 PGD/PGS cycles proceeded to embryo transfer in the stimulated cycles with one or two blastocysts replaced on day 5 (mean, 1.4). As shown in Table 2, the result of aCGH was further subdivided into two categories (PGS and PGD) based on indications. The ongoing pregnancy rates (pregnancy beyond 8-10 weeks of gestation) of PGS and PGD were 50.0% (11/22) and 34.9% (15/43), respectively.

Table 2. Results of PGS / PGD by aCGH in stimulated and frozen-thawed embryo transfer cycles

There were 26 cycles of FET in a natural cycle in which one or two biopsied and vitrified blastocysts were replaced (mean, 1.2), resulting in a pregnancy rate of 36.4% (4/11) in the PGS group and 66.7% (10/15) in the PGD group. Ongoing pregnancy rates in the PGS and PGD group were 36.4% (4/11) and 60.0% (9/15), respectively (Table 2). The miscarriage rates in the stimulated embryo transfer cycles and FET cycles were 21.2% (7/33) and 7.1% (1/14), respectively. The differences in ongoing pregnancy rate and miscarriage rate between stimulated embryo transfer and FET cycle were not statistically significant. All pregnant women following PGD for chromosomal abnormalities were referred to the Prenatal Counselling and Diagnosis team at Tsan Yuk Hospital for counselling and confirmation of the PGD result by prenatal diagnosis or postnatal cord blood karyotyping. Based on the available results of the confirmation tests, no misdiagnosis was found in this small series.

Discussion

The 13th data report of the ESHRE PGD Consortium includes a total of 1071 oocyte retrieval cycles for chromosomal abnormalities and 2979 oocyte retrieval cycles for PGS, resulting in a delivery rate of 21%-25% per transfer and an implantation rate of 22%-26%.1 The ongoing pregnancy rate and implantation rate of the present series are 34.9%-50.0% and 41.1%-45.7%, respectively.

As shown in Table 1, the percentage of transferrable embryos varies among different indications for PGD/PGS. In cases of PGD for chromosomal abnormalities, as expected, the lowest percentage of genetically transferrable embryos was found in the reciprocal translocation group (17.5%), followed by the Robertsonian translocation group (31.8%) and the mosaic Turner’s / Klinefelter’s syndrome group (32.7%). These data are in line with those of the ESHRE PGD consortium,1 of which the corresponding percentages are 16.6%, 33.5%, and 36.8%, respectively. The high proportion of unbalanced gametes can be explained by the segregation modes and behaviour of the translocated chromosomes during meiosis.20

In the PGS group (RM, RIF, AMA, and optional PGS), the overall percentage of genetically transferrable embryos was 27.5% (69/251), similar to that of the ESHRE PGD consortium (30%). It is noteworthy that there were no transferrable embryos in all four cases of AMA (median age, 42.5 years). It is well known that chromosomal aneuploidy increases exponentially with increasing maternal age.21 22 Therefore, patients with advanced age should be counselled accordingly before the initiation of PGS cycles.

The cancellation rate for PGD/PGS after initiation of stimulation was 15.8% (21/133) and the reason for cancellation in the great majority of cases was poor ovarian response (19/21). Furthermore, for those cases proceeding to biopsy, 42.0% (31/47) did not have an embryo transfer, mainly due to no normal/balanced embryos available. When a low percentage of normal/balanced embryos is expected, patients can consider pooling embryos from several stimulation cycles and perform PGD/PGD in a single batch. Such ‘batching’ can increase the chance of having normal/balanced embryos and allow selection of the best-quality genetically transferrable embryos for replacement in the PGD/PGS cycle, instead of having multiple cycles with no embryo transfer.

There were 26 cycles of vitrified-warmed blastocyst transfer (11 cycles after PGS and 15 cycles after PGD) performed during a natural cycle. The ongoing pregnancy rate per transfer in these natural cycles after PGD appeared to be higher than those with transfer in a stimulated cycle, while the miscarriage rate of transfer in the natural cycle was lower than that of transfer in a stimulated cycle. Such findings did not reach statistical significance due to the small number of cases, however. Some reports have suggested that transfer of embryos in a natural cycle may result in a higher pregnancy and implantation rate than in a stimulated cycle due to the better receptivity of the endometrium without gonadotropin stimulation.23 24 25 26

The limitation of the present study was the small number of cases for each indication of PGS. Moreover, it was not a randomised controlled trial. The usefulness of PGS by aCGH in these cases needs to be confirmed in a large randomised controlled trial. It is noteworthy that aCGH cannot detect mutation and/or small chromosomal aberrations (<10 Mb for Robertsonian translocation, mosaic sex chromosome aneuploidy and PGS; <5 Mb for reciprocal translocation and inversion). False results can be attributed to mosaicism of embryos, although no misdiagnosis was found in the present study.

Conclusions

The clinical outcomes of PGD and PGS in our unit were comparable to those reported internationally. A genetically transferrable embryo after PGD that is replaced during a natural cycle may improve the ongoing pregnancy rate and implantation rate when compared with transfer during a stimulated cycle.

Acknowledgements

We would like to thank the patients, nurses, clinicians, technicians, and embryologists at the Centre of Assisted Reproduction and Embryology, Queen Mary Hospital–The University of Hong Kong for their contribution in the PGD programme.

Declaration

All authors have disclosed no conflicts of interest.

References

1. De Rycke M, Belva F, Goossens V, et al. ESHRE PGD Consortium data collection XIII: cycles from January to December 2010 with pregnancy follow-up to October 2011. Hum Reprod 2015;30:1763-89. Crossref

2. DeUgarte CM, Li M, Surrey M, Danzer H, Hill D, DeCherney AH. Accuracy of FISH analysis in predicting chromosomal status in patients undergoing preimplantation genetic diagnosis. Fertil Steril 2008;90:1049-54. Crossref

3. Li M, DeUgarte CM, Surrey M, Danzer H, DeCherney A, Hill DL. Fluorescence in situ hybridization reanalysis of day-6 human blastocysts diagnosed with aneuploidy on day 3. Fertil Steril 2005;84:1395-400. Crossref

4. Velilla E, Escudero T, Munné S. Blastomere fixation techniques and risk of misdiagnosis for preimplantation genetic diagnosis of aneuploidy. Reprod Biomed Online 2002;4:210-7. Crossref

5. Wells D, Alfarawati S, Fragouli E. Use of comprehensive chromosomal screening for embryo assessment: microarrays and CGH. Mol Hum Reprod 2008;14:703-10. Crossref

6. Lee VC, Chow JF, Lau EY, Yeung WS, Ho PC, Ng EH. Comparison between fluorescent in-situ hybridisation and array comparative genomic hybridisation in preimplantation genetic diagnosis in translocation carriers. Hong Kong Med J 2015;21:16-22.

7. Bielanska M, Tan SL, Ao A. Chromosomal mosaicism throughout human preimplantation development in vitro: incidence, type, and relevance to embryo outcome. Hum Reprod 2002;17:413-9. Crossref

8. Munné S, Sandalinas M, Magli C, Gianaroli L, Cohen J, Warburton D. Increased rate of aneuploid embryos in young women with previous aneuploid conceptions. Prenat Diagn 2004;24:638-43. Crossref

9. Kuliev A, Cieslak J, Verlinsky Y. Frequency and distribution of chromosome abnormalities in human oocytes. Cytogenet Genome Res 2005;111:193-8. Crossref

10. Magli MC, Gianaroli L, Ferraretti AP, Lappi M, Ruberti A, Farfalli V. Embryo morphology and development are dependent on the chromosomal complement. Fertil Steril 2007;87:534-41. Crossref

11. Munné S, Chen S, Colls P, et al. Maternal age, morphology, development and chromosome abnormalities in over 6000 cleavage-stage embryos. Reprod Biomed Online 2007;14:628-34. Crossref

12. Hassold T, Hunt P. Maternal age and chromosomally abnormal pregnancies: what we know and what we wish we knew. Curr Opin Pediatr 2009;21:703-8. Crossref

13. Vanneste E, Voet T, Le Caignec C, et al. Chromosome instability is common in human cleavage-stage embryos. Nat Med 2009;15:577-83. Crossref

14. Alfarawati S, Fragouli E, Colls P, et al. The relationship between blastocyst morphology, chromosomal abnormality, and embryo gender. Fertil Steril 2011;95:520-4. Crossref

15. Rubio C, Rodrigo L, Mir P, et al. Use of array comparative genomic hybridization (array-CGH) for embryo assessment: clinical results. Fertil Steril 2013;99:1044-8. Crossref

16. Yang Z, Liu J, Collins GS, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet 2012;5:24. Crossref

17. Yang Z, Salem SA, Liu X, Kuang Y, Salem RD, Liu J. Selection of euploid blastocysts for cryopreservation with array comparative genomic hybridization (aCGH) results in increased implantation rates in subsequent frozen and thawed embryo transfer cycles. Mol Cytogenet 2013;6:32. Crossref

18. Ng EH, Yeung WS, Lau EY, So WW, Ho PC. High serum oestradiol concentrations in fresh IVF cycles do not impair implantation and pregnancy rates in subsequent frozen-thawed embryo transfer cycles. Hum Reprod 2000;15:250-5. Crossref

19. Chow JF, Yeung WS, Lau EY, et al. Singleton birth after preimplantation genetic diagnosis for Huntington disease using whole genome amplification. Fertil Steril 2009;92:828.e7-10.

20. Scriven PN, Handyside AH, Ogilvie CM. Chromosome translocations: segregation modes and strategies for preimplantation genetic diagnosis. Prenat Diagn 1998;18:1437-49. Crossref

21. Spandorfer SD, Davis OK, Barmat LI, Chung PH, Rosenwaks Z. Relationship between maternal age and aneuploidy in in vitro fertilization pregnancy loss. Fertil Steril 2004;81:1265-9. Crossref

22. Hassold T, Hall H, Hunt P. The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet 2007;16 Spec No. 2:R203-8.

23. Evans J, Hannan NJ, Edgell TA, et al. Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence. Hum Reprod Update 2014;20:808-21. Crossref

24. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Clinical rationale for cryopreservation of entire embryo cohorts in lieu of fresh transfer. Fertil Steril 2014;102:3-9. Crossref

25. Roque M. Freeze-all policy: is it time for that? J Assist Reprod Genet 2015;32:171-6. Crossref

26. Roque M, Valle M, Guimarães F, Sampaio M, Geber S. Freeze-all policy: fresh vs. frozen-thawed embryo transfer. Fertil Steril 2015;103:1190-3. Crossref

Management of traumatic patellar dislocation in a regional hospital in Hong Kong

Hong Kong Med J 2017 Apr;23(2):122–8 | Epub 12 Dec 2016

DOI: 10.12809/hkmj164872

ORIGINAL ARTICLE

Management of traumatic patellar dislocation in a regional hospital in Hong Kong

HL Lee, FHKCOS, FHKAM (Orthopaedic Surgery); WP Yau, FHKCOS, FHKAM (Orthopaedic Surgery)

Division of Sports and Arthroscopic Surgery, Department of Orthopaedics and Traumatology, Queen Mary Hospital, Hong Kong

This paper was presented at the Hong Kong Orthopaedic Association 35th Annual Congress, 7 November 2015, Hong Kong.

Corresponding author: Dr HL Lee (ricklhl@gmail.com)

A video clip showing management of traumatic patellar dislocation is available at www.hkmj.org

Full paper in PDF

Abstract

Introduction: The role of surgery for acute patellar dislocation without osteochondral fracture is controversial. The aim of this study was to report the short-term results of management of patellar dislocation in our institute.

Methods: Patients who were seen in our institution with patella dislocation from January 2011 to April 2014 were managed according to a standardised management algorithm. Pretreatment and 1-year post-treatment International Knee Documentation Committee score, Tegner activity level scale score, and presence of apprehension sign were analysed.

Results: A total of 41 patients were studied of whom 20 were first-time dislocators and 21 were recurrent dislocators. Among the first-time dislocators, there was a significant difference between patients who received conservative treatment versus surgical management. The conservative treatment group had a 33% recurrent dislocation rate, whereas there were no recurrent dislocations in the surgery group. There was no difference in Tegner activity level scale score or apprehension sign before and 1 year after treatment, however. Among the recurrent dislocators, there was a significant difference between those who received conservative treatment and those who underwent surgery. The recurrent dislocation rate was 71% in the conservative treatment group versus 0% in the surgery group. There was also significant improvement in International Knee Documentation Committee score from 67.7 to 80.0 (P=0.02), and of apprehension sign from 62% to 0% (P<0.01).

Conclusions: A management algorithm for patellar dislocation is described. Surgery is preferable to conservative treatment in patients who have recurrent patellar dislocation, and may also be preferable for those who have an acute dislocation.

New knowledge added by this study

This study reveals the short-term results regarding local management of traumatic patellar dislocation. A suggested treatment algorithm is provided that can help approach this problem systematically.

Implications for clinical practice or policy

The results of this study support surgery as the first-line treatment of recurrent patellar dislocation. It is inconclusive whether conservative treatment or surgery is preferable in first-time dislocators although there is a trend towards better results with surgery.

[Abstract in Chinese]

Introduction

Patellar dislocation is a common injury in young, active individuals and accounts for approximately 3% of all knee injuries. The overall incidence is about 1 in 1000.1 2 Without appropriate treatment, these injuries may result in significant morbidity, including significant limitations in activity and patellofemoral arthritis.3 4 The management of patellar dislocation must take into account numerous clinical factors including the number of dislocations, chronicity of the dislocation, bony alignment, and status of the articular cartilage.

The management of acute first-time patellar dislocators is controversial. Traditionally, these patients have been managed conservatively but the results of such treatment are highly variable and unpredictable. The recurrent instability rate following conservative treatment in these patients has been reported to be between 17% and 44%.1 5 Limitation of strenuous activity after conservative treatment was reported in 58% of these patients, and failure to return to sports activity in 55%.4 Therefore some authors have recommended early primary surgical stabilisation for this group of patients.3 6 7 Surgery is also indicated in patients who have concomitant osteochondral fractures.8

The management of recurrent patellar dislocators is less controversial. Studies have shown that in patients who have had two dislocations, the risk of further dislocation is as high as 50%.1 Most surgeons would recommend surgical stabilisation for these patients.

The aim of this study was to review and document the short-term results of management of patients with traumatic patellar dislocations in our institute, which is a university hospital that serves as a tertiary and quaternary referral centre in Hong Kong.

Methods

Patients with patellar dislocation who were seen in our institution from January 2011 to April 2014 were included in the current study. All patients were cared for according to the institution’s patellar dislocation management algorithm (Fig).

Figure. Management algorithm of patellar dislocation used at Queen Mary Hospital, Hong Kong

Patients followed up for less than 1 year were excluded from the study. Those who had chronic dislocations (persistent dislocation for more than 6 weeks’ duration) and a history of patellar surgery or osteochondral fracture detected on X-ray were also excluded.

The patellar dislocation management algorithm used in our institution is as follows. Patients are first categorised as first-time dislocators or recurrent dislocators. First-time dislocators are further subcategorised as an acute dislocator or subacute dislocator according to the time interval between presentation and time of injury. If this time interval is 3 weeks or less, they are considered acute dislocators; if more than 3 weeks, they are subcategorised as subacute dislocators.

For first-time acute dislocators, medial patellofemoral ligament (MPFL) repair surgery is advised. Preoperative magnetic resonance imaging (MRI) is not routinely performed. The exact site of MPFL tear is identified intra-operatively by combining knee arthroscopy and MPFL endoscopy. If the MPFL is found avulsed at the femoral origin or patellar insertion, it is repaired to bone using suture anchors. If the MPFL is torn at mid-substance, a direct end-to-end repair is performed. Minimal plication of the medial retinaculum was observed in all our cases. A hinged knee brace from full extension to 20-degree flexion is applied for 3 weeks, followed by patellar stabilisation orthosis for another 3 weeks. Supervised physiotherapy in terms of quadriceps strengthening exercises, range of motion training, and patellar mobilisation exercises is offered for 3 to 6 months and the patient is also advised to avoid pivoting sports for at least 6 months.

For first-time subacute dislocators, conservative treatment is offered. This includes wearing of a patellar stabilisation orthosis for a total of 6 weeks after the dislocation and a period of supervised physiotherapy (focusing on quadriceps strengthening exercises and range of motion training) for at least 6 weeks to 3 months. Patients are advised to avoid any pivoting sports for a total of 6 months. A similar regimen of conservative treatment is offered to those first-time acute dislocators who refuse surgical intervention. The whole course of rehabilitation usually lasts 4 to 6 months before the patient is permitted to resume full activity.

For recurrent dislocators, patients are advised to have MPFL reconstruction. Plain computed tomography of the knee is performed to measure the tibial tubercle–trochlear groove (TT-TG) distance. If this distance measures ≤20 mm, MPFL reconstruction surgery is advised. If this distance measures >20 mm, MPFL reconstruction and tibial tubercle osteotomy surgery for anteromedialisation of the tibial tubercle are advised. The rehabilitation protocol following MPFL reconstruction is the same as that for MPFL repair. For recurrent dislocators who refuse surgery, conservative treatment is advised. This consists of a 3- to 6-month course of supervised physiotherapy.

The following outcome measures were recorded before treatment and 1 year after treatment in our study patients: (1) International Knee Documentation Committee (IKDC) score; (2) Tegner activity level scale score; and (3) presence of apprehension sign on physical examination. The redislocation rate at 1 year after treatment was also measured for the different groups of treatment.

The IKDC score is a knee-specific self-evaluation score for reporting patient symptoms, function, and sports activity.9 Tegner activity level scale score is a functional score describing a patient’s activity level.10 The presence of apprehension sign was documented by one of the two observers, who were experienced sports surgeons in the authors’ institute. The test was performed with the patient lying supine on the examination couch. The knee was passively flexed to 20 degrees. A lateral displacing force was applied manually on the medial side of patella in an attempt to sublux the patella laterally. Apprehension sign was defined as positive if the patient reported a sense of subluxation or attempted to stop the examiner.

Data were analysed and compared with the Statistical Package for the Social Sciences (Windows version 23.0; SPSS Inc, Chicago [IL], US). The Wilcoxon signed-rank test (non-parametric, paired samples test) was used to compare IKDC score and Tegner activity level scale results before and after treatment within the same treatment group. The McNemar test (non-parametric, paired samples test) was used to compare the percentage of patients with apprehension sign before and after treatment within the same treatment group. The Mann-Whitney U test (non-parametric, independent samples test) was used to compare IKDC score as well as Tegner activity level scale results between conservative treatment group and surgery group. The Pearson’s Chi squared test (non-parametric, independent samples test) was used to compare the percentage of patients with apprehension sign as well as recurrent dislocation rate between conservative treatment group and surgery group. Whenever expected counts were less than five, Fisher’s exact test was used instead of Pearson’s Chi squared test. This study was done in accordance with the principles outlined in the Declaration of Helsinki.

Results

A total of 81 patients were identified. Of these, 40 patients were excluded—27 were excluded due to follow-up of less than 1 year, six due to osteochondral injury detected by X-ray, three due to chronic dislocation, two due to development of patellofemoral osteoarthritis, and two due to a history of patellar surgery (Table 1). This left us with 41 patients comprising 17 males and 24 females. Their mean age was 23.6 years (range, 13-44; standard deviation, 7.4 years). A summary of patient demographics is shown in Table 2.

Table 1. Patients excluded

Table 2. Patient demographics

There were 20 patients who were first-time dislocators and 21 patients who were recurrent dislocators. Among the first-time dislocators (n=20), 45% (n=9) were treated conservatively and 55% (n=11) were treated with MPFL repair surgery. Among the recurrent dislocators, 33% (n=7) were treated conservatively, 62% (n=13) were treated with MPFL reconstruction surgery, and 5% (n=1) were treated with combined tibial tubercle osteotomy and MPFL reconstruction surgery. Their results are summarised in Table 3.

Table 3. Results of different groups of patients preoperatively and 1 year post-treatment

Among the first-time dislocators who received conservative treatment (n=9), recurrent dislocation occurred in 33% (n=3) within 1 year of treatment. The findings are shown in Table 3. There were no statistically significant differences between the Tegner activity level scale or percentage of patients with apprehension sign before and 1 year after treatment.

Among the first-time dislocators who underwent MPFL repair surgery (n=11), intra-operative MPFL exploration showed 55% (n=6) of them had tears at the patellar insertion, 27% (n=3) had MPFL tear at the femoral origin, and 18% (n=2) had MPFL mid-substance tear (one of which was only a partial mid-substance tear). Preoperative MRI was performed in seven of the 11 patients. Among six of these seven patients, MPFL detected on preoperative MRI correlated with the tear site on intra-operative MPFL exploration. In the remaining patient, only a partial tear of MPFL at mid-substance was found intra-operatively; this was not detected by the preoperative MRI. Regarding the outcome of surgery, there were no recurrent dislocations within 1 year of surgery (Table 3). Apprehension sign was present in 88% before surgery and 9% 1 year after surgery (P=0.07, McNemar test). There were no statistically significant differences between the Tegner activity level scale or percentage of patients with apprehension sign before and 1 year after surgery.

Comparison of first-time dislocators who received conservative treatment with first-time dislocators who underwent MPFL repair surgery 1 year after treatment revealed no significant difference in IKDC score. There was a lower percentage of patients with apprehension sign (9% vs 33%) and a lower rate of redislocation in the MPFL repair surgery group (0% vs 33%, P=0.07, Fisher’s exact test) but the differences were not statistically significant.

Among the recurrent dislocators who received conservative treatment (n=7), recurrent dislocation occurred in 71% (n=5) of patients within 1 year of treatment (Table 3). Apprehension sign was present in 14% before treatment and 29% 1 year after treatment. There was no statistically significant difference between the IKDC score, Tegner activity level scale, or percentage of patients with apprehension sign before and 1 year after treatment.

Among the recurrent dislocators who underwent MPFL reconstruction surgery (n=13), there were no recurrent dislocations within 1 year of surgery (Table 3). Apprehension sign was present in 62% before surgery and no patients had apprehension sign 1 year after surgery. There were statistically significant improvements in the IKDC score (P=0.02, Wilcoxon signed-rank test), Tegner activity level scale score (P=0.04, Wilcoxon signed-rank test), as well as percentage of patients with apprehension sign (P<0.01, McNemar test).

One year after treatment, comparison of recurrent dislocators who received conservative treatment with recurrent dislocators who underwent MPFL reconstruction surgery revealed that the mean IKDC score was significantly better in the MPFL reconstruction surgery group (80.0 vs 67.7; P=0.02, Mann-Whitney U test). The redislocation rate was significantly lower in the MPFL reconstruction surgery group (0% vs 71%; P<0.01, Fisher’s exact test). There was a lower percentage of patients with apprehension sign in the MPFL reconstruction surgery group (0% vs 29%) although the difference was not statistically significant.

Discussion

For acute first-time patellar dislocators, it has been widely agreed that in the presence of concomitant osteochondral fracture, surgical treatment is indicated.11 The indication of surgery for acute first-time patellar dislocators without osteochondral fractures is controversial. The recurrent instability rate after conservative treatment in these patients has been reported to be 17% to 44%.1 5 It has traditionally been held that these patients should be treated conservatively.11 Nine prospective randomised controlled trials have compared conservative and surgical treatment in first-time dislocators and the results have been inconsistent.12 13 14 15 16 17 18 19 20 In their systematic review, Stefancin and Parker11 recommended conservative treatment for most patients after first-time dislocation, except those with concomitant osteochondral fracture and those with significant medial soft tissue damage who may benefit more from surgical treatment. Smith et al21 reviewed 11 studies that included five randomised controlled trials. They found that surgical treatment of patellar dislocation was associated with a significantly higher risk of patellofemoral joint osteoarthritis but a significantly lower risk of subsequent patellar dislocation compared with conservative treatment.21 A recent Cochrane review of six studies with 344 participants found that participants managed surgically had a significantly lower risk of recurrent dislocation following first-time dislocation at 2 to 9 years of follow-up compared with those managed conservatively.22 There were no differences in physical function scores. The authors, however, pointed out that the quality of evidence was very low because of the high risk of bias and the imprecision of the effect estimates.22 They recommended that adequately powered, multicentre, randomised controlled trials are needed to substantiate this evidence.22 Erickson et al23 carried out a systematic review of four meta-analyses on surgical treatment of first-time patellar dislocations. Three meta-analyses showed a lower subsequent patellar dislocation rate in first-time dislocators managed surgically compared with those managed conservatively, whereas one meta-analysis did not show any difference in redislocation rates. Using the combined results of all studies, the overall recurrent dislocation rate was 24% in the surgery group and 34.6% in the conservative treatment group. One meta-analysis found a significantly higher rate of patellofemoral osteoarthritis in the surgery group. There were no differences in functional outcome scores between the conservative treatment group and surgery group.23 Our study showed that conservative treatment and surgical treatment were both effective in restoring knee function at 1-year follow-up. Nonetheless there was a trend towards a lower rate of redislocation in the MPFL repair surgery group, although it did not reach statistical significance. This suggests that operative treatment may be more beneficial for this group of patients.

In the current study, for first-time dislocators with delayed presentation of more than 3 weeks, conservative treatment was advised. This was because a certain degree of healing of the torn MPFL in the elongated position with a variable amount of scar tissue in the gap was anticipated if the patient presented subacutely. As the operative protocol of direct repair of MPFL was adopted in this study, the presence of partial healing in an elongated position affects the decision of correct tension in the MPFL during direct repair. As a result, a conservative approach was adopted to minimise the possibility of overtensioning (which might lead to medial patellofemoral joint pain) or undertensioning (which might lead to recurrent instability).

For recurrent patellar dislocators, studies have shown a redislocation rate of up to 50%.1 Therefore, it has been widely agreed that recurrent dislocation is a strong indication for surgical treatment.24 Reconstruction of MPFL, tibial tubercle osteotomy, and trochleoplasty have all been well-described surgical procedures for management of recurrent patellar dislocators. Reconstruction of MPFL alone is indicated in the presence of a physiological TT-TG distance (<20 mm) and no significant trochlear dysplasia.25 Patients with increased TT-TG distance of >15 to 20 mm have been shown to have patellar instability.26 Thus, tibial tubercle osteotomy procedures, aiming to shift the tibial tubercle medially to correct the TT-TG distance to within physiological limits of around 9 to 15 mm, with or without concomitant MPFL reconstruction have been advocated for these patients.25 The cut-off point of 20 mm above which tibial tubercle osteotomy is indicated has been well accepted by most orthopaedic surgeons.26 27 28 29 30 One study has shown that 18% of recurrent patellar dislocators had TT-TG distances of >20 mm.31 For patients with significant trochlear dysplasia, trochleoplasty procedures have been advocated.25 There have been no prospective randomised controlled trials to date comparing conservative treatment and the various surgical treatment modalities for recurrent patellar dislocators. Short-term results of these various surgical procedures have been satisfactory, however. Our study demonstrated similar results to the current literature, showing a clear advantage in terms of knee function, return to activity, and apprehension in the MPFL reconstruction surgery group compared with the conservative treatment group.

There are several limitations of this study. First, the sample size was small and a large number of patients were lost to follow-up, making the study underpowered. This was reflected by the non-significant finding in the positive apprehension sign before (88%) and 1 year (9%) after MPFL repair in first-time dislocators (P=0.07, McNemar test). Second, we did not adjust for confounding factors for patellar dislocation, for example, patella alta, increased Q-angle, and ligamentous laxity. Third, one of the outcomes compared (apprehension sign) was highly assessor-dependent. Although the method of detecting apprehension sign was standardised and the number of assessors was limited to two, potential bias could still be introduced. In addition, no inter-observer or intra-observer repeatability tests were carried out. Fourth, the final assessment in the current study was performed at 12-month follow-up. This short follow-up may not allow adequate evaluation of postoperative outcome. Readers of the journal need to be aware of this during extrapolation of the conclusion of the current study to their clinical practice. Lastly, since there was only one recurrent dislocator who underwent tibial tubercle osteotomy, we are unable to conclude the results of this form of treatment.

Conclusions

A management algorithm for patella dislocation is presented. Repair of MPFL reduced the risk of recurrent dislocation in first-time dislocators.

Declaration

All authors have disclosed no conflicts of interest.

References

1. Fithian DC, Paxton EW, Stone ML, et al. Epidemiology and natural history of acute patellar dislocation. Am J Sports Med 2004;32:1114-21. Crossref

2. Hsiao M, Owens BD, Burks R, Sturdivant RX, Cameron KL. Incidence of acute traumatic patellar dislocation among active-duty United States military service members. Am J Sports Med 2010;38:1997-2004. Crossref

3. Hawkins RJ, Bell RH, Anisette G. Acute patellar dislocations. The natural history. Am J Sports Med 1986;14:117-20. Crossref

4. Atkin DM, Fithian DC, Marangi KS, Stone ML, Dobson BE, Mendelsohn C. Characteristics of patients with primary acute lateral patellar dislocation and their recovery within the first 6 months of injury. Am J Sports Med 2000;28:472-9.

5. Cofield RH, Bryan RS. Acute dislocation of the patella: results of conservative treatment. J Trauma 1977;17:526-31. Crossref

6. Sallay PI, Poggi J, Speer KP, Garrett WE. Acute dislocation of the patella. A correlative pathoanatomic study. Am J Sports Med 1996;24:52-60. Crossref

7. Ahmad CS, Stein BE, Matuz D, Henry JH. Immediate surgical repair of the medial patellar stabilizers for acute patellar dislocation. A review of eight cases. Am J Sports Med 2000;28:804-10.

8. Colvin AC, West RV. Patellar instability. J Bone Joint Surg Am 2008;90:2751-62. Crossref

9. Irrgang JJ, Anderson AF, Boland AL, et al. Development and validation of the international knee documentation committee subjective knee form. Am J Sports Med 2001;29:600-13.

10. Tegner Y, Lysholm J. Rating systems in the evaluation of knee ligament injuries. Clin Orthop Relat Res 1985;(198):43-9. Crossref

11. Stefancin JJ, Parker RD. First-time traumatic patellar dislocation: a systematic review. Clin Orthop Relat Res 2007;455:93-101. Crossref

12. Christiansen SE, Jakobsen BW, Lund B, Lind M. Isolated repair of the medial patellofemoral ligament in primary dislocation of the patella: a prospective randomized study. Arthroscopy 2008;24:881-7. Crossref

13. Bitar AC, Demange MK, D’Elia CO, Camanho GL. Traumatic patellar dislocation: nonoperative treatment compared with MPFL reconstruction using patellar tendon. Am J Sports Med 2012;40:114-22. Crossref

14. Camanho GL, Viegas Ade C, Bitar AC, Demange MK, Hernandez AJ. Conservative versus surgical treatment for repair of the medial patellofemoral ligament in acute dislocations of the patella. Arthroscopy 2009;25:620-5. Crossref

15. Nikku R, Nietosvaara Y, Aalto K, Kallio PE. Operative treatment of primary patellar dislocation does not improve medium-term outcome: A 7-year follow-up report and risk analysis of 127 randomized patients. Acta Orthop 2005;76:699-704. Crossref

16. Nikku R, Nietosvaara Y, Kallio PE, Aalto K, Michelsson JE. Operative versus closed treatment of primary dislocation of the patella. Similar 2-year results in 125 randomized patients. Acta Orthop Scand 1997;68:419-23. Crossref

17. Palmu S, Kallio PE, Donell ST, Helenius I, Nietosvaara Y. Acute patellar dislocation in children and adolescents: a randomized clinical trial. J Bone Joint Surg Am 2008;90:463-70. Crossref

18. Sillanpää PJ, Mäenpää HM, Mattila VM, Visuri T, Pihlajamäki H. Arthroscopic surgery for primary traumatic patellar dislocation: a prospective, nonrandomized study comparing patients treated with and without acute arthroscopic stabilization with a median 7-year follow-up. Am J Sports Med 2008;36:2301-9. Crossref

19. Sillanpää PJ, Mattila VM, Mäenpää H, Kiuru M, Visuri T, Pihlajamäki H. Treatment with and without initial stabilizing surgery for primary traumatic patellar dislocation. A prospective randomized study. J Bone Joint Surg Am 2009;91:263-73. Crossref

20. Petri M, Liodakis E, Hofmeister M, et al. Operative vs conservative treatment of traumatic patellar dislocation: results of a prospective randomized controlled clinical trial. Arch Orthop Trauma Surg 2013;133:209-13. Crossref

21. Smith TO, Song F, Donell ST, Hing CB. Operative versus non-operative management of patellar dislocation. A meta-analysis. Knee Surg Sports Traumatol Arthrosc 2011;19:988-98. Crossref

22. Smith TO, Donell S, Song F, Hing CB. Surgical versus non-surgical interventions for treating patellar dislocation. Cochrane Database Syst Rev 2015;(2):CD008106. Crossref

23. Erickson BJ, Mascarenhas R, Sayegh ET, et al. Does operative treatment of first-time patellar dislocations lead to increased patellofemoral stability? A systematic review of overlapping meta-analyses. Arthroscopy 2015;31:1207-15. Crossref

24. Koh JL, Stewart C. Patellar instability. Orthop Clin North Am 2015;46:147-57. CrossRef

25. Petri M, Ettinger M, Stuebig T, et al. Current concepts for patellar dislocation. Arch Trauma Res 2015;4:e29301. Crossref

26. Dejour H, Walch G, Nove-Josserand L, Guier C. Factors of patellar instability: an anatomic radiographic study. Knee Surg Sports Traumatol Arthrosc 1994;2:19-26. Crossref

27. Drexler M, Dwyer T, Dolkart O, et al. Tibial rotational osteotomy and distal tuberosity transfer for patella subluxation secondary to excessive external tibial torsion: surgical technique and clinical outcome. Knee Surg Sports Traumatol Arthrosc 2014;22:2682-9. Crossref

28. Paulos L, Swanson SC, Stoddard GJ, Barber-Westin S. Surgical correction of limb malalignment for instability of the patella: a comparison of 2 techniques. Am J Sports Med 2009;37:1288-300. Crossref

29. Pandit S, Frampton C, Stoddart J, Lynskey T. Magnetic resonance imaging assessment of tibial tuberosity–trochlear groove distance: normal values for males and females. Int Orthop 2011;35:1799-803. Crossref

30. Alemparte J, Ekdahl M, Burnier L, et al. Patellofemoral evaluation with radiographs and computed tomography scans in 60 knees of asymptomatic subjects. Arthroscopy 2007;23:170-7. Crossref

31. Köhlitz T, Scheffler S, Jung T, et al. Prevalence and patterns of anatomical risk factors in patients after patellar dislocation: a case control study using MRI. Eur Radiol 2013;23:1067-74. Crossref

Atrial fibrillation patients who sustained warfarin-associated intracerebral haemorrhage have poor neurological outcomes: results from a matched case series

Hong Kong Med J 2017 Apr;23(2):117–21 | Epub 24 Feb 2017

DOI: 10.12809/hkmj164953

ORIGINAL ARTICLE

Atrial fibrillation patients who sustained warfarin-associated intracerebral haemorrhage have poor neurological outcomes: results from a matched case series

MK Fong, MB, BS, FHKAM (Medicine)¹; B Sheng, MB, ChB, FHKAM (Medicine)¹; YP Chu, MB, BS, FHKAM (Medicine)¹; WT Wong, MB, ChB, MRCP¹; Patrick PK Lau, MB, ChB, FHKAM (Medicine)²; HY Wong, MB, BS, FHKAM (Medicine)³; KK Lau, MB, BS, FHKAM (Medicine)¹

¹ Department of Medicine and Geriatrics, Princess Margaret Hospital, Laichikok, Hong Kong

² Department of Rehabilitation, Kowloon Hospital, Argyle Street, Hong Kong

³ Department of Medicine, Queen Elizabeth Hospital, Jordan, Hong Kong

Corresponding authors: Dr MK Fong (keison722@hotmail.com)

Full paper in PDF

Abstract

Introduction: Coagulopathy-associated intracerebral haemorrhage has become increasingly common because of the rising demand in the ageing population for anticoagulation for atrial fibrillation. This study compared the clinical features and neurological outcomes of intracerebral haemorrhage in patients with atrial fibrillation who were prescribed warfarin with those who were not.

Methods: This was a retrospective matched case series of patients with intracerebral haemorrhage from three tertiary hospitals in Hong Kong from 1 January 2006 to 31 December 2011. Patients who developed intracerebral haemorrhage and who were prescribed warfarin for atrial fibrillation (ICH-W group) were compared with those with intracerebral haemorrhage and not prescribed warfarin (ICH-C group); they were matched for age and gender in 1:1 ratio. Clinical features and neurological outcomes were compared, and the impact of coagulopathy on haematoma size was also studied.

Results: We identified 114 patients in the ICH-W group with a mean age of 75 years. Both ICH-W and ICH-C groups had a median intracerebral haemorrhage score of 2. There was a non–statistically significant trend of higher intracerebral haemorrhage volume in the ICH-W group (12.9 mL vs 10.5 mL). The median modified Rankin Scale and the proportion with good recovery (modified Rankin Scale score ≤3) at 6 months were comparable. Nonetheless, ICH-W patients had higher hospital mortality (51.8% vs 36.0%; P=0.02) and 6-month mortality (60.5% vs 43.0%; P=0.01) than ICH-C patients. Overall, 60% of ICH-W patients had their admission international normalised ratio within the therapeutic range during intracerebral haemorrhage, and 14% had a subtherapeutic admission international normalised ratio. International normalised ratio at admission was not associated with intracerebral haemorrhage volume or neurological outcome.

Conclusion: Warfarin-associated intracerebral haemorrhage in patients with atrial fibrillation carried a higher stroke mortality than the non-warfarinised patients.

New knowledge added by this study

Warfarin-associated intracerebral haemorrhage (ICH) carries a high mortality.

Implications for clinical practice or policy

The reversal of coagulopathy after warfarin-associated ICH was often incomplete.
Given the high mortality after warfarin-associated ICH, newer oral anticoagulants may be a safer alternative in patients with a high risk of cerebral bleeding. As a class of drugs, they are associated with fewer ICHs.

[Abstract in Chinese]

Introduction

Atrial fibrillation (AF) is associated with an increased risk of stroke or systemic thromboembolism. Approximately 5% of AF patients develop stroke or other embolic events each year.1 Anticoagulation with warfarin, a vitamin K antagonist, reduces stroke risk in AF patients by 64%.2 It has been the drug of choice for many years in both primary and secondary stroke prevention in AF. Unfortunately, anticoagulation increases the risk of bleeding, and intracerebral haemorrhage (ICH) has been the most life-threatening bleeding complication of concern. This study aimed to compare the clinical features and neurological outcomes of ICH in warfarinised AF patients with those in non-warfarinised patients.

Methods

This was a retrospective matched case series of consecutive patients with first acute ICH admitted to the medical unit of three tertiary hospitals in Hong Kong—Princess Margaret Hospital (PMH) and Caritas Medical Centre (CMC) in Kowloon West, and Queen Elizabeth Hospital (QEH) in Kowloon Central—from 1 January 2006 to 31 December 2011. The three hospitals cover about one quarter of the 7 million population in Hong Kong. It is a general practice in Hong Kong that patients with acute stroke symptoms are admitted to the medical unit (to acute stroke unit first, and to general medical ward if acute stroke unit is full) for further management, with computed tomography (CT) brain scans done within 24 hours of admission. If ICH is identified, a neurosurgeon will be consulted for assessment. Therefore ICH patients in the medical unit are a good indication of the general ICH population.

We searched our electronic database for all patients aged 18 years or above who developed first ICH in the presence of anticoagulation with warfarin for non-valvular AF (ICH-W group) from the three hospitals, and matched them with a comparison group (ICH-C group) without taking warfarin at a 1:1 ratio for age (±1 year), gender, and admission year. The comparison group comprised patients from the medical unit of PMH (principal study centre) who had a first episode of ICH without anticoagulation, regardless of any AF. Patients with isolated subdural, subarachnoid, or intraventricular haemorrhage were excluded. We retrieved and compared the data regarding neurological impairment and investigation findings, estimated the ICH volume on CT through the ABC/2 method, and calculated the ICH score.3 4 Hospital mortality and 6-month modified Rankin Scale score (mRS, 0-6) were selected as primary and secondary outcomes, respectively. We used independent sample t test and Mann-Whitney U test for univariate comparisons of continuous variables (Glasgow Coma Scale score, ICH score, ICH volume, mRS), and Chi squared test for categorical variables. Descriptive summary statistics, where appropriate, are presented as mean (range) or median (interquartile range [IQR]). All calculations were two-end conducted at a 0.05 level of significance. The study was approved by the local ethics committee (KW/EX-12-057[52-06]), with the requirement of patient informed consent waived because of its retrospective nature.

Results

Overall, 114 patients were identified and recruited in the ICH-W group (37 from PMH, 8 from CMC, and 69 from QEH; Table 1) with a mean age of 75 years (range, 47-92 years) and a slight male predominance (56.1%). The same number of patients matched for age (±1 year) and gender were grouped for comparison (ICH-C). Both ICH-W and ICH-C groups had a median ICH score of 2, but there was a trend for higher ICH volume in ICH-W patients than in ICH-C patients (12.9 mL vs 10.5 mL) although it did not reach statistical significance. A total of 59 patients in ICH-W died during the same admission, and a further 10 patients had died by 6 months. The ICH-W patients had significantly higher hospital mortality (51.8% vs 36.0%; Chi squared test, P=0.02) and 6-month mortality (60.5% vs 43.0%; Chi squared test, P=0.01) than the ICH-C patients. The median mRS and the proportion with good recovery (mRS ≤3) at 6 months were comparable for the two groups (Table 1).

Table 1. Clinical characteristics and neurological outcomes

Two patients in the ICH-W group died before determination of international normalised ratio (INR). For the remaining 112, the admission INR was <2.0 in 16 (14.3%) patients, 2.0-3.0 in 66 (58.9%) patients, and >3.0 in 30 (26.8%) patients. The INR was re-checked in 85 patients after 12 hours and in 72 patients after 24 hours. The median INR was corrected from 2.6 (IQR, 2.1-3.1) to 1.4 (IQR, 1.2-1.7) at 12 hours post-event, and 1.3 (IQR, 1.1-1.5) at 24 hours post-event. The corresponding percentage of INR >1.5 was 96.4% (108/112) on admission, 35.3% (30/85) at 12 hours, and 22.2% (16/72) at 24 hours. No association was found between admission INR and ICH volume, hospital mortality, or 6-month mRS (Spearman’s rank correlation coefficient).

Regarding the warfarin reversal strategies, QEH had an in-patient protocol whereas PMH and CMC did not. Nevertheless, there was no significant difference in mortality rate among the three hospitals—hospital mortality/6-month mortality in PMH 18 (48.6%)/20 (54.1%), in CMC five (62.5%)/six (75.0%), and in QEH 36 (52.2%)/43 (62.3%). Prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), vitamin K1 (VitK1), factor VII, and transamin were used alone or in combination in our ICH-W patients. Their frequency was as follows: FFP alone (69, 60.5%), FFP + VitK1 (17, 14.9%), FFP + PCC (9, 7.9%), PCC alone (3, 2.6%), transamin alone (3, 2.6%), VitK1 alone (2, 1.8%), FFP + transamin (1, 0.9%), and FFP + factor VII (1, 0.9%). Nine (7.9%) patients received no treatment—two patients died before admission INR was available, three patients died soon after admission INR was available, three patients had admission INR of <1.5, and one patient was on warfarin and aspirin for ischaemic heart disease. The high variation in anticoagulation reversal strategy made it impossible for any valid comparison.

Discussion

Cardioembolic stroke related to AF carries significant morbidity, yet anticoagulation is not without risk. How to prevent stroke and at the same time minimise bleeding complications has always been a dilemma for physicians and patients. Risk assessment tools (eg CHA₂DS₂-VASc and HAS-BLED score, for assessment of thromboembolic and bleeding risk, respectively) have been developed to assist the decision making.5 6 It is important for clinicians to exercise individualised medical practice, however. In a recently published observation study on a large hospital cohort of Chinese AF patients from Hong Kong, the investigators found that the stroke risk in Chinese AF patients was higher than that in Caucasians at a given CHA₂DS₂-VASc score, and that excessive risk was more prominent in the low-risk group from CHA₂DS₂-VASc.7 At the same time, the ICH incidence in Chinese AF patients taking warfarin was also higher than that in Caucasians.8 These observations really drive clinicians towards a better anticoagulation strategy for Chinese AF patients.

Unfortunately ICH remains a significant threat even with very careful patient selection and treatment monitoring. Up to 25% of ICH can be associated with anticoagulant usage, and the rate is still increasing given the higher utilisation of anticoagulation in ageing populations with rising AF prevalence.9 10 Several features of warfarin-associated ICH in our patients deserve further elaboration, as listed below.

First, we found a large proportion (73.2%) of warfarin-associated ICH occurred when the INR was within or even below the therapeutic range (INR ≤3.0). Our findings were supported by a similar observation from another prospective study in which 68% of warfarin-associated ICH occurred at INR of ≤3.0.11 This shows that bleeding is increased even with an INR within the therapeutic range. Moreover, those ICH-W patients with a subtherapeutic INR reaffirm the high intrinsic ICH risk in AF patients who are old with multiple co-morbidities.

Second, we did not find any correlation between initial ICH volume and admission INR. The initial ICH volume in warfarinised and non-warfarinised patients was not significantly different. This is consistent with the results from some other studies.9 12 13 In contrast, Cucchiara et al14 reported larger haematoma volume in anticoagulant-associated ICH than spontaneous ICH, whereas Flaherty et al15 reported larger initial haematoma volume if admission INR was >3.0. It is reasonable to suppose that coagulopathy would have an impact on haematoma volume, but is difficult to confirm in clinical studies because it is hard to control other covariates that affect haematoma size. The relatively small number of subjects in the warfarin-associated ICH group is often underpowered to reach any solid conclusion. Nonetheless, other studies did show that warfarin use was a known predictor of haematoma expansion, and haematoma expansion an independent determinant of neurological outcomes in spontaneous ICH.12 14 16 All the consensus guidelines agree that coagulopathy should be reversed as soon as possible in warfarin-associated ICH.

Third, both the hospital and 6-month mortalities in our ICH-W patients were significantly higher than those in ICH-C patients (Table 1). This observation is highly consistent with other reports in which warfarin-associated ICH had higher mortality than patients without taking warfarin (Table 2).9 11 12 13 14 15 17 18 19 20 Our study adopted a matched case series design in order to eliminate the effect of age, and to minimise the age-related co-morbidities that are known predictors of poor neurological outcome from ICH. As a result, our selected ICH-C patients were older and probably had more co-morbidities than the general ICH patients. This explained the higher-than-usual mortality and poor neurological outcomes in our ICH-C group compared with other studies. Nonetheless, AF-related co-morbidity could not be controlled in this design, and we believe our observed difference in mortality and neurological outcomes is a compound effect from AF and warfarin use in the ICH-W patients.

Table 2. Effect of warfarin on mortality and initial ICH volume in different studies

Currently, the optimal therapy for coagulopathy reversal in warfarin-associated major bleeding is unclear and recommendations of international guidelines are mainly derived from consensus opinions. Treatment options include FFP, VitK1, PCC, and recombinant factor VIIa, in different combinations.21 One of the three study hospitals (QEH) had an in-house protocol for warfarin reversal. The other two hospitals provide guidelines only. Because of the incomplete data collection from this retrospective study design, we were unable to analyse the haematoma growth and warfarin reversals. The mortality, however, did not differ among the three hospitals.

Since 2010, newer oral anticoagulants have become available and provide an alternative to warfarin in AF stroke prevention. The three new oral anticoagulants—dabigatran, rivaroxaban, and apixaban22 23 24—might differ in efficacy, but the lower ICH rate compared with warfarin was a universal finding from their clinical trials, and is a class effect of these new agents. They should be considered in Chinese AF patients at a high risk of warfarin-associated ICH.

Limitations of study

As a retrospective study, this study has several limitations. First, the methods and timing of warfarin reversal were not standardised and could have affected the neurological outcome. Second, there was no protocol for serial CT brain and serial INR monitoring to investigate the effect of coagulopathy reversal on haematoma expansion, and the effect of haematoma expansion on neurological outcome. Third, we were uncertain about compliance with the coagulopathy reversal protocol in QEH, and were unable to comment on whether the standardised protocol could improve ICH outcome. Moreover, ICH-W patients were AF patients who had additional vascular risk factors (to justify the use of warfarin) that may not have been present in ICH-C patients. This difference could potentially affect the ICH outcome. Finally, other possible confounders such as smoking or alcohol use were not adjusted for in this retrospective study.

Conclusion

Warfarin-associated ICH in AF patients may be associated with higher stroke mortality. It could be a serious problem in Chinese AF patients who are known to have more warfarin-associated ICH.

Declaration

The authors declared no conflicts of interest in this study.

References

1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-8. Crossref

2. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67. Crossref

3. Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304-5. Crossref

4. Hemphill JC 3rd, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891-7. Crossref

5. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro heart survey on atrial fibrillation. Chest 2010;137:263-72. Crossref

6. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro heart survey. Chest 2010;138:1093-100. Crossref

7. Siu CW. One more “C” for CHA2DS2-VASc score? J Am Coll Cardiol 2015;65:1602-3. Crossref

8. Siu CW, Lip GY, Lam KF, Tse HF. Risk of stroke and intracranial hemorrhage in 9727 Chinese with atrial fibrillation in Hong Kong. Heart Rhythm 2014;11:1401-8. Crossref

9. Horstmann S, Rizos T, Lauseker M, et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol 2013;260:2046-51. Crossref

10. Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology 2007;68:116-21. Crossref

11. Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004;164:880-4. Crossref

12. Flibotte JJ, Hagan N, O’Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004;63:1059-64. Crossref

13. Sheth KN, Cushing TA, Wendell L, et al. Comparison of hematoma shape and volume estimates in warfarin versus non-warfarin-related intracerebral hemorrhage. Neurocrit Care 2010;12:30-4. CrossRef

14. Cucchiara B, Messe S, Sansing L, Kasner S, Lyden P, CHANT Investigators. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008;39:2993-6. Crossref

15. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008;71:1084-9. Crossref

16. Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:1175-81. Crossref

17. Flaherty ML, Haverbusch M, Sekar P, et al. Location and outcome of anticoagulant-associated intracerebral hemorrhage. Neurocrit Care 2006;5:197-201. Crossref

18. Zubkov AY, Mandrekar JN, Claassen DO, Manno EM, Wijdicks EF, Rabinstein AA. Predictors of outcome in warfarin-related intracerebral hemorrhage. Arch Neurol 2008;65:1320-5. Crossref

19. Huhtakangas J, Tetri S, Juvela S, Saloheimo P, Bode MK, Hillbom M. Effect of increased warfarin use on warfarin-related cerebral hemorrhage: a longitudinal population-based study. Stroke 2011;42:2431-5. Crossref

20. Seçil Y, Ciftçi Y, Tokuçoğlu F, Beckmann Y. Intracranial hemorrhages related with warfarin use and comparison of warfarin and acetylsalicylic acid. J Stroke Cerebrovasc Dis 2014;23:321-6. Crossref

21. Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion. Mayo Clin Proc 2007;82:82-92. Crossref

22. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51. Crossref

23. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. Crossref

24. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92. Crossref

Identification of fragile X pre-mutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay: implications for screening and prenatal diagnosis

Hong Kong Med J 2017 Apr;23(2):110–6 | Epub 3 Mar 2017

DOI: 10.12809/hkmj164936

ORIGINAL ARTICLE

Identification of fragile X pre-mutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay: implications for screening and prenatal diagnosis

Yvonne KY Cheng, MRCOG, FHKAM (Obstetrics and Gynaecology)¹; Christina SW Lin, MSc¹; Yvonne KY Kwok, PhD¹; YM Chan, MRCOG, FHKAM (Obstetrics and Gynaecology)¹; TK Lau, FRCOG, FHKAM (Obstetrics and Gynaecology)²; TY Leung, FRCOG, FHKAM (Obstetrics and Gynaecology)¹; KW Choy, PhD¹

¹ Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, Hong Kong

² Fetal Medicine Centre, Paramount Medical Centre, Hong Kong

Corresponding author: Dr KW Choy (richardchoy@cuhk.edu.hk)

Full paper in PDF

Abstract

Introduction: There is significant morbidity associated with fragile X syndrome. Unfortunately, most maternal carriers are clinically silent during their reproductive years. Because of this, many experts have put forward the notion of preconception or prenatal fragile X carrier screening for females. This study aimed to determine the prevalence of fragile X syndrome pre-mutation and asymptomatic full-mutation carriers in a Chinese pregnant population, and the distribution of cytosine-guanine-guanine (CGG) repeat numbers using a robust fragile X mental retardation 1 (FMR1) polymerase chain reaction assay.

Methods: This was a cross-sectional survey in prospectively recruited pregnant women from a university hospital in Hong Kong. Chinese pregnant women without a family history of fragile X syndrome were recruited between April 2013 and May 2015. A specific FMR1 polymerase chain reaction assay was performed on peripheral blood to determine the CGG repeat number of the FMR1 gene. Prenatal counselling was offered to full-mutation and pre-mutation carriers.

Results: In 2650 Chinese pregnant women, two individuals with pre-mutation alleles (0.08%, one in 1325) and one asymptomatic woman with full-mutation (0.04%, one in 2650) alleles were identified. The overall prevalence of pre-mutation and full-mutation alleles was 0.11% (1 in 883). Furthermore, 30 (1.1%) individuals with intermediate alleles were detected. In the 2617 women with normal CGG repeats, the most common CGG repeat allele was 30.

Conclusions: The overall prevalence of pre-mutation and asymptomatic full-mutation carriers in the Chinese pregnant population was one in 883, detected by a new FMR1 polymerase chain reaction assay.

New knowledge added by this study

This study reports the prevalence of fragile X pre-mutation carriers in Chinese pregnant women.
The prevalence of pre-mutation and asymptomatic full-mutation carriers was one in 883 and disproves the belief that carrier rates in Chinese are extremely low.

Implications for clinical practice or policy

Maternal fragile X carriers are not rare in a Chinese population. Women should be offered the option of carrier screening during the preconception period or prenatally.

[Abstract in Chinese]

Introduction

Fragile X syndrome (FXS) is the second leading genetic cause of intellectual disability after Down syndrome,1 affecting one in 4000 males and one in 8000 females.2 The typical phenotypes include behavioural abnormalities, autism, cognitive impairment, and dysmorphism such as large protruding ears, elongated face, and macroorchidism in male patients. This syndrome is caused by a defective fragile X mental retardation 1 (FMR1) gene located on the X chromosome, where there is an unstable cytosine-guanine-guanine (CGG) trinucleotide repeat in the 5’ untranslated region.3 Normally the number of CGG repeats is less than 44, but if it is more than 200 (full mutation), the FMR1 gene expression will be ‘shut down’ due to methylation of its promoter. The protein product, which is essential for normal neurodevelopment, is thus not produced. When the repeat number is between 55 and 200 (pre-mutation),4 the FMR1 gene can be expressed but the repeat number is potentially expandable to full mutation during its transmission to the next generation. Such risk of expansion is increased with the size of the repeat number, and is close to 100% when the size of CGG repeats is 100 or more. In addition, pre-mutation carriers are at risk of developing fragile X–associated primary ovarian insufficiency (FXPOI) and fragile X–associated tremor/ataxia syndrome (FXTAS) in late adult life, although they are mentally normal.5 6 Intermediate alleles are repeat numbers between 45 and 54, and individuals carrying theses alleles are at risk of expanding into pre-mutation but not into full mutation.7 8 9

Because of the significant morbidity associated with FXS, and since most maternal carriers are clinically silent during their reproductive years, many experts have put forward the notion of preconception or prenatal fragile X carrier screening for females.10 The prevalence of pre-mutation carriers will directly affect the efficacy and cost-effectiveness of screening, but this varies widely between different ethnic groups and countries. While it is well known that Caucasians and Jews have high carrier rates of 1 in 100-250,10 many studies in Chinese populations report an extremely low carrier rate.11 12 13 Among these studies, the largest included 10 046 newborn boys, but identified only six pre-mutation carriers (1 in 1674).13 These studies, however, were limited by the fact that the screening methods used were polymerase chain reaction (PCR) assays that were not accurate or were unable to amplify long CGG repeats.14 In addition, the screening of a low-risk Chinese pregnant population has not been studied.

Recently, we have validated a new fragile-X-related–specific PCR assay that utilises a low-cost capillary electrophoresis instrument and the FragilEase reagent kit (PerkinElmer Inc, Waltham [MA], US), and is able to detect CGG repeat numbers at a level as high as 1000.14 The repeat numbers analysed by this new assay were highly concordant with those obtained from the conventional reference method (PCR + Southern blot) in 112 archived samples, including 25 samples of full mutation (the largest allele size measured at 1380 repeats). The intra-assay (coefficient of variation <2.5%) and inter-assay imprecision was within 1 CGG repeat.14 The objectives of this study were to determine the prevalence of FXS pre-mutation carriers and the distribution of repeat numbers in the Chinese pregnant population in Hong Kong, using this FXS-specific PCR assay.

Methods

This was a prospective observational study conducted at a university hospital in Hong Kong between April 2013 and May 2015. Chinese pregnant women between 4 and 41 weeks of gestation, at or above the age of 18 years who could understand English or Chinese and give informed consent were eligible for the study. Eligible women were approached in the antenatal clinic or the antenatal ward by the research assistant at one convenient time-point once per day and invited to participate in the study. Women with a known family history of FXS were excluded to avoid an over-representation of the pre-mutation carrier rate in the general population, so that data obtained would be more useful in determining whether population-based screening is beneficial. Pre-test counselling was given by a research assistant with a bachelor’s and master’s degree in human genetics. Printed information about fragile X carrier testing was provided and included information about the clinical features and maternal inheritance of the disease. It was also explained to participants that genetic counselling would be offered if they were found to have an increased CGG repeat number of ≥45. Testing was entirely voluntary, and no payment was received by the participants. Written informed consent was obtained. Two millilitres of maternal blood was collected in an EDTA tube from each participant. The FMR1 CGG repeat result could be obtained within 1 day but study samples were processed in batches so results were available between 1 day and 7 months later. Women were informed prior to consenting that the result might not be available before delivery.

The FMR1 CGG repeat status of each sample was tested at a screen cut-off value of ≥45.14 The details of the PCR method are described below. All participants had the right to access personal data and study results. Positive test results (≥45 CGG repeats) would be made known to the participants, and genetic counselling would be provided. Where indicated, prenatal and postnatal diagnoses were offered by means of chorionic villus sampling or amniocentesis and cord blood or neonatal blood respectively, with analysis of CGG repeats in the extracted DNA from the sample using the same PCR method.

Approval for the study was obtained from the institutional review board of the Joint-Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (CRE-2013.055).

Polymerase chain reaction–only assay for detection of CGG repeats in FMR1 gene

DNA preparation

Genomic DNA was extracted from peripheral blood samples using DNeasy Blood & Tissue Kit according to the manufacturer’s protocol (Qiagen, Hilden, Germany) or using the automatic system, chemagic Prepito-D, following the manufacturer’s protocol (PerkinElmer, Turku, Finland).

Polymerase chain reaction analysis of fragile X mutations

The FMR1 repeat region of each DNA sample was amplified using the FragilEase PCR reagent kit following the manufacturer’s protocol (PerkinElmer). It involved a forward (TCA GGC GCT CAG CTC CGT TTC GGT TTC A) and a reverse primer (FAM-AAG CGC CAT TGG AGC CCC GCA CTT CC) anneal to FMR1-specific sequence upstream and downstream of the trinucleotide repeat region, respectively. Thermal cycle amplification of the highly GC-rich trinucleotide repeat region produced fragments whose size was directly related to the number of trinucleotide repeats present in the DNA sample. Two female reference DNA samples (one pre-mutation carrier [30/80 repeats] and one individual with full mutation [20/200 repeats]) for evaluating the analytical performance of the assay were obtained from the Coriell Institute for Medical Research (Camden, US). The known repeat sizes of the reference samples were concurrently amplified and used to calculate the CGG repeat numbers of the unknown samples.

Purification of the polymerase chain reaction product

Polymerase chain reaction products were purified using NucleoFast 96 PCR plate (MACHEREY-NAGEL GmbH &amp Co KG, Germany) or the PureLink PCR Micro Kit (Invitrogen, Carlsbad [CA], US). Purification procedures were performed according to the manufacturer’s instructions with a final elution volume of 20 µL.

Fragment sizing with microfluidic capillary electrophoresis

The fragment size for the sample was analysed using 2100 Bioanalyzer (Agilent Technologies, Santa Clara [CA], US). In this study, 3 µL of the purified PCR product and 3 µL of the 7500-size marker reagent (from an Agilent DNA 7500 kit) were loaded into each of the 12 wells of the Bioanalyzer chip. A standard curve was constructed from the two female reference samples (Coriell NA20240 [30/80 CGG repeats] and NA20239 [20/200 CGG repeats]) with known repeat size. This allowed the determination of CGG repeat size with higher accuracy.

Report of FMR1 fragment size

FraXsoft analysis software (PerkinElmer) was used to calculate the CGG repeat lengths by utilising the base pair size data exported from the bioanalyser. Fragment sizes that were below 200 CGG repeats were interpolated from their base-pair electrophoresis result using a linear regression constructed between the four allele values of the two Coriell female reference samples. Larger repeat sizes (>200 repeats) were calculated by extrapolation along the same regression line.14

Results

A convenient sample of 2650 Chinese pregnant women was recruited between 4 and 41 weeks of gestation. FMR1 allelic expansion was screened in each subject, and two pre-mutation carriers (0.08%, one in 1325) and one asymptomatic individual with full mutation (0.04%, one in 2650) who were unrelated were identified. The overall prevalence was therefore one in 883 (0.11%) or 11 per 10 000 (95% confidence interval, 3-36 per 10 000 using the Wilson method with continuity correction). These three women are described in detail below. There were also 30 (1.1%) women with CGG repeats who fell into the intermediate category. The remaining 2617 women screened were found to have normal CGG repeats, and the most common CGG repeat allele was 30. This distribution of allele frequencies for CGG repeats in the FMR1 gene in the population with normal CGG repeat numbers is shown in the Figure.

Figure. Distribution of allele frequencies for the number of CGG repeats in FMR1 gene in the 2617 normal pregnant women

One asymptomatic subject with full-mutation allele

The woman had FMR1 gene testing carried out during the third trimester and was found to have a full mutation with CGG repeat number of 35/401. She was phenotypically normal. She had completed junior high school education and was working in a fast food restaurant. Upon detailed questioning, she suspected that her brother and one of her maternal male cousins might have some autistic features, but she was not aware of any mental retardation, or any formal genetic diagnosis in either of these two relatives. Genetic counselling was given. Prenatal diagnosis was not performed since the woman had been tested during the third trimester and termination of pregnancy was not an option. She subsequently delivered a healthy baby girl. The parents were counselled about testing the baby for FXS but they declined and preferred to observe the development of their child first. The child was referred for follow-up of her development. The woman’s other family members also declined fragile X screening because they were phenotypically normal with no current reproductive plans.

Two subjects with pre-mutation allele

The first pre-mutation carrier was a 31-year-old nulliparous female with no features associated with FXS or family history of intellectual disability or autism. Testing of the FMR1 gene was done at 13 weeks and 4 days, and the result was available at 14 weeks and 4 days indicating a CGG repeat number of 30/70. The woman requested prenatal diagnosis for her female fetus following genetic counselling. Amniocentesis was performed at gestation 16 weeks and 4 days. The PCR analysis result was available at 17 weeks and 2 days, and revealed that the maternal pre-mutation allele had been transmitted to the fetus and expanded to CGG repeat number of 30/579, indicating the female fetus carried a full-mutation allele. Genetic counselling was provided and the couple opted for termination of pregnancy and planned for pre-implantation genetic diagnosis in future.

The second carrier was a 39-year-old female with normal phenotype and no family history of intellectual disability or autism. She had testing of the FMR1 gene at 20 weeks and 6 days of gestation. The result was available at 21 weeks and 2 days of gestation showing a CGG repeat number of 31/64, and her fetus was female. Following genetic counselling, the parents decided not to have any prenatal or postnatal diagnosis owing to the variable and unpredictable phenotype in full-mutation females.

Discussion

This is the largest study of the prevalence of fragile X pre-mutation carriers in Chinese pregnant women, as well as the largest one using this new FXS-specific PCR assay (FragilEase) in the Chinese population. The combined prevalence of pre-mutations and full mutations of FXS in normal asymptomatic pregnant Hong Kong Chinese women was as high as 0.11% (1 in 883). We included also one case of full mutation in our estimation of prevalence because some women with full mutations are apparently asymptomatic but are at risk of transmitting FXS to their offspring. Therefore, the combined prevalence would reflect more precisely the overall risk of transmitting FXS in the general population. Our finding is consistent with the recent publication by Huang et al,15 who identified one pre-mutation carrier in their population of 1113 Han Chinese (534 males and 579 non-pregnant females). Our finding also refutes the belief that FXS pre-mutations are extremely rare in Chinese.11 12 13 In fact, the incidence in Chinese is comparable with some of the incidences reported from Korea (1 in 1090).16

A standard capillary analyser is only capable of detecting and sizing FMR1 PCR products with less than 200 CGG repeats. Thus differentiating full mutations with greater than 200 CGG repeats from apparently homozygous normal female samples, and confirming full mutations, has historically required the Southern blot reflex test. The Southern blotting assay, however, is expensive, labour intensive, and requires a large amount of DNA making its use in screening impractical.13 The advantage of this FragilEase PCR assay is the ability to detect up to 1000 CGG repeats, so that even asymptomatic full-mutation individuals can be identified during routine screening, as shown in one of our cases. It has high throughput and high sensitivity of 99%.14 The cost for each fragile X assay is estimated to be only US$44, deduced from a parallel run of a minimum of four samples plus two reference standards on each Bioanalyzer chip, and this cost includes that of FragilEase reagent kit, DNA extraction kit, PCR-related consumables, Bioanalyzer kit, equipment maintenance, and staff costs. Processing of each chip takes 1 hour and a maximum of nine samples per chip can run. The low cost of this test is beneficial as a screening test.

Our study showing an incidence of one pre-mutation or full mutation of FXS in 883 pregnant Chinese women has important implications for counselling and implementation of a FXS carrier screening programme in Hong Kong and in China, as well as in countries where Chinese immigrants are numerous. It remains controversial whether FXS should be screened for, and which model should be adopted. Some experts advocate universal prenatal screening17 as it is much more effective in identification of pre-mutation carriers compared with case finding followed by cascade screening. The latest UK Health Technology Assessment (HTA) review18 indicated that the maximal rate of detection of female pre-mutation carriers by population screening is 60% whereas only 6% of carriers will be identified by active cascade screening. In their simulation model, the additional number of births of FXS children that could be avoided each year was estimated to be 15 with cascade screening compared with 39 with prenatal screening. Since family size tends to be small in many developed countries now, the effectiveness of cascade screening has become very limited. In Hong Kong, the average number of children per household is only 1.24.19 In mainland China, until 2015, families were allowed to have only one child. The chance of revealing a positive family history with affected siblings or close relatives is thus low. Furthermore, even though parents might be planning their second child, the first affected child would not have been diagnosed with FXS if very young. Such diagnosis is particularly difficult and is delayed in Hong Kong, China, or other Asia-Pacific regions where clinical genetic services are inadequate.20 The variable phenotypes of FXS may also be masked by the mixed education levels of the population in different geographical regions. Indeed, the patient in our study who carried a full mutation is a very good example of the limitation of cascade screening with an uncertain family history or without a formal genetic assessment.

Unlike first-trimester combined Down syndrome screening that requires intensive training and effort in ultrasound measurement and a stringent algorithm in risk calculation to achieve a 90% detection rate with a 5% false-positive rate,21 22 23 24 screening for fragile X carriers is relatively simple by a maternal blood test and is thus acceptable to most women. It can also be done before conception. Furthermore, once a carrier is identified, other carriers may be found through family screening. Hence the potential utility of this screening can be profound. In the validation study of FragilEase by Kwok et al,14 78 samples tested positive, of which one was classified as false positive. This sample was tested to have a CGG repeat number of 55 (pre-mutation) by FragilEase whereas Southern blot analysis determined the repeat number to be 53 (intermediate). This gives a false-positive rate of 1.3%. The false-positive result occurred because the CGG repeat number was at the lower limit of the pre-mutation range, such that a difference of 2 repeats led to an intermediate allele being classified in the pre-mutation range. We believe that this false-positive rate is overestimated, as the majority of the pre-mutation carriers do not have a repeat number at this lower limit that could lead to such a false-positive result. Although the positive predictive value calculated was 8.0%, assuming a fragile X pre-mutation carrier prevalence of one in 883, the performance of the test should be better because the positive predictive value was underestimated due to the overestimated false-positive rate.

There are no current data on the health care costs of caring for a FXS patient in Hong Kong or Asia. In the UK, the lifetime cost for each FXS patient is estimated to be UK$380 000 and the HTA model expects population screening to be a cost-effective strategy.18 In fact, it has been shown that health care professionals and families of patients with FXS are in favour of preconception or prenatal screening.25 26 Detection of pre-mutation alleles also offers information about the women’s own health, as they are at increased risk of FXPOI and FXTAS.27 The above factors may affect a woman’s fertility planning and allow informed choices not only in this pregnancy but also subsequent pregnancies.

Despite this, the UK National Screening Committee and the American College of Obstetricians and Gynecologists do not advocate universal screening,28 29 but rather screening in those with a family history of congenital intellectual disability, autism, or premature ovarian failure. There are concerns over the counselling about complex genetic mechanisms and the psychological impact of FXS when population screening is offered. The difficulties in counselling include (1) the variable phenotypes (eg female fetuses with full mutation) associated with FXS, and (2) identification of individuals with pre-mutation allele may lead to anxiety in these individuals because both FXPOI and FXTAS have no specific treatment. Another factor that limits population screening for fragile X is the access to prenatal care and screening, especially in rural areas of mainland China.

The strength of this study lies in its size. It is the largest study of the prevalence of fragile X pre-mutation carriers performed in the Chinese pregnant women. This study also demonstrated the feasibility of this validated FXS-specific PCR-based method (FragilEase) in the Chinese population.14 One limitation is that not all pregnant women were approached for the study and the study participants were recruited by convenient sampling. During the study period, approximately 13 600 Chinese women attended our hospital but only 2650 women were recruited. Women were recruited each day at one convenient time-point by the research assistant in the antenatal ward or clinic. This was not a true random sample and hence has doubtful representativeness. Nonetheless, as the largest obstetric hospital in Hong Kong with participants recruited from both antenatal clinic and obstetric wards, and a large sample size of 2650, we aimed to include a group most typical of the general obstetric population. Another limitation is that our cohort represented mainly the Southern Chinese population and not the entire Chinese population. Despite this, the findings of our study should provide a strong foundation for further large-scale national studies that may benefit our understanding of the carrier frequencies in different parts of China and the Asia-Pacific region. Further studies are also required to look into the different models of carrier screening programmes and their cost-effectiveness in our locale to determine which screening strategy is the most appropriate in the Chinese pregnant population.

Conclusions

The prevalence of pre-mutation and full-mutation alleles altogether in the asymptomatic Southern Chinese population was one in 883, and that for pre-mutation alleles alone was one in 1325. These figures are higher than those reported previously in small-scale studies, and indicate that FXS is a clinical condition not to be overlooked in our locale. Further studies of the prevalence in different areas of Asia may be beneficial to direct future screening strategies.

Acknowledgements

We would like to thank the research and laboratory staff of the Fetal Medicine Team, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong. We would also like to thank all the pregnant women and their families who participated in the study.

Declaration

This work was supported partially by funding from the Hong Kong Obstetrical and Gynaecological Trust Fund. PerkinElmer has supported some of the PCR study reagents, but has no role in the design of the study; collection, analysis, or interpretation of the data; writing, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

References

1. Sherman S. Epidemiology. In: Hagerman RJ, Silverman AC, editors. Fragile X syndrome: diagnosis, treatment, and research. Baltimore: The Johns Hopkins University Press; 1991: 69-97.

2. Coffee B, Keith K, Albizua I, et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet 2009;8:503-14. Crossref

3. Verkerk AJ, Pieretti M, Sutcliffe JS, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991;65:905-14. Crossref

4. Kronquist KE, Sherman SL, Spector EB. Clinical significance of tri-nucleotide repeats in fragile X testing: a clarification of American College of Medical Genetics guidelines. Genet Med 2008;10:845-7. Crossref

5. Jacquemont S, Leehey MA, Hagerman RJ, Beckett LA, Hagerman PJ. Size bias of fragile X premutation alleles in late-onset movement disorders. J Med Genet 2006;43:804-9. Crossref

6. Uzielli ML, Guarducci S, Lapi E, et al. Premature ovarian failure (POF) and fragile X premutation females: from POF to fragile X carrier identification, from fragile X carrier diagnosis to POF association data. Am J Med Genet 1999;84:300-3. Crossref

7. Nolin SL, Glicksman A, Ding X, et al. Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenat Diagn 2011;31:925-31. Crossref

8. Nolin SL, Brown WT, Glicksman A, et al. Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 2003;72:454-64. Crossref

9. Fernandez-Carvajal I, Lopez Posadas B, Pan R, Raske C, Hagerman PJ, Tassone F. Expansion of an FMR1 grey-zone allele to a full mutation in two generations. J Mol Diagn 2009;11:306-10. Crossref

10. Hill MK, Archibald AD, Cohen J, Metcalfe SA. A systematic review of population screening for fragile X syndrome. Genet Med 2010;12:396-410. Crossref

11. Chiang SC, Lee YM, Wang TR, Hwu WL. Allele distribution at the FMR1 locus in the general Chinese population. Clin Genet 1999;55:352-5. Crossref

12. Huang KF, Chen WY, Tsai YC, et al. Original article pilot screening for fragile X carrier in pregnant women of southern Taiwan. J Chin Med Assoc 2003;66:204-9.

13. Tzeng CC, Tsai LP, Hwu WL, et al. Prevalence of the FMR1 mutation in Taiwan assessed by large-scale screening of newborn boys and analysis of DXS548-FRAXAC1 haplotype. Am J Med Genet A 2005;133A:37-43. Crossref

14. Kwok YK, Wong KM, Lo FM, et al. Validation of a robust PCR-based assay for quantifying fragile X CGG repeats. Clin Chim Acta 2016;456:137-43. Crossref

15. Huang W, Xia Q, Luo S, et al. Distribution of fragile X mental retardation 1 CGG repeat and flanking haplotypes in a large Chinese population. Mol Genet Genomic Med 2015;3:172-81. Crossref

16. Han SH, Heo YA, Yang YH, Kim YJ, Cho HI, Lee KR. Prenatal population screening for fragile X carrier and the prevalence of premutation carriers in Korea. J Genet Med 2012;9:73-7. Crossref

17. Musci TJ, Moyer K. Prenatal carrier testing for fragile X: counseling issues and challenges. Obstet Gynecol Clin North Am 2010;37:61-70. Crossref

18. Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A. Screening for fragile X syndrome: a literature review and modelling study. Health Technol Assess 2003;7:1-106. Crossref

19. The Hong Kong Family Planning Association. The report on the Survey of Family Planning Knowledge, Attitude and Practice in Hong Kong 2012. Available from: http://www.famplan.org.hk. Accessed 21 Apr 2016.

20. Chopra M, Duan T. Rare genetic disease in China: a call to improve clinical services. Orphanet J Rare Dis 2015;10:140. Crossref

21. Leung TY, Chan LW, Law LW, et al. First trimester combined screening for trisomy 21 in Hong Kong: outcome of the first 10,000 cases. J Matern Fetal Neonat Med 2009;22:300-4. Crossref

22. Sahota DS, Leung TY, Fung TY, Chan LW, Law LW, Lau TK. Medians and correction of biochemical and ultrasound markers in Chinese undergoing first-trimester screening for trisomy 21. Ultrasound Obstet Gynecol 2009;33:387-93. Crossref

23. Leung TY, Chan LW, Leung TN, et al. First-trimester combined screening for trisomy 21 in a predominantly Chinese population. Ultrasound Obstet Gynecol 2007;29:14-7. Crossref

24. Sahota DS, Leung WC, To WK, Chan WP, Lau TK, Leung TY. Quality assurance of nuchal translucency for prenatal fetal Down syndrome screening. J Matern Fetal Neonatal Med 2012;25:1039-43. Crossref

25. Skinner D, Sparkman KL, Bailey DB Jr. Screening for fragile X syndrome: parent attitudes and perspectives. Genet Med 2003;5:378-84. Crossref

26. Acharya K, Ross LF. Fragile X screening: attitudes of genetic health professionals. Am J Med Genet A 2009;149:626-32. Crossref

27. Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA. Fragile-X syndrome and fragile X–associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 2007;6:45-55. Crossref

28. Antenatal screening for fragile X syndrome: external review against programme appraisal criteria for the UK National Screening Committee (UK NSC). UK National Screening Committee; Oct 2014.

29. ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. The American College of Obstetricians and Gynecologists Committee; Oct 2010.

Operative outcome of Hong Kong centenarians with hip fracture

Hong Kong Med J 2017 Feb;23(1):63–6 | Epub 14 Dec 2016

DOI: 10.12809/hkmj164823

ORIGINAL ARTICLE

Operative outcome of Hong Kong centenarians with hip fracture

MY Cheung, MB, ChB; Angela WH Ho, FHKCOS, FHKAM (Orthopaedic Surgery); SH Wong, FHKCOS, FHKAM (Orthopaedic Surgery)

Department of Orthopaedics and Traumatology, Caritas Medical Centre, Shamshuipo, Hong Kong

Corresponding author: Dr MY Cheung (jessicacheungmy@gmail.com)

An earlier version of this paper was presented as Free Paper Oral Presentation at the 34th Annual Congress of the Hong Kong Orthopaedic Association held in Hong Kong on 16 November 2014.

Full paper in PDF

Abstract

Introduction: International clinical guidelines recommend early surgical treatment for geriatric patients with hip fracture. There are, however, few data concerning the operative outcome of centenarians. This study aimed to report the epidemiology of hip fracture and postoperative mortality rate, and to discuss whether operation is justified in centenarians in Hong Kong.

Methods: This observational study was carried out in all public hospitals of Hong Kong. All patients aged 100 years or above who underwent hip fracture surgery in any public hospital between 1 January 2010 and 31 December 2013 were included. Their postoperative mean and median survival time was recorded.

Results: Of 114 centenarians, 96 (84%) were female. The age of patients ranged from 100 to 109 years, with the largest number (44%) aged 100 years. The follow-up interval ranged from 5 to 1619 days (median, 412 days; interquartile range, 683 days). The 1-month, 6-month, and 1-year mortalities were 8%, 25%, and 37%, respectively. By Kaplan-Meier analysis, the postoperative mean survival was 2 years 2 months (95% confidence interval, 680-936 days) and the median survival time was 2 years (interquartile range, 1234 days).

Conclusion: The 1-year mortality among Hong Kong centenarians with hip fracture was 37%, which is lower than the 41.1% in the general centenarian population in Japan. The median survival time after hip fracture surgery was 2 years, suggesting that surgery even at an extreme age is worthwhile to maintain quality of life. Extreme age should not be a barrier to operative treatment.

New knowledge added by this study

The postoperative 1-year mortality among Hong Kong centenarians with hip fracture was comparable to that of the general centenarian population in Japan.
The median postoperative survival time of the centenarians in this study was 2 years.

Implications for clinical practice or policy

Operative treatment should be offered to centenarians with hip fracture to maintain their quality of life. Extreme age should not be a barrier to hip fracture surgery.

[Abstract in Chinese]

Introduction

Fragility fracture is one of the common chronic diseases in geriatrics. The prevalence of femoral neck osteoporosis based on a hip T-score of < –2.5 was 47.8% in males and 59.1% in females in our previous study of 239 hip fractures.1 The incidence of hip fracture increases with age, and the incidence is high in the elderly (1639 per 100 000 in men and 3012 per 100 000 in women for the age-group of ≥85 years).2 3 A 2015 study of geriatric hip fracture showed that there was a steady increase in the incidence of geriatric hip fracture in Hong Kong.4 The overall 30-day and 1-year mortalities were 3.01% and 18.56%, respectively. Advancing age and male sex were associated with an increased mortality and a higher excess mortality rate following surgery.4

With the advances in medical technology, the population of centenarians is increasing both locally and internationally. In Hong Kong, the number of centenarians has increased 6.5-fold over the last 30 years, from 289 in 1981 to 1890 in 2011 (about 3/10 000).5 Hong Kong women have overtaken Japanese women for longevity, with an average life expectancy reaching 87.32 years in 2015 compared with 87.02 years in Japan, according to statistics from Japan’s Ministry of Health, Labour and Welfare.6 Advanced medical service and easy access to emergency services may contribute to this longevity. International clinical guidelines recommend early surgical treatment for geriatric patients with hip fracture once their medical condition has been optimised with the help of a geriatrician.7 There are, however, few data concerning the operative outcome of this group of oldest elderly. Although centenarians represent only a small subset of the elderly population, their number is expected to further increase.5 Therefore it is important for us to understand the surgical outcome for this particular group of patients to enable provision of the best care and effective use of limited health care resources. The aims of our study were to report the epidemiology of hip fracture and postoperative mortality rate, and to discuss whether surgery is justified in this group of patients.

Methods

This was an observational study of all patients aged 100 years or above who underwent hip fracture surgery in any public hospital in Hong Kong between 1 January 2010 and 31 December 2013. This study was done in accordance with the principles outlined in the Declaration of Helsinki. Data were retrieved from the Hospital Authority clinical database that included 99% of geriatric patients with hip fracture in Hong Kong.8 9 Patients with hip fracture aged 100 years or above were extracted from the Clinical Data Analysis and Reporting System using International Classification of Diseases code 820 under subdivision Operation Theatre Management System–linked diagnosis. Complications of initial hip surgery or periprosthetic fractures were excluded. Demographics, type of operation, and dates of admission, discharge, and death were retrieved. Mortality of the general population was retrieved using census data and the death registry of Hong Kong Special Administrative Region.

Data are shown as mean and 95% confidence interval, or median and interquartile range. Mortality and survival were calculated using Kaplan-Meier survival analysis. Analyses were performed using the Statistical Package for the Social Sciences (Windows version 16.0; SPSS Inc, Chicago [IL], US). Comparative tests between different groups were performed using Chi squared test. A P value of <0.05 was considered statistically significant.

Results

During the 4-year study period, 114 centenarians underwent surgery in Hong Kong for primary hip fracture, of whom 96 (84%) were female. The age of patients ranged from 100 to 109 years, with the largest number (44%) aged 100 years (Fig 1). The largest number of patients were admitted to hospitals in Kowloon West Cluster, and this accounted for 25%. Most were residents in the Eastern district (12%) and Sham Shui Po (11%) before admission. Overall, 62 (54%) patients were admitted from elderly care homes. Hip fracture surgery was performed as an emergency in 76 (67%) patients. Closed reduction and internal fixation of the femur was performed in 80 (70%) patients, partial hip replacement in 28 (25%), and other hip surgery in six (5%). Postoperative admission to an intensive care unit (ICU) or high dependency unit (HDU) was necessary in two patients. The mean length of stay in an acute ward was 13.3 days, with a median of 10.5 days.

Figure 1. Age distribution of centenarian hip fracture patients

Postoperative follow-up ranged from 5 to 1619 days (median, 412 days; interquartile range, 683 days). The 1-month, 6-month, and 1-year mortality rates were 8%, 25%, and 37%, respectively (Table 1). By Kaplan-Meier analysis, the postoperative mean survival was 2 years 2 months (95% confidence interval, 680-936 days) and the median survival time was 2 years (interquartile range, 1234 days) [Fig 2].

Table 1. Mortality at different time points for centenarians who underwent surgery for hip fracture

Figure 2. Kaplan-Meier survival curve of postoperative survival in centenarian hip fracture patients
The postoperative mean and median survival time was 2 years 2 months and 2 years, respectively (95% confidence interval, 680-936 days and 519-994 days, respectively)

Discussion

With an increase in life expectancy, the health care authority is likely to encounter more elderly patients with hip fracture. The cost of providing clinical care for centenarians imposes a substantial financial burden on our health care system. There are only a few publications that specifically examine the surgical outcome of centenarians following hip fracture surgery. Due to their limited sample size, these studies have failed to justify the need to operate on centenarians with hip fracture. A previous report by Tarity et al10 on 23 centenarians reported a 1-year mortality of 60% and concluded that operating on patients >100 years carried an acceptable mortality rate. Patil et al11 reported a high mobility rate of 77% and a low mortality rate of 8.3% in 13 centenarians, and concluded that hip fracture surgery yielded a good return on money spent and quality of life. Shabat et al12 reported a mortality rate of 48% in 23 centenarians and concluded that operated cases had shorter hospitalisation and patients with two or more co-morbid diseases had a higher mortality rate. Only one prospective review has reported the surgical outcome of patients aged ≥95 years with the largest sample size of 50 patients.13 They reported a mortality rate of 36% that was higher than that of a younger age-group. Predictors of mortality included the American Society of Anesthesiologists physical status classification system, number of co-morbidities, and active medical problems. Despite numerous studies in different parts of the world, there are no data for Asian patients.

In our study, the postoperative 1-year mortality rate for centenarians with hip fracture was 37%. The postoperative mortality rate of centenarians was higher than that of hip fracture patients aged >65 years.4 The mortality rate in this study was similar to that of the abovementioned studies. Nonetheless, Hong Kong is one of the countries/regions with the longest life expectancy, and we had the largest sample size of 114 patients compared with previous studies (Table 2 10 11 12 13).

Table 2. Comparison of different studies concerning the surgical outcome for centenarians who underwent surgery for hip fracture

Although two centenarians required ICU or HDU admission during their hospital stay, the postoperative 1-year mortality of 37% in our study is lower than the 41.1% for a general centenarian population in Japan (P<0.05).14 Those patients in our study also had a reasonable median postoperative survival of 2 years.

Previous studies have shown that the benefits of surgery are not confined to improving mobility, it also reduces other related complications, improves patient care, and is more cost-effective than other non-surgical treatments.15 16 17 Early multidisciplinary geriatric care also reduces in-hospital mortality and medical complications.18 Patients who have undergone hip fracture surgery can be transferred from an acute unit to rehabilitation as soon as they are medically stable. In this study, the mean length of stay on an acute ward was 13.3 days. Weight-bearing walking exercises can be initiated immediately after surgery so minimising complications related to being bedbound. This will also lower the inevitable costs of acute hospital care. Some of the centenarians in our study were able to walk independently with aid following rehabilitation. One of the most encouraging cases was a 104-year-old woman who underwent dynamic hip screw fixation surgery with subsequent cut-out and converted to cemented unipolar hemiarthroplasty 1 month after the initial operation. She was able to walk well with a frame after 2 weeks of rehabilitation and was finally discharged home.

A limitation of our study was its observational nature rather than being a prospective randomised controlled trial. It would be unethical, however, to randomise patients to have surgery or not and the sample size would be too small to provide enough statistical power to demonstrate any significant difference for this extreme of age. To the best of our knowledge, our sample size of 114 makes it the largest study to date of the surgical outcome of centenarians undergoing hip fracture surgery (Table 2). The present study undoubtedly provides insight into the treatment of centenarians with hip fracture and should prompt further research on this topic.

Conclusion

The postoperative 1-year mortality rate among Hong Kong centenarians with hip fracture was 37%, lower than the 41.1% in the general centenarian population of Japan. Centenarians also had a reasonable median survival of 2 years after hip fracture surgery. The mean length of stay in an acute ward was only 13.3 days. Therefore, surgery for hip fracture, even at extreme age, is worthwhile to maintain quality of life for affected patients. Extreme age should not be a barrier to operative treatment.

Declaration

All authors have disclosed no conflicts of interest.

References

1. Ho AW, Lee MM, Chan EW, et al. Prevalence of pre-sarcopenia and sarcopenia in Hong Kong Chinese geriatric patients with hip fracture and its correlation with different factors. Hong Kong Med J 2016;22:23-9. Crossref

2. Gullberg B, Johnell O, Kanis JA. World-wide projections for hip fracture. Osteoporos Int 1997;7:407-13. Crossref

3. Lau EM, Lee JK, Suriwongpaisal P, et al. The incidence of hip fracture in four Asian countries: the Asian Osteoporosis Study (AOS). Osteoporos Int 2001;12:239-43. Crossref

4. Man LP, Ho AW, Wong SH. Excess mortality for operated geriatric hip fracture in Hong Kong. Hong Kong Med J 2016;22:6-10.

5. Census and Statistics Department of the Hong Kong SAR Government. Hong Kong Population Projections 2012-2041. Available from: http://www.statistics.gov.hk/pub/B1120015052012XXXXB0100.pdf. Accessed Dec 2014.

6. Ministry of Health, Labour and Welfare, Government of Japan. Abridged life tables for Japan 2015. Available from: http://www.mhlw.go.jp/english/database/db-hw/lifetb15/index.html. Accessed Dec 2014.

7. British Orthopaedic Association. The care of patients with fragility fracture. September 2007. Available from: http://www.fractures.com/pdf/BOA-BGS-Blue-Book.pdf. Accessed Jun 2016.

8. Lau EM, Cooper C, Wickham C, Donnan S, Barker DJ. Hip fracture in Hong Kong and Britain. Int J Epidemiol 1990;19:1119-21. Crossref

9. Lau EM, Cooper C, Fung H, Lam D, Tsang KK. Hip fracture in Hong Kong over the last decade—a comparison with the UK. J Public Health Med 1999;21:249-50. Crossref

10. Tarity TD, Smith EB, Dolan K, Rasouli MR, Maltenfort MG. Mortality in centenarians with hip fractures. Orthopedics 2013;36:e282-7. Crossref

11. Patil S, Parcells B, Balsted A, Chamberlain RS. Surgical outcome following hip fracture in patients >100 years old: will they ever walk again? Surg Sci 2012;3:554-9. Crossref

12. Shabat S, Mann G, Gepstein R, Fredman B, Folman Y, Nyska M. Operative treatment for hip fractures in patients 100 years of age and older: is it justified? J Orthop Trauma 2004;18:431-5. Crossref

13. Holt G, Macdonald D, Fraser M, Reece AT. Outcome after surgery for fracture of the hip in patients aged over 95 years. J Bone Joint Surg Br 2006;88:1060-4. Crossref

14. Statistics Bureau, Ministry of Internal Affairs and Communications, the Government of Japan. Statistical Handbook of Japan 2013. Available from: http://www.stat.go.jp/english/data/handbook/pdf/2013all.pdf. Accessed Dec 2014.

15. Lyons AR. Clinical outcomes and treatment of hip fractures. Am J Med 1997;103:51S-64S. Crossref

16. Simunovic N, Devereaux PJ, Sprague S, et al. Effect of early surgery after hip fracture on mortality and complications: systematic review and meta-analysis. CMAJ 2010;182:1609-16. Crossref

17. Parker MJ, Myles JW, Anand JK, Drewett R. Cost-benefit analysis of hip fracture treatment. J Bone Joint Surg Br 1992;74:261-4.

18. Vidán M, Serra JA, Moreno C, Riquelme G, Ortiz J. Efficacy of a comprehensive geriatric intervention in older patients hospitalized for hip fracture: a randomized, controlled trial. J Am Geriatr Soc 2005;53:1476-82. Crossref

Adjuvant S-1 chemotherapy after curative resection of gastric cancer in Chinese patients: assessment of treatment tolerability and associated risk factors

Hong Kong Med J 2017 Feb;23(1):54–62 | Epub 14 Dec 2016

DOI: 10.12809/hkmj164885

ORIGINAL ARTICLE

Adjuvant S-1 chemotherapy after curative resection of gastric cancer in Chinese patients: assessment of treatment tolerability and associated risk factors

Winnie Yeo, FRCP, FHKAM (Medicine)¹; KO Lam, MB, BS, FHKAM (Radiology)²; Ada LY Law, MB, BS, FHKAM (Radiology)³; Conrad CY Lee, FRCP, FRCR⁴; CL Chiang, MB, ChB, FRCR⁵; KH Au, FHKCR, FHKAM (Radiology)⁶; Frankie KF Mo, MPhil, PhD⁷; TH So, BChinMed, MB, BS²; KC Lam, FHKCP, FHKAM (Medicine)⁸; WT Ng, MD³; L Li, FHKCP, FHKAM (Medicine)⁸

¹ Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong

² Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong

³ Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong

⁴ Department of Clinical Oncology, Princess Margaret Hospital, Laichikok, Hong Kong

⁵ Department of Clinical Oncology, Tuen Mun Hospital, Tuen Mun, Hong Kong

⁶ Department of Clinical Oncology, United Christian Hospital, Kwun Tong, Hong Kong

⁷ Comprehensive Clinical Trials Unit, Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong

⁸ Department of Clinical Oncology, Prince of Wales Hospital, Shatin, Hong Kong

Corresponding author: Prof Winnie Yeo (winnieyeo@cuhk.edu.hk)

Full paper in PDF

Abstract

Introduction: The use of adjuvant chemotherapy with S-1 (tegafur, gimeracil, and oteracil potassium) has been shown to improve the outcome of patients with gastric cancer. There are limited data on the tolerability of S-1 in Chinese patients. In this multicentre retrospective study, we assessed the toxicity profile in local patients.

Methods: Patients with stage II-IIIC gastric adenocarcinoma who had undergone curative resection and who had received S-1 adjuvant chemotherapy were included in the study. Patient demographics, tumour characteristics, chemotherapy records, as well as biochemical, haematological, and other toxicity profiles were extracted from medical charts. Potential factors associated with grade 2-4 toxicities were identified.

Results: Adjuvant S-1 was administered to 30 patients. Overall, 19 (63%) patients completed eight cycles. The most common grade 3-4 adverse events included neutropaenia (10%), anaemia (6.7%), septic episode (16.7%), diarrhoea (6.7%), hyperbilirubinaemia (6.7%), and syncope (6.7%). Dose reductions were made in 22 (73.3%) patients and 12 (40.0%) patients had dose delays. Univariate analyses showed that patients who underwent total gastrectomy were more likely to experience adverse haematological events (P=0.034). Patients with nodal involvement were more likely to report adverse non-haematological events (P=0.031). Patients with a history of regular alcohol intake were more likely to have earlier treatment withdrawal (P=0.044). Lower body weight (P=0.007) and lower body surface area (P=0.017) were associated with dose interruptions.

Conclusions: The tolerability of adjuvant S-1 in our patient population was similar to that in other Asian patient populations. The awareness of S-1–related toxicities and increasing knowledge of potential associated factors may enable optimisation of S-1 therapy.

New knowledge added by this study

In line with the published data, adjuvant S-1 therapy has a tolerable toxicity profile among local patients who have undergone curative resection for gastric cancer. Total gastrectomy and nodal involvement are potential factors associated with adverse events. Lower body weight and lower body surface area are potential factors associated with dose interruptions.

Implications for clinical practice or policy

For gastric cancer patients in whom adjuvant S-1 therapy is planned, close monitoring of those who have identifiable risk factors may enable early recognition of adverse events during therapy. This may enable earlier intervention with supportive therapy and improve treatment outcome.

[Abstract in Chinese]

Introduction

Gastric cancer is the second most common cause of cancer-related mortality worldwide, with 988 000 new cases and 736 000 deaths per year.1 Surgery is the main treatment for operable gastric cancer but recurrence rates are high and about 40% to 80% of patients develop relapsed disease after surgery. The use of adjuvant chemotherapy has been shown to improve patient outcome.2 3 4 5 After curative resection, common adjuvant chemotherapy regimens that have been recently adopted in many parts of Asia include oral administration of S-1 (tegafur, gimeracil, and oteracil potassium) based on the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) study conducted in Japan,4 as well as oxaliplatin-capecitabine combination chemotherapy based on the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer study.5 These studies have shown that adjuvant S-1 for 1 year or oxaliplatin-capecitabine combination chemotherapy for 6 months following curative gastrectomy with D2 lymph node dissection increases both overall survival (OS) and relapse-free survival in pathological stage II or III gastric cancer.4 5

S-1 is an oral anticancer agent comprising tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oteracil potassium (Oxo) at a molar ratio of 1:0.4:1.6 Tegafur is a prodrug of 5-fluorouracil (5-FU); CDHP is a potent reversible inhibitor of 5-FU degradation; and Oxo is an inhibitor of the enzyme orotate phosphoribosyltransferase (OPRT) that catalyses the phosphorylation of 5-FU.6 Pharmacokinetic analyses have confirmed that S-1 has potent anti-tumour activity, and oral S-1 administration results in a similar serum concentration of 5-FU to intravenous 5-FU whilst sparing patients the need for continuous intravenous infusion of 5-FU and consequent toxicity.7 Nonetheless early studies have also shown that toxicity profiles may differ between Asian and non-Asian patients. In earlier studies in Japanese patients, the dose-limiting toxicity was bone marrow suppression that occurred prior to gastrointestinal adverse events. In contrast, studies in non-Asian patients revealed that diarrhoea associated with abdominal discomfort and cramping was the principal dose-limiting toxicity and bone marrow suppression was not.8 This might be due to the varied activity of OPRT between different populations. In fact, OPRT activates 5-FU in the bowel mucosa; patients with higher OPRT activity might be expected to experience a higher incidence of gastrointestinal adverse effects prior to bone marrow toxicity.9

In the ACTS-GC study, the adverse events of adjuvant S-1 were reported to be generally mild, with 65.8% of patients being able to complete the planned 1 year of therapy.4 While it has been known that patients in the West have a different toxicity profile to their Japanese counterparts,10 there are limited data on tolerability of S-1 among Chinese patients. In this multicentre retrospective study, we assessed the toxicity and tolerability profiles of Hong Kong Chinese patients with gastric cancer who had received adjuvant S-1 chemotherapy.

Methods

This was a retrospective study carrying out between June 2013 and February 2016, and involved six local centres in Hong Kong: Pamela Youde Nethersole Eastern Hospital, Princess Margaret Hospital, Prince of Wales Hospital, Tuen Mun Hospital, Queen Mary Hospital, and United Christian Hospital. This study has been approved by the institutional ethics committee of each participating centre with patient consent waived. Patients with stage II-IIIC gastric adenocarcinoma according to American Joint Committee on Cancer,11 who had completed curative surgical treatment and who had undergone S-1 adjuvant chemotherapy, were included. Patients with stage IV disease and who had had prior therapy with S-1 in the neoadjuvant setting were excluded.

Adjuvant S-1 was started at least 3 weeks after curative surgery. The intended dose of S-1 was based on that published in the ACTS-GC trial,4 and was 40 mg/m² twice daily for 4 weeks followed by 2 weeks of rest for each cycle. Specifically, during the treatment weeks, patients with body surface area (BSA) of <1.25 m² received 80 mg daily; those with BSA of 1.25 m² to <1.5 m² received 100 mg daily; and those with BSA of ≥1.5 m² received 120 mg daily. As clinically indicated, dose reductions were considered one dose level at a time; in general, one dose level reduction refers to reducing the prior daily dose by 20 mg, eg from 120 mg to 100 mg daily. As renal impairment has been associated with increased incidence of myelosuppression, dose reduction by one dose level was made in patients who had a creatinine clearance of 40-49 mL/min. A maximum of eight 6-weekly cycles were administered. The dose of S-1 was reduced in patients with significant toxicities, as assessed by the respective clinician-in-charge. Complete and differential blood count and serum chemistry were performed before each 6-week cycle. All patients had mid-cycle follow-up with complete and differential blood counts and serum chemistry in the first cycle.

Patient charts were reviewed by investigators at each centre for background information. S-1 chemotherapy records, as well as biochemical and haematological profiles, were extracted. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (version 3.0).12 Adverse events were documented during chemotherapy and for 28 days after the last dose of S-1. Dose interruption was defined as a need for either any dose delay and/or dose reduction.

Clinical characteristics are summarised as number of patients and percentage (%) for categorical variables, and medians with ranges for continuous variables. The frequency of adverse events was tabulated. Factors independently associated with adverse events, dose interruptions, or earlier withdrawal of S-1 were identified using the Pearson’s Chi squared (χ²) test or the Fisher’s exact test if the expected number in any cell was less than five for categorical data or any cell with an expected count of less than one for categorical data, and t test or Wilcoxon rank-sum test for continuous data. A two-sided P value of <0.05 was considered significant. All statistical analyses were performed with SAS, version 9.3 (SAS Institute Inc, Cory [NC], US).

Disease-free survival (DFS) was calculated as the period from the date of surgery to the date of recurrence or death from any cause; OS was calculated as the period from the date of surgery to the date of death from any cause. Both DFS and OS were estimated using the Kaplan-Meier method.

Results

Characteristics of patients

Thirty patients met the eligibility criteria in the six centres during the study period and were enrolled in this study. Their baseline demographic and clinical characteristics are shown in Table 1.

Table 1. Baseline demographic and clinical characteristics (n=30)

There were 18 males and 12 females with a median age of 65.6 years. Of the patients, 27 (90%) had ECOG (Eastern Cooperative Oncology Group) performance status of 0 to 1. Total gastrectomy was performed in 11 (36.7%) patients and partial gastrectomy in 19 (63.3%). D2 dissection was performed in 26 (86.7%) patients and two had D1 dissection; the details of two other patients were unknown. The median number of lymph nodes resected was 31. Cancer stage II disease was present in 19 (63.3%) patients and stage III in 11 (36.7%).

Of the 30 patients, two (6.7%), two (6.7%), one (3.3%), two (6.7%), one (3.3%), three (10%), and 19 (63.3%) completed one, two, three, four, five, six, and eight cycles of S-1 adjuvant chemotherapy, respectively. At the time of data cut-off on 29 February 2016, one patient was still on S-1, having completed six cycles of treatment. The reasons for treatment withdrawal included toxicities (n=5, 16.7%), patient refusal (3, 10%), recurrence (2, 6.7%), and worsening of pre-existing Parkinson’s disease (1, 3.3%).

Patient survival

The median follow-up period was 25.3 months (range, 16.3-29.2 months). Three patients died and two experienced recurrence (lung and peritoneum). The 3-year DFS and OS rates were 80.2% and 85.9%, respectively (Fig).

Figure. Kaplan-Meier estimates of disease-free survival (DFS) and overall survival (OS)

Tolerability data

Table 2 presents the haematological and non-haematological adverse events experienced during treatment. Grade 3-4 haematological adverse events included neutropaenia (n=3, 10%), leukopaenia (1, 3.3%), and anaemia (2, 6.7%). Grade 3-4 non-haematological adverse events included non-neutropaenic septic episode (16.7%), diarrhoea (6.7%), hyperbilirubinaemia (6.7%), syncope (6.7%), reduced left ventricular ejection function (3.3%), gouty attack (3.3%), hypokalaemia (3.3%), subacute intestinal obstruction (3.3%), and urticaria (3.3%).

Table 2. Haematological and non-haematological adverse events (all grades)

Of note, 10 patients developed a septic episode; apart from one patient with grade 3 neutropaenic fever, the others were non-neutropaenic. Of the latter, four had grade 3 toxicity, four had grade 2, and one had grade 1 toxicity; in one patient with grade 2 toxicity, the infection was due to pulmonary tuberculosis. This latter patient had a history of ischaemic heart disease and he also developed grade 3 reduced left ventricular ejection function whilst on S-1, as noted above.

Two out of 30 patients were found to be positive for hepatitis B surface antigen. Of these two, one was prescribed prophylactic antiviral therapy and liver function remained normal apart from one isolated episode of grade 2 hyperbilirubinaemia that resolved spontaneously without other hepatic dysfunction; the other patient did not receive prophylactic antiviral therapy but his liver function remained normal throughout S-1 therapy.

There were no treatment-related deaths.

Dose interruptions

Of the 30 patients, 17 (56.7%) were commenced on a lower-than-intended dose of S-1. The reason for reducing the first dose was: impaired renal function (n=6; with creatinine clearance ranging from 41-48 mL/min), concern of toxicity (6), aged over 70 years (4), and borderline performance status (1); four of these patients had further dose reduction in subsequent cycles. Of the other 13 patients who had the full S-1 dose in cycle 1, five had a dose reduction from cycle 2 onwards.

Dose delays occurred in 12 (40%) patients; these were due to delayed bone marrow recovery (n=3), hypokalaemia (2, including 1 who also had delayed bone marrow recovery), diarrhoea (2), sepsis (2), hypoglycaemia (1), impaired renal function (1), reduced weight (1), and abdominal pain (1).

Risk factor analysis

Potential risk factors for adverse events were assessed (Table 3). Univariate analysis showed that total gastrectomy was significantly associated with haematological adverse events; 90.9% of patients who had total gastrectomy in contrast to 52.6% of the patients who had partial gastrectomy experienced grade 2-4 adverse events (P=0.034). On univariate analysis, nodal status was significantly associated with non-haematological adverse events; 76.2% of patients who experienced grade 2-4 adverse events had nodal disease, while only 33% of those who had grade 0-1 adverse events had nodal disease (P=0.031).

Table 3. Univariate analysis of risk factors for grade 2-4 adverse events

Potential risk factors for earlier withdrawal of S-1 and dose interruptions (dose reductions and/or dose delays) were assessed (Table 4). For earlier S-1 withdrawal, patients who had a history of regular alcohol intake were significantly more likely to have earlier treatment withdrawal than non-drinkers (80% vs 28%; P=0.044), while ever-smokers also had a tendency, though insignificant, for earlier withdrawal than never-smokers (67% vs 29%; P=0.095). For dose interruptions, univariate analysis showed lower body weight (P=0.007) and lower BSA (P=0.017) were significant associated factors, while lower body mass index (BMI) also had an increased tendency, though insignificant, for dose interruptions (P=0.055). The median body weight, BMI, and BSA of those patients who had dose interruptions were 54.5 kg, 21.4 kg/m², and 1.54 m², respectively; the corresponding data for those who did not require dose interruptions were 64.0 kg, 24.8 kg/m², and 1.67 m², respectively.

Table 4. Univariate analysis of risk factors for earlier S-1 withdrawal and dose interruptions

Discussion

Our study results indicate that adjuvant S-1 chemotherapy is feasible for our local patients after curative resection of gastric cancer. With increased awareness of the associated toxicity, S-1 can be offered safely as standard adjuvant therapy. The toxicities experienced by the studied patients were in line with previous findings in Asian patients.4 12 13 Grade 3-4 haematological adverse events included thrombocytopaenia and anaemia. Grade 3-4 non-haematological adverse events that occurred in 5% or more of the patients included non-neutropaenic septic episode, diarrhoea, hyperbilirubinaemia, and syncope.

Previous studies have investigated factors associated with adverse events during S-1 therapy. In a Korean study of 305 patients given adjuvant S-1 therapy,13 total gastrectomy was reported to be an independent risk factor for grade 3-4 haematological toxicities and age >65 years was an independent risk factor for grade 3 non-haematological toxicities. Independent risk factors for withdrawal and dose reductions included age >65 years and male gender. Total gastrectomy has also been reported to be associated with a significantly greater risk of serious adverse events in another study of Taiwanese gastric cancer patients receiving adjuvant S-1.14

The reason for the higher incidence of serious adverse events in patients who underwent total gastrectomy whilst receiving S-1 treatment is unknown. In an earlier study, a higher incidence of adverse reactions was observed among patients who received S-1 as adjuvant treatment after gastrectomy, compared with those who had unresectable or recurrent gastric cancer. The investigators suggested the limitation in food intake soon after extensive surgery as a possible cause of exacerbation of adverse reactions such as anorexia and nausea, and proposed that a delay in the start of drug administration after gastrectomy may prevent such adverse events.15 In another study, Taiwanese patients received palliative S-1 for advanced gastric cancer at a median initial dose of 37.0 mg/m². Twelve patients had single-dosing pharmacokinetic study on day 1, and seven took part in a multiple-dosing pharmacokinetic study on day 28. The results indicated that the steady-state pharmacokinetics of 5-FU, CDHP and Oxo could be predicted from single-dose pharmacokinetic study. Six patients who underwent gastrectomy had a similar pharmacokinetic profile to another six patients who did not undergo gastrectomy.16 Nonetheless, definitive data regarding the pharmacokinetic profile of S-1 components in patients who underwent different degrees of gastrectomy are lacking.

Other factors that have been reported to be associated with treatment-related adverse events include low body mass and impaired renal function.16 These were supported by the present study in which lower body weight, BMI, and BSA were associated with an increased likelihood of dose interruptions. Earlier reports have shown that impaired renal function will reduce CDHP clearance and result in a prolonged high concentration of 5-FU in plasma, and thereby lead to more severe myelosuppression.8 17 Although impaired renal function was not identified as a risk factor for adverse events in this study, it has to be noted that all patients who had subnormal creatinine clearance were offered S-1 at lower doses at treatment initiation; this could have prevented the occurrence of severe adverse events.

The present study was limited by its retrospective nature and the limited number of patients accrued. Although there is a lack of information about patient co-morbidities, the current data suggest that patients who had a history of regular alcohol intake had an increased likelihood of earlier treatment withdrawal. The survival data are immature due to short follow-up. The findings, however, lend support to a published report on the acceptable toxicity profile and tolerability of S-1 as adjuvant therapy after curative gastric surgery for gastric cancer.4 13 14 Potential risk factors for severe adverse events are suggested. Due to the small sample size and retrospective nature of this study, a prospective study with a larger patient population is needed to confirm these findings. An awareness of treatment-related adverse events as well as potential associated factors may aid clinicians in managing patients in whom S-1 therapy is planned, and thereby improve treatment compliance and clinical outcome.

Conclusions

Adjuvant S-1 therapy has a tolerable toxicity profile among local patients who have undergone curative resection for gastric cancer. For gastric cancer patients in whom adjuvant S-1 therapy is planned, those with identifiable risk factors should be closely monitored for adverse events during treatment. This may enable earlier intervention with supportive therapy and optimise treatment outcome.

Acknowledgements

The authors gratefully acknowledge Mr Edward Choi for his valuable statistical advice. We thank Drs Chi-ching Law, Hoi-leung Leung, and Chung-kong Kwan of the Department of Clinical Oncology, United Christian Hospital for their support in this study.

Declaration

This study has been supported by an educational grant from Taiho Pharma Singapore Pte. Ltd. W Yeo has received honorarium for advisory role for Eli Lilly, Novartis, Pfizer, and Bristol Myers Squibb and has received research grant from Novartis over the past 12 months. KO Lam has been an advisor for Amgen, Eli Lilly, Roche, Sanofi-Aventis, and has received honorarium from Amgen, Bayer, Eli Lilly, Merck, Sanofi-Aventis, Taiho and research grant from Bayer, Roche, and Taiho. Authors not named here have disclosed no conflicts of interest.

References

1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008: Cancer incidence and mortality worldwide: IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr. Accessed 12 Oct 2011.

2. Gallo A, Cha C. Updates on esophageal and gastric cancers. World J Gastroenterol 2006;12:3237-42. Crossref

3. GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group, Paoletti X, Oba K, et al. Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA 2010;303:1729-37. Crossref

4. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810-20. Crossref

5. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012;379:315-21. Crossref

6. Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs 1996;7:548-57. Crossref

7. Kubota T. The role of S-1 in the treatment of gastric cancer. Br J Cancer 2008;98:1301-4. Crossref

8. Hirata K, Horikoshi N, Aiba K, et al. Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug. Clin Cancer Res 1999;5:2000-5.

9. Chu QS, Hammond LA, Schwartz G, et al. Phase I and pharmacokinetic study of the oral fluoropyrimidine S-1 on a once-daily-for-28-day schedule in patients with advanced malignancies. Clin Cancer Res 2004;10:4913-21. Crossref

10. Ajani JA, Faust J, Ikeda K, et al. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol 2005;23:6957-65. Crossref

11. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. American Joint Committee on Cancer. Cancer Staging Manual. 7th ed. Chicago: Springer; 2010.

12. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176-81. Crossref

13. Jeong JH, Ryu MH, Ryoo BY, et al. Safety and feasibility of adjuvant chemotherapy with S-1 for Korean patients with curatively resected advanced gastric cancer. Cancer Chemother Pharmacol 2012;70:523-9. Crossref

14. Chou WC, Chang CL, Liu KH, et al. Total gastrectomy increases the incidence of grade III and IV toxicities in patients with gastric cancer receiving adjuvant TS-1 treatment. World J Surg Oncol 2013;11:287. Crossref

15. Kinoshita T, Nashimoto A, Yamamura Y, et al. Feasibility study of adjuvant chemotherapy with S-1 (TS-1; tegafur, gimeracil, oteracil potassium) for gastric cancer. Gastric Cancer 2004;7:104-9. Crossref

16. Chen JS, Chao Y, Hsieh RK, et al. A phase II and pharmacokinetic study of first line S-1 for advanced gastric cancer in Taiwan. Cancer Chemother Pharmacol 2011;67:1281-9. Crossref

17. Koizumi W, Kurihara M, Nakano S, Hasegawa K. Phase II study of S-1, a novel oral derivative of 5-fluorouracil, in advanced gastric cancer. For the S-1 Cooperative Gastric Cancer Study Group. Oncology 2000;58:191-7. Crossref

Pages