Pill splitting by patients is common globally. A German study observed that 24.1% of all drugs required splitting,1 and a Swiss study found that 10% of all discharged prescriptions contained pill splitting.2 In Sweden, 10% of 600 000 investigated prescriptions required splitting, and over 30% of the Swedish patients stated that they had problems dividing the tablets.3 The observed prevalence of pill splitting has been observed to range from 10% to >35% worldwide1 4 5 6 and was even higher in elderly patients (35-67%).6 7 One of the reasons for pill splitting is cost saving because it may result in institutions not needing to stock too many drug items in their formularies.1 In addition, drug splitting may achieve dose flexibility, particularly for patients requiring frequent dosing adjustment.8 Furthermore, some dosages may not be commercially available, especially those for off-label drug use. In these cases, splitting drugs may be essential.9 10 11 Nevertheless, it can also create other clinical issues including medication non-compliance, difficulties experienced by patients in handling unscored pills, drugs that crumble after splitting, and inappropriate drug splitting of extended release formulations, which may lead to treatment failure or toxicity.12 A published study reported that most hypertensive patients preferred not to split pills and that over 70% of patients were willing to pay more for medications with dosages that they did not need to split.13 Limited published studies have addressed this drug-related problem. In this study, we aimed to identify the effects of pill splitting on drug physiochemical properties and clinical outcomes among elderly cardiac patients.

A parallel design was adopted in this study. Patients were recruited from the Cardiac or Hypertension clinics of the Prince of Wales Hospital, Hong Kong. After medical records review, it was found that lisinopril, amlodipine, simvastatin, metformin, and perindopril were among the most commonly prescribed medications that required splitting in the two clinics. Therefore, patients who needed to split their pills when taking lisinopril, amlodipine, simvastatin, metformin, or perindopril were recruited. Patients were randomised into either group A (pill splitting with self-technique) or group B (pill splitting with instructions and training) after their first clinic visit. All patients were asked to sign an informed consent form before enrolment. Group A patients were asked to split drugs using their own technique and continue until their next clinic visit. Group B patients were given proper instruction by pharmacists or pharmacy students on using pill cutters at their first visit and were asked to cut their pills accordingly until their next clinic visit. Patients watched a 2-minute video that explained the reasons for using pill cutters and described the proper way to open the pill cutter, position the drug in the pill cutter, clean the pill cutter, and store the split pills. Subsequently, the pharmacist answered patients’ enquiries regarding the video or other questions related to pill splitting. The current study did not change any drug or dosage of the patient’s existing treatment regimens. Follow-up clinic visits were scheduled with mean duration between first and follow-up clinic visits of 23.1±7.3 weeks.

Chinese patients aged ≥65 years, both male and female, and currently prescribed one or more of metformin, lisinopril, perindopril, amlodipine, or simvastatin (which require splitting) were included in the current study. Patients with dementia or severe physical limitations such as hemiplegia, blindness, or upper limb contractures were excluded from the study.

In our pilot study, we found that the change in drug assays of metformin, atenolol, and amlodipine varied from 52.7% to 147.2% after splitting.14 In our previously published study, systolic blood pressure decreased significantly (from 152.38±18.80 mm Hg to 147.04±20.72 mm Hg, P=0.021) after pharmacist intervention.15 The sample size for the primary outcome was calculated based on a population standard deviation of 0.75, and that for the secondary outcomes was based on a population standard deviation of 0.85. To achieve a 5% significance level and 80% power, 30 and 45 patients in each group would be needed for the primary and secondary outcomes, respectively. We expected a 10% dropout rate, and therefore, at least 80 patients were recruited for each group. There were 193 total participants in this study.

The participants were randomised into group A or B using a computerised dynamic allocation programme and stratification according to types of medications taken, sex, age, and visit dates to ensure balanced patient allocation. All operations were performed by the same pharmacist who conducted the survey.

The primary outcome was the change of drug content before and after the pill splitting training. At baseline, patients in groups A and B were asked to split three tablets of the drugs that they were currently taking using their usual technique. At follow-up visit, group A patients were asked to split three tablets using their own technique, and group B patients were asked to split three tablets using a pill cutter. Two halved tablets were randomly selected for analysis each time. The halved tablets were weighed, and standard drug assays were performed. The drug content of metformin was assessed by ultraviolet-visible spectrophotometry; that of amlodipine, simvastatin, and perindopril was assessed by ultra-performance liquid chromatography; and that of lisinopril was assessed by high-performance liquid chromatography.

The secondary outcomes were the changes in clinical outcomes between before and after the pill splitting training, including the change in blood pressure measurements, haemoglobin A1c, and cholesterol levels, the changes in patients’ attitudes towards and acceptance of pill splitting, and the changes in patients’ knowledge about pill splitting. Haemoglobin A1c and lipid levels were usually collected in hospital 1 week before patients’ clinic visit. Upon initiating their clinic visits, patients had their blood pressures measured in the hospital’s nurse station before they met their physicians. Blood pressure, haemoglobin A1c, and cholesterol levels were collected at baseline and at follow-up visit, and the patients’ knowledge about and attitudes towards pill splitting were assessed by questionnaires.

Paired-samples t tests were used for intra-group comparisons, and independent-samples t tests were used for inter-group comparisons of mean tablet weight between before and after pill splitting training. Paired-samples t tests were also used to assess the changes in clinical outcomes. McNemar’s test was used for intra-group comparisons, and Fisher’s exact test (two-sided) was used for inter-group comparisons of content uniformity, change in patients’ acceptance towards pill splitting, and change in patients’ knowledge about pill splitting. A P value of <0.05 was considered statistically significant. All analyses were performed using the SPSS statistical programme (Windows version 25.0; IBM Corp, Armonk [NY], United States).

A total of 193 eligible patients were enrolled on or before 17 January 2019, and they had follow-up visits on or before 30 April 2019. The patients were randomised into group A (n=106) and group B (n=87). A total of 101 patients participated, of whom 47 from group A and 54 from group B returned for follow-up visit. Among them, 46 patients from group A and 47 patients from group B provided samples for assay. The primary outcome analysis was conducted on those patients, and the secondary outcomes analysis was conducted on the 101 patients who returned for follow-up visit. The patients’ demographic data are shown in Table 1.

The primary outcome was the change of drug content between before and after the pill splitting training. Patients were asked to split three tablets during each visit. Two halved tablets were randomly selected as samples. The samples were weighed, and assays were performed. The mean weight of the halved tablets at baseline and at follow-up visit is documented in Table 2. Table 3 shows the percentage of halved tablets that were within the assay specifications at baseline and at follow-up visit. The percentage of samples with both halved tablets within range was compared between groups A and B. In group A, the percentage in range increased from 39.13% to 47.82% (P=0.523), and the corresponding increase for group B was from 48.94% to 51.06% (P=1.000). The difference in drug assay results between groups A and B at baseline (P=0.406) and at follow-up visit (P=0.837) also did not reach statistical significance.

The correlation between pill cutting training and clinical outcomes is summarised in Table 4. The mean triglyceride in group B decreased significantly from 1.62±1.05 to 1.36±0.80 mmol/L (P=0.049), whereas the mean heart rate increased significantly from 73.97±11.01 to 77.92±12.72 bpm (P=0.026). In group B, there was also improvement in the mean diastolic blood pressure (from 73.40±14.39 to 73.05±9.33 mm Hg), high-density lipoprotein (from 1.40±0.39 to 1.46±0.44 mmol/L), low-density lipoprotein (from 1.87±0.88 to 1.85±0.73 mmol/L), and total cholesterol (from 3.98±0.93 to 3.91±0.85 mmol/L), but those differences did not reach statistical significance. In the overall cohort, improvements were seen in diastolic blood pressure (from 74.21±12.47 to 74.01±9.98 mm Hg), high-density lipoprotein (from 1.42±0.37 to 1.43±0.40 mmol/L), total cholesterol (from 3.90±0.97 to 3.88±0.96 mmol/L), and triglyceride (from 1.46±0.91 to 1.31±0.72 mmol/L), but the changes did not reach statistical significance.

In total, 57.43% of patients split their pills with their bare hands, followed by pill cutters (24.75%), knives (13.86%), and scissors (10.89%). The major reasons for not using pill cutters included: (1) the current method could split pills evenly (68.18%), (2) using pill cutters was time consuming (34.09%), and (3) the pills could not be split evenly by pill cutters (15.91%). The major reasons for using pill cutters included: (1) pills could be cut evenly (80.95%) and (2) the patient was able to exert force more easily (33.33%). In total, 29.70% and 24.75% of patients found pill splitting troublesome at baseline and at follow-up visit, respectively (the difference was not significant, P=0.063). The three major problems encountered by patients while splitting pills were (1) difficulty splitting the pills evenly (17.00%), (2) the pills easily fragmented (10.00%), and (3) difficulty seeing the pills clearly, as they were too small (9.00%). Overall, 61.00% of the patients claimed that they had no difficulties. Nevertheless, 98.21% preferred to take tablets with exact dosages so that no splitting would be required. Patients’ responses to other questions are listed in Table 5.

Table 6 shows that a significantly higher portion of patients in group B had a correct understanding of the following three questions after training: ‘Using pill cutters allows pills to be divided into more accurate doses’ (from 7.41% to 31.48%; P=0.002); ‘The pills should be put into the triangular tip of the pill cutter’ (from 9.26% to 31.48%; P=0.008); and ‘Pill cutters should be stored in a cool and dry place, away from sun or moisture’ (from 9.26% to 35.19%; P=0.003). In contrast, patients in group A did not show a statistically significant improvement in their understanding of any question. During the interview and evaluation of patients’ knowledge about pill splitting at baseline and at follow-up visit, we did not detect any patients with major physical or cognitive abnormalities.

Tablet splitting is a common practice in in-patient and out-patient settings,16 and it may be desirable in terms of dose adjustment, cost saving, and ease of swallowing.3 11 12 17 18 19 20 Nevertheless, it has been reported that splitting pills may cause drug instability, loss of drug due to powdering, uneven dosage, and reduced drug strength.21 22 It is generally understood that using tablet splitting devices can provide a more consistent dose.10 21 Previous studies have identified some characteristics that might affect the quality of halved tablets. Coated, unscored, and small tablets were found to be more difficult to cut.23 Individual pill cutting skill was another crucial factor that determined tablets’ uniformity.23 In the current study, only 24.75% of patients split pills using pill cutters, and only 14.43% of patients had received pill splitting training. Therefore, it is likely that the drug content in the halved tablets did not reach assay standards.

Previous studies mainly focused on the weight deviations among halved tablets, not on drug content.21 22 One study showed that more than one-third of sampled half-tablets did not meet the United States Pharmacopeia specifications.24 The measured drug content variations among half-tablets were: warfarin sodium (90.01%-109.40%), simvastatin (95.21%-111.35%), metoprolol succinate (82.77%-115.92%), metoprolol tartrate (94.83%-112.37%), citalopram (96.50-111.93%), and lisinopril (81.15%-125.72%). In another study, five of eight drugs failed to meet European Pharmacopoeia recommendations for tablet weight deviation after splitting, with 25% of samples deviating by >15% and 10% of samples deviating by >25%.23 The study drugs used were phenobarbitone (maximum deviation: 80.45%), digoxin (maximum deviation: 56.69%), chloroquine (maximum deviation: 48.97%), atenolol (maximum deviation: 45.37%), and doxycycline (maximum deviation: 43.97%). In the present study, both halves of the tablet were within the assay standard at baseline for 39.13% and 48.94% of the patients in groups A and B, respectively. After training, this percentage increased to 47.82% and 51.06%, respectively, but the improvement was not significant, and the percentage of tablets in range was still relatively low. The results corroborated those of previous studies.

Few studies have examined the effect of patient education on the drug content of split pills.25 26 In the current study, we found no significant improvement in content uniformity after pill splitting training. This may be because our patients were elderly patients who may not have been able to perform the task well after a single training session. Content uniformity after pill splitting may be improved if pills are split by pharmacists or qualified staff. A study of paediatric pharmacists suggested that tablets >8 mm could be split once to achieve an approximate half dose for paediatric use.27 Another study found a significant difference in splitting accuracy between nurses and laypersons.23 Nevertheless, only 39.29% of that study’s patients were eager to partake of pill splitting service, and only 18.18% were willing to pay extra money for it. Therefore, pill cutting service may not be practical without a financial incentive.

Triglyceride levels decreased significantly and heart rate increased significantly in group B patients after the intervention. Nevertheless, we did not evaluate the patients’ diet consumption or exercise levels, which may impact their triglyceride levels. No significant change in clinical outcomes was observed in other groups or other parameters. Because the studied drugs were lisinopril, perindopril, simvastatin, and amlodipine, which are not narrow-therapeutic-index drugs, these results were predictable and coincide with other studies that concluded that drugs with long half-life and wide therapeutic index are less likely to be affected.20 28 In view of the high variability of blood pressure measurements in the clinic, all patients were originally instructed to conduct daily blood pressure measurements at home using a portable blood pressure monitor. However, many patients did not measure their blood pressure daily or did not keep a proper self-record, so the clinical outcomes relied on the readings at clinic visits, which may not be consistent with their usual readings. In addition, management of chronic diseases like hypertension, diabetes mellitus, and dyslipidaemia could be influenced by multiple factors, and 3 months was a relatively short period for observation. The effect of drug content deviation after splitting on clinical outcomes may be more obvious in antibiotics or drugs with narrow therapeutic index (eg, digoxin).23 29 30

In the current study, we focused on the effect of pill splitting on drug content. Nevertheless, pill splitting may have other effects on drugs. The pill may carry a bitter taste, as the coating is broken, and the active ingredients may be more susceptible to moisture after exposure.31 Over 70% of patients prepared a sufficient quantity of pills for more than 1 day each time. In total, 36.63% of patients cut for 2 days to 1 week, 26.73% cut for 1 week to 1 month, and 6.93% cut for more than 1 month each time. Exposing the cut pills for too long may increase the risk of crushing or cracking.19 In total, 83.93% of patients found pill splitting training helpful, and the intervention produced significant improvement in patients’ knowledge about pill splitting. This study has identified the major difficulties encountered by patients and the reasons behind their choices. Those problems should be addressed in future patient education. More than half of patients split pills with their bare hands, and the majority of patients who did not use pill cutters thought their own methods could divide pills evenly and that the use of pill cutters was time consuming. The major obstacles patients faced were the difficulties in splitting pills evenly and that the pills fragmented easily. Overall, 98.21% of patients preferred to take tablets with the exact dosage instead of splitting pills. Previous studies also found that dispensing the exact dosage would be more favourable.23 32 Nevertheless, if pill splitting is unavoidable, pharmacists should encourage patients to split coated, unscored, or irregularly shaped tablets with pill cutters to reduce crushing or fragmenting. Pharmacists should also educate patients about the appropriate way to use and clean pill cutters and remind patients to seek doctors’ or pharmacists’ advice before cutting any pills.21 23 33

This project has several limitations. First, the participants’ dropout rate was high, which might result in attrition bias. Compared with group A, a higher proportion of group B patients returned for follow-up visits. The statistically significant improvement in clinical outcomes among group B patients might be caused by their higher awareness about their own health instead of the effectiveness of the pill splitting method. There were limited human resources to make phone calls to patients between the baseline and face-to-face follow-up visits, which could have served as a reminder for patients to attend follow-up visits and perform home monitoring of their blood pressure and their pill splitting methods.

Second, dietary consumption and exercise levels were not evaluated, even though they may affect the clinical outcomes. Third, participants’ education level, household income, and major caregivers were not collected at baseline. Only approximately 65% of participants who attended follow-up visits provided such information. These confounding factors might affect patients’ ability to understand and memorise the steps of using pill cutters, thus affecting the content uniformity of their split pills. The effects of patients’ characteristics on their knowledge and pill splitting skills were not assessed in the current study.

This study revealed that content uniformity can hardly be achieved after pill splitting by patients. No significant difference in clinical outcomes was observed after pill splitting training. It is preferable for pills with doses that do not require splitting to be provided, considering the assay results and patients’ preference. Currently, there is inadequate patient education about pill splitting. Pharmacists should educate patients to use pill cutters properly if splitting is inevitable.

Concept or design: VWY Lee, FYH Fong, BPY Yan.
Acquisition of data: VWY Lee, FYH Fong, BPY Yan.
Analysis or interpretation of data: JTS Li.
Drafting of the manuscript: JTS Li.
Critical revision of the manuscript for important intellectual content: VWY Lee.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

As an editor of the journal, BPY Yan was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

We thank the technicians at the School of Pharmacy, The Chinese University of Hong Kong for carrying out the drug physiochemical tests and the staff at Prince of Wales Hospital for arranging the logistics for patient counselling.

This study was supported by the Health and Medical Research Fund, Food and Health Bureau, Hong Kong SAR Government (#14152111). The funder had no role in study design, data collection/analysis/interpretation, or manuscript preparation.

Ethical approval was obtained from The Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Clinical trial registration no.: CREC Ref No. 2017.014). Patient consent was obtained upon enrolment. The trial protocol can be obtained as requested.

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