9.3.1. Evidence to recommendations
The GDG considered that review of prescribed medicines is most commonly undertaken in clinical settings as part of management of patients and their medical problems. In this setting it is seen as integral to continuing care and not separate from it. The GDG considered that all levels of medicine review as described in ‘Room for Review’ take place in this setting and have a role. Revisiting a decision to prescribe medicines and exploring patients medicine-taking behaviour was considered by the GDG to be part of the dynamic process that long-term medicine prescribing required.
The research evidence primarily addresses medicine reviews that take place separate from the delivery of clinical care, often by practitioners who do not have access to clinical history and notes. These have been a recent development and have primarily involved pharmacists. Most of the evidence on reviews by pharmacists comes from studies that targeted older adults on multiple medicines. Many studies include quite complex pharmaceutical care programmes where the interventions consists of a number of components including education and follow-up which the GDG considered more intensive than is currently provided in any type of medicine review provided in the UK.
Medicine review can have benefits for the patient but evidence was conflicting whether this led to improvements in adherence to prescribed medicine.
The GDG were particularly concerned that reviews of medicine carried out remote from the clinical settings needed to feed back to clinicians who were involved in prescribing and other aspects of care. Increasing the number of medicine reviews and the personnel involved in carrying them out might not be effective if communication and follow up is not achieved.
The GDG were clear that the lack of research on reviews conducted as part of clinical care should not indicate that these were not of value. Review of medicines will continue to be part of delivery of health care. As responses to medicine can change over time, both in terms of patient behaviour (adherence) and clinical outcomes, a process of medicine review is likely to be necessary and be part of on-going processes of decision-making and medicine-taking. An informal review of medicine should continue as part of good clinical practice but it is not possible to recommend precise timings for formal medicine reviews outside the clinical setting.
9.3.2. Methods of the evidence review
The titles and abstracts of studies retrieved by an electronic search for medicine review were scanned for relevance to the question of whether medicine review increases adherence to medicines. Any potentially relevant publications were obtained in full text. These were then reviewed to identify the most appropriate evidence to help answer the question and to ensure that the recommendations are based on the best available evidence. This process required four main tasks: selection of relevant studies; assessment of study quality; synthesis of the results; and grading of the evidence.
This paper includes a narrative summary of the included evidence, following the agreed reviewing protocol:
Types of studies - randomised controlled trials (RCTs) of medicine review interventions to increase adherence.
Types of participants - people prescribed medicine for a medical condition. Medicine review performed by any healthcare professional or trained personnel.
Setting - carried out in the community.
Duration of studies - no time limit specified for this evidence review.
Types of interventions - any medicine review (as implying face to face meeting between the patient and the health care professional doing the review) interventions intended to change adherence to prescribed medicine. The content and delivery of interventions are not standardised in the literature. The term ‘pharmaceutical care programme’ is used and this applies to pharmacist led programmes which assess medicine use, develop an intervention and provide long term follow-up to patients including liaison with the prescriber. Some of these interventions provide intensive support. Some subjective assessment of studies was required as content is often not well defined. Many of studies on interventions to increase adherence used pharmacists to carry out the intervention but we have included here only studies that were carried out in the community and were providing general review rather than disease specific support.
Types of outcome measures - any prescribed medicine adherence outcomes which changed as a result of the medicine review. Outcomes relevant to patient involvement were reported as part of the evidence review.
9.3.3. Evidence review
Of the RCTs found relating to medicine review, many had to be excluded as they did not have adherence outcomes. Instead they focused on hospital readmissions, care home admissions, death and cost-effectiveness. One high quality RCT conducted by Zermansky (2002)258 for HTA could not be included as there were no specific adherence outcomes. Zermansky (2002) studied whether a trained pharmacist could conduct effective clinical medicine reviews of elderly patients who were on repeat prescriptions from their GP. The participants were 65 years or over on repeat medicine, who were not resident in a nursing or residential home and were not terminally ill. The study lasted 12 months and the intervention involved the pharmacist assessing the patient, their illnesses and their medicine regimen and making recommendations. The primary outcome measure was the number of repeat medicine changes per patient, which was 2.2 in the intervention group and 1.9 in the control group (Difference of 0.31, 95% CI 0.06 to 0.57), p=0.02). The secondary outcome was the effect on cost of medicine. There was a rise in repeat medicine items for both groups, but this was statistically significantly less for the intervention group (intervention mean 0.2, s.d=1.55; control mean 0.4, s.d=1.53, difference −0.2, 95% CI, −0.4 to −0.1). The cost saving for the intervention group compared to the control group was £4.75 per 28-day month, a total of £61.75 per patient per year.
A systematic review (Holland 2007) focusing specifically on pharmacist-led medicine review was found. However the primary outcome of interest was reduction of hospital admissions and deaths in older people and adherence was a secondary outcome. The studies included all forms of medicine review for checking and optimising the patients’ medicine regimens apart from those with only knowledge and/or adherence outcomes. They reported that 14 of the trials included adherence, with 7 reporting a statistically significant effect and 7 reporting a statistically non-significant positive effect.
The term ‘pharmaceutical care programme’ is also used in the literature and this generally applies to pharmacist-led programmes which assess medicine use, develop an intervention and provide long term follow up to patients. Although more intensive that any programmes currently delivered in the UK we included these studies as it was important to assess whether such structured and intensive support was either clinically or cost-effective.
Some subjective assessment of the studies was necessary as the content of the reviews and pharmaceutical programmes is not always clearly defined.
9.3.3.1. RCTs conducted in the UK
Sturgess (2003)249 measured a structured pharmaceutical care programme provided to elderly patients by community pharmacists 191 elderly patients with a mean age of 73.1 ± 5.0 for the intervention group and 74.2 ± 6.3 for the control group. This RCT was conducted in Northern Ireland. In the intervention pharmacists assessed patients to identify medicine-related problems. A number of information sources were used by intervention pharmacists during this assessment procedure including: the patient (via informal questioning), the patient’s GP, study questionnaires and computerised medicine records. During the assessment, pharmacists were asked to document any identified medicine-related problems and to form with the patient an intervention and monitoring plan e.g. education, implementation of adherence improving strategies. Pharmacists visited patients at home to assess storage of medicines where problems were identified.
Self-reported compliance: between-group analysis at each assessment point indicated that a statistically significantly higher proportion of intervention patients were compliant with their medicine at 12 (intervention group: 40.4%, control group: 24.4%) and 18 (intervention group: 47.3%, control group: 14.7%) months compared to control patients (p<0.05) (6 months: intervention group: 34.5%, control group: 29.4%). Analysis of change in compliance during the study (change in compliance status compared to that reported at baseline) showed that a statistically significantly higher proportion of intervention patients changed from non-compliant to compliant compared to control patients (intervention 13.4% vs. control 9.1%) and a statistically significantly higher proportion of control patients changed from compliant to non-compliant compared to intervention patients at 18 months (control 36.4% vs. intervention 4.5%).
Lowe (2000)248 determined whether a medicine review and education programme influenced elderly patients’ compliance and knowledge compared to a control group in a RCT. 161 participants, mean age 77.5 (sd=65–96) for the intervention group and 75 (sd=65–88) for the control group, mainly female (67%), living with spouse or relative 55% (intervention group) and 57% (control group) and prescribed an average of 4 medicines (ranging from 1 to 8). The RCT was conducted in a GP practice in Leeds, UK. An investigator visited patients and filled in a structured questionnaire regarding their medicines, which medicine had been used and patients’ understanding and ability to take medicines. The investigator then reported the findings to doctors where there was a need to reduce dosage and discontinue medicine, then liaised with the pharmacist for modifications to medicine containers. At the second visit after a month they delivered 1 months supply of medicine and removed any other prescribed medicines. They discussed the regimen, the purpose of the medicines and the correct way to take them, with the use of a reminder chart if needed. At 3 weeks follow-up participants were given a further months supply and assessed on their knowledge and compliance, by counting the medicines left from the last visit. The mean compliance score was 91.3% for the intervention group (95% CI, 89% to 94%) and 79.5% for the control group (75% to 84%), which was statistically significantly different (p<0.0001).
N.B This study was under 6 month’s duration but the patients were followed up twice at 3 week to monthly intervals and the study was of particular relevance.
Begley (1997)251 assessed the influence of domiciliary pharmacy visits on medicine management in sample of elderly people recently discharged from hospital to their own homes. Patients were aged 75 years or older. The study included one intervention group receiving home visits and counselling, in which structured patient interviews were conducted during the domiciliary visits and consisted of six sections: patient information; medicine knowledge; Patient dexterity; abbreviated mental test; medicine management; and compliance with medicine regimen. Patients were seen during 12 months. There were two control groups: one which was the control and received visits only (called V group), and other which was the control group that received traditional pharmaceutical services with no visits except for the beginning and the end of the study (NV group).
At each visit there were statistically significant differences between the groups in terms of distribution of patients at the various levels of compliance (p<0.001). Compliance was higher at 3 months and 12 months for the intervention group compared to the other control groups (p<0.001), despite the low compliance value for the intervention group at the 12 month visit. Patients in the intervention group who increased their compliance rates between visits also increased their medicine knowledge scores (p<0.005). Mean scores for medicine knowledge did not differ significantly (statistically) between the groups at any of the visits, although the mean score for the intervention group increased significantly (statistically) between the initial and the two weeks visits (p=0.001). There were no changes for patient dexterity scores between groups at any point of the study. Contacts with GP and health workers was lower for the intervention group than for the control (V) in each of the four time periods (p<0.01).
Bernsten (2001)250 conducted a multicentre RCT in seven European countries including the UK that evaluated a pharmaceutical care programme provided to elderly patients (aged 65 or older) taking 4 or more medicines by community pharmacists. A total of 1290 intervention patients and 1164 control patients were recruited. The programme interventions included: 1) educating the patient about their medicine regimen and their condition; 2) implementing compliance-improving interventions such as medicine reminder charts; 3) rationalising and simplifying medicine regimens in collaboration with the patients GP. This was a continuous process throughout the 18 months of the study.
Generally, the programme had some positive effects on humanistic health outcomes such as satisfaction with treatment, and sign and symptom control, and on economic outcomes, but had less impact than anticipated on medicine therapy, medicine knowledge and compliance with medicine. An analysis of changes in compliance during the study indicated that at 18 months a statistically significantly higher proportion of the intervention patients changed from being noncompliant to compliant compared with the control groups (p=0.028). Intervention patients rated the services provided higher that the control at 6 and 18 months (p<0.05). There was a small statistically significant increase in satisfaction in the intervention group over time (baseline vs. 12 months p=0.039).
Nazareth (2001)252 compared patients who had been discharged from hospital with a discharge plan with those who had a standard discharge letter. This RCT included 362 patients from four hospitals in central London. The participants had a mean age was 84 years in both groups (s.d=5.2 and 5.4 respectively), mainly female (62% and 66%), white (97%) with a mean of three chronic medical conditions and prescribed a mean of 6 medicines (s.d=2). The discharge plan included assessing the prescribed medicine, rationalising the medicine and assessing patients’ medicine management, knowledge and support. The participants were then followed up 7 to 14 days later at home by community pharmacists who compared medicine-taking with prescribed medicines and their understanding and adherence to the medicine regimen. They intervened when necessary and provided medicine counselling, disposal of excess medicines and liaison with GPs. There was no statistically significant difference in adherence to medicines for either group at 3 months or at 6 months.
9.3.3.2. RCTs conducted outside the UK
Lipton (1994)253 assessed the impact of clinical pharmacists’ consultations on medicine regimens, compliance, and health service use of 706 geriatric hospitalized patients discharged on 3 or more medicines. The RCT was conducted in the USA. Mean age was 74.6 in the experimental group and 74.4 in the control group. Pharmacists consulted with experimental patients at discharge and 3 months thereafter, and with physicians as needed. Controls received usual care. At 6–8 weeks after enrolment, experimental patients were more knowledgeable about regimens than controls. At 12–14 weeks, they were on fewer medicines and less complex regimens, and had better compliance scores p<0.001). There was no effect on service use or charges, perhaps due to inadequate sample size and lack of targeted medicine group’s analysis.
Hanlon (1996)254 was an RCT which compared the effects on elderly outpatients who had an additional pharmacist intervention with those who received usual care from their physician. Most of the patients were male (98% in the intervention and 100% in the control group), white (79% and 75% respectively), married (65.7% intervention, 85.4% control), with baseline compliance rates of 73% and 74% respectively. The mean age of participants was 70 years old. The RCT was conducted in Durham, North Carolina. Before attending the physician the pharmacist reviewed their medical records and medicine lists to ascertain their current medicine use, medicine-related problems and to evaluate their needs by applying the Medicine Appropriateness Index. Their findings were then reported to the physician. The Pharmacist educated the patient on medicine-related problems and encouraged compliance through strategies such as medicine reminders and written patient materials. They reviewed safe medicine use and the importance of discussing medicines with physicians. There were no statistically significant differences between the groups at the end of the follow-up period with regard to medicine compliance (77.4% of intervention group and 76.1% of control group complied, p=0.88).
Chisholm (2001)210 studied the compliance rates of patients who received a clinical pharmacist intervention in addition to usual care compared to control patients after a renal transplant. The RCT included 24 participants, 75% male with a mean of 49 years (s.d=10 years) and 58.3% Caucasian, 37.5% African-American and 1 Hispanic. The RCT was conducted in Augusta, Georgia, USA. The Pharmacist obtained medicine histories and reviewed medicines monthly. They made recommendations to the nephrologists and counselled the patients on their medicine, including instructing how to use the medicine. Patients were encouraged to call them with any questions. The patients were assessed on their understanding of their medicine and advised on how to enhance compliance.
At 12 months the compliance rate was statistically significant for the intervention group 96.1% (s.d=4.7%) compared to the control group 81.6% (s.d=11.5%), p<0.001. For 6 of the 12 months there were differences in compliance rates (64 to 100% for control group and 89 to 100% for the intervention group) with the intervention group always at a higher rate (p<0.05). The duration that patients complied for also differed with the intervention group remaining 75% compliant each month compared to only 33.3% of the control group (p<0.05).
Taylor (2003)255 conducted an RCT of patients attending a community-based physician and compared those who additionally received a Pharmacist intervention to a control group. The majority of participants were women (63.6% in the intervention group vs 72.2% in the control group, p=0.445), most were white (60.6% vs 61.1%, p=.966) with a mean age of 64.4 and 66.7 years respectively (p=0.467), the majority were married 75.8% vs 72.2 (p=0.935) with 12 years mean education. They were taking on average six medicines each. The RCT was set in medicine clinics in Alabama, USA.
The pharmacists evaluated the patients’ medicine, reviewed medical records and examined medicine history to determine compliance and complications with medicine. Therapeutic recommendations were made to the physicians and the pharmacists made follow-up visits to patients, gave individualised education and were available to answer questions. Patients’ responses to medicines were monitored and their medicine regimens consolidated, dosage frequency was reduced and medicine reminders and techniques for using certain devices were taught.
The number within the intervention group to have compliance scores of 80–100% increased by 15% but there was no change for the control group (time period not stated). By 12 months this difference was not statistically significant, 100% of patients in the intervention group versus 88.9% (s.d=6.3) of the control group had compliance scores of 80–100%, p=0.115). At baseline this was 84.9% (s.d=6.7) and 88.9% respectively (s.d=5.8, p=0.728).
The most frequently sited reasons for not complying with medicine were forgetting to take the medicines (n=10), having too many to take (n=9), finding it hard to read or understand the directions (n=4) and too much trouble to take (n=4).
Grymonpre (2001)256 compared the impact on geriatric patients who received pharmaceutical care compared to those patients who did not in a RCT. Most of the patients were female (75% intervention vs 83% control, p=0.254), aged 77 (s.d=8.0 to 9.0), Caucasian (100%) and lived alone 61% vs 77% respectively, p=0.018. The RCT was conducted in a community-based health clinic in Manitoba, Winnipeg, Canada. Volunteers and staff were trained to conduct a comprehensive medicine review which was utilised by the pharmacist to identify and document potential and actual medicine-related issues and to address these with the patient and they physician. Their use of prescribed and non-prescribed medicines, social medicines, home remedies, regimen, adherence and communication with GPs, problems or side effects with medicines were all assessed. The recommendations were given in a letter to physicians and the patients were followed up by the pharmacist when required to monitor therapeutic endpoints and sort out any problems that had arisen.
The mean number of mediations adhered to at follow-up was 87 ± 46 for the intervention and 85 ± 41 for the control group, p=0.895, showing no statistically significant difference in adherence.
Sookaneknun (2004)257 compared hypertensive patients assigned to a pharmacist-involved group with those who had no pharmacist involvement, with the objective of stabilising blood pressure. The participants of the RCT included 235 patients, mean age 63 years old and mainly female (64% in intervention and 71% in control group). The RCT was conducted in Thailand. The intervention group’s blood pressure was measured every month by the pharmacist and they assessed the patients understanding of medicines, adherence and reviewed adverse effects from the medicines. Medicine counselling was given and medicine-related problems were identified, resolved and prevented. The recommendations for change of medicine regimen were given to the physicians. The adherence at pre-test was not statistically significantly different but at post-test the treatment group had statistically significantly increased adherence compared to the control group, Pre-test adherence of 80% or more was found in 51% of the treatment group and 56% of the control group. At post-test this had increased to 63% for the treatment group and had remained constant (55%) for the control group (p=0.014).
Quality of studies
The quality of many of the RCTs was low. This was mainly due to the possibility of bias occurring within the methodology.
