Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care
Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care by A Selak and colleagues (BMJ 2014;348:g3318).
Why do the study?
The past few decades have witnessed a shift in the global health burden from infectious diseases to non-communicable diseases. Ischaemic heart disease is now the primary cause of disability adjusted life years, with high blood pressure a leading risk factor. Recognising the threat posed by non-communicable diseases, the World Health Assembly in 2012 adopted a target of a 25% relative reduction in mortality from non-communicable diseases by 2025. The World Heart Federation has set a target to provide at least 50% of eligible people at risk of cardiovascular disease with necessary drug treatment to prevent heart attack and stroke.
The rise in cardiovascular disease has been paralleled by increased life expectancy globally, with more people requiring multiple drugs for multiple conditions as they get older. International guidelines recommend antiplatelet treatment, statins, and one or more blood pressure lowering drugs in patients with established cardiovascular disease. However, treatment coverage globally remains poor. Poor adherence to medication may be due to many reasons, including the complexity of a regimen, socioeconomic considerations, poor patient-provider interaction, lack of access, or patient related factors such as physical or cognitive impairment.
Fixed dose combination drugs, or polypills, which combine multiple drugs in a single tablet, offer the promise of improving adherence by simplifying the treatment regimen. The IMPACT (Improving Adherence using Combination Therapy) Trial was conducted to find out whether fixed dose combination drugs improve adherence and control of risk factors in primary care settings in New Zealand and to assess satisfaction of patients and providers with this regimen.
What did the authors do?
The authors conducted an open label, randomised controlled trial to assess the effectiveness of fixed dose combination treatment (a polypill) in practice. A randomised controlled trial provides the experimental setting to establish causality between a treatment and the outcome. Participants are randomly allocated to receive the intervention so that any factors that may potentially affect the outcome are equally distributed between the control and intervention arms of the trial. In an open label design, both participants and researchers are aware of the treatment assigned. In this trial, participants in the intervention arm received one pill comprising four drugs, and participants in the control arm received multiple pills. As one objective of the study was to assess preference for a one pill regimen over multiple pills it was impossible for participants to be blinded to treatment group.
The study recruited 513 adults with established cardiovascular disease or at high risk of disease from 91 general practices in two regions of New Zealand. Five year risk was calculated in accordance with New Zealand guidelines by using the Framingham equation for cardiovascular disease. After they had given written informed consent, participants were randomly allocated to receive fixed dose combination treatment (n=256) or usual care (n=257) by using a centralised randomisation service. Both the intervention and control groups began at a similar baseline. This indicates that the randomisation process ensured that any variables that could affect the outcome (age, risk factors, etc) were comparable between the two groups. Figure 1 1 shows the flow of participants through the trial. The diagram is a part of the CONSORT statement—a checklist of items that must be reported in papers describing randomised controlled trials. Standard reporting guidelines for different study designs can be found on the website of the EQUATOR network, which aims to improve the transparency and accuracy of reporting health research.
Participants were managed by their general practitioners, who were encouraged to follow established New Zealand cardiovascular disease management guidelines, irrespective of treatment allocation. In the intervention arm, general practitioners had the choice of two fixed dose combinations. Both combinations contained aspirin 75 mg, simvastatin 40 mg, and lisinopril 10 mg, with atenolol 50 mg in one combination and hydrochlorothiazide 12.5 mg in the other.
The primary outcomes measured were patients’ self reported adherence to treatment at 12 months, and change in blood pressure and low density lipoprotein cholesterol from baseline. Secondary outcome measures included barriers to adherence, reasons for stopping fixed dose combination treatment, serious adverse events, cardiovascular events, and quality of life (EuroQol EQ-5D).
In addition, researchers correlated data from drug dispensing logs with participants’ self reported adherence. General practitioners were invited to complete a post-trial survey on the acceptability of the fixed dose combination treatment. Participants were asked to rate ease of taking the prescribed treatment on a five-point Likert scale (from “very easy” to “very difficult”).
The authors used an intention to treat analysis, which helps maintain the advantages of random allocation because participants are analysed within the allocated group even if they have withdrawn or failed to comply with the intended intervention.
What did they find?
The authors found a 75% increase in self reported adherence to fixed dose combination treatment at 12 months compared with those on usual treatment (81% v 46%, relative risk 1.75, 95% confidence interval 1.52 to 2.03, P<0.001). Fixed dose combination treatment did not, however, reduce blood pressure or low density lipoprotein cholesterol beyond usual care at 12 months. The number of serious adverse events was similar in both treatment groups. National drug dispensing data showed close concordance with the self reported adherence outcome.
More than one third of participants taking a fixed dose combination discontinued their treatment before the end of the trial. The most common reasons for discontinuation were decision by the medical practitioner or a possible side effect. Overall, 89% (227/256) of general practitioners in the fixed dose combination group rated it as satisfactory or very satisfactory for starting treatment (206/227, 91%), blood pressure control (180/220, 82%), cholesterol control (170/218, 78%), tolerability (181/223, 81%), and prescribing according to local guidelines (185/219, 84%). Improved treatment adherence was stated as the most important advantage of fixed dose combination treatment, whereas lack of flexibility in modulating the treatment regimen emerged as the main disadvantage. At 12 months, most participants reported that they found taking their prescribed drugs very easy or easy (224/246, 91% fixed dose combination v 212/246, 86% usual care, P=0.09).
What are the strengths and limitations of this study?
The biggest strength of the study was that it was conducted in primary care, where multimorbidity is commonly managed. Participants were recruited by their general practitioners, who maintained responsibility for their care throughout the trial. They were required to purchase the prescribed pills from local pharmacists using standard copayments. Findings from clinical research carried out in controlled experimental settings often have limited applicability to actual practice. This study presents a realistic picture of the feasibility of a polypill strategy in the management of cardiovascular disease risk. Most participants stayed in the trial to its completion, with minimal loss to follow-up, and primary outcome data are available for 95-97% of participants. This makes the findings more robust.
A limitation is that the study examined the effect of fixed dose combination drugs on control of risk factors and not clinical outcomes, such as cardiovascular events or mortality. The open label design, although unavoidable, may influence reporting of adherence, ease of use, and adverse events. Self reported adherence is a subjective measure. It may not accurately reflect compliance compared with monitoring prescriptions purchased by patients or maintaining a record of pills taken. The findings may also be more immediately relevant to primary care settings in New Zealand. Local prescribing practices and organisation of health services need to be considered in applying this strategy to other healthcare settings. Also, treatment rates of participants of the trial were much higher than the national average (82% (191/233) of participants with established cardiovascular disease were taking an antiplatelet, statin, and at least one blood pressure lowering drug, compared with 59% nationally). This limits understanding of the effectiveness of the polypill strategy to improve adherence among those most in need and currently taking few or no preventive drugs.
What does the study mean?
The study provides evidence of effectiveness of a fixed dose combination strategy in improving multidrug treatment adherence in patients at cardiovascular risk. High levels of acceptability were reported among patients and providers for the regimen. Fixed dose combination pills could help increase coverage of preventive treatment for cardiovascular disease. Further research must seek to understand barriers to compliance among populations not taking treatment and reasons for discontinuation, so that appropriate interventions at the individual, population, and health system levels can be developed.Anita Jain, India editor, The BMJ
Correspondence to: firstname.lastname@example.org
Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned; not externally peer reviewed.
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Cite this as: Student BMJ 2014;22:g4217