Fixed dose combinations of cardiovascular drugs

Drug treatment for cardiovascular disease remains inadequate globally,1 and many adults with cardiovascular disease or a high risk of cardiovascular disease receive no drug treatment. In response, the World Health Organization and its member states have agreed on a target to treat 50% of eligible adults with a multidrug regimen by 2025 as part of its wider “25×25” goal: to reduce the burden of premature, non-communicable, chronic diseases by 25% by 2025.2

Fixed dose combinations, or polypills, combine multiple drugs into one tablet and often include an antiplatelet agent, a lipid lowering drug, and at least one blood pressure lowering drug. Fixed dose combinations improve adherence to treatment for people with hypertension and HIV by approximately 25%.3 They are also an attractive drug delivery mechanism for adults with cardiovascular disease, not just to achieve the 50% drug treatment and premature mortality targets of the 25×25 goal but more specifically to reduce the global burden of cardiovascular disease.

In a linked paper, Selak and colleagues (doi:10.1136/bmj.g3318) sought to evaluate the effect of two fixed dose combination treatments on self reported adherence, blood pressure, and lipid levels in primary care patients from New Zealand with cardiovascular disease or a high risk of cardiovascular disease.4 The IMPACT (IMProving Adherence using Combination Therapy) trial builds on the 2012 UMPIRE5 and 2014 Kanyini-GAP trials,6 which evaluated the same fixed dose combination preparations using similar protocols in European and Indian secondary care settings and in Australian general practices, respectively, as part of the Single Pill to Avert Cardiovascular Events (SPACE) collaboration.7

The IMPACT investigators found a 75% increase in self reported adherence at 12 months (81% v 46%; relative risk 1.75, 95% confidence interval 1.52 to 2.03) among participants randomized to receive a fixed dose combination treatment, compared with controls receiving usual care. The SPACE collaboration defines adherence as taking an antiplatelet, a lipid lowering drug, and at least two blood pressure lowering drugs. As expected, the beneficial effect of fixed dose combination treatments on adherence was attenuated when the investigators restricted their definition to an antiplatelet, a lipid lowering drug, and at least one blood pressure lowering drug (88% v 73%; 1.20, 1.10 to 1.31), which is a similar effect size to that reported by previous trials of fixed dose combinations in other disease states. Treatment with a fixed dose combination did not help reduce blood pressure or lipid levels at 12 months beyond usual care, and the number of serious adverse events did not differ between the groups. Treatment rates were higher than national estimates among participants in both groups, and drug changes were made solely at the discretion of the treating doctor.

The IMPACT trial, like all previous trials on fixed dose combinations, was not designed to evaluate the effects of fixed dose combination treatments on clinical outcomes, such as cardiovascular events or all cause death.8 Skeptics may ask what the new trial adds to previous work from this collaboration and others. From my perspective, there are three important innovations. Firstly, participants in both trial arms had to make out of pocket payments at local pharmacies for their treatment to control any potential biases associated with payment for or access to treatment. Secondly, the authors used administrative data from these pharmacies to validate participants’ self reported adherence. Finally, the IMPACT trial recruited a high proportion (50%) of indigenous Māori participants, which enhanced external validity.

Despite the initial enthusiasm and evidence of effectiveness, fixed dose combination treatments will not be a panacea. More than one third of participants taking a fixed dose combination in IMPACT discontinued their treatment before the end of the trial. “Medical practitioner decision” was the most commonly cited reason, highlighting the importance in gaining support from clinicians in the deployment of fixed dose combination treatment. Fixed dose combinations seem to encourage drug initiation more than maintenance, as evidenced by the similar, gradual decline in adherence over the study period in both intervention and control groups, after the initial increase in the intervention group. Finally, more than 1 of every 3 participants experienced a serious adverse event during the study period, including many non-vascular events, which highlights the importance of comorbidities associated with cardiovascular disease. Clinicians, researchers, and policy makers must continue to emphasize concomitant interventions at the population level that help maintain cardiovascular health throughout the life course.

As with developers of hypertension guidelines before them,9 writers of secondary prevention guidelines now have evidence to encourage fixed dose combination as a strategy to improve adherence to a multidrug treatment regimen, particularly for those who have difficulty managing multiple individual drugs. Fixed dose combinations, both current and future preparations, are another set of tools to help doctors and their patients reduce the burden of cardiovascular disease. They are not a complete replacement for current regimens.

Future studies will need to explore how best to use fixed dose combinations, including how to identify adults who are struggling to manage multidrug regimens, the triggers that might prompt a switch to fixed dose combinations, and how to engage patients fully in these treatment decisions.

Fixed dose combinations of cardiovascular drugs seem to be one of the most, if not the most, feasible options to improve adherence to treatment on the scale required to achieve WHO’s 50% treatment goal. Now approved in 14 countries with differential pricing strategy based on national income, fixed dose combination treatment looks poised for sustained growth and diversification after more than a decade of anticipation. How much future complexity in fixed dose combination treatment helps or harms remains to be seen. The IMPACT investigators, like trialists before them, should be congratulated for their research to help tackle the difficult challenge of improving adherence to important cardiovascular treatments.