• hypertension

In 2011, the United Nations General Assembly adopted the Political Declaration on Noncommunicable Diseases (NCDs) to acknowledge the threat of the rising non-communicable disease epidemic occurring globally, but predominantly impacting low-income and middle-income countries (LMICs). In response, WHO developed a global monitoring framework to track progress in the prevention and control of major non-communicable diseases—cardiovascular disease, cancer, chronic lung diseases and diabetes—and their key risk factors.1 Part of that framework included nine voluntary goals aiming to achieve a 25% reduction in premature mortality from NCDs by 2025. Three of these goals are relevant to discussions about the use of fixed-dose combination (FDC) medication—25% reduction in raised blood pressure, 50% coverage of drug therapy and counselling, and 80% coverage of essential NCD medications and technology.

Currently, despite the availability of a plethora of cheap, effective drugs (including blood pressure–lowering medications, cholesterol-lowering medications and antiplatelet drugs), the majority of people globally at highest risk are not receiving recommended therapy for the prevention of heart attacks and strokes.2 In patients with hypertension, the single leading cause of mortality globally and biggest risk factor for cardiovascular disease generally, only about a third of those with documented hypertension are receiving treatment with only approximately one-half of those treated in high-income countries and about one-quarter in LMICs achieving blood pressure control.3 If WHO goals are to be achieved, clearly novel strategies and a different approach are required.

In this context, there is potential for FDC therapy (single medications that contain a combination of two or more active ingredients), implemented as part of a broader health systems approach, to help achieve these goals, particularly in cardiovascular disease.

The rationale for using FDCs is well established in communicable diseases such as malaria, tuberculosis and HIV/AIDS where reduction in pill burden, simplification of medication regime and standardisation of dosing have significantly contributed to treatment coverage and control rates. Additionally, the potential health system benefits of streamlined supply chain and logistics, and lower production, storage and dispensing costs address additional barriers. In the area of cardiovascular disease, use of combination therapy in the management of hypertension is broadly accepted with the majority of patients requiring multiple drugs to reach their blood pressure targets. This is reflected in the widespread availability of combination blood pressure–lowering therapy in high-income markets. ‘Polypills’, FDCs including blood pressure–lowering medications, cholesterol lowering medications ± an antiplatelet agent, are also increasingly available; however, uptake is still limited and concerns remain over their implementation into clinical practice.4

Availability of FDCs (both blood pressure–lowering drugs alone or as polypills) in LMIC in the public sector is very limited as no combinations are yet included in WHO’s essential medicines list. Although this guidance is not so relevant to high-income countries with alternate processes for deciding on drug availability, the Essential Medicines List is followed closely by LMIC, who may see WHO endorsement as a prerequisite for consideration of a new concept such as provision of NCD treatment via FDCs. In 2017, WHO, in response to three sequential applications for polypills to be included on the essential medicines list (along with a separate request for a blood pressure–lowering combination), included a note in the 20th Essential Medicines List that ‘Fixed-dose combinations for non-communicable diseases may have advantages over the single medicines given concomitantly, including increased adherence and reduced pill burden. The potential value of fixed-dose combinations of currently listed essential medicines, with regulatory approval and demonstrated bioavailability for the management of chronic non-communicable diseases, is recognised’.

Guidelines such as the 2017 American Heart Association Hypertension guidelines5 as well as the 2013 European Society of Hypertension clinical guidelines6 already endorse the use of FDCs in hypertension to improve adherence, with initiation of treatment with multiple drugs recommended in patients with blood pressure >20/10 mm Hg above their target. The soon-to-be-released 2018 European Society of Hypertension guidelines have also been announced to be broadening their recommendations to acknowledge that combination therapy is now recognised as the most effective initial treatment strategy in most patients, with no specific threshold for initiation of combination therapy. For polypills, however, the 2016 European Guidelines on cardiovascular disease prevention in clinical practice cautiously advised that sufficient evidence was not available to define where they fit into a global strategy for cardiovascular disease prevention.7

The evidence is therefore accumulating and being recognised in multiple areas that FDCs for non-communicable disease management have great potential to improve control of cardiovascular disease risk factors. However, implementation and scale-up of FDCs for cardiovascular disease also requires further evaluation and should be implemented as part of a broader strategy to ensure appropriate and safe integration into established health systems with appropriate evaluation of challenges and advantages compared with established workflows. Part of this process includes investigation and documentation of potential safety issues generated by introducing new concepts into established treatment paradigms. Such research is best done by analysing usage and outcomes within the context of routine clinical practice rather than in clinical trials. Clinical trials are necessary for establishing efficacy and safety profiles of combination drugs but not as useful for safety profiles of routine usage within a complex health system outside the bounds of a highly structured clinical trial. Increased availability of large electronic administrative datasets from routine clinical practice is facilitating such analyses.

Moriarty and colleagues8 have used one such dataset to investigate risks of medication errors with use of combination blood pressure–lowering therapy. Usage of combination therapy, often with associated usage of brand names which mask drug components, has the potential to increase prescribing errors by clinicians, specifically the potential for therapeutic duplication as well as drug–drug interactions. This study used retrospective prescribing data in Ireland during 2015 to investigate whether in fact this was a real safety concern. The key advantages to this study are that it uses a large amount of routinely collected claims data for drugs prescribed within usual practice, not as part of a clinical trial, and that it is retrospective and thus would not have influenced physician prescribing practice. Limitations include that the claims data only cover 40% of the population and the included population is not generalisable to the broader population. However, the authors note that there is coverage of 95% of the population over the age of 70, an age group particularly susceptible to medication errors and to consequential harm, morbidity and mortality.9 Additionally, there is the potential for confounding due to it being observational data which the authors have attempted to take into account with adjustment of available variables, although available data were limited. It also must be noted that there is poor generalisability to LMIC settings where greatest burden of hypertension lies, along with the greatest potential for benefit.

The findings, however, are reassuring for high-income settings. There was no difference in the proportion of drug–drug interactions, although it was noted that absolute rates of interactions were quite high in both groups. Although drug duplication in the FDC group was double that in the single drug group, the absolute difference was very low (less than 1% of total script volume). It is intriguing that the authors note common use of computerised decision support tools and yet medication error rates remain significant. Further investigation as to how clinical decision support systems  (CDSS) tools manage combination therapies may assist in improved design and reduction in errors; however, alert fatigue and other human factors may well be of greater importance. What is not clear from this study, and a potential next step for researchers, is to link these claims data to other administrative datasets to determine adverse patient outcomes from these increased numbers of drug–drug interactions.

The authors correctly note that the potential safety issues raised in this study in relation to drug duplication should be interpreted in the context of the potential patient benefit of use of FDCs. A recent study by Verma and colleagues10 using administrative and clinical datasets demonstrated benefit of use of FDCs on adherence to blood pressure–lowering medication (as expected from the previous literature) and also demonstrated an 11% reduction in clinical outcomes including death or hospitalisation for acute myocardial infarction, heart failure or stroke. They also noted no differences in hospitalisation for hyponatraemia or hypokalaemia which they included as a safety marker.

The availability of such large datasets to examine the ‘real-life’ impact of broader implementation of combination therapy is providing, and will continue to provide, important complementary insights to that of the clinical trial literature. This study adds to that growing literature around the safety profile of the use of combination therapy to manage high blood pressure. Such usage is becoming more prevalent and will continue to do so with increasing incorporation into clinical practice guidelines and growing evidence of significant clinical benefit.

However, similar datasets and experience are still limited in the area of polypill (ie, blood pressure–lowering, statin and antiplatelet combination therapy) use across all economic strata as well as use of combination blood pressure–lowering therapy in LMICs. These are areas where there is large potential for impact on the global epidemic of cardiovascular disease; however, additional research and therefore appropriate caution is required when considering implementation and scale-up.