A step in the global effort to control hypertension: Fixed dose combination antihypertensive drugs

Abstract

Several fixed dose combinations (FDCs) of antihypertensive drugs have recently been added to the World Health Organization model list of essential medications. FDCs have advantages in the management of hypertension compared to single drug tablets including improved adherence, greater blood pressure lowering and are associated with reduced cardiovascular complications. FDCs can also reduce ethnic, and age‐related variation in blood pressure lowering and have similar or reduced adverse effects relative to single‐drug therapy. Best hypertension control practices from the World Health Organization HEARTS program advocates the use of FDC in simple directive treatment protocols. FDC in simple directive protocols was viewed as a key success factor in the control of chronic infections (eg, tuberculosis, HIV). Unfortunately, implementing simple directive protocols with FDC has had substantial opposition from hypertension experts. Hypertension organizations and experts need to familiarize themselves with best practices in hypertension control, their supporting evidence and to become advocates.

Increased blood pressure is the single most important modifiable risk for death and a major driver of non‐communicable disease (NCD) globally.1 Controlling hypertension is perhaps the single most effective and feasible clinical mechanism to reduce NCD death and disability by reducing cardiovascular, cerebrovascular, and renal diseases. Hence, hypertension has been viewed as a major entry point for patients to the health care system for the prevention of NCD and is a major global target of the World Health Assembly, World Health Organization, and the philanthropic organization, Resolve To Save Lives.2, 3, 4

Through the HEARTS program, developed by the World Health Organization in partnership with multiple other organizations including the World Hypertension League, global best practices for hypertension control have been established.4 HEARTS outlines critical health system changes that are required for a feasible, effective global public health approach to hypertension control. Needed health system changes include a reliable and affordable supply of a high quality core set of antihypertensive medications including fixed dose combinations (FDCs), easily accessible patient‐centered team‐based care, accurate and systematic evaluation of blood pressure at all clinic visits, community based screening for hypertension that is closely linked to the health system and ensures the majority of people with hypertension are identified, use of a simple directive diagnostic and therapeutic treatment protocol, use of a hypertension registry with performance reporting, and regular (3‐5 year) population blood pressure surveys.

The vast majority of 1.13‐1.4 billion people with hypertension should be managed by primary care close to where they live and work.5, 6 The effort to control hypertension is aligned with another major effort to empower and build universal primary care and its capacity globally.7 Ultimately, global hypertension control requires a vast expansion of primary care and achieving hypertension control needs to be a major priority for primary care.

Unfortunately, experience indicates that implementing specific global best clinical practices in hypertension are often opposed by hypertension specialists. Some specialists may be unaware of the evidence supporting the best practices, the need for a public health approach vs individualized care or of the difficulties in implementing complex speciality generated hypertension recommendations in primary care. Increasing the effectiveness, simplicity, and feasibility of recommended hypertension interventions are critical to the ability to adhere to recommendations by both primary care clinicians and patients.

One of the interventions which has been advocated has been to use FDC antihypertensive drugs in simple directive protocols.8 Initial opposition from some specialists to simple directive protocols has been and continues to be almost universal and is an obstacle to population hypertension control. Although there are increasingly successful examples of implementation of simple directive protocols, few have incorporated FDCs. One of the major barriers to FDCs was recently overcome. On July 9, 2019, the World Health Organization added several FDC antihypertensive medications to the model list of essential medications9 (Table 1). This follows a precedent set by including FDCs for the management of chronic infectious diseases (ie, HIV and tuberculosis).9 Simple treatment protocols with FDCs were considered one of the success factors of the public health approach to control HIV and tuberculosis.

Table 1.

Fixed dose combination antihypertensive medications in the World Health Organization model list of essential medications

Lisinopril and amlodipine

Lisinopril and hydrochlorothiazide

Telmisartan and amlodipine

Telmisartan and hydrochlorothiazide

Briefly, there are several advantages of FDC antihypertensive drugs. Approximately, 70% of people with hypertension require two or more antihypertensive medications for hypertension control.8 In clinical trials, use of FDC therapy resulted in improved patient adherence and had more rapid and greater blood pressure lowering compared to use of single drug medications.10, 11 In cohort studies, FDCs were associated with improved patient outcomes.12 In many countries, government‐approved FDC antihypertensive medications require rigorous clinical trials that evaluate both blood pressure lowering and adverse effects and result in a highly rational evidence‐based drug combination. In contrast, in clinical practice, drug combinations are often suboptimal or even recommended against.13 FDCs in the WHO model list of essential medications have been in rigorous clinical trials are generic and long‐acting and can be administered once a day.9 FDCs can be less costly especially where drug dispensing fees for prescriptions are high (ie, one vs two dispensing fees). Furthermore, the use of FDCs can reduce ethnic and age‐related variation in blood pressure lowering and have similar or reduced drug adverse effects relative to single‐drug therapy.8 Triple combination FDC antihypertensive medications may also have a significant role in optimizing hypertension control versus up‐titrating the doses of two‐drug therapy.14, 15

To have an influential position impacting hypertension control in communities, nations and globally, hypertension researchers, specialists, and organizations need to rapidly learn, adopt, and promote global best public health practices. Critical roles relating to FDCs include, leading by example in personally using FDCs, advocacy for using FDCs including in educational and training sessions with primary care and by conducting research. There remain significant research questions about optimum FDCs in terms of drug classes, specific drugs, drug doses, and number of drugs to be combined. The efficacy, adverse effects and role of triple and quadruple drug FDCs needs significant research. Understanding geographic variation in efficacy and adverse effects of FDCs based on known geographic variation in genetics, obesity, dietary sodium, and potassium and physical activity is important to delineate. Advocacy is required to ensure the national reliable availability of low‐cost high quality FDCs, for national subsidies for the FDCs in the WHO model list of essential medications and for widespread clinical use.

In many countries, FDCs are not currently widely available or affordable; while in other countries, FDCs are widely available and less costly but infrequently prescribed. FDCs are a step in the global effort to control hypertension, whether an insignificant small step or a large step depends in part on hypertension specialists and their organizations adopting, advocating, and researching their optimum role.

CONFLICT OF INTEREST

NRCC was a paid consultant to the Novartis Foundation (2016‐2017) to support their program to improve hypertension control in low‐ to middle‐income countries which includes travel support for site visits and a contract to develop a survey. NRCC has provided paid consultative advice on accurate blood pressure assessment to Midway Corporation (2017) and is an unpaid member of World Action on Salt and Health (WASH).

Campbell NRC. A step in the global effort to control hypertension: Fixed dose combination antihypertensive drugs. J Clin Hypertens. 2019;21:1426–1428. 10.1111/jch.13683