Abstract and Introduction

Abstract

Hypertension remains the most prevalent chronic disease in the world, and its adequate treatment results in predictable reductions in cardiovascular morbidity and mortality. However, most hypertensive subjects do not achieve goal blood pressure despite availability of multiple antihypertensive agents with various pharmacological mechanisms of action and relatively few side effects. We review the reasons for low hypertension control rates, including factors that affect patients' adherence to therapy, number of agents required to achieve goal blood pressure, pathophysiology-based selection of therapy and diagnosis of resistant hypertension. Within this framework, we discuss the possible impact of a single-pill, triple-therapy combination with an antagonist of the renin–angiotensin system, a calcium-channel blocker and a diuretic. We focus on possible differential diagnostic implications in terms of refractoriness to treatment, and therapeutic implications in terms of successful blood pressure control. We conclude that a single-pill, triple-therapy combination may improve control of hypertension by enhancing compliance, by achieving blood pressure goal rapidly and by reducing physician inertia in prescribing adequate antihypertensive therapy. We also suggest that such a combination may lead to improved accuracy in diagnosing resistant hypertension in general practice, avoiding unnecessary further workup and referrals to hypertension specialists.

Introduction

Six decades of epidemiological and clinical research have provided unequivocal evidence for the role of hypertension as a cardiovascular and renal risk factor and for the benefit of antihypertensive therapy. Concomitantly, pharmaceutical research has resulted in the development of a large armamentarium of antihypertensive drugs with a variety of mechanisms of action that address the diverse pathophysiologies of essential hypertension. Despite this extraordinary progress, control rates of hypertension, although somewhat improved, remain dismal, even in developed, wealthy societies. The sobering disparity between the science and its clinical application has resulted in the understanding that future developments in the field must address strategies to bridge the gap between them.

Epidemiology has established hypertension as a risk factor for cardiovascular disease in studies of large and diverse populations, and has quantified such risk with extreme accuracy. A meta-analysis containing data on 12.7 million patient-years of follow up documented that minor differences in blood pressure (2mmHg) have a major impact on ischemic heart disease or stroke mortality (7% and 10% decreases, respectively) [Lewington et al. 2002].

The demonstration, in 1959, by Kincaid-Smith that blood pressure reduction dramatically increased survival in subjects with malignant hypertension [Harington et al. 1959] began the journey of investigation that documented analogous results in subjects with progressively lower levels of diastolic blood pressure [VA and NIH-sponsored trials: Neaton et al. 1993; Hypertension Detection and Follow-up Program Cooperative Group, 1982; Veterans Administration Cooperative Study Group on Antihypertensive Agents 1970, 1967] in those with isolated systolic hypertension (SHEP [Cooperative Research Group 1991] and Syst-Eur [Tuomilehto et al. 1999]) and most recently, in the 'superelderly' (HYVET [Beckett et al. 2008]). The most striking observation of these studies is that pharmacological reduction of blood pressure removes the risks of stroke and ischemic heart disease by a magnitude almost equal to that predicted by epidemiology, a feature that is perhaps unique to the treatment of hypertension. This emphasizes the need to translate scientific knowledge to the health of the population.

Control rates of blood pressure among all hypertensive subjects in the US are 33% [Ong et al. 2007], worse in Europe [Chamontin et al. 2001], and even worse in developing countries [Gu et al. 2002]. They are calculated according to target blood pressure goals derived from clinical trials (<>et al. 2008].

Reasons for low hypertension control rates are multiple (Table 1), and much has been written about methods to improve them. This review will focus on the rationale for combining three antihypertensive agents in a single pill, a conceivable pharmaceutical development in the near future, to improve control rates of hypertension.