ASH Position Article
Combination therapy in hypertension

https://doi.org/10.1016/j.jash.2010.02.005Get rights and content

Abstract

The goal of antihypertensive therapy is to abolish the risks associated with blood pressure (BP) elevation without adversely affecting quality of life. Drug selection is based on efficacy in lowering BP and in reducing cardiovascular (CV) end points including stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy exerts some effect on long-term outcomes, it is evident that BP reduction per se is the primary determinant of CV risk reduction. Available data suggest that at least 75% of patients will require combination therapy to achieve contemporary BP targets, and increasing emphasis is being placed on the practical tasks involved in consistently achieving and maintaining goal BP in clinical practice. It is within this context that the American Society of Hypertension presents this Position Paper on Combination Therapy for Hypertension. It will address the scientific basis of combination therapy, present the pharmacologic rationale for choosing specific drug combinations, and review patient selection criteria for initial and secondary use. The advantages and disadvantages of single pill (fixed) drug combinations, and the implications of recent clinical trials involving specific combination strategies will also be discussed.

Introduction

The goal of antihypertensive therapy is to abolish the risks associated with blood pressure (BP) elevation without adversely affecting quality of life. Epidemiologic studies and clinical trials have been used to define individual risk and set appropriate BP targets,1, 2, 3 recognizing that these targets reflect expert consensus based on available data and are subject to revision as additional evidence is obtained.4 Drug selection is based on efficacy in lowering BP and in reducing cardiovascular (CV) end points including stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy exerts some effect on long-term outcomes, it is evident that BP reduction per se is the primary determinant of CV risk reduction. As a result, there has been a progressive lowering of BP targets in large segments of the hypertensive population, including diabetics and patients with established renal or vascular disease.1, 2, 3, 5 At the same time, increasing emphasis is being placed on the practical tasks involved in consistently achieving and maintaining goal BP in clinical practice.

It is within this context that the American Society of Hypertension presents this Position Paper on Combination Therapy for Hypertension. It will address the scientific basis of combination therapy, present the pharmacologic rationale for choosing specific drug combinations, and review patient selection criteria for initial and secondary use. The advantages and disadvantages of single pill (fixed) drug combinations (SPC) and the implications of recent clinical trials involving specific combination strategies will also be discussed.

Section snippets

Combination Therapy: A Practical Necessity

The ability to maintain constant or near-constant BP in response to various stressors is central to homeostasis, and the human organism has redundant physiologic mechanisms for regulating arterial pressure. BP is determined primarily by three factors: renal sodium excretion and resultant plasma and total body volume, cardiac performance, and vascular tone.6 These factors control intravascular volume, cardiac output, and systemic vascular resistance, which are the immediate hemodynamic

Efficacy

Rational combination therapy is based on the deliberate coadministration of two or more carefully selected antihypertensive agents. Inclusion of drugs known to reduce the long-term incidence of CV end points is highly preferred. A fundamental requirement of any combination is evidence that it lowers BP to a greater degree compared with monotherapy with its individual components. This is achieved by combining agents that either interfere with distinctly different pressor mechanisms or

Specific Drug Combinations

There are seven major classes of antihypertensive drugs and multiple members of each class; therefore, the number of possible combinations is quite large. In this position paper, two-drug combinations involving classes of pharmacologic agents that reduce CV end points (diuretics, CCBs, ACE inhibitors, ARBs, β-blockers) are emphasized. Combinations of three or more drugs are not reviewed. Specific combinations are designated as preferred or acceptable based on the considerations outlined

ACE Inhibitors + ARBs

Although sometimes useful for proteinuria reduction and in the treatment of symptomatic patients with heart failure, the combination of an ACE inhibitor and an ARB is not recommended for the treatment of hypertension. ACE/ARB combinations produce little additional BP reduction compared with monotherapy with either agent alone. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, patients receiving the ACE inhibitor/ARB combination showed no improvement in

Patient Selection: Initial Therapy

Because most patients with hypertension will require two to three drugs to achieve BP control, the pivotal questions for initial therapy are as follows.

  • Should treatment be started with monotherapy or a combination?

  • If two drugs are initiated, should they be administered as single entities or an SPC?

Although there is limited scientific evidence to answer these questions definitively, several considerations support the use of initial combination therapy in most patients with hypertension.

Summary Recommendations

  • Use combination therapy routinely to achieve BP targets

  • Use only preferred or acceptable two-drug combinations (Table)

  • Initiate combination therapy routinely in patients who require ≥20/10 mm Hg BP reduction to achieve target BP

  • Initiate combination therapy in stage 1 patients (at the physician's discretion), especially when the second agent will improve the side effect profile of initial therapy

  • Use SPCs rather than separate individual agents in circumstances where convenience outweighs other

Acknowledgments

This article was reviewed by Raymond R. Townsend, MD, and Matthew R. Weir, MD.

The American Society of Hypertension Writing Group Steering Committee: Barry J. Materson, MD, MBA, Chair; Henry R Black, MD; Joseph L. Izzo, Jr., MD; Suzanne Oparil, MD; and Michael A. Weber, MD.

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