Rationale for Fixed-Dose Combinations in the Treatment of Hypertension

Abstract

Single-drug therapy remains the preferred way to begin treatment of hypertension, although in many patients this is unable to bring blood pressure (BP) to goal levels. Single-drug therapy, even when maximally titrated, is at best only modestly effective in normalising BP in Stage-I or II hypertension, which represents the majority of the hypertensive population. It is increasingly appreciated that the elusive goal of a ‘normal’ BP is achieved only if multi-drug therapy is employed. This is especially so when considered in the context of today’s lower BP goals. The options for multi-drug therapy are quite simple: either fixed-dose combination therapy or drugs added sequentially one after another to then arrive at an effective multi-drug regimen. Advocates exist for both approaches.

A considerable legacy, dating to the 1950’s, exists for fixed-dose combination therapies. The rationale to this approach has remained constant. Fixed-dose combination therapy successfully reduces BP because two drugs, each typically working at a separate site, block different effector pathways. In addition, the second drug of such two-drug combinations may check counter-regulatory system activity triggered by the other. For example, a diuretic and β-blocker combination may find the diuretic correcting the salt-and-water retention which occasionally accompanies β-blocker therapy. The pattern of adverse effects also differs with fixed-dose combination therapy, in part, because less drug is generally being given. In addition, one component of a fixed-dose combination therapy can effectively counterbalance the tendency of the other to produce adverse effects. For example, the peripheral oedema, that accompanies calcium channel antagonist therapy, occurs less frequently when an ACE inhibitor is co-administered. ACE inhibitors improve, if not eliminate, the peripheral oedema associated with calcium channel antagonists because of their proven ability to cause venodilation. In addition, diuretic therapy-induced volume contraction may generate a state of secondary hyperaldosteronism and thereby electrolyte abnormalities such as hypokalaemia and/or hypomagnesaemia. In many cases, the co-administration of either an ACE inhibitor or an angiotensin II receptor blocker with a diuretic corrects the aforementioned electrolyte disturbances.

Fixed-dose combination therapy has a proven record of reducing BP. This form of treatment has been available for close to a half-century. Over that period of time, many physicians have taken advantage of this therapeutic approach even when academic opinion was less than charitable to this concept. Academic opinion is rarely immutable and occasionally irrelevant to prescription practice. Prescription practice is driven by many considerations including ease of use, cost and tolerance of a therapy. Most importantly, the therapeutic pathway taken should successfully result in goal BP being reached in a large number of those treated. Unfortunately, despite the simplicity of the concept behind fixed-dose combination therapy, its success will ultimately rest on cost. If made truly cost-competitive, it will gain an increasing share of the hypertensive market. If not, market forces will relegate it to a secondary role for hypertension treatment.