Benefits of combination therapy in hypertensive patients with associated coronary artery disease: a subgroup with specific demands

Although prevention of coronary artery disease (CAD) is one of the main goals of antihypertensive therapy, when first seen hypertensive patients often have associated CAD. These patients need a therapy that can exert an acute anti-ischemic action, such as ad hoc relief of angina pectoris, and can also reduce the incidence of myocardial infarction (MI) or reinfarction. Reduction in blood pressure (BP) alone does not appear to be adequate because in hypertensive patients CAD is a complex and multifactorial process involving not only hemodynamic, neurohormonal, and metabolic factors but also hypertension-induced myocardial and vascular structural changes, which appear independently to contribute to risk for CAD. In theory, antihypertensive combination therapy, by summing the different effects of various drugs, appears to have a greater capacity for comprehensive management of hypertensive patients with CAD. Simultaneous administration of angiotensin-converting enzyme (ACE) inhibitors and calcium-channel blockers appears to be particularly effective. In several clinical trials with long-term follow-up, ACE inhibitor therapy has been associated with a substantial reduction in the risk for major ischemic events. The antiproliferative action of ACE inhibitors on myocardium and the vascular wall, their hemodynamic effects, antiatherogenic actions, neurohormonal attenuation, and certain genetic issues may account for the ability of this class of drugs to reduce the risk for CAD-related events. Although ACE inhibitors can be expected to increase coronary blood flow when the renin-angiotensin system is activated and to reduce BP, ventricular filling pressure, and sympathetic drive, thus far an acute anti-ischemic action of these drugs has not been demonstrated. Unlike ACE inhibitors, which usually have class-specific effects, there are important differences in the clinical effects of various calcium antagonists. The first generation of dihydropyridine calcium-entry blockers has failed to demonstrate efficacy in secondary prevention of coronary artery events. However, verapamil reduces mortality in patients with normal left ventricular function. The antihypertensive efficacy of verapamil, its antiatherogenic action, and its ability to reverse left ventricular hypertrophy, to improve diastolic function, and to interfere with endothelium-derived contracting factors may also account for the improved survival of patients with CAD treated with this drug. Moreover, verapamil is also effective in the treatment of all types of angina because it reduces myocardial oxygen consumption as a result of its hypotensive effect and its ability to reduce heart rate, and it may also improve oxygen delivery to the myocardium because of its action on coronary vasodilatation. It is also important to consider that ACE inhibitors and calcium antagonists often induce the same beneficial effects through different mechanisms, thus allowing a synergistic action when the two classes of drugs are administered together.