Combination Therapy for Hypertension: An Update

For many years, multiple medications have been used in the management of hypertension. Numerous effective combinations were available in the 1960s and '70s and were used extensively in many clinical trials. ¹ , ² For example, in the Hypertension Detection and Follow‐up Program, three drugs, a rauwolfia compound, a thiazide diuretic, and hydralazine, a vasodilator, were used with good results. ³ Fixed‐dose combinations have also existed for many years, including thiazide diuretic/potassium‐sparing agents, combinations of thiazide diuretics and β blockers, diuretics/angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs)/diuretics, and ACE inhibitors/calcium channel blockers (CCBs). Although the concept is not new, interest in combination therapy has lagged until recent years. ⁴ Data from large trials over the past 15–20 years indicate that more than one medication has been necessary to reduce blood pressure and decrease morbidity/mortality in a majority of patients with hypertension ⁵ , ⁶ , ⁷ , ⁸ , ⁹ ; these have rekindled the interest in this approach to management.

Recent trials have appeared to be reporting as Drug‐A‐compared‐with‐Drug‐B studies, but all of these have actually evaluated multiple medications. For example, the recent trials with ARBs in patients with diabetes or renal disease evaluated the results of an ARB plus other medications (usually a diuretic) compared with multiple medications that did not include an ARB. The bottom line is that most monotherapies will not reduce blood pressure to goal levels in a majority of patients—investigators continue to search for the ideal combination.

In trials where diuretics were used in combination with β blockers, excellent results have been obtained. When a diuretic is added to an ACE inhibitor or an ARB, results are significantly better in both African‐American and white patients than when either drug is used alone in moderately large doses. When a small dose of the β blocker is added to a small dose of a diuretic in a fixed combination, blood pressure lowering is substantially greater than when moderate doses of a CCB or ACE inhibitor are used, but few studies have been carried out to determine cardiovascular disease outcome when a fixed‐dose combination is compared with other therapies.

This month's supplement to The Journal of Clinical Hypertension reviews the concept of multiple drug therapy, specifically as it relates to an ACE inhibitor/CCB fixed‐dose combination. It is edited by George Bakris, MD, of the Rush Presbyterian‐St. Luke's Medical School, with articles by Tom Giles, MD, FACC, of Louisiana State University, New Orleans; Ken Jamerson, MD, of the University of Michigan School of Medicine, Ann Arbor; and Michael Weber, MD, of State University of New York Downstate College of Medicine in Brooklyn. These well‐known investigators review data on combination therapy and stress that the use of two medications with different modes of action represents a reasonable approach to the management of hypertension. For example, an ACE inhibitor like benazepril has a profound effect on the renin‐angiotensin‐aldosterone system whereas a CCB like amlodipine is a potent vasodilator. Theoretically, this should be an ideal combination to lower blood pressure and reduce morbidity/mortality. Data indicate that small doses of these agents in combination reduce blood pressure to a greater degree than either drug alone and that the combination has a favorable effect on some vascular abnormalities in hypertension. These authors review the protocol of an ongoing study that is designed to determine if the use of the fixed‐dose combination of an ACE inhibitor and CCB will reduce cardiovascular events in patients with hypertension more than a combination of an ACE inhibitor and a thiazide diuretic.

Although some physicians may be reluctant to use combination therapy, Bakris and colleagues present compelling arguments for their use. Percentages of responders and blood pressure lowering is greater than with monotherapy; to an effective dose and adherence to therapy are improved if combinations are used.

The Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, ¹⁰ as well as other national committees, has recommended that combination therapy is appropriate initial treatment for patients with Stage 2 hypertension (i.e., blood pressure ≥160/100 mm Hg) or even in some Stage 1 hypertensives (blood pressure of 140–160/90–100 mm Hg) who have other significant risk factors such as diabetes and coronary heart disease.

Perhaps we should return to the era 40 or more years ago when combination therapy was an accepted approach to the management of hypertension even though individual medications were not ideal. The difference now is that the drugs used in combination, that is, ACE inhibitor/diuretics, ARBs/diuretics, β blockers/diuretics, or CCB/ACE inhibitors are generally more effective with fewer side effects than the medications that were used in the 1960s and '70s.