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Should Low-Dose Combinations of Blood Pressure Drugs Be Used?


Am Fam Physician. 2004 Feb 1;69(3):669-671.

At 65 years of age, every 10-mm Hg reduction in systolic or 5-mm Hg reduction in diastolic blood pressure reduces stroke risk by about 35 percent and ischemic heart disease events by about 25 percent. Many drugs lower blood pressure, but selecting the optimal agent, dosage, or combination remains a problem. Law and colleagues conducted a systematic review of the five principal categories of blood pressure treatments to clarify the best therapy.

They identified randomized controlled trials of thiazides, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in the treatment of hypertension. An extensive search revealed 354 trials that met study criteria. The researchers defined efficacy as the reduction in systolic and diastolic blood pressure for a specified dose of the study agent minus any change in the placebo group. Similarly, adverse effects attributable to each drug were estimated after subtraction of effects reported by the placebo group. In 50 of the trials, two different categories of drug were tested separately and in combination.

Average Reductions* in Blood Pressure over 24 Hours (Treated Minus Placebo) According to Category of Drug and Dosage

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The studies included 40,000 treated patients and 16,000 patients given placebo. The individual drugs produced similar, dose-related changes in blood pressure, with cheaper drugs performing comparably to the more expensive agents (Table 1). All drugs were more effective when the initial blood pressure was highest. The 50 studies of drugs given in combination showed additive effects. Conversely, adverse effects were not additive when drugs were combined. When drugs were given individually at standard dosages, angiotensin II receptor blockers had the lowest reported rates of adverse effects, and thiazides had the highest rate (Table 2).

Persons with One or More Adverse Effects Attributable to Treatment,* According to Category of Drug and Dosage

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The authors conclude that all five categories of antihypertensive drugs are effective. They note that with one half of the standard dosage, the reduction in blood pressure is about 20 percent less than at the standard dosage, but adverse effects are significantly reduced. They conclude that using half-strength combinations of several drugs could provide effective blood pressure control with fewer adverse effects. They calculate that combinations of one, two, and three drugs at one half of the standard dosage would reduce stroke risk by 29, 49, and 63 percent, respectively. The corresponding reductions in ischemic heart disease events are estimated as 19, 34, and 46 percent. Because the adverse effects of ACE inhibitors and angiotensin II receptor antagonists are no higher at standard and half dosages, using either of these agents at the standard dosage plus a half strength of another agent is estimated to reduce stroke risk by 66 percent and ischemic heart disease events by 49 percent.

Law MR, et al. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. June 28, 2003;326:1427–31.

editor's note: After a lifetime of trying to stamp out polypharmacy and simplify drug regimens for patients, does this article indicate we should use multiple agents in low-dose combinations? The arguments are certainly persuasive, and the authors call for low-dose combinations to be the first treatment option in hypertension despite the absence of any randomized controlled trials of this approach. Until a low-dose combination in a single pill becomes available, the added risk of error and cost of prescribing three agents makes one hesitant to follow this advice. The addition of another agent at half strength to an ACE inhibitor or angiotensin II receptor antagonist is a more attractive option.—A.D.W.



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