The excellent historical perspective on fixed-dose combination therapies for hypertension by Epstein and Bakris1 did not include discussion of the earliest combination medications for hypertension. Their article misstated that fixed-dose combinations have always included a diuretic as a component until the release of an angiotensin-converting enzyme inhibitor—calcium antagonist combination this year. A look even further back in history reveals the earlier existence of several nondiuretic combination medications that illustrate the very principles used to justify the resurging interest in combination antihypertensives.
Reserpine and other rauwolfia derivatives were offered in fixed-dose combination with a variety of medications during the 1950s, before diuretics were even approved for the treatment of hypertension. The combination of rauwolfia and veratrum (a parasympathomimetic agent) was marketed as Verapene, a medication that enhances antihypertensive efficacy but avoids side effects by reducing the dose of the component antihypertensives.2 In an era when anxiety and hypertension were