Triple fixed-dose combination therapy: back to the past.

In this issue of Hypertension, Calhoun et al1 report on a large (n 2271), short (9 weeks of treatment after 4 weeks of washout and placebo), well-designed, properly controlled, international randomized trial of a triple combination of a diuretic (D; hydrochlorothiazide [HCTZ]), a dihydropyridine calcium channel blocker (DHPCCB; amlodipine [A]), and an angiotensin reception blocker (ARB; valsartan [V]) in volunteers who had a mean sitting (MS) diastolic blood pressure (BP; MSDBP) of 100 mm Hg. The results support what all would have anticipated: the use of 3 antihypertensive medications with different mechanisms of action would lead to a greater drop in BP than would combinations of any 2 of the 3 drugs given as 2-drug combinations. In fact, any other result would have been news, because combination therapy has many obvious advantages and some disadvantages compared with single-drug therapy (Tables 1 to 3). The main result was that the triple combination reduced MS BP by 40/25 mm Hg, whereas the 2-drug combination of the ARB/D achieved a 32/20-mm Hg reduction, and the ARB/DHPCCB combination lowered MSBP by 34/ 22 mm Hg, whereas the DHPCCB/D combination dropped MSBP by 31/19 mm Hg. All of these differences were highly statistically significant, thanks in part to the large sample size. More important, the differences between these regimens, a minimum of 8/5 mm Hg for ARB/D versus the triple therapy, 6/3 mm Hg for ARB/DHPCCB versus the triple therapy, and 8/5 mm Hg for D/DHPCCB versus the triple therapy, are also clinically relevant. The study was large enough for a reliable comparison of prespecified subgroups: age ( 65 years versus 65 years); ethnicity (whites versus blacks and Hispanics versus nonHispanics); sex; and those with entry systolic BPs of 180 mm Hg and 180 mm Hg. In all of the subgroups evaluated, highly statistically significant reductions in both MSDBP and MSSBP were observed. All of these combinations were not only effective at lowering BP but were also well tolerated. The most common adverse reactions were dizziness, an expected adverse effect from lowering BP; edema, a common nuisance adverse effect with DHPCCBs; and headache, seen frequently with DHPCCBs. Serious adverse events and those leading to discontinuation of treatment were unusual ( 1%) with all of the regimens. There were no significant metabolic abnormalities, although again, as expected, the regimens containing D did show a modest reduction in serum K (0.39 mmol/L in the A/D group, 0.16 mmol/L in the A/D/V group, and 0.08 mmol/L in the V/D group). A/V increased serum K by 0.04 mmol/L. All of the combinations reduced MSDBP to 90 mm Hg but failed to lower MSSBP to 140 mm Hg. The only regimen that reduced MSSBP to 140 mm Hg and MSDBP to 90 mm Hg was the triple combination. The subjects whose MSSBP remained 140 mm Hg on 3 drugs at full or nearly full doses, one of which is a D, would be defined as having resistant hypertension by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.2 Though some may disagree about the definition or whether the dose of D used was a full dose, a patient who is receiving these 3 classes of drugs at these doses and is still not at goal is a candidate for additional drug(s).2 In many ways, this study and the benefits of triple-drug combinations return us to the dawn of the era of effective pharmacological treatment of hypertension (Figures 1 and 2). It was the triple-drug combination of reserpine, hydralazine, and HCTZ as Ser-Ap-Es (Ciba-geigy) that was the basis for the first clinical trial, the Veterans Affairs Cooperative Study,