Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs.

OBJECTIVE: Hypertension guidelines recommend initial treatment with a beta-blocker or diuretic and adding the other drug where blood pressure is not controlled. We hypothesized that systematic rotation through the major classes of antihypertensive drugs would demonstrate substantial differences in the pattern of an individual patient's response, and suggest a more rational approach to choosing best treatment. DESIGN: Thirty-four young hypertensives (age 28-55, median 47) rotated in a double-blind, Latin-square, crossover fashion through 6 weeks of treatment each with amlodipine, doxazosin, lisinopril, bisoprolol, bendrofluazide and placebo. Blood pressure was measured at each visit. 'Best' drug, defined by efficacy and tolerability, was repeated at the end. RESULTS: Rotation doubled the number of patients reaching target blood pressure (systolic < 140 mmHg) on one drug (P = 0.03). All five drugs were represented among the 'best' drugs. In six patients, the blood pressure on 'best' drug was at least 10 mmHg lower than on any other. Response to the 'best' drug was highly correlated (r = 0.79) with its previous administration. By contrast, there were only weak correlations between responses to pairs of drugs, except for angiotensin-converting enzyme (ACE) inhibitor (A) with beta-blocker (B), and calcium blocker (C) with diuretic (D) - each r = 0.71, P < 0.005). In these young patients, the majority of patients (23/34) responded best to a drug suppressing the renin system (A and B). CONCLUSIONS: Patients vary reproducibly in their response to initial treatment, and switching among drugs can increase the efficacy of monotherapy. The results support an AB/CD scheme for choosing therapy, in which the first drug is taken from one of these pairs, and uncontrolled patients switch to one of the other pair.

Influence of drugs and gender on the arterial pulse wave and natriuretic peptide secretion in untreated patients with essential hypertension.

Recent studies have suggested a differential influence of mean pressure and pulse pressure on myocardial infarction and stroke, and differences among the major drugs in their efficacy at preventing these individual endpoints. We hypothesized that antihypertensive drugs have differing influences upon the pulse wave even when their effects on blood pressure are the same. We studied 30 untreated hypertensive patients, aged 28-55 years, who were rotated through six 6-week periods of daily treatment with amlodipine 5 mg, doxazosin 4 mg, lisinopril 10 mg, bisoprolol 5 mg, bendrofluazide 2.5 mg or placebo. The best drug was repeated at the end of the rotation. Blood pressure readings and radial pulse tonometry (by Sphygmocor) were performed at each visit, and blood was taken for measurement of levels of atrial natriuretic peptide and brain natriuretic peptide (BNP). The Sphygmocor derivation of the central aortic pulse wave was used to measure time for transmission of the reflected wave (T(R)) and the augmentation index (AI), which is the proportional increase in systolic pressure due to the reflected wave. There was a dissociation between the effects of the drugs on blood pressure and pulse wave analysis. Bisoprolol caused the greatest falls in blood pressure and T(R), but was the only drug to increase AI. This paradoxical response to bisoprolol was associated with a 3-fold increase in plasma BNP levels. There was a smaller elevation of BNP in women compared with men, as described previously, and this elevation also was associated with significantly higher values of AI. Other drugs reduced AI, and this was associated with a significant decrease in BNP by amlodipine. In conclusion, antihypertensive drugs differ in their short-term effects on augmentation of the systolic pulse wave and secretion of BNP from the heart, regarded as a sensitive measure of strain on cardiomyocytes. These differences may help to explain cause-specific differences in outcome in recent trials.