Can Large-Scale Trials or Meta-Analyses Demonstrate Blood Pressure–Independent Effect of Angiotensin Receptor Blockers?
To the Editor:
In the recent quantitative overview, Wang et al1 showed that amlodipine provided more protection against stroke and myocardial infarction than other antihypertensive drugs, including angiotensin receptor blockers (ARBs), although they concluded that blood pressure (BP) differences largely accounted for cardiovascular outcome among different kinds of drugs. They also concluded that more studies are needed to demonstrate whether certain drugs or classes of drugs might possess BP-independent influence on certain outcome measures. However, it is somewhat questionable whether the accumulation of large-scale clinical trials or their meta-analyzes could provide more conclusive information.
It is plausible that the BP-lowering effect of the renin-angiotensin system blockers, including ARBs, depends on the magnitude of the renin-angiotensin system activity. It is known that the patients with low-renin hypertension, such as black and salt-sensitive hypertensive patients, do not respond well to the renin-angiotensin system blockers. Recently, we reported that reduction in ambulatory BP by telmisartan was significantly smaller in hypertensive patients with lower renin levels (<0.65 ng/mL per hour) than in those with higher levels (≥0.65 ng/mL per hour).2 Based on these findings, we hypothesize that the fact that there are responders and nonresponders to ARBs may become obscure by averaging BP data in large-scale clinical trials or their meta-analyses.
To ascertain our hypothesis, we took notice of SDs in BP in large-scale clinical trials. Of the 12 trials in the overview by Wang et al,1 7 trials (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Anglo-Scandinavian Cardiac Outcomes Trial, Losartan Intervention for Endpoint Reduction in Hypertension Trial, Morbidity and Mortality After Stroke Trial, Study on Cognition and Prognosis in the Elderly Trial, Valsartan Antihypertensive Long-Term Use Evaluation, and Candesartan Antihypertensive Survival Evaluation in Japan Trial) reported SDs in BP at study entry and end. SD in BP treated by lisinopril at the end of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial was greater than those treated by the other 2 classes of drugs (lisinopril: 17.9/10.7 mm Hg, chlorthalidone: 15.2/9.8, and am-lodipine: 14.9/9.9). More notably, SDs in BPs treated by ARBs at end of the Morbidity and Mortality After Stroke, Valsartan Antihypertensive Long-Term Use Evaluation, and Candesartan Antihypertensive Survival Evaluation in Japan trials were all greater than those treated by calcium antagonists (eprosartan: 16.7/8.9 mm Hg, nitrendipine: 15.6/8.8 mm Hg in the Morbidity and Mortality After Stroke Trial; valsartan: 17.6/9.8 mm Hg, amlodipine: 15.0/9.0 mm Hg in the Valsartan Antihypertensive Long-Term Use Evaluation; and candesartan: 13.0/9.7 mm Hg, amlodipine: 11.8/8.2 in the Candesartan Antihypertensive Survival Evaluation in Japan Trial). Greater SDs in BP in the ARB-based treatment group appear to indicate that there are wide variations in BP response to ARBs, confirming that there are responders and nonresponders to ARBs. Therefore, it is probable that responders derive more outcome benefit from ARBs, whereas nonresponders derive less outcome benefit from these agents. In contrast, smaller SDs in BP in the calcium antagonist–based treatment groups, especially in the amlodipine-based treatment groups, may indicate that this class of drugs confers an outcome benefit by reducing BP to a relatively similar degree independent of patient backgrounds, including the renin-angiotensin system profiles.
Wang JG, Li Y, Franklin SS, Safar M. Prevention of stroke and myocardial infarction by amlodipine and angiotensin receptor blockers: a quantitative overview. Hypertension. 2007; 50: 181–188.
Minami J, Ishimitsu T, Matsuoka H. Levels of plasma renin activity before treatment and therapeutic response to telmisartan in essential hypertension. Am J Hypertens. In press.