Is There Overlap in Blood-pressure Response to the Blockers of the Renin-Angiotensin System Between Lower and Higher Renin Subjects?

To the Editor: We read the recent article by Moran et al.1 with great interest. They concluded that the majority of African Americans and Caucasians had a similar blood-pressure response to a fixed dose of ramipril. Their study provides useful and valuable information on the choice of antihypertensive drugs. In addition, we agree with Moran et al.1 and other investigators2 on the point that there is considerable overlap in the blood-pressure response to a standard dose of angiotensin-converting enzyme (ACE) inhibitors between African Americans and Caucasians. However, we would like to make several comments on the article by Moran et al.1 First, to date, several studies using ACE inhibitors and angiotensin receptor blockers (ARBs) have shown that the blood-pressure response in African Americans is less than in Caucasians.3 While a higher dose of ACE inhibitors may be more effective in African Americans and while the hypotensive mechanisms between ACE inhibitors and ARBs differ substantially, it is also plausible that the blockers of the renin–angiotensin system (RAS) exert blood-pressure lowering effects dependent on renin status. Recently, we reported that reduction in the 24-hour, daytime, and nighttime ambulatory blood pressure was significantly lower in Japanese patients with lower renin levels (<0.65 ng/ml/hour) than in those with higher levels (≥0.65 ng/ml/hour); changes in the 24-hour, daytime, and nighttime ambulatory blood pressure were significantly and inversely correlated with the pretreatment levels of plasma renin activity.4 We obtained similar results regarding another ARB, valsartan (J. Minami, T. Ishimitsu, and H. Matsuoka, unpublished data). Other investigators also reported similar results following the use of ambulatory blood-pressure monitoring.5 It is well known that African Americans more frequently have low-renin, high-volume hypertension.6 However, it is also plausible that there are wide variations in plasma renin status among African Americans and it is likely that there is considerable overlap in the blood-pressure response to the RAS blockers between African Americans and Caucasians.1,2 However, theoretically speaking, it is assumed that there is little overlap in the blood-pressure response to the RAS blockers between subjects with lower renin levels and those with higher renin levels. Although pretreatment plasma aldosterone levels were significantly lower in African Americans than in Caucasians in the study by Moran et al.,1 the lack of any measurements of plasma renin levels may limit the interpretation of the results. Second, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),7 where 35% of the study patients were African Americans, the lisinopril group had significantly higher five-year systolic blood pressure by 2 mm Hg and significantly higher six-year rates of combined cardiovascular disease than the chlorthalidone group. More notably, in the subgroup comparisons of the ALLHAT,7 it was observed that the beneficial effects of lisinopril seemed less than that of chlorthalidone in the prevention of stroke and coronary heart disease among African American patients. Recently, we took note of standard deviations (SDs) in blood pressure in large-scale clinical trials.8 To the best of our knowledge, no investigators have been interested in SDs in blood pressure in large-scale clinical trials. We have found that in the majority of large-scale clinical trials, SDs in both systolic and diastolic blood pressure levels in those treated by the RAS blockers, were greater than those treated with other classes of drugs such as diuretics and calcium antagonists. In the ALLHAT,7 SDs in the blood-pressure levels in the chlorthalidone, amlodipine, and lisinopril groups at study entry were comparable (15.7 mm Hg systolic and 10.0–10.2 mm Hg diastolic), while the SD in the blood-pressure levels in the lisinopril group at study end (17.9 mm Hg systolic and 10.7 mm Hg diastolic) were substantially greater than those in the chlorthalidone group (15.2 mm Hg systolic and 9.8 mm Hg diastolic) and the amlodipine group (14.9 mm Hg systolic and 9.9 mm Hg diastolic). Greater SDs in the blood-pressure levels in the lisinopril group appears to indicate that there were wide variations in the blood-pressure response to lisinopril and there were responders and non-responders to lisinopril. Lastly, judging from Table 1 in the article by Moran et al.1 the pretreatment nighttime ambulatory blood-pressure levels were considerably lower in Caucasians than African Americans by 8 mm Hg systolic and 4 mm Hg diastolic. This is well in agreement with the earlier finding that being African American is an independent predictor of non-dipper status.9 However, was there any possibility that this difference was responsible for the attenuated hypotensive effect of ramipril on the nighttime ambulatory blood pressure in Caucasians whose mean nighttime ambulatory blood pressure before treatment was only 129 mm Hg systolic and 75 mm Hg diastolic? In recent years, the effectiveness of antihypertensive drugs has been considered to be derived primarily from the blood pressure-lowering effect itself rather than the characteristic actions of various classes of antihypertensive drugs. Thus, low-renin hypertensive subjects with suppressed RAS activity are less likely to derive benefit from the RAS blockers. The theory proposed by Laragh10 that there are two types of hypertension, i.e., R hypertension primarily driven by renin-induced vasoconstriction and V hypertension that is sodium-volume dependent, is a useful and valuable one for making a choice of antihypertensive drugs, and this theory should be applied to the treatment of hypertension on the basis not of ethnicity/race but of appropriate measurement of pretreatment levels of plasma renin activity. The authors declared no conflict of interest.