Race-based Therapy for Hypertension: Possible Benefits and Potential Pitfalls

Keith C. Ferdinand; Daphne P. Ferdinand

Disclosures

Expert Rev Cardiovasc Ther. 2008;10(6):1357-1366. 

In This Article

Renin-angiotensin-aldosterone System Blockade in Black Individuals

The effectiveness of blocking RAAS for antihypertensive efficacy and cardiovascular benefit in Blacks is controversial, specifically when compared with therapy with ACEIs and ARBs. Nevertheless, one approach to RAAS blockade may actually be equally or more effective in Blacks, especially with severe or resistant hypertension.[39,40] Aldosterone antagonists, such as spironolactone and eplerenone, are often added to a two- or three-drug regimen and are effective antihypertensive therapy in Blacks. Low-dose spironolactone lowered BP, on average, by an additional 25 mmHg systolic and 12 mmHg diastolic in a university hypertension clinic.[39] The BP-lowering effect was similar for both the African-American and White patients who were being treated. Similarly, amiloride, which antagonizes the epithelial sodium channel and functions as an indirect aldosterone antagonist, when added to spironolactone or alone in African-Americans patients, improved BP control (12.2 mmHg systolic and 4.8 mmHg diastolic for amiloride alone and 14.1 mmHg and 5.1 mmHg in combination).[40] These findings suggest that patients with resistant hypertension, defined as an above-target BP despite three medications of different classes, which is more common among African-Americans, may benefit from aldosterone antagonists.[41]

Clinical outcomes trial information regarding the potential for ACEIs and ARBs is obtained from the African-Americans Study of Kidney Disease (AASK), ALLHAT, INVEST and the Losartan Intervention for End-Point Reduction in Hypertension (LIFE). Additionally, safety data was obtained in the Omapatrilat Cardiovascular Treatment Assessment versus Enalapril (OCTAVE) study. General comments can be made regarding clinical efficacy trials with ACEI, ARBs and β-blockers. There appears to be a great deal of consistency in antihypertensive effect, with less BP-lowering achieved using monotherapy with these agents than with thiazide diuretics and long-acting CCBs in Blacks. Data regarding side effects are informative since they may impact clinical utility and adherence, specifically with ACEIs in Blacks and Asians, which caused increased cough and angioedema.

In AASK, therapy based on ramipril was compared with metoprolol succinate and amlodipine. The ACEI demonstrated renoprotective benefit in African-Americans with hypertensive nephropathy, especially with proteinuria.[42] On the other hand, as previously noted, lisinopril-based therapy in Blacks was less effective than chlorthalidone for the treatment of stroke and CVD in ALLHAT. In INVEST, successful BP reduction and clinical outcomes in Blacks compared with Whites was noted with verapamil SR and higher doses of the ACEI trandolapril.

Interestingly, African-Americans have a substantially increased incidence of ACEI-associated angioedema compared with Whites. Although the cause of increased rates of angioedema in Blacks is unclear, it may be related to enhanced kinin effects from the inhibition of kininase II. This increased risk cannot be attributed to the effects of dose, the specific ACEI or concurrent medications. Angioedema, although rare, may have potentially serious consequences including death. In an analysis of the incidence and characteristics of angioedema in the double-blind OCTAVE trial, carried out in 12,634 patients randomized to enalapril and 12,608 randomized to omapatrilat, the increased rate of angioedema in Blacks was confirmed.[43] Omapatrilat was a novel antihypertensive agent that inhibited both neutral endopeptidase and ACE. Angioedema was three times more likely to occur among Black patients compared with Whites (1.62 vs 0.55%) for enalapril and remained higher for Blacks in the omapatrilat group. Moreover, in ALLHAT, there was a higher rate of angioedema with lisinopril in Blacks: 0.7% (23 of 3,210 patients) in Blacks versus 0.32% (15 of 5,844 patients) in non-Blacks.[36] Therefore, based on the ALLHAT trial and other studies, Blacks were noted to have two- to three-times higher incidence and, perhaps, more florid angioedema versus Whites with ACEIs.[43,44,45]

Clinical studies demonstrate similar BP-lowering effects to ACEIs for ARBs, but the specific effectiveness for outcomes with ARBs in Blacks is unclear. In the LIFE study, there were only 533 Blacks of 9193 total patients with hypertension and LV hypertrophy.[46,47] Patients were randomized to the ARB regimen with losartan versus the β-blocker regimen with atenolol and, in the Black cohort, losartan was less effective at decreasing cardiovascular morbidity and mortality, including stroke. This subgroup finding, with a small sample size (6%), may have been due to chance. A recently approved RAAS-blocking antihypertensive agent is the oral direct-renin inhibitor aliskiren, and the effectiveness of BP-lowering with monotherapy of this agent in Blacks is unclear. In a dose-ranging study of 672 patients (61.3% Caucasian), aliskiren provided significant antihypertensive effects.[48] However, the magnitude of BP reduction was smaller in the subgroup of Black patients compared with Whites. The authors considered this finding consistent with the concept that the antihypertensive efficacy of renin-system blockade is lower in Black patients than Whites.

Similarly, despite potentially less BP-lowering as monotherapy with β-blockers in Blacks, with compelling indications clinicians should utilize β-blockers (e.g., postmyocardial infarction and HF).[10] A recently approved β-blocker for the US market, nebivolol, has been shown to be as effective in Blacks for BP-lowering, as for the general population.[49] This novel vasodilatory β-blocker may improve nitric oxide availability, a factor of potential benefit in Blacks.[49]

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