Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension

Abstract

Background: Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood.

Methods: Using systematic-phased approach, PRA's clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed.

Results: EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by -15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%.

Conclusions: PRA at the previously established 0.60-0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs.

Trial registration: NCT01203852, NCT00246519, NCT00005520.

Keywords: African Americans; European Americans; blood pressure; hypertension; plasma renin activity.

© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Flow chart showing the analytic steps undertaken in this study according to Pletcher’s systematic-phased approach. Abbreviations: AA, African American; EA, European American; GERA, Genetic Epidemiology of Responses to Antihypertensives; NPV, negative predictive value; PEAR, Pharmacogenomics Evaluation of Antihypertensive Responses; PPV, positive predictive value; PRA, plasma renin activity; RCTs, randomized controlled clinical trials; ROC, receiver operating characteristic; SBP, systolic blood pressure.

Figure 2.

Adjusted mean differences in systolic blood pressure (SBP) response (mean, 95% confidence interval (CI)) to chlorthalidone vs. metoprolol by plasma renin activity (PRA) subgroup in PEAR-2 EA and AA participants. All values are adjusted for baseline SBP. A positive value in the adjusted SBP response difference indicates a participant had a better response to metoprolol than to chlorthalidone, whereas a negative value in the adjusted SBP response difference indicates a participant had a better response to chlorthalidone than to metoprolol. Abbreviations: AA, African American; EA, European American; PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses.

Figure 3.

Receiver operating characteristic curve of plasma renin activity (PRA) biomarker in PEAR-2 EA participants (n = 134), where the vertical axis shows whether or not the difference in systolic blood pressure response to chlorthalidone than that to metoprolol was at least 5 mm Hg better. The area under the curve (AUC) was 0.69 (95% confidence interval (CI) = 0.60 to 0.76, P = 0.0001); the optimal cut point value with the highest Youden index (0.33) was 0.6 ng/ml/hour with a sensitivity of 48.3% and a specificity of 85.1%. Abbreviations: EA, European American; PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses;.

Figure 4.

Pooled adjusted mean differences in systolic blood pressure (SBP) response (mean, 95% confidence interval (CI)) to hydrochlorothiazide (HCTZ) vs. atenolol/candesartan in a meta-analysis of PEAR-1 and GERA AA cohorts by the different PRA subgroups based on the PEAR-2-derived plasma renin activity (PRA) cut point. All the values are adjusted for baseline SBP. A positive value in the pooled adjusted SBP response difference indicates AA participant had a better response to atenolol/candesartan than to HCTZ, whereas a negative value in the pooled adjusted SBP response difference indicates AA participant had a better response to HCTZ than to atenolol/candesartan. Abbreviations: AA, African American; GERA, Genetic Epidemiology of Responses to Antihypertensives; PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses.