Abstract
BACKGROUND
Several approaches to initiation of antihypertensive therapy have been suggested. These include thiazide diuretics (TDs) as the first drug in all patients, initial drug selection based on age and race criteria, or therapy selection based on measures of plasma renin activity (PRA). It is uncertain which of these strategies achieves the highest control rate with monotherapy in Stage-I hypertension. We sought to compare control rates among these strategies.
METHODS
We used data from the Pharmacogenomic Evaluation of Antihypertensive Responses study (PEAR) to estimate control rates for each strategy: (i) TD for all, (ii) age- and race-based strategy: Hydrochlorothiazide (HCTZ) for all blacks and for whites ≥50 years and a renin-angiotensin system inhibitor (atenolol) for whites <50 years) or (iii) a PRA based strategy: HCTZ for suppressed PRA (<0.6ng/ml/h) and atenolol for non-suppressed PRA (≥0.6ng/ml/h) despite age or race. Hypertension was confirmed prior to treatment with HCTZ (148 blacks and 218 whites) or with atenolol (146 blacks and 221 whites).
RESULTS
In the overall sample, using clinic blood pressure (BP) response, the renin-based strategy was associated with the greatest control rate (48.9% vs. 40.8% with the age and race-based strategy ( P = 0.0004) and 31.7% with the TD for all strategy ( P < 0.0001)). The findings were similar using home or by 24-hour ambulatory BP responses and within each racial subgroup.
CONCLUSIONS
A strategy for selection of initial antihypertensive drug therapy based on PRA was associated with greater BP control rates compared to a thiazide-for-all or an age and race-based strategy.
Keywords: antihypertensive drug therapy, atenolol, beta-blocker, blood pressure, hydrochlorothiazide, hypertension, plasma renin activity, thiazide diuretic.
INTRODUCTION
Elevated blood pressure (BP) is the most important risk factor for death and disability worldwide, affecting more than one billion individuals and causing an estimated 9.4 million deaths every year. Hypertension (HTN) is a major independent risk factor for stroke, chronic kidney disease, coronary artery disease, and heart failure. In the United States, more than $47.5 billion is spent each year on high-BP management. 1
Despite the availability of numerous drug options, the overall control rate among adults with HTN in the United States remains low at 52%. 2 , 3 The percentage of hypertensives in the optimal BP range is 18.6%. 2 Non-adherence, which increases as the number of drugs required increases 4 is the major reason for low-BP control rate. 5 Thus, for initial therapy, identification of the drug most likely to be effective in BP reduction is important.
HTN treatment guidelines suggest a thiazide diuretics (TDs) as the agent of first choice for initial therapy of most people with uncomplicated HTN (TD strategy). 6 However, BP response to any single antihypertensive drug is characterized by significant interindividual variation. 7 , 8 This variation in response is believed to be secondary to variation in the pathophysiologic mechanisms causing HTN and heterogeneity in the counterregulatory physiological responses to BP reduction. 9 , 10 The renin-angiotensin-aldosterone system (RAAS) plays a major role in BP regulation and the activity of this system varies among individuals with HTN. 11 , 12
Initial drug selection based on an estimation of the activity of the RAAS has been extensively supported by Laragh and colleagues. 13 , 14 This strategy is based on the hypothesis that individuals with high (non-suppressed) plasma renin activity (PRA) have vasoconstriction-dependent HTN mediated by angiotensin II, directing initial therapy to drugs that directly block renin release or the formation or action of angiotensin II (RAS inhibitors), while individuals with low (suppressed) PRA are hypothesized to have sodium volume–dependent HTN, directing initial therapy to a diuretic. 14
Others have suggested that age and race criteria can serve as useful surrogates for PRA. In this strategy, a TD is recommended for older whites or blacks of any age and a RAS blocker is recommended for younger whites.
In a previous study of adults with stage 1 HTN, we demonstrated that initial drug selection based on PRA was associated with higher BP control rates compared to drug selection based on age and race criteria or TD as the initial drug of choice for all. 15 In this previous study, the angiotensin receptor blocker candesartan was used as the RAS blocker and BP response was based on change in office BP. The objective of the present study is to confirm our previous findings in a separate cohort using a different RAS blocking drug (atenolol) and using more comprehensive measures of BP response including both home and 24-hour ambulatory BP in addition to office measures.
METHODS
Study population
This study is a retrospective analysis of data previously collected in the PEAR-1 study. The PEAR-1 study was a prospective, multicenter, randomized, open-label, parallel group study with a primary focus on identifying the genetic determinants of antihypertensive and adverse metabolic responses to a TD (hydrochlorothiazide (HCTZ)), a beta-blocker (atenolol) and their combination. Full details of the PEAR study methodology have been reported elsewhere. 16
Briefly, the study cohort consisted of males and females, of any race and ethnicity, aged 17 to 65 at enrollment who had newly diagnosed, untreated, or known mild-to-moderate essential HTN (stage 1–2 primary HTN defined by average home diastolic BP (DBP) >85mm Hg and office DBP >90mm Hg) treated with two or fewer antihypertensive medications. Study participants were enrolled at the University of Florida (Gainesville, FL), Emory University (Atlanta, GA) and Mayo Clinic (Rochester, MN). Following enrolment, all antihypertensive therapy was discontinued in treated participants. After an average washout period of 4 weeks, HTN was confirmed and participants were randomly assigned to receive monotherapy with either atenolol or HCTZ. Participants received 50mg of atenolol daily or 12.5mg of HCTZ daily, titrated to 100mg daily or 25mg daily respectively, if BP remained above 120/70mm Hg after 3 weeks. Participants remained on drug monotherapy for a total of 9 weeks. Home BP was monitored throughout the 9-week treatment period and 24-hour ambulatory BP was measured at the end of the washout period and repeated at the end of the treatment period. All individuals provided written informed consent to participate. The study was approved by the institutional review board at each study site.
Patients were excluded if they had an office or average home SBP >180mm Hg or DBP >110mm Hg, secondary forms of HTN (including sleep apnea), isolated systolic HTN, known cardiovascular disease, heart rate <55 beats per minute (bpm) in the absence of beta-blocker therapy, diabetes mellitus (type 1 or 2) or screening fasting blood glucose >126mg/dl, primary renal disease, concomitant diseases treated with BP-lowering medications, or chronic treatment with BP-elevating drugs
Laboratory analyses
Plasma samples were assayed in duplicate or triplicate, and participant’s average values were used in the analyses. Plasma analytes were measured on a Hitachi 911 Chemistry Analyzer (Roche Diagnostics, Indianapolis, IN). PRA was measured by radioimmunoassay of angiotensin I according to the method of Sealey using reagents purchased from DiaSorin (Stillwater, MN). The incubation period for angiotensin I generation was 3 hours. 17
Statistical analyses
Data were summarized by calculating means and SDs or medians and upper and lower quartiles for quantitative variables and percentages for categorical variables. P values for differences in quantitative variables were calculated using analysis of variance for variables that were normally distributed and the Mann–Whitney rank sum test for quantitative variables that were not normally distributed. In all analyses, statistical significance was inferred when P < 0.05. Office BP was considered controlled if it was <140mm systolic and <90mm Hg diastolic at the end of drug therapy. The corresponding values indicating control for home BP were <135mm Hg systolic and <85mm Hg diastolic and for 24-hour ABMP were <130mm Hg systolic and <80mm Hg diastolic. Control rates were calculated for the following three strategies: (i) HCTZ for all subjects (TD strategy); (ii) HCTZ for all black subjects and for white subjects aged ≥50 years, with atenolol for white subjects aged <50 years (age and race strategy); and (iii) HCTZ if PRA < 0.6ng/ml/h (suppressed PRA) and atenolol if PRA ≥ 0.6ng/ml/h (non-suppressed PRA; PRA strategy).
A formal test of the null hypothesis of equality of BP control rates between two strategies was because each strategy involves a choice between one of two antihypertensive drugs within each of eight age, race, and PRA strata. Within each of these eight strata, the difference in BP control rates was calculated as the difference between two binomial proportions as previously described. 15
RESULTS
Sample description
The overall sample consisted of 294 (40%) black subjects and 439 (60%) white subjects; 391 (53.3%) were women. On average, subjects were overweight or obese (body mass index = 30.8±5.6kg/m 2 ), had a clinic SBP of 151.7 (±12.6) mm Hg and clinic DBP of 98.5 (±6.1) mm Hg ( Table 1 ). There were no significant differences between the treatment groups (atenolol vs. HCTZ) in mean age, gender, BMI, baseline BP (in all settings/measures), heart rate, and baseline PRA. This was true between the overall treatment groups and between treatment groups within each racial subgroup.
Table 1.
Subject characteristics
| Overall | Black | White | |||||
|---|---|---|---|---|---|---|---|
| Atenolol | HCTZ | P value | Atenolol | HCTZ | P value | ||
| No (%) | 733 (100%) | 146 | 148 | 221 | 218 | ||
| Age, years | 49.0 (9.2) | 47.3 (8.5) | 47.4 (8.7) | 0.8795 | 49.9 (9.5) | 50.4 (9.3) | 0.5793 |
| Female No. (%) | 391 (53.3%) | 104 (71.2%) | 92 (62.2%) | 0.0990 | 105 (47.5%) | 90 (41.3%) | 0.1892 |
| BMI kg/m 2 | 30.8 (5.6) | 31.4 (6.3) | 31.5 (5.4) | 0.8990 | 30.4 (5.7) | 30.3 (5.0) | 0.8923 |
| Baseline Clinic SBP | 151.7 (12.6) | 151.2 (12.2) | 151.8 (13.4) | 0.6627 | 151.5 (12.4) | 152.2 (12.5) | 0.5668 |
| Post-treatment Clinic SBP | 138.9 (15.0) | 142.6 (16.7) | 136.2 (14.5) | 0.0005 | 136.1 (14.8) | 141.0 (13.6) | 0.0003 |
| Systolic Clinic BP (End − Baseline) | −12.8 (14.9) | −8.6 (16.8) | −15.6 (14.4) | 0.0001 | −15.4 (15.0) | −11.2 (13.0) | 0.0017 |
| Baseline Clinic DBP | 98.5 (6.1) | 98.9 (6.8) | 99.4 (6.2) | 0.5042 | 98.0 (5.8) | 98.1 (5.9) | 0.8369 |
| Post-treatment Clinic DBP | 90.1 (9.4) | 91.4 (10.2) | 90.1 (8.6) | 0.2667 | 86.1 (9.0) | 93.1 (8.4) | <0.0001 |
| Diastolic Clinic BP (End − Baseline) | −8.4 (9.1) | −7.5 (9.7) | −9.3 (8.7) | 0.1086 | −11.9 (9.2) | −5.0 (7.3) | <0.0001 |
| Baseline Home SBP | 145.8 (10.4) | 145.0 (10.5) | 147.3 (11.6) | 0.0692 | 145.1 (9.6) | 146.2 (10.1) | 0.2430 |
| Post-treatment Home SBP | 137.2 (12.5) | 141.9 (13.1) | 135.6 (13.3) | 0.0001 | 134.0 (12.5) | 138.4 (10.2) | 0.0001 |
| Systolic Home BP (End − Baseline) | −8.7 (9.9) | −3.1 (10.4) | −11.7 (9.7) | <0.0001 | −11.1 (9.5) | −7.8 (8.5) | 0.0002 |
| Baseline Home DBP | 93.8 (6.0) | 94.0 (6.4) | 95.2 (6.5) | 0.1109 | 92.9 (5.6) | 93.6 (5.5) | 0.1663 |
| Post-treatment Home DBP | 87.3 (8.2) | 89.8 (8.5) | 88.3 (8.3) | 0.1239 | 83.0 (7.4) | 89.3 (6.9) | <0.0001 |
| Diastolic Home BP (End − Baseline) | −6.5 (6.7) | −4.2 (6.6) | −6.9 (6.6) | 0.0004 | −9.9 (6.5) | −4.3 (5.4) | <0.0001 |
| Baseline 24-hour ambulatory SBP | 138.5 (11.0) | 137.5 (10.1) | 139.0 (12.3) | 0.2715 | 138.1 (10.5) | 139.2 (11.2) | 0.3040 |
| Post treatment 24-hour ambulatory SBP | 127.6 (11.5) | 130.4 (12.4) | 126.2 (10.8) | 0.0036 | 123.7 (10.8) | 130.6 (10.8) | <0.0001 |
| Systolic 24-hour ambulatory (End − Baseline) | −10.9 (10.7) | −6.4 (10.7) | −13.0 (9.5) | <0.0001 | −14.3 (10.6) | −8.9 (10.3) | <0.0001 |
| Baseline 24-hour ambulatory DBP | 87.3 (8.0) | 87.0 (8.1) | 87.8 (7.8) | 0.4310 | 87.0 (7.3) | 87.5 (8.7) | 0.5228 |
| Post treatment 24-hour ambulatory DBP | 79.9 (8.4) | 81.0 (8.7) | 79.9 (7.7) | 0.2742 | 76.3 (7.2) | 82.7 (8.6) | <0.0001 |
| Diastolic 24-hour ambulatory (End − Baseline) | −7.2 (7.8) | −5.5 (7.3) | −7.8 (7.2) | 0.0105 | −10.5 (8.0) | −4.7 (7.2) | <0.0001 |
| Baseline Renin | 1.0 (1.1) | 0.6 (0.6) | 0.6 (0.8) | 0.6705 | 1.3 (1.3) | 1.2 (1.2) | 0.7074 |
| Post treatment Renin | 1.3 (1.7) | 0.3 (0.4) | 1.5 (1.7) | <0.0001 | 0.5 (0.6) | 2.5 (2.1) | <0.0001 |
| P value (change in renin after treatment) | 0.0076 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | ||
| Number of Baseline Renin < 0.6 | 335 (47.1%) | 95 (66.4%) | 99 (70.2%) | 0.4937 | 67 (31.0%) | 74 (34.9%) | 0.3935 |
| Number of End Renin < 0.6 | 327 (52.2%) | 113 (89.0%) | 50 (38.8%) | <0.0001 | 146 (78.9%) | 18 (9.7%) | <0.0001 |
| Renin (End − Baseline) | 0.3 (1.6) | −0.2 (0.5) | 0.9 (1.5) | <0.0001 | −0.8 (1.2) | 1.3 (1.7) | <0.0001 |
| Heart rate, bpm (end of washout) | 77.6 (9.4) | 79.7 (9.1) | 78.9 (9.6) | 0.5141 | 76.7 (9.2) | 76.3 (9.5) | 0.6599 |
| Heart rate, bpm after treatment | 72.5 (11.4) | 68.7 (9.7) | 81.0 (9.5) | <0.0001 | 63.9 (7.7) | 77.8 (9.6) | <0.0001 |
| P value (change in heart rate with treatment) | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 | ||
Abbreviations: BMI, body mass index; bpm, beats per minute; DBP, diastolic blood pressure; HCTZ, Hydrochlorothiazide; SBP, systolic blood pressure. Continuous variables were summarized as mean (standard deviation) with P values for the differences between groups calculated using the analysis of variance test. Discrete variables were summarized as frequency (group percentage) with P values for the differences between groups calculated using the χ 2 test. Statistical significance was inferred when P < 0.05. SAS version 9.3 (SAS Institute, Cary, NC) or higher was used for analyses.
Heart rate and PRA decreased significantly in both racial subgroups treated with atenolol ( P < 0.0001 for both). In contrast, heart rate and PRA increased significantly in both racial subgroups treated with HCTZ ( P < 0.0001 for both).
In black subjects overall: clinic, home and 24-hour ambulatory SBP and DBP responses were greater with HCTZ than with atenolol ( P = 0.0001 and P = 0.109 for clinic BP, P < 0.0001 and P = 0.0004 for home BP and P < 0.0001 and P = 0.01 for 24-hour ambulatory BP). In white subjects overall, the reverse was true—clinic, home and 24-hour ambulatory SBP and DBP responses were greater with atenolol than with HCTZ ( P = 0.0017 and P < 0.0001 for clinic BP, P = 0.0002, and P < 0.0001, for home BP and P < 0.0001 and <0.0001 for 24-hour ambulatory BP).
BP control rate by treatment strategy
In the overall sample, the strategy of drug selection based on pretreatment PRA was associated with the highest control rate for all BP response measures: clinic BP (48.9% with the PRA strategy vs. 40.8% with the age and race strategy [ P = 0.0004] and 31.7% with the TD strategy ( P < 0.0001), home BP 42.6% with the PRA strategy vs. 36.1% with the age and race strategy ( P = 0.0026) and 26.4% with the TD strategy ( P < 0.0001)) and 24-hour ambulatory BP (61.3% with the PRA strategy vs. 51.6% with the age and race strategy ( P < 0.0001) and 43.9% with the TD strategy ( P < 0.0001, Table 2 ).
Table 2.
Overall blood pressure control rates by treatment strategy
| Treatment strategy | Clinic BP (<140/90) | Home BP (<135/85) | 24-hour ambulatory BP (<130/80) |
|---|---|---|---|
| TD | 31.7 | 26.4 | 43.9 |
| Age–Race | 40.8 | 36.1 | 51.6 |
| PRA | 48.9 | 42.6 | 61.3 |
| Age–Race vs. TD P value | <0.0001 | <0.0001 | <0.0001 |
| PRA vs. TD P value | <0.0001 | <0.0001 | <0.0001 |
| PRA vs. Age–Race P value | 0.0004 | 0.0026 | <0.0001 |
Blood pressure control rate defined as percentage of subjects with BP < 140/90mm Hg for clinic, < 135/85 for home BP and < 130/80 for 24-hour ambulatory BP. Thiazide diuretic (TD) strategy was hydrochlorothiazide in all subjects. Age/race strategy was hydrochlorothiazide in all black subjects and in white subjects aged ≥50 years and atenolol in white subjects aged <50 years. Plasma renin activity (PRA) strategy was hydrochlorothiazide for pretreatment PRA < 0.6ng/ml/h and atenolol for pretreatment PRA ≥ 0.6ng/ml/h.
In blacks, the strategy of drug selection based on pretreatment PRA was also associated with a higher control rate than drug selection based on the other two strategies, both of which directed the use of a TD for all subjects: clinic BP 46.7% with the PRA strategy vs. 41.4% for both the age and race strategy and TD strategy ( P = 0.08 for both), home BP 37% with the PRA strategy vs. 33.6% for both the age and race strategy and TD strategy ( P = 0.25 for both) and 24-hour ambulatory BP 57.9% with the PRA strategy vs. 52.6% for both the age and race strategy and TD strategy ( P = 0.099 for both; Table 3 ). The higher control with the PRA strategy was largely due to a higher control rate with atenolol than HCTZ in blacks with non-suppressed PRA (clinic BP 54.2% vs. 35.7%; P = 0.08, home BP 37.5% vs. 26.8% P = 0.25 and 24-hour ambulatory BP 62.5% vs. 45.2%, P = 0.1; Table 4 ). In blacks with suppressed PRA, the control rate was higher with HCTZ than with atenolol (clinic BP 43.4% vs. 14.3%, P < 0.0001, home BP 36.8% vs. 17.4%, P = 0.002 and 24-hour ambulatory BP 55.7% vs. 37.8%, P = 0.011; Table 4 ).
Table 3.
Comparing blood pressure control between black and white based on the location and treatment strategy
| Clinic blood pressure | Home blood pressure | 24-hour ambulatory blood pressure | ||||
|---|---|---|---|---|---|---|
| Black | White | Black | White | Black | White | |
| TD | 41.1 | 25.4 | 33.6 | 21.6 | 52.6 | 38.2 |
| Age–race | 41.1 | 40.6 | 33.6 | 37.7 | 52.6 | 50.9 |
| PRA | 46.7 | 50.3 | 37 | 46.3 | 57.9 | 63.5 |
| Age–race vs. TD P value | — | <0.0001 | — | <0.0001 | — | <0.0001 |
| PRA vs. TD P value | 0.08 | <0.0001 | 0.2530 | <0.0001 | 0.0994 | <0.0001 |
| PRA vs. age–race P value | 0.08 | 0.0020 | 0.2530 | 0.0044 | 0.0994 | <0.0001 |
Control rates were calculated for the following four strategies: (i) hydrochlorothiazide (HCT) for all subjects (TD strategy); (ii) HCT for all black subjects and for white subjects aged ≥50 years, with atenolol for white subjects aged <50 years (age/race strategy); and (iii) HCT if plasma renin activity (PRA) < 0.6ng/ml/h (suppressed PRA) and atenolol if PRA ≥ 0.6ng/ml/h (non-suppressed PRA; PRA strategy).
Table 4.
Clinic blood pressure control rates for each drug by PRA and age criteria
| Blood pressure control rate, % | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall sample | Black subjects | White subjects | ||||||||||
| Drug | PRA < 0.6ng/ml/h | PRA ≥ 0.6ng/ml/h | PRA < 0.6ng/ml/h | PRA ≥ 0.6ng/ml/h | Aged <50 years | Aged ≥50 years | PRA < 0.6ng/ml/h | PRA ≥0.6ng/ml/h | Aged <50 years | Aged ≥50 years | ||
| Clinic | HCT | 35 | 28.9 | 43.4 | 35.7 | 40.5 | 42.2 | 23.8 | 26.8 | 26.1 | 25.4 | |
| Atenolol | 21.2 | 62.4 | 14.3 | 54.2 | 25.3 | 30.5 | 30.6 | 65.1 | 63.5 | 46.4 | ||
| P value | 0.0040 | <0.0001 | <0.0001 | 0.0795 | 0.0344 | 0.1791 | 0.3452 | <0.0001 | <0.0001 | 0.0005 | ||
| Home | HCT | 34.4 | 18.9 | 36.8 | 26.2 | 34.5 | 32.8 | 31.3 | 16.7 | 21.7 | 22.2 | |
| Atenolol | 22.4 | 50.8 | 17.4 | 37.5 | 21.8 | 27.1 | 29.2 | 55.0 | 59.4 | 36.8 | ||
| P value | 0.0120 | <0.0001 | 0.0019 | 0.2521 | 0.0650 | 0.4915 | 0.7801 | <0.0001 | <0.0001 | 0.0113 | ||
| 24-hour ambulatory | HCT | 51.1 | 37.2 | 55.7 | 45.2 | 57.1 | 46.9 | 45.0 | 34.8 | 42.4 | 35.7 | |
| Atenolol | 45.3 | 71.1 | 37.8 | 62.5 | 50.6 | 39.0 | 55.6 | 73.8 | 71.9 | 64.8 | ||
| P value | 0.2756 | <0.0001 | 0.0105 | 0.1009 | 0.3891 | 0.3772 | 0.1937 | <0.0001 | <0.0001 | <0.0001 | ||
Abbreviations: HCT, hydrochlorothiazide; PRA, plasma renin activity.
In white subjects, the strategy of drug selection based on pretreatment PRA was also associated with a higher control rate than drug selection based on either of the other 2 strategies for all BP measures: clinic BP 50.3% with the PRA strategy vs. 40.6% with the age and race strategy ( P = 0.002) and 25.4% with the TD strategy ( P < 0.0001), home BP 46.3% with the PRA strategy vs. 37.7% with the age and race strategy ( P = 0.004) and 21.6% with the TD strategy ( P < 0.0001) and 24-hour ambulatory BP 63.5% with the PRA strategy vs. 50.9% with the age and race strategy ( P < 0.0001) and 38.2% with the TD strategy ( P < 0.0001; Table 3 ).
Consistent with the findings in blacks with non-suppressed PRA, control rates were higher with atenolol than with HCTZ in whites with non-suppressed PRA—clinic BP 65.1% vs. 26.8%; P < 0.0001, home BP 55 % vs. 16.7%; P < 0.0001 and 24-hour ambulatory BP 73.8% vs. 34.8%, P < 0.0001; Table 4 ). However, in contrast to the findings in blacks, control rates in whites with suppressed PRA were not significantly different between atenolol and HCTZ. In addition, in whites control rates were also higher with atenolol than with HCTZ in both age strata (aged <50 years: clinic BP: 63.5 % vs. 26.1%, P < 0.0001, home BP: 59.4% vs. 21.7% P < 0.0001 and 24-hour ambulatory BP: 71.9% vs. 42.4%, P < 0.0001; aged ≥50 years: clinic BP: 46.4% vs. 25.4 %, P = 0.0005, home BP: 36.8% vs. 22.2% P = 0.01 and 24-hour ambulatory BP: 64.8% vs. 35.7%, P < 0.0001.
Effect of race and age on PRA
Within each age stratum (< or ≥50 years of age), the proportion in each PRA stratum differed significantly by race ( P < 0.0001 for all comparisons; Table 5 ). The majority of blacks were in the suppressed PRA stratum (PRA < 0.6ng/ml/h) with no difference in the proportion within each PRA stratum across age strata. In contrast, the majority of whites were in the non-suppressed PRA stratum (PRA ≥ 0.6ng/ml/h) with an increase in the proportion of suppressed PRA subjects in the aged ≥50 year stratum. Therefore, age influenced PRA status in whites more than in blacks.
Table 5.
Effect of race and age on PRA classification
| Age < 50 | Age ≥ 50 | |||||
|---|---|---|---|---|---|---|
| PRA classification | White subjects ( n = 188) | Black subjects ( n = 171) | P value | White subjects ( n = 251) | Black subjects ( n = 123) | P value |
| Suppressed PRA, No. (%) | 41 (22%) | 109 (64%) | <0.0001 | 100 (40%) | 85 (69%) | <0.0001 |
| Non-suppressed PRA, No. (%) | 140 (74%) | 56 (33%) | <0.0001 | 147 (59%) | 34 (28%) | <0.0001 |
Abbreviation: PRA, plasma renin activity.
Effects of race, age, and renin classification on differences in response to HCTZ vs. atenolol
Differences in office systolic and DBP responses (mean, 95% confidence interval (CI)) with HCTZ vs. atenolol for each racial subgroup overall and by age/PRA strata within each racial subgroup are shown in Figure 1 . All values were adjusted for baseline BP, age, and sex.
Figure 1.
Differences in office ( a ) systolic (SBP) and ( b ) diastolic blood pressure (DBP) response (mean, 95% confidence interval (CI)) with hydrochlorothiazide (HCT) vs. atenolol for each racial subgroup overall and by age/plasma renin activity (PRA) strata.
Overall in blacks, compared to treatment with atenolol, treatment with HCTZ was associated with a greater decrease in both mean SBP response (by −7mm Hg (95% CI = −3.4 to −10.7mm Hg; P = 0.0001)) and mean DBP response (by −1.7mm Hg (95% CI = −0.42 to −3.88mm Hg; P = 0.11)).
In blacks with suppressed PRA, compared to treatment with atenolol, treatment with HCTZ was associated with a greater decrease in both mean SBP response (by −10.6mm Hg (95% CI = −6.3 to −14.9mm Hg; P < 0.0001)) and mean DBP response (by −4.26mm Hg (95% CI −1.9 to −6.6; P = 0.0005)) and this response difference was consistent across age strata.
In young blacks with non-suppressed PRA, compared to treatment with HCTZ, treatment with atenolol was associated with a greater decrease in both mean SBP response (by −6.12mm Hg (95% CI −1.8 to 14, P = 0.13) and mean DBP response (by −6.78mm Hg (95% CI −1.3 to −12.3; P = 0.015)). However, in older blacks with non-suppressed PRA, there were no differences in responses between HCTZ and atenolol.
Overall, in whites, compared to treatment with HCTZ, treatment with atenolol was associated with a greater decrease in both mean SBP response (by −4.22mm Hg [95% CI = -1.5 to −6.9mm Hg]; P = 0.0017) and DBP response (by −6.9mm Hg [95% CI = −5.3 to −8.5mm Hg]; P < 0.0001).
In whites with suppressed PRA, there was no difference in response with atenolol compared to HCTZ for either SBP or DBP ( P = 0.26, and P = 0.12 respectively); this was also true in both age strata. In whites with non-suppressed PRA, compared to treatment with HCTZ, treatment with atenolol was associated with a greater decrease in both mean SBP response (by −7.7mm Hg [95% CI = −4.4 to −11mm Hg; P <0.0001]) and DBP response (by −9.4mm Hg [95% CI −7.4 to −11.3]; P < 0.0001) and this response difference was consistent across age strata.
The findings above were also observed for the home and 24-hour ambulatory BP responses, shown in Supplementary Figures 1 and Supplementary Data .
DISCUSSION
In choosing an initial medication for treatment of uncomplicated HTN, three strategies have been suggested to help guide selection. These strategies are TD for all or drug selection based on age and race criteria or PRA. The results of the present analysis confirm our previous findings that drug selection based on PRA is associated with a higher BP control rate than either alternative strategy. This was true for the sample overall and for each racial subgroup. The present study not only confirms the previous study but also extends it to a different RAS blocker and to more robust measures of BP response that included home and ambulatory BP responses.
Beta-blockers are known to inhibit the RAAS. A study conducted by Laragh and colleagues found that beta-blocker therapy (propranolol) reduced plasma renin levels by blocking sympathetically (beta-1)-mediated renin release by the kidney in subjects with several types of HTN. 18 Their results demonstrated a strong correlation between reduction in PRA (by about 75%) and reductions in BP. Propranolol was also found to reduce aldosterone levels. They concluded that blocking the RAAS pharmacologically was a practical therapeutic strategy for HTN. Another study revealed that treating hypertensive subjects with a beta-blocker suppressed angiotensin II and PRA simultaneously. 19 Along with suppression of renin release, some evidence also exists suggesting that beta blockade could potentially inhibit intrarenal conversion of prorenin to renin. 19 , 20 Although beta-blockers lower BP through renin-dependent and renin-independent mechanisms (reduced heart rate and cardiac output), multiple studies have favored a greater effect in subjects with non-suppressed renin. 18 , 21
As expected, the baseline home BP was lower than the baseline clinic BP. Thus, the absolute BP responses to treatment were less when measured by home than by office BP. Overall in black subjects, average systolic BP response was greater to the TD (HCTZ) than to the RAAS blocking drug (atenolol). This is consistent with previous studies that were conducted by Schwartz et al . 15 and others. 22 An adequate explanation for this is that the majority of hypertensive black subjects have suppressed values of PRA, which our study confirmed.
As previously reported in whites, average BP response to the RAAS-blocking drug was greater than to the TD. This can be partially explained by the higher prevalence of non-suppressed PRA in whites. 15 However, our data suggest that not all of the racial difference in response to atenolol vs. HCTZ can be explained by differences in PRA status. This is demonstrated by the observation that although the BP control rate was higher with atenolol than HCTZ overall in whites, and especially for the subgroup with non-suppressed PRA in both age strata, BP control rate was not higher with HCTZ than atenolol in whites with suppressed PRA.
Without considering PRA status, young whites (<50) responded better to atenolol than HCTZ for both systolic and diastolic ( P = 0.004 and P < 0.0001, respectively). However, BP response was similar with HCTZ and atenolol among older whites (>50) except the DBP ( Figure 1 ).
In older whites (>50), non-suppressed PRA predicted a greater BP response to atenolol than HCTZ ( Table 6 ); whereas in younger whites response was greater with atenolol than HCTZ regardless of PRA status. This explains why the PRA strategy was superior to the TD for all strategy previously recommended by the Joint National Committee 7, 23 and the age and race strategy that directs selection of HCTZ for all older whites.
Table 6.
Comparing the delta change in systolic and diastolic BP between hydrochlorothiazide and atenolol in subgroups
| Change in BP | |||||
|---|---|---|---|---|---|
| Black subjects aged <50 | White subjects aged ≥50 | ||||
| With non-suppressed renin (PRA ≥ 0.6) | With non-suppressed renin (PRA ≥ 0.6) | ||||
| Systolic BP | Diastolic BP | Systolic BP | Diastolic BP | ||
| Clinic | HCT | −8.4 | −4.4 | −10 | −3.9 |
| Atenolol | −14.5 | −11.2 | −18 | −12.5 | |
| P value | 0.13 | 0.015 | 0.0016 | <0.0001 | |
| Home | HCT | −8.5 | −4.9 | −7.8 | −4.2 |
| Atenolol | −6.2 | −6.3 | −13.4 | −10.1 | |
| P value | 0.33 | 0.47 | 0.0004 | <0.0001 | |
| 24-hour ambulatory | HCT | −8.7 | −6.5 | −8.7 | −3.8 |
| Atenolol | −10.5 | −8.2 | −17.2 | −11.0 | |
| P value | 0.53 | 0.37 | <0.0001 | <0.0001 |
Abbreviations: BP, blood pressure; HCT, hydrochlorothiazide; PRA, plasma renin activity.
In contrast, in blacks, non-suppressed PRA predicted a greater BP response to atenolol than to HCTZ in young individuals ( Table 6 ). The greater response in young blacks with non-suppressed PRA to atenolol than to HCTZ explains why the PRA strategy was superior to the other two strategies that directed treatment with HCTZ for all individuals.
Previous research conducted by Laragh and colleagues supported measurement of PRA in all hypertensive patients to direct initial antihypertensive drug selection. 13 , 14 However, this approach has been controversial and not adopted in most published guidelines. A study conducted by the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents (VACSG) that included a sample of 1,031 hypertensive black and white men randomized to six different monotherapies concluded that combining age (younger or older than 60 years) and race (black or white) was as effective as measuring PRA for initial drug selection and was preferable because it did not require the additional time and expense of laboratory measurements. 24
The results of our study demonstrate that in white subjects ≥50 years of age, knowledge of PRA status provided additional information for drug selection, as atenolol was significantly more effective than HCTZ in this group when PRA was non-suppressed. However, atenolol was more effective than HCTZ in all whites <50 years of age regardless of PRA status. These results indicate that a RAS blocking agent (atenolol) is preferred in whites <50 years of age across PRA strata and in subjects older than 50 years with non-suppressed PRA.
In black subjects, knowledge of PRA status also provides additional information for drug selection as atenolol was significantly more effective in blacks <50 years of age when PRA was non-suppressed whereas in older blacks HCTZ was significantly more effective than atenolol regardless of PRA status. These results indicate that a TD is preferred in blacks ≥50 years of age across PRA strata and in blacks <50 years of age with suppressed PRA.
Based on these observations, a combination of PRA and age and race criteria may be the most effective strategy for selecting initial antihypertensive drug therapy. We propose an optimal strategy that combines age and race and PRA for drug selection. 15 This strategy directs a RAS blocker for all whites <50 years of age without measurement of PRA, whereas for whites ≥50 years of age drug selection should be based on PRA measurement. Drug selection in blacks <50 years of age would be guided by PRA measurement, whereas blacks ≥50 years of age would be given a diuretic without measurement of PRA.
The results of the present study should be viewed in light of its limitations. This was a retrospective analysis of data from a multicenter prospective randomized study. Additionally, our study population was limited to individuals who were aged <60 years, precluding the assessment of the predictive value of age on drug response in those who are above the age of 60. Assessment of BP control rates by selection strategy is limited to a relatively short period of observation. Long-term control with each drug was not assessed. Another limitation is that the practical application of renin profiling would be facilitated by a point-of-care renin test, which is currently not available.
CONCLUSION
These results suggest that initial antihypertensive drug selection based on PRA is associated with greater BP control than selection based on age and race criteria or a strategy that recommends a TD for all.
SUPPLEMENTARY MATERIAL
Supplementary materials are available at American Journal of Hypertension ( Supplementary Data ).
DISCLOSURE
The authors declared no conflict of interest.
Supplementary Material
ACKNOWLEDGMENT
This study had financial support from the Pharmacogenomics Research Network (PGRN U01 GM074492) and the National Center for Advancing Translational Sciences Clinical and Translational Science Award (NIH NCATS: UL1 TR000064, UL1TR000454, UL1 TR000135). PEAR efforts at the Mayo Clinic were also supported by funds from the Mayo Foundation.
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