Age-Race Subgroup Compared With Renin Profile as Predictors of Blood Pressure Response to Antihypertensive Therapy

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1 Clinical Cardiology Age-Race Subgroup Compared With Renin Profile as Predictors of Blood Pressure Response to Antihypertensive Therapy Richard A. Preston, MD, MBA; Barry J. Materson, MD, MBA; Domenic J. Reda, MS; David W. Williams, MS; Robert J. Hamburger, MD; William C. Cushman, MD; Robert J. Anderson, PhD; for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents Context. Renin profiling and age-race subgroup may help select single-drug therapy for stage 1 and stage 2 hypertension. Objective. To compare the plasma renin profiling and age-race subgroup methods as predictors of response to single-drug therapy in men with stage 1 and 2 hypertension as defined by the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Design. The Veterans Affairs Cooperative Study on Single-Drug Therapy of Hypertension, a randomized controlled trial. Setting. Fifteen Veterans Affairs hypertension centers. Patients. A total of 1105 ambulatory men with entry diastolic blood pressure (DBP) of 95 to 109 mm Hg, of whom 1031 had valid plasma and urine samples for renin profiling. Interventions. Randomization to 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem (sustained release), or prazosin. Main Outcome Measure. Treatment response as assessed by percentage achieving goal DBP ( 90 mm Hg) in response to a single drug that corresponded to patients renin profile vs a single drug that corresponded to patients age-race subgroup. Results. Clonidine and diltiazem had consistent response rates regardless of renin profile (76%, 67%, and 80% for low, medium, and high renin, respectively, for clonidine and 83%, 82%, and 83%, respectively, for diltiazem for patients with baseline DBP of ). Hydrochlorothiazide and prazosin were best in lowand medium-renin profiles; captopril was best in medium- and high-renin profiles (low-, medium-, and high-renin response rates were 82%, 78%, and 14%, respectively, for hydrochlorothiazide; 88%, 67%, and 40%, respectively, for prazosin; and 51%, 83%, and 100%, respectively, for captopril for patients with baseline DBP of ). Response rates for patients with baseline DBP of 95 to 99 mm Hg by age-race subgroup ranged from 70% for clonidine to 90% for prazosin for younger black men, from 50% for captopril to 97% for diltiazem for older black men, from 70% for hydrochlorothiazide to 92% for atenolol for younger white men, and from 84% for hydrochlorothiazide to 95% for diltiazem for older white men. Patients with a correct treatment for their renin profile but incorrect for age-race subgroup had a response rate of 58.7%; patients with an incorrect treatment for their renin profile but correct for age-race subgroup had a response rate of 63.1% (P =.30). After controlling for DBP and interactions with treatment group, age-race subgroup (P.001) significantly predicted response to single-drug therapy, whereas renin profile was of borderline significance (P =.05). Conclusions. In these men with stage 1 and stage 2 hypertension, therapeutic responses were consistent with baseline renin profile, but age-race subgroup was a better predictor of response. JAMA. 1998;280: AMONG the more controversial issues in the practice of medicine is thechoiceof an initial antihypertensive agent in patients with stage 1 and stage 2 hypertension. 1-3 Inthegeneralpopulation,67% of hypertensive patients have stage 1 hypertension (diastolic blood pressure [DBP], mm Hg) and 22% have stage 2 hypertension ( mm Hg). 4 These groups are the most likely to benefit from single-drug therapy. Primary hypertension demonstrates heterogeneity in its response to specific types of drug therapy. Available antihypertensive drug classes elicit widely varying blood pressure responses among equally hypertensive patients. Although this phenomenon is generally recognized among clinicians, it has been addressed by relatively few large clinical trials. While the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC VI 1 ) recommends a diuretic or -blocker as the first- From the Division of Clinical Pharmacology, Department of Medicine (Dr Preston) and the Department of Medicine (Dr Materson), University of Miami School of Medicine, Miami, Fla; Cooperative Studies Program, Edward Hines Jr Veterans Affairs Hospital, Hines, Ill (Messrs Reda and Williams and Dr Anderson); Renal Section, Veterans Affairs Medical Center, Boston, Mass (Dr Hamburger); and Preventive Medicine Section, Veterans Affairs Medical Center, Memphis, Tenn (Dr Cushman). For a complete list of the members of the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents, see Am J Cardiol. 1996;78: Corresponding author and reprints: Richard A. Preston, MD, MBA, Division of Clinical Pharmacology and Pharmacokinetics and Clinical Research Center, Department of Medicine, University of Miami School of Medicine, 1500 NW 12th Ave, 15th Floor, West Tower, Miami, FL Clinical Cardiology section editors: Bruce Brundage, MD, University of California, Los Angeles School of Medicine; Margaret A. Winker, MD, Senior Editor, JAMA. This article is one of a series sponsored by the American Heart Association JAMA, October 7, 1998 Vol 280, No. 13 Predictors of Blood Pressure Response to Antihypertensive Therapy Preston et al

2 line agent, other antihypertensive medications are suggested for special conditions. Some data suggest that the renin profile is useful for evaluating the pathophysiology of primary hypertension and for planning its treatment The investigators of these studies suggest that the renin-profile model may be used to prospectively choose an initial antihypertensive drug, in addition to screening for secondary causes of hypertension and to estimate cardiovascular risk. These investigators suggest that biochemical stratification of patients by renin profile provides insight into the mechanisms contributing to hypertension and can be useful in predicting response to a particular antihypertensive drug. For example, diuretic therapy would be most effective in low-renin hypertension and least effective when renin levels are high. 5-6,8-10 Conversely, angiotensin-converting enzyme inhibitors and -adrenergic blockers, which potentially would be effective in patients with high renin levels, are expected to be less effective in low-renin hypertension. Therefore, plasma renin profiles have an important theoretical role in targeting specific antihypertensive therapies for the individual patient and for identifying drugs that may be ineffective. However, this model has not been tested prospectively in large numbers of patients comparing different classes of antihypertensive agents. A second method for selection of an initial antihypertensive agent is by age-racesubgroup. 11,12 Recently,theDepartment of Veterans Affairs Cooperative Study Group on Antihypertensive Agents published a trial of 1292 patients and determined that patients had different responses to different antihypertensive drugs based on their age-race subgroups. Specifically, younger black men responded best to diltiazem and atenolol, younger white men responded best to captopril and atenolol, older black men responded best to diltiazem or hydrochlorothiazide, and older white men responded best to atenolol or diltiazem. 11,12 To determine whether renin profiling or age-race subgroup identifies which antihypertensive drug is most likely to be effective as a single agent, we analyzed data from the Veterans Affairs Cooperative Study The objectives of this study were as follows: (1) to determine the response rates to each of 6 classes of antihypertensive agents based on renin profile and baseline DBP in a large study population, (2) to determine whether patients would respond to drugs in a manner compatible with that predicted by the renin-profile model for selecting an antihypertensive drug, and (3) to compare the response rates and changes in systolic blood pressure (SBP) and DBP of the renin-profile method ith the age-race subgroup method of choosing an initial antihypertensive agent in patients with stage 1 and stage 2 hypertension. METHODS Study Design The design of this study has been previously reported. 11,12 At the time of randomization, patients with a DBP of 95 to 109 mm Hg after receiving a placebo for 2 weeks were assigned with equal probability in a double-blind manner to 1 of 7 treatmentgroups:placeboor1of 6study drugs. Randomization was stratified by participating site. The drugs and their 24-hour doses(listed from initial to maximum dose) were hydrochlorothiazide (12.5, 25, and 50 mg daily), atenolol (25, 50, and 100 mg daily), clonidine (0.2, 0.4, and 0.6 mg in divided doses given twice daily), captopril (25, 50, and 100 mg in divided doses given twice daily), prazosin (4, 10, and 20 mg in divided doses given twice daily), and a sustained-release preparation of diltiazem (120, 240, and 360 mg in divided doses given twice daily). Prazosin was started at 1 mg given twice daily for 2 days to minimize the risk of hypotension with the first dose. All medications were started at the lowest dose, and the dose was increased every 2 weeks, as required, until a goal DBP of less than 90 mm Hg was reached without intolerance to the drug on 2 consecutive visits or until the maximal drug dose was reached. The blood pressure during treatment was taken as the mean of the blood pressures recorded during the last 2 visits during the titration phase. The group of patients randomized to placebo was not included in this analysis. We compared response rates (percentageofthoseachievinggoaldbp 90 mm Hg at the end of titration) and respective changes in SBP and DBP on the various drugs according to renin profile and baseline DBP. 5 This model indicates that a patient with a high-renin profile should respond best to either an angiotensin-converting enzyme inhibitor or a -blocker. On the other hand, a patient with a low-renin profile should respond to a thiazide diuretic, an 1 -blocker, or a calcium antagonist. 6 Patients with medium renin levels could receive any of the 6 drugs. We compared values of response rate and change in SBP and DBP for renin profile matched patients with the values obtained for patients receiving drugs that were found by our previous study to have the highest response rates based on age-race subgroup. 11,12 In this model, we selected the best 2 drugs from each age-race subgroup and determined the combined response rates and respective changes in SBP and DBP. The subgroups selected were younger ( 60 years) black patients receiving diltiazem or atenolol, older black patients receiving diltiazem or hydrochlorothiazide, younger white patients receiving captopril or atenolol, and older white patients receiving atenolol or diltiazem. We chose the best 2 drugs in each category because in any particular patient, there may be reasons for not prescribing a particular agent, or there may be adverse effects that result in use of the given drug being discontinued. Accordingly, we allowed for the possibility that the best drug in each category might not be suitable in every case. Renin Profiling Renin profiling was performed during the prerandomization phase while the patient was taking single-blind placebo medication. The patients reported to the hypertension unit by 8 AM and a blood sample for plasma renin activity was collected in a vacuum tube (B-D Vacutainer, Becton Dickinson, Franklin Lakes, NJ) containing potassium-edta at room temperature. The sample was centrifuged at room temperature within 1 hour of collection for 10 to 12 minutes at 1000g to 1200g. The plasma was separated, transferred to a polystyrene test tube (taking care not to include erythrocytes), and quick-frozen in a dry ice acetone or dry ice alcohol mixture. It was then sent to a central laboratory(r.j.h.) on dry ice along with an aliquot of a 24- hour urine specimen that had been collected over the previous 24 hours. Plasma samples that thawed before arrival at the central laboratory were excluded from the analysis. Plasma renin activity was determined by quantifying angiotensin I generated from endogenous substrate using the technique developed by Haber et al 14 as modified for use in our laboratory. 15 A radioimmunoassay kit (Clinical Assays, Gamma Coat 125I Plasma Renin Activity RadioimmunoassayKit,Travenol-GenentechDiagnostics, Cambridge, Mass) was used. Angiotensin I was generated at a ph of 5.5 using EDTA and phenylmethylsulfonylfluoride for inhibition of angiotensinconverting enzyme and angiotensinases. Sample dilution was minimized by using only 0.1 ml of buffer to adjust the ph of 1.0 ml of plasma. A standard generation time of 1.5 hours was used; samples having a plasma renin activity of 0.77 nmol L 1 h 1 (1.0 ng/ml/h) or less were reincubated for a total of 18 hours The coefficients of variation for replicate determination of the same samples used to JAMA, October 7, 1998 Vol 280, No. 13 Predictors of Blood Pressure Response to Antihypertensive Therapy Preston et al 1169

3 standardize the method were 5.6% (n = 24, 4 separate analyses) and of samples within a single assay, 4.7% (n = 12). A standard renin profiling curve was constructed by using normal volunteers who were given 3 test diets: less than 75 mmol/d (low), 75 to 150 mmol/d (medium), and more than 150 mmol of sodium/d (high) with a potassium content of 50 to 80 mmol/d. Patients from the current study were categorized as having low-, medium-, or high-renin essential hypertension if their values fell below, within, or above the 90% confidence limits for this plasma renin activity vs sodium excretion curve Statistical Methods To determine whether the treatment groups were comparable at baseline, we compared mean age, SBP, heart rate, 24-hour urine sodium excretion, and body mass index (a measure of weight in kilograms divided by the square of height in meters) using 1-way analysis of variance (ANOVA). 21 If the ANOVA P value was statistically significant, we used the Tukey test to determine which pairs of treatments were different. 21 We compared race distributions across treatments using the 2 test. If this was statistically significant, we used the Grizzle-Starmer-Koch method to determine which pairs of treatments were different. 22 To compare the renin profile and agerace subgroup methods, we performed a matched pairs analysis. In this analysis, each patient was classified according to whether he was matched or mismatched for each method. A 2 2 table was formed that defined 4 groups: (1) renin matched, age-race subgroup matched; (2) renin matched, age-race subgroup Table 1. Renin Profile by Age-Race Subgroup mismatched; (3) renin mismatched, agerace subgroup matched; and (4) renin mismatched, age-race subgroup mismatched. The statistical comparison essentially evaluated whether group 2 or 3 had a higher response rate, DBP change, or SBP change. For example, if group 2 had a higher response rate than group 3, then the renin-profile method would be considered more accurate than the agerace subgroup method. We used logistic regression analysis to determine whether baseline ageracesubgroup, andreninprofileweresignificant predictors of response. 23 This analysis included evaluation of interactions between age-race subgroup and drug and between renin profile and drug. The SAS system (version 6; SAS Statistical Software, Cary, NC) was used for all statistical analysis. 24 All statistical tests were 2-sided. The criterion for statistical significance was P.05. RESULTS General Characteristics of the Patients Baseline characteristics of the 1105 patients were well balanced across the 6 treatment groups, including 24-hour urinary sodium excretion. 11,12 The mean (SD) age of the 470 younger patients (those 60 years) was 50 (8) years, and for the 635 older patients (those 60 years) it was 66 (4) years. Low Renin Medium Renin High Renin Low Age-Race Medium Age-Race High Age-Race Subgroup N n Renin, % Distribution n Renin, % Distribution n Renin, % Distribution Younger black Older black Younger white Older white Renin Profile by Age and Race Of the 1105 patients randomized to drug therapy, 1031 provided valid plasmaurine pairs for analysis. Of these, 653 (63.3%) were classified as having lowrenin, 232 (22.5%) as having mediumrenin, and 146 (14.2%) as having highrenin profiles. The renin profile by agerace subgroup is shown in Table 1. Response Rates and Blood Pressure Changes The logistic regression analysis determined the most important predictor of response to a single drug to be baseline DBP (P.001). Clonidine and diltiazem had high response rates regardless of renin profile (Table 2). Hydrochlorothiazide and prazosin performed best in patients with low-renin and medium-renin profiles. Captopril performed best in patients with medium-renin and high-renin profiles. As shown in Table 3, clonidine and diltiazem had high response rates regardless of age or race. Hydrochlorothiazide and prazosin produced poorer blood pressure responses in younger white patients, while captopril did worst among older black patients. Using matched pairs analysis, we found no significant differences between the renin profile and age-race subgroup methods for choosing an initial antihypertensive agent with regard to response rate, change in SBP, or change in DBP (Table 4). For the renin-matched, age-race subgroup mismatched patients, the response rate was 58.7% compared with 63.1% for the renin-mismatched, agerace subgroup matched patients (P =.30). For the changes in these groups were 10.7 and 11.5 mm Hg, respectively (P =.28). The SBP changes were 12.9 mm Hg and 10.5 mm Hg, respectively (P =.06). When age-race subgroup and renin profile were considered simultaneously in the logistic regression analysis, agerace subgroup was found to be a better predictor than renin profile (Table 5). The P value for age-race subgroup and its interactions with treatment group addedtoamodelthatonlyincludedbaseline DBP and treatment group was P.001.ThePvalueforreninprofileand its interactions with treatment group addedtoamodelthatincludedonlybaseline DBP and treatment group was.05. In the presence of renin profile, adding age-racesubgrouptothemodelproduced an incremental improvement, whereas Table 2. Response Rate: Percentage of Patients Reaching Goal Diastolic Blood Pressure (DBP) by Renin Subgroup and Baseline DBP* Antihypertensive Drug (n = 408) Low Renin Medium Renin High Renin (n = 245) (n = 151) (n = 81) (n = 100) (n = 46) Hydrochlorothiazide Atenolol Captopril Clonidine Diltiazem Prazosin *Goal DBP was less than 90 mm Hg at the end of the titration period JAMA, October 7, 1998 Vol 280, No. 13 Predictors of Blood Pressure Response to Antihypertensive Therapy Preston et al

4 Table 3. Response Rate: Percentage of Patients Reaching Goal Diastolic Blood Pressure (DBP) by Age-Race Subgroup and Baseline DBP* Antihypertensive Drug (n = 139) Younger Black Older Black Younger White Older White (n = 108) (n = 172) (n = 114) (n = 140) (n = 83) (n = 256) (n = 93) Hydrochlorothiazide Atenolol Captopril Clonidine Diltiazem Prazosin *Goal DBP was less than 90 mm Hg at the end of the titration period. Table 4. Response Rate and Changes in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Using Renin Profile vs Age-Race Subgroup Methods for Choice of an Initial Antihypertensive Agent the converse was not true. When agerace subgroup and its interactions were added to a model that included baseline treatment group, renin profile, and its interactions, the P value for the agerace subgroup component of the model was.001. When renin profile and its interactions were added to a model that included baseline treatment group, and age-race subgroup and its interactions, the P value for the renin-profile component of the model was.14. COMMENT The renin profiles in our study group (Table 1) are consistent with known renin-profile patterns. The black patients Age-Race Subgroup Method Renin Profile Method Correct Incorrect Combined Response Rate, %* Correct Incorrect Combined Change in SBP, mm Hg Correct 13.9 (10.0) 12.9 (11.8) 13.3 (11.1) Incorrect 10.5 (11.7) 11.2 (11.9) 11.0 (11.8) Combined 12.8 (10.6) 12.3 (11.8) Change in mm Hg Correct 13.7 (5.8) 10.7 (6.9) 11.9 (6.6) Incorrect 11.5 (7.0) 10.6 (6.3) 10.8 (6.4) Combined 13.0 (6.2) 10.7 (6.5) *P =.30 for comparison of renin profile method to age-race subgroup method. P =.06 for comparison of renin profile method to age-race subgroup method. Values are mean (SD). P =.28 for comparison of renin profile method to age-race subgroup method. Values are mean (SD). Table 5. Logistic Regression Model for Response by Age-Race Subgroup vs Renin Profile Subgroup* Factors Included in the Model Model 1: Age-Race Model 2: Renin Profile Model 3: Age-Race, Renin Profile Treatment group Baseline DBP Age, race, age*race (and interactions with treatment group) Renin profile (and interactions with treatment group) C-index Concordance rate, % *Values are P values unless otherwise indicated. Ellipses indicate that variable was not included in the model. DBP indicates diastolic blood pressure. Age*race indicates an interaction term. C-index indicates variability explained by the model. Concordance rate indicates concordance between blood pressure response and model including DBP and age-race subgroup (1); DBP and renin profile (2); or age-race subgroup, and renin profile (3). tended toward low-renin profiles while the white patients tended toward medium- and high-renin profiles. More than 70% of black patients had low-renin profiles, compared with less than 55% of whites. The results of response rate by blood pressure stage and by renin subgroup (Table 2) show that patients with stage 1 hypertension had the highest response rates to the individual drugs, but the response rates for the patients with stage 2 hypertension were not trivial. Diltiazem, clonidine, and atenolol had the best observed response rate in the patients with stage 2 hypertension, but this may have been at least in part due to relatively high doses permitted at the last titration step (diltiazem [sustained release], 360 mg; clonidine, 0.6 mg; and atenolol, 100 mg). Captopril had only a 14% observed response rate for stage 2 hypertension, but the maximum dose allowed was only 100 mg. Hydrochlorothiazide was capped at 50 mg, but this probably is a reasonable upper limit. Prazosin was used at its maximum recommended dose, but was less effective for patients with stage 2 hypertension. For patients with stage 1 hypertension and a low-renin profile, prazosin, diltiazem, and hydrochlorothiazide had the highest response rates; clonidine and diltiazem were best for stage 2 hypertension. For patients with stage 1 hypertension and normal-renin profiles, diltiazem, captopril, and hydrochlorothiazide had the highest response rates; diltiazem, clonidine, and hydrochlorothiazide were best for stage 2 hypertension. Patients with stage 1 hypertension and high-renin profiles had the best response from captopril, atenolol, and diltiazem; for stage 2 hypertension, diltiazem, atenolol, and clonidine were best. Clonidine and diltiazem had high response rates for both stage1andstage2hypertensionirrespective of the renin profile. Our comparison of renin profiling and age-race subgroup for selection of an initial antihypertensive drug does not reveal a significant difference between the 2 methods (Table 4). The low response of the group with medium renin levels in the renin-profiling method may be due to the random assignment of the patients with medium renin levels to any of the 6 antihypertensive drugs. Actually, strict application of the renin-profiling method requires performing a captopril test by which additional patients with renindependent hypertension may be identified. Accordingly, we recalculated the overall response rate of the reninprofile patients substituting the higher figure 72.3% for the medium-renin response rate that was found for the patients with high-renin levels randomized to captopril or atenolol rather than the lower figure of 61.6% that was obtained by random assignment. The resulting figure is 68.6% for the renin- JAMA, October 7, 1998 Vol 280, No. 13 Predictors of Blood Pressure Response to Antihypertensive Therapy Preston et al 1171

5 profile method. Nevertheless, we could demonstrate no statistical difference between the 2 methods. When both age-race subgroup and renin profile are considered simultaneously for selection of an antihypertensive drug, age-race subgroup is the more powerful predictor and renin profile has no additional predictive benefit after age-race subgroup is considered. Our study addresses the choice of an initial antihypertensive agent with respect to its efficacy in long-term lowering of blood pressure. We have not addressed References 1. Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med. 1997;157: Weber MA, Laragh JH. Hypertension: steps forward and steps backward: the Joint National Committee fifth report. Arch Intern Med. 1993; 153: Tobian L, Brunner HR, Cohn JN, et al. Modern strategies to prevent coronary sequelae and stroke in hypertensive patients differ from the JNC V consensus guidelines. Am J Hypertens. 1994;7(pt 1): Hypertension Detection and Follow-up Program Cooperative Group. The Hypertension Detection and Follow-up Program: a progress report. Circ Res. 1977;40(suppl I):I-106 I Laragh JH, Sealey JE. Renin system understanding for analysis and treatment of hypertensive patients: a means to quantify the vasoconstrictor elements, diagnose curable renal and adrenal causes, assess risk of cardiovascular morbidity, and find the best-fit drug regimen. In: Laragh JH, Brenner BM. Hypertension: Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press Ltd; 1995: Blumenfeld JD, Mann SJ, Laragh JH. Clinical evaluation and differential diagnosis of the individual hypertensive patient. In: Laragh JH, Brenner BM. Hypertension: Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press Ltd; 1995: other potential applications of the reninprofiling method such as screening for secondary forms of hypertension or categorization of hypertensive patients in terms of overall cardiovascular risk. Although we did not perform a detailed cost analysis, the implications for cost savings inusingtheage-racemethodvsthereninprofiling method (which requires additional laboratory testing and a 24-hour urine collection) are clear. It is important to note that our study subjects responded according to renin profile, consistent with prior clinical trials and published algorithms. However, classifying patients according to agerace subgroups is as good a predictor of antihypertensive response as renin profiling. We conclude that age-race subgroup is a useful predictor of antihypertensive response to drug therapy. 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