SINGLE-DRUG THERAPY FOR HYPERTENSION IN MEN A Comparison of Six Antihypertensive Agents with Placebo BARRY J. MATERSON, M.D., DOMENIC J. REDA, M.S., WILLIAM C. CUSHMAN, M.D., BARRY M. MASSE, M.D., EDWARD D. FREIS, M.D., MAHENDR S. KOCHAR, M.D., ROBERT J. HAMBURGER, M.D., CAROL FYE, R.PH., MS., RAJ LAKSHMAN, PH.D., JOHN GOTTDIENER, M.D., ELI A. RAMIREZ, M.D., AND WILLIAM G. HENDERSON, PH.D., FOR THE DEPARTMENT OF VETERANS AFFAIRS COOPERATIVE STUDY GROUP ON ANTIHYPERTENSIVE AGENTS* Abstract Background. Characteristics such as age and race are often cited as determinants of the response of blood pressure to specific antihypertensive agents, but this clinically important issue has not been examined in sufficiently large trials, involving all standard treatments, to determine the effect of such factors. Methods. In a randomized, double-blind study at 15 clinics, we assigned 1292 men with diastolic blood pres- sures of 95 to 109 mm Hg, after a placebo washout period, to receive placebo or one of six drugs: hydrochlorothiazide (12.5 to 50 mg per day), atenolol (25 to 100 mg per day), captopril (25 to 100 mg per day), clonidine (0.2 to 0.6 mg per day), a sustained-release preparation of diltiazem (120 to 360 mg per day), or prazosin (4 to 20 mg per day). The drug doses were titrated to a goal of less than 90 mm Hg for maximal diastolic pressure, and the patients continued to receive therapy for at least one year. Resulfs. The mean (&SD) age of the randomized pa- tients was 59tlO years, and 48 percent were black. The average blood pressure at base line was 152?14/99*3 T HE initial treatment for hypertension has changed as drugs with pharmacologic properties permitting single-drug therapy have become avail- able. In their 1988 report, the Joint National Com- mittee on Detection, Evaluation, and Treatment of High Blood Pressure' considered the selection of ini- tial treatment on the basis of demographic character- istics. Previous cooperative studies by the Department of Veterans Affairs have supported the recommenda- tions of the Joint National Committee, such as propos- ing that beta-blockers be considered equal to thiazide diuretics in the initial antihypertensive therapy of white patients2x3 and recommending the use of capto- pril as initial single-drug therapy.4,5 We and others have also observed differential racial responses to anti- hypertensive drugs. *-* Speculation that demographic characteristics would predict clinically important dif- ferences in the antihypertensive efficacy of various drugs and permit better selection of single-drug thera- py has not been substantiated by a placebo-controlled, From the Cooperative Studies Program of the Medical Research Service, Department of Veterans Affairs. Address reprint requests to Dr. Materson at the Veterans Affairs Medical Center (141), 1201 NW 16th St., Miami, FL 33125. Supported by the Cooperative Studies Program of the Department of Veter- ans Affairs Medical Research Service and by an unrestricted grant to Friends of Medical Research, Inc. (a not-for-profit foundation), from Marion Merrell Dow, Inc. Presented in part at the American Heart Association Scientific Sessions, Ana- heim, Calif., November II, 1991. *The members of the study group are listed in the Appendix. mm Hg. Diltiazem therapy had the highest rate of success: 59 percent of the treated patients had reached the blood- pressure goal at the end of the titration phase and had a diastolic blood pressure of less than 95 mm Hg at one year. Atenolol was successful by this definition in 51 per- cent of the patients, clonidine in 50 percent, hydrochloro- thiazide in 46 percent, captopril in 42 percent, and prazo- sin in 42 percent; all these agents were superior to placebo (success rate, 25 percent). Diltiazem ranked first for younger blacks (~60 years) and older blacks (260 years), among whom the success rate was 64 percent, captopril for younger whites (success rate, 55 percent), and atenolol for older whites (68 percent). Drug intoler- ance was more frequent with clonidine (14 percent) and prazosin (12 percent) than with the other drugs. Conclusions. Among men, race and age have an im- portant effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of a drug. (N Engl J Med 1993;328:914-21.) prospective randomized trial of representative drugs from each of the major therapeutic classes. We studied different classes of antihypertensive drugs used as single-drug therapy. Our primary objec- tives were to determine the efficacy of each drug in lowering blood pressure, the ability to control blood pressure over time, and the incidence of termination of treatment for medical reasons. We also compared short-term efficacy and long-term control in the var- ious drug classes according to age and race. Neither cost nor quality-of-life issues were studied. METHODS Study Design and Selection of Patients Male veterans being evaluated as outpatients entered a washout phase lasting from four to eight weeks before randomization, during which they received one placebo tablet twice daily administered in a single-blind fashion. The criteria for inclusion were an age of 21 years or older, written informed consent, and a reasonable expecta- tion that the patient's diastolic blood pressure would be between 95 and 109 mm Hg with placebo. Patients were excluded from the study if they had any of a number of medical conditions listed elsewhere.* Each patient underwent routine laboratory testing and electrocardiography. Interviews to gather information on side ef- fects were conducted at the second visit and each subsequent visit. The base-line blood pressure was calculated as the average of the readings obtained at the last two clinic visits in the period before *See NAPS document no. 05006 for five pages of supplementary material. Order from NAPS c/o Microfiche Publications. P.O. Box 3513. Grand Central Station, New York, NY 10163-3513. Remit in advance (in U.S. funds only) $7.75 for photocopies or $4 for microfiche. Outside the U.S. and Canada, add postage of $4.50 ($1.75 for microfiche postage). There is a $15 invoicmg charge for all orders filled before payment. Reprinted from the New England Journal of Medicine 328~914-921 (April l), 1993 Vol. 328 No. 13 SINGI&DRUG THERAPY FOR HYPERTENSION IN MEN - MATERSON ET AL. 915 randomization. Compliance was determined on the basis of the patient's clinic attendance and a count of pills. Patients were ran- domized if their mean diastolic blood pressure on two consecutive visits was bctwcen 95 and 109 mm Hg and if the values did not differ by more than 6 mm Hg between visits. At the time of randomization, the patients were assigned in a double-blind manner7 to receive placebo or one of the six study drugs. They then entered a titration phase of four to eight weeks. The drugs and their doses (listed from low to medium to high) 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 rn! in divided doses givrn twice daily), prazosin (4, 10, and 20 mg in dwided doses given twice daily). a sustained-release preparation of diltiazem (120, 240, and 360 mg in divided doses given twice daily), and placebo. Prazo- sin was started at I mg given twice daily for two 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 two wwks, as required, until a diastolic blood pressure of less than 90 mm Hg was reached without intolerance to the drug on two con- srcutive visits or until the maximal drug dose was reached. The blood pressure during treatment was taken as the mran of the blood pressures recorded during the last two visits during the titration phase. Patients whose diastolic blood pressure had reached the goal (a reading of less than 90 mm Hg) on two consecutive visits during the titration phase entered a maintenance phase for at least one year. During this period. interim visits were permitted in order to adjust the dose of drug as needed to maintain the diastolic blood pressure at 99 mm Hg or less and to reduce adverse effects. Control was defined as a diastolic blood pressure of less than 95 mm Hg at one year. Success was drfined as attainment of the blood-pressure goal during titration and the maintenance of controlled blood pressure for one year. After the maintenance phase, each patient entered a four-week placebo washout phase. Patients who had been randomly assigned to clonidinc therapy had their doses tapered down over a two-week prriod to avoid withdrawal symptoms. The protocol was approved by an institutional review board at each of the 15 participating medical centers and by a central hu- man-studies committee. Measurement of Blood Pressure Trained registered nurses or physicians' assistants used standard sphygmomanometers with appropriately sized cuffs to determine blood pressure. The patients were seated with ar? arm supported at the level of the heart after five minutes of rest. The disappearance of the Korotkoff sounds defined the diastolic blood pressure. The mean of three readings taken one minute apart was used as the blood pressure at that clinic visit. Adverse Drug Reactions and Termination of Treatment A 31.item checklist was used to inquire about the patients' syrnp- toms. The patients were encouraged to describe their symptoms at each visit. All withdrawals from the study protocol were evaluated blindly by the study chairman and classified as administrative or medical. hledical withdrawals were further analyzed blindly to de- termine whether they were due to an adverse drug reaction. Statistical Analysis The prunary outcome measure was the rate of treatment success (the percentage of randomized patients who reached the blood- pressure goal during the titration phase and maintained control of blood pressure for one year). The rate at which the goal for blood pressure was achieved during the titration phase and the rate of termination due to adverse reactions were secondary outcome meas- ures. The significance of each outcome measure was determined by a chi-square test of homogeneity for a two-by-seven contingency table. All results are reported according to an intention-to-treat analy- sis. SAS software' was used for all analyses. Chi-square tests of homogeneity" were performed to compare the proportions for all categorical responses in the seven treatment groups, whereas analy- sis of variance was used to compare the means for all continuous responses in these groups. When the results were significant at PsO.05, differences between pairs of treatments were tested with pairwise contrasts for proportions or Tukey's procedure for means." In these analyses, it is inappropriate to report individual P values for each of the 15 possible pairwise comparisons. Instead, a P value of 0.05 was selected for each group of 15 pairwise compari- sons and used to identify the subgroups of treatment pairs that were significantly different. All P values were two-tailed. RESULTS Characteristics of the Patients We randomly assigned 1292 patients to the seven treatment groups. Their base-line characteristics (Ta- ble 1) were well balanced across the seven treatment groups. The mean (&SD) age of the 546 younger pa- tients (those less than 60 years old) was 5028 years, and for the 746 older patients (those 60 years old or older) it was 66k4 years. A total of 137 patients with- drew from the study during the titration period, and 410 patients did not qualify for the maintenance phase; the remaining 745 patients entered the mainte- nance phase. Of these, 145 withdrew from the study during the first year of the maintenance phase, and 65 withdrew thereafter; 535 entered the final placebo pe- riod. Thus, 41 percent of the patients initially ran- domized completed the study. Blood-Pressure Response during the Titration Phase During the titration phase, there were significant (P16OmmHg 367 (28) 54 (22) 49 (17) 135 (33) 126 (38) 140-159 mm Hg 691 (54) 133 (54) 151 (52) 220 (54) 179 (54) Diastolic blood pressure Mean (mm Hg) 99?3 99+3 loo?4 98-t3 loo-t3 100-109 mm Hg 456 (35) X9 (36) 125 (43) 102 (25) 133 (40) 95-99 mm Hg 836 (65) 157 (64) 166 (57) 306 (75) 197 (60) Heart rate (beats/min) 74+11 75-tll 76?11 73?11 74t11 Body-mass index? 2925 2925 2925 2924 2825 Cigarette smoking Current 412 (32) 69 (28) 139 (48) 84 (21) 118 (36) FOIlTIe 557 (43) 103 (42) 87 (30) 229 (56) 134 (41) NW3 323 (25) 74 (30) 65 (22) 95 (23) 78 (24) Ethanol consumption (drinks/day) Oor3 64 (5) 25 (IO) 13 (4) 15 (4) IO (3) Antibypertensive treat- 916 (71) 164 (67) 196 (67) 303 (74) 241 (73) ment at screening 916 THE NEW ENGLAND JOURNAL OF MEDICINE April 1. 1993 (Table 2), the proportion of patients reaching the goal for diastolic blood pressure (<90 mm Hg), and the proportion of patients with systolic blood pressure be- low 140 mm Hg. The pairwise comparisons indicated that the mean decrement in diastolic blood pressure was greater with diltiazem than with all the other active drugs except clonidine; clonidine and atenolol were more effective than captopril. The proportion of patients reaching the goal for diastolic pressure was higher with diltiazem than with hydrochlorothiazide, pra- zosin, or captopril; patients taking clonidine or ateno- 101 reached this goal at a rate similar to that of patients taking the other drugs (Fig. 1). In the case of systolic pressure, the proportion of patients with readings below 140 mm Hg was higher with clonidine and hydrochlorothiazide than with prazosin, captopril, or placebo (Fig. 1). The effects of diltiazem and aten- 0101 were not significantly different from those of the other active agents. The effects of prazosin and captopril were not significantly different from those of placebo. The response profile for each dosage of medication during the titration phase (Table 3) showed that a high proportion of patients with a response reached the goal for that phase at the lowest dosage: 12.5 mg of hydrochlorothiazide once a day (45 percent), 25 mg of atenolol once a day (49 percent), 0.1 mg of clonidine twice a day (48 percent), and 2 mg of prazosin twice a day (48 percent). The group as- signed to diltiazem had the highest proportion of re- sponses, but many of these patients required the high- er dosage. Blood-Pressure Response during the Maintenance Phase The 745 patients who reached the goal for diastolic blood pressure without intolerable side effects entered a maintenance phase of at least one year and contin- ued to receive blinded therapy. During this phase there were small increases in systolic and diastolic blood pressure (42 11 and 2*6 mm Hg, respectively). The percentage of patients with initial control of blood pressure in whom the diastolic blood pressure remained below 95 mm Hg at one year was similar for all treatment groups (P = 0.926), ranging from 82 percent (for hydrochlorothiazide) to 75 percent (for prazosin). For the primary study end point, the proportion of patients initially randomized who responded to thera- py and maintained a diastolic pressure below 95 mm Hg after one year of treatment, there were signifi- cant (P-CO.001) differences between treatments (Fig. 2). This rate of treatment success reflects the initial blood-pressure response, the number of patients who did not withdraw because of side effects or other causes, and the degree to which control was main- tained. The pairwise comparisons show that diltiazem was more effective than captopril or prazosin. All the treatments were superior to placebo. Blood-Pressure Response According to Age and Race Race and, to a somewhat lesser extent, age were powerful influences on the response of blood pressure to individual drugs. Data obtained at the end of the titration phase (Table 2) indicate statistically signifi- cant differences between drugs. Figure 3 shows the criterion of a 15 percent difference in efficacy between two or more drugs, the difference specified in the study design to be clinically important. There were no statistically significant differences according to age and race with respect to mean changes in either systolic or diastolic blood pressure from base line to the end of the titration phase (Table 2). Blood pressure was reduced by 1 1 +- lO/lO+ 7 mm Hg for 243 younger whites, by 9? 1 l/9*8 mm Hg for 288 younger blacks, by 12+12/12?6 mm Hg for 405 older whites, and by 1 l+ 12/l 1 * 7 mm Hg for 330 older blacks. There were significant differences be- Table 2. Average Reductions in Blood Pressure from Base Line to the End of the Titration Phase,* Diastolic pressure (mm Hg) All patients 188 iOk6 BC 176 12+6 B 188 10+7 c 177 1226 AB 182 14+5 A 186 11k-7 BC 186 5*7 D Younger whites 34 7*6 BC 37 13?6 A 39 lo+-7 AB 32 13+5 A 38 13a5 A 32 1016 AB 31 4+7 c Younger blacks 48 1026 AB 34 Ilk9 AB 44 9+7 B 39 10+7 B 37 1425 A 42 8?8 BC 44 4+6 C Older whites 60 Ii?6 A 57 13*6 A 55 11+5 A 60 14+5 A 52 14?5 A 58 14+6 A 63 627 B Older blacks 44 12*6 AB 47 II?5 BC 48 7+7 CD 45 12+7 AB 53 15'-5 A 49 11+6 BC 44 527 D Systolic pressure (mm W All patients 188 14?11 AB 176 Ilk12 BC 188 9?10 c 177 16213 A 182 1319 AB 186 12?12 BC 186 3?10 D Younger whites 34 12211 AB 37 14?11 AB 39 II?9 ABC 32 16?12 A 38 II'-9 ABC 32 8+9 BC 31 5+10 c Younger blacks 48 14'-9 A 34 7+11 BC 44 8-11 AB 39 13210 AB 37 14?10 A 42 8+12 AB 44 OS?10 c Older whites 60 13t12 A 57 12214 A 5.5 Ilk9 A 60 17?13 A 52 12+9 A 58 17-tl2 A 63 31-10 B Older blacks 44 16+11 A 47 9+ll BCD 48 7?12 CD 45 17?15 A 53 1527 AB 49 13?13 ABC 44 3+11 D *On each line, pairs of tmattnent~ that arc not assigned at least one letter in c~rnnmn are statistically different; e.g., for diastohc blood pressure in all patients, hydrochlorothtazide (BC) 8s different from placebo (D) and diltiazem (A), but not from atenolol (B), captoptil (CL clonidine (AB), or prawsin (BC). The letters progress from the hghest (A) to the lowest (D) magttttude ofdifference ne one-way analyst of variance must be statistically significant (PSO 05) in order to justify this p&vise analysis. The numbers of patients in the subgroups do not total the numbers shown for atl patients because 17 patients were studied who were neither black nor white. Reductions in blood pressure are reported as means *SD. Vol. 328 No. 13 SINGLE-DRUG `THERAPY FOR HYPERTENSION IN MEN - MATERSON ET AL. 917 75 I 18E 0 b l- PiO.0 55 65 I 7E 178 57 188 - 56 188 L 188 CAF PLA DILT CLON ATEN HCTZ PRE 01 1 80 P