Comparison of Propranolol and Hy~ro~hlorothiazid~ for the. ,lnitial Treatment of Hypertension I: Results of. Short-term Titration With .Emphasis on Racial Differences in Response Veterans Administration Cooperative Study Group on Antihypertensive Agents e We -compared hydrochforothlazide and propranolol hydrochloride for monotherapy of hypertension by a double-blind study of 683 men who were titrated to less than 90 mm HQ diastolic BP or to 640 mg of propranolol or 209 mg of hydrochlorothiaride. Propranolol reduced systolic BP from 148.0f 14.4 (SD) to 134.8+ 18.3 mm Hg and diastolic BP from 101.6+4.8 to 90.5f7.6 mm Hg. Hydrochlorothiazide lowered both systolic BP more effectively from 146.5r 15.8 to 128.8& 12.2 mm Hg and diastolic BP from 101.3 -t-4.5 to 89.4k8.5 mm Hg. In blacks, hydrochlorothiazide lowered systolic BP 20.3t 14.3 mm Hg Y 6.2i 12.2 mm Hg for propranolol; hydrochloiothiaride reduced diastolic BP 13.Ok7.0 mm Hg v 9.5f7.0 for propranolol. In whites, the systolic BP reductions were 15.3& %2.0 mm Hg for hydrochlorothiazide v 13.2 f 13.1 mm Hg for propranolol; diastolic BPS were 10-Q+ 5.7 mm Hg for hydrochioroth~azide and 12.62 5.6 mm HQ for propranolol. In blacks treated with hydrochlorothiazlde, 71.3% achieved diastolic BP of less than QO mm Hg, v 53.5% with propranolol. There was no racial difference in dose response to propranoloj, but blacks required much less hydrochlorothtazide to achieve control. We conclude that in thts short-term study propranolol was as efficacious as hydrochlorothlazide In whites, but the latter was more effective than propranqlol In blacks. (JAMA 1982;248: 1996-2003) ALTHOUGH its exact mechanism oi action remains unknown,' propranolol hydrochloride and related Badrener- gic blocking drugs have become some of the most important antihyperten- sive agents .other than thiazide diuretics?' Propranolol is remarkably free of disturbing side effects,' and `one authority .in the United States now recommends that it be used in place of thiazides as "step 1" in the "step-care method" for treating hy- be ho p 2004. From the Cooperative Studies Program, Medical Reeearch Service of the Veterans Admtdatratton, pertension', as it has be& used in .Mnea. Ill. Europe. This. trend. is accentuated by Presented in wart at the American Heart Associa- the fact that diuretics commonly tion Scisnti~c Ski. Qellaa, &IV ia, 1981. Reprint requests to the Veterane Adminirtratton induce a variety of biochemical sid;! Medical Center (11 I). 1201 NW 16th St. Miami. FL effects: including hypokalemia, hy- 33125 (Barry J. h4aterson. MD). peruricemia, and hyperglycemia, and most recently have been associated with increased levels of serum choles- terol and triglycerides?' Some au- thorities also believe that thiazides cause impotence and other subjective side effects. A Veterani Administration Coop- erative Study comparing propranolol alone and in various combinations with other drugs to a standard regi- men of hydroch~orothi~ide and re- serpine" indicated that, although not as effective as the standard regimen, propranolol alone controlled the BP in 52% of patients with mild to moderate hypertension, which ap- proximates the magnitude of thiazide efficacy. The present study was designed to compare propranolol and hydrochlo- rothiazide in a double-blind, con- trolled clinical trial to determine if one drug is superior to the other in terms of efficacy, adverse `effects, or both. We also sought to determine the validity of the step-care algorithm in that it calls for the administration of diuretic as a step 1 drug to patients with hypertension. SUBJECTS AND METHODS Thi`s phase IV, double-blind, random- ized, parallel study involved 906 patients in seven VA Medical Centers. Nonhospital- ized male veterans aged 21 to 65 years with miid to moderate hypertension and 1996 JAMA, f&t 22129, 1962-Vol 246. No. 16, Prppranoloi and Hydr~hlorothiazide, Part I-VA Study Group an averyye untreated seated diastolic BP of $5 to 114 mm Hg composed the study population. Patients previously trerted for hypertension underwent a two-week wash- out period before the placebo period. Patients with known hy~r~nsitivity to either prapranolol, hydrochlorothistide. or other sulfonamide derivatives were ex- cluded. In addition, the presence of any one of the conditions liated in Table 1 excluded s patient. Informed consent for each patient was obtained in accordance with US Depatt- ment of Health, Education, and Welfare and VA guidelines. This study was approved by a central evaluation commit- tee and human research committee as well as by similar committees in the patticipat- ing medical centers. Safety criteria for discontinuing patient participation in the study are listed in Table 2. After a single-blind placebo baseline observation period of four weeks, 683 patients whose diastolic BP were 95 to 114 mm Hg and who were compliant for two consecutive visits were randomized to one of the two double-blind regimens (pro- pranolol or hydrochlorothiazide). This was followed by a ten-week dose-finding peri- od, during which the clinic at.& titrated the blinded drug upward until goa BP (90 mm Hg diastolic or less) was reached. Visits were scheduled every two weeks for the first four titration steps and at weekly intervals for the last two. Patients were withdrawn from the study if diastolic pressure on any visit was 120 mm Hg or greater. The code name for the identical- appearing tablets containing either pro- pranolol or hydr~hlorothiazide was "pro- pazide." The six strengths of both prepa- rations were referred to as propazide B, C, D, E, F, and G. Propazide A was the placebo used during the prerandomization period. When propazide wris proptanolol, the doses B to G were 40,80,120. 160,240. and 320 mg administered twice daily. When propazide was hydtochlorothiazide, doses B and C were 25 mg, D and E were 60 mg, and F and C were 100 mg adminis- tered twice daily. Although patients were generally advised to limit salt intake, there was no systematic control of their diet. Patients were required to return their medication bottles at each visit. The remaining tablets were counted in another room, and patients were deemed to be compliant if they had consumed not less than 80% nor more than 110% of the prescribed number of tablets. Trained observers, experienced in the use of a mercury sphygmomanometer. made all BP determinations. The fifth phase, or disappearance of the Korotkoff sounds, in the seated position was used as the index of diastolic pressure. History and physical examination were recorded, and the chest roentgenogram, ECG, and basic laboratory tests were performed during the placebo period. The experimen- tal RP was delined as the average diastolic BP on the last t*o consecutive visits at the same dose level. Laboratory evaluations included a com- plete blood cell count, urinalysis, and biochemical profile. These were performed bn multichannel automated analyzers using the same methods for each hospital. Five of the centers determined baseline nnd stimulated plasma renin activity and 24-hour urinary excretion of sodium, potassium, and creatinine. The remaining centers performed modified glucose tolet- ante tests. These special tests will be the subject of separate communications. This study was designed by a committee that included biostatisticians, some of whom participated in the analysis of these data and in the monitoring of the study. Paired and unpaired Student's 1 tests and X' tests were used to assess statistically significant differences (defined as P-z.05) between group9 of data. Patients who attained goal BP on two consecutive visits prior to titration to the maximum dose of propazide (level G) were "rapidly advanced" to visit 10. All patients reaching visit 10. whether by full titration or rapid advancement, were entered inta a one-year chronic treatment phase if their diastolic BP was less than 100 mg Ng and if they were at least 6 mm Hg less than their original baseline value at randomiza- tion. A total of 394 patients (80.2% of 491 reaching visit 10) entered the chronic treatment phase and are the subject of a separate report. When there was less than one year remaining in the study, 119 new patients who reached the end of the dose- finding phase were terminated because of time limitations. A total of 610 patients completed the dose-finding phase. When patients were terminated from the study, they were given a card of blister-packaged tablets that gradually tapered the ptopazide dose to zero in two weeks. Blister cards were marked and coded to begin at a dose one step below the level at the time of termination. RESULTS Comperebllity of Groups Of the 906 patients entering this study, 683 (75.4%) met the require- ments for randomization. The most JAMA, Ckt 22129. 1982-Vol 248, No. 16 Propranolol and llydrochlorothiaride, Part I-VA Study Group lQQ7 patients. There was no sibilant difference I in the number of patienta who . . t"Pmfmzide" was ffw coda rumme for Menliesl-appearing trbbts c~~~alnfng slthsr propranofol hydrochk. achieved goal BP (propianolol, 57.0%; hydrochlorothiazide, 64.1%). This seemed, however, to result from a balance of opposing effects. Propran- 0101 was somewhat more effective in whites (propranolol, 61.7%; hydro- chlorothiazide, 55.3% ), but the differ- ence did not achieve statistical signif- icance; however, hydr~hlorothi~ide was substantially more effective in blacks (71.3% v 53.5%; P=.OOl). Although there was no predeter- mined systolic pressure defined as a goal in this protocol, we examined the percentage of patients with systolic pressure equal to or less than 140 mm Hg as another measure of drug effica- cy. Hydrochlorothiazide was signifi- cantly more effective'(84.9W ir 65.8%; P<.OOl) in the total group, in black patients (87.7% t, 64.1%; Pc.001). and in the white patients (81.6% u 68.0%;. P=.O15). In contrast to these between drug differences, there were no significant racial differences in systolic pressure goal effect within each drug group. Propranolol was associated with a systolic BP reduc- tion to or less than 140 mm Hg in 64.1% of black patients and 68.0% of whites, compared with 87.7% black and 81.6% white associated with hydrochlorothiazide. Table 6 displays four negative aspects of treatment with the two drugs. The percent of patients re- maining at or above 160 mm Hg systolic or 100 mm Hg diastolic can be taken as a measure of drug failure. There were significantly fewer systol- ic failures for hydrochlorothiazide, with the greatest difference being a 9.4% failure rate for whites taking propranofol compared with 1.4% for whites taking hydrochlorothiazide (P<.OOl). There were significantly more diastolic failures in black patients compared with white pa- tients taking propranolol (17.6% v 8.6%; P=.O4), but not in those taking hydrochlorothiazide (7.6% v 10.6%). `l-wcl hdicates PeroxYsmal llockmmt dyspnea: AV. atrioventrlcular. rids or hydmchkrothbzfde. common causes for prerandomization dropout were noncompliance funcoop- erative or unreliable, 26%; pill count violations, 16%) and BP above or below the randomization criteria (26%). The 683 patients were random- ized equally (340 to propranolol, 343 to hydrochlorothiazide), and the groups were statistically afike in regard to age, weight, race, and prior treatment (Table 3), heart rate and BP (Table 4), and baseline faboratory data (Table 5). By design, randomiza- tion within each clinic was also equal, but some clinics had a higher percent- age of blacks than others. BP and Heart Rata Changes Table 4 displays the eirects of pro- pranolol and hydrochlorothiazide on BP and heart rate. Propranolol was associated with a lowering of the heart rate by 16 beats per minute, whereas hydrochlorothiazide admin- istration resulted in an increase of 2.7 beats per minute. Both drugs effectively lowered both systolic and diastolic BP; hydrochlo- .rothiazide was significantly more elective for systolic (P<.OOt), but of borderline significance as more effec- tive for diastolic (P=.O3). Hydrochfo- rothiazide excelled over propranofof significantly (P<.OOl) in lowering sistolic BP in the total group because of its greater efficacy in black patients. Although hydrochlorothia- zide was associated with a reduction of systolic pressurd 2.1 mm Hg more than propranolol in white patients, the diflerence was not significant. Hydrochlorothiazide was also more effective in reducing diastolic pres- sure in the total group even though propranolo1 was morr' effective by 1.7 mm Hg (P=.O2) in the white One coijcern relevant to any treat- ment mode is whether a substantial number of patients have an effect opposite to that intended. Table 6 displays the percentages of patients who had an actual increase of 1 or more mm Hg incleystofic or diastolic pressure. Nearly one' fifth of the 1898 _ JAMA, Ott 22129, 1982-Vol 248, No. 16 Propranolol and Wydrc-chlorothiatide. Pail I-VA Study Group Table 4.-Baseline Data and Eflecl of Treatmenl on Heart Rate and BP' E W.Qf 10.0 72.4 f I 1.6 <.ooI 8vcnacW.~mnr 0 14e.Of 14.4 14&t&f IIHI Ml E -__. 1M.O f m.5 T?iii.bi 12.2 -cool Msstdk BP, mm Ho B IOl.6fl.Q IOI.3f4.5 NS E Qo.ai 7.0 88.4f0.5 .M AB~W.-)(o -10.4f f2.S -tksi 1s.s