Comparison of Propranolol and Hydrochlorothiazide for the Initial Treatment of Hypertension |. Results of Short-term Titration With Emphasis on Racial Differences in Response Veterans Administration Cooperative Study Group on Antihypertensive Agenis ® We compared hydrochlorothlazide and propranolol hydrochloride for monotherapy of hypertension by a double-blind study of 683 men who wera — titrated to less than 90 mm Hg diastolic BP or to 640 mg of propranolol or 200 mg of hydrochlorothiazide. Propranolol reduced systolic BP from 146.0+ 14.4 (SD) to 134.8 + 16.3 mm Hg and diastolic BP from 101.6+ 4.6 to 90.5+7.6 mm Hg. Hydrochiorothlazide lowered both systolic BP more effectively from 146.5+ 15.8 to 128.84 12.2 mm Hg and diastolic BP from 101.3+4.5 to 89.4+6.5 mm Hg. In blacks, hydrochlorothiazide lowered systolic BP 20.3414.3 mm Hg vy 8.2+12.2 mm Hg for propranolol; hydrochlorothlazide reduced diastolic BP 13.0+7.0 mm Hg v 9.5+7.0 for propranolol. In whites, the systolic BP reductions were 15.3+ 12.0 mm Hg for ‘hydrochiorothiazide v 13.2 13.1 mm Hg for propranolol; diastolic BPs were -10.9+5.7 mm Hg for hydrochlorothiazide and 12.6+6.6 mm Hg for propranolol. In blacks treated with hydrochlorothiazide, 71.3% achieved diastolic BP of less than 90 mm Hg, ¥ 53.5% with propranolol. There was no racial difference in dose response to propranolol, but blacks required much ‘less hydrochlorothiazide to achleve control. We conclude that in this short-term study propranolol was as efficacious as hydrochlorothiazide In whites, but the latter was more effective than propranolol in blacks. _ (JAMA 1982;248: 1996-2003) - ALTHOUGH its exact mechanism of action remains unknown,’ propranolol hydrochloride and related §-adrener- - gie 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- See also p 2004. From the Cooperative Studies Program, Medical — Research Service of = Veterana Administration, ‘Hines, fil. , Presented in part at the American Heart Associa- tion Scientific Session, Dallas, Nov 18, 1981. Reprint requests to the Veterans Administration - ' Medical Center (111), 1201 NW 16th St, Miami, FL - .83125 (Barry J. Materson, MD). 1996 JAMA, Oct 22/29, 1982-—-Vol 248, No. 16° pertension’. as it has been used in Europe. This-trend is accentuated by the fact that diuretics commonly induce a variety of biochemical side effects,’ including hypokalemia, hy-' ‘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 Veterans Administration Coop- erative Study comparing propranolol alone and in various combinations with other drugs to a standard regi- men of hydrochlorothiazide 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 — This 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 mild to moderate hypertension and Propranolol and Hydrochlorothiazide, Part ~VA Study Group an average untreated seated diastolic BP of 95 te 114 mm Hg composed the study population. Patients previously treated for hypertension underwent a two-week wash- out period before the placebo period. Patients with known hypersensitivity to either propranolol, hydrochlorothiazide, or other sulfonamide derivatives were ex- cluded. In addition, the presence of any one of the conditions listed in Table 1 excluded a patient. Informed consent for each patient was obtained in accordance with US Depart- 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 participat- 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 hydrochiorothiazide). This was followed by a ten-week dose-finding peri- od, during which the clinic staff titrated the blinded drug upward until goal 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 hydrochlorothiazide 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 was propranolol, the doses B to G were 40, 80, 120, 160, 240, and 320 mg administered twice daily. | When propazide was hydrochlorothiazide, doses B and C were 25 mg; D and E were 50 mg; and F and G 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 JAMA, Gct 22/29, 1982-—Vol 248, No. 16 “on multichannel Table 1.—Exctusion Criteria* Serum creatinine level greater then 2.6 mg/dl close 8 syndrome ‘ Atrial fibrillation Patients with primary cardiac vaive diseene Attargic rhinitis during pollen season amphetamine, ard Ne dertvatives Colt dar dhe with the Malignancy, including leukemia and tymphome depression Patients with known gout History of drug or narcotic abuse Chronic conjunctivitis or psoriasis A meen untreated or poet-washout diaetolic pressure > 114 mm He or <06 mm Hg Hypertensive retinopathy (K-W scale) greater than grade fi History of hypertensive encephalopathy or stroke within ex montha Myocerdie! infarction within eb monthe or engine pectoris greeter than New York Heart Aseoolation Sinus bradycardia (<80 beete per minute) or heart block greater than fret degree, or W-P-W Frank congestive heart faituce or left ventriculer tellure evidenced by at feast two of ihe following: (1) recent dyspnea of orthopnes not of pulmonary origin; (2) ventricular diastolic gallop: (3) basal pulmonary rales; and (4) cardiothoracic ratio greater than 0.6 > Patients with Raynaud's disease or symptomatic and objective peripheral vascular disease Bronchial aethms or chronic obstructive pulmonery dieease Putnonary hypertension or frank right ventricular failure due to primary or chronic pulmonary dieonse Patienta receiving adrenergic augmention paychotropic drugs including MAO inhibitors, ption of rh Pheochromocytoma, primary aldoateroniam, or Cushing’s ayndrome Diabetes meliitus it unstable, of preadult onset, or requiring pharmacologic treatment History or evidence of peychiatrically documented noneltuational, clinically important mental Patients regularly using transgendental meditation, biofeedback reteiation, or similar techniques Severe alcohol abuses sufficient to Interfere with compkance Obeelty: pationts should be within 30% of expected weight /helght relationship for applicable ape Patients who have not given written Informed consent told arthwitic *K-W indicates Kelth-Wagner scale; W-P-W, Woltl-Parkinson-White syndrome; MAO, monoamine oxidase. and physical examination were recorded, and the chest roentgenogram, ECG, and basic laboratory tests were performed during the placebo period. The experimen- tal BP was defined 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 automated analyzers using the same methods for each hospital. Five of the centers determined baseline and stimulated plasma renin activity and 24-hour urinary excretion of sodium, potassium, and creatinine. The remaining centers performed modified glucose toler- ance 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 ¢ tests and ‘x’ tests were used to assess statistically significant differences (defined as P<.05) between groups of data. Patients who attained goal BP on two consecutive visits prior to titration to the maximum dose of propazide (level G) were Propranolol and Hydrochlorothiazide, Part i—VA Study Group “rapidly advanced” to visit 10. All patients reaching visit 10, whether by full titration or rapid advancement, were entered into 3 one-year chronic treatment phase if their diastolic BP was less than 100 mg Hg 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 propazide 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 Comparabllity of Groups Of the 906 patients entering this study, 683 (75.4%) met the require- ments for randomization. The most 1997 Table 2. -—Criteria for Discontinuing Therapy * Whenever the patient decides thet ft te in hia best interest to be withdrawn from the etudy Whenever the investigator deerme it necessary or in the pationt’s beet interest Severe adverse effecte Development of myocardial infarction of development of or worsening of angine pectoris Bradyoardia < 40 beats per minute in sitting position symptomatic. smymptomatic, continue medication and eee in one week. © bradycardia <40 beate per minute persiats, remove patient trom the study Development of bronchia! aethma Arrhytheniaa such ae atria! fibrillation or Mutter Development of congestive heert failure. Insemuch as this ia one of the critical assesement events and in order that objective data be obtained. © patient will be considered to have congestive ‘heart failure if two of the following four findings are present: (1) significant dyapnee defined as increasing exertional dyspnea, orthopnea and PND: (2) ankle edema—grade 2 or more out of a possible grede 4; (3) bansitar ralea or pleural effusion not due to pulmonary disease by x-ray fim: (4) ventricular diastolic gaop (S-3). Dissecting hematoma of the sorte Acute hypertensive encephalopathy Thrombocytopenic purpura or agranulocytosis Greater than firat-degree AV block Pulmonary embollem or kifarction Paychiatrically confirmed dapressive etate phenomenon Wterruption of therapy for more than 21 days chronic treatment phase . Seated diastolic BP > 119 mm Hg on any visit proparidet - New striate retinal hermorrhages in mors than one quadrant, new cotton wool exudates or . papledema in optic fund associated with hypertension and not with diabetes or other disease. This finding ta to be confirmed by a second observer, preferably en ophthalmologiet Cerebral hamorrhage, subarachnoid hemorrhage, or cerebral thrombosia . Serum creatinine level greater than 2.5 mg/dL and 60% higher than baseline Development of symptomatic and objective peripheral vascular insufficiency or Raynaud's Development of rash, confirmed by dermatologiat and considered to be drug induced Development of eye comptaints with objective slit-lamp findings by ophthalmologist or objective findings on eye examination that the ophthalmologist cannot explain on the beals of a routine ophthalmologic diagnosls and that he feels in any way could be related lo the drug therapy Patient falling to meat two consecutive clinic appointments without a legitimate excuse or Patient falling to take at least 80% of the atudy medication on three consecutive visits during the Severe, symptomatic hypotension with diastolic BP > 80 mm Hg and on the lowest dose of . “PND indicates paroxysmal nocturnal dyspnea; AV, atrioventricular. t'Propazide” was the code name for identical-appearing tablets containing either propranolol hydrochto- ride of hydrochlorothiazide. common causes for prerandomization dropout were noncompliance (uncoop- 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 alike in regard to age, weight, race, and prior treatment (Table 3), heart rate and BP (Table 4), and baseline laboratory 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 Rate Changes Table 4 displays the effects 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, 1998 JAMA, Oct 22/29, 1982—Vol 248, No. 16 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 effective for systolic (P<.001), but of borderline significance as more effec- tive for diastolic (P=.03). Hydrochlo- rothiazide excelled over propranolol significantly (P<.001) in lowering systolic BP in the total group because of its greater efficacy in black patients. Although hydrochlorothia- zide was associated with a reduction of systolic pressure 2.1 mm Hg more than propranolol in white patients, the difference was not significant. Hydrochlorothiazide was also more effective in reducing diastolic pres- sure in the total group even though propranolol was more effective by 1.7 mm Hg (P=.02) in the white patients. There was no significant difference * in the number of patients who achieved goal BP (propranolol, 57.0%; hydrochlorothiazide, 64.1%). This seemed, however, to result from a balance of opposing effects. Propran- olol was somewhat more effective in whites (propranolol, 61.7%; hydro- chlorothiazide, 55.3%), but the differ- ence did not achieve statistical signif- icance; however, hydrochlorothiazide was substantially more effective in blacks (71.3% v 53.5%; P=.001). 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- ey. Hydrochlorothiazide was signifi- cantly more effective (84.9% v 65.8%; P<.001) in the total group, in black patients (87.7% v 641%; P<.00%), and in the white patients (81.6% v 68.0%;. P=.015). 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 94% failure rate for whites taking propranolol compared with 1.4% for whites taking hydrochlorothiazide (P<.001). There were significantly more diastolic failures in black patients compared with white pa- tients taking propranolol (17.6% »v 86%; P=.04), but not in those taking hydrochlorothiazide (7.6% v 10.6%). One concern 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 inesystolic or diastolic pressure. Nearly one’ fifth of the Propranolol and Hydrochlorothiazide, Part I—VA Study Group Table 3.— Baseline Demographic Data and Prior Treatment Status” Propranolol Hydroehioride Hydrechtorethiaside N 340 . 343 - Age, yr , 40.6296 0.6208 Weight, kg 86.64 16.0 O8.7+ 14.1 % Bleck 87.7 66.8 Prior treatment etatue, % No prior presoription 96.8 90.1 Dturetic fone 17.8 18,7 Nondlurete alone eo - 92 Diuretic plus nondiurefic 38.2 26.8 Unknown medication "a4 as “Age and weight are expressed as mean + SD. None of theee differences is statistically significant. Table 4.—-Baseline Data and Effect of Treatment on Heart Rate and BP* Propreanoto! ? Hydrochloride Hydrochtorothlazide Veet Heart rate, bpm 8 76.04 10.4 76.74 11.8 NS & 80.9 + 10.0 TOA <.001 Byetolic BF, mm Hy ® 148.04 14.4 146.8 + 16.8 na E 134.03 16.3 ‘Jie.a+ 12.2 <.001 Diastolic BP, mm Hg a 101.6448 101.9448 NS E 90.64 7.4 80.4465 04 & Bystolic BP, mm Ha 10.44 19.8 —18 Ts 18.8 <.001 w 19.24 18.1 ~ 18.94 12.0 NS 8 - 8.24 12.9 ~20.84 14.3 <.001 A Diastolic BP, mm Ha —10.847.0 ~12.046.8 0a w —12.646.6 ~10.9+6.7 02 8 —0.547.0 -19.0+7.0 <.001 % reaching goal 87.0 841 NS % whites at goal OUT 56.3 NS % blacks al goal $3.3 713 <.001 % S140 mn Hg aystotict 65.8 84.9 <.001 % white S140 mm Ho systolic} 68.0 81.8 O18 % black & 140 men Hg systolic? 64.4 87.7 <.001 *Numbers are mean + SO. 8 indicates baseline; E, traatment end point: A BP «E-B; goal=BP <90 mn Hg diastolic; bpm, beats per minute. 1Comperison of propranolol v hydrochlorothiazide. Based on treatment endpoint presaures. patients receiving propranolol in- creased their systolic pressure, with the bulk of these among blacks . (24.1%) but still twice the number of failures in whites for propranolol as for hydrochlorothiazide. There were far fewer patients who increased their diastolic pressure; however, there were significantly more such failures in blacks taking propranolol than whites (10.0% v 3.1%; P=.04). If only the patients who had an increase of more than 10 mm Hg systolie are counted, then 6.4% of the total pro- pranolol and 0.3% of the total hydro- chlorothiazide population would be included. For white patients, 4.7% receiving propranolol v 0.7% receiv- ing hydrochlorothiazide had systolic pressure increases of more than 10 mm Hg. The respective values for black patients are 7.6% and 0.0%. JAMA, Oct 22/29, 1982—Vol 248, No. 16 Only three patients experienced a systolic BP increase in excess of 20 mm Hg. All were taking propranolol; ‘two were black. The magnitude of diastolic pressure increase was smaller. Six patients (five black) taking propranolol had a diastolic pressure increase of more than 5 mm Hg »v two black patients taking hydrochlorothiazide. The Figure displays the drug dose required to achieve goa! BP in all of the patients where diastolic BP was reduced to less than 90 mm Hg on two - consecutive visits. The first titration _ step of hydrochlorothiazide (25 mg twice daily) controlled 52.0% of the patients who achieved goal BP, com- pared with 149% of the patients treated with propranolol hydrochle- ride who achieved control at. the first level (40 mg twice daily). The second Propranolot and Hydrochlorothiazide, Part |—VA Study Group level (50 mg twice daily) of hydrochlo- -rothiazide controlled an additional 29.0% (81% for both doses combined), while propranolol hydrochloride had to be titrated to the fourth step (160 mg twice daily) to contro! a total of 80.2% of responders. It is interesting that change of hydrochlorothiazide to levels C, E, and G, which effected no actual change in drug dose, were nevertheless associated with an in- crease of 18.5%, 10.0%, and 9.5% responders, respectively. Terminations A total of 73 (10.7%) of the patients were dropped from the study after randomization. Of these, 42 (57.5%) were in the propranolol group and 31 were taking hydrochlorothiazide. The difference was not significant. Termi- nations were classified as either med- ical (adverse reactions, BP out of control, intolerable symptoms, or se- rious abnormal laboratory results) or administrative (interruptions in treatment for more than 21 days, uncooperative or unreliable in keep- ing appointments, unrelated intercur- rent illness, or withdrawal of con- sent). Each termination was reviewed by several different observers to try’ to determine that an administrative termination was not more likely owing to a medical reason (eg, a patient refusing to return because he was having apparently intolerable symptoms caused by propazide). Med- ical terminations occurred in 13 (3.8%) of the patients receiving pro- pranolol and six (1.7%) of the patients receiving hydrochlorothia- zide (x’=2.0036; P=.157). Termina- tions related to propranolol were due to diastolic BP greater than 119 mm Hg in four, intolerable symptoms such as lethargy, dreams, depression, dizziness, nausea, blurred vision, and headache in four, elevated blood glu- cose levels in two, and one each of skin rash, bronchospasm, and conges- tive heart failure with wheezing. Ter- minations related to hydrochlorothia- zide were due to diastolic BP higher than 119 mm Hg in two, intolerable symptoms such as diuresis, weakness, dyspnea, chest tightness, headache, and fatigue in two, and abnormal laboratory data in two. One of the latter was a compulsive water and beer drinker who had a history of hyponatremia. A “flulike’ syndrome 1999 Table 5.—Serum Concentration of Selected Substances at Baseline and at the End of Drug Titration” Prepranciel Hydrochioride Mydrechiorethieside Teat “ll vt Ww a ” aa Pt w 8 * rt Urea nitrogen, B 13.7437 4644.4 13.2433 001 14.023.9 18.2443. 130236 <.001 NS ang / dl. E 1486438 16.0434 139434 <.001 18.7446 ae 179248 162748 NS <.001 E-B £1431 <.001 16233 O7T+29 08 28244 <00f 2.0246 3.4248 009 <.001 Creatinine, 8 12202 eee 12202 1.240.2 cL) 1.2202 1.1202 1.220.2 NS NS mgd. E 1.22402 Lee 1.2402 1220.2 NS 1.2202 i 1.2402 1.9403 002 ONS E-8 0440.2 003 §«OS+0.2 0420.2 ns 07203 <.00) 02402 18203 008 ONS Potnesium, B 42404 4274048 9 4.17406 02 4.2407 4.36400 4.17204 or NS mEq/t E 44404 _.. 481404 431403 <.001 3.6408 .. 949406 306408 006 <.001 - E~8 1840.4 <.00t .24¢0.4 1340.4 04 —.67+0.9 <.00t — 8821.4 ~- $620.6 <.00t <.001 Ghuocee, 8 100423 109423 98+ 25 ns 100+ 28 106 + 20 er221 002 ws mg/dl. E 102420 Lae 107 #20 06420 <.00f 1080423 Lee 110221 102424 003 NS €-8 40217 <.001 6216 $418 we 4.0223 ,004 4226 4az17 NS ws Uric acid, B 8441.3 662413 6.33414 Ns eo4+14 O87413 8.80+1.6 NS NS mg/dl. & 6641.3 hae 6.68+1.2 6.584 1.3 NS 6021.7 wee 794416 0.14218 NS <.001 E-B 9s. 2141.0 NS 1940.9 2241.0 NS 147234 <.001 138418 1.86413 NS = <,001 Calcium, 8 906408 ... 0.44408 9.60205 NS 9.9209 0.34407 @89741.6 ns NS maid. E 4404 ... O81¢08 9.48404 OOF Ba+0.4 0.0020.4 8.7140.4 08 <.001 €~-B -06408 NS ~12406 -~.0140.5 ns 3140.9 <.001 2840.8 421.0 ws <.001 Cholesterol, Q. 221447 2204 48 222447 NS 228+ 47 —— sO 40 299245° NS NS maidl — 27i4e 221248 214443 NS 231% 48 264¢6t “22048 = NS <.001 E-B -6.2433 Ot 1436 ~O431 NS 8.8439 <.001 7 t 44-ge 10x34 NS <.001 Trigtycerides, 8 1864140, 208+177 198406 <.0O1 184+ 108 2224210 1644189", 002 NS mid. & 014180... 2344180 1804101 <.001 2204275 2784980 861724477 002 NS €-B 274181 <.001 Stzt7a 2ies ‘hs 944200 NS ° 6849268 142281 NS NS *Valuees are given as mean + SD; B indicates baseline; E, experimental. +P velue for difference between E and 8 for all patients in that treaiment group. $P valve for the differences in E, 8, and E-8 between white and black patients in thel treatment group. §P value for the ditferences in B, E, and E-6 between propranolol and hydrochiorothiazide treatment group. Table 6.— Selected Negative Parameters of BP Effect of Both Drugs’ Al Patients Proprenciol Hydrochloride . Hydrochtorothlazide Orug Propranolol Hydrochiore- ares Patients Hydrochioride tharide P w a ? w 8 P % DEP 2 100 13.8 9.0 NS a8 17.8t 04 10.8 7.6t NS % SBP Z 100 8.1 1.6 <.001 @.4t r.4t ws 14 t.8t we % sBPt 19.8 nt <.001 14.1 24.14 04 rr. t.0t NS % DBP! 7.0 6.4 a NS 8.1 10.0 .04 8.7 47 nS *P valuee are for the significance of the difference between the pair to the laf. NS=P>.05. DAP indicates diastolic BP; SBP, aystolic BP. tindicaies a significant difference between the effect of the two drugs in the same race. developed, and he was discovered .to have a serum sodium level of 108 mEq/L. Propazide administration was discontinued. He responded to treatment with normal saline and was discharged feeling well. He was subsequently rechallenged with hy- drochlorothiazide, had successful re- duction of his BP, and remained nor- monatremic. Seven white and six black patients taking propranolol were withdrawn for medical reasons, compared with five white and one black patient taking hydrochlorothia- zide. Patient complaints will be dis- cussed in detail in a separate report. In essence, this study indicated that there were no unexpected complaints. 2000 JAMA, Oct 22/29, 1982—Vol 248, No. 16 Symptoms related to the CNS were significantly more frequent in pa- tients taking propranolol. Diarrhea was more common with propranolol, and constipation was associated with hydrochlorothiazide. Both drugs were associated with a low level of sexual dysfunction, but significantly more occurred in the patients taking hydro- chlorothiazide; they also had more complaints of decreased libido. Se- lected laboratory values are displayed in Table 5. COMMENT These data demonstrate that in the short-term titration period studied, hydrochlorothiazide was generally more efficacious than propranolol in lewering BP. An important part of this effect was racial, with blacks being more likely to respond to hydro- chlorothiazide than to propranolol. On the other hand, there was not much difference in response to the two drugs in the white patients. The differences that were demonstrated were in favor of hydrochlorothiazide for systolic pressure and propranolol for diastolic pressure. The diastolic pressure difference may have been caused by the lower heart rate, in that more time was permitted for diastolic runoff. The observations on those patients who had an actual increase in BP suggest a potential risk, especially for black patients treated with proprano- Propranolol and Hydrochlorothiazide, Part |—VA Study Group Dose Required to Achieve Goal BP, mg 100 80 701 60 50 % Achieving Goal BP 30 20 10 80 All White Black Propranolol Hydrochloride WY UY Yyy All White Black Hydrochlorothiazide Distribution of drug dose required to achieve goal BP (<90 mm Hg). Only patients who actually achieved goal BP are included. Numbers in bars indicate drug dose in milligrams. For hydrochlorothiazide, lower of two identical numbers indicates first titration step, and higher indicates second, or ‘‘dummy,” titration step. ‘All’ represents biack and white groups combined. There was no racial effect in dose for propranolol hydrochloride, but there was superior response (P=.004) for black patients taking hydrochlorothiazide. lol monotherapy. The risk was also present for white patients, but to a lesser extent. One of the main reasons for initiat- ing this study was the question of whether or not it was appropriate to begin the drug treatment of hyper- tension with a diuretic routinely, as had been proposed by the Joint National Committee. on Detection, Evaluation, and Treatment of High Blood Pressure,” or to begin with a §-blocker. This empirical approach is at odds with the more elaborate volume-vasoconstriction scheme of Laragh, who recommended that drug therapy be selected on the basis of renin profiling. If profiling could not be done, he suggested that proprano- lol should be used as the step-one drug ,gnd diuretic added only if it failed. If the two drugs lowered BP, propranolol could be withdrawn to determine whether the BP would be controlled with diuretic alone. Obvi- ously, this schema is more compli- cated and requires more patient visits than the less individualized step-care system. The data presented herein seem to support the general use of diuretic as a first-line drug, especially for black patients. Even in the white population, diuretic seemed to have JAMA, Oct 22/29, 1982—Vol 248, No. 16 - hypertension in blacks. little if any disadvantage with respect to propranolol. . Major studies on hypertension in the United States have included a large black population that is dispro- portionate even to the fraction of blacks in the United States. Studies from Europe and the United Kingdom tend to include few or no blacks, so that the established habits on each side of the Atlantic would tend to be reinforced by their selection of pa- tients. Several other studies have sug- gested that blacks are less responsive to B-adrenergie blocking agents than are whites.”** Abson et al’ could induce significant BP reduction in Zimbabwean blacks only with a high dose (200 mg) of atenolol. The results were also less favorable than in a prior study of white patients.” See- dat compared atenolol! (100 mg) with chlorthalidone (25 mg) in 24 Zulus. Chlorthalidone produced a small ef- fect and atenolol no effect, but the combination was effective. He con- cluded that “beta-blockers should not be regarded as baseline treatment of The mechanisms for the observed differences in drug response are not known. Examination of the prelimi- nary data on 24-hour sodium and potassium excretion shows that there was no racial difference in sodium excretion (and, therefore, consump- tion), but that blacks excreted only - about 60% of the quantity of potas- sium excreted by whites. Possibly this may be a reflection of a lower dietary intake of potassium-rich fresh fruits, vegetables, and lean meats by blacks, but data are lacking to support this point. The electrolyte excretion data will be presented separately. There is some evidence to suggest that a reduced potassium intake in compari- son. with sodium may contribute to hypertension. For example, potas- sium is said to have a natriuretic effect.” Watson et al” studied pooled cross-section data from 662 black and white females in regard to systolic BP and urinary electrolyte excretion. They found the urinary sodium/ potassium ratio to be directly related to systolic BP and suggested a moder- ating role for potassium. Luft et al’ conducted a detailed study of 347 normotensive black and white men and women. The urine sodium/potas- sium exeretion ratio was higher in blacks by about 50%, and blacks were less efficient than whites in handling an acute sodium load. Many workers have explored the reasons for the observed racial differ- ences in hypertension. Gillum” has carefully reviewed data in regard to differences in genetic factors and per- sonal characteristics including skin color, renal physiology, endocrine fac- tors, autonomie nervous system func- tion, cardiac function, and environ- mental factors. He pointed out the difficulties of separating specific fac- tors from numerous confounding var- iables. Plasma volume is more likely to be expanded in blacks than in whites, and plasma renin activity tends to be lower.” Mitas et al” studied blood volume and plasma renin activity (PRA) in 29 normotensive persons, including 14 blacks, and 36 hyperten- sive persons, nine of whom were black. They found differences in vol- ume and PRA between blacks and whites that they believed to reflect basic racial differences. On the other hand, Messerli et al* studied 126 black and white patients with essen- tial ‘hypertension and found that, when matched for age or level of Propranofol and Hydrochlorothiazide, Part |—-VA Study Group 2001 arterial BP, systemic hemodynamics were similar. They concluded that the basic. pathophysiology of hyperten- sion was not different in black patients with essential. hypertension. Holland et al” used three methods— intravenous furosemide test, ambula- tion during placebo treatment, and ambulation during spironolactone and hydrochlorothiazide treatment— to determine renin status in 26 black hypertensive women. In only seven did the three methods coincide. They concluded that “since black women with both low and normal renin activ- ity are quite responsive to diuretics, renin classification to guide initial antihypertensive selection is not war- ranted.’ Plasma renin data from our study will be presented separately. A curious absence of hypertension seems to occur in blacks with sickle cell disease.* This may be due to the salt-wasting nephropathy of sickle cell disease. Other possibly important racial dif- ferences include difference in the oua- bain-resistant pathway of RBC cation transport.” The difference in re- sponse to drugs does not appear to be related to differences in aldosterone excretion” or plasma norepinephrine concentration.” It is possible that blacks have some deficiency in the kallikrein-kinin natriuretic vasodila- tor system”; however, the observed differences might be due to other factors such as dietary sodium and potassium intake. White hypertensive / persons have greater dopamine-f- hydroxylase activity than blacks.” This study confirmed the relative ease of titration with hydrochlorothi- azide in that 80% of the patients responded by the second titration step, whereas four titration steps above the initial dose with proprano- lol were required to reach the same goal. In practice, however, many phy- sicians might not include the 240-mg level and, thereby, would reduce the number of steps to three. Also, it is likely that patients who did not respond to 320 mg of propranolol or 100 mg of hydrochlorothiazide would have a “step-2” drug added rather than continue the titration upward. In the total group, an average of 268 mg of propranolol and 93 mg. of hydrochlorothiazide was required to achieve control. White patients re- quired an average of 269 mg of pro- .2002 JAMA, Oct 22/29, 1982—Vot 248, No. 16_ pranolol hydrochloride, blacks 267 mg. White patients required 114 mg of hydrochlorothiazide, blacks 79 mg (P=.004). Thirty-eight patients (19.0% } who failed to achieve goal BP while taking 100 mg of hydrochloro- thiazide did achieve goal when they received 200 mg. This suggests that. 100 mg is not necessarily maximal. Our observation of continued re- sponse to hydrochlorothiazide on the same dose after a dummy titration step suggests that it is important to provide enough time for a response to hydrochlorothiazide before titrating upward. Interim visits no doubt serve to reinforce salt restriction, com- pliance, and a sense of confidence in the therapist, which are independent of drug effect per se. Patients who are nearing goal BP ought to be given more time to respond rather than being titrated upward at once or having another drug added. Considerable attention has been paid to the metabolic adverse effects of both propranolol and hydrochloro- thiazide. Most studies that have looked at these laboratory changes have been cross-sectional studies of changes induced by relatively acute pharmacologic manipulation. This study falls into that category. We indeed did demonstrate statistically significant increases in serum urea nitrogen, uric acid, calcium, and cho- lesterol levels with hydrochlorothia- zide acutely as compared with pro- pranolol over the short term. We also observed a statistically signifi- cant decrement in the serum potassi- um level with hydrochlorothiazide, whereas the potassium level tended to inerease with propranolol. The biolog- ical significance of these changes ha not been fully elucidated. , The issue of hypokalemia perhaps has been the one most vigorously debated. If the work of Holland and co-workers” showing an increase in ventricular ectopic activity associated with hypokalemia is confirmed, then it would seem to be necessary to pay considerably more attention to even trivial. decrements in serum potas- sium. Indeed, Caralis et al“ have evidence that diuretics do increase ventricular ectopic activity, but only in a susceptible patient population consisting of elderly patients with identifiable, preexisting organic heart disease. The present data suggest that many of the responders to hydrochlo- rothiazide achieved their benefit at low doses of the drug. Use of these lower doses of diuretic should cause less perturbation of serum potassium levels.” It is also possible that these short- or intermediate-term cross- sectional studies are not providing a representative picture of long-term maintenance therapy. Berglund and Andersson* demonstrated that in a group of patients followed for six years there were no material differ- ences between the metabolic adverse effects of propranolol and hydrochlo- rothiazide. If this is true for the long term, then it is possible that there might be undue concern over the short-term changes. If the observations from an acute study of the effects of ethanol con- sumption on propranolol clearance” can be extrapolated to habitual alco- hol abusers, then an additional poten- tial disadvantage of propranolol might be identified. Ethanol inges- tion increases metabolic clearance of propranolol and decreases its antihy- pertensive effect. The extent to which this might have diminished the effi- eacy of propranolol compared with hydrochlorothiazide in our study is not known. Cost of drugs is a factor that may be easily forgotten. In a federal hospi- tal the cost of 50 mg of hydrochloro- thiazide twice daily for 30 days is 60 cents, whereas the cost of 160 mg of propranolol hydrochloride twice daily for 30 days is $14.40 in 1982 dollars. The actual cost to the patient in a community pharmacy will vary, but is usually much higher. , CONCLUSION This short-term trial of drug monotherapy for patients with mild to moderate hypertension demon- strated that hydrochlorothiazide was at least as effective as propranolol for white patients and was superior to propranolol in blacks. Furthermore, hydrochlorothiazide proved less likely to elevate BP in those patients who did not respond to treatment and required fewer titration steps to achieve control than propranolol. Nevertheless, what is good for groups of patients does not necessarily obtain for a given individual. Thera- peutic decisions must continue to rest Propranolol and Hydrochlorothiazide, Part |~—VA Study Group on specific indications, contraindica- tions, simplicity of titration, patient acceptance, potential undesirable ef- feets, and cost. This study was supported by a grant from Ayerst Laboratories, Inc. The 906 patients who volunteered to partici- pate in this study, the clinie secretaries, Hines Coordinating Center support staff, hospital research pharmacists, and numerous other peo- ple contributed to the success of this cooperative project. Clydie Mae Denson prepared the manu- script. The following persons participated in this study: Cochairmen: Edward D. Freis, MD (Washing- ton, DC) and Barry J. Materson, MD (Miami). Principal investigators: Frederick N. Talmers, 1. Lewis P: The essential action of propranclol in hypertension. Am J Med 1976;,60:837-852. ~ 2. Lorimer AR, Dunn FG, Jones JV, et al: Beta-adrenoreceptor blockade in hypertension. Am J Med, 1976;60:877-885. 3. Holland OB, Kaplan NM: Propranolol in the treatment of hypertension. N Hngl J Med 1976; 294:930-936. 4. Stephen SA: Unwanted effects of proprano- lol. Am J Cardiol 1966;18:463-472. 5. Laragh JH: Modern system for treating high blood pressure based on renin profiling and vasoconstriction-volume analysis: A primary role for beta blocking drugs such as propranolol. Am J Med 1976;61:797-810. 6. Laragh JH: The proper use of newer diuret- ics. Ann Intern Med 1967;67:606-613. 7. Ames RP, Hill P: Elevation of serum lipid levels during diuretic therapy of hypertension. Am J Med 1976;61:748-757. 8. Chrysant SG, Neller GK, Dillard B, et al: Effects of diuretics on lipid metabolism in patients with essential hypertension. Angiology 1976;27:707-711. 9. Reichgott MJ: Problems of sexual function in patients with hypertension. Cardiovasc Med 1979;4:149-156. 10. Propranolol in the treatment of essential hypertension, Veterans Administration Cooper- ative Study Group on Antihypertensive Agents. JAMA 1977;237:2303-2310. 11. Report of the Joint National Committee on Detection, Evaluation and Treatment of High _Blood Pressure: A cooperative study. JAMA 1977;287:255-261: 12. Humphreys GS, Delvin DG: Ineffective- ness of propranolol in hypertensive Jamaicans. Br Med J 1968;2:601-603. 18. Hollifield JW, Sherman K, Slaton PG: Age, race and sex as a determinant of successful antihypertensive therapy. Prev Med 1978;7:111. 14: Seedat YK: Trial of atenolol and chlorthal- idone for hypertension in black South Africans. Br Med J 1980;281:1241-1248. 15. Abson CP, Levy LM, Eyherabide G: Once- JAMA, Oct 22/29, 1982—Vol 248, No. 16 MD (Allen Park, Mich); William C. Cushman, MD (Jackson, Miss); Harold Schnaper, MD (Bir- mingham, Ala); Thomas J. White, MD (Mem- phis); Khin Mae Hla, MD, and Orlando Fernan- dez, MD.(Miami); Eli A. Ramirez, MD (San Juan, Puerto Rico); Ibrahim Khatri, MD (Washington, DC). Nurses: Barbara Gregory, RN, and Madeline Metcalfe, RN (Washington, DC); Julie Pawelak, RN (Allen Park, Mich); Pauline Derrington, RN (Jackson, Miss); Susan Reece, RN, and Kristina Grossman, RN (Memphis); Mary H. Smith, RN, and Eileen Haran, RN (Miami); Maria Natal, RN (San Juan,‘ Puerto Rico); Donald Quinn, PA (Birmingham, Ala). Biostatisticians: Bor Ming Ou, MS, Samuel B. Lindle, PhD, Domenic Reda, MS. Special renin laboratory: Walter Flamenbaum, MD, and Robert Hamburger, MD. Central research pharmacist: Larry Young, RPh. References daily atenolol in hypertensive Zimbabwean blacks: A double-blind trial using two different doses. S Afr Med J 1981;60:47-48. 16. Moser M, Lunn J: Comparative effects of pindolol and hydrochlorothiazide in black hyper- tensive patients. Angiology 1981;32:561-566. 17. Nilsson OR, Karlberg BE, Ohlsson 0, et al: Atenolol administered once daily in primary hypertension: Effects on blood pressure in rela- tion to pre-treatment plasma renin activity. Acta Med Scand 1979;206:303-308. 18. Meneely GR, Battarbee HD: High sodium- low potassium environment and hypertension. Am J Cardiol 1976;38:768-785. 19, Watson RL, Langford HG, Abernethy J, et al: Urinary electrolytes, body weight, and blood pressure: Pooled cross-sectional results. among four groups of adolescent females. Hypertension 1980;2(part 2):193-198. 20. Luft FC, Grim CE, Fineberg N, et al: Effects of volume expansion and contraction in normotensive whites, blacks, and subjects of different ages. Circulation 1979;59:643-€50. 21. Gillum RF: Pathophysiology of hyperten- sion in blacks and whites: A review of the basis of racial blood pressure differences. Hyperten- sion 1979;1:468-475. 22. Chrysant SG, Danisa K, Kem DC, et alk: Racial differences in pressure, volume and renin interrelationships in essential hypertension. Hy- pertension 1979;1:136-141, 28. Mitas JA I, Helle R, Levy SB, et al: Racial analysis of the volume-renin relationship in _ human hypertension. Arch Intern Med 1979, 189:157-160. . 24, Messerli FH, DeCarvalho JGR, Christie B,, et al: Essential hypertension in black and white subjects: Hemodynamic findings and fluid vol- ume state. Am J Med 1979;67:27-31. 25. Holland OB, Gomez-Sanchez C, Fairchild C, et al: Role of renin classification for diuretic treatment of black hypertensive patients. Arch Intern Med 1979;139:1365-1370. 26. Johnson CS, Giorgio AJ: Arterial blood pressure in adults with sickle cell disease. Arch” Operations Coromittee: F. Gilbert McMahon, MD, Ray Gifford, Jr, MD, and C. Morton Haw- kins, PhD. . Consultants: James R. Oster, MD, Ezra Lamdin, MD (Ayerst Laboratories), Shig Ochi, PhD, and J. R. Thomas, MD. Hines Cooperative Studies Program Coordinating Center Human Rights Committee: Jennie McKoy; Patrick Moran; Mary Davidson, PhD; Kenneth Elmer; Rev Martin Feldbush. Cooperative Studies Program Central Administra- tion: James A. Hagans, MD, PhD, and Ping Huang, PhD (VA Central Office, Washington, © DC); Kenneth James, PhD, and William G. Henderson, PhD (Cooperative Studies Program Coordinating Center, Hines, Il); Mike Sather, RPh, MS (Cooperative Studies Program Re- search Pharmacy Coordinating Center, Albu- querque). Intern Med 1981;141:891-893. 27. Woods KL, Beevers DG, West M: Familial abnormality of erythrocyte cation transport in essential hypertension. Br Med J 1981,282:1186- 1188. 28. Gomez-Sanchez CE, Holland OB: Urinary tetrahydroaldosterone and aldosterone-18-glu- curonide excretion in white and black normal subjects and hypertensive patients. J Clin Endo- crinol Metabol 1981;52:214-219. 29. Sever PS, Peart WS, Davies IB, et al: Ethnic differences in blood pressure with obser- , vations on noradrenaline and renin: A hospital hypertensive population. Clin Exp Hypertens 1979;1:745-760. 30. Sever PS, Gordon G, Peart WS, et al: Blood pressure and its correlates in urban and tribal Africa. Lancet 1980;2:60-64. $1. Warren SE, O’Connor DT: Does a renal vasodilator system mediate racial differences in essential hypertension? Am J Med 1980;69:425- 429. : 32. Levy SB, Frigon RF, Stone RA: Plasma dopamine-beta-hydroxylase activity and blood pressure variability in hypertensive man. Clin Endocrinol 1979-11:187-199. 38. Holland OB, Nixon JV, Kuhnert LaV: Diuretic-induced ventricular ectopic activity. Am J Med 1981;70:762-768. $4. Caralis P, Perez-Stable E, Materson RB, et al Ventricular ectopy and diuretic-induced hypokalemia in hypertensive patients, ab- stracted. Clin Res 1981;29:832A. / 35. Materson BJ, Oster JR, Michael UF, et. al: Dose response to chlorthalidone in patients with mild hypertension: Efficacy of lower dose. Clin Pharmacol Ther 1978;24:192-198. 36. Berghind G, Andersson 0: Beta-blockers or diuretics in hypertension? A six year follow~ _up of blood pressure and metabolic side effects. Lancet 1981;1:744-747. 87. Sotaniemi EA, Anttila M, Rautio A, et ak: Propranolol and sotalol metabolism after a drinking party. Clin Pharmacol Ther 1981; 29:705-716. \ Propranolol and Hydrochlorothiazide, Part |—VA Study Group , 2003.