Oxprenolol vs Propranolol : A Randomized, Double-Blind, Multiclinic Trial in Hypertensive Patients Taking Hydrochlorothiazide VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP SUMMARY Oxprenolol (0) or propranolol (P) was randomly added double-blind to the regimen of 260 patients with mild and moderate hypertension who had not responded to hydrochlorothiazide (H) alone. Both beta-adrenergic blocking agents were titrated over a range of 120 to 360 mg per day while H was continued. After 6 months of treatment, reduction of diastolic blood pressure (DBP) to below 90 mm Hg and at least 5 mm Hg less than the initial DBP was achieved in 50% of patients receiving P+H and 27% of patients taking O+H (p < 0.001). P+H lowered BP an additional 10.5/9.8 mm Hg compared with 6.8/7.0 mm Hg for O+H (JJ < 0.02). Reduction in heart rate was less after OSH (average, 8.4/min) than after P+H (average, 12.3/min, p < 0.01). The number of dropouts, morbid events, and reported side effects between the two regimens was not significantly different except that more patients complained of impotence with P+H than with O+H (p < 0.05). ~HypertenGon 3: 250-256, 1981) KEY WORDS * beta adrenergic blockers * controlled therapeutic trial * cooperative study . antihypertensive drugs U SE of beta-adrenergic blocking agents in the treatment of hypertension has increased rapidly since the introduction of propran- 0101 15 years ago. Propranolol, a nonselective beta- adrenergic blocking agent without intrinsic sym- pathomimetic activity, was the first of these agents to be widely used clinically. Consequently, it is often used as a reference standard for comparison with other beta-adrenergic blocking drugs.`, * Differences in pharmacology, hemodynamics, antihypertensive effects, and side effects make it important to carry out controlled trials comparing the various beta- adrenergic blocking drugs to assess clinically relevant differences. Oxprenolol (Trasicor) is a highly specific, but non- selective, beta-adrenergic blocking agent with membrane-stabilizing properties similar to those of From participating Veterans i\dministration Medical Centers in Washington, D.C.; Jackson, Mississippi; Allen Park, Minnesota; Memphis. Tennessee; Miami, Florida: and San Juan, Puerto Rico. This paper *as prepared by the Veterans Admmistration Coopera- tive Study Group on Antihypertensive Agents. For a complete list of participants see Acknowledgments. Supported by the Cuoperarive Studie\ Program of the Veterans Administration Mcdlcal Research Scruicc. The material presented in this paper has never been published elsewhere. Address for reprints: J. R. Thomas, M.D.. Veterans Administra- tion Medical Center. 1030 JelTerson 4venue, Memphis, Tennessee 3X104. Received May 15, 19X0; revision accepted August 28, 1980. propranolol. Unlike propranolol, however, it also has intrinsic sympathomimetic activity (ISA).3m7 Ox- prenolol has beta-adrenergic blocking activity com- parable to propranolols but its negative inotropic effect is less pronounced. `9 7* 0 This latter property of oxprenolol should lessen the risk of heart failure or ex- cessive bradycardia as compared with the administra- tion of propranolol or cardioselective blocking agents such as metroprolol or atenolol. This study was designed to compare the efficacy of oxprenolol and propranolol in the treatment of patients with hypertension, defined as a diastolic blood pressure (DBP) of 95 through 114 mm Hg, whose blood pressure (BP) was not adequately lowered with the administration of hydrochlorothiazide alone. Methods Male veterans between the ages of 2 1 and 64 years, whose DBP was in the range of 95 to 114 mm Hg, were recruited primarily in the admitting room and outpatient clinics, and less frequently among hospitalized patients. Patients with severe complicated hypertension, serious systemic disease, and those with preexisting conditions that would interdict the use of the drug regimens, were excluded from the study. Atrial fibrillation was an exclusion factor because ac- curate determination of BP would be impossible. A list of the exclusions is presented in Appendix A. 250 OXPRENOLOL VS PROPRANOLOL/ Veterans Administration Cooperative Study Group 251 Prior therapy was discontinued for at least 4 weeks before the patients entered the trial. The nature of the study was explained to them, and their written in- formed consent was obtained. The study was approved by the Human Use Committee at each hospital and conformed to the principles of the Helsinki declara- tion. A history was then taken and a physical ex- amination performed. Chest roentgenogram (if not taken in the previous 3 months), ECG, complete blood cell count, urinalysis, and determinations of fasting serum glucose, potassium, uric acid, cholesterol, triglycerides, and creatinine were obtained. In addi- tion, antinuclear antibody, SGOT, and alkaline phosphatase levels were determined as indices for drug toxicity. Slit lamp examination, skin surveillance, and fluorescent antinuclear antibody tests (FANA) were performed prior to randomization and at 3-month in- tervals. A checklist of the known side effects associated with the administered drugs was reviewed with the patient at each visit. The BP readings were taken in the right arm by means of a standard mercury sphygmomanometer three times in the sitting position at each clinic visit. The DBPs reported represent the average of the three fifth-phase Korotkoff readings taken with the patient in the sitting position. Pulse rate was recorded at each clinic visit. Placebo Period The pretreatment BP and the compliance of the patient were determined during the prerandomization period. Following a drug washout period of 4 weeks, if patients were on prior therapy they were given a bottle containing placebo, identical in appearance to the drugs used in the active drug period. They were in- structed to take one capsule three times daily and to return the bottle with the remaining medication to the clinic on each visit. Patients were included in the trial if their average DBP on two successive clinic visits was in the range of 95 to 114 mm Hg provided they had taken 90% or more of the prescribed medications. A maximum of four biweekly visits were allowed to fulfill these requirements. Hydrochlorothiazide (HCTZ) Period and Postrandomization Period Patients meeting the placebo trial period criteria were placed on HCTZ 25 mg three times daily, and the placebo was continued. Each patient was seen biweekly for two clinic visits and, if the average DBP was less than 90 mm Hg, was dropped from the study. However, if after 4 weeks of therapy with HCTZ the average DBP was greater than 89 mm Hg, propranolol or oxprenolol was randomly assigned in a double-blind manner 40 mg three times daily while the HCTZ was continued. Doses of the beta-adrenergic blocking agents were titrated at biweekly intervals to the peak dose of 120 mg three times daily or until goal BP was achieved. The latter was defined as a DBP less than 90 mm Hg and at least 5 mm Hg below the prerandomization level. After reaching the peak dose level, patients whose DBP exceeded 104 mm Hg dur- ing two clinic visits 2 weeks apart were removed from the trial. Other reasons for termination of participa- tion included the development of symptomatic hypotension, serious side effects of the blocking agents, development of systemic diseases, or serious complications of hypertension (Appendix B). Results Prerandomization Losses Of the 418 patients entering the study, 105 patients (25.1%) were dropped during the placebo phase. Of these, 49 were dismissed because of lack of com- pliance, 40 due to a BP outside the acceptable range, and 16 due to miscellaneous causes. HCTZ was administered to 3 13 of the 418 patients entering the pretrial placebo period. During this HCTZ phase, 53 patients were dropped: 39 because the DBF fell to below 90 mm Hg, seven for failing to return to the clinic, two because the DBP was greater than 114 mm Hg, and five for miscellaneous reasons. Comparability of Randomized Groups Oxprenolol or propranolol was randomly assigned double-blind to 260 patients qualifying for randomiza- tion. Of this number, 2 11 patients completed 6 months of treatment. The characteristics of the patients ran- domly assigned to oxprenolol or propranolol were nearly identical in all respects examined (table 1). More blacks than whites were lost during the preran- domization period. The primary reason for more white patients advancing to the HCTZ phase was that more blacks demonstrated noncompliance; 26 blacks but only two whites failed to return to clinic. Eleven blacks and seven whites had BPS too low to be in- cluded in the study, while 14 blacks and eight whites were excluded because of a DBP greater than 114 mm Hg. There were no significant differences between the regimens in either the dropout rates or in the causes for the 49 dropouts that occurred in the postrandom- ization phase (table 2). Changes in Blood Pressure A major objective of the study was to compare the percent of patients on each regimen who achieved goal BPS after 1, 3, and 6 months of therapy. The values used for 1 and 3 months are the average DBPs recorded on the particular monthly visit, whereas the value at 6 months represents the average of the deter- minations taken at both 5 and 6 months. Fifty-three patients taking propranolol achieved goal BP pressure at 1 month, 59 at 3 months, and 54 at 6 months. Forty-four patients taking oxprenolol achieved goal BP at I month, 29 at 3 months, and 28 at 6 months (table 3). The differences between the regimens in the percentage of patients at goal BP was significant @ < 0.001) at 3 and 6 months. 252 HYPERTENSION VOL 3, No 2, MARCH-APRIL 1981 TABLE 1. Characteristics of Patients Entering and Completing Study Entering Placed on HCTZ Randomized Completing Study Propranolol Oxprenolol Propranolol Oxprenolol No. of Patients Age, v-s Race White Black Other Weight, kg Blood pressure, mm Hg Systolic: Pretreatment Post HCTZ Reduction Diastolic: Pretreatment Post HCTZ Reduction Heart rate, beats/min Serum potassium, mEq/liter Creatinine, mg/lOO ml Uric acid, mg/lOO ml 418 313 130 130 50.3 i 0.47 50.8 i 0.4 50.0 k 0.7 51.2 It 0.7 188 (45%) 159 (51%) 71 (55%) 68 (52%) 229 (55%) 153 (49%) 59 (45%) 61 (47'%) 1 (0%) 1 (0%) 0 co'%) 1 (1%) 86.5 f 0.7 86.2 _t 0.8 87.7 t 1.2 85.2 + 1.3 150.7 150.5 149.3 150.3 104.0 103.9 104.1 104.2 78.2 zt 0.5 77.9 f 0.6 77.8 i 0.9 78.4 f 1.1 4.25 + 0.2 4.24 k 0.2 4.21 + .04 4.25 k .04 1.17 i 0.1 1.17 * 0.1 1.18 k .02 1.16 i .02 6.73 e 0.7 6.71 + 0.7 6.73 k .11 6.73 31 .ll 107 50.9 * 0.7 59 (55%) 58 (55%) 48 (45%~) 45 (44%) 0 (0%) 1 (1%) 86.4 k 1.3 85.0 k 1.5 149.4 137.9 11.5* 104.0 99.5 4.5* 77.4 i 0.9 4.22 i .04 4.23 + ,051 1.18 * .02 6.72 k .12 6.68 t .I0 104 51.2 i 0.8 150.6 137.9 12.7* 104.1 99.2 4.9* 77.3 + 1.3 1.16 + .02 *Using paired t test; t > 3.291, p < 0.001. tMean i standard error number. HCTZ = hydrochlorothiazide. The mean BP levels before and after treatment are shown in table 4. The mean reduction of SBP and DBP associated with the administration of propranolol at I month was 9.8/9.0 mm Hg, at 3 months 10.8/10.4 mm Hg, and at 6 months, 10.5/9.8 mm Hg. For those taking oxprenolol, the mean reduc- tions were 7.6/7.9 mm Hg at 1 month, 7.3/7.3 mm Hg at 3 months, and 6.8/7.0 mm Hg at 6 months. The TABLE 2. Losses Following Randomization Regimen Cause Propranolol Oxprenolol Improper entry or noncompliance: Noncompliance Improperly randomized Miscellaneous Clinical events: Pulmonary emboli and death Congestive heart failure Diabetes-insulin dependent Prior brain infarct with recurrent symptoms Persistent BP > 104 mm Hg Side effects: Depression Photosensitivity due to HCTZ Total 12 9 3 3 3 6 1 1 0 0 1 2 2 0 1 23 26 0 0 2 1 2 HCTZ = hydrochlorothiazide mean reductions were significantly different between propranolol and oxprenolol at 3 and 6 months for both DBP (p < 0.001) and SBP @ < 0.05). Pulse Rate, Body Weight, and Blood C'hemistries Pulse rate declined in both groups but significantly more in the propranolol group (table 5), the mean decrease being 12.4/min following propranolol as compared to 8.4/min after oxprenolol (II < 0.01). At 6 months, three patients receiving propranolol as com- pared to none on oxprenolol exhibited a pulse rate of 50/min or lower. No patient exhibited bradycardia of this degree prior to randomization. Body weight increased significantly in both groups, but the mean increases were less than 1.5 kg. There was no significant difference in the degree of weight gain between the propranolol and oxprenolol groups. Serum creatinine and uric acid levels revealed similar but insignificant changes before and after treatment with both regimens. Although serum potassium concentration increased significantly in both treatment groups @ < O.Ol), the magnitude was small and there was no significant difference between the oxprenolol and the propranolol patients. Side Effects Subjective side effects not present prior to ran- domization but which were volunteered or elicited after randomization were varied and numerous (table OXPRENOLOL VS PROPRANOLOL/J'eferans Administration Cooperafive Study Group 253 TAHLK 3. Percent of Patients Attaining Diastolic Blood Pressures Averaging Below 90 mm Hg and at Least 5 mm Hg Less than Initial Pressure 1 Month 3 Months 6 Months Treatment No. `% No. 7% No. % Propranolol 53 50% 59 55%* 54 50%* Oxprenolol 44 43% 29 28% 28 27% `Chi-square > 10.83; p < 0.001 6). Impotence was the only significant side effect noted between regimens, in 24% of the propranolol-treated patients as compared to 14% of those receiving ox- prenolol (p < 0.05). Wheezing and peptic ulcer symp- toms were additional side effects that were more frequently encountered with propranolol than with ox- prenolol, although the difference did not reach the level of significance. However, this could have oc- curred by chance in view of the large number of different side effects reported (table 6). There were no significant differences noted between groups with re- spect to other side effects. Weakness, lethargy, ortho- static dizziness, itching of the eyes, and dyspnea were the most frequent complaints. Several of these oc- curred in the same patient in many instances. In view of the oculomucocutaneous syndrome reported with practolol,`" 209 patients underwent slit lamp examinations at specified intervals. There was no evidence in any of the patients either by this examina- tion, by physical examination, or by the FANA test of the presence of this syndrome. TAn1.E 4. Mean Systolic and Diastolic Blood Pressures Before Treatment and at I,3 and 6Months after Treatment Blood pressure, mm/Hg Propranolol Oxprenolol At randomization 137.9199.5 137.9/99.2 At 1 month 128.1/90.5 130.3191.3 At 3 months 127.1/89.1 130.6/91.9 At 6 months* 127.4/89.7 131.1/92.2 Mean reduction at 6 months -10.5/-9.8 -6.81-7.0 *Average of BP for 5th and 6th month. Discussion Results of the present study are presented for the patients completing the trial rather than for all patients randomized. We believe this analysis is more meaningful than to include the dropouts, and seems justified for the following reasons. First, the number of dropouts after randomization was relatively small and was approximately equal in the two treatment groups, being 23 of 130 patients or 17% of those ran- domized to propranolol and 26 of 130 or 20% of those randomized to oxprenolol. Second, as can be seen in table 2, the reasons for termination of the trial were not significantly different between therapeutic regimens. In particular, excessive BP was an uncom- mon cause for termination in both groups of patients. The most frequent reason was noncompliance, usually failure to return to clinic, which occurred nearly equally in the two groups. It would seem very unlikely, therefore, that the observed differences in an- tihypertensive effectiveness between oxprenolol and TAHLE 5. Mean Changes and Standard Errors in Pulse Rate, Body Weight, Serum K, Creatinine, and liric Arid at 6 Months Propranolol Oxprenolol Difference between drugs Pulse rate (beatsimin) At randomization 79.8 i 0.9 79.3 i 1.2 0.5 i 1.6 At 6 months 67.4 dc 1.0 70.9 i 1.0 -3.5 i 1.4* Change -12.4 i 1.0: -8.4 zt 1.1: -4.0 i 1.51 Weight (kg) At randomization 85.4 k 1.3 83.7 f 1.4 1.7 * 1.7 At 6 months 86.8 * 1.3 84.8 f 1.5 2.0 * 2.0 Change +1.4 f 0.3: +1.1 i 0.3: 0.3 i- 0.4 Serum potassium (mEq/liter) At randomization 3.71 i 0.04 3.58 f 0.05 0.13 i 0.06* At 6 months 3.85 i 0.05 3.77 i 0.05 0.08 + 0.07 Change +0.14 * 0.05' +0.19 k 0.06t -0.05 i- 0.08 Serum creatinine (mg/lOO ml) At randomization 1.22 _t 0.02 1.21 i 0.02 0.01 * 0.03 At 6 months 1.23 + 0.02 1.20 + 0.02 0.03 It 0.03 Change +0.01 i 0.02 -0.01 * 0.02 0.02 It 0.03 Uric acid (mg/lOO ml) At randomization 8.04 + 0.16 7.97 + 0.18 0.07 i 0.24 At 6 months 8.03 f 0.14 8.07 f 0.16 0.04 f 0.21 Change -0.01 f 0.18 +0.10 AZ 0.14 -0.11 f 0.23 Paired t test used within each regimen and two sample t test for differences between regimens. *t > 1.96; p < 0.05. tt > 2576; p < 0.01. :t > 3.291; p < 0.001. 254 HYPERTENSlON VOL 3, No 2, MARCH-APRIL 1981 TABLE 6. New Side Effects (Volunteered and Elicited) after Randomization for 211 Patients Completing the Study Side effect Propranolol Oxprenolol patients patients No. % No. % Lethargy 19 18 21 20 Depression 5 5 5 5 Nightmares 8 8 11 11 Edema 4 4 3 3 Syncope 2 2 2 2 Vertigo 13 12 13 13 Weakness 23 22 27 26 Wheezing 8 8 3 3 Dyspnea 19 18 15 14 Angina 10 9 10 10 Palpitations 12 11 9 9 Ulcer Symptoms 11 10 6 6 Anorexia 8 8 3 3 Impotence 26 24 14 14* PND 5 5 3 3 Skin Rash 10 9 16 15 Postural Dizziness 21 20 17 16 Claudication 4 4 6 6 Itching Eyes 20 19 14 14 Other 52 49 56 54 *chi-square > 3.84; p < 0.05. propranolol could be due to bias introduced by omit- ting the patients who were terminated from the study. Propranolol was significantly more effective in lowering BP than oxprenolol after the third month of treatment. Not only did a higher percentage of patients receiving propranolol achieve goal BP at 6 months than those taking oxprenolol (50% versus 27%) but they also showed a greater reduction in the mean SBP and DBP (-10.5/9.8 mm Hg vs -6.8/7.0 mm Hg). While this difference is not great, it should be noted that the present study was not designed to test the effectiveness of oxprenolol and propranolol in lowering mean BP. Rather, the major objective was to determine what percentage of patients would achieve a goal level of BP. After the goal level was reached, there was no further increase in dose. Hence, the lowest tolerable levels of BP probably were not at- tained. The setting of a therapeutic goal below 90 mm Hg also seems to be in keeping with standard clinical practice, as most clinicians appear to use this goal in treating their patients. Of the 54 patients receiving propranolol who achieved goal BP at 6 months, 27 also were at goal BP at 1 and 3 months. Only 15 patients receiving ox- prenolol achieved goal BP at all of these clinic visits. Seventy-nine patients taking propranolol as compared to 53 patients receiving oxprenolol achieved goal BP either at 1, 3, or 6 months during the course of the study. The percentage of propranolol-treated patients who achieved goal BP remained relatively constant from the tirst to the sixth month of treatment. However, the percent responders to oxprenolol fell sharply after the first month. In the oxprenolol-treated group, the percentage of patients achieving goal BP dropped from 43% at 1 month, to 28% at 3 months, to 27% at 6 months. It is not clear why the oxprenolol- treated patients exhibited a smaller percentage of responders after the first posttreatment month. Various sources of bias were examined as possible causes for the difference in response between the two treatment groups. With respect to the severity of the hypertension, the mean SBP and DBP were nearly identical for the two groups, that is, 137.9/99.5 mm Hg for propranolol and 137.9/99.2 mm Hg for ox- prenolol. In addition to the similarity of the means, the BP distribution also was not significantly different (table 7). Furthermore, the response of the patients to HCTZ was similar, the reduction averaging 11.5/4.5 mm Hg for patients later assigned to propranolol and 12.7/4.9 mm Hg for those randomized to oxprenolol. There also were no significant differences with respect to age, race, heart rate, and serum creatinine between the two groups. The lesser response to oxprenolol is not explained by a failure to titrate the dosage of the drug ap- propriately. Indeed, the dosages after 6 months were considerably higher with oxprenolol than with propranolol. At 6 months, the oxprenolol dosage had been titrated to the allowed maximum of 360 mg daily in 65 of the 76 patients who had not reached goal BP as compared to 39 of 53 similar patients receiving propranolol. The principal reason for failure to titrate all of these patients to the maximum with either drug was noncompliance. At 3 months, the proportion of patients receiving the maximal dose of oxprenolol was 55% as compared to 37% in the propranolol group; at 6 months, the proportion was 73% and 53% respec- tively. Thus, dosages were titrated to the maximum allowed in a significantly higher percentage of patients receiving oxprenolol than in those receiving propranolol (p < 0.01). The presence of 19% dropouts during the trial could represent a source of bias. While such a possibility cannot be entirely ruled out, it seems unlikely for the following reasons: first, the number of dropouts in each group were nearly the same, 22 for propranolol vs 26 for oxprenolol. Second, the various reasons for the losses, including noncompliance, morbid events, increased BP and side effects, were distributed essen- tially equally between the two regimens. Also, the in- cidence of nonterminating side effects were com- parable in the two treatment groups. It seems unlikely, therefore, that bias caused by dropouts, dissimilar groups of patients, initial respon- siveness to diuretics, distribution of initial BPS, inap- propriate titration of dosages, or incidence of side effects could account for the lesser antihypertensive response to oxprenolol. Another possible explanation for the lesser an- tihypertensive effect of oxprenolol is that its intrinsic OXPRENOLOL VS PROPRANOLOL/Veteruns Administration Cooperative Studl' Group 255 TABLE 7. Prerandomization Diastolic Blood Pressures (DBP) by Therapeutic Regimen for 211 Patients Complet- ing the Study No. of Patients Per Regimen DBP (mm Hg) Propranolol Oxprenolol 90 ~ 94 28 29 95 - 99 28 24 100 - 104 27 33 > 104 24 18 2. F 5 chi square = 1.74, ns. E sympathomimetic activity may have antagonized the depressor effect of the beta-adrenergic blockade. Sup- porting this possibility was the observation that the pulse rates of patients taking oxprenolol were greater than in the patients receiving propranolol. A pressor effect has been reported in occasional patients follow- ing large doses of pindolol,8 which is another beta- adrenergic blocking drug with ISA properties." How- ever. no conclusions can be drawn from the present data concerning this question because the study was not designed to test for ISA specifically. The results of the present trial are at variance with those previously reported. Andersson et al.`* com- pared the reduction in BP obtained with the ad- ministration of oxprenolol vs propranolol in a small group of patients and concluded that the two drugs had significant and approximately equal antihyperten- sive activity. A similar conclusion was reached by Materson et al.13 after randomly assigning the beta blockers to a group of 24 patients who had not responded to HCTZ. However, their data does show a 4 mm Hg greater DBP decrease in favor of propranolol 0, < 0.05 supine, p < 0.025 standing). Patients in these two studies were treated for only 8 weeks in contrast to 6 months in the current study. Gavras et al.14 randomly allocated one of the two beta- adrenergic blocking agents to 20 patients whose BP had not responded adequately to HCTZ. Treatment with 180 to 480 mg daily of the blocking agents and the diuretic was continued for 7 months. Both drugs reduced SBP and DBP similarly, propranolol by - 12/ I I and oxprenolol by -24/ 15 mm Hg. Because of its ISA, oxprenolol may have certain ad- vantages over propranolol such as less tendency to bronchoconstriction and less interference with myo- cardial contractility. With respect to the contractility, systolic time intervals recorded during the present study are being analyzed by methods previously de- scribedI and will be reported in a later communica- tion. In addition, Gavras et al.14 found greater sup- pression of the diuretic-induced increase in plasma renin activity with oxprenolol than with propranolol. Nevertheless, despite these various observations, it may be concluded from the present trial that in a significantly higher percentage of men with mild hypertension propranolol controlled the BP more effectively than oxprenolol. 4. I ( 6 x 4. 3 Acknowledgments List of Participants Chairman: J. R. Thomas, M.D., Memphis, TN `articipants, Stations, Participating Investigators, and Nurse ipecialists: from Jackson. Mississippi, Leo Elson, M.D. Deceased). Miles Ulrych, M.D., Carol Wigley, and Pauline Ierrineton: from Washineton. D.C.. Edward D. Freis, M.D., ially fhaughnessy, Barbara Gregory, and Madeline Metcalfe; rom Miami. Florida, James Oster, M.D.. Chea Haran, and vlary Smith; from San Juan, Puerto Rico: Eli A. Ramirez, vl.D., and Maria Natal; from Memphis, Tennessee, Thomas white, M.D.. Susan Reece, and Jane Bowen; from Allen Park, vlinnesota: Frederick Talmers, M.D. and Julie Pawelak. kecutive Committee: J. R. Thomas, M.D. (Chairman), vlemphis, Tennessee; Eli A. Ramirez, M.D., San Juan, Puerto lice; Edward Freis, M.D.. Washington, D.C.; Leo Elson, M.D. Deceased), Jackson, Mississippi; James Oster, M.D., Miami, `lorida: Frederick Talmers, M.D., Allen Park, Minnesota; and Thomas J. White, M.D., Memphis, Tennessee. liostatistics and Research Data Processing: Hines Cooperative ;tudies Program Coordinating Center, Hines, Illinois: ChieJ Kenneth James. Ph.D.; .SII& Biostatis/iciuns: Arthur Johnson, `h.D., Jack Becktel, MS., Bor-Ming Ou, M.S., and Tom rosch, Ph.D.; Programmer: Selina MO, MS.; Sfarisrical lssi.~ranrs and Keypunch Operators: Mary Novich and Melva -yn Davis. Ientral Research Pharmacy: Chief: Mike Sather, R.Ph., MS.; vlarina Chang, R.Ph.; John P. Van Eeckhout, R.Ph., and Cheryl Smith, Technician. Operations Committee: Sibley Hoobler, M.D. (Chairman), Ann Irbor, Michigan; William Smith, M.D., San Francisco, Califor- lia; C. Morton Hawkins, M.D., Houston, Texas. human Rights Committee: John Cooper (Chuirman), Hines, Ilinoia: Elizabeth M. Butler, Chicago, Illinois; Roy Lawrence, `h.D.. J.D., Hinsdale. Illinois; Edgard Perez, Chicago Heights, Illnoi\: The Rev. .Martin W. Feldbush, Hinsdale, Illinois. id-Hoc Consultants: Harold Schnaper. M.D. (Consultant to the Executive Committee), Birmingham, Alabama; Edward Freis, M.D. (Consultant to the Executive Committee and Special -ahoratory Support), Washington. D.C.: H. M. Perry, M.D., ;t. Louis, Missouri; and Barry J. Materson, M.D., Miami, :lorida. Central Administration Cooperative Studies Program: James A. Hagans, M.D., Ph.D., (ChitA; Marian Brault, and Ping Huang, Ph.D., Stq&f Assis!anrs. References Andersson 0, Berglund G: Practolol-propranolol. A com- parlson of antihypertensive effects. Acta Med Stand 196: 479, I974 Berglund G, Hansson L: A within-patient comparison of alprenolol and propranolol in hypertension. Acta Med Stand 193: 547. I973 Fitzgerald JD: Perspectives in adrenergic beta-receptor blockade. Clin Pharmacol Ther 10: 292, 1969 Fitzgerald JD, Wale JL, Austin M: The hemodynamic effects of (+)-propranolol. dextropranolol, oxprenolol. practolol and sotalol in anesthetized dogs. Eur J Pharmacol 17: 123, 1972 Vaughan William EM, Papp JG: The effect of oxprenolol on cardiac intracellular potentials in relation to its antiarrhythmic, local anesthetic and other properties. Postgrad Med J 46 (suppl): 22, 1970 Meier M: Effects of oxprenolol on cardiac contractile force, heart rate. and coronary circulation. Postgrad Med J 46 (suppl): 15, I970 Majid PA, Sharma B, Saxton C, Stoker JB, Taylor SH: Haemodynamic effects of oxprenolol in hypertensive patients. Postgrad Med J (suppl): 67, 1970 256 HYPERTENSION VOL 3, No 2, MARCH-APRI[ 1981 8. 9. IO. I I. 12. 13. 14. 15. Brunner H, Hedw*all PR, and Meier, M: General concepts in the use of beta blockers: the relative roles of specific and un- specific effects. Naunyn Schmiedebergs Arch Pharmacol 269: 219, 1971 Rivier JL, Nissiotis E, Jaeger M: Comparison of immediate hemodynamic effects of three beta-adrenergic blocking agents. Postgrad Med J (suppl): 44, 1970 Felix RH, Ive FA. Dahl MG: Cutaneous and ocular reactions to practolol. Br Med J 4: 321, 1974 Waal-Manning HJ, Simpson FO: Letter: Paradoxical effect 01 pindolol. Br Med J 3: 155. 1975 Andersson 0, Berglund G, Bergman H, Cramer K, Fagerberg S, Forsberg S, Johnson V, Lundkvist L. Rutle 0, Sjolyst R: Antihypertensive effect and side effects of treatment with beta blockers - a comparative study between oxprenolol and propranolol. Curr Ther Res 19: 43, 1976 Materson BJ, Michael UF, Oster JR, Michael UR. Perez- Stable EC: Antihypertensive effectiveness of oxprenolol and propranolol. Clin Pharmacol Ther 20: 142, 1976 Gavras I, Gavras H. Sullivan P. Tifft C, Chobanian A, Brunner H: t\ comparative study of the effects of oxprenolol versus propranolol in essential hypertension. J Clin Pharmacol 19: 8, 1979 Kyle MC, Freis ED: Serial measurements of systolic time inter- vals: effects of propranolol alone and combined with other agents in hypertensive patients. Hypertension 2: I I I, 1980 Appendix A Exclusion Criteria Complications of Hypertensive State History or findings of grade III or IV hypertensive neuroretinopathy Cerebral hemorrhage Hypertensive encephalopathy Dissecting aneurysm of the aorta. Surgically Curable Hypertension Serum Creatinine Greater than 2 mg/dl Collagen Vascular Disease (with the exception of rheumatoid arthritis) Conditions Interdicting Use of Proposed Drugs History of depression Duodenal ulcer Greater than 1st degree heart block Asthma Obstructive lung disease with COT pulmonale or asthmatic wheezes Symptomatic and objective peripheral arterial in- sufficiency or a history of Raynaud's phenomenon or disease Diabetes requiring treatment other than diet Active liver disease including cirrhosis Psoriasis, keratitis, positive antinuclear antibody test on two successive determinations Chronic ophthalmologically proven conjunctivitis. Patient Unreliable Unwilling or unable to participate. Appendix B Criteria for Termination Blood Pressure Outside Protocol Range Hypotensive Symptoms with BP less than 90 mm Hg with minimal allowed dose of test drug Failure to Take Protocol Medications for 3 Consecutive Weeks Possible Deleterious Pharmacological Effects of Beta Blockers Bronchial asthma Congestive heart failure Peripheral vascular insufficiency (or Raynaud's phenomenon) Depression confirmed by a psychiatrist Gastrointestinal bleeding or peptic ulcer Arthralgia, dermatitis or symptoms suggesting lupus erythematosus Ophthalmological complaints not explained by ophthalmologist on any basis other than patient's drug therapy. Major Cardiovascular Complications of Hypertension or Atherosclerosis Central nervous system Heart Aorta Kidneys.