Comparison of safety and efficacy of carvedilol and metoprolol in stable angina pectoris

Comparison of Safety and Efficacy of Carvedilol and Metoprolol in Stable Angina Pectoris Reinhard van der Does, MD, Ulrike Hauf-Zachariou, MD, Egon Pfarr, MSc, Werner Holtbru¨gge, PhD, Steffen Ko ¨ nig, Mark Griffiths, PhD, and Avijit Lahiri, MB, BS, MSc In a double-blind, randomized, 3-month multicenter study, the safety and tolerability and the antianginal and anti-ischemic efficacy of carvedilol 25 to 50 mg twice daily were assessed in comparison with metoprolol 50 to 100 mg twice daily in younger and elderly patients with stable angina. After a 7-day placebo run-in at the end of which a symptom-limited bicycle ergometric exercise was performed, 368 patients were randomly allocated to the parallel treatment groups. After 4 weeks of therapy with a low dose, a further exercise test was performed and patients were titrated in single-blind fashion to the higher dose if the increase in total exercise time was <1 minute, and there was no safety concern. After a further 8 weeks of treatment a third exercise test was performed. Carvedilol low dose/ high dose was shown to be at least as safe and well tolerated as metoprolol low dose/high dose both in younger and elderly patients. There were no hitherto unknown adverse events and no marked change in the

types of events after increase of the doses. Early adverse events after treatment initiation or uptitration were equal with both medications, indicating no particular risk associated with carvedilol’s vasodilatory action. No rebound phenomena were observed. Both drugs showed good antianginal and anti-ischemic efficacy, with marked increases on uptitration including patients >65 years of age. However, in the doses selected, which appeared equipotent with respect to b blockade, carvedilol’s improvement of time to 1-mm ST-segment depression was statistically significantly greater than that of metoprolol. This could be due to its additional vasodilatory or antioxidative actions. Based on the safety and efficacy data of the present study, use of the higher of the 2 recommended doses of carvedilol and metoprolol appears justified in younger and elderly patients without adequate therapeutic control at lower doses. Q1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;83:643– 649)

arvedilol is a competitive antagonist of b1, b2, and a1 adrenoceptors,1– 4 is a powerful antioxidant, and inhibits cytotoxicity from oxygen radicals, which are properties not shared by any other b blockers. It suppresses vascular smooth muscle cell proliferation and migration and preserves the structural and functional integrity of the vasculature under various pathologic conditions in vivo, e.g., vascular hypertrophy and remodeling.5–7 It has marked cardioprotective properties8 –11 which, among other mechanisms, may also be due to the inhibition of activation and accumulation of polymorphonuclear leukocytes in the ischemic myocardium9,12,13 and the antioxidant activity of the drug. In various studies in patients with chronic stable angina pectoris, it was both efficacious and safe.14 –18 In patients with congestive heart failure of both ischemic and nonischemic origin, it improved cardiac function, clinical symptomatology, and survival19,20,21 and was effective and safe given early after myocardial infarction.22 Carvedilol was shown to protect against in vivo low-density lipoprotein oxida-

tion in hypertensive patients23 and had mild beneficial effects, comparable to those of captopril, on lipid profile in a cohort of hypertensive patients with dyslipidemia.24 The present study was undertaken to further investigate the safety of the higher of the 2 recommended doses of carvedilol in both younger and elderly patients who did not adequately respond to the lower dose, and the question of whether the use of this dose appears warranted on the basis of a risk/benefit assessment, particularly in the elderly. Metoprolol was chosen as comparative agent as it is one of the most widely used b blockers and is devoid of distinct additional pharmacologic properties, such as vasodilatation.

C

From the IST Studien Therapeutica GmbH, Mannheim; Boehringer Mannheim GmbH, Department of Clinical Research, Mannheim, Germany; and Northwick Park Hospital, Harrow, United Kingdom. This study was supported by a grant from Boehringer Mannheim. Manuscript received May 27, 1998; revised manuscript received and accepted October 6, 1998. Address for reprints: Ulric /ke Hauf-Zachariou, MD, Boehringer Mannheim GmbH, Sandhofer Strasse 116, D-68305 Mannheim, Germany. ©1999 by Excerpta Medica, Inc. All rights reserved.

METHODS Male or female (postmenopausal or using reliable contraceptive methods) treated or untreated patients (#80 years) with chronic angina pectoris, stable for at least the preceding 2 months, were eligible for inclusion into the present study if they had exertional angina with symptoms improving after taking shortacting nitrates or after a period of rest. Coronary heart disease had to be documented by either a previous angiography (.70% narrowing of a major coronary vessel) or myocardial infarction (electrocardiogram or cardiac enzymes), or a previous positive exercise test with occurrence of angina and ST-segment depression. Patients had to be capable of performing upright 0002-9149/99/$–see front matter PII S0002-9149(98)00960-6

643

TABLE I Major Exclusion Criteria Contraindications to study drugs or exercise testing Other forms of angina pectoris (vasospastic, unstable) Myocardial infarction or cardiac surgery within 3 months Main stem stenosis Ventricular aneurysm Marked left ventricular hypertrophy Hypertrophic subaortic stenosis Hemodynamically relevant valvular defects Decompensated cardiac failure Orthostasis Phlebothrombosis Disorders of impulse formation/conduction (e.g., resting heart rate ,45 beats/min, bundle branch block, pacemaker) Obstructive airways disease Insulin-dependent diabetes mellitus Relevant hepatic impairment Gross obesity Alcohol or drug abuse Epilepsy Concomitant drugs interfering with the study objectives (e.g., other antianginal agents) Participation in another clinical study within 30 days

bicycle ergometric exercise tests and not to be regarded at risk while temporarily receiving placebo. Informed consent was obtained from all subjects before any study-related procedures. To be randomized to active treatment (asymmetric randomization of 2:1 in favor of carvedilol, block sizes of 6), patients had to have undergone 1 exercise test limited by moderate anginal pain associated with horizontal or downsloping ST-segment depression on exercise versus rest by $1 mm, 60 ms after the J point at the end of the placebo run-in. The placebo run-in lasted 7 days for patients with nonpermitted previous medication (a blockers, b blockers, calcium-antagonists, long-acting nitrates, digitalis, quinidine, monoamine oxidase inhibitors, phenothiazines, tricyclic antidepressants, rifampicin) and 3 days for others. Major exclusion criteria are listed in Table I. The study consisted of a placebo washout/run-in (period I), active-treatment periods II and III, and a tapering-off period. After randomization patients were treated with low-dose carvedilol (25 mg twice daily) or metoprolol (50 mg twice daily) for 4 weeks (period II). However, during the first 2 days the carvedilol group received 12.5 mg twice daily, followed by a forced titration to 25 mg twice daily. Then the second exercise test was performed and patients were titrated in a single-blind fashion to the higher dose (carvedilol 50 mg twice daily or metoprolol 100 mg twice daily, respectively) if the increase in total exercise time was ,1 minute, provided resting systolic blood pressure was $100 mm Hg, resting heart rate was $50 beats/ min, and there were no adverse events believed to be aggravated by the dose escalation. After a further 8 weeks of active treatment, i.e., after at least 8 weeks on the final dose (period III) the third exercise test was performed. Study medication was then tapered off during 3 to 6 days (Figure 1). All study medication (placebo, carvedilol, metoprolol) was provided as opaque capsules of identical size and shape. Tests 644 THE AMERICAN JOURNAL OF CARDIOLOGYT

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were performed to ensure that encapsulation did not alter the dissolution rate of metoprolol. Adverse events volunteered by subjects or observed by the investigator were recorded regardless of their nature (cardiovascular or other) and regardless of whether a causal relation to study medication was assumed. Safety laboratory tests (hemoglobin, potassium, g-glutamyltransferase, alanine aminotransferase, creatinine) were performed at the beginning and at the end of the study. Symptom-limited erect bicycle ergometric exercise was performed at approximately the same time of the day, 12 hours (range 8 to 14) after the preceding dose of placebo or active medication. Patients were requested to refrain from smoking, eating and drinking 2 hours before the test and from using nitrates prophylactically. If nitrates had been used within 2 hours, the exercise test was rescheduled. The same test protocol was used at all centers for all patients. The initial workload was 50 W, and increased by 25 W every 2 minutes. A 12-lead standard electrocardiogram was recorded at rest. A short electrocardiogram strip was recorded from chest leads V1 to V6 every minute during exercise and at the end of the test. ST-segment depression was measured using the lead with the most marked changes, and time to onset of 1-mm STsegment depression was recorded at the earliest changes by $1 mm in any of the leads. Systolic blood pressure was measured at the end of each exercise stage; diastolic blood pressure was only measured at rest. The electrocardiogram was continuously monitored during exercise and for at least 5 minutes into recovery. Efficacy end points with respect to analysis of total (symptom-limited) exercise time were moderate anginal pain and/or ST-segment depression by .4 mm. For patients with end points other than those just mentioned, the exercise test was evaluated up to its break-off. They were then considered as censored for analysis of the time-to-event distribution (i.e., as being no longer at risk of stopping the test due to an efficacy end point). Censoring was used, analogously, for the variables time to angina and time to 1-mm ST-segment depression in patients without exercise-induced angina and ST-segment depression, respectively. The study was conducted in accordance with the Declaration of Helsinki as amended in Venice and Tokyo and with the Committee for Proprietary Medicinal Products/Good Clinical Practice Note for Guidance. Before the start of the study, the trial protocol was approved by the independent ethics committee of the Landesa¨rztekammer Baden-Wu¨rttemberg, Germany, as well as the responsible local committees. Statistical methods: All adverse events reported during the study were included in the safety analysis. The proportions of patients with at least 1 adverse event (primary variable) were compared among the treatment groups, and the proportions of younger and older patients with at least 1 adverse event were compared within the treatment groups using Fisher’s exact test. In addition, 95% confidence intervals for the proporMARCH 1, 1999

FIGURE 1. Trial schedule.

TABLE III Percentages of Patients With Adverse Events

TABLE II Patient Characteristics Carvedilol (n 5 247*)

Metoprolol (n 5 120)

Carvedilol

Age (yr) 62 (56; 68) 61 (56; 67) Height (cm) 170 (165; 176) 170 (165; 176) Weight (kg) 75 (69; 83) 77 (70; 82) Men 178 (72%) 85 (71%) Women 69 (28%) 35 (29%) Smokers 35 (14%) 23 (19%) Systemic hypertension 94 (38%) 39 (33%) Diabetes mellitus 38 (15%) 15 (13%) Dyslipidemia 80 (32%) 37 (31%) Previous medication: b-blocking agents 65 (26%) 36 (30%) Calcium antagonists 59 (24%) 23 (19%) Coronary vasodilators 123 (50%) 67 (56%) Anterior myocardial infarction 23 (9%) 13 (11%) Posterior myocardial 44 (18%) 20 (17%) infarction Positive angiography 56 (23%) 26 (22%) 1-vessel disease 32 (13%) 12 (10%) 2-vessel disease 13 (5%) 10 (8%) 3-vessel disease 11 (5%) 4 (3%) *One patient with missing data. Data are given as medians and quartiles, where applicable, otherwise no. (%) is used.

Period/ Ages (yr) Periods II, III All ,65 $65 Period II All Period III HD, all HD, ,65 HD, $65

No. (at risk) 248 147* 100*

Metoprolol

% (with AE) 25 (20, 31) 23 (17, 30)† 29 (21, 39)†

No. (at risk)

}

120 74 46

% (with AE) 30 (23, 39) 29 (19, 40)† 33 (21, 47)†

248

16

120

19

91 51 40

11 8 15

47 27 20

15 11 20

}

*One patient with age missing. † Fisher’s exact test; all p values .0.1. AE 5 adverse event; HD 5 high dosing. Numbers in parentheses are confidence limits.

baseline value as covariate. Other efficacy analyses were performed using Wilcoxon’s signed rank test for within-group comparisons.

RESULTS tions were calculated. Time to occurrence of the first adverse event for each patient individually was compared using the Kaplan-Meier estimation. Incidences of adverse events were calculated for the different active treatment periods (i.e., periods II and III for all patients and for subgroups as described in the first paragraph of the results) and were compared in an explorative manner. The efficacy variables—symptom-limited total exercise time, time to occurrence of 1-mm ST-segment depression, and time to onset of anginal pain—were compared between the treatment regimens using the Kaplan-Meier technique and a Cox proportional-Hazards model with factor treatment and

In all, 393 patients were enrolled in the study. Of these, 25 discontinued the study before randomization (adverse events, n 5 2; selection error, n 5 12; others, n 5 11), 368 patients were randomized to 27 trial centers in Europe (Germany 20 centers, United Kingdom 4 centers, and Romania 3 centers). Because of the 2:1 randomization, the carvedilol group encompassed 248 patients and the metoprolol group 120 patients. Period II was completed by 345 patients and period III by 332 patients. Dropouts for occurrence of adverse events refer to 15 patients during period II (carvedilol, n 5 12 [5%]; metoprolol, n 5 3 [3%]) and 9 patients during period III (carvedilol, n 5 6 [3%]; metoprolol, n 5 3 [3% 5 1). All randomized patients took at least

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645

Adverse events: The percentage of carvedilol patients who sustained any adverse event on active treatment was lower than that of metoprolol patients (25% vs 30%), but this difference was not statistically significant (p 5 0.137, 2-tailed) which was also supported by 95% confidence intervals (Table III). Likewise, the KaplanMeier curves for individual time to occurrence of an adverse event did not suggest a relevant difference between treatments (Figure 2). Elderly patients ($65 years) appeared to be more prone than younger patients (,65 years) to experience adverse events. However, the differFIGURE 2. Kaplan-Meier survival curves for time to onset of first adverse event on active therapy, separated for treatment groups. ence was relatively small and p values (from 2-tailed Fisher’s exact test) for comparisons were .0.1 in both treatment groups. As for all patients, regardless of age, TABLE IV Patients of the High-Dose Subpopulations With at the percentage of elderly subjects with adverse events Least One Adverse Event (separated for periods II and III) was slightly lower in the carvedilol than in the metoCarvedilol Metoprolol prolol group. The same holds true for all patients and (n 5 91) (n 5 47) elderly patients receiving treatment with high-dose Ages (yr) No. (at risk) No. (at risk) carvedilol and metoprolol, respectively (Table III). Within the groups of patients who needed high ,65 51 27 doses, the proportions of carvedilol and metoprolol $65 40 20 % (with AE) % (with AE) patients with adverse events slightly increased after Period II doubling of the doses (Table IV). A comparison with All 6 11 the changes in the low-dose groups did not suggest ,65 6 15 that the longer observation during period III compared $65 5 5 Period III with that of period II was relevant in this context and All 11 15 seemed to confirm the notion that adverse events tend ,65 8 11 to occur predominately during the early phases of $65 15 20 fixed-dose regimens. In either of the high-dose groups, AE 5 adverse event. however, the percentages of patients with adverse events during period III were lower than those of all patients in either of the initial treatment groups on low 1 dose of active medication and were included in the doses during period II (Table III). To identify any first-dose phenomena possibly asanalysis of safety (n 5 368). Patient characteristics and previous antianginal medication were similar in sociated with vasodilatation “early adverse events” the 2 treatment groups (Table II). In 345 patients a were listed for days 1 and 2 of period II (predosing), titration decision was made and patients were trans- days 3 and 4 of period II (start of low-dose carvedilol), ferred to period III. Considering the dose during pe- and days 1 and 2 of period III for patients treated with riod III and patient age the following subgroups re- high doses. There was no difference for the first 2 or sulted: carvedilol low dose (younger patients, n 5 9; 4 days during period II between the proportions of older patients, n 5 50), carvedilol high dose (younger patients with adverse events on carvedilol and metopatients, n 5 51; older patients, n 5 40), metoprolol prolol, which is devoid of any vasodilatory properties. low dose (younger patients, n 5 46; older patients, Similarly, within the first 2 days of treatment with the n 5 21), metoprolol high dose (younger patients, n 5 high dose, patients taking carvedilol did not have more adverse events than those taking metoprolol. 27; older patients, n 5 20). The duration of active drug treatment was similar Generally, no predominance of elderly patients with for the 2 treatment groups and for all subgroups com- respect to the occurrence of early adverse events was pared (dose and age groups). A total of 24 patients observed. After discontinuation of the study medica(carvedilol, n 5 17; metoprolol, n 5 7, i.e., 23 drop- tion there were no events indicative of rebound efouts plus 1 metoprolol patient who completed period fects. Among the various types of adverse events assoII with missing exercise test data) of the safety population (n 5 368) had no exercise test data on active ciated with active therapy, dizziness was the most treatment and were excluded from the intention-to- frequent effect in the carvedilol group (4.8%), but this treat population of efficacy (344 patients, carvedilol occurrence was similar in the metoprolol group (5.0%). Next in frequency in the carvedilol group [n 5 231], metoprolol [n 5 113]). 646 THE AMERICAN JOURNAL OF CARDIOLOGYT

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,0.05 in a 2-sided test procedure) indicates that carvedilol patients may have had a lower risk of STCarvedilol (n 5 248) Metoprolol (n 5 120) segment depression during exercise than metoprolol patients, and that No. (with AE) % (with AE) No. (with AE) % (with AE) carvedilol’s anti-ischemic efficacy Dizziness 12 4.8 6 5.0 during physical exertion may have Bronchitis 9 3.6 3 2.5 been somewhat more marked than Asthenia 8 3.2 3 2.5 Headache 8 3.2 4 3.3 that of metoprolol (see KaplanBack pain 6 2.4 2 1.7 Meier curves, Figure 3). There was Gastroenteritis 4 1.6 4 3.3 practically no change in total exerSinusitis 4 1.6 1 0.8 cise time at visit 3 versus baseline Upper respiratory infection 3 1.2 4 3.3 Angina pectoris 2 0.8 — — within either of the high-dose Dyspepsia 2 0.8 — — groups. However, after the patients Dyspnea 2 0.8 — — had been uptitrated, clinically releGastritis 2 0.8 — — vant improvements were achieved Postural hypotension 2 0.8 — — both in patients of all ages (carveMyocardial ischemia 2 0.8 2 1.7 Nervousness 2 0.8 1 0.8 dilol, 141 seconds; metoprolol, Diarrhea 1 0.4 2 1.7 155 seconds, medians) and in the Malaise 1 0.4 1 0.8 elderly (carvedilol, 151 seconds; AE 5 adverse event. metoprolol, 160 seconds, medians). When data at the maximal com(with similar results in the metoprolol group) were parable exercise stage were compared, no differences bronchitis, asthenia, headache, back pain, sinusitis, between the treatment groups for baseline values and gastroenteritis, and upper respiratory tract infections. changes versus baseline were noted for ST-segment Also, if only cardiac adverse events (angina pectoris, depression, which was reduced by approximately 40% myocardial ischemia) are considered, proportions of with either medication. Similarly, clinically relevant patients remained similar in the 2 groups. All other reductions (with all p values for the within-group events occurred in ,1% of patients in the carvedilol comparisons ,0.001) in heart rate, systolic blood pressure, and rate-pressure product were obtained in group (Table V). There was 1 death during surgery 3 months after both groups. The decrease in rate-pressure product, the end of the study, clearly unrelated to study medi- which is correlated with myocardial oxygen consumpcation. Further serious adverse events refer to collapse tion, was somewhat more marked in the carvedilol and episodes of bradycardia, supraventricular tachy- group (Table VI). With respect to reasons for exercise termination cardia, dyspnea with sweating and wheezing, atrial fibrillation, left main stenosis, suspected prostatic car- with active therapy there were no differences between cinoma, and unstable angina pectoris (1 case each) in the treatment groups. During the last test, .50% of the carvedilol group and loosening of hip prosthesis (1 the patients terminated their exercise because of modcase), unstable angina pectoris (2 cases), colon cancer, erate angina pectoris and about 30% because of physand myocardial infarction 6 weeks after the end of the ical exhaustion. study (1 case each) in the metoprolol group. Other safety variables: No changes in any of the DISCUSSSION laboratory variables or body weight were observed, The treatment regimen of carvedilol low dose/high and there was no difference between patients dose was at least as safe and well tolerated as that of treated with low or high doses. Resting blood pres- metoprolol low dose/high dose both in younger and sure and heart rate in the sitting position were elderly patients with chronic stable angina pectoris. reduced versus placebo baseline to a similar extent With neither regard to the incidence nor regard to the with both treatments. types of adverse events, a relevant difference between Exercise test variables: The 3 major exercise test the groups was noted. Elderly patients tended to susvariables—symptom-limited total exercise time, time tain adverse events more frequently than younger pato onset of anginal pain, and time to onset of 1-mm tients. This difference, however, was neither clinically ST-segment depression—were analyzed using sur- important nor statistically significant. A slight invival methodology (Cox analysis and Kaplan-Meier crease in the frequency of adverse events without a technique). For all 3 variables, clinically important change in the pattern of events was noted when paimprovements at visit 4 (end of active therapy apart tients were switched to higher doses. However, the from tapering off) versus visit 2 (baseline) were noted risk of inducing adverse events by a dose increase in for both treatment regimens (Table VI). Carvedilol patients who do not sufficiently respond to low dosing improved time to 1-mm ST-segment depression does not appear to be any greater than that of initiating compared with metoprolol. The point estimator for therapy with carvedilol (or metoprolol) in a group of the risk ratio of 1.386 (95% confidence interval patients in whom dosing requirements are not yet from 1.045 to 1.839, corresponding to a p value known (i.e., at the beginning of therapy). No particular TABLE V Types of Adverse Events on Active Treatment (all adverse events that occurred in at least 2 patients)

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647

TABLE VI Exercise Test Data Carvedilol (n 5 231) Visit 2 (baseline) Total exercise time (s) Time to angina (s) Time to ST depression (s) Heart rate (beats/min) Systolic blood pressure (mm Hg) Rate-pressure product (mm Hg min21)

360 (292; 450) 300 (240; 410) 260 (180; 357)

Metoprolol (n 5 113)

V4–V2

Visit 2 (baseline)

160 (0; 1120) 177 (120; 1140) 175.5 (147; 1154)

361 (300; 480) 320 (250; 415) 247.5 (180; 360)

Hemodynamic Data at Maximal Comparable Exercise 123 (113; 140) 215 (226; 24) 126 (114; 142) 180 (162; 195) 212 (220; 24) 175 (160; 186) 215.3 (190; 259) 242.8 (264; 215) 214.7 (189; 254)

V4–V2 160 (0; 1120) 176 (125; 1155) 160 (0; 1146) 213 (222; 24) 210 (217; 0) 233.5 (251; 27)

For all of the above variables and both treatment groups the results from all tests on changes between visits (Wilcoxon signed rank tests) were statistically significant (p , 0.001). Data are expressed as medians and quartiles.

titrating them according to their individual therapeutic response. Acknowledgment: We thank all participating investigators for their contribution to the study.

1. Feuerstein GZ, Poste G, Ruffolo R. Carvedilol update III: rationale for use in congestive heart failure. Drugs Today 1995;31(suppl F):1–23. 2. Nichols AJ, Sulpizio AC, Ashton DJ, Hieble JP, Ruffolo RR. In vitro pharmacologic profile of the novel b-adrenoceptor antagonist and vasodilator, carvedilol. Pharmacology 1989;39:327–336. 3. Nichols AJ, Sulpizio AC, Ashton DJ, Hieble JP, Ruffolo RR. The interaction of the enantiomers of carvedilol with a1-b1-adrenoceptors. Chirality 1989;1:265– 270. FIGURE 3. Kaplan-Meier survival curves for time to onset of 1-mm ST-segment de4. Sponer G, Bartsch W, Strein K, Mu¨ller-Beckmann B, pression at visit 4, separated for treatment groups. Bo¨hm E. Pharmacological profile of carvedilol as a b-blocking agent with vasodilating and hypotensive properties. J Cardiovasc Pharmacol 1987;9:317–327. 5. Ohlstein EH, Douglas SA, Sung CP, Yue T-L, Louden Arleth A, Poste G, Ruffolo RR, Feuerstein GZ. Carvedilol, a cardiovascular risk regarding adverse events early after treatment C, drug, prevents vascular smooth muscle cell proliferation, migration, and neoininitiation or after increase of the doses and no rebound timal formation following vascular injury. Proc Natl Acad Sci USA 1993;90: 6189 – 6193. phenomena were observed. 6. Ohlstein EH, Vickery L, Arleth A, Barone F, Sung CP, Camden A, McCartney Both treatment regimens produced clinically im- L. Carvedilol, a novel cardiovascular agent, inhibits development of vascular and portant improvements in signs and symptoms of ef- ventricular hypertrophy in spontaneously hypertensive rats. Clin Exp Hypertens fort-induced angina and myocardial ischemia. Carve- 1994;16:163–177. 7. Douglas SA, Vickery-Clark LM, Louden C, Ruffolo RR, Feuerstein GZ, dilol, however, appeared to exert a somewhat greater Ohlstein EH. Acute pretreatment with carvedilol is sufficient for inhibition of anti-ischemic effect as indicated by the variable time neointima formation following rat carotid artery balloon angioplasty. Pharmacol 1994;5:65–72. to 1-mm ST-segment depression. This difference may Commun 8. Hamburger SA, Barone FC, Feuerstein GZ, Ruffolo RR. Carvedilol (Kredex) be limited to the doses used in our study. However, reduces infarct size in a canine model of acute myocardial infarction. Pharmabecause the 2 regimens, based on exercise heart rate, cology 1991;43:113–120. 9. Bril A, Slivjak M, DiMartino MJ, Feuerstein GZ, Linee P, Poyser RH, Ruffolo were equipotent with respect to b blockade, carve- RR, Smith EF. Cardioprotective effects of carvedilol, a novel b-adrenoceptor dilol’s vasodilatory and antioxidative effects may antagonist with vasodilating properties, in anaesthetised minipigs: comparison propranolol. Cardiovasc Res 1992;26:518 –525. have contributed to its beneficial influence on myo- with 10. Feuerstein GZ, Hamburger SA, Smith EF, Bril A, Ruffolo RR. Myocardial cardial ischemia. In the subgroups of patients who protection with carvedilol. J Cardiovasc Pharmacol 1992; 19(suppl 1):138 –141. were uptitrated, a marked increase in antianginal and 11. Feuerstein GZ, Ruffolo RR. Comparison of the ability of two vasodilating -blockers, carvedilol and celiprolol, to reduce infarct size in a pig model of acute anti-ischemic efficacy was observed in younger and bmyocardial infarction. Pharmacol Commun 1994;5:1:57– 63. elderly subjects. Because there was no further change 12. Lopez BL, Christopher TA, Yue T-L, Ruffolo RR, Feuerstein GZ, Ma X-L. in patients taking the low dose beyond the first 4 Carvedilol, a new b-adrenoceptor blocker and free radical scavenger, attenuates myocardial ischemia-reperfusion injury in hypercholesterolemic rabbits. J Pharweeks of treatment, high dosing and not prolonged macol Exp Ther 1995;273:64 –71. treatment appears responsible for these improvements. 13. Yue T-L, Wang X, Gu J-L, Ruffolo RR, Feuerstein GZ. Carvedilol, a new b-adrenoceptor blocker, inhibits oxidation of low-density lipoproUptitration of carvedilol and metoprolol under the vasodilating teins by vascular smooth muscle cells and prevents leukocyte adhesion to smooth conditions stipulated in our study protocol appears muscle cells. J Pharmacol Exp Ther 1995;273:1442–1449. justified for younger and elderly patients. Added effi- 14. Kaski JC, Rodriguez-Plaza L, Brown J, Maseri A. Efficacy of carvedilol (BM a new beta-blocking drug with vasodilating properties, in exercisecacy, which is often sought from combination treat- 14.190), induced ischemia. Am J Cardiol 1985;56:35– 40. ment, may easily be obtained in many patients by 15. Rodrigues EA, Lahiri A, Hughes LO, Kohli RS, Whittington JR, Raftery EB.

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