comparison of nifedipine gastrointestinal therapeutic system and atenolol on antianginal efficacies...

Comparison of Nifedipine Gastrointestinal Therapeutic System and Atenolol on

Antianginal Efficacies and Exercise Hemodynamic Responses in

Stable Angina Pectoris Wayne A. Wallace, MD, Karen L. Wellington, RN, Mitchell A. Chess, MD, and

Chang-seng Liang, MD, PhD

A gastrointestinal therapeutic system (GITS) of nifedipine has been developed to provide a once daily dosing, and predictable, relatively constant plasma concentrations. This study compared the antianginal efficacy of nifedipine GITS with a onc&ay preceptor blocker, atenolol. Seveu teen patients with documented coronary artery disease and stable stress-induced angina pectoris were studied during a 2-week, single-blind, placebo baseline phase and a 12.week randomized, doubleblind, active drug crossover efficacy phase, using the bicycle exercise test and amba latory electrocardiographic recordings. Patients exercised significantly longer wlth nifedlpine GITS (883 + 47 seconds) and atenolol(908 -c 44 seconds) than with placebo (794 + 41 seconds). Nifedipine GtTS reduced systolic blood pressure at all stages of exercise compared with placebo but, because heart rate tended to increase more dur ing nifedipine therapy, there was no difference in rate-pressure products between the placebo and nifedipine GUS periods. In contrast, atenolol reduced heart rate, systolic blood pressure and rate pressure product during exercise compared with placebo. Whereas left ventricular ejection fra& tions (by radionuclide angiocardiography) iu creased with exercise, the maximal increase was smaller with atenolol than with placebo and nifedipine. The net increase in left ventricular ejection fraction at the end of exercise was greater with nifedipine than with placebo or atenolol. Ambulatory electrocardiograms showed only a small number of ischemic events. Neither nifedipine GITS nor atenolol reduced the number of ischemic events or total duration of ST-seg- merit deviations significantly. It is concluded that nifedipine GlTS is as effective an antian@nal agent as atenolol, but the hemodynamic effects

From the Cardiology Unit, Departments of Medicine and Radiology, University of Rochester Medical Center, Rochester, New York. This study was supported in part by a grant from Pfizer Laboratories, New York, New York. Manuscript received May 4, 1993; revised manuscript received and accepted July 9, 1993.

Address for reprints: Chang-seng Liang, MD, PhD, Cardiology Unit, Box 679, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642.

of the 2 agents differ. Left ventricular ejection fraction increases more with nifedipine than with atenolol during bicycle exercise.

(Am J Cardiol1994;73:2*28)

N ifedipine increases angina threshold during exercise and reduces angina1 frequency and nitroglycerin consumption in patients with coronary

artery disease.’ Its antianginal efficacies equal those of P-receptor blocking agents,2-6 long-acting nitrates7s and other calcium antagonists?,1o However, because of rap- id gastrointestinal absorption and a short plasma half- life, nifedipine is administered 2 to 4 times a day. Fur- thermore, to maintain an effective average plasma con- centration, its doses are necessarily large to cause high plasma levels immediately after administration,tt which may cause headache and flushing, 2 major reasons for the drug intolerance. Recently a gastrointestinal therapeutic system (GITS)12 was developed to provide a constant delivery of the drug up to 24 hours and therefore can be administered once a day. This nifedipine delivery produces predictable, relatively constant plasma levels, reduces the incidence of headache and flushing, and improves compliance.13,14 Studies have shown that nifedipine GITS is an effective agent,15 and is as efficacious as the standard formulation.13J4J6 However, its comparative values with other antianginal drugs as monotherapy for angina have not been established. The present study was undertaken to compare the antianginal efficacies of nifedipine GITS with those of atenolol, a P-receptor blocker with a long half-life, Like nifedipine GITS, atenolol can be administered once a day. The present study also included an assessment of left ventricular function during exercise using radionuclide angiocardiography and total ischemic burden as measured by continuous ambulatory electrocardiograms. Since nifedipine does not block the chronotropic and inotropic effects of catecholamines, we speculated that left ventricular function could be better preserved during exercise by nifedipine GITS than by atenolol.

METHODS The study protocol was approved by the University

of Rochester Research Subjects Review Board. Patients 35 to 75 years of age, men or women beyond childbear-

NIFEDIPINE AND ATENOLOL IN STABLE ANGINA 23

ing potential with documented coronary artery disease and a history of stress-induced angina pectoris were recruited, and all signed the consent form. The diagnosis of coronary artery disease was continned by a coronary angiogram, showing 250% narrowing of at least 1 major coronary artery, a prior transmural myocardial infarction, or a positive exercise tolerance test. All patients had had symptoms of stable angina for at least 1 month before study entry. No patient with acute myocardial infarction during the preceding month was included. Patients who had coronary artery bypass surgery or per- cutaneous tm.nsluminal coronary angioplasty 26 months previously and currently had stable angina were included in the study.

Patients were excluded for cardiac, noncardiac and drug reasons. Cardiac reasons were left ventricular hy- pertrophy, intraventricular conduction defects, digitalis intake, congestive heart failure, ventricular aneurysm, and ST-segment abnormalities that would make electrocardiographic interpretation for ischemia difficult. Non- cardiac reasons included: (1) presence of any severe disease; (2) need for a-adrenergic antagonists, sympatho- mimetics or methylxanthines; (3) history of chronic or intermittent diarrhea; (4) chronic use of laxatives; (5) history of documented diverticulitis, partial or complete gastrectomy or small bowel resection; and (6) history of noncompliance. Patients could not receive long-acting nitrates, other P-receptor blockers or calcium blockers during the study period, nor could they have received investigational drugs within the prior month.

Protocol: The study was divided into a 2-week, single-blind, placebo baseline phase and a 1Zweek double- blind, active drug crossover treatment phase. During the baseline phase patients received blinded therapy with

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FIGURE 1. Effects of nifedipine gastrointestinal therapeutic system (GllS) and atenolol on the angina1 frequency emI nitroglycerin consumption in 17 subjects with chronic stable angina pectoris. Bars denote SEM. Asterisks indicate values that differ eignilicantly from placebo et p <O.OS. There was no diirence between nifedipine GITS and etenolol.

placebo tablets daily after tapering off of all oral antianginal therapy. A complete medical history, physical ex- amination, a blood chemistry profile, complete blood counts, urinalysis, chest x-ray and electrocardiogram were obtained. After a training bicycle test, a baseline bicycle stress radionuclide angiocardiogram and 48-hour Holter electrocardiograms were recorded.

The second phase consisted of two 6-week crossover periods, each having a 3-week titration period and a 3- week efficacy period. Patients were randomized by a computer-generated randomization code to receive either nifedipine GITS (30, 60, 90 or 120 mg) or atenolol (50, 100 or 150 mg) once a day. The medications were titrated gradually over 3 weeks from their lowest to maximal doses according to symptoms and adverse effects. Patients who received 1 active study medication (e.g., atenolol) were also given the placebo of the opposite medication (e.g., nifedipine GITS). At the end of the lirst study drug period, patients crossed over to the opposite regimen for another 6 weeks. Patients were instructed to keep a diary of each anginal attack and the use of sub- lingual nitroglycerin. Forty-eight-hour Holter recording and stress radionuclide angiocardiograms were obtained during both efficacy periods.

Twenty-three patients were recruited for the study. One patient died during the screening phase. Twenty-two patients were eligible and randomized to receive active study medications. Five patients were excluded from the study because of worsening angina (1 taking atenolol), refusal to continue (1 taking nifedipine GITS) and leg edema with and without lethargy (3 taking nifedipine GITS).

Stress radionuclide angiocardiograms: Symptom- limited exercise radionuclide angiocardiograms were recorded 23 hours after a light meal, 210 hours after smoking, and approximately 24 hours after the administration of the study medication. An upright bicycle ergometer protocol was used in which patients exercised in 3-minute stages, initially at 200 kpm/min, followed by an increase of 100 kpm/min for each subsequent stage. Blood pressure, heart rate and electrocardiogram were obtained at rest, at the completion of each stage of exercise, at the onset of characteristic angina1 pain, at peak exercise and during recovery. Heart rate and systolic blood pressure were multiplied to yield the heart rate-systolic blood pressure product (double product).

A resting radionuclide angiocardiogram was recorded after intravenous injection of 25 mCi of technetium- 99m pertechnetate with the patient sitting on the bicycle ergometer. Scans were then obtained during the last 2 minutes of each stage of exercise and 4 to 6 minutes after recovery. The global left ventricular ejection fraction was determined by an investigator (M.A.C.) who was not involved in the exercise test or drug allocation.

Ambulatory electrocardiographic recordings: Pa- tients were instructed to perform their usual activities and to keep an angina1 diary and activity log during ambulatory electrocardiographic monitorings. The tapes were analyzed at the conclusion of the study by an experienced research staff at Northeastern Scanning Service (Rochester, New York) without knowledge of drug allocation. An episode of significant ST-segment

24 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 JANUARY 1, 1994

MGLE I Hemodynamic Responses to Bicycle Exercise

Variable Placebo Nifedipine

GITS Atenolol

Heart rate (beats/min) Stage III Onset of angina End of exercise

Systolic blood pressure (mm Hg) Stage III Onset of angina End of exercise

Double product (mm Hg x beatslmin) State Ill Onset of angina End of exercise

123 e 4 123 f 5 144 f 5

172 2 5 170 k 5 185 t 6

21,112 +- 1,045 21,060 zk 1,002 26,535 r 1,155

121 rt3 129 rt 4 146 + 5

164 f 5 167 +- 5 173 f 5*

19,858 ? 987 21,570 f 1,013 25,196 zk 1,106

93 zk 3*t 99 +- 4*t

118 +- 5*t

146 t 7*t 152 +- 6*t 166 rt: 8*

13,828 +- l,084*t 15,119 +- 898*t 19,624 + l,277*t

*p ~0.05 verws placebo; tp ~0.05 versus nifedipine GITS. Values are mean 2 SEM; n = 17. GITS = gastrointestinal therapeutic system.

changes was defined as ST-segment deviations >O.l mV 80 ms after the J point, persisting in consecutive beats for at least 1 minute. The number and the total duration of episodes with >O.l mV ST-segment deviation were measured.

Statistics: Results are expressed as mean f SEM. The data from crossover periods were analyzed by anal- ysis of variance to assess differences in treatment responses. Values obtained at the end of the efficacy periods were compared with baseline values (week 2) using the paired t test. Differences were considered significant if p cO.05.

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RESULTS Seventeen patients (15 men and 2 women) complet-

ed both drug efficacy periods. They ranged in age from 42 to 68 years (mean 54 f 2), with a body weight of 83 f 2 kg and height 173 f 2 cm. All patients had positive exercise tolerance test results. Coronary artery disease was further documented in all patients by either a history of acute myocardial infarction (n = 12) or positive results on coronary angiography (n = 12), or both (n = 7). The maximal tolerated maintenance daily doses of nifedipine GITS and atenolol were 91 f 5 and 124 AI 9 mg, respectively. The 2 drugs differed in effects on heart rate and systolic blood pressure at rest. Unlike atenolol, which reduced resting heart rate (56 f 2 beats/min) and systolic pressure (119 IL 4 mm Hg), nifedipine GITS had no effects on heart rate (76 f 3 vs 79 rf: 2 beats/min) or systolic arterial pressure (126 AI 3 vs 129 + 3 mm Hg) compared with placebo.

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Figure 1 shows that nifedipine GITS and atenolol reduced the frequency of angina compared with baseline placebo, but there were no significant differences between the 2 drugs. The 2 agents also reduced the number of nitroglycerin tablets consumed, but the differences when compared with placebo did not reach sta- tistical significance.

60 -

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0 1 2 3 4 5 6 7 Rest

Exercise Stage

Figure 2 shows the changes in heart rate, systolic L FlGURE 2. Effects of nifedipine gastrointestinal therapeutic arterial pressure and left ventricular ejection fraction system (GlTS) and atenolol on the heart rate, systolic blood _--. . _ -_ _ _ _ ___^ _ ._ - __ during exercise at baseline and at 2 drug periods. Dur- pressure (BP) ana lelt ventricular (LV) ejection fraction re-

ing the baseline test, all patients completed the &st 3 sponses to bicycle exercise. All patients completed the first

stages, but fewer patients finished the ensuing 3 stages 3 stages of exercise. The numbers of patients who complet-

of exercise. The total duration of exercise was 794 & 41 4 the subsequent aw are even in pamnma in me top pane/, Bars denote SEM.


seconds at baseline. Comparatively, patients exercised significantly longer while taking nifedipine GITS (883 f 47 seconds) or atenolol (908 + 44 seconds). Most patients complained of chest pain during the baseline test, but as the duration of exercise became longer, pro- portionately more patients gave fatigue or shortness of breath as reasons for requesting termination of the test while taking the active study medications. In patients who complained of chest pain during exercise, the differences in time to onset of angina, however, did not differ significantly among the 3 tests (514 k 57, 601 k 48, and 545 + 66 seconds, respectively).

Atenolol reduced heart rate and systolic blood pressure responses at all stages of exercise (Figure 2). The exercise double product was also reduced by atenolol at stage 3, onset of angina and end of exercise (Table I).

TABLE II Adverse Reactions

Symptoms Placebo Nifedipine

GITS Atenolol

Lethargy Headache Flushing Ankle edema Dizziness Decreased libido Constipation Diarrhea Nausea Any of above

2 2 0 0 0 0 0 0 0 4

4

3 5 0 0 2 0 1

13

Each patient may have reported > 1 adverse reaction during each phase. GITS = gastrointestinal therapeuticsystem.

I I

Placebo Nifedipine GITS

Atenolol I

1 I

FlGllRE 3. The effects of nifedipine gastrointestinal them peutic system (GITS) and atenolol on the maximal increase in left ventricular ejection fraction during exercise and the increases in left ventricular ejection fraction at end of exer cise. Bars denote SEM. As&f&s indicate values that differ signlf~cantly from placebo at p cO.05. mer5 indicate values that diier significantly from nifedipine GITS at p ~0.05.

The increase in systolic blood pressure was also atten- uated by nifedipine GITS, but unlike atenolol, nifedipine GIRTS had no effect on the heart rate or double product response to exercise (Table I).

Left ventricular ejection fraction was not affected by nifedipine GITS or atenolol at rest (Figure 2). It increased gradually with exercise, but as the end of exercise approached, it either reached a plateau or fell toward the baseline. Atenolol reduced the maximal increase of left ventricular ejection fraction compared with placebo and nifedipine (Figure 3). It also reduced the increase in left ventricular ejection fraction at the end of exercise compared with nifedipine GITS.

Figure 4 shows that neither the number of episodes of ST-segment deviation (>l mm) nor the total duration of ST-segment deviation on 48-hour ambulatory elec- trocardiography differed among the placebo, atenolol and nifedipine GITS periods.

Many adverse reactions were reported during the placebo and active drug periods (Table II). Four patients complained of fatigue and headache during the placebo phase. The number of patients complaining of fatigue and headache was similar between atenolol and nifedipine GITS periods, but flushing and ankle edema were present only in patients receiving nifedipine GITS. Decreased libido occurred in 1 patient during atenolol treatment; it disappeared when the therapy was crossed over to nifedipine GITS.

DISCUSSION Our present study shows that nifedipine GITS reduced

the frequency of an&a and improvedexercise tole trance

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4. Neither nifedipine gastrointestinal therapeu iC system (Gil) nor atenolol affected the number of events of ST-segment deviation or duration of ST-segment deviation in 4Ehour ambulatory electrocardiographic recordings. lndivid ual values and mean + SEM are shown. There were no statistically signiicant differences among the groups.

26 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 JANUARY 1,1994

in patients with chronic stable angina pectoris compared with placebo. Its beneficial effect on exercise tolerance was present 24 hours after the preceding maintenance dose, demonstrating that its therapeutic efficacy was maintained over 24 hours. The results are consistent with a previous exercise test study,16 in which patients were allotted to receive nifedipine GITS or placebo, along with their usual p-blocker therapy, for 2 weeks. Exercise tests showed sign&ant increases in time to angina with nifedipine GITS at 8 and 24 hours after dosing. The mag- nitude of improvements and plasma concentrations of nifedipine were similar at the 2 time points. In our study, nifedipine GlTS therapy was maintained for 6 weeks, and our results indicate that the beneficial effect of nifedipme GITS persists over this longer time period. However, because the nifedipine and placebo therapies were neither randomized nor double-blinded in our study, our conclu- sions on the antianginal efficacies of nifedipine GITS over placebo should be conlirmed by studies using a standard placebo-controlled design.

The primary purpose of our crossover study was to compare the effects of nifedipine GITS and atenolol, both of which were titrated to the maximal efficacy and tolerance. The daily maintenance doses of nifedipine GITS were higher than those of conventional nifedipine capsules used in our prior studies,1,7,9 suggesting that the new formulation of nifedipine is better tolerated. Only 1 patient developed headache with nifedipine GITS, but leg edema and flushing occurred in over one third of the patients. However, because there were more adverse reactions and dropouts among patients receiving nifedipine GITS than atenolol, atenolol was better tolerated than nifedipine GITS.

Our present study shows that although exercise duration was increased to a similar extent by nifedipine GlTS and atenolol, the 2 agents have different hemodynamic effects. Atenolol significantly decreased heart rate, systolic pressure and rate-pressure product at all levels of exercise. Similar changes in rate-pressure product also have been reported with atenolo12 and other B-receptor blockers such as propranolol.5:17-19 In contrast, nifedipine GITS significantly decreased systolic pressure only at the end of exercise, and had no effect on rate-pressure product during exercise. The results suggest that the improvement in exercise tolerance produced by atenolol is caused by reducing cardiac work and myocardial oxygen demand. Nifedipine GITS did not detectably de- crease myocardial oxygen demand and therefore may have increased myocardial blood flow. Nifedipine has been shown to increase coronary blood flow in humans at rest,2@23 and in dogs both at rest and during maximal exercise.24 Nifedipine, like other calcium antagonists, may be expected to increase coronary blood flow not only by a direct relaxant effect on vascular smooth mus- cle, but also by inhibition of sympathetically mediated constriction of normal and diseased coronary arteries that occurs during exercise.25

In addition to the increase in coronary blood flow during exercise, Walsh et a124 found that nifedipine had no effect on left ventricular contractility during exercise in dogs. The negative inotropic effect of nifedipine, which is well documented in vitro, is not apparent in

intact subjects because of normal compensatory mecha- nisms. Similarly, results of our present study indicate that nifedipine GlTS affected neither the resting left ventricular ejection fraction nor the maximal increase in left ventricular ejection fraction during exercise in patients with stable angina. In contrast, although atenolol had no effect on resting left ventricular ejection h-action, it reduced the maximal increase in left ventricular ejection fraction during exercise. These differences on maximal left ventricular ejection ,$-action cannot be explained by differences in systolic blood pressure or heart rate among the groups. Most likely, atenolol acted to-reduce the exercise-induced maximal left ventricular ejection by blocking the P-receptor-mediated inotropic effects of catecholamines.

After having reached the maximal values during exercise, left ventricular ejection fraction either remained at a plateau or decreased at the end of exercise. The de- crease in left ventricular ejection fraction probably was caused in part by myocardial ischemia during maximal exercise. Because left ventricular ejection fraction was better preserved at the end of exercise in the nifedipine GITS phase, nifedipine GITS probably reduced the ischemia-induced myocardial depression. The difference between maximal ejection fraction and ejection fraction at the end of exercise was also smaller in the atenolol phase compared with placebo, suggesting that atenolol might have also reduced myocardial ischemia during exercise.

There were no prior studies of effects of nifedipine GITS on exercise left ventricular ejection fractions. Of the limited studies that compared the effects of calcium antagonists and B-receptor blockers on exercise ejection fractions, the results are contradictory. Findlay et al2 found no increase in left ventricular ejection fraction during exercise (measured by radionuclide angiocardiography) in patients taking atenolol, but there was an increase in patients taking conventional nifedipine. Oth- er studies17,26 have shown that patients receiving diltiazem had a higher exercise ejection fraction than those receiving propranolol. In contrast, similar increases were noted in left ventricular ejection fraction during exercise with the conventional nifedipine and propranolol.5

In the present study ambulatory electrocardiograms showed that neither atenolol nor nifedipine GITS reduced the number of ischemic events and total duration of ST-segment depression (total ischemic burden). Our fmdings differ from prior studies showing that conventional nifedipine27 and P-blockers like atenolo1,4,28,29 propranolo130 and metoprolo131 reduced ischemic events and total ischemic burden. In addition, conventional nifedipine was considered equally effective as atenolol in decreasing ischemic events and total ischemic burden in 1 study.28 However, in other studies, it has been found to be less efficacious than the B blockers4,29-31 and calcium blockers.32,33 Although the reasons for the differences in results among the studies cannot be ascertained with certainty, they could have been related to the differences in patient populations studied, or the doses administered. In our present study, patients exhibited only mild anginal symptoms and few episodes of ischemic ST-segment deviations, which could have made it dilli-


cult to demonstrate beneficial effects of any antianginal medication.

Acknowledgmontz We thank Andrea Moore, Mar- garet Youngman, Amy Mohan, and Barbara C. Entz for their technical and secretarial support.

1. Sherman LG, Liang C-s. Nifedipine in chronic stable angina: a double-blind placebo-controlled crossover trial. Am .I Cardiol 1983;51:7@6-711. 2. Fiidlay IN, MacLeod K, Ford M, Gillen G, Elliott A, DSrgie HJ. Treatment of angina pectoris with nifedipine and atenolol: efficacy and effect on cardiac function. Br Heart J 1986;55:240-245. 8. Shapiro W, Narahara KA, Kostis JB, Thandroyen F, Z&man LR. Comparison of atenolol and nifedipine in chronic stable angina pectoris. Am J Cardiol 1989;64: 186-190. 4. Quyyumi AA, Crake T, Wright CM, Mockus LJ, Fox KM. Medical treatment of patients with severe exertional and rest angina: double blind comparison of beta blocker, calcium antagonist, and nitrate. Br Heart J 1987;57:50.%5 11. fi. Higginbotham MB, Morris KG, Coleman RE, Cobb FR Comparison of nifedipine alone with propranolol alone for stable angina pectoris including hemodynsmics at rest and during exercise. Am .I Cardiol 1986;57,1022-1028. & Kawanisbi DT, Reid CL, Morrison EC, Rabimtoola SH. Response of angina and ischemia to long-term treatment in patients with chronic stable angina: a double- bliid randomized individualized dosing trial of nifedipine, propranolol~and their combiition. J Am Co11 Card@ 1992;19:409-417. 7. Lisng C-s, CopIin B, Wellington K. Comparison of antianginal efficacy of nifedipine and isosorbide dinitrate incbronic stable angina: a long-term, randomized, doubleblind, crossover study. Am J Cardiol 1985;55:9E-14E. 8. Al&as F, Chambers J, Jefferies S, Jackson G. A random&d double-blind crossover study of isosorbide mononitrate and nifedipine retard in chronic stable angina. Iti J Cardiol 19X9:24: 191-196. 9. Wallace WA, Wellington KL, Murphy GW, Liang C-s. Comparison of antianginal &icacies and exercise hemodynamic effects of nifedipine and diltiazem in stable angina pectoris. Ant J Cardiol 1989;63:414418. 10. Kliie WP, Kvill L, Dempsey EE, Grace M. A randomized double-blind comparison of diltiazem and nifedipine in stable angina. .I Am Co11 Cardiol 1988;12: 1562-1567. 11. Chung M, Reitberg DP, Gaffney M, Singleton W. Clinical pharmacokinetics of nifedipine gastrointestinal therapeutic system: a controlled-release formulation of nifedipine. Am J Med 1987;83(suppl 6B):lC-14. 12. Swanson DR, Barclay BL, Wong PSL, Theeuwes F. Niiedipine gastrointestinal therapeutic system. Am J Med 1987;83(suppl 68):s9. 13. Vetrovec GW, Parker VE, Cole S, Procacci PM Tabatmik B, Terry R Nifedi- pine gastrointestinal therapeutic system in stable angina pectoris: results of a mul- ticenter open-label crossover comparison with standard nifedipine. Am J Med 1987; 83(suppl 6B):24-29. 14. Vetrovec GW. Once-daily therapy for angina pectoris with nifedipine gastrointestinal therapeutic system. Am J Med 1989;86(suppl lA):28-32. I!% Parmley WW, Nesto RW, Singh BN, Deanfield J, Gottheb SO and the N-CAP study group. Attenuation of the circadian patterns of myocardial ischemia with nifedipine GITS in patients with chronic stable angina. J Am Co11 Cardiol 1992; 19: 13X0-1389. 16. Bittar N. Usefulness of nifedipine for myocardial ischemia and the nifedipine

gastrointestinal therapeutic system. Am J Cardiol 1989;64:31F-34F. 17. Schroeder JS, Hung J, Lamb IH, Connolly SJ, Jntzy KR, Goris ML. Diltiamm and propranolol, alone and in combination, on exercise performance and left ventricular function in patients with stable effort angina: a double-blind randomized, and placebo-controlled study. Acta Pharmcol Toxic01 1985;57(suppl II):5560. l8. Kenny J, Kiff P, Holmes J, Jewitt DE. Beneficial effects of diltiazem and propranolol, alone and in combination, in patients with stable angina pectmis. Br Heart J 1985;53:43-46. 19. O’Hara MJ, Khurmi NS, Bowles MJ, Subramanian VB, Don+ CJ, Raftery EB. Comparison of diltiazem at two dose levels with proprsnolol for treatment of sta ble angina pectoris. Am J Cardiol 19X4:54:477-481. 20. Tenis S, Bourdillon PD, Cheng DT, Pitt B. Direct cardiac and peripheral vascular effects of intracomnaty and intravenous nifedipine. Am J Cardiol 1986;58: 25-30. 21. Malacoff RF, Lorell BH, Mudge GH Jr, Hohnan BL, Idoine J, Bifolck L, Cohn PF. Beneficial effects of nifedipine on regional myocardial blood flow in patients with coronary arteIy disease. Circulation 1982;65(suppl 1):1-32-I-37. 22. Kaltenbach M, Schulz W, Kober G. Effects of nifedipine after intravenous and intracoronary administration. Am J Cardiol 197%44:X32-838. 23. Engel H-J, Lichtlen PR. Beneficial enhancements of coronary blood flow by nifedipine. Comparison with nitroglycerin and S-blocking agents. Am J Med 1981; 71:6584X6. 24. Walsh RA, Cleary IX, G’Rourke RA. Effects of calcium entry blockade on left ventricular dynamics in exercising dogs. Am J Phykl 1986;251:H656-H663. 25. Gage JE, Hess OM, Mu&anti T, Ritter M, Grimm J, Krayenbuehl HP. Vaso- constriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: reversibility by nitroglycerin. Circulation 1986;73:865- 876. 26. Anderson JL, Wagner JM, Datz FL, Christian PE, Bray BE, Taylor AT. Com- parative effects of diltiazem, propranolol, and placebo on exercise performance using radionuclide ventriculography in patients with symptomatic coronary artery disease: results of a double-blind, randomized, crossover study. Am Heart J 1984107: 698-706. 27. Nest0 RW, Phillips RT, Kett KG, McAuliffe LS, Roberts M, Hegarty P. Effect of nifedipine on total ischemic activity and circadian distribution of myocardial ischemic episodes in angina pectoris. Am J Cardiol 1991;67:12&132. 28. Hi JA, Gonzalez JI, Kolb R, Pepine CJ. Effects of atenolol alone, nifedipine alone and their combmation on ambulant myccardial ischemia. Am J Cardiol 1991; 67:671-575. 29. Mulcahy D, Cunningham D, Crean P, Wright C, Keegan J, Quyyumi A, Park A, Fox K. Circadian variation of total ischaemic burden and its alteration with anti- snginal agents. Lancet 1988;2:755-759. 30. Stone PH, Gibson RS, Glasser SP, DeWood MA, Parker JD, Kawanishi DT, Crawford MH, Messineo FC, Shook TL, Raby K, Curds DG, Hoop RS, Young PM, Braunwald E, and the ASIS Study Group. Comparison of proprsnoloi, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. Circulation 1990;82:1962-1972. 31. Egstrup K. Randomized double-blind comparison of metoprolol, nifedipine, and their combination in chronic stable angina: effects on total ischemic activity and heart rate at onset of ischemia. Am Heart J 1988; 116971-978. 32. Subramanian VB, Bowles MJ, Khnrmi NS, Davis AB, Raftery EB. Rsndom- ized double-blind comparison of verapamil and nifedipine in chronic stable angina. Am J Cardiol 1982;50:696-703. 33. Frishman W, Charlap S, Kimmel B, Teicher M, Cinnamon J, Allen L, Strom J. Diltiazem, nifedipine, and their combination in patients with stable angina pectoris: effects on angina, exercise tolerance, and the ambulatory electrocardiographic ST segment. Circulation 1988;77:774786.

28 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 JANUARY 1,1994

comparison of nifedipine gastrointestinal therapeutic system and atenolol on antianginal efficacies...

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