Efficacy and safety of sustained-release diltiazem in stable angina pectoris

Efficacyand Safety of Sustained-Release Diltiazem in Stable AnginaPectoris DONALD A. WEINER, MD, SALLY S. CUTLER, BS, and MICHAEL D. KLEIN, MD

The safety and efficacy of a sustained-release preparation of diltiazem (diltiazem-SR), with dose levels of 240 and 360 mg/day, were assessed In 16 patients with stable angina of effort. A double-blind, placebo-controlled, randomized, crossover protocol was used. Diltiazem-SR, when given twice daily, reduced the frequency of weekly angina1 attacks from 9.3 f 10.4 with placebo to 3.7 f 4.7 with 240 mg/day and to 3.1 f 4.7 with 360 mg/day (both p
T

he effectivenessof diltiazem, a calcium slow-channel blocking drug, in the treatment of exertional angina is well documented in short-terml-ll and longterm*2**3 controlled studies. One of its major drawbacks,however, is its short half-life,14which requires a daily dosescheduleof 3 or 4 times per day for patients with angina pectoris. This study was undertaken to evaluate the efficacy and safety of a new sustained-releasepreparation of diltiazem (diltiazemSR) in patientswith exertional angina using 2 different dosagesin a controlled protocol.

Methods Study group: The study group consistedof 18 men, aged 59 f 6 years, enrolled from November 1983 through August 1984. All patients had both chronic stable anginapectoris,with at least 5 episodesof angina per week and an abnormal treadmill exercise test response.The latter was defined as the presenceof 1 mm or more of horizontal or downsloping ischemic ST-segmentdepressionlasting 80 ms after the J point compared with the tracing at standing rest and exercise-limiting angina.Coronary artery diseasewas documented in 16 patients by coronary angiography or prior myocardial infarction. Of the 13 patients whc From the Evans Memorial Department of Clinical Research and the Department of Medicine, University Hospital, Boston University Medical Center, Boston, Massachusetts. This study was supported in part by a Grant-in-Aid from the Marion Laboratories, Inc., Kansas City, Missouri. Manuscript received April 8, 1985; revised manuscript received June 7, 1985, accepted June 10, 1985.

Address for reprints: Donald A. Weiner, MD, University Hospital, Department of Cardiology, 75 East Newton Street, Boston, Massachusetts 02118.

cebo phase to 519 f 177 seconds during the 2400 mg/day dose and to 506 f 162 seconds during the 360~mg/day dose of diltiazem-SR (both p
underwent angiography,5 had l-vessel, 3 had &vessel and 5 had 3-vesseldisease.No patient had congestive heart failure, myocardial infarction within the last 3 months, sinus bradycardia (less than 45 beats/min], diastolic systemic blood pressuremore than 115mm Hg, second- or third-degree atrioventricular block, or renal or hepatic disease.Each patient signed an informed consentform approvedby the Institutional Review Board at Boston University Medical Center. Study design: All antianginal medications were discontinued in each patient by a time period of at least 5 drug half-lives before entering the study. Patients were allowed to take nitroglycerin asneededto abort angina1attacks,but were instructed not to take any prophylactically. No other cardioactive medications were administered. The protocol consistedof a single-blind, placebocontrolled phase followed by a randomized,doubleblind, crossoverphase(Fig. 1).Patientswere evaluated weekly throughoutthe study by the sameresearchassistant and physician. Evaluation included a physical examination, electrocardiogramat rest, blood specimens for a hematologic screen and biochemical profile, urinalysis, and tabulation of angina1attacksin a diary. Patient compliance was verified by counting study capsulesand by measuring blood levels. The single-blind phasebeganwith a l-week placebo period followed by a l-week dose-titrationphasein which each patient received diltiazem-SR in increasing dosesof 120.240and 360mg/day for 2 dayseachto ascertaindrug safety.Three capsulesweregiven every 12 hours,consistingof active drug with or without placebo.The patientsthen entereda &week randomized, double-blind, crossover phase, during which they were given either 120mg of diltiazem-SR twice daily, 180 mg of diltiazem-SR twice daily, or identical-ap-

January

TABLE

I

Results

of the Double-Blind

Crossover

1, 1986

THE AMERICAN

JOURNAL

OF CARDIOLOGY

Volume

57

7

Comparlson Diltiazem-SR

Placebo Angina1 episodes per week Time to angina (set) Treadmill time (set) ST-segment deviation Onset (set) Peak (mm) Heari rate (beatslmin) Rest Submaximal exercise Peak exercise Systolic blood pressure (mm !ig) Rest Submaximal exercise Peak exercise Rate-pressure product (beatslmin-mm Hg* IO+) Rest Submaximal exercise Peak exercise Diltiazem plasma Concentrations (rig/ml) * p
240 in&lay

360 mg/day

9.3 + 10.4 318 i 160 410 f 180

3.7 f 4.7’ 394 l 171’ 519 f 177’

3.1 f 4.7’ 420 f 198’ 506 zk 182’

376 & 173 1.2 f 0.8

471 f 1.2 f

175’ 0.8

451 l 1.1 l

195’ 0.9

84f 109f8 119%

11 15

76 f 103f 121 f

9’ 11 16

75 f 100 f 120 f

14’ 14’ 17

128 f 154 f 162 f

17 14 18

124i9 151 f 169 f

15 18

123 f 16 150 f 13 163 zlz 17

94f8’ 157 f 30 205 f 29 152 f 53

92f 11’ 151 f 27’ 196 f 29 241 f 68

107 f 12 169 f 24 193 f 27 0

diltlazem.

pearing placebo capsules for 1 week each following a 3 X 3 Latin square design. Six squares were involved, for which period effects were removed separately in each square during the randomization process.l5 Exercise testing: Five treadmill exercise tests were performed during the 5-week protocol (Fig. 1) using a modification of the Bruce protocol. A 3-minute warmup stage (1.7 mph and 5% grade) was followed by the standard Bruce protocol. l6 A l&lead electrocardiogram was recorded at rest and at l-minute intervals during exercise and recovery until the ST segments and the heart rate resembled the baseline tracing. The blood pressure was recorded at rest, at the end of each stage of exercise, at the onset of angina and during recovery. The patients exercised to a symptom-limited endpoint, consisting of moderate angina, dyspnea or fatigue. The following variables were analyzed on the exercise test: total exercise time; time to onset of angina; time to onset of 1 mm of ST depression; peak ST depression; and heart rate, systolic blood pressure, and rate-pressure product at rest, at the end of the first 3 minutes of exercise [submaximal) and at maximal exercise. All tests were performed 12 hours after ingestion of the study capsules. Blood levels: Diltiazem blood levels were measured at the end of each week during the double-blind phase (Fig. l), 12 hours after the study capsules were ingested. Plasma diltiazem concentration was measured by gas chromatography.17 Statistical analyses: During the double-blind phase, the differences from the baseline values before placebo were analyzed using an analysis of variance for a Latin square design. Duncan’s multiple comparison procedure was used to compare the 3 treatments

for the parameters at rest and during peak exercise. The frequency of angina1 attacks was compared using paired t tests. Hemodynamic measurements at submaximal exercise were analyzed using a &way analy sis of variance to compare the 3 treatments. A p value was considered significant at the 50.05 level. All values are expressed as mean f standard deviation.

Results Blood diltiazem levels: In no patient were diltiazem blood levels detectable after 1 week of placebo. Mean diltiazem levels were 152 f 53 rig/ml (range 85 to 251) after 1 week of 240 mg/day of diltiazem-SR and 246 f 70 rig/ml [range 144 to 370) after 1 week of 360 mg/day. Effect on angina: Diltiazem-SR resulted in a significant 60% reduction in the frequency of angina1 attacks during the 240-mg/day dose and a 67% reduction during the 360-mg/day dose (Table I, Fig. 2) compared

I-SW.

0

stmd

‘I

1

I’CWble

2

Blind ,-‘I

3

4

Weok

FIGURE

1. Protocol

deslgn.

ElT

= exercise

treadmill

test.

6

8

SUSTAINED-RELEASE

DILTIAZEM

FOR ANGINA

with the crossover placebo values. There were no differences between the 2 doses of diltiazem-SR. Effect on hemodynamics: At rest, the heart rate was significantly reduced with diltiazem-SR, by an average of 8 beats during the 240-mg/day dose and by 9 beats during the 360 mg/day dose (Table I]. Systolic blood pressure was not affected. At submaximal exercise, heart rate and rate-pressure product during the 360-mg/day dose were significantly reduced (Table I). No differences were observed in these variables at maximal exercise. Exercise performance: Treadmill time was significantly increased, by 27%, after the 240-mg/day dose and by 23% after the 360 mg/day dose (Fig. 2) compared with the crossover placebo values. The time to onset of angina was similarly prolonged by both doses of diltiazem-SR (Table I). Twelve patients (67%) taking the MO-mg/day dose and 10 patients (56%) taking the 360-mg/day dose showed a 20% or greater increase in treadmill time compared with the corresponding placebo values (Fig. 3). However, in 3 patients exercise capacity decreased markedly when the dose of diltiazem-SR was increased from 240 to 360 mg/day. One of these 3 patients had a further reduction in angina1 attacks, from 8 to 4 per week, with the larger dose. Each of these 3 patients had a different sequence of medication during the S-week randomization period, and each had a 70% or greater increase in diltiazem blood levels with the 360- compared with the 240mg/day dose. Electrocardiographic effects: Diltiazem-SR significantly delayed the onset of ST-segment depression by 1.6 minutes while patients were taking 240 mg/day and by 1.3 minutes after 360 mg/day (Table I). The maximal ST-segment depression was not affected by diltiazem-SR. The PR interval was 166 f 16 ms at rest and significantly increased to 169 f 16 ms after 240 mg/day of diltiazem-SR (p = 0.05) and to 174 f 19 ms

‘p40.01 20. Angina1

15-

vt

placebo

after 360 mg/day (p = 0.011. There were no significant changes in the QRS or QT intervals. Placebo effects: Treadmill time and time to onset of angina were not significantly different among the initial baseline exercise test before entry into the protocol (398 f 136 and 294 f 141 seconds, respectively), the single-blind placebo test (404 f 167 and 306 f 155 seconds, respectively) and the double-blind placebo test (410 f 180 and 318 f 160 seconds, respectively). Adverse effects: All doses of diltiazem-SR were extremely well tolerated. One patient reported mild pedal edema after receiving the 240-mg/day dose. There were no important changes in the biochemical or hematologic screening tests after administration of diltiazem-SR.

Discussion Effectiveness of sustained-release dfltiazem: The present study has documented, in a placebo-controlled protocol, the efficacy of diltiazem-SR when used twice daily in patients with chronic stable angina pectoris. Subjective improvement was shown by a reduction in the frequency of angina1 attacks and objective benefit was manifested by an increase in exercise capacity. The doses of 240 and 360 mg/day of diltiazem-SR were both effective, but no substantial differences were found between the 2 doses. The lack of a dose-response effect may, in part, be a result of the performance of the tests at trough blood levels (12 hours after a dose) rather than at peak levels. Thirtythree percent and 44% of the patients receiving 240 and 360 mg of diltiazem-SR, respectively, had a 20% or less increase in their treadmill times. These patients could not be distinguished from the patients with better responses either by baseline clinical, angiographic or exercise test characteristics or by randomization sequence during the crossover phase. Mechanism of antianginal effect: The heart rate, which is a major determinant of myocardial oxygen demand, was reduced at submaximal exercise. Thus, while taking diltiazem-SR, the patients exercised longer because the heart rate increased more slowly, lead-

t . .

. 1

l

r

*

Treadmlll Time (see)

‘ii 800 -3 700ii 600 F 500= 400. E 300 ii7 200 E loo-

p40.01

J

t

Placebo

Dlltiazem-SR

(mglday)

FIGURE 2. Elfect of sustained-release dlltiarem (Diltiazem-SR) therapy compared with placebo on the number of anginai attacks per week and the treadmill time in the double-blind crossover phase. Values are expressed as mean f standard deviation.

240

Dlltlszem-SR

360

tmg/dry)

FIGURE 3. individual values for treadmill time for each placebo and sustalned-release diitiazem (Dlltiazem-SR) The mean f standard deviation for treadmill time with after 360 mglday of diitiazem-SR are shown.

patient after therapy. placebo and

J~~uw’

ing to a reduction in myocardial oxygen demand as a given external workload. This effect is similar to that with the regular formulation of diltiazem.5r7-g We could not demonstrate a reduction in the peak STsegment depression at a similar rate-pressure product, as has been found in other studies of calcium antagonists.5~gJ8V1g Blood levels of diltiazem: There was a wide scatter in the blood diltiazem levels after a fixed daily dose of diltiazem-SR was administered, which could be explained by the interpatient variability in first-pass hepatic extraction of diltiazem-SR. The blood diltiazem levels 12 hours after daily doses of 240 and 360 mg of diltiazem-SR (152 f 53 and 246 f 70 rig/ml, respectively) were similar to the blood levels obtained in a previous study 2 hours. after daily doses of 240 and 360 mg of the regular formulation of diltiazem (183 f 63 and 274 f 102 rig/ml, respectivelyJ7 Despite the increased mean diltiazem levels with a dose of 360 mg/day of diltiazem-SR, there was no subjective or objective improvement demonstrated at this higher dose. Even, the 3 patients whose exercise capacity deteriorated when they took 360 mg/day had an increase in their blood diltiazem levels, from 123 f 46 rig/ml with 240 mg/day to 255 f 76 rig/ml with 360 mg/day. Adverse effects: One patient had mild pedal edema while taking 240 mg/day of diltiazem-SR. No other adverse effects occurred. The mean heart rate at rest was reduced an average of 8 beats/min, but the patients remained asymptomatic. The PR interval increased an average of 6 ms but no patient had secondor third-degree atrioventricular block. Our patients were carefully screened for evidence of congestive heart failure and sinoatrial and atrioventricular conduction disease. Diltiazem-SR may cause more adverse effects in patients with these conditions, especially if concomitant medications are given that cause similar adverse effects, such as ,B-adrenergic blocking agents. Limitations of the study: There were certain limitations inherent in the study design. A short evaluation period of 1 week was used during the double-blind phase, and no buffer placebo period occurred between the 3 crossover phases. Thus, drug carryover effects could have occurred during certain sequences of randomization. However, the analysis of variance technique used adjusts treatment means for any detectable carryover effects; therefore, the p values determined reflect an appropriate analysis of this design. The absence of detectable blood diltiazem levels in any patient receiving placebo suggests that no important lingering effects from diltiazem were likely to be exerted after 1 week with administration of placebo. Another consideration inherent in any protocol using multiple exercise test procedures over several weeks or months is that enhanced treadmill performance may be a result of training effects rather than

1, 1986

THE

AMERICAN

JOURNAL

OF CARDIOLOGY

Volume

57

9

drug benefit. 19-22Comparison of the exercise tests performed while the patients were not taking active medication showed no differences in exercise performance, suggesting the absence of an important training effect, ibhi~11 IMY partly be a result of the short duration of the protocol.

References 1. Koiwaya Y. Nakamura M, Mitsutake A, Tanaka S, Takeshita A. Increased exercise tolerance after oral diltiazem, a calcium antagonist, in angina pectoris. Am Heart J 1981;101:143-149. 2. Low RI, Takeda P, Lee G, Mason DT, Awan NA. DeMaria AN. Effects of diltiazem-induced calcium blockade upon exercise capacity in effort angina due to chronic coronary artery disease. Am Heart J 1981;101:713-718. 3. Hossack KF. Pool PE. Steele P, Crawford MH, DeMaria AN, Cohen LS. Ports TA. Efficacy of diltiazem in angina of effort: a multicenter trial. Am J Cardiol l982;49:567-572, 4. Strauss WE, McIntyre KM, Parisi AF, Shapiro W. Safety and efficacy of diltiazem hydrochloride for the treatment of stable angina pectoris: report of a cooperative clinical trial. Am J Cardiol 1982;49:580-566. 5. Wagniart P. Fereuson RI. Chaitman BR. Achard F, Benacerraf A. Delanguenhigen B, MorX B, Pa&rnac A, Bourassa MG. Increased exercise tolerance and reduced electrocardiographic ischemia with diltiazem in patients with stable angina pectoris. Circulation 1982;66:23-28. 6. Petru MA, Crawford MH. Sorenson SG, Chaudhuri TK. Levine S, O’Rourke RA. Short- and long-term efficacy of high-dose oral diltiazem for angina due to coronary artery disease: a placebo-controlled, randomized, double-blind crossover study. Circulation 1983;68:139-147. 7. Lindenberg BS, Weiner DA, McCabe CH, Cutler SS, Ryan TJ. Klein MD. Efficacy and safety of incremental doses of diltiazem for the treatment of stable angina pectoris. JACC 1983:2:1129-1133. 8. Bala Subramanian V. Khurmi NS. Bowles MI, O’Hara M. Raftery EB. Obiective evaluation of three dose levels of diltiazem in batients with chronic stable angina. JACC 1983;1:1144-1153. ’ 9. Go M Jr, Hollenberg M. Improved efficacy of high-dose versus mediumand low-dose diltiazem therapy for chronic stable angina pectoris. Am J CardioJ 1984;53:669-673. 10. Hung J, Lamb IH, Connolly SJ, Jutzy KR. Goris ML. Schroeder JS. The effect ,,-~ of-, diltiazem and DronranoJoJ. alone and in combination. on exercise performance and left v&tr;cuJar Junction in patients with stable effort angina: a double-blind. randomized, and placebo-controlled study. Circulation 1983:68:560-567.

11. Anderson JL. Wagner JM, Datz FL, Christian PE, Bray BE, Taylor AT. Comparative 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 1984:107:698-706. 12. Pool PE, Seagren SC. Long-term efficacy of diltiazem in chronic stable angina associated with atherosclerosis: effect on treadmill exercise. Am J Cardiol 1982;49:573-577, 13. Hossack K, Kannagi T, Day B, Bruce RA. Long-term study of high-dose diltiazem in chronic stable exertional angina. Am Heart J 1984;207:1215-1220. 14. Zelis RF, Kinney EL. The pharmacokinetics of diltiazem in healthy American men. Am J Cardiol 1982;49:529-532. 15. Cochran WG. Cox GM. Experimental Designs. New York: John Wiley 8 Sons, 1957:133-139.

16. Bruce RA, Hornsten TR. Exercise stress testing in evaluation of patients with ischemic heart disease. Prog Cardiovasc Dis 1969;11:371-390. 17. Rovei V, Mitchard M. Morselli PL. Simple. sensitive and specific gas chromatographic method for the quantification of diltiazem in human body fluids. J Chromatogr 1977;138:391-397. 18. Muller HS, Chahine RA. Interim report of multicenter double-blind placebo-controlled studies of nifedipine on chronic stable angina. Am J Med 1981;71:645-657.

19. Brodsky SJ, Cutler SS. Weiner DA, McCabe CH, Ryan TJ, Klein MD. Treatment of stable angina of effort with verapamil. A double-blind placebocontrolled randomized crossover study. Circulation 1982;66:569-574. 20. Smokler PE. MacAlpin RV, Alvaro A, Kattus AA. Reproducibility of a multistage near-maximal treadmill test for exercise tolerance in angina pectoris. Circulation 1973;48:346-353. 21. Hossack KF, Bruce RA. Improved exercise performance in persons with stable angina pectoris receiving diltiazem. Am J Cardiol 1981;47:95-101. 22. Harston WE, Friesinger GC. Variability of response to beta receptor blockade for angina pectoris in clinical trials: a study of pindolol. Am J Cardiol 1982;50:722-727.