- Email: [email protected]
Effect of diltiazem slow-release formulation on silent myocardial ischemia in stable coronary artery disease
Effect of Dittiazem Slow-Release Formulation on Silent Myocardial lschemia in Stable Coronary Artery Disease Martin Juneau,
MD,
Pierre Thbroux, MD, David Waters, MD, for the Canadian Multicenter Diltiazem Study Group
6llentnlyocardlallsclKunlalsassodatedwlth adverseoutwmeln severalsubsetsofcoronaly arbrydlseasepathts.lhbsartklepresenUresuRsofa~,raMombd,doubl8-bllndstudyoftheeffectsof~lnsd-relaasedlltlazem(l6O~twkedally)on-k epbodesin6OpatienteWlthdOCU-coronaryarterydkease.llmnmnageofthestudy pophtknwas6Oyearsand92%wefemalehlhe meannunWrofepkodesofslkntkcheunlaper patlent was 5.8 (placebo) and 2.8 (drtlaslem), a 50% rductkn @
(p <0.001).Thlsstdy Bthatsustailled-releawdlMazem cans&ntfkantIyreduce theMquancyandtotaldurationofsbntl.schemkepisodes. (Am J Cardkl l992;es:206-2SD)
From the Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada. Address for reprints: Martin Juneau, MD, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, HlT lC8, Canada.
308
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
A
s reviewed recently by Pepine,’ results of several studies indicate that silent myocardial ischemia occurs frequently in patients with stable coronary artery disease and carries important prognostic implications in several patient subsets.Although it is still unknown whether reduction of silent ischemia will favorably affect prognosis, research on the efficacy of antianginal drugs to reduce or prevent silent ischemia appears justified. Several small studies24 and 3 larger studies7-9 have shown that p blockers can reduce the frequency and duration of asymptomatic ST-depression episodesdetected on ambulatory electrocardiographic (ECG) monitoring. Two small studies suggest that nifedipine’,” as monotherapy can reduce asymptomatic ST-depression episodes, whereas several studies do not show any effiVerapamil was reported to be effective in cacye9~“g12 reducing silent ischemic episodes in 1 study.12 Nitrates have been shown to be effective as monotherapy in only 1 study of 28 postmyocardial infarction patients.13 Diltiazem was shown to be effective in reducing silent ischemia in 3 small controlled studies,1’,‘4,‘5 whereas Stone et a1,8in a large study, reported that the effect of diltiazem on silent ischemia was not significant. The present placebo-controlled, randomized, double-blind study was designed to determine the effect on silent ischemia of sustained-release diltiazem. Because of the spontaneous variability, of silent ischemia as measured on ambulatory ECG monitoring, the assessmentof the study drug was done using 72-hour monitoring periods. Sixty patients meeting the P&lent shction: following 3 criteria were included: (1) documented coronary artery disease by coronary angiography showing coronary stenosiswith 2 50% lumen diameter reduction by angiography, a documented preMARCH 6. 1992
vious myocardial infarction (MI), or a positive thallium-201 exercise test showing a reversible perfusion defect; (2) a positive treadmill exercise test using the Bruce protocol with 2 1 mm horizontal or downsloping ST-segment depression measured 0.08 ms after the J-point, with or without angina; and (3) an ambulatory ECG recording showing the presence of at least 10 minutes of silent ST-segment depression of 2 1 mm or at least 4 episodes of ST-segment depression lasting 2 1 minute each, during any 1 of 3 24-hour periods of ambulatory ECG. The total duration of the screening ambulatory ECG was 72 hours (3 x 24 hr). All antianginal agents and any other drug that could interfere with the interpretation of STsegment changes were withdrawn at least 7 days prior to the screening visit. Only sublingual nitroglycerin was allowed during the study. Study design: The study was randomized, double-blind, and placebo-controlled. Following a 7-day single-blind placebo run-in screening phase, patients received sustained-release diltiazem capsules 180 mg twice daily or matching placebo capsules for 2 consecutive 1Cday double-blind treatment phases. Each patient received each of the 2 treatments in a random sequence according to a 2 x 2 Latin-square design. A first exercise test and a 72-hour ambulatory ECG were performed at the beginning of the placebo run-in phase to determine eligibility. The symptom-limited exercise tests were done according to the Bruce protocol. Exercise-induced ischemia was defined as 2 1 mm ST-segment depression, horizontal or downsloping, measured at 0.08 seconds after the J-point, on at least 3 consecutive beats. The exercise tests were performed at the beginning of the screening phase and at the end of each double-blind treatment phase just before the end of the 72-hour continuous ambulatory ECG recording period. It was performed in the morning, 2-3 hours after ingestion of the study drug. A 72-hour continuous ambulatory ECG was obtained at the start of the placebo run-in phase to determine eligibility and at the end of each treatment phase. All tapes were analyzed blindly at the Montreal Heart Institute using the Cardio Data MK 4 playback system. Intraobserver variability was assessed by rereading blindly 50 randomly selected tapes. The correlation between the 2 readings for the same patient was 0.93 for the number of episodes and 0.91 for the total duration. Interobserver reliability was assessed by having 50 randomly selected tapes interpreted by an independent laboratory. Correlations between the 2 inde-
TABLE I Characteristics the Study
of the Study Population
Clinical Age (yr)
59.9 f 8
at Entry into
(range 42-79)
Sex
Male Female Previous myocardial infarction Previous hypertension Diabetes mellitus Previous smokers Nonsmokers Angina episodes (no./week) CCS Functional class 1 2 3 Electrocardiographic Q-wave present First-degree AV block Significant arrhythmias Angiographic No. with coronary angiography l-vessel disease 2-vessel disease 3-vessel disease CCS = Canadian
Cardiovascular
56 4 18 14 0 37 51. 1.22 ? 2.4
(93%) (7%) (32%) (23%) (0) (64%) (85%)
44 13 III
(73%) (22%) (5%)
24 4 1
(40%) (6.6%) (1.6%)
44 15 17 12
(73%)
Society; AV = atrioventricular.
pendent readings for the same patient were 0.87 for the number of episodes and 0.90 for the total duration of ischemic episodes. RESULTS The characteristics of the study population are shown in Table I. The mean age was 60 years and 93% of the patients were male. Most patients were nonsmokers with few angina episodes per week. Coronary artery disease was documented by previous MI in 32%, by coronary angiography in 73%, and by reversible perfusion defect on thallium-201 exercise testing in 48% of the patients. Exercise m Results of the exercise tests are shown in Table II. Heart rate and rate-pressure products both at rest and at peak exercise were significantly lower with diltiazem compared with placebo. ST-segment depression occurred in 54 patients during the placebo test and in 45 patients during the diltiazem test. Total exercise duration improved significantly with diltiazem. Time to l-mm ST-segment depression improved with diltiazem from 296 seconds to 341 seconds, a 15% increase. The amplitude of maximal ST-segment depression was reduced significantly from 2.25 mm to 1.78 mm with diltiazem. monltorAmbulatory ekctroca rdiographk ing: As shown in Figure 1, the mean number of episodes of silent ischemia per patient was 5.6 with placebo and 2.8 with diltiazem, representing a 50% reduction (p < 0.0001). The cumulative duration of A SYMPOSIUM:
MYOCARDIAL
ISCHEMIA
SiB
TABLE II Hemodynamic, Clinical, and Electrocardiographic Results of Exercise Testing
Hemodynamic Rest Heart rate (bpm) Systolic BP (mm Hg) Rate-pressure product Peak exercise Heart rate (bpm) Systolic BP (mm Hg) Rate-pressure product Clinical ST depression With angina Without angina Reason for stopping Pain and/or ST depression Fatigue and/or dyspnea Total exercise duration (s) Electmcardiographic Time to l-mm ST depression ts) Time to maximum ST depression Maximum ST depression (mm)
Screening
Placebo
Diltiazem
p* Value
74.5 f 11.2 134.3 f 13.7 10,032 2 1,981
77.0 f 12.2 128.7 f 14.6 9,945 2 2,157
68.8 f 12.5 128.4 f 15.4 8,910 f 2,218
0.0001 0.9 0.0001
140.6 2 18.6 175.3 2 24.3 24,861 2 5,849
143.7 2 17.3 172.3 f 21.3 24,894 f 4,998
134.7 f 17.5 174.7 f 24.5 23,733 + 5,401
0.0001 0.2 0.01
60 (100%) 17 (28%) 43 (72%)
54 (90%) 15 (28%) 39 (72%)
45 (75%) 1(2%) 44 (98%)
28 (46%) 31(51%) 420 2 121
21(35%) 39 (64%) 467 f 156
12 (20%) 48 (80%) 494 + 143
0.05 0.0004
257 f. 132 403 f 113 2.38 f 0.83
296 f 154 447 + 156 2.25 k 1.03
341 2 148 479 2 141 1.78 f 1.09
0.005 0.005 0.0002
0.03 < 0.0001
*p values compare placebo and diltiazem tests. bpm = beats per minute; BP = blood pressure.
ST-segment depression was also reduced from 119 to 67 minutes (p < O.OOl),a 44% reduction. The beneficial effect of diltiazem was maintained throughout the circadian cycle, as shown in Figure 2. The percent reduction in silent ischemic episodes was 54% from midnight to 6 AM, 48% from 6 AM to noon, 57% from noon to 6 PM, and 47% from 6 PM to midnight. The average heart rate during the 72-hour placebo monitoring period was 74 beats/min compared with 68 beats/min during diltiazem treatment. This difference was significant (p
between 9 PM and 6 AM was associated with a decreased incidence of ST-segment depression. The correlation between the change in heart rate at each hour and the number of episodes of ST-segment depression during the corresponding hour was significant during both placebo and diltiazem. As expected, the slope is flatter with diltiazem Figure 3. DISCUSSlDN
In this study, slow-release diltiazem used as a monotherapy reduced the number of episodes of silent ischemia by 50% and its cumulative duration by 44%. Exercise test parameters were also improved significantly, as already reported in a recent randomized control multicenter trial.16 Several small studies have shown that l3blockers can significantly reduce the number of episodes and the duration of silent ischemia. The magnitude of this reduction is reported to be SO-75%. In a 250
8-
p = 0.0001
p = 0.0001
a
Placebo
826
THE AMERICAN
Diitiazem
JOURNAL
OF CARDIOLOGY
Placebo
VOLUME
Diitiazem
69
MARCH
I 6, 1992
I
I 6
0
I
I 12
I
I 10
I
I 24
I
I 24
Time of day
-
Placebo --*
l
0.0
I-
I
I 6
I 12 Time
0.0 -
I
Diltiazem
I 18
of day
I 1 I m DiWazem q
q
1
Placebo
y-0.2505+0.0351x
R-0.56
I
0.6 -
t H B
0.4 L1
i z' 0.2 -
.
.
0.0 -10
I -5
I
I
-7 0
I 5
I
I 10
A Heall rate (bpm)
A SYMPOSIUM: MYOCARDIAL ISCHEMIA‘
m
study using 10 patients, Quyyumi et al,’ have demonstrated that labetolol reduced the frequency and duration of ST-segment depression by 56% and 73%, respectively. Imperi et a1,3using metopro101 in 9 patients, have shown a very significant reduction in the total duration of silent ischemia (156 + 65 minutes to 20 ? 15 minutes) and the frequency of episodes (from 8 + 2 to 2 + 2). Willich et al: using a sample of 10 patients, have shown that metoprolol decreased the number of episodes of silent ischemia from 26 to 4 and the total duration of ST depression from 735 to 84. Chierchia et al,6 in a study using 10 patients, showed a 63% decrease in silent ischemic episodes with atenolol compared with placebo. Dargie et al5 obtained similar results in 16 patients treated with propranolol. In a larger study (n = 73) using propranolol, Khurmi et al7 have demonstrated a significant reduction in the number of episodes of asymptomatic ST depression from 6.5 + 0.7 to 3.4 + 0.6. The total duration of ST-segment depression was reduced from 74 -C 10 minutes to 26 f 10 minutes. In a multicenter randomized controlled trial (n = 50), Stone et al8 showed a marked reduction of asymptomatic ST-segment depression with propranolol. Feng et all3 have studied the effect of isosorbide5-mononitrate in 28 patients recovering from acute MI. The number of episodes of silent ischemia decreased by 88% and the duration by 94%. Schneeweiss and Marmor17 have reported the effect of transdermal nitroglycerin patch in 8 patients. Other antianginal medications were not discontinued during this study (nifedipine, propranolol, or atenolol). The number of episodes of asymptomatic ST-segment depression was reduced from 9.25 + 5.52 to 2.4 + 2.0. Nifedipine as monotherapy was shown to be effective in 2 small studies. Nesto et allo reported a reduction in the number of ischemic episodes from 63 with placebo to 18 with nifedipine. The total duration of ST-segment depression was reduced from 927 (placebo) to 260 (nifedipine) minutes. Dargie et al5 using propranolol and nifedipine showed that the 2 drugs were significantly more effective than placebo in reducing silent ischemic episodes. Several studies have shown no efficacy with nifedipine a10ne9*” or when it was added to current antianginal medications,““8”9 but 1 study by Cohn et alaohas shown that nifedipine is effective in reducing silent ischemia as an added treatment. Bala Subramanian et al,12in a double-blind study comparingnifedipine andverapamil (n = 24), showed that verapamil markedly reduced silent ischemic 848
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
episodes compared with placebo, whereas nifedipine did not. Khurmi et a&l4 in a study with 15 patients, have shown the efficacy of diltiazem in reducing the number of episodes of ST-segment depression by 44%. In this double-blind crossover study, propranolol was also used and reduced the number of episodes of silent ischemia by 87%. Bonetti et al” compared diltiazem with atenolol and atenolol plus nifedipine. The number of ischemic episodes was reduced by 75% by atenolol, 74% by diltiazem, and 80% by atenolol plus nifedipine. On the other hand, diltiazem was not shown to be effective by Stone et al* in a study comparing propranolol, nifedipine, and diltiazem. Diltiazem reduced the number of episodes of asymptomatic ST-segment depression per day by 17% (p = 0.08) but had no effect on the mean duration of ischemia per episode or on cumulative duration of silent ischemia per 24 hours. Only propranolol was shown to be effective in significantly reducing the number of episodes (57%), the mean duration of each episode (58%), and the cumulative duration of silent ischemia per 24 hours (87%). The results of the present study are in accordance with the results of Khurmi et all4 and Bonetti et a1.l’ Why our results differed from the study by Stone et al’ is not clear. Mechanism UPactlom ST-segment depression occurred at a slower heart rate with diltiazem than with placebo and no circadian variation in the efficacy of diltiazem was found. Second, the frequency of ST-segment depression appeared to be modulated more by changes in heart rate than by the absolute heart rate. An accelerating heart rate was associated with a higher frequency of ischemic episodes, and the reverse was also true. These observations suggest that one of the mechanisms involved in the pathogenesis of silent ischemia could be a rapid rate of change in myocardial oxygen demand and that diltiazem could have a beneficial effect by attenuating rapid increases in demand. Implkaths Oc the study: This study demonstrates that sustained-release diltiazem can significantly reduce the frequency and the total duration of silent ischemic episodes, thus extending the previously well-documented antianginal activity of the drug.” Whether medical reduction of silent ischemia will favorably alter prognosis is not known. This issue is currently being investigated by clinical trials. Until this answer is known, the routine treatment of silent ischemia cannot be recommended. MARCH 6, 1992
REFERENCES l. Pepine CJ. Is silent ischemia a treatable risk factor in patients with angina pectoris? Cirrulntion 1990,82(sup~12):11-135-B-142. 2. Oqyumi AA, Wright C, Mockus I, ShackeIl M, Sutton GC, Fox KM. Effects of combined alpha and beta adrencceptor bkxkade in patients with angina pectoris. Br Hemi .I 1985;53:47-52. a Imperi GA, Lambert CR, Coy K, Lopez L, Pepine CJ. Effects of titrated beta blockade (metoprolol) on silent myocardii iscliemia in ambulatory patients with coronary artery disease. Am I Cardid 1987;60:519-5%. 4. Wiich SN, Pohjola-Smtonen S, Bhatia SJS, Shook TL, Tofler GH, MuIIer JE, Curtii DG, Wiiams GH, Stone PH. Suppression of silent ischemia by metoprolol without alteration of morning increase of platelet aggregability in patients with stable coronary artery disease. CaaJation 1989;79:557-565. 9. Dargie HJ, Lynch PG, Krikler DM, Harris L, Krikler S. Niiedipine and propranolol: a beneficial drug interaction.Am Jkfed 1981;71:67-2. 8. Chierchia S, Glazier JJ, Geroso S. A single-blind, placebo-contmlled study of effects of stenolol on transient ischemia in “mixed” angina. Am J Cardid 1987;60:36A-4&4. 7. Khurml NS, Bowies MJ, O’Hara MJ, Raftery EB. Effect of propranoIoI on indices of intermittent myocardiaI ischemia, assessed by exercise testing and ambulatory ST-segment monitoring. Chin Ca&iol1986;9:391-397. 8. Stone PH, Gibson RS, Glasser SP, Deyoad MA, Parker JD, Kawanishi DT, Crawford MH, Messinco FC, Shook TI, Raby K, Curtis DG, Hoop RS, Young PM, Braunwald E, and ASIS Study Group. Comparison of propranoI& diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Clrculati 1990;82:1%2-1972. 9. Egstrup K. Randomized doubleblind comparison of metoprolol, nifedipme, and their combination in chronic stable anpina: effects on total ischemic activity and heart rate at onset of ischemia.h HeartJ 1988;116:971-978. 10. N&o RW, PhilIips RT, Kett KG, McAulifTe IS, Roberts M, Hegarty P. EEect of nifedipine on total ischemic activity and circadian distribution of myocardiil ischemic episodes in angina pectoris. Am I Cur&l 1991;67:12&132. =Frishman W, Charlap S, Kimmel B, Teicher M, Cinnamon J, Allen L, Strum J. Diltiazem, nifedipine, and their combination in patients with stable angina pectoris: effects on angina, exercise tolerance, and the ambulatory ekctrocardiographic ST segment. Circ&tion 1988,n:774-786. il. BaIa Suhramanian V, Bowles MJ, Khmmi NS, Davies AB, Raftery EB. Rationale for the choice of calcium antagonists in chronic stable angina. Am J ca&1982;50:11~1179. ill. Feng J, Feng XI-I, Schneeweiss A Efficacy of isawrbide-S-mono&rate on painful and silent myucardial ischemia after myocardial infarction. Am J Cwdid 1990;65(suppl):32.&35J. l4. Khurmi NS, O’Hara UT, Bow1e.s MJ, Raftery EJ3. Effect of diltiazem and propranolol on myccardial ischaemia during unre&icted daily liie in patients with effort-induced chronic stable angina pectoris. Ew J Chin Pharmaod 1987;32: 443-447. lS. Bonetti F, Paxaldi A, Rossetti PE, Margonato A, Chierchia SL. Dietential action of beta blockers and Ca-antagonists in preventing “da@ life” ischaemia. Eur Heart J 1989;1O(suppl):53. l6. Kliie WP, Juneau M, Grace M, bh& WJ, F’llugfelder P, Maranda CR, Wamica W, Chin C, Annable L, Dempsey E, Waters D. Usefulness of sustained-release diltiazem for stable angina pectoris. Am J Car&l 1989;64:12491252. 17. Schneeweiss A, Marmor A. Transdermal nitroglycerin patches for silent my-dial ischemia during antianginal treatment. Am J Carddol1988;61:36E38E. l8. Mukahy D, Cunningham D, Crean P, Wright C, Keegan J, Quyymni A, Park A, Fox K Circadian variation of total ischemic burden and its alteration with anti-al agents. Lancer 1988;i:751-759. l.9. Stone PH, Ware J9 DcWood MA, Gore JM, Eiih RI-I, Pie&o DA, Parisi AF, Nesto RW, Boden WE, Sharma SC, Vlay SC, Ennis LE, Gianelly RE, Tmi ZG, McCall NT, Curtis DG, Cbierchia S, Maseri A, Braunwald E. The
efficacy of the addition of nifediiine in patients with mixed angina compared to patients with classic &xtional angina: a mttlticenter, randomized, doubleblind, place~ntmlkzd clinical trikl.Am He&J 1988$16:%1-971. 20. Cohn PF, Vetrovec GW, Nesto R, Gerber FR, and the Total Ischemia Awareness Program Investigators. The n&dip&-total ischemia awareness program: a national survey of painful and painless mywardial ischemia including results of antiischemic therapy. Am J C&Z 1989;63:534-539.
DSCUSSlDN
Queatkn: In your study, you must have certainly had some patients who exhibited more striking effects from diltiazem than those shown by other patients. In the patients who had more dramatic decreases in episodes of silent ischemia during diltiazem therapy, did you observe a different pattern of their ischemic activity, particularly through the 24-hour period? h. Juneau: There were some patients who clearly responded more than others, and some who had total elimination of their ischemic episodes. However, we could not discern any circadian pattern or any other pattern in the parameters we measured. Question: One of the goals of your study was to explore the mechanisms underlying the efficacy of diltiazem in the treatment of silent ischemia. This has been a very controversial issue. Could you shed some light on these mechanisms? Dr. Juneau: We believe that the efficacy of diltiazem was achieved mainly through the slowing of the heart rate. Examination of the data shows that the slowing of the heart rate was consistent during the 24 hours, and that there was a nearly parallel effect on ischemic episodes. Queatkn: Your data show a decrease in frequency of; silent ischemic episodes despite an average high heart rate during the day. Were your data analyzed to determine if heart rate increments were associated with ischemic episodes? Dr. Juneau: Yes, they were. We observed the number of episodes per hour and analyzed the correlation between changes in the heart rateeither plus or minus-and the number of episodes. These data showed a striking correlation between the changes in heart rate and the number of episodes. The slope was flatter with diltiazem.
A SYMPOSIUM: MYOCARDIAL ISCHEMIA
M
MD,
Pierre Thbroux, MD, David Waters, MD, for the Canadian Multicenter Diltiazem Study Group
6llentnlyocardlallsclKunlalsassodatedwlth adverseoutwmeln severalsubsetsofcoronaly arbrydlseasepathts.lhbsartklepresenUresuRsofa~,raMombd,doubl8-bllndstudyoftheeffectsof~lnsd-relaasedlltlazem(l6O~twkedally)on-k epbodesin6OpatienteWlthdOCU-coronaryarterydkease.llmnmnageofthestudy pophtknwas6Oyearsand92%wefemalehlhe meannunWrofepkodesofslkntkcheunlaper patlent was 5.8 (placebo) and 2.8 (drtlaslem), a 50% rductkn @
(p <0.001).Thlsstdy Bthatsustailled-releawdlMazem cans&ntfkantIyreduce theMquancyandtotaldurationofsbntl.schemkepisodes. (Am J Cardkl l992;es:206-2SD)
From the Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada. Address for reprints: Martin Juneau, MD, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, HlT lC8, Canada.
308
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
A
s reviewed recently by Pepine,’ results of several studies indicate that silent myocardial ischemia occurs frequently in patients with stable coronary artery disease and carries important prognostic implications in several patient subsets.Although it is still unknown whether reduction of silent ischemia will favorably affect prognosis, research on the efficacy of antianginal drugs to reduce or prevent silent ischemia appears justified. Several small studies24 and 3 larger studies7-9 have shown that p blockers can reduce the frequency and duration of asymptomatic ST-depression episodesdetected on ambulatory electrocardiographic (ECG) monitoring. Two small studies suggest that nifedipine’,” as monotherapy can reduce asymptomatic ST-depression episodes, whereas several studies do not show any effiVerapamil was reported to be effective in cacye9~“g12 reducing silent ischemic episodes in 1 study.12 Nitrates have been shown to be effective as monotherapy in only 1 study of 28 postmyocardial infarction patients.13 Diltiazem was shown to be effective in reducing silent ischemia in 3 small controlled studies,1’,‘4,‘5 whereas Stone et a1,8in a large study, reported that the effect of diltiazem on silent ischemia was not significant. The present placebo-controlled, randomized, double-blind study was designed to determine the effect on silent ischemia of sustained-release diltiazem. Because of the spontaneous variability, of silent ischemia as measured on ambulatory ECG monitoring, the assessmentof the study drug was done using 72-hour monitoring periods. Sixty patients meeting the P&lent shction: following 3 criteria were included: (1) documented coronary artery disease by coronary angiography showing coronary stenosiswith 2 50% lumen diameter reduction by angiography, a documented preMARCH 6. 1992
vious myocardial infarction (MI), or a positive thallium-201 exercise test showing a reversible perfusion defect; (2) a positive treadmill exercise test using the Bruce protocol with 2 1 mm horizontal or downsloping ST-segment depression measured 0.08 ms after the J-point, with or without angina; and (3) an ambulatory ECG recording showing the presence of at least 10 minutes of silent ST-segment depression of 2 1 mm or at least 4 episodes of ST-segment depression lasting 2 1 minute each, during any 1 of 3 24-hour periods of ambulatory ECG. The total duration of the screening ambulatory ECG was 72 hours (3 x 24 hr). All antianginal agents and any other drug that could interfere with the interpretation of STsegment changes were withdrawn at least 7 days prior to the screening visit. Only sublingual nitroglycerin was allowed during the study. Study design: The study was randomized, double-blind, and placebo-controlled. Following a 7-day single-blind placebo run-in screening phase, patients received sustained-release diltiazem capsules 180 mg twice daily or matching placebo capsules for 2 consecutive 1Cday double-blind treatment phases. Each patient received each of the 2 treatments in a random sequence according to a 2 x 2 Latin-square design. A first exercise test and a 72-hour ambulatory ECG were performed at the beginning of the placebo run-in phase to determine eligibility. The symptom-limited exercise tests were done according to the Bruce protocol. Exercise-induced ischemia was defined as 2 1 mm ST-segment depression, horizontal or downsloping, measured at 0.08 seconds after the J-point, on at least 3 consecutive beats. The exercise tests were performed at the beginning of the screening phase and at the end of each double-blind treatment phase just before the end of the 72-hour continuous ambulatory ECG recording period. It was performed in the morning, 2-3 hours after ingestion of the study drug. A 72-hour continuous ambulatory ECG was obtained at the start of the placebo run-in phase to determine eligibility and at the end of each treatment phase. All tapes were analyzed blindly at the Montreal Heart Institute using the Cardio Data MK 4 playback system. Intraobserver variability was assessed by rereading blindly 50 randomly selected tapes. The correlation between the 2 readings for the same patient was 0.93 for the number of episodes and 0.91 for the total duration. Interobserver reliability was assessed by having 50 randomly selected tapes interpreted by an independent laboratory. Correlations between the 2 inde-
TABLE I Characteristics the Study
of the Study Population
Clinical Age (yr)
59.9 f 8
at Entry into
(range 42-79)
Sex
Male Female Previous myocardial infarction Previous hypertension Diabetes mellitus Previous smokers Nonsmokers Angina episodes (no./week) CCS Functional class 1 2 3 Electrocardiographic Q-wave present First-degree AV block Significant arrhythmias Angiographic No. with coronary angiography l-vessel disease 2-vessel disease 3-vessel disease CCS = Canadian
Cardiovascular
56 4 18 14 0 37 51. 1.22 ? 2.4
(93%) (7%) (32%) (23%) (0) (64%) (85%)
44 13 III
(73%) (22%) (5%)
24 4 1
(40%) (6.6%) (1.6%)
44 15 17 12
(73%)
Society; AV = atrioventricular.
pendent readings for the same patient were 0.87 for the number of episodes and 0.90 for the total duration of ischemic episodes. RESULTS The characteristics of the study population are shown in Table I. The mean age was 60 years and 93% of the patients were male. Most patients were nonsmokers with few angina episodes per week. Coronary artery disease was documented by previous MI in 32%, by coronary angiography in 73%, and by reversible perfusion defect on thallium-201 exercise testing in 48% of the patients. Exercise m Results of the exercise tests are shown in Table II. Heart rate and rate-pressure products both at rest and at peak exercise were significantly lower with diltiazem compared with placebo. ST-segment depression occurred in 54 patients during the placebo test and in 45 patients during the diltiazem test. Total exercise duration improved significantly with diltiazem. Time to l-mm ST-segment depression improved with diltiazem from 296 seconds to 341 seconds, a 15% increase. The amplitude of maximal ST-segment depression was reduced significantly from 2.25 mm to 1.78 mm with diltiazem. monltorAmbulatory ekctroca rdiographk ing: As shown in Figure 1, the mean number of episodes of silent ischemia per patient was 5.6 with placebo and 2.8 with diltiazem, representing a 50% reduction (p < 0.0001). The cumulative duration of A SYMPOSIUM:
MYOCARDIAL
ISCHEMIA
SiB
TABLE II Hemodynamic, Clinical, and Electrocardiographic Results of Exercise Testing
Hemodynamic Rest Heart rate (bpm) Systolic BP (mm Hg) Rate-pressure product Peak exercise Heart rate (bpm) Systolic BP (mm Hg) Rate-pressure product Clinical ST depression With angina Without angina Reason for stopping Pain and/or ST depression Fatigue and/or dyspnea Total exercise duration (s) Electmcardiographic Time to l-mm ST depression ts) Time to maximum ST depression Maximum ST depression (mm)
Screening
Placebo
Diltiazem
p* Value
74.5 f 11.2 134.3 f 13.7 10,032 2 1,981
77.0 f 12.2 128.7 f 14.6 9,945 2 2,157
68.8 f 12.5 128.4 f 15.4 8,910 f 2,218
0.0001 0.9 0.0001
140.6 2 18.6 175.3 2 24.3 24,861 2 5,849
143.7 2 17.3 172.3 f 21.3 24,894 f 4,998
134.7 f 17.5 174.7 f 24.5 23,733 + 5,401
0.0001 0.2 0.01
60 (100%) 17 (28%) 43 (72%)
54 (90%) 15 (28%) 39 (72%)
45 (75%) 1(2%) 44 (98%)
28 (46%) 31(51%) 420 2 121
21(35%) 39 (64%) 467 f 156
12 (20%) 48 (80%) 494 + 143
0.05 0.0004
257 f. 132 403 f 113 2.38 f 0.83
296 f 154 447 + 156 2.25 k 1.03
341 2 148 479 2 141 1.78 f 1.09
0.005 0.005 0.0002
0.03 < 0.0001
*p values compare placebo and diltiazem tests. bpm = beats per minute; BP = blood pressure.
ST-segment depression was also reduced from 119 to 67 minutes (p < O.OOl),a 44% reduction. The beneficial effect of diltiazem was maintained throughout the circadian cycle, as shown in Figure 2. The percent reduction in silent ischemic episodes was 54% from midnight to 6 AM, 48% from 6 AM to noon, 57% from noon to 6 PM, and 47% from 6 PM to midnight. The average heart rate during the 72-hour placebo monitoring period was 74 beats/min compared with 68 beats/min during diltiazem treatment. This difference was significant (p
between 9 PM and 6 AM was associated with a decreased incidence of ST-segment depression. The correlation between the change in heart rate at each hour and the number of episodes of ST-segment depression during the corresponding hour was significant during both placebo and diltiazem. As expected, the slope is flatter with diltiazem Figure 3. DISCUSSlDN
In this study, slow-release diltiazem used as a monotherapy reduced the number of episodes of silent ischemia by 50% and its cumulative duration by 44%. Exercise test parameters were also improved significantly, as already reported in a recent randomized control multicenter trial.16 Several small studies have shown that l3blockers can significantly reduce the number of episodes and the duration of silent ischemia. The magnitude of this reduction is reported to be SO-75%. In a 250
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THE AMERICAN
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MARCH
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A SYMPOSIUM: MYOCARDIAL ISCHEMIA‘
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study using 10 patients, Quyyumi et al,’ have demonstrated that labetolol reduced the frequency and duration of ST-segment depression by 56% and 73%, respectively. Imperi et a1,3using metopro101 in 9 patients, have shown a very significant reduction in the total duration of silent ischemia (156 + 65 minutes to 20 ? 15 minutes) and the frequency of episodes (from 8 + 2 to 2 + 2). Willich et al: using a sample of 10 patients, have shown that metoprolol decreased the number of episodes of silent ischemia from 26 to 4 and the total duration of ST depression from 735 to 84. Chierchia et al,6 in a study using 10 patients, showed a 63% decrease in silent ischemic episodes with atenolol compared with placebo. Dargie et al5 obtained similar results in 16 patients treated with propranolol. In a larger study (n = 73) using propranolol, Khurmi et al7 have demonstrated a significant reduction in the number of episodes of asymptomatic ST depression from 6.5 + 0.7 to 3.4 + 0.6. The total duration of ST-segment depression was reduced from 74 -C 10 minutes to 26 f 10 minutes. In a multicenter randomized controlled trial (n = 50), Stone et al8 showed a marked reduction of asymptomatic ST-segment depression with propranolol. Feng et all3 have studied the effect of isosorbide5-mononitrate in 28 patients recovering from acute MI. The number of episodes of silent ischemia decreased by 88% and the duration by 94%. Schneeweiss and Marmor17 have reported the effect of transdermal nitroglycerin patch in 8 patients. Other antianginal medications were not discontinued during this study (nifedipine, propranolol, or atenolol). The number of episodes of asymptomatic ST-segment depression was reduced from 9.25 + 5.52 to 2.4 + 2.0. Nifedipine as monotherapy was shown to be effective in 2 small studies. Nesto et allo reported a reduction in the number of ischemic episodes from 63 with placebo to 18 with nifedipine. The total duration of ST-segment depression was reduced from 927 (placebo) to 260 (nifedipine) minutes. Dargie et al5 using propranolol and nifedipine showed that the 2 drugs were significantly more effective than placebo in reducing silent ischemic episodes. Several studies have shown no efficacy with nifedipine a10ne9*” or when it was added to current antianginal medications,““8”9 but 1 study by Cohn et alaohas shown that nifedipine is effective in reducing silent ischemia as an added treatment. Bala Subramanian et al,12in a double-blind study comparingnifedipine andverapamil (n = 24), showed that verapamil markedly reduced silent ischemic 848
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
episodes compared with placebo, whereas nifedipine did not. Khurmi et a&l4 in a study with 15 patients, have shown the efficacy of diltiazem in reducing the number of episodes of ST-segment depression by 44%. In this double-blind crossover study, propranolol was also used and reduced the number of episodes of silent ischemia by 87%. Bonetti et al” compared diltiazem with atenolol and atenolol plus nifedipine. The number of ischemic episodes was reduced by 75% by atenolol, 74% by diltiazem, and 80% by atenolol plus nifedipine. On the other hand, diltiazem was not shown to be effective by Stone et al* in a study comparing propranolol, nifedipine, and diltiazem. Diltiazem reduced the number of episodes of asymptomatic ST-segment depression per day by 17% (p = 0.08) but had no effect on the mean duration of ischemia per episode or on cumulative duration of silent ischemia per 24 hours. Only propranolol was shown to be effective in significantly reducing the number of episodes (57%), the mean duration of each episode (58%), and the cumulative duration of silent ischemia per 24 hours (87%). The results of the present study are in accordance with the results of Khurmi et all4 and Bonetti et a1.l’ Why our results differed from the study by Stone et al’ is not clear. Mechanism UPactlom ST-segment depression occurred at a slower heart rate with diltiazem than with placebo and no circadian variation in the efficacy of diltiazem was found. Second, the frequency of ST-segment depression appeared to be modulated more by changes in heart rate than by the absolute heart rate. An accelerating heart rate was associated with a higher frequency of ischemic episodes, and the reverse was also true. These observations suggest that one of the mechanisms involved in the pathogenesis of silent ischemia could be a rapid rate of change in myocardial oxygen demand and that diltiazem could have a beneficial effect by attenuating rapid increases in demand. Implkaths Oc the study: This study demonstrates that sustained-release diltiazem can significantly reduce the frequency and the total duration of silent ischemic episodes, thus extending the previously well-documented antianginal activity of the drug.” Whether medical reduction of silent ischemia will favorably alter prognosis is not known. This issue is currently being investigated by clinical trials. Until this answer is known, the routine treatment of silent ischemia cannot be recommended. MARCH 6, 1992
REFERENCES l. Pepine CJ. Is silent ischemia a treatable risk factor in patients with angina pectoris? Cirrulntion 1990,82(sup~12):11-135-B-142. 2. Oqyumi AA, Wright C, Mockus I, ShackeIl M, Sutton GC, Fox KM. Effects of combined alpha and beta adrencceptor bkxkade in patients with angina pectoris. Br Hemi .I 1985;53:47-52. a Imperi GA, Lambert CR, Coy K, Lopez L, Pepine CJ. Effects of titrated beta blockade (metoprolol) on silent myocardii iscliemia in ambulatory patients with coronary artery disease. Am I Cardid 1987;60:519-5%. 4. Wiich SN, Pohjola-Smtonen S, Bhatia SJS, Shook TL, Tofler GH, MuIIer JE, Curtii DG, Wiiams GH, Stone PH. Suppression of silent ischemia by metoprolol without alteration of morning increase of platelet aggregability in patients with stable coronary artery disease. CaaJation 1989;79:557-565. 9. Dargie HJ, Lynch PG, Krikler DM, Harris L, Krikler S. Niiedipine and propranolol: a beneficial drug interaction.Am Jkfed 1981;71:67-2. 8. Chierchia S, Glazier JJ, Geroso S. A single-blind, placebo-contmlled study of effects of stenolol on transient ischemia in “mixed” angina. Am J Cardid 1987;60:36A-4&4. 7. Khurml NS, Bowies MJ, O’Hara MJ, Raftery EB. Effect of propranoIoI on indices of intermittent myocardiaI ischemia, assessed by exercise testing and ambulatory ST-segment monitoring. Chin Ca&iol1986;9:391-397. 8. Stone PH, Gibson RS, Glasser SP, Deyoad MA, Parker JD, Kawanishi DT, Crawford MH, Messinco FC, Shook TI, Raby K, Curtis DG, Hoop RS, Young PM, Braunwald E, and ASIS Study Group. Comparison of propranoI& diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Clrculati 1990;82:1%2-1972. 9. Egstrup K. Randomized doubleblind comparison of metoprolol, nifedipme, and their combination in chronic stable anpina: effects on total ischemic activity and heart rate at onset of ischemia.h HeartJ 1988;116:971-978. 10. N&o RW, PhilIips RT, Kett KG, McAulifTe IS, Roberts M, Hegarty P. EEect of nifedipine on total ischemic activity and circadian distribution of myocardiil ischemic episodes in angina pectoris. Am I Cur&l 1991;67:12&132. =Frishman W, Charlap S, Kimmel B, Teicher M, Cinnamon J, Allen L, Strum J. Diltiazem, nifedipine, and their combination in patients with stable angina pectoris: effects on angina, exercise tolerance, and the ambulatory ekctrocardiographic ST segment. Circ&tion 1988,n:774-786. il. BaIa Suhramanian V, Bowles MJ, Khmmi NS, Davies AB, Raftery EB. Rationale for the choice of calcium antagonists in chronic stable angina. Am J ca&1982;50:11~1179. ill. Feng J, Feng XI-I, Schneeweiss A Efficacy of isawrbide-S-mono&rate on painful and silent myucardial ischemia after myocardial infarction. Am J Cwdid 1990;65(suppl):32.&35J. l4. Khurmi NS, O’Hara UT, Bow1e.s MJ, Raftery EJ3. Effect of diltiazem and propranolol on myccardial ischaemia during unre&icted daily liie in patients with effort-induced chronic stable angina pectoris. Ew J Chin Pharmaod 1987;32: 443-447. lS. Bonetti F, Paxaldi A, Rossetti PE, Margonato A, Chierchia SL. Dietential action of beta blockers and Ca-antagonists in preventing “da@ life” ischaemia. Eur Heart J 1989;1O(suppl):53. l6. Kliie WP, Juneau M, Grace M, bh& WJ, F’llugfelder P, Maranda CR, Wamica W, Chin C, Annable L, Dempsey E, Waters D. Usefulness of sustained-release diltiazem for stable angina pectoris. Am J Car&l 1989;64:12491252. 17. Schneeweiss A, Marmor A. Transdermal nitroglycerin patches for silent my-dial ischemia during antianginal treatment. Am J Carddol1988;61:36E38E. l8. Mukahy D, Cunningham D, Crean P, Wright C, Keegan J, Quyymni A, Park A, Fox K Circadian variation of total ischemic burden and its alteration with anti-al agents. Lancer 1988;i:751-759. l.9. Stone PH, Ware J9 DcWood MA, Gore JM, Eiih RI-I, Pie&o DA, Parisi AF, Nesto RW, Boden WE, Sharma SC, Vlay SC, Ennis LE, Gianelly RE, Tmi ZG, McCall NT, Curtis DG, Cbierchia S, Maseri A, Braunwald E. The
efficacy of the addition of nifediiine in patients with mixed angina compared to patients with classic &xtional angina: a mttlticenter, randomized, doubleblind, place~ntmlkzd clinical trikl.Am He&J 1988$16:%1-971. 20. Cohn PF, Vetrovec GW, Nesto R, Gerber FR, and the Total Ischemia Awareness Program Investigators. The n&dip&-total ischemia awareness program: a national survey of painful and painless mywardial ischemia including results of antiischemic therapy. Am J C&Z 1989;63:534-539.
DSCUSSlDN
Queatkn: In your study, you must have certainly had some patients who exhibited more striking effects from diltiazem than those shown by other patients. In the patients who had more dramatic decreases in episodes of silent ischemia during diltiazem therapy, did you observe a different pattern of their ischemic activity, particularly through the 24-hour period? h. Juneau: There were some patients who clearly responded more than others, and some who had total elimination of their ischemic episodes. However, we could not discern any circadian pattern or any other pattern in the parameters we measured. Question: One of the goals of your study was to explore the mechanisms underlying the efficacy of diltiazem in the treatment of silent ischemia. This has been a very controversial issue. Could you shed some light on these mechanisms? Dr. Juneau: We believe that the efficacy of diltiazem was achieved mainly through the slowing of the heart rate. Examination of the data shows that the slowing of the heart rate was consistent during the 24 hours, and that there was a nearly parallel effect on ischemic episodes. Queatkn: Your data show a decrease in frequency of; silent ischemic episodes despite an average high heart rate during the day. Were your data analyzed to determine if heart rate increments were associated with ischemic episodes? Dr. Juneau: Yes, they were. We observed the number of episodes per hour and analyzed the correlation between changes in the heart rateeither plus or minus-and the number of episodes. These data showed a striking correlation between the changes in heart rate and the number of episodes. The slope was flatter with diltiazem.
A SYMPOSIUM: MYOCARDIAL ISCHEMIA
M