- Email: [email protected]
Antianginal Drug Therapy for Silent Myocardial Ischemia
Cardiova.~cular
Pharmacotherapy I
0025-7125/88 $0.00 + .20
Antianginal Drug Therapy for Silent Myocardial Ischemia
William H. Frishman, MD,* and Mark Teicher, MDt
Nitrates, 1 ~-adrenergic blocking drugs, 13 a- ~-adrenergic blocking drugs,17 and calcium antagonists,32 used alone and in combination, have been shown to be effective in the management of symptomatic ischemic heart disease by relieving angina pectoris and reducing the intensity of associated myocardial ischemia. Recently, close attention has been given to the problem of silent ischemia, or ischemia without symptoms. This condition was recognized more than a half century ago when some asymptomatic patients were shown to have reversible electrocardiogram (ECG) changes suggestive of myocardial ischemia during the Master's two-step examination. Recently, technology has been developed to identifY asymptomatic transient ischemic episodes using the ambulatory ECG. 9 Positron emission imaging techniques have validated that these silent ischemic episodes are indicative of true myocardial ischemia.lO The pioneering contributions of Cohn, Maseri, Pepine, Deanfield, Selwyn, and their associates have clearly demonstrated the frequent occurrence of silent ischemic episodes in patients with symptomatic angina and coronary artery disease documented by angiography. ri, 22, 25, 29 Gottlieb and Gerstenblith have demonstrated the unfavorable prognosis of continued silent ischemia in patients with unstable angina. 19 Thus, all antianginal therapies must also be shown to be anti-ischemic if the problem of silent ischemia is to be dealt with in a satisfactory manner. M ultiple studies now available have shown favorable effects of nitrates, ~-adrenergic blockers, 26, 30 a- ~-adrenergic blockers,31 and calcium antagonists on episodes of asymptomatic transient myocardial ischemia observed by ambulatory ECG monitoring in patients with angina and/or coronary 'Professor of Medicine, Albert Einstein College of Medicine; and Director of Medicine, Hospital of the Albert Einstein College of Medicine, Bronx, New York tFellow, Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
Adapted from Frishman WH, Teicher M: Antianginal drug therapy for silent myocardial ischemia, Am Heart J 114:140-147, 1987; with permission Medical Clinics of North America-Vo!' 72, No, 1, January 1988
185
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WILLIA\!
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artery disease. 2.3 This article reviews the clinical experiences with these drugs in silent myocardial ischemia. NITRATES Nitroglycerin Nitroglycerin and sustained-release nitrate preparations have been shown to be successful in acute prophylactic therapy against painful transient myocardial ischemia-angina pectoris. 1 In patients with stable angina pectoris, Schang and Pe pine found that the hourly sublingual administration of nitroglycerin could prevent or markedly reduce the frequency of symptomatic (silent) ischemic episodes detected on an ambulatory monitoring ECG device. 29 They also observed that only 25 per cent of the recorded ischemic episodes in their study were related to pain. The asymptomatic ischemic episodes recorded on the ECG occurred at heart rates and activity levels well below those expected to cause ischemia. Pepine and associates recently observed that in patients with left ventricular motion abnormalities on left ventriculography and with no associated pain, low-dose intravenous nitroglycerin could favorably reverse these changes. 26 These painless regional ventricular contraction abnormalities were thought to be related to asymptomatic myocardial ischemia, because all the patients with these changes had important coronary artery disease in the distribution of the abnormally contracting myocardial segment or wall motion activity. The success of nitroglycerin, they concluded, was related to successful management of silent myocardial ischemia. Shell and colleagues reported the results of an open-label study evaluating the effects of transdermal nitroglycerin on painful and silent myocardial ischemia (ECG evidence of ST segment depression), determined from a specialized 24-hour ambulatory ECG system. 30. 31 Eight patients already on l3-blockers were up-titrated with larger patch doses of nitroglycerin until all symptomatic episodes were abolished. Patients received a mean nitroglycerin patch dose of 10.4 mg per 24 hours (range, 5 to 20 mg). There was a significant reduction in the frequency of ischemic events (80 per cent of ischemic episodes were noted to be painless) (Fig. 1). The duration of ischemia over 24 hours was also reduced from 95.8 min per 24 hours to 17 min per 24 hours with nitroglycerin therapy (Fig. 2). These investigators concluded that transdermal nitroglycerin patches were useful not only for the treatment of angina pectoris but also for the more commonly observed painless ischemic episodes. The long-term effects of nitroglycerin therapy were not evaluated in this study. These same investigators are now performing a double-blind, placebo-controlled crossover trial to confirm the findings of their initial short-term open-label study. Isosorbide Dinitrate The anti-ischemic effects of isosorbide dinitrate were evaluated in 12 patients who had frequent transient myocardial ischemic episodes at rest,
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Figure 1. Effect of transdermal nitroglycerin on number of ischemic events in patients already on f3-blockers. The number includes both symptomatic and asymptomatic events (n = 8). A significant reduction in events per 24 hours is observed with nitroglycerin. (From Shell WE, Kivowitz CF, Rubins SB, et al: Mechanisms and therapy of silent myocardial ischemia: The effect of transdermal nitroglycerin. Am Heart J 112:222-229, 1986; with permission.)
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with a variable degree of coronary atherosclerosis and vasospastic angina. II In the trial, constant blood levels of isosorbide were administered intravenously for 12 to 24 hours, alternating with equal periods of normal saline administration. During the placebo periods, continuous ECG monitoring revealed frequent episodes of ST segment elevation and depression, most of them without associated pain. These ischemic episodes were significantly reduced or abolished with isosorbide. The authors concluded that isosorbide dinitrate was useful for managing symptomatic and asymptomatic ischemic episodes in patients with vasospastic angina.
100
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Figure 2. Effect of transdermal nitroglycerin duration of ischemia per 24 hours. A significant reduction in ischemia duration is observed with nitroglycerin (n = 8). (From Shell WE, Kivowitz CF, Rubins SB, et al: Mechanisms and therapy of silent myocardial ischemia: The effect of transdennal nitroglycerin. Am Heart J 112:222229, 1986; with permission.)
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Conclusion From preliminary studies, nitrates appear to be effective drugs for the management of both painful and silent ischemic episodes. However, studies with more rigid study designs using long-term oral treatment protocols need to be done. ADRENERGIC BLOCKERS a-Adrenergic Blockers Although a-blockers are vasodilators, their clinical utility in symptomatic ischemia is not yet defined. 12 There are no reports yet describing effects of a-adrenergic blockers on silent myocardial ischemia. I3-Adrenergic Blockers For more than 20 years,13 l3-adrenergic blockers have been a clinical mainstay oflong-term antianginal therapy. Beneficial effects on stable angina are well known, but some controversy was raised regarding their utility as monotherapy in vasospastic angina syndromes. 14 Certainly, in combination with nitrates and calcium antagonists, their usefulness in all forms of angina has been proven beyond question. 13 As will be discussed later in the section on calcium antagonists, propranolol as monotherapy has been shown to be as effective as verapamil and nifedipine in reducing both painful and silent ischemic episodes (evidenced on the ambulatory ECG) in patients with angina pectoris. When combined with nifedipine, the combination appears more effective than with either drug alone. Seventy-three patients, aged 41 to 75 years, with established stable exertional angina pectoris, were studied in a double-blind fashion to confirm the efficacy of 80 mg propranolol administered three times daily and to examine its effects on ST segment changes in the ECG by ambulatory ST segment monitoring and exercise testing, using on-line computer analysis. 21 During ambulatory monitoring, episodes of ST segment depression were significantly reduced by propranolol compared with placebo treatment. The total duration of ST segment depression was also Significantly reduced by active treatment, and the maximal depth of ST segment depressiOll was reduced. Exercise time was improved by propranolol. The authors concluded that propranolol was an effective antianginal agent that also improves the ST segment changes during controlled, as well as uncontrolled, conditions related to the drug's ability to lower the heart rate and rate-pressure product. In another study, 81 patients with unstable angina were treated with maximal nitrate and calcium channel blocker (nifedipine) therapy, where propranolol or placebo was added as additional treatment. 18 There was a greater reduction in symptomatic episodes of angina and nitroglycerin consumption with propranolol. Continuous ECG recordings for ischemic ST segment changes revealed fewer daily ischemic episodes (painful or silent) in the propranolol group than in the placebo group and a shorter
189
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Figure 3. Effects of propranolol (n = 42) and placebo (n = 39) in patients with unstable angina already receiving nitrates and l3-blockers. The number and duration of ischemic episodes per 24 hours as detected by continuous two-channel electrocardiograph monitoring during the first two days of study are shown. There were significantly fewer episodes and a shorter daily duration of ischemia in the propranolol group. (From Gottlieb SO, Weisfeldt ML, Ouyang P, et al: Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: A randomized, double-blind, placebo-controlled trial. Circulation 73:331-337, 1986; with permission.)
duration of ischemia (Fig. 3). The authors concluded that the addition of propranolol in patients with unstable angina receiving nitrates and nifedipine reduces the frequency and duration of symptomatic and silent ischemic episodes. Cohn and colleagues studied the effects of propranolol in 11 patients with coronary artery disease and ECG evidence of silent myocardial ischemia on exercise testing. 7 Using gated radionuclide imaging of the left ventricle, they demonstrated improved global ventricular functioning with [3-blocker therapy (propranolol, timolol) compared to baseline. They concluded that [3-adrenergic blockade can effectively improve the abnormalities in exercise left ventricular function in patients with coronary artery disease and silent myocardial ischemia. The antianginal effects of atenolol and pindolol were compared in patients with effort angina and nocturnal angina. 28 Pindolol, 5 mg three times daily, and atenolol, 100 mg daily, were given for 5 days each in a double-blind, randomized manner. Daytime and nocturnal resting heart rates and the frequency of angina were significantly reduced by atenolol compared to pindolol. The duration of exercise was significantly increased, and the frequency, duration, and magnitude of daytime and nocturnal episodes of ST segment depression on ambulatory ECG monitoring were reduced by atenolol. The investigators concluded that resting heart rate reduction is important in the management of effort and nocturnal angina and that partial agonist activity in a [3-blocker may not be a desirable property. (X-
[3-Adrenergic Blockers
Labetalol, the first (X- [3-adrenergic blocker marketed in the world, has been shown to be effective in the treatment of hypertensive patients with
190
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FRISH:\IAl\ AND MARK TEICHEH
angina pectoris by lowering blood pressure and reducing anginal episodes. 17 Quyyumi and associates compared placebo to labetalol in patients with chronic stable angina pectoris. 27 They observed that compared to placebo, labetalol reduced the frequency of angina and exercise tolerance far longer. The drug reduced heart rate and the frequency and duration of ST segment depressions on ambulatory monitoring by 56 and 73 per cent, respectively, compared to placebo. Conclusion Most [3-adrenergic blockers and the (X- [3-blocker labetalol appear to be effective in reducing both painful and silent ischemic episodes, when used alone or in combination with other antianginal drugs. CALCIUM ANTAGONISTS Verapamil The calcium antagonist verapamil is similar in structure to papaverine.
It has vasodilator and electrophysiologic activities that have allowed the
drug to be used in patients with supraventricular arrhythmias, stable and unstable angina, and systemic hypertension. 32 Johnson and colleagues studied 16 patients with documented variant angina (Prinzmetal type) in a placebo-controlled study of verapamil. 20 This study was complicated by the fact that patients were on concomitant therapy that included isosorbide dinitrate and digoxin. Patients were randomized to receive either verapamil or placebo for 4 months after a 1month placebo run-in period. The patients were then crossed over to receive the other regimen for an additional 4 months. Episodes of angina, nitroglycerin consumption, and transient ST-segment shifts detected on a weekly ambulatory ECG examination were assessed. As shown in Figure 4, episodes of angina per week and nitroglycerin consumed per week were reduced, as were transient ischemic ECG changes, many of which were unassociated with pain. The same group of investigators compared the effects of nifedipine to verapamil in a similar group of patients with variant angina ..33 This was not a direct comparison though, because verapamil was administered as part of a blinded, placebo-controlled study, whereas nifedipine was administered in open-label fashion to patients who had already completed the blinded trial. In comparing the effects of the two drugs, both drugs appeared equally effective in reducing angina attacks, nitroglycerin consumption, and transient ischemic episodes observed on a weekly ambulatory ECG examination. In a study of patients with unstable vasospastic angina at rest who were studied in a hospital setting, verapamil but not propranolol significantly reduced the number of symptomatic and asymptomatic episodes of transient ischemia detected by continuous ECG monitoring. 24 These investigators concluded that verapamil was more effective than propranolol in patients with unstable angina.
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Figure 4. Effects of verapamil in patients with vasospastic angina. Average numbers of anginal episodes per week, nitroglycerin tablets consumed per week, and transient ST-segment deviations on ambulatory ECG monitoring in 16 patients during the fom 2-month treatment periods with placebo and verapamil are shown. All figmes are reported as the mean ± SEM. Treatment periods marked with the same letter (a or b) are statistically indistinguishable at p = 0.05; in turn, treatment periods with different letters are statistically distinguishable at p < 0.05. (From Johnson SM, Mauritson OR, Willerson JT, et al: A controlled trial of verapamil for Prinzmetal's variant angina. N Engl J Med 304:862-866, 1981; with permission.)
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Bala Subramanian and associates examined 22 patients with stable angina pectoris, comparing propranolol, 240 mg per day, to verapamil, 360 mg per day, in a double-blind, placebo-controlled trial. 2 Patients were only receiving the study drugs. Although these investigators found verapamil to prolong exercise time more effectively than did propranolol, they could discern no differences between the drugs in their favorable effects on transient ischemia detected on an ambulatory ECG. These same investigators compared nifedipine (30 mg per day) to verapamil (360 mg per day) in 28 patients with chronic stable angina, using a similar protocol. 3 Overall, they showed verapamil to be more effective than nifedipine in prolonging exercise time. However, unlike the previous study comparing propranolol to verapamil, they demonstrated that verapamil was more effective than nifedipine in reducing ischemic episodes on the ambulatory ECG. They also noted that some patients demonstrated increased ischemic episodes with nifedipine. The investigators proposed that the different effects of nifedipine and verapamil on episodes of ambulatory ST-segment depression were related to the different effects the two drugs have on heart rate. 3 In conclusion, all the published data would suggest that verapamil is
192
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an effective drug for reducing painful and silent episodes of transient ischemia in patients with variant angina (Prinzmetal type), unstable angina, and stable angina. Nifedipine The dihydropyridine compound nifedipine is a calcium antagonist similar in structure to the newer calcium antagonists (nitrendipine, nicardipine, nimodipine, nivaldipine, amlodipine, etc.). It is an extremely potent coronary and systemic vasodilator that is clinically useful in patients with hypertension and/or angina pectoris. It has a different hemodynamic profile than does verapamil, which relates to the increased sympathetic nervous system activity observed after nifedipine administration that is not seen with verapami1. 32 Nifedipine has been studied in patients with episodes of silent ischemia with conflicting reports regarding the drug's efficacy. As mentioned earlier, investigators in an uncontrolled study of patients with variant angina have shown a favorable effect of nifedipine on episodes of symptomatic and asymptomatic myocardial ischemia detected by continuous ambulatory ECG monitoring. 33 Oakley and colleagues treated six men with severe angina with propranolol or nifedipine, and propranolol plus nifedipine, while episodes of both painful and silent ECG ST-segment depressions were recorded by ambulatory monitoring. 23 All three treatment regimens reduced the total number of ischemic episodes, both painful and silent, but the combination of propranolol plus nifedipine was significantly superior to either drug alone. Dargie and associates evaluated the actions of nifedipine and propranolol and their combination in patients with stable angina pectoris. 8 They used doses of nifedipine of 30 and 60 mg per day and propranolol 240 and 480 mg per day, administered in three divided doses as monotherapies and in combination. They observed that both drugs in the doses administered improved exercise tolerance, reduced angina attack frequency, and reduced nitroglycerin consumption. Combination therapy was only slightly better than monotherapy. Sixty per cent of the ischemic episodes detected by ambulatory ECG monitoring in this study were silent. As shown in Figure 5, both propranolol and nifedipine monotherapies reduced episodes of STsegment depression, both painful and silent, in a similar fashion. Combination therapy was slightly better than either monotherapy. A single-blind, randomized, parallel design study of patients with stable angina undergoing ambulatory ECG monitoring found 12 patients with silent ischemic episodes at rest. 5 In six of seven patients, silent ischemia was reduced or eliminated while patients were taking nifedipine. In contrast, only one of five patients showed improvement while taking pindolol. In contrast to the studies showing favorable effects of nifedipine on silent myocardial ischemia, Bala Subramanian and associates, as noted previously, could find no favorable effect on this parameter using similar doses of nifedipine in patients with stable angina. 3 Similar technologies were used to assess transient myocardial ischemia in these studies, and
193
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Figure 5. Effects of nifedipine, propranolol, and their combination on the number of transient ST-segment deviations on ambulatory ECG monitoring in 16 patients. A, Episodes of ST-segment depression on placebo (PI), nifedipine 30 mg per day (Nw), and nifedipine 60 mg per day (N 6o )' B, Episodes of ST-segment depression on ambulatory monitoring on placebo (PI), propranolol 240 mg per day (1'210), and propranolol 480 mg per day (P4S0). C, Episodes of ST-segment depression on ambulatory monitoring on placebo (PI), nifedipine 30 mg per day plus propranolol 240 mg per day (N 3o + 1'240), and nifedipine 60 mg per day and propranolol 480 mg per day (1\60 + 1'480). Values are mean ± SEM. (From Dargie HJ, Lynch PG, Krikler DM, et al: Nifedipine and propranolol: A beneficial drug interaction. Am J Med 71:676-682, 1981; with permission.)
heart rates on nifedipine therapy were similar. The explanation for this difference is not yet apparent. In conclusion, nifedipine appears to be effective when used alone or in combination with f3-blockers for silent myocardial ischemia; however, this observation has not been a universal one; more clinical studies with the drug are necessary. Diltiazem The benzothiazepine compound diltiazem is structurally unrelated to other vasodilators. It has different hemodynamic actions than nifedipine and different electrophysiologic actions than nifedipine and verapamil. 32 The drug is clinically useful in patients with angina and/or hypertension and appears to be useful in reducing morbidity and mortality in patients who survived subendocardial wall myocardial infarction. There is a paucity of data regarding the effects of diltiazem on silent myocardial ischemia. Frishman and colleagues studied the effects of diltiazem on the ambulatory ECG designed for ST-segment analysis. l5 In this placebo-controlled, double-blind study of 20 patients with chronic stable angina, diltiazem, 360 mg per day, was found to reduce episodes of angina and nitroglycerin consumption, while improving exercise tolerance, when compared to placebo therapy. Diltiazem was found to reduce the number of episodes of silent ischemia detected over a 24-hour period. The drug also reduced the length of the individual episodes. Combination therapy with nifedipine provided no further advantage. With abrupt withdrawal of active therapy, patients returned to their pretreatment states with no evidence of an overshoot. In conclusion, diltiazem appears to be effective in the management of silent and painful ischemic episodes in patients with chronic stable angina. There is no information yet available regarding the effects of diltiazem on
194
WILLlAM
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FRISIIMAN AND MARK TEICIIEH
Table 1. Effects of Antianginal Drug Therapies on Silent Ischemia in Variolls Angina Syndromes VARIAKT DRUG
Nitrates Nitroglycerin Isosorbide dinitrate Nitroglycerin patch j3-blocker/nitrate/calcium blocker combination j3-Blockers Atenolol Pindolol Propranolol Propranolollnifedipine combination Propranolollnifedipine/nitrate combination (X- j3-Blocker Labetalol Calcium Blockers Diltiazem Diltiazem/nifedipine combination Nifedipine Verapamil A ntiplatelet Agent Aspirin -
=
STABLE
UNSTABLE
(PHlKZMETALj
ANGINA
ANGINA
ANGINA
BEFERENCES
+
26,29 11 30, 31 27
+ +
NAD NAD NAD NAD
+
NAD NAD NAD NAD NAD
28 5,28 21, 23 8,23 18
+
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NAD
27
+ +
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NAD NAD NAD
15 15 3,5,8, 23 2, 3, 20, 24, 33
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NAD
+
+1NAD
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+
NAD
NAD = no published data available; no effect.
+
+
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+
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NAD
+
NAD favorable effect; +1-
4 conflicting reports;
silent ischemic episodes in patients with variant and unstable angina syndromes. COMBINATION DRUG THERAPY
As described throughout this article, antianginal drugs used in combination may provide greater efficacy in managing painful and silent ischemic episodes than with monotherapy. More work needs to be done, however, comparing different combination regimens for management of myocardial ischemia. ANTIPLATELET DRUGS
Antiplatelet drugs have been suggested for the management of ischemia because platelet activation may be playing an important role in various forms of angina. 15 Aspirin
Aspirin is now approved for the management of unstable angina and for prolonging life in survivors of acute myocardial infarction. 16 Cherchia
ANTIANCINAL DRUG TIlERAPY FOR SILENT MYOCARDIAL ISCHEMIA
195
and colleagues examined the effects of intravenously administered aspirin in patients with vasospastic angina and concluded that the drug was not efiective in preventing myocardial ischemia, including painless episodes.4 In the study using ambulatory ECG recordings, they observed 129 ischemic episodes before aspirin (26 with pain and 103 without pain) and 146 episodes after aspirin (32 with pain and 114 without pain). Similarly, the duration of ischemic episodes did not change with administration of aspirin. The aspirin dose reduced thromboxane ~2levels to 3 per cent of control levels. Repeated ambulatory monitoring during management with combined high-dose nitrates and calcium antagonists showed that the number of ischemic episodes was reduced to less than 20 per cent of those recorded during aspirin administration. SUMMARY Many of the available nitrate preparations, ~-adrenergic blockers, and calcium antagonists appear to be useful in patients with painful and silent ischemic episodes detected on the ECG (Table 1). More controlled studies need to be done using standardized methodologies for assessing silent myocardial ischemia, to evaluate and compare the different antianginal medications. It is fortunate, however, that the nitrates, ~-blockers, and calcium antagonists, used alone and in combination, appear to have favorable effects not only on painful ischemic episodes but also on those ischemic episodes not associated with pain. REFERENCES
J: The use of nitroglycerin and long-acting nitrates in angina pectoris. In Weiner D, Frishman WH (eds): Therapy of Angina Pectoris. New York, Marcel Dekker, 1986, pp 53~82 Bala Subramanian V, Bowles MJ, Davies A, Raftery E: Calcium channel blockade as primary therapy for stable angina pectoris. A double-blind, placebo-controlled comparison of verapamil and propranolol. Am J Cardiol 50:1158~1l63, 1982 Bala Subramanian V, Bowles MJ, Khurmi J\'S, et al: Rationale for the choice of calcium antagonists in chronic stable angina: An objective double-blind, placebo-controlled comparison ofnifedipine and verapamil. Am J CardioI50:1173~1l79, 1982 Chierchia S, DeCaterina R, Crea F, et al: Failure of thromboxane A2 blockade to prevent attacks of vasospastic angina. Circulation 66:702~ 705, 1982 Cocco G, Strozzi C, Chu D, et al: Therapeutic effects of pindolol and nifedipine in patients with stable angina pectoris and asymptomatic resting ischemia. Eur J Cardiol 1O:59~69, 1979 Cohn PF: Silent myocardial ischemia: Dimensions of the problem in patients with and without pain. Am J Med 80(Suppl 4C):3~8, 1986 Cohn PF, Brown El, Swinford R, Atkins H: Effect of beta blockade on silent regional left ventricular wall motion abnormalities. Am J Cardiol 57:521~526, 1986 Dargie HJ, Lynch PG, Krikler DM, et al: ;\Iifedipine and propranolol: A beneficial drug interaction. Am J Med 71:676-682, 1981 Deanfield JE, Shea MJ, Ribiero P, et al: Transient ST-segment depression as a marker of myocardial ischemia during daily life. Am J Cardiol 54:119.5~2000, 1984 Deanfield JE, Shea MJ, Selwyn AP: Clinical evaluation of transient myocardial ischemia during daily life. Am J Med 79(Sllppl 3A):18~24, 1985
1. Abrams
2. 3. 4. 5. 6. 7. 8. 9. 10.
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FRISHMAN AND ~ARK TEICHER
11. Distante A, Maseri A, Severi S: Management of vasospastic angina at rest with continuous infusion of isosorbide dinitrate: A double crossover study in a coronary care unit. Am J CardioI44:533-539, 1979 12. Frishman WHo The alpha-adrenergic blocking drugs. In Cardiovascular Drug Therapy. Chicago, Year Book Medical Publishers, 1986, pp 137-152 13. Frishman WHo Beta-adrenergic blockade for the treatment of angina pectoris. In Weiner D, Frishman WH (eds): Therapy of Angina Pectoris. New York, Marcel Dekker, 1986, pp 83-144 14. Frishman WHo Multifactorial actions of beta-adrenergic blocking drugs in ischemic heart disease: Current concepts. Circulation 67:111-118, 1983 15. Frishman W, Charlap S, Kimmel B, et al: Diltiazem compared to nifedipine and combination treatment in stable angina (abstract). Clin Res 34:398A, 1986 16. Frishman WH, Miller KP: Platelets and anti-platelet therapy in ischemic heart disease. Curr Prob Cardiol11:71-136, 1986 17. Frishman WH, Strom JA, Kirschner M, et al: Labetalol therapy in patients with systemic hypertension and angina pectoris: Effects of combined alpha and beta adrenoceptor blockade. Am J CardioI48:917-928, 1981 18. Gottlieb SO, Weisfeldt ML, Ouyang P, et al: Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: A randomized, double-blind, placebo-controlled trial. Circulation 73:331-337, 1986 19. Gottlieb SO, Weisfeldt ML, Ouyang P, et al: Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med 314:1214-1219, 1986 20. Johnson SM, Mauritson DR, Willerson JT, Hillis LD: A controlled trial of verapamil for Prinzmetal's variant angina. N Engl J Med 304:862-866, 1981 21. Khurmi NS, Bowles MJ, O'Hara MJ, Raftery EB: Effect of propranolol on indices of intermittent myocardial ischemia, assessed by exercise testing and ambulatory STsegment monitoring. Clin Cardiol 9:391-397, 1986 22. Maseri A, Chierchia S, Davies G, Glazier J: Mechanisms of ischemic cardiac pain and silent myocardial ischemia. Am J Med 79(Suppl 3A):7-11, 1985 23. Oakley GDG, Fox KM, Dargie HI, Selwyn AP: Objective assessment of treatment in severe angina. Br Med J 289:1540, 1979 24. Parodi 0, Simonetti I, L'Abbate A, et al: Verapamil versus propranolol for angina at rest. Am J Cardiol 50:923-928, 1982 25. Pepine CJ: Clinical aspects of silent myocardial ischemia in patients with angina and other forms of coronary heart disease. Am J Med 80(Suppl 4C):25-34, 1986 26. Pepine CJ, Feldman RL, Ludbrook P, et al: Left ventricular dyskinesia reversed by intravenous nitroglycerin: A manifestation of silent myocardial ischemia. Am J Cardiol 58:38B-42B, 1986 27. Quyyumi AA, Wright C, Mockus L, et al: Effects of combined alpha- and betaadrenoceptor blockade in patients with angina pectoris: A double-blind study comparing labetalol with placebo. Br Heart J 53:47-52, 1985 28. Quyyumi AA, Wright C, Mockus L, et al: Effects of partial agonist activity in betablockers in severe angina. Br Med J 289:951-953, 1984 29. Schang SJ, Pepine CJ: Transient asymptomatic ST-segment depression during daily activity. Am J Cardiol 39:396-402, 1977 30. Shell WE: Mechanisms and therapy of silent myocardial ischemia and the effects of transdermal nitroglycerin. Am J Cardiol 56:231-271, 1985 31. Shell WE, Kivowitz CF, Rubins SB, See J: Mechanisms and therapy of silent myocardial ischemia: The effect of transdermal nitroglycerin. Am Heart J 112:222-229, 1986 32. Weiner D: Calcium antagonists for the treatment of angina pectoris. In Weiner D, Frishman WH (eds): Therapy of Angina Pectoris. New York, Marcel Dekker, 1986, pp 145-204 33. Winniford MD, Johnson SJ, Mauritson DR, et al: Verapamil therapy for Prinzmetal's angina: Comparison with placebo and nifedipine. Am J Cardiol 50:913-918, 1982 Hospital of the Albert Einstein College of Medicine 1825 Eastchester Road Bronx, NY 10461
Pharmacotherapy I
0025-7125/88 $0.00 + .20
Antianginal Drug Therapy for Silent Myocardial Ischemia
William H. Frishman, MD,* and Mark Teicher, MDt
Nitrates, 1 ~-adrenergic blocking drugs, 13 a- ~-adrenergic blocking drugs,17 and calcium antagonists,32 used alone and in combination, have been shown to be effective in the management of symptomatic ischemic heart disease by relieving angina pectoris and reducing the intensity of associated myocardial ischemia. Recently, close attention has been given to the problem of silent ischemia, or ischemia without symptoms. This condition was recognized more than a half century ago when some asymptomatic patients were shown to have reversible electrocardiogram (ECG) changes suggestive of myocardial ischemia during the Master's two-step examination. Recently, technology has been developed to identifY asymptomatic transient ischemic episodes using the ambulatory ECG. 9 Positron emission imaging techniques have validated that these silent ischemic episodes are indicative of true myocardial ischemia.lO The pioneering contributions of Cohn, Maseri, Pepine, Deanfield, Selwyn, and their associates have clearly demonstrated the frequent occurrence of silent ischemic episodes in patients with symptomatic angina and coronary artery disease documented by angiography. ri, 22, 25, 29 Gottlieb and Gerstenblith have demonstrated the unfavorable prognosis of continued silent ischemia in patients with unstable angina. 19 Thus, all antianginal therapies must also be shown to be anti-ischemic if the problem of silent ischemia is to be dealt with in a satisfactory manner. M ultiple studies now available have shown favorable effects of nitrates, ~-adrenergic blockers, 26, 30 a- ~-adrenergic blockers,31 and calcium antagonists on episodes of asymptomatic transient myocardial ischemia observed by ambulatory ECG monitoring in patients with angina and/or coronary 'Professor of Medicine, Albert Einstein College of Medicine; and Director of Medicine, Hospital of the Albert Einstein College of Medicine, Bronx, New York tFellow, Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
Adapted from Frishman WH, Teicher M: Antianginal drug therapy for silent myocardial ischemia, Am Heart J 114:140-147, 1987; with permission Medical Clinics of North America-Vo!' 72, No, 1, January 1988
185
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WILLIA\!
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artery disease. 2.3 This article reviews the clinical experiences with these drugs in silent myocardial ischemia. NITRATES Nitroglycerin Nitroglycerin and sustained-release nitrate preparations have been shown to be successful in acute prophylactic therapy against painful transient myocardial ischemia-angina pectoris. 1 In patients with stable angina pectoris, Schang and Pe pine found that the hourly sublingual administration of nitroglycerin could prevent or markedly reduce the frequency of symptomatic (silent) ischemic episodes detected on an ambulatory monitoring ECG device. 29 They also observed that only 25 per cent of the recorded ischemic episodes in their study were related to pain. The asymptomatic ischemic episodes recorded on the ECG occurred at heart rates and activity levels well below those expected to cause ischemia. Pepine and associates recently observed that in patients with left ventricular motion abnormalities on left ventriculography and with no associated pain, low-dose intravenous nitroglycerin could favorably reverse these changes. 26 These painless regional ventricular contraction abnormalities were thought to be related to asymptomatic myocardial ischemia, because all the patients with these changes had important coronary artery disease in the distribution of the abnormally contracting myocardial segment or wall motion activity. The success of nitroglycerin, they concluded, was related to successful management of silent myocardial ischemia. Shell and colleagues reported the results of an open-label study evaluating the effects of transdermal nitroglycerin on painful and silent myocardial ischemia (ECG evidence of ST segment depression), determined from a specialized 24-hour ambulatory ECG system. 30. 31 Eight patients already on l3-blockers were up-titrated with larger patch doses of nitroglycerin until all symptomatic episodes were abolished. Patients received a mean nitroglycerin patch dose of 10.4 mg per 24 hours (range, 5 to 20 mg). There was a significant reduction in the frequency of ischemic events (80 per cent of ischemic episodes were noted to be painless) (Fig. 1). The duration of ischemia over 24 hours was also reduced from 95.8 min per 24 hours to 17 min per 24 hours with nitroglycerin therapy (Fig. 2). These investigators concluded that transdermal nitroglycerin patches were useful not only for the treatment of angina pectoris but also for the more commonly observed painless ischemic episodes. The long-term effects of nitroglycerin therapy were not evaluated in this study. These same investigators are now performing a double-blind, placebo-controlled crossover trial to confirm the findings of their initial short-term open-label study. Isosorbide Dinitrate The anti-ischemic effects of isosorbide dinitrate were evaluated in 12 patients who had frequent transient myocardial ischemic episodes at rest,
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Figure 1. Effect of transdermal nitroglycerin on number of ischemic events in patients already on f3-blockers. The number includes both symptomatic and asymptomatic events (n = 8). A significant reduction in events per 24 hours is observed with nitroglycerin. (From Shell WE, Kivowitz CF, Rubins SB, et al: Mechanisms and therapy of silent myocardial ischemia: The effect of transdermal nitroglycerin. Am Heart J 112:222-229, 1986; with permission.)
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with a variable degree of coronary atherosclerosis and vasospastic angina. II In the trial, constant blood levels of isosorbide were administered intravenously for 12 to 24 hours, alternating with equal periods of normal saline administration. During the placebo periods, continuous ECG monitoring revealed frequent episodes of ST segment elevation and depression, most of them without associated pain. These ischemic episodes were significantly reduced or abolished with isosorbide. The authors concluded that isosorbide dinitrate was useful for managing symptomatic and asymptomatic ischemic episodes in patients with vasospastic angina.
100
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Figure 2. Effect of transdermal nitroglycerin duration of ischemia per 24 hours. A significant reduction in ischemia duration is observed with nitroglycerin (n = 8). (From Shell WE, Kivowitz CF, Rubins SB, et al: Mechanisms and therapy of silent myocardial ischemia: The effect of transdennal nitroglycerin. Am Heart J 112:222229, 1986; with permission.)
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Conclusion From preliminary studies, nitrates appear to be effective drugs for the management of both painful and silent ischemic episodes. However, studies with more rigid study designs using long-term oral treatment protocols need to be done. ADRENERGIC BLOCKERS a-Adrenergic Blockers Although a-blockers are vasodilators, their clinical utility in symptomatic ischemia is not yet defined. 12 There are no reports yet describing effects of a-adrenergic blockers on silent myocardial ischemia. I3-Adrenergic Blockers For more than 20 years,13 l3-adrenergic blockers have been a clinical mainstay oflong-term antianginal therapy. Beneficial effects on stable angina are well known, but some controversy was raised regarding their utility as monotherapy in vasospastic angina syndromes. 14 Certainly, in combination with nitrates and calcium antagonists, their usefulness in all forms of angina has been proven beyond question. 13 As will be discussed later in the section on calcium antagonists, propranolol as monotherapy has been shown to be as effective as verapamil and nifedipine in reducing both painful and silent ischemic episodes (evidenced on the ambulatory ECG) in patients with angina pectoris. When combined with nifedipine, the combination appears more effective than with either drug alone. Seventy-three patients, aged 41 to 75 years, with established stable exertional angina pectoris, were studied in a double-blind fashion to confirm the efficacy of 80 mg propranolol administered three times daily and to examine its effects on ST segment changes in the ECG by ambulatory ST segment monitoring and exercise testing, using on-line computer analysis. 21 During ambulatory monitoring, episodes of ST segment depression were significantly reduced by propranolol compared with placebo treatment. The total duration of ST segment depression was also Significantly reduced by active treatment, and the maximal depth of ST segment depressiOll was reduced. Exercise time was improved by propranolol. The authors concluded that propranolol was an effective antianginal agent that also improves the ST segment changes during controlled, as well as uncontrolled, conditions related to the drug's ability to lower the heart rate and rate-pressure product. In another study, 81 patients with unstable angina were treated with maximal nitrate and calcium channel blocker (nifedipine) therapy, where propranolol or placebo was added as additional treatment. 18 There was a greater reduction in symptomatic episodes of angina and nitroglycerin consumption with propranolol. Continuous ECG recordings for ischemic ST segment changes revealed fewer daily ischemic episodes (painful or silent) in the propranolol group than in the placebo group and a shorter
189
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Figure 3. Effects of propranolol (n = 42) and placebo (n = 39) in patients with unstable angina already receiving nitrates and l3-blockers. The number and duration of ischemic episodes per 24 hours as detected by continuous two-channel electrocardiograph monitoring during the first two days of study are shown. There were significantly fewer episodes and a shorter daily duration of ischemia in the propranolol group. (From Gottlieb SO, Weisfeldt ML, Ouyang P, et al: Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: A randomized, double-blind, placebo-controlled trial. Circulation 73:331-337, 1986; with permission.)
duration of ischemia (Fig. 3). The authors concluded that the addition of propranolol in patients with unstable angina receiving nitrates and nifedipine reduces the frequency and duration of symptomatic and silent ischemic episodes. Cohn and colleagues studied the effects of propranolol in 11 patients with coronary artery disease and ECG evidence of silent myocardial ischemia on exercise testing. 7 Using gated radionuclide imaging of the left ventricle, they demonstrated improved global ventricular functioning with [3-blocker therapy (propranolol, timolol) compared to baseline. They concluded that [3-adrenergic blockade can effectively improve the abnormalities in exercise left ventricular function in patients with coronary artery disease and silent myocardial ischemia. The antianginal effects of atenolol and pindolol were compared in patients with effort angina and nocturnal angina. 28 Pindolol, 5 mg three times daily, and atenolol, 100 mg daily, were given for 5 days each in a double-blind, randomized manner. Daytime and nocturnal resting heart rates and the frequency of angina were significantly reduced by atenolol compared to pindolol. The duration of exercise was significantly increased, and the frequency, duration, and magnitude of daytime and nocturnal episodes of ST segment depression on ambulatory ECG monitoring were reduced by atenolol. The investigators concluded that resting heart rate reduction is important in the management of effort and nocturnal angina and that partial agonist activity in a [3-blocker may not be a desirable property. (X-
[3-Adrenergic Blockers
Labetalol, the first (X- [3-adrenergic blocker marketed in the world, has been shown to be effective in the treatment of hypertensive patients with
190
WILLlAM
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angina pectoris by lowering blood pressure and reducing anginal episodes. 17 Quyyumi and associates compared placebo to labetalol in patients with chronic stable angina pectoris. 27 They observed that compared to placebo, labetalol reduced the frequency of angina and exercise tolerance far longer. The drug reduced heart rate and the frequency and duration of ST segment depressions on ambulatory monitoring by 56 and 73 per cent, respectively, compared to placebo. Conclusion Most [3-adrenergic blockers and the (X- [3-blocker labetalol appear to be effective in reducing both painful and silent ischemic episodes, when used alone or in combination with other antianginal drugs. CALCIUM ANTAGONISTS Verapamil The calcium antagonist verapamil is similar in structure to papaverine.
It has vasodilator and electrophysiologic activities that have allowed the
drug to be used in patients with supraventricular arrhythmias, stable and unstable angina, and systemic hypertension. 32 Johnson and colleagues studied 16 patients with documented variant angina (Prinzmetal type) in a placebo-controlled study of verapamil. 20 This study was complicated by the fact that patients were on concomitant therapy that included isosorbide dinitrate and digoxin. Patients were randomized to receive either verapamil or placebo for 4 months after a 1month placebo run-in period. The patients were then crossed over to receive the other regimen for an additional 4 months. Episodes of angina, nitroglycerin consumption, and transient ST-segment shifts detected on a weekly ambulatory ECG examination were assessed. As shown in Figure 4, episodes of angina per week and nitroglycerin consumed per week were reduced, as were transient ischemic ECG changes, many of which were unassociated with pain. The same group of investigators compared the effects of nifedipine to verapamil in a similar group of patients with variant angina ..33 This was not a direct comparison though, because verapamil was administered as part of a blinded, placebo-controlled study, whereas nifedipine was administered in open-label fashion to patients who had already completed the blinded trial. In comparing the effects of the two drugs, both drugs appeared equally effective in reducing angina attacks, nitroglycerin consumption, and transient ischemic episodes observed on a weekly ambulatory ECG examination. In a study of patients with unstable vasospastic angina at rest who were studied in a hospital setting, verapamil but not propranolol significantly reduced the number of symptomatic and asymptomatic episodes of transient ischemia detected by continuous ECG monitoring. 24 These investigators concluded that verapamil was more effective than propranolol in patients with unstable angina.
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Figure 4. Effects of verapamil in patients with vasospastic angina. Average numbers of anginal episodes per week, nitroglycerin tablets consumed per week, and transient ST-segment deviations on ambulatory ECG monitoring in 16 patients during the fom 2-month treatment periods with placebo and verapamil are shown. All figmes are reported as the mean ± SEM. Treatment periods marked with the same letter (a or b) are statistically indistinguishable at p = 0.05; in turn, treatment periods with different letters are statistically distinguishable at p < 0.05. (From Johnson SM, Mauritson OR, Willerson JT, et al: A controlled trial of verapamil for Prinzmetal's variant angina. N Engl J Med 304:862-866, 1981; with permission.)
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Bala Subramanian and associates examined 22 patients with stable angina pectoris, comparing propranolol, 240 mg per day, to verapamil, 360 mg per day, in a double-blind, placebo-controlled trial. 2 Patients were only receiving the study drugs. Although these investigators found verapamil to prolong exercise time more effectively than did propranolol, they could discern no differences between the drugs in their favorable effects on transient ischemia detected on an ambulatory ECG. These same investigators compared nifedipine (30 mg per day) to verapamil (360 mg per day) in 28 patients with chronic stable angina, using a similar protocol. 3 Overall, they showed verapamil to be more effective than nifedipine in prolonging exercise time. However, unlike the previous study comparing propranolol to verapamil, they demonstrated that verapamil was more effective than nifedipine in reducing ischemic episodes on the ambulatory ECG. They also noted that some patients demonstrated increased ischemic episodes with nifedipine. The investigators proposed that the different effects of nifedipine and verapamil on episodes of ambulatory ST-segment depression were related to the different effects the two drugs have on heart rate. 3 In conclusion, all the published data would suggest that verapamil is
192
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FRlSH\lAN A'JD ""IABK TEICHEB
an effective drug for reducing painful and silent episodes of transient ischemia in patients with variant angina (Prinzmetal type), unstable angina, and stable angina. Nifedipine The dihydropyridine compound nifedipine is a calcium antagonist similar in structure to the newer calcium antagonists (nitrendipine, nicardipine, nimodipine, nivaldipine, amlodipine, etc.). It is an extremely potent coronary and systemic vasodilator that is clinically useful in patients with hypertension and/or angina pectoris. It has a different hemodynamic profile than does verapamil, which relates to the increased sympathetic nervous system activity observed after nifedipine administration that is not seen with verapami1. 32 Nifedipine has been studied in patients with episodes of silent ischemia with conflicting reports regarding the drug's efficacy. As mentioned earlier, investigators in an uncontrolled study of patients with variant angina have shown a favorable effect of nifedipine on episodes of symptomatic and asymptomatic myocardial ischemia detected by continuous ambulatory ECG monitoring. 33 Oakley and colleagues treated six men with severe angina with propranolol or nifedipine, and propranolol plus nifedipine, while episodes of both painful and silent ECG ST-segment depressions were recorded by ambulatory monitoring. 23 All three treatment regimens reduced the total number of ischemic episodes, both painful and silent, but the combination of propranolol plus nifedipine was significantly superior to either drug alone. Dargie and associates evaluated the actions of nifedipine and propranolol and their combination in patients with stable angina pectoris. 8 They used doses of nifedipine of 30 and 60 mg per day and propranolol 240 and 480 mg per day, administered in three divided doses as monotherapies and in combination. They observed that both drugs in the doses administered improved exercise tolerance, reduced angina attack frequency, and reduced nitroglycerin consumption. Combination therapy was only slightly better than monotherapy. Sixty per cent of the ischemic episodes detected by ambulatory ECG monitoring in this study were silent. As shown in Figure 5, both propranolol and nifedipine monotherapies reduced episodes of STsegment depression, both painful and silent, in a similar fashion. Combination therapy was slightly better than either monotherapy. A single-blind, randomized, parallel design study of patients with stable angina undergoing ambulatory ECG monitoring found 12 patients with silent ischemic episodes at rest. 5 In six of seven patients, silent ischemia was reduced or eliminated while patients were taking nifedipine. In contrast, only one of five patients showed improvement while taking pindolol. In contrast to the studies showing favorable effects of nifedipine on silent myocardial ischemia, Bala Subramanian and associates, as noted previously, could find no favorable effect on this parameter using similar doses of nifedipine in patients with stable angina. 3 Similar technologies were used to assess transient myocardial ischemia in these studies, and
193
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Figure 5. Effects of nifedipine, propranolol, and their combination on the number of transient ST-segment deviations on ambulatory ECG monitoring in 16 patients. A, Episodes of ST-segment depression on placebo (PI), nifedipine 30 mg per day (Nw), and nifedipine 60 mg per day (N 6o )' B, Episodes of ST-segment depression on ambulatory monitoring on placebo (PI), propranolol 240 mg per day (1'210), and propranolol 480 mg per day (P4S0). C, Episodes of ST-segment depression on ambulatory monitoring on placebo (PI), nifedipine 30 mg per day plus propranolol 240 mg per day (N 3o + 1'240), and nifedipine 60 mg per day and propranolol 480 mg per day (1\60 + 1'480). Values are mean ± SEM. (From Dargie HJ, Lynch PG, Krikler DM, et al: Nifedipine and propranolol: A beneficial drug interaction. Am J Med 71:676-682, 1981; with permission.)
heart rates on nifedipine therapy were similar. The explanation for this difference is not yet apparent. In conclusion, nifedipine appears to be effective when used alone or in combination with f3-blockers for silent myocardial ischemia; however, this observation has not been a universal one; more clinical studies with the drug are necessary. Diltiazem The benzothiazepine compound diltiazem is structurally unrelated to other vasodilators. It has different hemodynamic actions than nifedipine and different electrophysiologic actions than nifedipine and verapamil. 32 The drug is clinically useful in patients with angina and/or hypertension and appears to be useful in reducing morbidity and mortality in patients who survived subendocardial wall myocardial infarction. There is a paucity of data regarding the effects of diltiazem on silent myocardial ischemia. Frishman and colleagues studied the effects of diltiazem on the ambulatory ECG designed for ST-segment analysis. l5 In this placebo-controlled, double-blind study of 20 patients with chronic stable angina, diltiazem, 360 mg per day, was found to reduce episodes of angina and nitroglycerin consumption, while improving exercise tolerance, when compared to placebo therapy. Diltiazem was found to reduce the number of episodes of silent ischemia detected over a 24-hour period. The drug also reduced the length of the individual episodes. Combination therapy with nifedipine provided no further advantage. With abrupt withdrawal of active therapy, patients returned to their pretreatment states with no evidence of an overshoot. In conclusion, diltiazem appears to be effective in the management of silent and painful ischemic episodes in patients with chronic stable angina. There is no information yet available regarding the effects of diltiazem on
194
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Table 1. Effects of Antianginal Drug Therapies on Silent Ischemia in Variolls Angina Syndromes VARIAKT DRUG
Nitrates Nitroglycerin Isosorbide dinitrate Nitroglycerin patch j3-blocker/nitrate/calcium blocker combination j3-Blockers Atenolol Pindolol Propranolol Propranolollnifedipine combination Propranolollnifedipine/nitrate combination (X- j3-Blocker Labetalol Calcium Blockers Diltiazem Diltiazem/nifedipine combination Nifedipine Verapamil A ntiplatelet Agent Aspirin -
=
STABLE
UNSTABLE
(PHlKZMETALj
ANGINA
ANGINA
ANGINA
BEFERENCES
+
26,29 11 30, 31 27
+ +
NAD NAD NAD NAD
+
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28 5,28 21, 23 8,23 18
+
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NAD
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NAD NAD NAD
15 15 3,5,8, 23 2, 3, 20, 24, 33
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NAD = no published data available; no effect.
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4 conflicting reports;
silent ischemic episodes in patients with variant and unstable angina syndromes. COMBINATION DRUG THERAPY
As described throughout this article, antianginal drugs used in combination may provide greater efficacy in managing painful and silent ischemic episodes than with monotherapy. More work needs to be done, however, comparing different combination regimens for management of myocardial ischemia. ANTIPLATELET DRUGS
Antiplatelet drugs have been suggested for the management of ischemia because platelet activation may be playing an important role in various forms of angina. 15 Aspirin
Aspirin is now approved for the management of unstable angina and for prolonging life in survivors of acute myocardial infarction. 16 Cherchia
ANTIANCINAL DRUG TIlERAPY FOR SILENT MYOCARDIAL ISCHEMIA
195
and colleagues examined the effects of intravenously administered aspirin in patients with vasospastic angina and concluded that the drug was not efiective in preventing myocardial ischemia, including painless episodes.4 In the study using ambulatory ECG recordings, they observed 129 ischemic episodes before aspirin (26 with pain and 103 without pain) and 146 episodes after aspirin (32 with pain and 114 without pain). Similarly, the duration of ischemic episodes did not change with administration of aspirin. The aspirin dose reduced thromboxane ~2levels to 3 per cent of control levels. Repeated ambulatory monitoring during management with combined high-dose nitrates and calcium antagonists showed that the number of ischemic episodes was reduced to less than 20 per cent of those recorded during aspirin administration. SUMMARY Many of the available nitrate preparations, ~-adrenergic blockers, and calcium antagonists appear to be useful in patients with painful and silent ischemic episodes detected on the ECG (Table 1). More controlled studies need to be done using standardized methodologies for assessing silent myocardial ischemia, to evaluate and compare the different antianginal medications. It is fortunate, however, that the nitrates, ~-blockers, and calcium antagonists, used alone and in combination, appear to have favorable effects not only on painful ischemic episodes but also on those ischemic episodes not associated with pain. REFERENCES
J: The use of nitroglycerin and long-acting nitrates in angina pectoris. In Weiner D, Frishman WH (eds): Therapy of Angina Pectoris. New York, Marcel Dekker, 1986, pp 53~82 Bala Subramanian V, Bowles MJ, Davies A, Raftery E: Calcium channel blockade as primary therapy for stable angina pectoris. A double-blind, placebo-controlled comparison of verapamil and propranolol. Am J Cardiol 50:1158~1l63, 1982 Bala Subramanian V, Bowles MJ, Khurmi J\'S, et al: Rationale for the choice of calcium antagonists in chronic stable angina: An objective double-blind, placebo-controlled comparison ofnifedipine and verapamil. Am J CardioI50:1173~1l79, 1982 Chierchia S, DeCaterina R, Crea F, et al: Failure of thromboxane A2 blockade to prevent attacks of vasospastic angina. Circulation 66:702~ 705, 1982 Cocco G, Strozzi C, Chu D, et al: Therapeutic effects of pindolol and nifedipine in patients with stable angina pectoris and asymptomatic resting ischemia. Eur J Cardiol 1O:59~69, 1979 Cohn PF: Silent myocardial ischemia: Dimensions of the problem in patients with and without pain. Am J Med 80(Suppl 4C):3~8, 1986 Cohn PF, Brown El, Swinford R, Atkins H: Effect of beta blockade on silent regional left ventricular wall motion abnormalities. Am J Cardiol 57:521~526, 1986 Dargie HJ, Lynch PG, Krikler DM, et al: ;\Iifedipine and propranolol: A beneficial drug interaction. Am J Med 71:676-682, 1981 Deanfield JE, Shea MJ, Ribiero P, et al: Transient ST-segment depression as a marker of myocardial ischemia during daily life. Am J Cardiol 54:119.5~2000, 1984 Deanfield JE, Shea MJ, Selwyn AP: Clinical evaluation of transient myocardial ischemia during daily life. Am J Med 79(Sllppl 3A):18~24, 1985
1. Abrams
2. 3. 4. 5. 6. 7. 8. 9. 10.
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11. Distante A, Maseri A, Severi S: Management of vasospastic angina at rest with continuous infusion of isosorbide dinitrate: A double crossover study in a coronary care unit. Am J CardioI44:533-539, 1979 12. Frishman WHo The alpha-adrenergic blocking drugs. In Cardiovascular Drug Therapy. Chicago, Year Book Medical Publishers, 1986, pp 137-152 13. Frishman WHo Beta-adrenergic blockade for the treatment of angina pectoris. In Weiner D, Frishman WH (eds): Therapy of Angina Pectoris. New York, Marcel Dekker, 1986, pp 83-144 14. Frishman WHo Multifactorial actions of beta-adrenergic blocking drugs in ischemic heart disease: Current concepts. Circulation 67:111-118, 1983 15. Frishman W, Charlap S, Kimmel B, et al: Diltiazem compared to nifedipine and combination treatment in stable angina (abstract). Clin Res 34:398A, 1986 16. Frishman WH, Miller KP: Platelets and anti-platelet therapy in ischemic heart disease. Curr Prob Cardiol11:71-136, 1986 17. Frishman WH, Strom JA, Kirschner M, et al: Labetalol therapy in patients with systemic hypertension and angina pectoris: Effects of combined alpha and beta adrenoceptor blockade. Am J CardioI48:917-928, 1981 18. Gottlieb SO, Weisfeldt ML, Ouyang P, et al: Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: A randomized, double-blind, placebo-controlled trial. Circulation 73:331-337, 1986 19. Gottlieb SO, Weisfeldt ML, Ouyang P, et al: Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med 314:1214-1219, 1986 20. Johnson SM, Mauritson DR, Willerson JT, Hillis LD: A controlled trial of verapamil for Prinzmetal's variant angina. N Engl J Med 304:862-866, 1981 21. Khurmi NS, Bowles MJ, O'Hara MJ, Raftery EB: Effect of propranolol on indices of intermittent myocardial ischemia, assessed by exercise testing and ambulatory STsegment monitoring. Clin Cardiol 9:391-397, 1986 22. Maseri A, Chierchia S, Davies G, Glazier J: Mechanisms of ischemic cardiac pain and silent myocardial ischemia. Am J Med 79(Suppl 3A):7-11, 1985 23. Oakley GDG, Fox KM, Dargie HI, Selwyn AP: Objective assessment of treatment in severe angina. Br Med J 289:1540, 1979 24. Parodi 0, Simonetti I, L'Abbate A, et al: Verapamil versus propranolol for angina at rest. Am J Cardiol 50:923-928, 1982 25. Pepine CJ: Clinical aspects of silent myocardial ischemia in patients with angina and other forms of coronary heart disease. Am J Med 80(Suppl 4C):25-34, 1986 26. Pepine CJ, Feldman RL, Ludbrook P, et al: Left ventricular dyskinesia reversed by intravenous nitroglycerin: A manifestation of silent myocardial ischemia. Am J Cardiol 58:38B-42B, 1986 27. Quyyumi AA, Wright C, Mockus L, et al: Effects of combined alpha- and betaadrenoceptor blockade in patients with angina pectoris: A double-blind study comparing labetalol with placebo. Br Heart J 53:47-52, 1985 28. Quyyumi AA, Wright C, Mockus L, et al: Effects of partial agonist activity in betablockers in severe angina. Br Med J 289:951-953, 1984 29. Schang SJ, Pepine CJ: Transient asymptomatic ST-segment depression during daily activity. Am J Cardiol 39:396-402, 1977 30. Shell WE: Mechanisms and therapy of silent myocardial ischemia and the effects of transdermal nitroglycerin. Am J Cardiol 56:231-271, 1985 31. Shell WE, Kivowitz CF, Rubins SB, See J: Mechanisms and therapy of silent myocardial ischemia: The effect of transdermal nitroglycerin. Am Heart J 112:222-229, 1986 32. Weiner D: Calcium antagonists for the treatment of angina pectoris. In Weiner D, Frishman WH (eds): Therapy of Angina Pectoris. New York, Marcel Dekker, 1986, pp 145-204 33. Winniford MD, Johnson SJ, Mauritson DR, et al: Verapamil therapy for Prinzmetal's angina: Comparison with placebo and nifedipine. Am J Cardiol 50:913-918, 1982 Hospital of the Albert Einstein College of Medicine 1825 Eastchester Road Bronx, NY 10461