Pharmacologic management of ischemic heart disease with ,&blockers and calcium channel blockers In myocardial ischemia P-blockers reduce myocardiai oxygen demand, improve flow toward ischemic regions, and have mild antiplatelet and antiarrhythmic effects. These agents are effective in chronic stable angina and unstable angina. In chronic myocardial ischemia, the B-blockers timolol, metoproloi, atenoiol, and propranolol have cardioprotective effects, reducing overall mortality and the incidence of recurrent myocardial infarction. Calcium channel blockers, which reduce myocardial oxygen demand and improve oxygen supply, are effective in the treatment of chronic stable angina, vasospastic angina, and unstable angina. Although calcium channel blockers generally have no effect or adverse effects when used as primary therapy for acute myocardial infarction, diltiazem (when used concomitantly with nitrates or @-blockers) has been shown to reduce the incidence of reinfarction in patients after non-0 wave myocardial infarction. (AM HEART J 1990; 120:739.)
David L. Pearle, MD, Washington,
DC.
Until relatively recently, the dominant paradigm for myocardial ischemia centered on fixed atherosclerotic lesions that limit flow through coronary arteries. Therapy was understood in terms of manipulation of myocardial oxygen demand. In recent years investigations have led to the understanding that flow through diseased coronary arteries is a result of dynamic factors in addition to fixed atherosclerotic lesions. Coronary artery spasm, as seen in variant or Prinzmetal’s angina, is relatively rare. Physiologic changes in coronary vasomotion are common, even in patients with chronic stable angina. Acute coronary syndromes, such as unstable angina, acute myocardial infarction, and perhaps sudden death, result from complex, ulcerated plaques characterized by an interaction between endothelial damage, platelet aggregation, thrombosis, and spasm. Based on this evolving understanding of pathophysiology, pharmacologic therapy for myocardial ischemia includes not only conventional antiischemic drugs, such as &blockers, calcium channel blockers, and nitrates, but also antiplatelet drugs (such as aspirin), thrombolytic agents, and antithrombotic agents (such as heparin and warfarin). Emerging evFrom the Division of Cardiology, Georgetown University Medical Center. Reprint requests: David L Pearle, MD, Division of Cardiology, Georgetown University Medical Center, Washington, DC 20007. 410122497
idence also suggests that lipid-lowering therapy and other interventions can stabilize or reduce the size of atherosclerotic lesions and that such effects might alter both the long-term prognosis of patients with myocardial ischemia and the incidence of plaque rupture and acute ischemic events. The present discussion, which is confined to nitrates, &blockers, and calcium channel blockers, considers only a limited part of the spectrum of pharmacologic therapy for myocardial ischemia. NITRATES
In use for more than 100 years, nitrates have been demonstrated to be effective in chronic stable angina, coronary vasospasm, unstable angina, and myocardial infarction. They have the advantage of being the least expensive of the conventional antiischemic drugs. The issue of attenuation or tolerance has been more clearly understood with the use of continuous nitrate therapy. Although nitrate-free intervals are a partial solution, such intervals entail a time period when the patient is unprotected. &BLOCKERS
In myocardial ischemia, B-blockers exert their primary effect by reducing myocardial oxygen demand. They also improve flow toward ischemic regions and have mild antiplatelet effects. In addition, their competitive antagonism of adrenergic tone results in
739
September
740
Pearle
antiarrhythmic effects against both supraventricular and ventricular arrhythmias.’ @Blockers have been clearly demonstrated to be effective in chronic stable angina1 and unstable angina. 2~3 In chronic myocardial ischemia, @-blockers are distinguished from other agents by their documented “cardioprotection’‘-reducing overall mortality, sudden death, and recurrent myocardial infarction in survivors of acute myocardial infarction. This cardioprotective property, which has not been demonstrated in nitrates or calcium channel blockers, has been demonstrated in a number of trials with several different ,&blockers. The clearest demonstration of efficacy has been with the ,&blockers timolol,4 metoprolol,5 and propranolol.6 B-Blockers with intrinsic agonist or sympathomimetic actions do not seem to confer cardioprotection.73 8 In the United States, B-blockers have not been as widely used as in Europe for survivors of acute myocardial infarction. The approach in the United States has been to stratify patients according to the degree of risk. A high risk of future cardiac events is defined by evidence of left ventricular dysfunction, ongoing ischemia (either angina or a positive exercise test), the presence of complex ventricular ectopy, or a history of prior myocardial infarction. Patients falling into high- or intermediate-risk groups tend to be managed by anatomic interventions, such as bypass surgery or angioplasty. ,&Blockade should certainly be used in high-risk patients who are not candidates for these anatomic treatments. Low-risk patients with myocardial infarction derive approximately the same benefit from ,&blockade as do high-risk patients, approximately a 30% reduction in total mortality.g Since the risk of an adverse event in these patients is low, a large number of patients must be treated for several years to save one life. Therefore, the riskbenefit ratio must be carefully considered, and a decision to treat such patients with @blockers remains a matter of judgment. There is no conclusive evidence that B-blockers have cardioprotective effects during therapy for chronic stable angina or in patients whose myocardial infarction occurred more than 3 years earlier. Because of the low incidence of new events in these patients, a large number of patients would have to be studied for an extended period of time to obtain data on these effects. Therefore, it is a clinical judgment whether data obtained during the postmyocardial infarction period can be extrapolated to patients with chronic stable angina. Several large trials with P-blockers used early in the course of acute myocardial infarction have demonstrated their efficacy in reducing in-hospital mortality. Analysis of statistically pooled data from two
American
1990
Heart Journal
of these trials-the First International Study of Infarct Survival (ISIS I) and the Metoprolol in Acute Myocardial Infarction (MIAMI) trials-suggests that in-hospital mortality is reduced approximately 15% .l”p l1 These trials studied the early administration of intravenous B-blockers followed by oral pblocker therapy. Excluding patients with severe hypotension, severe heart failure, and bradycardia, about 70% to 85% of patients with myocardial infarction are candidates for such therapy, which significantly reduces chest pain and the incidence of supraventricular and ventricular arrhythmias and improves late left ventricular function. Findings of the National Institutes of Healthsponsored Thrombolysis in Myocardial Infarction Phase II (TIM1 II) trial12 suggest that metoprolol, when given early and in conjunction with thrombolytic therapy, significantly reduces the incidence of nonfatal reinfarction and recurrent ischemia. No improvement in ventricular function or mortality was demonstrated, but baseline mortalities were low in patients receiving thrombolytic therapy (with or without concomitant P-blockers), so that a reduction would be difficult to demonstrate. CALCIUM
CHANNEL
BLOCKERS
Calcium channel blockers are widely used in the management of patients with ischemic heart disease. These drugs not only reduce myocardial oxygen demand but also improve oxygen supply. Calcium channel blockers have been demonstrated to be effective in therapy for chronic stable angina,13 vasospastic angina,14, l5 and unstable angina.2, 3 Several large studies have failed to show that they have any benefit when used as primary therapy for acute myocardial infarction. ‘6 l7 Pooled data from such studies suggest that they may have an adverse effect on in-hospital mortality.18 Calcium channel blockers should be studied in conjunction with thrombolytic therapy for acute myocardial infarction because of favorable experimental data on this combination. An exception to the negative findings with calcium channel blockers in myocardial infarction has been the data generated in the Diltiazem Reinfarction Trial.lg In this study, patients with non-Q wave myocardial infarction, who are at high risk for reinfarction, were randomized to diltiazem therapy or placebo 24 to 72 hours after infarction. Eighty percent of these patients received nitrates concomitantly, and approximately half received p-blockers concomitantly. The study demonstrated a significant reduction in reinfarction in the diltiazem-treated patients at 2 weeks. Although these data have been widely accepted, they apply to patients with non-Q wave rather than Q wave myocardial infarction. In
Volume Number
Table
120 3
Phurmacologic
therapy
of
ischemic heart disease
74 1
I. Selection of antiischemic drugs Drug Concomitant
condition
Hypertension Hypotension Congestive heart failure &Blocker required Sick sinus syndrome Atrioventricular block Sinus tachycardia Paroxysmal supraventricular Bronchospasm Peripheral vascular disease
Nifedipine
++ + + + + tachycardia
2k + ++
Verapamil
+ + ++ + + +
Diltiazem
+ 2 f f + + + +
Nitrate
P-Blocker
+
++
+ + + + iz It + +
+ + -t
++, Strongly indicated; -, contraindicated; +, indicated; +, possibly useful.
many institutions, patients with non-Q wave infarctions undergo early coronary angiography, with subsequent anatomic therapy with bypass surgery or angioplasty. If this approach is used, the applicability of the diltiazem data is less clear. Conclusions from the Diltiazem Reinfarction Trial are often extrapolated to patients with acute myocardial infarction treated with thrombolytic therapy. The argument is that successful reperfusion reproduces the pathophysiology of non-Q wave infarction, since such patients have more subtotally than totally occluded infarct-related coronary arteries. The recent TIM1 II B data,12 which demonstrated the efficacy of metoprolol in combination with thrombolytic therapy in reducing early postmyocardial infarction, angina, and reinfarction, are more applicable to patients receiving thrombolytic therapyuntil calcium channel blockers are studied in this setting. An important question is whether calcium channel blockers have the cardioprotective effects of &blockers. Several early trials with verapamil20 and nifedipine161 17p21failed to demonstrate cardioprotection. More recently, the Multicenter Diltiazem Postinfarction Trial,22 which is very similar in design to P-blocker postinfarction trials, failed to demonstrate a reduction in mortality or in cardiac events in patients treated with diltiazem after myocardial infarction. A subgroup analysis suggested that a favorable effect in patients without heart failure or depressed left ventricular function (80% of the patients studied) was negated by an adverse effect in the minority (20%) with pulmonary congestion (based on chest x-ray films) or depressed ejection fraction. Although it has been argued that a beneficial effect on cardiac event rates can be anticipated if patients with heart failure are excluded, such a conclusion must be tempered by the limitations inherent in subgroup analysis. If the conclusion is accepted, there remain
questions about the safety of diltiazem with heart failure.
in patients
CONCLUSIONS
Nitrates, calcium channel blockers, and &blockers are valuable as therapy for myocardial ischemia. In acute myocardial infarction, @-blockers and nitrates are effective as primary therapy, whereas calcium channel blockers are not. When metoprolol is used in conjunction with thrombolytic therapy in patients with acute myocardial infarction, the combination reduces angina and reinfarction. In patients with non-Q wave myocardial infarction, diltiazem reduces the incidence of in-hospital reinfarction. Of these three classes of drugs, only P-blockers decrease the mortality in survivors of acute myocardial infarction over several years. In chronic stable angina, all three classes of drugs are effective, and the selection of therapy is often based on the patients’ concomitant medical conditions and the drugs’ side effects. For example, a patient with angina and hypertension might be treated first with a p-blocker or calcium channel blocker rather than a nitrate, since the former agents also treat hypertension. A patient with heart failure and angina might be treated most safely with a nitrate as first-line therapy. Table I illustrates how the selection of antiischemic therapy can be tailored to concomitant factors. The availability of three classes of drugs, with a wide range of agents in each class, has improved physicians’ ability to select appropriate antiischemic therapy for each patient. REFERENCES
1, Frishman WH. &Adrenoreceptor antagonists: new drugs and new indications. N Engl J Med 1981;305:500-6. 2. HINT Research Group. Early treatment of unstable angina in the coronary care unit: a randomized, double-blind placebo-controlled comparison of recurrent ischemia in patients treated with nifedipine or metoprolol or both. Br Heart J 1986,56:400-13.
742
3.
4.
5.
6.
7.
8.
9.
10.
11. 12.
13.
Pearle
American
Muller JE, Turi ZG, Pearle DL, et al. Nifedipine and conventional therapy for unstable angina pectoris: a randomized double-blind comparison. Circulation 1984;69:728-39. Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-7. Hialmarson A. Elmfeldt D. Herlitz J. et al. Effect on mortalitv of”metoprolol’in acute myocardial infarction: a double-blind randomised trial. Lancet 1981;2:823-7. Beta Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction: mortality results. JAMA 1982;247:1707-14. Taylor SH, Silke B, Ebbutt A, Sutton GC, Prout BJ, Burley DM. A long-term prevention study with oxprenolol in coronary heart disease. N Engl J Med 1982;307:1293-301. Australian and Swedish Pindolol Study Group. The effect of pindolol on the two-year mortality after complicated myocardial infarction. Eur Heart J 1983;4:367-75. Olsson G, Rehnquist N, Sjogren A, et al. Long-term treatment with metoprolol after myocardial infarction: effect on 3-year mortality and morbidity. J Am Co11 Cardiol 1985;5:1428-37. ISIS-l (First International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-i. Lancet 1986;2:57-66. The MIAMI Trial Research Groun. Metonrolol in acute myocardial infarction (MIAMI). A randomized placebo-controlled international trial. Eur Heart J 1985;6:199-226. The TIM1 Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1989;320:618-27. Kustak WJ, Pflugfelder P. Cooperative effects of calcium entry blocking drugs, beta-blocking drugs, and their combination in patients with chronic stable angina. Circulation 1987; 75(suppl V):V114-21. 1
September 1990 Heart Journal
Antman E, Muller J, Goldberg S. Nifedipine therapy for coronary artery spasm: experience in 127 patients. N Engl J Med 1980;302:1269-73. 15. Pepine CJ, Feldman RL, Hill JA, Conti CR, Mehta J, Hill C, Scott E. Clinical outcome after treatment of rest angina with calcium blockers: comparative experience during the initial year of therapy with diltiazem, nifedipine, and verapamil. AM 14.
HEART J 1983;106:1341-7. 16.
17.
18. 19. 20.
21.
22.
Muller JE, Morrison J, Stone P, et al. Nifedipine therapy for patients with threatened and acute myocardial infarction: a randomized, double-blind, placebo-controlled comparison. Circulation 1984;69:740-7. Sirnes PA, Overskeld K, Pedersen TR, et al. Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: the Norwegian Nifedipine Multicenter Trial. Circulation 1984;70:628-44. Yusuf S, Wittes 3, Friedman L. Overview of results of randomized clinical trials in heart disease. I. Treatments following myocardial infarction. JAMA 1988;260:2088-93. Gibson RS, Boden WE, Theroux P, et al. Diltiazem and reinfarction in patients with non-Q wave myocardial infarction. N Engl J Med 1986;315:423-9. Danish Multicenter Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Am J Cardiol 1984;54:243-283. Neufeld HN. Calcium antagonists in secondary prevention after acute myocardial infarction: the Secondary Prevention Reinfarction Nifedipine Trial (SPRINT). Eur Heart J 1986; 7:51-2. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988,319:385-92.
David L. Pearle, MD, Washington,
DC.
Until relatively recently, the dominant paradigm for myocardial ischemia centered on fixed atherosclerotic lesions that limit flow through coronary arteries. Therapy was understood in terms of manipulation of myocardial oxygen demand. In recent years investigations have led to the understanding that flow through diseased coronary arteries is a result of dynamic factors in addition to fixed atherosclerotic lesions. Coronary artery spasm, as seen in variant or Prinzmetal’s angina, is relatively rare. Physiologic changes in coronary vasomotion are common, even in patients with chronic stable angina. Acute coronary syndromes, such as unstable angina, acute myocardial infarction, and perhaps sudden death, result from complex, ulcerated plaques characterized by an interaction between endothelial damage, platelet aggregation, thrombosis, and spasm. Based on this evolving understanding of pathophysiology, pharmacologic therapy for myocardial ischemia includes not only conventional antiischemic drugs, such as &blockers, calcium channel blockers, and nitrates, but also antiplatelet drugs (such as aspirin), thrombolytic agents, and antithrombotic agents (such as heparin and warfarin). Emerging evFrom the Division of Cardiology, Georgetown University Medical Center. Reprint requests: David L Pearle, MD, Division of Cardiology, Georgetown University Medical Center, Washington, DC 20007. 410122497
idence also suggests that lipid-lowering therapy and other interventions can stabilize or reduce the size of atherosclerotic lesions and that such effects might alter both the long-term prognosis of patients with myocardial ischemia and the incidence of plaque rupture and acute ischemic events. The present discussion, which is confined to nitrates, &blockers, and calcium channel blockers, considers only a limited part of the spectrum of pharmacologic therapy for myocardial ischemia. NITRATES
In use for more than 100 years, nitrates have been demonstrated to be effective in chronic stable angina, coronary vasospasm, unstable angina, and myocardial infarction. They have the advantage of being the least expensive of the conventional antiischemic drugs. The issue of attenuation or tolerance has been more clearly understood with the use of continuous nitrate therapy. Although nitrate-free intervals are a partial solution, such intervals entail a time period when the patient is unprotected. &BLOCKERS
In myocardial ischemia, B-blockers exert their primary effect by reducing myocardial oxygen demand. They also improve flow toward ischemic regions and have mild antiplatelet effects. In addition, their competitive antagonism of adrenergic tone results in
739
September
740
Pearle
antiarrhythmic effects against both supraventricular and ventricular arrhythmias.’ @Blockers have been clearly demonstrated to be effective in chronic stable angina1 and unstable angina. 2~3 In chronic myocardial ischemia, @-blockers are distinguished from other agents by their documented “cardioprotection’‘-reducing overall mortality, sudden death, and recurrent myocardial infarction in survivors of acute myocardial infarction. This cardioprotective property, which has not been demonstrated in nitrates or calcium channel blockers, has been demonstrated in a number of trials with several different ,&blockers. The clearest demonstration of efficacy has been with the ,&blockers timolol,4 metoprolol,5 and propranolol.6 B-Blockers with intrinsic agonist or sympathomimetic actions do not seem to confer cardioprotection.73 8 In the United States, B-blockers have not been as widely used as in Europe for survivors of acute myocardial infarction. The approach in the United States has been to stratify patients according to the degree of risk. A high risk of future cardiac events is defined by evidence of left ventricular dysfunction, ongoing ischemia (either angina or a positive exercise test), the presence of complex ventricular ectopy, or a history of prior myocardial infarction. Patients falling into high- or intermediate-risk groups tend to be managed by anatomic interventions, such as bypass surgery or angioplasty. ,&Blockade should certainly be used in high-risk patients who are not candidates for these anatomic treatments. Low-risk patients with myocardial infarction derive approximately the same benefit from ,&blockade as do high-risk patients, approximately a 30% reduction in total mortality.g Since the risk of an adverse event in these patients is low, a large number of patients must be treated for several years to save one life. Therefore, the riskbenefit ratio must be carefully considered, and a decision to treat such patients with @blockers remains a matter of judgment. There is no conclusive evidence that B-blockers have cardioprotective effects during therapy for chronic stable angina or in patients whose myocardial infarction occurred more than 3 years earlier. Because of the low incidence of new events in these patients, a large number of patients would have to be studied for an extended period of time to obtain data on these effects. Therefore, it is a clinical judgment whether data obtained during the postmyocardial infarction period can be extrapolated to patients with chronic stable angina. Several large trials with P-blockers used early in the course of acute myocardial infarction have demonstrated their efficacy in reducing in-hospital mortality. Analysis of statistically pooled data from two
American
1990
Heart Journal
of these trials-the First International Study of Infarct Survival (ISIS I) and the Metoprolol in Acute Myocardial Infarction (MIAMI) trials-suggests that in-hospital mortality is reduced approximately 15% .l”p l1 These trials studied the early administration of intravenous B-blockers followed by oral pblocker therapy. Excluding patients with severe hypotension, severe heart failure, and bradycardia, about 70% to 85% of patients with myocardial infarction are candidates for such therapy, which significantly reduces chest pain and the incidence of supraventricular and ventricular arrhythmias and improves late left ventricular function. Findings of the National Institutes of Healthsponsored Thrombolysis in Myocardial Infarction Phase II (TIM1 II) trial12 suggest that metoprolol, when given early and in conjunction with thrombolytic therapy, significantly reduces the incidence of nonfatal reinfarction and recurrent ischemia. No improvement in ventricular function or mortality was demonstrated, but baseline mortalities were low in patients receiving thrombolytic therapy (with or without concomitant P-blockers), so that a reduction would be difficult to demonstrate. CALCIUM
CHANNEL
BLOCKERS
Calcium channel blockers are widely used in the management of patients with ischemic heart disease. These drugs not only reduce myocardial oxygen demand but also improve oxygen supply. Calcium channel blockers have been demonstrated to be effective in therapy for chronic stable angina,13 vasospastic angina,14, l5 and unstable angina.2, 3 Several large studies have failed to show that they have any benefit when used as primary therapy for acute myocardial infarction. ‘6 l7 Pooled data from such studies suggest that they may have an adverse effect on in-hospital mortality.18 Calcium channel blockers should be studied in conjunction with thrombolytic therapy for acute myocardial infarction because of favorable experimental data on this combination. An exception to the negative findings with calcium channel blockers in myocardial infarction has been the data generated in the Diltiazem Reinfarction Trial.lg In this study, patients with non-Q wave myocardial infarction, who are at high risk for reinfarction, were randomized to diltiazem therapy or placebo 24 to 72 hours after infarction. Eighty percent of these patients received nitrates concomitantly, and approximately half received p-blockers concomitantly. The study demonstrated a significant reduction in reinfarction in the diltiazem-treated patients at 2 weeks. Although these data have been widely accepted, they apply to patients with non-Q wave rather than Q wave myocardial infarction. In
Volume Number
Table
120 3
Phurmacologic
therapy
of
ischemic heart disease
74 1
I. Selection of antiischemic drugs Drug Concomitant
condition
Hypertension Hypotension Congestive heart failure &Blocker required Sick sinus syndrome Atrioventricular block Sinus tachycardia Paroxysmal supraventricular Bronchospasm Peripheral vascular disease
Nifedipine
++ + + + + tachycardia
2k + ++
Verapamil
+ + ++ + + +
Diltiazem
+ 2 f f + + + +
Nitrate
P-Blocker
+
++
+ + + + iz It + +
+ + -t
++, Strongly indicated; -, contraindicated; +, indicated; +, possibly useful.
many institutions, patients with non-Q wave infarctions undergo early coronary angiography, with subsequent anatomic therapy with bypass surgery or angioplasty. If this approach is used, the applicability of the diltiazem data is less clear. Conclusions from the Diltiazem Reinfarction Trial are often extrapolated to patients with acute myocardial infarction treated with thrombolytic therapy. The argument is that successful reperfusion reproduces the pathophysiology of non-Q wave infarction, since such patients have more subtotally than totally occluded infarct-related coronary arteries. The recent TIM1 II B data,12 which demonstrated the efficacy of metoprolol in combination with thrombolytic therapy in reducing early postmyocardial infarction, angina, and reinfarction, are more applicable to patients receiving thrombolytic therapyuntil calcium channel blockers are studied in this setting. An important question is whether calcium channel blockers have the cardioprotective effects of &blockers. Several early trials with verapamil20 and nifedipine161 17p21failed to demonstrate cardioprotection. More recently, the Multicenter Diltiazem Postinfarction Trial,22 which is very similar in design to P-blocker postinfarction trials, failed to demonstrate a reduction in mortality or in cardiac events in patients treated with diltiazem after myocardial infarction. A subgroup analysis suggested that a favorable effect in patients without heart failure or depressed left ventricular function (80% of the patients studied) was negated by an adverse effect in the minority (20%) with pulmonary congestion (based on chest x-ray films) or depressed ejection fraction. Although it has been argued that a beneficial effect on cardiac event rates can be anticipated if patients with heart failure are excluded, such a conclusion must be tempered by the limitations inherent in subgroup analysis. If the conclusion is accepted, there remain
questions about the safety of diltiazem with heart failure.
in patients
CONCLUSIONS
Nitrates, calcium channel blockers, and &blockers are valuable as therapy for myocardial ischemia. In acute myocardial infarction, @-blockers and nitrates are effective as primary therapy, whereas calcium channel blockers are not. When metoprolol is used in conjunction with thrombolytic therapy in patients with acute myocardial infarction, the combination reduces angina and reinfarction. In patients with non-Q wave myocardial infarction, diltiazem reduces the incidence of in-hospital reinfarction. Of these three classes of drugs, only P-blockers decrease the mortality in survivors of acute myocardial infarction over several years. In chronic stable angina, all three classes of drugs are effective, and the selection of therapy is often based on the patients’ concomitant medical conditions and the drugs’ side effects. For example, a patient with angina and hypertension might be treated first with a p-blocker or calcium channel blocker rather than a nitrate, since the former agents also treat hypertension. A patient with heart failure and angina might be treated most safely with a nitrate as first-line therapy. Table I illustrates how the selection of antiischemic therapy can be tailored to concomitant factors. The availability of three classes of drugs, with a wide range of agents in each class, has improved physicians’ ability to select appropriate antiischemic therapy for each patient. REFERENCES
1, Frishman WH. &Adrenoreceptor antagonists: new drugs and new indications. N Engl J Med 1981;305:500-6. 2. HINT Research Group. Early treatment of unstable angina in the coronary care unit: a randomized, double-blind placebo-controlled comparison of recurrent ischemia in patients treated with nifedipine or metoprolol or both. Br Heart J 1986,56:400-13.
742
3.
4.
5.
6.
7.
8.
9.
10.
11. 12.
13.
Pearle
American
Muller JE, Turi ZG, Pearle DL, et al. Nifedipine and conventional therapy for unstable angina pectoris: a randomized double-blind comparison. Circulation 1984;69:728-39. Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-7. Hialmarson A. Elmfeldt D. Herlitz J. et al. Effect on mortalitv of”metoprolol’in acute myocardial infarction: a double-blind randomised trial. Lancet 1981;2:823-7. Beta Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction: mortality results. JAMA 1982;247:1707-14. Taylor SH, Silke B, Ebbutt A, Sutton GC, Prout BJ, Burley DM. A long-term prevention study with oxprenolol in coronary heart disease. N Engl J Med 1982;307:1293-301. Australian and Swedish Pindolol Study Group. The effect of pindolol on the two-year mortality after complicated myocardial infarction. Eur Heart J 1983;4:367-75. Olsson G, Rehnquist N, Sjogren A, et al. Long-term treatment with metoprolol after myocardial infarction: effect on 3-year mortality and morbidity. J Am Co11 Cardiol 1985;5:1428-37. ISIS-l (First International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-i. Lancet 1986;2:57-66. The MIAMI Trial Research Groun. Metonrolol in acute myocardial infarction (MIAMI). A randomized placebo-controlled international trial. Eur Heart J 1985;6:199-226. The TIM1 Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1989;320:618-27. Kustak WJ, Pflugfelder P. Cooperative effects of calcium entry blocking drugs, beta-blocking drugs, and their combination in patients with chronic stable angina. Circulation 1987; 75(suppl V):V114-21. 1
September 1990 Heart Journal
Antman E, Muller J, Goldberg S. Nifedipine therapy for coronary artery spasm: experience in 127 patients. N Engl J Med 1980;302:1269-73. 15. Pepine CJ, Feldman RL, Hill JA, Conti CR, Mehta J, Hill C, Scott E. Clinical outcome after treatment of rest angina with calcium blockers: comparative experience during the initial year of therapy with diltiazem, nifedipine, and verapamil. AM 14.
HEART J 1983;106:1341-7. 16.
17.
18. 19. 20.
21.
22.
Muller JE, Morrison J, Stone P, et al. Nifedipine therapy for patients with threatened and acute myocardial infarction: a randomized, double-blind, placebo-controlled comparison. Circulation 1984;69:740-7. Sirnes PA, Overskeld K, Pedersen TR, et al. Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: the Norwegian Nifedipine Multicenter Trial. Circulation 1984;70:628-44. Yusuf S, Wittes 3, Friedman L. Overview of results of randomized clinical trials in heart disease. I. Treatments following myocardial infarction. JAMA 1988;260:2088-93. Gibson RS, Boden WE, Theroux P, et al. Diltiazem and reinfarction in patients with non-Q wave myocardial infarction. N Engl J Med 1986;315:423-9. Danish Multicenter Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Am J Cardiol 1984;54:243-283. Neufeld HN. Calcium antagonists in secondary prevention after acute myocardial infarction: the Secondary Prevention Reinfarction Nifedipine Trial (SPRINT). Eur Heart J 1986; 7:51-2. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988,319:385-92.
