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The role of calcium antagonists in the treatment of myocardial ischemia
The role of calcium antagonists of myocardial ischemia
in the treatment
Calcium antagonists are often prescribed for treatment of ischemic heart disease. Therapeutic activity is achieved by reducing myocardial oxygen requirements and by increasing blood supply in ischemic heart disease associated with coronary artery spasms. The efficacy of calcium antagonists depends on the type and clinical presentation of ischemic heart disease: (1) In vasospastic angina (variant angina, short episodes of angina at rest), first-line therapy with calcium antagonists will reduce the number of ischemic episodes,and improve long-term prognosis. (2) In effort angina the efficacy of calcium antagonists is comparable with that of /? blockers. (3) In unstable angina the use of calcium antagonists is controversial. Large-scale studies with nifedtpine showed no benefit when it was given alone but an additive effect in patients pretreated with j3 blockers. In contrast, ditttaarem and verapamil appear to have comparable efficacy to fi blockers in patients with unstable angina. (4) After myocardi’al infarction the results of treatment with calcium antagonists have been disappointing. Nifedipine and verapamil did not reduce mortality or the incidence of reinfarction. In one study diltiazem significantly reduced the rate of reinfarction in patients who had had a non-Q wave infarction, but in a recent large-scale multicenter trial it had no effect on mortality and cardiac events in patients with evidence of both Q- and non-Q wave infarctions. Other secondary preventative measures against reinfarction, such as the use of @-blockers and aspirin, appear to be more effective than calcium antagonists. The most frequently prescribed calcium antagonists, verapamil, diltiarem, and nifedipine, each of which represents a different chemical class, have in general similar efficacy in vasospastic and effort angina. Their different pharmacologic profile, such as the slowing of heart rate with verapamil or diltiazem and a more marked vasodilatation with nifedipine and other dthydropyridines, may become clinically relevant in individual patients. The new dihydropyridine derivatives have a pharmacologic profile comparable to that of nifedipine but some of these compounds, especially amlodipine, have more favorable pharmacokinetics, such as a prolonged elimination half-life. These agents may offer the advantage of a more practical dosage regimen for long-term treatment in patients with ischemic heart disease. (AM HEART J 1989; 118:1093.)
Ferenc Follath,
MD, Basel, Switzerland
The primary therapeutic objective in patients with ischemic heart disease is usually the relief and prevention of symptomatic (and silent) episodes of myocardial ischemia. Furthermore, drug treatment and interventional measures such as angioplasty or coronary artery bypass should also influence the natural history of the underlying coronary artery disease and improve long-term prognosis. Antianginal drugs act by reducing myocardial oxygen demand, by increasing myocardial oxygen supply via coronary vasodilatation, or both. Calcium antagonists exert both of these pharmacologic effects and so belong to From the Division University Hospital
of Clinical Pharmacology, (Kantonsspital).
Reprint requests: Ferenc Follath, University Hospital, Kantonsspital, 4/0/15300
Department
of Medicine,
MD, Division of Clinical Pharmacology, Basel, CH 4031 Basel, Switzerland.
the most important group of drugs in the treatment of ischemic heart disease. In this short review the efficacy of calcium antagonists in the various forms of ischemic heart disease will be discussed and compared to that of organic nitrates and fi blockers. VASOSPASTIC ANGINA ANGINA AT REST)
(VARIANT
ANGINA,
Coronary artery spasm may be the cause of myocardial ischemia in patients with otherwise normal coronary vessels or may aggravate the perfusion deficit in patients with stenotic coronary arteries. In classic variant angina, calcium antagonists reduce the number of ischemic episodes by 80 % to 99 % .le3 Angina at rest in patients with coronary artery disease also responds to nifedipine, verapamil, or diltiazem to the same degree producing a decrease in the incidence of ischemic episodes of >60% .4 In
1093
1094
November 1989 American Heart Journal
Follath
comparative studies with nifedipine and the organic nitrate, isosorbide dinitrate, the extent of symptomatic improvement was comparable; however, side effects were more frequent with isosorbide dinitrate.5, 6 The combination of isosorbide dinitrate with verapamil showed significant additive effects in patients with frequent episodes of variant angina. In contrast to these drugs which produce coronary vasodilatation, the P-blockers are ineffective in patients with angina at rest and should therefore not be prescribed alone.8 EFFORT
ANGINA
Calcium antagonists achieve symptomatic improvement in patients with exercise-induced ischemic chest pain by lowering left ventricular afterload and thus reducing myocardial oxygen requirements. Verapamilg and diltiazemlO also slow the heart rate at rest and during exercise and reduce the rate-pressure product, whereas dihydropyridines may produce a slight tachycardia.l’ This difference in pharmacologic profile between calcium antagonists may explain that in some comparative studies verapamil appears to be more effective than nifedipine.12 In addition, a more intensive vasodilatation after administration of rapidly acting nifedipine capsules may reduce the coronary perfusion pressure below a critical level and aggravate the ischemic symptoms.13s l4 However, by careful stepwise dose titration and by use of slow-release nifedipine preparations these adverse reactions can usually be avoided. Contrary to single-drug treatment, nifedipine and other dihydropyridine derivatives offer a practical advantage when a combination with a P-blocker is required, since these agents do not influence sinus node function or AV conduction and therefore do not increase the risk of bradyarrhythmias. Opinions vary as to whether treatment in patients with stable effort angina should begin with a pblocker or a calcium antagonist. In controlled comparative studies, both types of drugs are equally effective.lOt 15vl6 In patients with severe symptoms, the combination of calcium antagonists and pblockers has an additive effect, reducing the incidence and severity of myocardial ischemia more than either drug alone.17y ls UNSTABLE
ANGINA
The use of calcium antagonists in the treatment of unstable angina is controversial. Whereas verapamillg and diltiazem20 significantly reduce the number of episodes of ischemia in this condition, two recent large-scale trials with nifedipine showed no therapeutic benefit unless the patients were
already pretreated with a /3-blocker.2’s 22 In the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT), the incidence of recurrent ischemia or myocardial infarction within the first 48 hours of treatment was higher with nifedipine than with placebo (47% vs 37%) respectively). However, such events were significantly reduced by the combination of metoprolol and nifedipine. Therefore patients with unstable angina should receive adequate pblockade before treatment with nifedipine: this is probably also the case with other dihydropyridines. In view of the important role of platelet aggregation and thrombosis in unstable angina, the treatment now includes low-dose aspirin23, 24or heparinz5 which have been shown to reduce the incidence of myocardial infarction and death by 50 % to 70 % . CALCIUM ANTAGONISTS INFARCTION
AFTER ACUTE
MYOCARDIAL
The results of the use of calcium antagonists as secondary prevention after myocardial infarction have been disappointing. Neither verapamilF6 nifedipine,27 nor diltiazem28 had significant effects on mortality or on the rate of nonfatal recurrent infarctions. In the multicenter diltiazem postinfarction tria1,28 a different outcome was observed in groups of patients with or without x-ray signs of left ventricular failure; in patients without pulmonary congestion the hazard ratio of cardiac events was reduced to 0.77 by diltiazem, whereas in patients with pulmonary congestion the relative risk was increased to 1.41. Thus diltiazem treatment in patients with left ventricular dysfunction may be detrimental. The only positive secondary prevention trial with a calcium antagonist was that reported by Gibson et al.,” who administered diltiazem within 24 to 72 hours after the onset of symptoms of a non-Q wave myocardial infarction. During an observation period of 14 days reinfarction occurred in 9.3% of patients in the placebo group and in 5.2% in the diltiazem group (p = 0.029). Further investigations are necessary to determine whether diltiazem or other calcium antagonists could exert a protective effect in certain subgroups of patients with acute myocardial infarction. Such studies should be performed not against placebo but against @blockers, which have significantly reduced the incidence of sudden death and reinfarction in several large-scale trials.s0 NEW CALCIUM
ANTAGONISTS
Verapamil, nifedipine, and diltiazem remain the most widely used calcium antagonists, but a number of new agents have recently become available, which may improve the therapeutic possibilities in ischemic
Volume 118 Number 5, Part 2
Calcium
antagonists
in ischemic heart disease
10%
Verapamil
Felodipine
Amlodipine
I H lsradipine
Nisoldipine
Fig. 1. Chemical structures of some calcium antagonists: em, a benzothiazepine analog; others are dihydropyridine
heart disease (Fig. 1). Most of these drugs belong to the dihydropyridine group and have a pharmacologic profile comparable with that of nifedipine.31 The potential advantage of these new calcium antagonists lies in their more favorable pharmacokinetics and especially their prolonged elimination half-lives.32 Nitrendipine, nisoldipine, isradipine, and felodipine have ts values of 6 to 12 hours, with a corresponding prolongation of antiischemic effects.33p 34 One of the interesting new agents is amlodipine with an elimination half-life of 35 to 50 hours.35l36 In patients with chronic stable angina, a single daily dose was sufficient to significantly increase exercise performance.37 Such calcium antagonists may greatly facilitate long-term treatment in patients with ischemic heart disease.
verapamil, analogs.
a phenylalkylamine
analog; diltiaz-
and ,&blockers have additive effects and improve ischemic symptoms more than either drug alone. In unstable angina, aspirin or heparin can be used in conjunction with P-blockers and calcium antagonists. After myocardial infarction findings on the use of calcium antagonists as secondary prevention have been disappointing. Results of large-scale studies have not shown a reduction in mortality or in the rate of reinfarction. The new calcium antagonists with prolonged elimination half-lives may offer a practical advantage for long-term treatment of patients with vasospastic or effort angina. REFERENCES
1. Antman E, Muller J, Goldberg S, et al. Nifedipine 2.
CONCLUSIONS
Calcium antagonists are highly effective antianginal drugs and represent a significant therapeutic advance in the treatment of ischemic heart disease. The combination of reduced myocardial oxygen demand and increased myocardial blood flow in patients with coronary artery spasm explains the high therapeutic success rate in variant angina. Verapamil, nifedipine, and diltiazem have comparable efficacy to P-blockers in effort angina. In combination, calcium antagonists
A Nitrendipine
3.
4.
5.
therapy for coronary artery spasm. N Engl J Med 1980;302:1267-73. Johnson SM, Mauritson DR, Willerson JT, Hillis LD. A controlled trial of verapamil for Prinzmetal’s variant angina. N Engl J Med 1981;304:862-6. Schroeder JS, Lamb IH, Bristow MR, Ginsburg R, Hung J, McAuley BJ. Prevention of cardiovascular events in variant angina by long-term diltiazem therapy. J Am Co11 Cardiol 1983;116:1507-11. Pepine CJ, Feldman RL, Hill JA, et al. Clinical outcome after treatment of rest angina with calcium blockers: comparative experience during the initial year of therapy with diltiazem, nifedipine, and verapamil. AM HEARTJ 1982;106:1341-7. Ginsburg R, Lamb IH, Schroeder JS, Hu M, Harrison DC. Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary artery spasm. AM HEARTJ 1982;103:44-8.
1096
November 1989 American Heart Journal
Follath
6. Hill JA, Feldman RL, Pepine CJ, et al. Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm. Am J Cardiol1982;49:431. 8. I. Winniford MD, Gabliani G, Johnson SM, Mauritson DR, Fulton KL, Hillis LD. Concomitant calcium antagonist plus isosorbide dinitrate therapy for markedly active variant angina. AM HEART J 1984;108:1269-72. 8. Parodi 0, Simonetti I, Michelassi C, et al. Comparison of verapamil and propranolol therapy for angina pectoris at rest: a randomized, multiple crossover, controlled trial in the coronarv care unit. Am J Cardiol 1986:57:899-906. 9. Brodsky SJ, Cutler SS, Weiner DA, McCabe CH, Ryan TJ, Klein MD. Treatment of stable angina of effort with verapamil: a double-blind, placebo-controlled randomized crossover study. Circulation 1982;66:569-79. 10. Hung J, Lamb IH, Connolly SJ, Jutzy KR, Goris ML, Schroeder JS. The effect of diltiazem and propranolol, alone and in combination, on exercise performance and left ventricular function in patients with stable effort angina: a doubleblind, randomized, and placebo-controlled study. Circulation 1983;68:560-7. 11. Dawson JR, Whitaker NHG, Sutton GC. Calcium antagonist drugs in chronic stable angina. Comparison of verapamil and nifedipine. Br Heart J 1981;46:508-12. 12. Subramanian VB, Bowles MJ, Khurmi NS, Davies AB, Raftery EB. Rationale for the choice of calcium antagonists in chronic stable angina. An objective double-blind placebo-controlled comparison of nifedipine and verapamil. Am J Cardiol 1982;50:1173-9. hyper13. Boden WE, Korr KS, Bough EW. Nifedipine-induced tension and myocardial ischemia in refractory angina pectoris. JAMA
1985;253:1131-5.
14. Deanfield J, Wright C, Fox K. Treatment of angina pectoris with nifedipine: importance of dose titration. Br Med J 1983;286:1467-70. 15. Lvnch P. Dar&e H. Krikler S. Krikler D. Obiective assessment of antianginal treatment: a double-blind comparison of propranolol, nifedipine, and their combination. Br Med d 1980;2:184-6. 16. Subramanian VB, Bowles MJ, Davies AB, Raftery EB. Combined therapy with verapamil and propranolol in chronic stable angina. Am J Cardiol 1982;49:125-32. 17. Johnston DL, Lesoway R, Humen DP, Kostuk WJ, Mickle P. Clinical and hemodynamic evaluation of propranolol in combination with verapamil, nifedipine and diltiazem in exertional angina pectoris: a placebo controlled, double-blind, randomized, crossover study. Am J Cardiol 1985;55:680-7. 18. Morse JR. Comparison of combination nifedipine-propranolol and diltiazem-propranolol with high-dose diltiazem monotherapy for stable angina pectoris. Am J Cardiol1988;62:1028-_I---~
7-
“-
24. 25. 26. 27.
28. 29.
30. 31.
32. 33. 34.
I
19. Mehta J, Conti CR. Verapamil therapy for unstable angina pectoris: review of double-blind placebo-controlled randomized clinical trials. Am J Cardiol 1982;50:919-22. 20. Theroux P, Taeymans Y, Morissette D, Bosch X, Pelletier CH, Waters DD. A randomized study comparing propranolol and diltiazem in the treatment of unstable angina. J Am Co11Cardiol 1985;5:717-22. 21. Muller JE. Morrison J. Stone PH. et al. Nifedipine therapy for patients with threatened acute myocardial infarction: arandomized, double-blind, placebo-controlled comparison. Circulation 1984;69:740-7. 22. Report of the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group. Early treatment of unstable angina in the coronary care unit: a randomised, double blind, placebo controlled comparison of recurrent ischaemia in patients treated with nifedipine or metoprolol or both. Br Heart J 1986;56:400-13. 23. Lewis HD, Davis JW, Archibald DG, et al. Protective effects
35.
36. 37.
of aspirin against acute myocardial infarction and death in men with unstable angina. N Ens1 d Med 1983:309:396-403. Cairns JA, Gent M, Singer J, et ai Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter study. N Engl J Med 1985;313:1369-75. Theroux P, Quimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319:1105-l 1. Danish Study Group on verapamil in myocardial infarction. Verapamil in acute myocardial infarction. Eur Heart J 1984;5:516-28. Israeli Sprint Study Group. Secondary prevention reinfarction Israeli nifedipine trial (SPRINT). A randomised intervention trial of nifedipine in patients with acute myocardial infarction. Eur Heart J 1988;9:354-64. 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. Gibson RS, Boden WE, Theroux P, et al and the Diltiazem Reinfarction Study Group. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction. N Engl J Med 1986;315:423-9. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71. Silke B, Frais MA, Midtbo KA, et al. Comparative hemodynamic dose-response effects of five slow calcium channelblocking agents in coronary artery disease. Clin Pharmacol Ther 1987;42:381-7. Follath F, Taeschner W. Clinical pharmacology of calcium antagonists. J Cardiovasc Pharmacol 1988;12(suppl 6):S98SlOO. Scardi S, Pandullo C, Pivotti F, Ceschia G, Pollavini G. Acute effects of felodipine in exertional angina pectoris. Am J Cardiol 1988;61:691-5. Schmoeckel M, Arendt RM, Hauck R, Schultheiss HP. Acute and chronic effects of nitrendipine on hemodynamics and myocardial ischemia in patients with combined angina pectoris and hypertension. J Cardiovasc Pharmacol 1988;12(suppl 4):S170-4. Faulkner JK, McGibney D, Chasseaud LF, Perry JL, Taylor IW. The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 reneated oral doses given once dailv. Br J Clin Pharmacol i986;22:21-5. ” Laher MS, Kelly JG, Doyle GD, et al. Pharmacokinetics of amlodipine in renal impairment. J Cardiovasc Pharmacol 1988;12(suppl 7):S60-3. Kinnard DR, Harris M, Hossack KF. Amlodipine in angina pectoris: effect on maximal and submaximal exercise performance. J Cardiovasc Pharmacol 1988;12(suppl 7):SllO-13.
GROUP DISCUSSION Question from the floor.
Would you please expand further on the difference between the dihydropyridine calcium antagonists and other structural types of calcium antagonists in patients with stable angina. F. Follath. There is some debate as to whether a true difference exists between dihydropyridines and verapamil and diltiazem in such patients. In a few studies better efficacy with verapamil and diltiazem has been found, whereas in others no difference was seen. One thing is clear from all studies; verapamil and diltiazem do reduce resting and exercise heart rates, and if we believe that heart rate has anything to do with myocardial ischemia, then it appears logical that in some patients this difference would
Volume 118 Number 5, Part 2
be of clinical relevance. Thus if a patient does not respond adequately to a dihydropyridine calcium antagonist, it is justified to try another type of calcium antagonist, for example, diltiazem or verapamil. This might be necessary in patients who cannot he given P-blockers for some reason, such as preexisting left ventricular dysfunction. J. M. Detry (Brussels, Belgium). Do you think that it is useful in several instances to combine verapamil or diltiazem with a dihydropyridine? F. Follath. The combination of P-blockers and calcium antagonists is clearly effective. However, I am not convinced by the data published until now that a combination of different calcium antagonists will really have a major advantage compared to a single drug used in effective doses. K. Fox. Surely the problem with such an approach is that it depends on the pathophysiologic mechanisms involved in individual patients and how the drug is being profiled against the different mechanisms. For example, results from one study showed that a combination of a fl blocker and either a calcium antagonist or a nitrate was beneficial, but when a third drug was added a detrimental effect was produced, perhaps because of coronary steal. It is difficult to make broad statements, and treatments have to be adjusted against the pathophysiology and the differences in coronary blood flow involved in individual patients. P. Deedwania. Many of the studies that evaluated combination therapy have not necessarily used maximal doses of individual agents and that is one of the major problems, We showed that if nitrates and calcium antagonists (in our work, diltiazem) are compared and if either of the agents is used at maximal doses, adding another agent in patients with stable angina does not really provide significant additional benefit. In that particular study the doses were maximized to a point the patient could tolerate without side effects. Before we rush into combination therapy we should keep in mind that it is necessary to use the maxi-
Calcium
antagonists
in ischemic heart disease
1097
mal tolerated doses of individual agents and that is one of the weaknesses of many studies with combinations that have been reported. F. Follath. The problem of maximal tolerated doses is a difficult one. Sometimes combinations of lower doses of ,& blockers and lower doses of calcium antagonists may be better tolerated by outpatients. The question of long-term tolerance is of great importance, and the different new cal.cium antagonists may have an advantage with regard to improved tolerance. However, I am often disappointed in my own patients whom I treat with new drugs that were well tolerated in published trials. Many patients seem to have more problems than I would have expected. I think that the long-term tolerance of these drugs will only be established by their long-term use in outpatient practice. There is always some distortion between reported rates of side effects and tolerance in patient groups from clinical studies and in everyday practice. Question from the floor. How would you assessefficacy of a drug in a patient with stable effort angina? Would you perform Holter monitoring or only evaluate the patient with exercise stress testing? The physiopathology of ischemic episodes in an ambulatory situation might be different from the physiopathology of ischemia in the hospital where the patient undergoes stress testing. F. Follath. This is clearly an important point. Results of recent studies have shown that the prognostic importance of ischemic episodes occurring during everyday activities is higher than for episodes resulting from exercise testing. Exercise testing in the laboratory is an artificial situation, and probably long-term monitoring of ischemic episodes, both painful and painless, during everyday activities is more relevant to what happens to patients. Unfortunately, at the present time it is not possible to check all patients treated for coronary artery disease with Holter monitoring.
in the treatment
Calcium antagonists are often prescribed for treatment of ischemic heart disease. Therapeutic activity is achieved by reducing myocardial oxygen requirements and by increasing blood supply in ischemic heart disease associated with coronary artery spasms. The efficacy of calcium antagonists depends on the type and clinical presentation of ischemic heart disease: (1) In vasospastic angina (variant angina, short episodes of angina at rest), first-line therapy with calcium antagonists will reduce the number of ischemic episodes,and improve long-term prognosis. (2) In effort angina the efficacy of calcium antagonists is comparable with that of /? blockers. (3) In unstable angina the use of calcium antagonists is controversial. Large-scale studies with nifedtpine showed no benefit when it was given alone but an additive effect in patients pretreated with j3 blockers. In contrast, ditttaarem and verapamil appear to have comparable efficacy to fi blockers in patients with unstable angina. (4) After myocardi’al infarction the results of treatment with calcium antagonists have been disappointing. Nifedipine and verapamil did not reduce mortality or the incidence of reinfarction. In one study diltiazem significantly reduced the rate of reinfarction in patients who had had a non-Q wave infarction, but in a recent large-scale multicenter trial it had no effect on mortality and cardiac events in patients with evidence of both Q- and non-Q wave infarctions. Other secondary preventative measures against reinfarction, such as the use of @-blockers and aspirin, appear to be more effective than calcium antagonists. The most frequently prescribed calcium antagonists, verapamil, diltiarem, and nifedipine, each of which represents a different chemical class, have in general similar efficacy in vasospastic and effort angina. Their different pharmacologic profile, such as the slowing of heart rate with verapamil or diltiazem and a more marked vasodilatation with nifedipine and other dthydropyridines, may become clinically relevant in individual patients. The new dihydropyridine derivatives have a pharmacologic profile comparable to that of nifedipine but some of these compounds, especially amlodipine, have more favorable pharmacokinetics, such as a prolonged elimination half-life. These agents may offer the advantage of a more practical dosage regimen for long-term treatment in patients with ischemic heart disease. (AM HEART J 1989; 118:1093.)
Ferenc Follath,
MD, Basel, Switzerland
The primary therapeutic objective in patients with ischemic heart disease is usually the relief and prevention of symptomatic (and silent) episodes of myocardial ischemia. Furthermore, drug treatment and interventional measures such as angioplasty or coronary artery bypass should also influence the natural history of the underlying coronary artery disease and improve long-term prognosis. Antianginal drugs act by reducing myocardial oxygen demand, by increasing myocardial oxygen supply via coronary vasodilatation, or both. Calcium antagonists exert both of these pharmacologic effects and so belong to From the Division University Hospital
of Clinical Pharmacology, (Kantonsspital).
Reprint requests: Ferenc Follath, University Hospital, Kantonsspital, 4/0/15300
Department
of Medicine,
MD, Division of Clinical Pharmacology, Basel, CH 4031 Basel, Switzerland.
the most important group of drugs in the treatment of ischemic heart disease. In this short review the efficacy of calcium antagonists in the various forms of ischemic heart disease will be discussed and compared to that of organic nitrates and fi blockers. VASOSPASTIC ANGINA ANGINA AT REST)
(VARIANT
ANGINA,
Coronary artery spasm may be the cause of myocardial ischemia in patients with otherwise normal coronary vessels or may aggravate the perfusion deficit in patients with stenotic coronary arteries. In classic variant angina, calcium antagonists reduce the number of ischemic episodes by 80 % to 99 % .le3 Angina at rest in patients with coronary artery disease also responds to nifedipine, verapamil, or diltiazem to the same degree producing a decrease in the incidence of ischemic episodes of >60% .4 In
1093
1094
November 1989 American Heart Journal
Follath
comparative studies with nifedipine and the organic nitrate, isosorbide dinitrate, the extent of symptomatic improvement was comparable; however, side effects were more frequent with isosorbide dinitrate.5, 6 The combination of isosorbide dinitrate with verapamil showed significant additive effects in patients with frequent episodes of variant angina. In contrast to these drugs which produce coronary vasodilatation, the P-blockers are ineffective in patients with angina at rest and should therefore not be prescribed alone.8 EFFORT
ANGINA
Calcium antagonists achieve symptomatic improvement in patients with exercise-induced ischemic chest pain by lowering left ventricular afterload and thus reducing myocardial oxygen requirements. Verapamilg and diltiazemlO also slow the heart rate at rest and during exercise and reduce the rate-pressure product, whereas dihydropyridines may produce a slight tachycardia.l’ This difference in pharmacologic profile between calcium antagonists may explain that in some comparative studies verapamil appears to be more effective than nifedipine.12 In addition, a more intensive vasodilatation after administration of rapidly acting nifedipine capsules may reduce the coronary perfusion pressure below a critical level and aggravate the ischemic symptoms.13s l4 However, by careful stepwise dose titration and by use of slow-release nifedipine preparations these adverse reactions can usually be avoided. Contrary to single-drug treatment, nifedipine and other dihydropyridine derivatives offer a practical advantage when a combination with a P-blocker is required, since these agents do not influence sinus node function or AV conduction and therefore do not increase the risk of bradyarrhythmias. Opinions vary as to whether treatment in patients with stable effort angina should begin with a pblocker or a calcium antagonist. In controlled comparative studies, both types of drugs are equally effective.lOt 15vl6 In patients with severe symptoms, the combination of calcium antagonists and pblockers has an additive effect, reducing the incidence and severity of myocardial ischemia more than either drug alone.17y ls UNSTABLE
ANGINA
The use of calcium antagonists in the treatment of unstable angina is controversial. Whereas verapamillg and diltiazem20 significantly reduce the number of episodes of ischemia in this condition, two recent large-scale trials with nifedipine showed no therapeutic benefit unless the patients were
already pretreated with a /3-blocker.2’s 22 In the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT), the incidence of recurrent ischemia or myocardial infarction within the first 48 hours of treatment was higher with nifedipine than with placebo (47% vs 37%) respectively). However, such events were significantly reduced by the combination of metoprolol and nifedipine. Therefore patients with unstable angina should receive adequate pblockade before treatment with nifedipine: this is probably also the case with other dihydropyridines. In view of the important role of platelet aggregation and thrombosis in unstable angina, the treatment now includes low-dose aspirin23, 24or heparinz5 which have been shown to reduce the incidence of myocardial infarction and death by 50 % to 70 % . CALCIUM ANTAGONISTS INFARCTION
AFTER ACUTE
MYOCARDIAL
The results of the use of calcium antagonists as secondary prevention after myocardial infarction have been disappointing. Neither verapamilF6 nifedipine,27 nor diltiazem28 had significant effects on mortality or on the rate of nonfatal recurrent infarctions. In the multicenter diltiazem postinfarction tria1,28 a different outcome was observed in groups of patients with or without x-ray signs of left ventricular failure; in patients without pulmonary congestion the hazard ratio of cardiac events was reduced to 0.77 by diltiazem, whereas in patients with pulmonary congestion the relative risk was increased to 1.41. Thus diltiazem treatment in patients with left ventricular dysfunction may be detrimental. The only positive secondary prevention trial with a calcium antagonist was that reported by Gibson et al.,” who administered diltiazem within 24 to 72 hours after the onset of symptoms of a non-Q wave myocardial infarction. During an observation period of 14 days reinfarction occurred in 9.3% of patients in the placebo group and in 5.2% in the diltiazem group (p = 0.029). Further investigations are necessary to determine whether diltiazem or other calcium antagonists could exert a protective effect in certain subgroups of patients with acute myocardial infarction. Such studies should be performed not against placebo but against @blockers, which have significantly reduced the incidence of sudden death and reinfarction in several large-scale trials.s0 NEW CALCIUM
ANTAGONISTS
Verapamil, nifedipine, and diltiazem remain the most widely used calcium antagonists, but a number of new agents have recently become available, which may improve the therapeutic possibilities in ischemic
Volume 118 Number 5, Part 2
Calcium
antagonists
in ischemic heart disease
10%
Verapamil
Felodipine
Amlodipine
I H lsradipine
Nisoldipine
Fig. 1. Chemical structures of some calcium antagonists: em, a benzothiazepine analog; others are dihydropyridine
heart disease (Fig. 1). Most of these drugs belong to the dihydropyridine group and have a pharmacologic profile comparable with that of nifedipine.31 The potential advantage of these new calcium antagonists lies in their more favorable pharmacokinetics and especially their prolonged elimination half-lives.32 Nitrendipine, nisoldipine, isradipine, and felodipine have ts values of 6 to 12 hours, with a corresponding prolongation of antiischemic effects.33p 34 One of the interesting new agents is amlodipine with an elimination half-life of 35 to 50 hours.35l36 In patients with chronic stable angina, a single daily dose was sufficient to significantly increase exercise performance.37 Such calcium antagonists may greatly facilitate long-term treatment in patients with ischemic heart disease.
verapamil, analogs.
a phenylalkylamine
analog; diltiaz-
and ,&blockers have additive effects and improve ischemic symptoms more than either drug alone. In unstable angina, aspirin or heparin can be used in conjunction with P-blockers and calcium antagonists. After myocardial infarction findings on the use of calcium antagonists as secondary prevention have been disappointing. Results of large-scale studies have not shown a reduction in mortality or in the rate of reinfarction. The new calcium antagonists with prolonged elimination half-lives may offer a practical advantage for long-term treatment of patients with vasospastic or effort angina. REFERENCES
1. Antman E, Muller J, Goldberg S, et al. Nifedipine 2.
CONCLUSIONS
Calcium antagonists are highly effective antianginal drugs and represent a significant therapeutic advance in the treatment of ischemic heart disease. The combination of reduced myocardial oxygen demand and increased myocardial blood flow in patients with coronary artery spasm explains the high therapeutic success rate in variant angina. Verapamil, nifedipine, and diltiazem have comparable efficacy to P-blockers in effort angina. In combination, calcium antagonists
A Nitrendipine
3.
4.
5.
therapy for coronary artery spasm. N Engl J Med 1980;302:1267-73. Johnson SM, Mauritson DR, Willerson JT, Hillis LD. A controlled trial of verapamil for Prinzmetal’s variant angina. N Engl J Med 1981;304:862-6. Schroeder JS, Lamb IH, Bristow MR, Ginsburg R, Hung J, McAuley BJ. Prevention of cardiovascular events in variant angina by long-term diltiazem therapy. J Am Co11 Cardiol 1983;116:1507-11. Pepine CJ, Feldman RL, Hill JA, et al. Clinical outcome after treatment of rest angina with calcium blockers: comparative experience during the initial year of therapy with diltiazem, nifedipine, and verapamil. AM HEARTJ 1982;106:1341-7. Ginsburg R, Lamb IH, Schroeder JS, Hu M, Harrison DC. Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary artery spasm. AM HEARTJ 1982;103:44-8.
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6. Hill JA, Feldman RL, Pepine CJ, et al. Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm. Am J Cardiol1982;49:431. 8. I. Winniford MD, Gabliani G, Johnson SM, Mauritson DR, Fulton KL, Hillis LD. Concomitant calcium antagonist plus isosorbide dinitrate therapy for markedly active variant angina. AM HEART J 1984;108:1269-72. 8. Parodi 0, Simonetti I, Michelassi C, et al. Comparison of verapamil and propranolol therapy for angina pectoris at rest: a randomized, multiple crossover, controlled trial in the coronarv care unit. Am J Cardiol 1986:57:899-906. 9. Brodsky SJ, Cutler SS, Weiner DA, McCabe CH, Ryan TJ, Klein MD. Treatment of stable angina of effort with verapamil: a double-blind, placebo-controlled randomized crossover study. Circulation 1982;66:569-79. 10. Hung J, Lamb IH, Connolly SJ, Jutzy KR, Goris ML, Schroeder JS. The effect of diltiazem and propranolol, alone and in combination, on exercise performance and left ventricular function in patients with stable effort angina: a doubleblind, randomized, and placebo-controlled study. Circulation 1983;68:560-7. 11. Dawson JR, Whitaker NHG, Sutton GC. Calcium antagonist drugs in chronic stable angina. Comparison of verapamil and nifedipine. Br Heart J 1981;46:508-12. 12. Subramanian VB, Bowles MJ, Khurmi NS, Davies AB, Raftery EB. Rationale for the choice of calcium antagonists in chronic stable angina. An objective double-blind placebo-controlled comparison of nifedipine and verapamil. Am J Cardiol 1982;50:1173-9. hyper13. Boden WE, Korr KS, Bough EW. Nifedipine-induced tension and myocardial ischemia in refractory angina pectoris. JAMA
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14. Deanfield J, Wright C, Fox K. Treatment of angina pectoris with nifedipine: importance of dose titration. Br Med J 1983;286:1467-70. 15. Lvnch P. Dar&e H. Krikler S. Krikler D. Obiective assessment of antianginal treatment: a double-blind comparison of propranolol, nifedipine, and their combination. Br Med d 1980;2:184-6. 16. Subramanian VB, Bowles MJ, Davies AB, Raftery EB. Combined therapy with verapamil and propranolol in chronic stable angina. Am J Cardiol 1982;49:125-32. 17. Johnston DL, Lesoway R, Humen DP, Kostuk WJ, Mickle P. Clinical and hemodynamic evaluation of propranolol in combination with verapamil, nifedipine and diltiazem in exertional angina pectoris: a placebo controlled, double-blind, randomized, crossover study. Am J Cardiol 1985;55:680-7. 18. Morse JR. Comparison of combination nifedipine-propranolol and diltiazem-propranolol with high-dose diltiazem monotherapy for stable angina pectoris. Am J Cardiol1988;62:1028-_I---~
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19. Mehta J, Conti CR. Verapamil therapy for unstable angina pectoris: review of double-blind placebo-controlled randomized clinical trials. Am J Cardiol 1982;50:919-22. 20. Theroux P, Taeymans Y, Morissette D, Bosch X, Pelletier CH, Waters DD. A randomized study comparing propranolol and diltiazem in the treatment of unstable angina. J Am Co11Cardiol 1985;5:717-22. 21. Muller JE. Morrison J. Stone PH. et al. Nifedipine therapy for patients with threatened acute myocardial infarction: arandomized, double-blind, placebo-controlled comparison. Circulation 1984;69:740-7. 22. Report of the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group. Early treatment of unstable angina in the coronary care unit: a randomised, double blind, placebo controlled comparison of recurrent ischaemia in patients treated with nifedipine or metoprolol or both. Br Heart J 1986;56:400-13. 23. Lewis HD, Davis JW, Archibald DG, et al. Protective effects
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of aspirin against acute myocardial infarction and death in men with unstable angina. N Ens1 d Med 1983:309:396-403. Cairns JA, Gent M, Singer J, et ai Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter study. N Engl J Med 1985;313:1369-75. Theroux P, Quimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319:1105-l 1. Danish Study Group on verapamil in myocardial infarction. Verapamil in acute myocardial infarction. Eur Heart J 1984;5:516-28. Israeli Sprint Study Group. Secondary prevention reinfarction Israeli nifedipine trial (SPRINT). A randomised intervention trial of nifedipine in patients with acute myocardial infarction. Eur Heart J 1988;9:354-64. 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. Gibson RS, Boden WE, Theroux P, et al and the Diltiazem Reinfarction Study Group. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction. N Engl J Med 1986;315:423-9. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71. Silke B, Frais MA, Midtbo KA, et al. Comparative hemodynamic dose-response effects of five slow calcium channelblocking agents in coronary artery disease. Clin Pharmacol Ther 1987;42:381-7. Follath F, Taeschner W. Clinical pharmacology of calcium antagonists. J Cardiovasc Pharmacol 1988;12(suppl 6):S98SlOO. Scardi S, Pandullo C, Pivotti F, Ceschia G, Pollavini G. Acute effects of felodipine in exertional angina pectoris. Am J Cardiol 1988;61:691-5. Schmoeckel M, Arendt RM, Hauck R, Schultheiss HP. Acute and chronic effects of nitrendipine on hemodynamics and myocardial ischemia in patients with combined angina pectoris and hypertension. J Cardiovasc Pharmacol 1988;12(suppl 4):S170-4. Faulkner JK, McGibney D, Chasseaud LF, Perry JL, Taylor IW. The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 reneated oral doses given once dailv. Br J Clin Pharmacol i986;22:21-5. ” Laher MS, Kelly JG, Doyle GD, et al. Pharmacokinetics of amlodipine in renal impairment. J Cardiovasc Pharmacol 1988;12(suppl 7):S60-3. Kinnard DR, Harris M, Hossack KF. Amlodipine in angina pectoris: effect on maximal and submaximal exercise performance. J Cardiovasc Pharmacol 1988;12(suppl 7):SllO-13.
GROUP DISCUSSION Question from the floor.
Would you please expand further on the difference between the dihydropyridine calcium antagonists and other structural types of calcium antagonists in patients with stable angina. F. Follath. There is some debate as to whether a true difference exists between dihydropyridines and verapamil and diltiazem in such patients. In a few studies better efficacy with verapamil and diltiazem has been found, whereas in others no difference was seen. One thing is clear from all studies; verapamil and diltiazem do reduce resting and exercise heart rates, and if we believe that heart rate has anything to do with myocardial ischemia, then it appears logical that in some patients this difference would
Volume 118 Number 5, Part 2
be of clinical relevance. Thus if a patient does not respond adequately to a dihydropyridine calcium antagonist, it is justified to try another type of calcium antagonist, for example, diltiazem or verapamil. This might be necessary in patients who cannot he given P-blockers for some reason, such as preexisting left ventricular dysfunction. J. M. Detry (Brussels, Belgium). Do you think that it is useful in several instances to combine verapamil or diltiazem with a dihydropyridine? F. Follath. The combination of P-blockers and calcium antagonists is clearly effective. However, I am not convinced by the data published until now that a combination of different calcium antagonists will really have a major advantage compared to a single drug used in effective doses. K. Fox. Surely the problem with such an approach is that it depends on the pathophysiologic mechanisms involved in individual patients and how the drug is being profiled against the different mechanisms. For example, results from one study showed that a combination of a fl blocker and either a calcium antagonist or a nitrate was beneficial, but when a third drug was added a detrimental effect was produced, perhaps because of coronary steal. It is difficult to make broad statements, and treatments have to be adjusted against the pathophysiology and the differences in coronary blood flow involved in individual patients. P. Deedwania. Many of the studies that evaluated combination therapy have not necessarily used maximal doses of individual agents and that is one of the major problems, We showed that if nitrates and calcium antagonists (in our work, diltiazem) are compared and if either of the agents is used at maximal doses, adding another agent in patients with stable angina does not really provide significant additional benefit. In that particular study the doses were maximized to a point the patient could tolerate without side effects. Before we rush into combination therapy we should keep in mind that it is necessary to use the maxi-
Calcium
antagonists
in ischemic heart disease
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mal tolerated doses of individual agents and that is one of the weaknesses of many studies with combinations that have been reported. F. Follath. The problem of maximal tolerated doses is a difficult one. Sometimes combinations of lower doses of ,& blockers and lower doses of calcium antagonists may be better tolerated by outpatients. The question of long-term tolerance is of great importance, and the different new cal.cium antagonists may have an advantage with regard to improved tolerance. However, I am often disappointed in my own patients whom I treat with new drugs that were well tolerated in published trials. Many patients seem to have more problems than I would have expected. I think that the long-term tolerance of these drugs will only be established by their long-term use in outpatient practice. There is always some distortion between reported rates of side effects and tolerance in patient groups from clinical studies and in everyday practice. Question from the floor. How would you assessefficacy of a drug in a patient with stable effort angina? Would you perform Holter monitoring or only evaluate the patient with exercise stress testing? The physiopathology of ischemic episodes in an ambulatory situation might be different from the physiopathology of ischemia in the hospital where the patient undergoes stress testing. F. Follath. This is clearly an important point. Results of recent studies have shown that the prognostic importance of ischemic episodes occurring during everyday activities is higher than for episodes resulting from exercise testing. Exercise testing in the laboratory is an artificial situation, and probably long-term monitoring of ischemic episodes, both painful and painless, during everyday activities is more relevant to what happens to patients. Unfortunately, at the present time it is not possible to check all patients treated for coronary artery disease with Holter monitoring.