Thrdioprotection” Icium Antagonists
Not All Are Created Equal
Franz H. Messerli, MD he term “cardioprotection” (“Myokardschutz”)” was coined by Fleckenstein’ more than 2 decades ago to describe the salutatory effects of calcium antagonists on isoproterenol-induced myocardial necrosis. A few years later Nayler et al,* by using verapamil, succeeded in protecting the heart muscle from ischemic injury, an effect that was subsequently documented for other calcium antagonists as we11.3,4These early experimental studies were extended by a variety of clinical and experimental findings attesting to the cardioprotective effect of calcium antagonists. Thus, calcium antagonists were reported to: (1) improve coronary flow; (2) reduce afterload; (3) suppress ventricular arrhythmias; (4) diminish myocardial cell damage by preventing intracellular calcium overload during episodes of ischemia; (5) diminish platelet aggregation in contrast to ,l3 blockers; (6) exert antiatheromatous effects in some animal models; and (7) reduce left ventricular hypertrophy and enhance left ventricular filling not only by improving the active relaxation process but also distensibility-these latter effects seem to be most pronounced in patients with arterial hypertension and can be expected to translate into a therapeutic benefit only after sustained therapy. These promising experimental reports seemed to attest to the attractiveness of calcium antagonists in the treatment of myocardial infarction and coronary artery disease. Recent angiographic studies with verapami15 and nifedipine,h documenting a beneficial effect on coronary stenoses, support the animal data (although they showed no decrease in mortality). However, the attractiveness of calcium antagonists was decidedly put into question less than a year ago by Held et a1,7 who systematically reviewed 28 randomized trials, creating a data base of more than 19,000 patients. They came to the conclusion that “calcium antagonists do not reduce the risk of initial or recurrent infarction or death when given routinely to patients with acute myocardial infarction,” and therefore they discouraged the prophylactic use of calcium antagonists during or after acute myocardial infarction. From the Qchsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana. Manuscript received and accepted June 8, 1990. Address for reprints: Franz H. Messerli, MD, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, Louisiana 70121. “cardioprotection” has become a wastebasket *Unfortunately, term for all kinds of beneficial effects that drug therapy may exert on the heart, ranging from suppression of ventricular ectopy to a decrease in cardiac death rate.
This review was extensively commented on in the lay press, and The Wall Street Journal8 discussed it under the heading “Calcium Channel Blockers Called Ineffective Against Heart Disease.” The disheartening findings and recommendations flew in the face of most of our colleague cardiologists who routinely had been using calcium antagonists in more than 40% of patients after uncomplicated myocardial infarction.9 Held et al7 nevertheless indicated that there was a slight trend toward fewer reinfarctions in patients treated with verapamil and diltiazem (although there was no effect on mortality) and that therefore the data were consistent with the possibility that calcium antagonists that reduced heart rate might reduce the risk of reinfarction. They candidly suggested that this hypothesis “should therefore be interpreted with caution and specifically examined in further trials.” This is exactly what Fischer Hanson and co-workerst” did in a carefully designed double-blinded, randomized, placebo-controlled, multicenter trial assessing the “cardioprotective” effects of verapamil after acute myocardial infarction, The Danish Verapamil Infarction Trial (DAVIT TI).‘O Their previous study, the DAVIT 1,” failed to show a significant reduction of overall mortality or reinfarction rate after 6 months of verapamil treatment. A retrospective subanalysis, however, demonstrated a highly significant reduction in mortality only in the subset of patients who received verapamil from day 2 to day 180. Encouraged by this subanalysis, the investigators embarked on a new study, the DAVIT II, in which treatment was started between day 7 and day 15 after the acute myocardial infarction. As can be seen elsewhere in this issue, DAVIT II documented a significant reduction in the reinfarction rate in the verapamil group when compared with the placebo group, although the difference in the overall mortality rates failed to reach statistical significance. However, by combining data from DAVIT I with DAVIT II, creating a data base of more than 3,100 patients, a reduction of about 25% in major events and deaths was documented in verapamil-treated patients when compared with results in those taking placebo. The results of DAVIT II are provocative, but leave several important questions unanswered: Since “cardioprotection” was documented only when verapamil therapy was begun 1 week after the acute myocardial infarction, how should patients be protected during these first days of the postinfarction period? What are the clinical criteria that allow the practicing physician to decide whether a patient is a candidate for verapam or
THE AMERICAN
JOURNAL
OF CARDIOLOGY
OCTOBER
1. 1990
a p blocker? Should verapamil and a ,0 blocker be combined in certain patients and, if so, can the effect of the two drugs on reinfarction rate be expected to be additive? Is this cardioprotective effect specific to verapamil or can it be considered as a class effect-provided that the calcium antagonist is given 1 week after the acute myocardial infarction? What then are the conclusions that we can draw from the DAVIT II data and how do they fit into the realm of the review by Held and collaborators? Calcium antagonists are a heterogeneous group of drugs. Conceivably, cardioprotective properties (decrease in the reinfarction rate and/or mortality) may vary from one agent to the other and reach clinical significance only in those calcium antagonists that diminish heart rate, as Held et al suggested. Conversely, some calcium antagonists, by producing profound reflexive cardioacceleration, may increase myocardial oxygen requirements and thereby paradoxically increase the risk of myocardial infarction in susceptible patients. Of note, calcium antagonists may also adversely affect prognosis when given during myocardial infarction or very early in the postinfarction period because, in this situation in patients who have a total occlusion, they may merely produce a negative inotropic effect. It seems, therefore, that patients with a noncomplete occlusion and/or good collateral circulation and no symptoms and signs of congestive heart failure are the best candidates for cardioprotective treatment with verapamil. This view is supported and extended by data from the Multicenter Diltiazem Postinfarction Trial Research Group documenting diltiazem to exert a clinical benefit only in patients without pulmonary congestion12 and in those with non-Q-wave infarction.13 Preliminary data indicate that the reduction in reinfarction rate was more pronounced in patients with a history of hypertension.i4 Does the DAVIT II study annihilate the conclusions of the thorough review of Held et al, demonstrating no effects of calcium antagonists after myocardial infarction? Certainly not. However, it should replace therapeutic nihilism (i.e., all calcium antagonists are useless
856
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
in patients with myocardial infarction) by cautious optimism (i.e., certain calcium antagonists, such as verapamil, are beneficial in selected patients in the postinfarction period, significantly reduce reinfarction rates, and may prolong life).
REFERENCES 1. Fleckenstein A. Specific inhibitors and promoters of calcium action in the excitation-contraction coupling of heart muscle and their role in the production or prevention of myocardial lesions. In: Harris P, Opie L, eds. Calcium and the Heart. Proceedings of the Meeting of the European Section of the International Study Group for Research in Cardiac Metabolism. New York: Academic Press, 1970;135~188. 2. Nayler WG, Grau A, Slade A. A protective effect of verapamil on hypoxic heart muscle. Cardiooasc Res 1976:l O:650m662. 3. Fleckenstein A. History of calcium antagonists. Circ Res /983;52(supp/ f)t316. 4. Nagao T, Matlib MA, Franklin D, Millard RW, Schwartz A. Effects of diltiazem, a calcium antagonist, on regional myocardial function and mitochondria after brief coronary occlusion. J Mel Cell Cardiol 1980;12:29-43. 5. Kober G, Schneider W, Kaltenbach M. Can the progression of coronary sclerosis be influenced by calcium antagonists? J Cardiouasc Pharmacol 1989; 13(suppl4):S2-S6. 6. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost S, Deckers JW, and the INTACT Group Investigators. Retardation of angiographic progression of coronary artery disease by nifedipine. Lance? 1990;335:1109-1113. 7. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:/187-1192. 8. Lublin JS. Calcium channel blockers called ineffective against heart disease. Review of 28 studies claims the drugs can’t prevent either attacks or deaths. The Wall Street Journal, November 10, 1989;B4. 9. Hlatky MA, Cotugno HE, Mark DB, O’Connor C, Califf R. Trends in physician management of uncomplicated acute infarction, 1970 to 1987. Am J Cardiol 1988;6/:515-518. 10. The Danish Study Group on Verapamil in Myocardial Infarction. The effect of verapamil on mortality and major events after myocardial infarction. The Danish verapamil infarction trial 11 (DAVIT II). Am J Cardio/l990;66:779-785. 11. The Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Eur Heart J /984:5:516-528. 12. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385-392. 13. Gibson RS, Boden WE, Theroux P, Strauss HD, Pratt CM, Gheorghiade M, Capone RJ, Crawford MH, Schlant RC, Kleiger RE, Young PM, Schechtman K, Perryman MB, Roberts R, and The Diltiazem Reinfarction Study Group. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction: results of a double-blind, randomized multicenter trial. N Engl J Med 1986;3/5:423S429. 14. Moss AJ, Rubison M, Oakes D, Carleen E, Eberly S, Brown M, and the Multicenter Diltiazem Postinfarction Trial (MDPIT) Research Group. Effect of diltiazem on long-term outcome in post-infarction patients with a history of hypertension (abstr). Circulation 1989;(suppl ll)8O:lI:II-268.
Not All Are Created Equal
Franz H. Messerli, MD he term “cardioprotection” (“Myokardschutz”)” was coined by Fleckenstein’ more than 2 decades ago to describe the salutatory effects of calcium antagonists on isoproterenol-induced myocardial necrosis. A few years later Nayler et al,* by using verapamil, succeeded in protecting the heart muscle from ischemic injury, an effect that was subsequently documented for other calcium antagonists as we11.3,4These early experimental studies were extended by a variety of clinical and experimental findings attesting to the cardioprotective effect of calcium antagonists. Thus, calcium antagonists were reported to: (1) improve coronary flow; (2) reduce afterload; (3) suppress ventricular arrhythmias; (4) diminish myocardial cell damage by preventing intracellular calcium overload during episodes of ischemia; (5) diminish platelet aggregation in contrast to ,l3 blockers; (6) exert antiatheromatous effects in some animal models; and (7) reduce left ventricular hypertrophy and enhance left ventricular filling not only by improving the active relaxation process but also distensibility-these latter effects seem to be most pronounced in patients with arterial hypertension and can be expected to translate into a therapeutic benefit only after sustained therapy. These promising experimental reports seemed to attest to the attractiveness of calcium antagonists in the treatment of myocardial infarction and coronary artery disease. Recent angiographic studies with verapami15 and nifedipine,h documenting a beneficial effect on coronary stenoses, support the animal data (although they showed no decrease in mortality). However, the attractiveness of calcium antagonists was decidedly put into question less than a year ago by Held et a1,7 who systematically reviewed 28 randomized trials, creating a data base of more than 19,000 patients. They came to the conclusion that “calcium antagonists do not reduce the risk of initial or recurrent infarction or death when given routinely to patients with acute myocardial infarction,” and therefore they discouraged the prophylactic use of calcium antagonists during or after acute myocardial infarction. From the Qchsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana. Manuscript received and accepted June 8, 1990. Address for reprints: Franz H. Messerli, MD, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, Louisiana 70121. “cardioprotection” has become a wastebasket *Unfortunately, term for all kinds of beneficial effects that drug therapy may exert on the heart, ranging from suppression of ventricular ectopy to a decrease in cardiac death rate.
This review was extensively commented on in the lay press, and The Wall Street Journal8 discussed it under the heading “Calcium Channel Blockers Called Ineffective Against Heart Disease.” The disheartening findings and recommendations flew in the face of most of our colleague cardiologists who routinely had been using calcium antagonists in more than 40% of patients after uncomplicated myocardial infarction.9 Held et al7 nevertheless indicated that there was a slight trend toward fewer reinfarctions in patients treated with verapamil and diltiazem (although there was no effect on mortality) and that therefore the data were consistent with the possibility that calcium antagonists that reduced heart rate might reduce the risk of reinfarction. They candidly suggested that this hypothesis “should therefore be interpreted with caution and specifically examined in further trials.” This is exactly what Fischer Hanson and co-workerst” did in a carefully designed double-blinded, randomized, placebo-controlled, multicenter trial assessing the “cardioprotective” effects of verapamil after acute myocardial infarction, The Danish Verapamil Infarction Trial (DAVIT TI).‘O Their previous study, the DAVIT 1,” failed to show a significant reduction of overall mortality or reinfarction rate after 6 months of verapamil treatment. A retrospective subanalysis, however, demonstrated a highly significant reduction in mortality only in the subset of patients who received verapamil from day 2 to day 180. Encouraged by this subanalysis, the investigators embarked on a new study, the DAVIT II, in which treatment was started between day 7 and day 15 after the acute myocardial infarction. As can be seen elsewhere in this issue, DAVIT II documented a significant reduction in the reinfarction rate in the verapamil group when compared with the placebo group, although the difference in the overall mortality rates failed to reach statistical significance. However, by combining data from DAVIT I with DAVIT II, creating a data base of more than 3,100 patients, a reduction of about 25% in major events and deaths was documented in verapamil-treated patients when compared with results in those taking placebo. The results of DAVIT II are provocative, but leave several important questions unanswered: Since “cardioprotection” was documented only when verapamil therapy was begun 1 week after the acute myocardial infarction, how should patients be protected during these first days of the postinfarction period? What are the clinical criteria that allow the practicing physician to decide whether a patient is a candidate for verapam or
THE AMERICAN
JOURNAL
OF CARDIOLOGY
OCTOBER
1. 1990
a p blocker? Should verapamil and a ,0 blocker be combined in certain patients and, if so, can the effect of the two drugs on reinfarction rate be expected to be additive? Is this cardioprotective effect specific to verapamil or can it be considered as a class effect-provided that the calcium antagonist is given 1 week after the acute myocardial infarction? What then are the conclusions that we can draw from the DAVIT II data and how do they fit into the realm of the review by Held and collaborators? Calcium antagonists are a heterogeneous group of drugs. Conceivably, cardioprotective properties (decrease in the reinfarction rate and/or mortality) may vary from one agent to the other and reach clinical significance only in those calcium antagonists that diminish heart rate, as Held et al suggested. Conversely, some calcium antagonists, by producing profound reflexive cardioacceleration, may increase myocardial oxygen requirements and thereby paradoxically increase the risk of myocardial infarction in susceptible patients. Of note, calcium antagonists may also adversely affect prognosis when given during myocardial infarction or very early in the postinfarction period because, in this situation in patients who have a total occlusion, they may merely produce a negative inotropic effect. It seems, therefore, that patients with a noncomplete occlusion and/or good collateral circulation and no symptoms and signs of congestive heart failure are the best candidates for cardioprotective treatment with verapamil. This view is supported and extended by data from the Multicenter Diltiazem Postinfarction Trial Research Group documenting diltiazem to exert a clinical benefit only in patients without pulmonary congestion12 and in those with non-Q-wave infarction.13 Preliminary data indicate that the reduction in reinfarction rate was more pronounced in patients with a history of hypertension.i4 Does the DAVIT II study annihilate the conclusions of the thorough review of Held et al, demonstrating no effects of calcium antagonists after myocardial infarction? Certainly not. However, it should replace therapeutic nihilism (i.e., all calcium antagonists are useless
856
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
in patients with myocardial infarction) by cautious optimism (i.e., certain calcium antagonists, such as verapamil, are beneficial in selected patients in the postinfarction period, significantly reduce reinfarction rates, and may prolong life).
REFERENCES 1. Fleckenstein A. Specific inhibitors and promoters of calcium action in the excitation-contraction coupling of heart muscle and their role in the production or prevention of myocardial lesions. In: Harris P, Opie L, eds. Calcium and the Heart. Proceedings of the Meeting of the European Section of the International Study Group for Research in Cardiac Metabolism. New York: Academic Press, 1970;135~188. 2. Nayler WG, Grau A, Slade A. A protective effect of verapamil on hypoxic heart muscle. Cardiooasc Res 1976:l O:650m662. 3. Fleckenstein A. History of calcium antagonists. Circ Res /983;52(supp/ f)t316. 4. Nagao T, Matlib MA, Franklin D, Millard RW, Schwartz A. Effects of diltiazem, a calcium antagonist, on regional myocardial function and mitochondria after brief coronary occlusion. J Mel Cell Cardiol 1980;12:29-43. 5. Kober G, Schneider W, Kaltenbach M. Can the progression of coronary sclerosis be influenced by calcium antagonists? J Cardiouasc Pharmacol 1989; 13(suppl4):S2-S6. 6. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jost S, Deckers JW, and the INTACT Group Investigators. Retardation of angiographic progression of coronary artery disease by nifedipine. Lance? 1990;335:1109-1113. 7. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:/187-1192. 8. Lublin JS. Calcium channel blockers called ineffective against heart disease. Review of 28 studies claims the drugs can’t prevent either attacks or deaths. The Wall Street Journal, November 10, 1989;B4. 9. Hlatky MA, Cotugno HE, Mark DB, O’Connor C, Califf R. Trends in physician management of uncomplicated acute infarction, 1970 to 1987. Am J Cardiol 1988;6/:515-518. 10. The Danish Study Group on Verapamil in Myocardial Infarction. The effect of verapamil on mortality and major events after myocardial infarction. The Danish verapamil infarction trial 11 (DAVIT II). Am J Cardio/l990;66:779-785. 11. The Danish Study Group on Verapamil in Myocardial Infarction. Verapamil in acute myocardial infarction. Eur Heart J /984:5:516-528. 12. The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385-392. 13. Gibson RS, Boden WE, Theroux P, Strauss HD, Pratt CM, Gheorghiade M, Capone RJ, Crawford MH, Schlant RC, Kleiger RE, Young PM, Schechtman K, Perryman MB, Roberts R, and The Diltiazem Reinfarction Study Group. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction: results of a double-blind, randomized multicenter trial. N Engl J Med 1986;3/5:423S429. 14. Moss AJ, Rubison M, Oakes D, Carleen E, Eberly S, Brown M, and the Multicenter Diltiazem Postinfarction Trial (MDPIT) Research Group. Effect of diltiazem on long-term outcome in post-infarction patients with a history of hypertension (abstr). Circulation 1989;(suppl ll)8O:lI:II-268.
