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Verapamil and angiotensin-converting enzyme inhibitors in patients with coronary artery disease and reduced left ventricular ejection fraction
Verapamil and Angiotensin-Converting Enzyme Inhibitors in Patients with Coronary Artery Disease and Reduced Left Ventricular Ejection Fraction J. Fischer Hansen, MD, PhD, Lisbeth Tingsted, MD, Verner Rasmussen, MD, Johnny K. Madsen, MD, and Christian M. Jespersen, MD, DMSC Verapamil is effective as antianginal medication but contraindicated in patients with congestive heart failure. Angiotensin-converting enxyme (ACE) inhibitors improve survival in patienk with congestive heart failure but have limited effect on patients with angina pectoris. No studies have been published on the combined treatment with verapamil and ACE inhibitors in patients with stable angina pectoris and left ventricular dysfunction. We performed an open study in 14 patients with angina pectoris and ejection fraction <40%. The patients received verapamil 180 mg and trandolapril2 mg twice daily for 3 months. We found a significant increase in
ejection fraction from 28~6 to 35~ 1 T (p <0.03), wall motion index from 1.020.3 to 1.2kO.3 (p <0.03), exercise duration from 6.922.5 to 7.722.9 minutes (p co.01 ), and ratio of exercise to rest rate-pressure product from 2.2kO.4 to 2.520.6 (p <0.02). Use of nitroglycerin and number of ‘angina pectoris attacks were both significantly reduced after 3 months of treatment. These findings support the hypothesis that the combination of verapamil and trandolapril is useful in patienk with attenuated left ventricular function and angina pectoris. (Am J Cardiol 1996;77: 16D2 1 D)
erapamil, the first synthetized phenylalkylamine V calcium channel antagonist, is used in the treatment of a large variety of diseases, e.g., stable an-
Angiotensin-converting enzyme (ACE) inhibitors are strong arteriolar vasodilators that inhibit sympathetic drive l5 and prevent remodeling and dilation of the left ventricle after an acute myocardial infarction I6 and in patients with chronic congestive heart failure.” Opie’s group I8 demonstrated in pigs that the ACE inhibitor trandolapril prevented a fall in the ventricular fibrillation threshold during ischemia, ventricular fibrillation during reperfusion, and inhibited cardiac ACE activity. These effects have been used to explain the beneficial effect of ACE inhibitors on survival in postinfarct patients ‘9-2’ and in patients with symptomatic or asymptomatic attenuated left ventricular function.22.23 Although ACE inhibitors did not prevent attacks of angina in patients with heart failure and stable angina pectoris,24 they prevented ischemia by vasodilation and unloading of left ventricle and may prevent ventricular and supraventricular arrhythmias for the same reasons.25-28 Treatment of angina pectoris in patients with congestive heart failure and systolic dysfunction of the left ventricle can be difficult and is often based on use of vasodilators, e.g., long-acting nitrates. Another possibility might be to combine the anti-ischemit properties of verapamil with the vasodilator properties of an ACE inhibitor. Another advantage may be that both types of drugs inhibit the neuroendocrine system.29 However, we need further information about the consequences of this combination in patients with stable angina and attenuated left ventricular function. For these reasons, we decided to conduct an open study in patients with angina pectoris and left ventricular dysfunction on the effect of combined treatment with verapamil and trandolapril on left ventricular function evaluated from isotope ventriculography, echocardiography, exercise test-
gina, vasospastic angina, hypertension, supraventricular tachycardia, atria1 fibrillation, and secondary prophylaxis after an acute myocardial infarction.‘,’ The effect of verapamil is explained by vasodilator, negative inotropic and chronotropic properties, and protection of myocardial cell structures and function during ischemia.2 Verapamil is considered contraindicated in patients with heart failure,3 but in the Second Danish Verapamil Infarction Trial (DAVIT II) long-term 18-month treatment with verapamil in postinfarct patients was associated with a significant reduction in the use of diuretics compared with placebo treated patients,435 This effect of verapamil could be explained by prevention of stunning and hibernation, which may be major causes of congestive heart failure in patients with coronary artery diseases.6 Verapamil has been proven to prevent deterioration of diastolic function during ischemia in patients with coronary artery disease.7-9 Verapamil prevents the reduction of the fibrillation threshold lo and the conduction delay, which may predispose to ventricular arrhythmias, caused by myocardial ischemia.” Further, verapamil reduces the liberation of catecholamines during ischemia, ‘* circulating catecholamines during long-term treatment, l3 and myocardial oxygen consumption.‘4 From the Department of Cardiology and Physiology, Hvidovre University Hospital, This study was supported by a grant from Germany. Address for reprints: J. Fischer Hansen, Cardiology, Hvidovre University Hospital, mark.
16D
0 1996 by Excerpt0 All rights reserved.
Medica,
Inc.
Department of Clinical Copenhagen, Denmark. Knoll AG, Ludwrgshafen, MD, PhD, Department of DK-26.50 Hvidovre, Den-
0002-9149/96/$15.00 PII SOOO2-9149(96)00303-7
r
TABLE
I Findings
at Start
and Termination
of Trial
Medication Patients
Serum creatinine (pmol/L) Plasma urea (mmol/L) Serum potassium (mmol/L) Serum sodium (mmol/L) Exercise duration (min) Increase in rate-pressure product Cardiothoracic index Left ventricular ejection fraction Left ventricular wall motion index Ventricular ectopic beats (mean/h) ST depression >O. 1 mV Episodes/24 h Minutes/24 h Maximal (mV)
[no.)
Start
14
from rest to exercise
95+ 5.4 + 3.9 2 14123 6.9 2 2.2 2 50.4 k 28 2 1 .o 2 174 ?
14 14 14 13 13 14 13 11 13 13
3 Months 18
1.0 0.4 2.5 0.4 4.6 6 0.3 250
25 k 34 126 + 216 1.6 + 1.4
96% 5.72 4.0 ‘139t3 7.7 ? 2.5 ? 49.6 k 35 k 1.2 ? 100 2
p Value*
19 1.3 0.3 2.9 0.6 4.7 11 0.3 159
NS NS NS NS
0.01 0.02 NS 0.03 0.03 NS
11 221 36 +- 80 0.11 20.11
NS NS NS
* NS = not significant.
ing, and Holter monitoring. At the same time, we evaluated changes in clinical chemical parameters and chest radiographs.
METHODS
AND
PATIENTS
Included were patients with stable angina pectoris, with a left ventricular ejection fraction <40%, in New York Heart Association function group II-III, able to perform an exercise test on a bicycle ergometer, which should demonstrate an ST-segment depression, horizontal or downsloping, of at least 0.1 mV. Exclusion criteria: Excluded were patients treated with vasodilators within the last 2 weeks, and with QRS ~0.12 set, significant valvular heart disease, sinoatrial block, 2nd or 3rd degree atrioventricular block, atria1 fibrillation, known intolerance to ACE inhibitors and verapamil, serum creatinine level >200 pmol/L, and inability or unwillingness to give written informed consent. Medication: Trial medication consisted of 1 capsule once daily for 2 weeks and then 1 capsule twice daily for 10 weeks. A capsule contained verapamil 180 mg and trandolapri12 mg. Treatment period: Treatment started after the patient had been in a stable clinical phase for at least 2 weeks without change in medication and without treatment with vasodilators apart from sublingual nitroglycerin to treat attacks of angina pectoris. Hoiter monitoring: Twenty-four-hour ambulatory electrocardiographic (ECG) monitoring was made using 2 channel tape recorders (SpaceLabs 90205) and analyzed semiautomatically by a computer program (SpaceLabs FT 3000) .30 Significant ST deviation was defined as ST depression of at least 0.1 mV or ST elevation above 20.15 mV measured 60 msec after the J point. All ST episodes were visually checked and were required to last at least 1 minute and be separated from adjacent ST episodes by at least 1 minute. Chest radiographs: Cardiothoracic index was measured on a standing chest radiograph in the anteroposterior projection. inclusion
criteria:
Other techniques: Isotope ventriculography of the left ventricle was used to determine left ventricular ejection fraction.31 Echocardiography was performed in accordance with established recommendations.32 Wall motion index was calculated from a 9-segment mode1.33 Clinical chemical parameters were analyzed in accordance with the standard methods of Hvidovre University Hospital. Angina pectoris attacks and nitroglycerin consumption were recorded by the patient. Statistical methods: Student’s t test for paired data was used to compare measurements at start and at the end of the treatment period; p <0.05 is considered statistically significant. Ethics: Written informed consent was obtained from all patients. The study was approved by the local ethical committee.
RESULTS Patients: Twenty-one patients started treatment with trial medication. Seven patients stopped for the following reasons: 1 patient did not want to continue in the study after 2 weeks, 1 patient was not compliant and stopped after 2 weeks, 2 were stopped by the treating physician (1 because the patient was offered bypass surgery); in none of these 4 patients were adverse effects reported. A fifth patient was seen in the outpatient clinic because he complained of worsening dyspnea 50 days after treatment start. Clinical examination, chest radiograph, and electrocardiogram were unchanged without signs of heart failure or myocardial ischemia; trial medication was stopped but 3 days later the patient was admitted after a short episode of lipotymia (fainting). Again, no signs of heart failure or myocardial ischemia was found, but the patient died 3 hours after admission after cardiac arrest due to ventricular fibrillation. Autopsy was not allowed, but most likely the patient died from a new myocardial infarction. A sixth patient died from pneumonia 10 days after treatment start. Autopsy demonstrated unexpectedly a malignant lymphoma, but no reinfarction was found. And finally a seventh A SYMPOSIUM:
CALCIUM
ANTAGONISM
IN CAD
170
n = 13 minutes 16
n = 13
%
start
70
3 months
start
3 months
60
14
2
6.9k2.5
p eo.01
,.
7.A2.9
p co.03
28.2k5.7
35.2* 11 .I
0 0 FIGURE 1. Exercise medication.
duration
at start and after
3 months
on trial
FIGURE 3. left vent&jar tope ventriculogmphy
ejection fraction evaluated from isoat start and after 3 montlis of trial medica-
n = 13
n = 11
2
5
start
3 months
start 4
‘.5
jnths ----_
-----
---
I>> ----___
----__
------¤
0.5 1
1.0*0.3 2.21k0.4
p CO.02
p co.03
1.2 io.3
2.53k0.6 0
0 FIGURE 2. Ratio of exercise to resti rate-pressure start and after 3 months on trial m 3 ration.
product
FIGURE 4. Echocardiographic wall motion index at start cation.
at
patient had been on trial medication for 11 weeks when she was found dead, probably a case of sudden cardiac death as she had been doing well in the study period and had been in daily contact with a daughter without uttering complaints to her. Twelve men and 2 women with a mean age 65 years (range, 51-77) completed the study. All patients had a history of angina pectoris, 5 had 1 and 7 had 2 previous myocardial infarcts. Myocardial ixhemia: Information about nitroglycerin consumption and angina pectoris attacks reported by the patients was available in 13 patients. Prior to study start, the number of angina pectoris attacks was reported to be a mean of 7 per week (range, l-20) and of nitroglycerin consumption was 18D
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and
determined left ventricular after 3 months on trial medi-
a mean of 9 per week (range, 1 - 25 ) . At the end of the study period based on the last 4 weeks, the corresponding figures were angina pectoris 2 per week (range, O-8; p <0.02) and nitroglycerin consumption of 3 per week (range, 0- 13; p <0.02). Holter monitoring did not demonstrate any statistically significant changes in number of ventricular ectopic beats or of ST-segment depressions (Table I). No patient had ST elevations. left ventricular function: Exercise duration increased slightly but significantly (Figure 1) and was associated with a significant increase in the ratio of systolic arterial blood pressure times heart rate from rest to exercise (Figure 2). Left ventricular ejection fraction increased significantly (Figure 3)) as did left JUNE
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1996
ventricul7.r M.J.~.motion index (Figure 4). Cardiothoracic j!lde x c;? unchanged. No sigri :,r~i :hanges were recorded in serum creatinine .+‘:I I III i.; ea, serum potassium, or serum sodium (i :I; !c I>. Diure’ ir~&nerrt iiive patients did not receive diuretics, ::.rients were treated with bendroflumethiazide I ..\ - IO mg/day, and 4 patients with furosemide A:i J-- 160 mg/ day, unchanged from start to the end of ehc ‘JI~:dy period. One patient was treated with furosemici _I 40 mg/day at start and with furosemide 160 mg/ci:iy at the enr, rhe last patient was treated with fu:-o!;elr,ide 120 rr\;Tand spironolactone 100 mg/ day at !h? :;i:lrt and fur;.;sernide 160 mg/day and spironolact
Calcium antagonists and ACE inhibitors trials: Calcium ‘antagonists are prescribed
in various
to a large number of patients with reduced ejection fraction or clinical heart failure as evaluated from the SOLVD study 22,23in which 3 1% and 35%, the SAVE study l9 in which 42%, the AIRE study2’ in which 16%, and the Survival of Myocardial Infarction Long-term Evaluation (SMILE) tria12’ in which 10% of the patients were treated with calcium channel antagonists at randomization. Limited information is available about the events in patients treated compared with those not treated by calcium channel antagonists. No information is available about the type of calcium channel antagonist used nor the indication for the use of a calcium antagonist in patients included in these 5 studies. DISCUSSION In SAVE, the mortality rate in calcium channel Many attempts have been made to use calcium antagonist-treated patients was 24.8% in placeboantagonists in the treatment of congestive heart fail- and 20.6% in captopril-treated patients, correspondure.34-36 The basis is the vasodilator effect with af- ing to a risk reduction of 19% (95% confidence interload reduction and dilation of the coronary arteries terval [CI], -7,38). In patients not treated with calwith improvement of oxygen supply and reduction cium channel antagonists, the corresponding figures of oxygen demand. So far, no long-term clinical were placebo 24.6% and capto ril 20.4%, risk restudy has demonstrated a beneficial clinical effect. duction 19% (95% CI, -2,36). li These disappointing results might be due to the negFrom the AIRE study, less information is availative inotropic effect of calcium antagonists or to a able. Mortality rate was significantly reduced in padeterioration of oxygen supply to the myocardium tients prescribed a calcium channel antagonist and due to fall in arterial diastolic blood pressure with given ramipril when compared with placebo, with a reduction of coronary blood fiow and perhaps reflex relative hazard of 0.59. In patients not prescribed tachycardia and increased use of oxygen.3 calcium channel antagonists, a significant beneficial One possible reason for development of conges- effect of ramipril versus placebo was also observed, tive heart failure or attenuation of left ventricular relative hazard of 0.76.20 No information is available systolic function in patients with coronary artery dis- of the mortality rate in calcium channel antagonistease is stunning due to repeated periods of myocarversus non-calcium channel antagonist-treated padial ischemia.‘j This might be prevented by verap- tients. In the SOLVD trials, information is available amil,7-9 which has been demonstrated to be an effective antianginal agent in patients with stable an- about the effect of enalapril compared with placebo gina pectoris.37 In DAVIT II, which compared the on myocardial infarction or hospitalization for aneffect of verapamil versus placebo in postinfarct pa- gina pectoris. In calcium channel antagonist-treated tients, use of diuretics was significantly lower in the patients, the event rates were placebo 36.1%, enaverapamil compared with the placebo group after lapril 29.7% (reduction of risk ratio of 21%; 95% CI, 9,3 1) and in patients not receiving calcium chan12 months, an effect that might be explained by prevention of ischemia by veraparnil.“*538 nel antagonists 19.7% versus 16.4% (reduction of ACE inhibitors have been demonstrated effec- risk ratio of 22%; 95% CI, 11,32) .25 tively to reduce mortality in postinfarct patients with In the SMILE study21 the calcium channel antagcongestive heart failure in the Acute Infarction Ra- onist-treated patients had an event rate of 15.8% in mipril Efficacy (AIRE) study,” in patients with left placebo and 2.7% in zofenopril-treated patients (p = ventricular ejection fraction <40% in the Survival 0.005; risk ratio of 14%; 95% CI, 3,66). The corand Ventricular Enlargement (SAVE) trial, l9 and in responding figures in patients not on calcium channel patients with ejection fraction <35% with21 or withantagonists were 10.0% and 7.6% (p = 0.12; risk out22 clinical symptoms of congestive heart failure ratio of 74%; 95% CI, 51,107). in the Studies of Left Ventricular Dysfunction From these findings in the AIRE, SAVE, (SOLVD) trials. The ACE inhibitor captopril was SOLVD, and SMILE trials, it is not possible to denot found to be effective in prevention of stable an- termine if the combination of treatment with an ACE gina pectoris in patients with heart failure.24 ACE inhibitor and a calcium channel antagonist has a inhibitors seem to prevent myocardial ischemia by harmful, a beneficial, or no effect in patients with unloading of the left ventricle, by prevention of di- heart failure or low ejection fraction with or without lation and remodeling of the left ventricle both in previous myocardial infarction. postinfarct patients l6 and in patients with an ejection Present study: No systematic observations are fraction <35%, l7 by inhibition of local ACE activ- available concerning the combined effect of calcium ity, ‘* and by attenuation of the activation of the sym- channel antagonists and ACE inhibitors in patients pathetic nervous system.13,15”9 with stable angina pectoris and ejection fraction A SYMPOSIUM: CALCIUM ANTAGONISM
IN CAD
19D
~40%. A study on the combination of verapamil and enalapril in patients with systemic hypertension was recently published; this study demonstrated an improvement of left ventricular function evaluated from isotope ventriculography.41 We wanted to conduct the present open study to see if the combination of verapamil and trandolapril would be beneficial to left ventricular function. As demonstrated in the figures, after 3 months of treatment, left ventricular ejection fraction and wall motion index were increased, there was improvement in exercise capacity, and an increase in rate-pressure product from rest to exercise was demonstrated. Results of Holter monitoring are in accordance with reduced myocardial ischemia, as is the reduction in number of angina pectoris attacks and in nitroglycerin consumption. No deterioration was found in renal function evaluated from serum creatinine or plasma urea, and serum potassium and serum sodium were unchanged. Except in 1 patient, use of diuretics was unchanged. This study thus demonstrated that an improvement of left ventricular function took place during treatment with a combination of verapamil and trandolapril. Of course, it cannot be excluded that such an improvement would have taken place on treatment with trandolapril alone in accordance with the improvement of left ventricular function demonstrated in the SOLVD studies.” The anti-ischemic effect of verapamil might explain the effect, too.42 Also, attenuation of an activated neuroendocrine system might be important.29 The next steps in the evaluation of the combined effect of trandolapril and verapamil will be first a double-blind pilot study of 100 postinfarct patients with congestive heart failure comparing the clinical effect of trandolapril versus trandolapril plus verapamil; second, a double-blind study comparing the same drugs in patients with stable angina pectoris and left ventricular ejection fraction <40%. 1. Opie LH. Clinical use of calcium antagonist drugs. Boston: Kluwer Academic Publishers, 1990. 2. Opie LH. Myocardial protection by calcium antagonists. New York: Author’s Publishing House, 1994. 3. Packer M. Pathophysiological mechanisms underlying the adverse effect of calcium channel-blocking drugs in patients with chronic heart failure. Circulation 1989;8O(suppl IV):IV-59-IV-67. 4. 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 (DAVIT) II. Am .I Cardiol 1990;66:779-785. 5. Danish Study Group on Verapamil in Myocardial Infarction. Secondary prevention with verapamil after myocardial infarction. Am J Cardiol1990;66:331401. 6. Nayler WC?. Calcium antagonists, stunning, hibernation: an overview. In: Opie LH, cd. Stunning, Hibernation and Calcium in Myocardial Ischemia and Reperfusion. Boston: Kluwer Academic Publishers, 1992226-234. 7. Betocchi S, Piscione F, Perrone-Filardi P, Pace L, Capelli-Bigazzi M, Alfano B, Ciarmiello A, Salvatore M, Condorelli M, Chiariello M. Effects of intravenous verapamil on left ventricular relaxation and filling in stable angina pectotis. Am J Cardiol 1990;66:818-825. 8. Lahiri A, Rodriges AE, Caboni PR, Raftery ER. Effect of long term treatment with calcium antagonists on left ventricular diastolic function in stable angina pectoris and heart failure. Circulation 1990;81 (suppl III):III-130-111-138. 9. Serato JF, Zaret BL, Schuhnan DS, Black HR, Soufer R. Usefulness of verapamil on congesti\re heart failure associated with abnormal left ventricular filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981-986. 20D
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10. Trandroyen FT, Higginson L, Opie LH. The influence of verapamil and its isomers on vulnerabiity to ventricular fibrillation during acute myocardial ischemia and adrenergic stimulation in isolated rat heart. .I Mel Cell Cardiol 1986;18:645-649. 11. Peter T, Fujimoto T, Hamatnoto H, Mandel WJ. Comparative study of the effects of slow calcium inhibiting agents on ischemia-induced conduction delay as relevant to the genesis of ventricular fibrillation. Am Hearf J 1983;106: 10231028. 12. Richardt
Cl, Haass M, Schamig A. Calcium antagonists and cardiac noradrenaline release in ischemia. J Mel Cell Cardiol 1991;23:269-277. 13. Wall& NH, Held C, Rehnqvist N, Hjemdahl P. Platelet aggregability in viva is attenuated by verapamil but not metoprolol in patients with stable angina pectoris. Am J Cardiol 1995;75:1-6. 14. Chung N, Wu X, Ritman EL. LV oxygen consumption and pressure-volume area: role of norepinepbrine and verapamil. Am .I Physiol 1991;261:H77-H82. 15. Young JB. Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials. Cardiovasc Drugs Ther 1995;9:89-102. 16. Sutton M St J, Pfeffer MA, Plappert T, Rouleau JL, Moye LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S, Menapace FJ, Parker JO, Lewis S, Sestier F, Gordon DF, McEvan P, Bernstein V, Braunwald E, SAVE Investigators. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effect of captopril. Circulation 1994;89:68-75.
17. Greenberg B, Quinones MA, Koilpillar C, Limacher M, Shindler D, Benedict C, Shelton B, SOLVD Investigators. Effect of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiographic substudy. Circulation 1995;91:25732581. 18. Muller CA, Opie LH, Peisach M, Pineda CA. Chronic oral treatment with the angiotensin-converting enzyme inhibitor, trandolapril decreases ventricular fibrillation in acute ischemia and reperfusion. Eur Heart J 1994;15:988-996. 19. Pfeffer MA, Braunwald E, MoyC L, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins M, SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992;327:669-677. 20. The Acute Infarction
Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lance? 1993;342:821-828. 21. Ambrosioni E, Borghi C, Magnani B, SMILE Study Investigators. The effect of angiotensin-converting enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-85. 22. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293-302. 23. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med 1992;327:685-691. 24. Cleland JGF, Henderson E, McLenachan J, Findlay IN, Dargie HJ. Effect of captopril, an angiotensin-converting enzyme inhibitor in patients with angina pectoris and heart failure. JAm Coil Cardiol 1991;17:733-739. 25. Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancer 1992;340:1173-1178. 26. Segaard P, Getzsche C-O, Ravkilde J, Thygesen K. Effects of captopril on ischemia and dysfunction of the left ventricle after myocardial infarction. Circulation 1993;87:1093-1099, 27. Ssgaard P, Gstzsche C-O, Ravkilde J, Nergaard A, Thygesen K. Ventricular arrhythmias in the acute and chronic phases after acute myocardial infarction. Effect of intervention with captopril. Circulation 1994;90: lOl- 107. 28. Rutherford JD, Pfeffer MA, Moyd LA, Davis BR, Flaker GC Kowey PR, Lamas GA, Miller HS, Packer M, Rouleau JL, Braunwald E, SAVE Investigators. Effect of captopril on ischemic events after myocardial infarction. Results of the survival and ventricular enlargement trial. Circulation 1994;90:1731-1738. 29. Remme WJ, Kruyssen DACM, Look MP, Bootsma M, deLeeuw PW. Systemic and cardiac neuroendocrine activation and severity of myocardial ischemia in humans. JAm Co11 Cardiol 1994;23:82-91. 30. Jespersen CM, Rasmussen V. Detection of myocardial ischemia by transthoracic leads in ambulatory electrocardiographic monitoring. Br Heart J 1992;68:286-290. 31. Marving J, Heilund-Carlsen PF, Chraxnmer-Jorgensen B, Gadsbell N, Jensen BH. Are right and left ventricular ejection fractions equal? Ejection fractions in normal subjects and in patients with first acute myocardial infarction. Circulation 1985;72:502-514. 32. American Society of Echocardiography Committee on Standards, subcommittee on Quantitation of Two-Dimensional Echocardiograms. Reconnnendations for quantitation of the left ventricle by two-dimensional echocardiography. JAm Sot Echocardiogr
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33. Heger JJ, Weyman AE, Warm LS, Dillon JC, Feigenbaum H. Cross sectional echocardiography in acute myocardial infarction: detection and localization of regional left ventricular asynergy. Circularion 1979;60:53 l-538. 34. Goldstein RE, Buccuzzi SJ, Cruess D. Diltiazem increases late onset congestive heart failure in post infarct patients with early reduction in ejection fraction. Circulation 1991;83:52-60. 35. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahimtoola SH. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbid dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990;82:1954-1961. 36. Littler WA, Sheridan DJ, UK Study Group. Placebo controlled trial of felodipine in patients with mild to moderate heart failure. Br Heart J 1995;73: 428-433. 37. Cutler NR, Anders RJ, Jhee SS, Sramek JJ, Awan NA, Bultas I, Lahiri A,
Woroszylska M. Placebo-controlled evaluation of three doses of a controlledonset, extended-release formulation of verapamil in the treatment of stable angina pectoris. Am .I Cardid 1995;75: 1102- 1106.
38. Jespersen CM, DAVIT Study Group. The effect of verapamil on major events in patients with impaired cardiac function recovering from acute myocardial infarction. Eur Heart .I 1993;14:540-545. 39. Lindsay HSJ, Zaman AG, Cowan JC. ACE-iibitotx after myocaniial infarction: patient selection or treatment for all. Br Heart J 1995;73:397-400. 40. MovC LA. Pfeffer MA. Won CC. Davis BR. G&man E. Haves D. Famham DJ, Randall OS, Dinh H, LoId JMO, Koper&th AJ, Hager
A SYMPOSIUM:
CALCIUM
ANTAGONISM
IN CAD
21D
ejection fraction from 28~6 to 35~ 1 T (p <0.03), wall motion index from 1.020.3 to 1.2kO.3 (p <0.03), exercise duration from 6.922.5 to 7.722.9 minutes (p co.01 ), and ratio of exercise to rest rate-pressure product from 2.2kO.4 to 2.520.6 (p <0.02). Use of nitroglycerin and number of ‘angina pectoris attacks were both significantly reduced after 3 months of treatment. These findings support the hypothesis that the combination of verapamil and trandolapril is useful in patienk with attenuated left ventricular function and angina pectoris. (Am J Cardiol 1996;77: 16D2 1 D)
erapamil, the first synthetized phenylalkylamine V calcium channel antagonist, is used in the treatment of a large variety of diseases, e.g., stable an-
Angiotensin-converting enzyme (ACE) inhibitors are strong arteriolar vasodilators that inhibit sympathetic drive l5 and prevent remodeling and dilation of the left ventricle after an acute myocardial infarction I6 and in patients with chronic congestive heart failure.” Opie’s group I8 demonstrated in pigs that the ACE inhibitor trandolapril prevented a fall in the ventricular fibrillation threshold during ischemia, ventricular fibrillation during reperfusion, and inhibited cardiac ACE activity. These effects have been used to explain the beneficial effect of ACE inhibitors on survival in postinfarct patients ‘9-2’ and in patients with symptomatic or asymptomatic attenuated left ventricular function.22.23 Although ACE inhibitors did not prevent attacks of angina in patients with heart failure and stable angina pectoris,24 they prevented ischemia by vasodilation and unloading of left ventricle and may prevent ventricular and supraventricular arrhythmias for the same reasons.25-28 Treatment of angina pectoris in patients with congestive heart failure and systolic dysfunction of the left ventricle can be difficult and is often based on use of vasodilators, e.g., long-acting nitrates. Another possibility might be to combine the anti-ischemit properties of verapamil with the vasodilator properties of an ACE inhibitor. Another advantage may be that both types of drugs inhibit the neuroendocrine system.29 However, we need further information about the consequences of this combination in patients with stable angina and attenuated left ventricular function. For these reasons, we decided to conduct an open study in patients with angina pectoris and left ventricular dysfunction on the effect of combined treatment with verapamil and trandolapril on left ventricular function evaluated from isotope ventriculography, echocardiography, exercise test-
gina, vasospastic angina, hypertension, supraventricular tachycardia, atria1 fibrillation, and secondary prophylaxis after an acute myocardial infarction.‘,’ The effect of verapamil is explained by vasodilator, negative inotropic and chronotropic properties, and protection of myocardial cell structures and function during ischemia.2 Verapamil is considered contraindicated in patients with heart failure,3 but in the Second Danish Verapamil Infarction Trial (DAVIT II) long-term 18-month treatment with verapamil in postinfarct patients was associated with a significant reduction in the use of diuretics compared with placebo treated patients,435 This effect of verapamil could be explained by prevention of stunning and hibernation, which may be major causes of congestive heart failure in patients with coronary artery diseases.6 Verapamil has been proven to prevent deterioration of diastolic function during ischemia in patients with coronary artery disease.7-9 Verapamil prevents the reduction of the fibrillation threshold lo and the conduction delay, which may predispose to ventricular arrhythmias, caused by myocardial ischemia.” Further, verapamil reduces the liberation of catecholamines during ischemia, ‘* circulating catecholamines during long-term treatment, l3 and myocardial oxygen consumption.‘4 From the Department of Cardiology and Physiology, Hvidovre University Hospital, This study was supported by a grant from Germany. Address for reprints: J. Fischer Hansen, Cardiology, Hvidovre University Hospital, mark.
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0 1996 by Excerpt0 All rights reserved.
Medica,
Inc.
Department of Clinical Copenhagen, Denmark. Knoll AG, Ludwrgshafen, MD, PhD, Department of DK-26.50 Hvidovre, Den-
0002-9149/96/$15.00 PII SOOO2-9149(96)00303-7
r
TABLE
I Findings
at Start
and Termination
of Trial
Medication Patients
Serum creatinine (pmol/L) Plasma urea (mmol/L) Serum potassium (mmol/L) Serum sodium (mmol/L) Exercise duration (min) Increase in rate-pressure product Cardiothoracic index Left ventricular ejection fraction Left ventricular wall motion index Ventricular ectopic beats (mean/h) ST depression >O. 1 mV Episodes/24 h Minutes/24 h Maximal (mV)
[no.)
Start
14
from rest to exercise
95+ 5.4 + 3.9 2 14123 6.9 2 2.2 2 50.4 k 28 2 1 .o 2 174 ?
14 14 14 13 13 14 13 11 13 13
3 Months 18
1.0 0.4 2.5 0.4 4.6 6 0.3 250
25 k 34 126 + 216 1.6 + 1.4
96% 5.72 4.0 ‘139t3 7.7 ? 2.5 ? 49.6 k 35 k 1.2 ? 100 2
p Value*
19 1.3 0.3 2.9 0.6 4.7 11 0.3 159
NS NS NS NS
0.01 0.02 NS 0.03 0.03 NS
11 221 36 +- 80 0.11 20.11
NS NS NS
* NS = not significant.
ing, and Holter monitoring. At the same time, we evaluated changes in clinical chemical parameters and chest radiographs.
METHODS
AND
PATIENTS
Included were patients with stable angina pectoris, with a left ventricular ejection fraction <40%, in New York Heart Association function group II-III, able to perform an exercise test on a bicycle ergometer, which should demonstrate an ST-segment depression, horizontal or downsloping, of at least 0.1 mV. Exclusion criteria: Excluded were patients treated with vasodilators within the last 2 weeks, and with QRS ~0.12 set, significant valvular heart disease, sinoatrial block, 2nd or 3rd degree atrioventricular block, atria1 fibrillation, known intolerance to ACE inhibitors and verapamil, serum creatinine level >200 pmol/L, and inability or unwillingness to give written informed consent. Medication: Trial medication consisted of 1 capsule once daily for 2 weeks and then 1 capsule twice daily for 10 weeks. A capsule contained verapamil 180 mg and trandolapri12 mg. Treatment period: Treatment started after the patient had been in a stable clinical phase for at least 2 weeks without change in medication and without treatment with vasodilators apart from sublingual nitroglycerin to treat attacks of angina pectoris. Hoiter monitoring: Twenty-four-hour ambulatory electrocardiographic (ECG) monitoring was made using 2 channel tape recorders (SpaceLabs 90205) and analyzed semiautomatically by a computer program (SpaceLabs FT 3000) .30 Significant ST deviation was defined as ST depression of at least 0.1 mV or ST elevation above 20.15 mV measured 60 msec after the J point. All ST episodes were visually checked and were required to last at least 1 minute and be separated from adjacent ST episodes by at least 1 minute. Chest radiographs: Cardiothoracic index was measured on a standing chest radiograph in the anteroposterior projection. inclusion
criteria:
Other techniques: Isotope ventriculography of the left ventricle was used to determine left ventricular ejection fraction.31 Echocardiography was performed in accordance with established recommendations.32 Wall motion index was calculated from a 9-segment mode1.33 Clinical chemical parameters were analyzed in accordance with the standard methods of Hvidovre University Hospital. Angina pectoris attacks and nitroglycerin consumption were recorded by the patient. Statistical methods: Student’s t test for paired data was used to compare measurements at start and at the end of the treatment period; p <0.05 is considered statistically significant. Ethics: Written informed consent was obtained from all patients. The study was approved by the local ethical committee.
RESULTS Patients: Twenty-one patients started treatment with trial medication. Seven patients stopped for the following reasons: 1 patient did not want to continue in the study after 2 weeks, 1 patient was not compliant and stopped after 2 weeks, 2 were stopped by the treating physician (1 because the patient was offered bypass surgery); in none of these 4 patients were adverse effects reported. A fifth patient was seen in the outpatient clinic because he complained of worsening dyspnea 50 days after treatment start. Clinical examination, chest radiograph, and electrocardiogram were unchanged without signs of heart failure or myocardial ischemia; trial medication was stopped but 3 days later the patient was admitted after a short episode of lipotymia (fainting). Again, no signs of heart failure or myocardial ischemia was found, but the patient died 3 hours after admission after cardiac arrest due to ventricular fibrillation. Autopsy was not allowed, but most likely the patient died from a new myocardial infarction. A sixth patient died from pneumonia 10 days after treatment start. Autopsy demonstrated unexpectedly a malignant lymphoma, but no reinfarction was found. And finally a seventh A SYMPOSIUM:
CALCIUM
ANTAGONISM
IN CAD
170
n = 13 minutes 16
n = 13
%
start
70
3 months
start
3 months
60
14
2
6.9k2.5
p eo.01
,.
7.A2.9
p co.03
28.2k5.7
35.2* 11 .I
0 0 FIGURE 1. Exercise medication.
duration
at start and after
3 months
on trial
FIGURE 3. left vent&jar tope ventriculogmphy
ejection fraction evaluated from isoat start and after 3 montlis of trial medica-
n = 13
n = 11
2
5
start
3 months
start 4
‘.5
jnths ----_
-----
---
I>> ----___
----__
------¤
0.5 1
1.0*0.3 2.21k0.4
p CO.02
p co.03
1.2 io.3
2.53k0.6 0
0 FIGURE 2. Ratio of exercise to resti rate-pressure start and after 3 months on trial m 3 ration.
product
FIGURE 4. Echocardiographic wall motion index at start cation.
at
patient had been on trial medication for 11 weeks when she was found dead, probably a case of sudden cardiac death as she had been doing well in the study period and had been in daily contact with a daughter without uttering complaints to her. Twelve men and 2 women with a mean age 65 years (range, 51-77) completed the study. All patients had a history of angina pectoris, 5 had 1 and 7 had 2 previous myocardial infarcts. Myocardial ixhemia: Information about nitroglycerin consumption and angina pectoris attacks reported by the patients was available in 13 patients. Prior to study start, the number of angina pectoris attacks was reported to be a mean of 7 per week (range, l-20) and of nitroglycerin consumption was 18D
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and
determined left ventricular after 3 months on trial medi-
a mean of 9 per week (range, 1 - 25 ) . At the end of the study period based on the last 4 weeks, the corresponding figures were angina pectoris 2 per week (range, O-8; p <0.02) and nitroglycerin consumption of 3 per week (range, 0- 13; p <0.02). Holter monitoring did not demonstrate any statistically significant changes in number of ventricular ectopic beats or of ST-segment depressions (Table I). No patient had ST elevations. left ventricular function: Exercise duration increased slightly but significantly (Figure 1) and was associated with a significant increase in the ratio of systolic arterial blood pressure times heart rate from rest to exercise (Figure 2). Left ventricular ejection fraction increased significantly (Figure 3)) as did left JUNE
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ventricul7.r M.J.~.motion index (Figure 4). Cardiothoracic j!lde x c;? unchanged. No sigri :,r~i :hanges were recorded in serum creatinine .+‘:I I III i.; ea, serum potassium, or serum sodium (i :I; !c I>. Diure’ ir~&nerrt iiive patients did not receive diuretics, ::.rients were treated with bendroflumethiazide I ..\ - IO mg/day, and 4 patients with furosemide A:i J-- 160 mg/ day, unchanged from start to the end of ehc ‘JI~:dy period. One patient was treated with furosemici _I 40 mg/day at start and with furosemide 160 mg/ci:iy at the enr, rhe last patient was treated with fu:-o!;elr,ide 120 rr\;Tand spironolactone 100 mg/ day at !h? :;i:lrt and fur;.;sernide 160 mg/day and spironolact
Calcium antagonists and ACE inhibitors trials: Calcium ‘antagonists are prescribed
in various
to a large number of patients with reduced ejection fraction or clinical heart failure as evaluated from the SOLVD study 22,23in which 3 1% and 35%, the SAVE study l9 in which 42%, the AIRE study2’ in which 16%, and the Survival of Myocardial Infarction Long-term Evaluation (SMILE) tria12’ in which 10% of the patients were treated with calcium channel antagonists at randomization. Limited information is available about the events in patients treated compared with those not treated by calcium channel antagonists. No information is available about the type of calcium channel antagonist used nor the indication for the use of a calcium antagonist in patients included in these 5 studies. DISCUSSION In SAVE, the mortality rate in calcium channel Many attempts have been made to use calcium antagonist-treated patients was 24.8% in placeboantagonists in the treatment of congestive heart fail- and 20.6% in captopril-treated patients, correspondure.34-36 The basis is the vasodilator effect with af- ing to a risk reduction of 19% (95% confidence interload reduction and dilation of the coronary arteries terval [CI], -7,38). In patients not treated with calwith improvement of oxygen supply and reduction cium channel antagonists, the corresponding figures of oxygen demand. So far, no long-term clinical were placebo 24.6% and capto ril 20.4%, risk restudy has demonstrated a beneficial clinical effect. duction 19% (95% CI, -2,36). li These disappointing results might be due to the negFrom the AIRE study, less information is availative inotropic effect of calcium antagonists or to a able. Mortality rate was significantly reduced in padeterioration of oxygen supply to the myocardium tients prescribed a calcium channel antagonist and due to fall in arterial diastolic blood pressure with given ramipril when compared with placebo, with a reduction of coronary blood fiow and perhaps reflex relative hazard of 0.59. In patients not prescribed tachycardia and increased use of oxygen.3 calcium channel antagonists, a significant beneficial One possible reason for development of conges- effect of ramipril versus placebo was also observed, tive heart failure or attenuation of left ventricular relative hazard of 0.76.20 No information is available systolic function in patients with coronary artery dis- of the mortality rate in calcium channel antagonistease is stunning due to repeated periods of myocarversus non-calcium channel antagonist-treated padial ischemia.‘j This might be prevented by verap- tients. In the SOLVD trials, information is available amil,7-9 which has been demonstrated to be an effective antianginal agent in patients with stable an- about the effect of enalapril compared with placebo gina pectoris.37 In DAVIT II, which compared the on myocardial infarction or hospitalization for aneffect of verapamil versus placebo in postinfarct pa- gina pectoris. In calcium channel antagonist-treated tients, use of diuretics was significantly lower in the patients, the event rates were placebo 36.1%, enaverapamil compared with the placebo group after lapril 29.7% (reduction of risk ratio of 21%; 95% CI, 9,3 1) and in patients not receiving calcium chan12 months, an effect that might be explained by prevention of ischemia by veraparnil.“*538 nel antagonists 19.7% versus 16.4% (reduction of ACE inhibitors have been demonstrated effec- risk ratio of 22%; 95% CI, 11,32) .25 tively to reduce mortality in postinfarct patients with In the SMILE study21 the calcium channel antagcongestive heart failure in the Acute Infarction Ra- onist-treated patients had an event rate of 15.8% in mipril Efficacy (AIRE) study,” in patients with left placebo and 2.7% in zofenopril-treated patients (p = ventricular ejection fraction <40% in the Survival 0.005; risk ratio of 14%; 95% CI, 3,66). The corand Ventricular Enlargement (SAVE) trial, l9 and in responding figures in patients not on calcium channel patients with ejection fraction <35% with21 or withantagonists were 10.0% and 7.6% (p = 0.12; risk out22 clinical symptoms of congestive heart failure ratio of 74%; 95% CI, 51,107). in the Studies of Left Ventricular Dysfunction From these findings in the AIRE, SAVE, (SOLVD) trials. The ACE inhibitor captopril was SOLVD, and SMILE trials, it is not possible to denot found to be effective in prevention of stable an- termine if the combination of treatment with an ACE gina pectoris in patients with heart failure.24 ACE inhibitor and a calcium channel antagonist has a inhibitors seem to prevent myocardial ischemia by harmful, a beneficial, or no effect in patients with unloading of the left ventricle, by prevention of di- heart failure or low ejection fraction with or without lation and remodeling of the left ventricle both in previous myocardial infarction. postinfarct patients l6 and in patients with an ejection Present study: No systematic observations are fraction <35%, l7 by inhibition of local ACE activ- available concerning the combined effect of calcium ity, ‘* and by attenuation of the activation of the sym- channel antagonists and ACE inhibitors in patients pathetic nervous system.13,15”9 with stable angina pectoris and ejection fraction A SYMPOSIUM: CALCIUM ANTAGONISM
IN CAD
19D
~40%. A study on the combination of verapamil and enalapril in patients with systemic hypertension was recently published; this study demonstrated an improvement of left ventricular function evaluated from isotope ventriculography.41 We wanted to conduct the present open study to see if the combination of verapamil and trandolapril would be beneficial to left ventricular function. As demonstrated in the figures, after 3 months of treatment, left ventricular ejection fraction and wall motion index were increased, there was improvement in exercise capacity, and an increase in rate-pressure product from rest to exercise was demonstrated. Results of Holter monitoring are in accordance with reduced myocardial ischemia, as is the reduction in number of angina pectoris attacks and in nitroglycerin consumption. No deterioration was found in renal function evaluated from serum creatinine or plasma urea, and serum potassium and serum sodium were unchanged. Except in 1 patient, use of diuretics was unchanged. This study thus demonstrated that an improvement of left ventricular function took place during treatment with a combination of verapamil and trandolapril. Of course, it cannot be excluded that such an improvement would have taken place on treatment with trandolapril alone in accordance with the improvement of left ventricular function demonstrated in the SOLVD studies.” The anti-ischemic effect of verapamil might explain the effect, too.42 Also, attenuation of an activated neuroendocrine system might be important.29 The next steps in the evaluation of the combined effect of trandolapril and verapamil will be first a double-blind pilot study of 100 postinfarct patients with congestive heart failure comparing the clinical effect of trandolapril versus trandolapril plus verapamil; second, a double-blind study comparing the same drugs in patients with stable angina pectoris and left ventricular ejection fraction <40%. 1. Opie LH. Clinical use of calcium antagonist drugs. Boston: Kluwer Academic Publishers, 1990. 2. Opie LH. Myocardial protection by calcium antagonists. New York: Author’s Publishing House, 1994. 3. Packer M. Pathophysiological mechanisms underlying the adverse effect of calcium channel-blocking drugs in patients with chronic heart failure. Circulation 1989;8O(suppl IV):IV-59-IV-67. 4. 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 (DAVIT) II. Am .I Cardiol 1990;66:779-785. 5. Danish Study Group on Verapamil in Myocardial Infarction. Secondary prevention with verapamil after myocardial infarction. Am J Cardiol1990;66:331401. 6. Nayler WC?. Calcium antagonists, stunning, hibernation: an overview. In: Opie LH, cd. Stunning, Hibernation and Calcium in Myocardial Ischemia and Reperfusion. Boston: Kluwer Academic Publishers, 1992226-234. 7. Betocchi S, Piscione F, Perrone-Filardi P, Pace L, Capelli-Bigazzi M, Alfano B, Ciarmiello A, Salvatore M, Condorelli M, Chiariello M. Effects of intravenous verapamil on left ventricular relaxation and filling in stable angina pectotis. Am J Cardiol 1990;66:818-825. 8. Lahiri A, Rodriges AE, Caboni PR, Raftery ER. Effect of long term treatment with calcium antagonists on left ventricular diastolic function in stable angina pectoris and heart failure. Circulation 1990;81 (suppl III):III-130-111-138. 9. Serato JF, Zaret BL, Schuhnan DS, Black HR, Soufer R. Usefulness of verapamil on congesti\re heart failure associated with abnormal left ventricular filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981-986. 20D
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10. Trandroyen FT, Higginson L, Opie LH. The influence of verapamil and its isomers on vulnerabiity to ventricular fibrillation during acute myocardial ischemia and adrenergic stimulation in isolated rat heart. .I Mel Cell Cardiol 1986;18:645-649. 11. Peter T, Fujimoto T, Hamatnoto H, Mandel WJ. Comparative study of the effects of slow calcium inhibiting agents on ischemia-induced conduction delay as relevant to the genesis of ventricular fibrillation. Am Hearf J 1983;106: 10231028. 12. Richardt
Cl, Haass M, Schamig A. Calcium antagonists and cardiac noradrenaline release in ischemia. J Mel Cell Cardiol 1991;23:269-277. 13. Wall& NH, Held C, Rehnqvist N, Hjemdahl P. Platelet aggregability in viva is attenuated by verapamil but not metoprolol in patients with stable angina pectoris. Am J Cardiol 1995;75:1-6. 14. Chung N, Wu X, Ritman EL. LV oxygen consumption and pressure-volume area: role of norepinepbrine and verapamil. Am .I Physiol 1991;261:H77-H82. 15. Young JB. Reduction of ischemic events with angiotensin-converting enzyme inhibitors: lessons and controversy emerging from recent clinical trials. Cardiovasc Drugs Ther 1995;9:89-102. 16. Sutton M St J, Pfeffer MA, Plappert T, Rouleau JL, Moye LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S, Menapace FJ, Parker JO, Lewis S, Sestier F, Gordon DF, McEvan P, Bernstein V, Braunwald E, SAVE Investigators. Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effect of captopril. Circulation 1994;89:68-75.
17. Greenberg B, Quinones MA, Koilpillar C, Limacher M, Shindler D, Benedict C, Shelton B, SOLVD Investigators. Effect of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiographic substudy. Circulation 1995;91:25732581. 18. Muller CA, Opie LH, Peisach M, Pineda CA. Chronic oral treatment with the angiotensin-converting enzyme inhibitor, trandolapril decreases ventricular fibrillation in acute ischemia and reperfusion. Eur Heart J 1994;15:988-996. 19. Pfeffer MA, Braunwald E, MoyC L, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins M, SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992;327:669-677. 20. The Acute Infarction
Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lance? 1993;342:821-828. 21. Ambrosioni E, Borghi C, Magnani B, SMILE Study Investigators. The effect of angiotensin-converting enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-85. 22. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293-302. 23. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med 1992;327:685-691. 24. Cleland JGF, Henderson E, McLenachan J, Findlay IN, Dargie HJ. Effect of captopril, an angiotensin-converting enzyme inhibitor in patients with angina pectoris and heart failure. JAm Coil Cardiol 1991;17:733-739. 25. Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancer 1992;340:1173-1178. 26. Segaard P, Getzsche C-O, Ravkilde J, Thygesen K. Effects of captopril on ischemia and dysfunction of the left ventricle after myocardial infarction. Circulation 1993;87:1093-1099, 27. Ssgaard P, Gstzsche C-O, Ravkilde J, Nergaard A, Thygesen K. Ventricular arrhythmias in the acute and chronic phases after acute myocardial infarction. Effect of intervention with captopril. Circulation 1994;90: lOl- 107. 28. Rutherford JD, Pfeffer MA, Moyd LA, Davis BR, Flaker GC Kowey PR, Lamas GA, Miller HS, Packer M, Rouleau JL, Braunwald E, SAVE Investigators. Effect of captopril on ischemic events after myocardial infarction. Results of the survival and ventricular enlargement trial. Circulation 1994;90:1731-1738. 29. Remme WJ, Kruyssen DACM, Look MP, Bootsma M, deLeeuw PW. Systemic and cardiac neuroendocrine activation and severity of myocardial ischemia in humans. JAm Co11 Cardiol 1994;23:82-91. 30. Jespersen CM, Rasmussen V. Detection of myocardial ischemia by transthoracic leads in ambulatory electrocardiographic monitoring. Br Heart J 1992;68:286-290. 31. Marving J, Heilund-Carlsen PF, Chraxnmer-Jorgensen B, Gadsbell N, Jensen BH. Are right and left ventricular ejection fractions equal? Ejection fractions in normal subjects and in patients with first acute myocardial infarction. Circulation 1985;72:502-514. 32. American Society of Echocardiography Committee on Standards, subcommittee on Quantitation of Two-Dimensional Echocardiograms. Reconnnendations for quantitation of the left ventricle by two-dimensional echocardiography. JAm Sot Echocardiogr
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33. Heger JJ, Weyman AE, Warm LS, Dillon JC, Feigenbaum H. Cross sectional echocardiography in acute myocardial infarction: detection and localization of regional left ventricular asynergy. Circularion 1979;60:53 l-538. 34. Goldstein RE, Buccuzzi SJ, Cruess D. Diltiazem increases late onset congestive heart failure in post infarct patients with early reduction in ejection fraction. Circulation 1991;83:52-60. 35. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahimtoola SH. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbid dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990;82:1954-1961. 36. Littler WA, Sheridan DJ, UK Study Group. Placebo controlled trial of felodipine in patients with mild to moderate heart failure. Br Heart J 1995;73: 428-433. 37. Cutler NR, Anders RJ, Jhee SS, Sramek JJ, Awan NA, Bultas I, Lahiri A,
Woroszylska M. Placebo-controlled evaluation of three doses of a controlledonset, extended-release formulation of verapamil in the treatment of stable angina pectoris. Am .I Cardid 1995;75: 1102- 1106.
38. Jespersen CM, DAVIT Study Group. The effect of verapamil on major events in patients with impaired cardiac function recovering from acute myocardial infarction. Eur Heart .I 1993;14:540-545. 39. Lindsay HSJ, Zaman AG, Cowan JC. ACE-iibitotx after myocaniial infarction: patient selection or treatment for all. Br Heart J 1995;73:397-400. 40. MovC LA. Pfeffer MA. Won CC. Davis BR. G&man E. Haves D. Famham DJ, Randall OS, Dinh H, LoId JMO, Koper&th AJ, Hager
A SYMPOSIUM:
CALCIUM
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21D