Cardiovascular Drugs and Therapy 1995;9:503-507 © Kluwer Academic Publishers, Boston. Printed in U.S.A.

ACE Inhibitors and Calcium Antagonists in the Treatment of Congestive Heart Failure

J o r g e n F i s c h e r H a n s e n

DAVIT Study Group, Department of Cardiology, Hvidovre University Hospital, Copenhagen, Denmark

Summary. The increased mortality after myocardial in- farction is related to the risk of reinfarction, sudden death, and the development and progression of heart failure; in con- gestive heart failure it is due to the progression of heart fail- ure and sudden death. ACE inhibitors have been proven to prevent cardiovascular events, especially the progression of heart failure, in postinfarct patients with reduced ejection fraction and heart failure in the SAVE and AIRE trials. In patients with congestive heart failure, ACE inhibitor treat- ment has prevented cardiovascular death and reduced mor- bidity due to progressive heart failure in the SOLVD trials. In post-myocardial infarction patients, the calcium antagonist nifedipine did not affect mortality or morbidity; diltiazem improved prognosis in patients without congestive heart fail- ure and in patients with non-Q-wave infarction; and vera- pamil improved prognosis by prevention of reinfarction and sudden death. Combination treatment with both verapamil, which has pronounced antiischemic properties and prevents sudden death and reinfarction, and an ACE inhibitor, which prevents the progression of heart failure, is a possibility for future cardiovascular therapy that should be evaluated.

Cardiovasc Drugs Ther 1995;9:503-507

Keg Words. myocardial infarction, ACE inhibitor, calcium antagonists, heart failure

Combination therapy ~ t h calcium antagonists and angiotensin converting enzyme (ACE) inhibitors might be possible in the treatment of patients with congestive heart failure and ischemic heart disease. The purpose of this paper is to discuss the results of trials with calcium antagonists and ACE inhibitors in patients with congestive heart failure and postinfarct patients, and to present a rationale for a combination of the two types of drugs in postinfarct patients with congestive heart failure.

S t u d i e s w i t h A C E I n h i b i t o r s

Hear t fa i lure The influence of treatment with an ACE inhibitor on survival and on the progression of heart failure in pa- tients with a left ventricular ejection fraction less than 35% was tested in the Studies on Left Ventricular Dysfunction (SOLVD) treatment [1] and prevention [2] trials. The SOLVD treatment trial included pa- tients with congestive heart failure taking drugs other

than ACE inhibitors as part of conventional therapy for congestive heart failure. The SOLVD prevention trial included patients not receiving diuretics, digoxin, or vasodilators. All patients in the prevention trial were in New York Heart Association functional class I and II. In the treatment trial 68% were in functional class I and II, 30% in class III, and 2% in class IV. Patients with angina were excluded. The prevention trial included 4228 patients, and the treatment trial included 2569 patients.

In the SOLVD treatment trial enalapril treatment was associated with a significant risk reduction of 16% in total mortality. Risk reduction of death due to pro- gressive heart failure was 22% (p = 0.009), due to arrhythmias (= sudden death?) was 10% (NS), and due to reinfarction was 28% (NS). Furthermore, the risk of hospitalization due to congestive heart failure was significantly reduced by 26% (p = 0.0001). The findings in the SOLVD prevention trial were essen- tially the same, demonstrating a 37% reduction in the risk of progression of heart failure in the enalapril- treated patients (p = 0.001). When combining the re- sults of the two SOLVD trials, the risk of myocardial infarction was reduced by 23% (p = 0.001) [3] and of unstable angina by 20% (p = 0.001) [4].

The most convincing effect on end points in both SOLVD trials was found in the patients with the low- est ejection fraction. In the treatment trial a signifi- cant 24% reduction in risk of death was observed in enalapril-treated patients with ejection fractions less than 30%, while a nonsignificant 7% increase in risk of death was found in patients with ejection fractions of 30-35%. The same trend was found in the preven- tion trial, that is, in enalapril- compared with placebo- treated patients a significant 32% risk reduction in death or hospitalization for congestive heart failure in patients with ejection fractions below 28%, a reduc- tion of 19% in patients with an ejection fraction of

Address for correspondence: Jcrgen Fischer Hansen, MD, PhD, De- partment of Cardiology, 146, Hvidovre Hospital, DK-2650 Hvidovre, Denmark.

Received 1 October 1994, receipt~review time 108 days, accepted in revised form 10 April 1995.

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504 Hansen

28-32%, and a nonsignificant 6% increase in patients with ejection fractions of 33-35%. The overall risk reduction of death in the enalapril- treated patients in the SOLVD treatment trial was 12% (NS) in patients with heart failure due to isch- emia compared with a 27% significant reduction in pa- tients with other reasons for heart failure [1]. In the combined trials the risk reduction for "myocardial in- farction or hospitalization for angina" was significantly reduced both in patients with heart failure due to isch- emia (18%) and in patients with heart failure for other reasons (43%) [4].

In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) [5], which included 253 patients in New York Heart Association func- tional group IV treated with enalapril or placebo, the mortality rate after 1 year was significantly reduced by enalapril (36% vs 52%). The beneficial effect of enalapril was related to the prevention of progression of heart failure. No effect was seen on sudden death.

In conclusion, ACE inhibitors reduce total mortal- ity in patients with congestive heart failure, primarily by prevention of the progression of heart failure. The effect is only demonstrated in patients with ejection fractions less than 30% and is most pronounced in pa- tients without ischemic heart disease.

Postinfarct studies The SAVE trial [6] included 1116 placebo and 1115 captopril-treated patients with ejection fractions less than 40% from 3 to 16 days after a myocardial in- farction. None of the patients had overt heart failure or myocardial ischemia at randomization. After an av- erage of 42 months, the risk of death in captopril- treated patients was significantly reduced by 19%, the risk of reinfarction was reduced by 25%, and the risk of progressive heart failure was reduced by 22%. Cap- topril primarily prevented death due to progression of heart failure, had no effect on fatal reinfarction, and had a limited nonsignificant effect on sudden death. The risk reduction of death in captopril-treated patients was 24% (95% confidence limits 6, 38) in pa- tients with ejection fractions less than 32%, compared with 6% (95% confidence limits -29, 32) in patients with ejection fractions between 40% and 32%.

The Acute Infarction Ramipril Efficacy (AIRE) study [7] investigated the effect of ramipril (1014 pa- tients) versus placebo (992 patients) on mortality and morbidity. The patients had clinical signs compatible with heart failure during the acute phase but were clinically stable without overt heart failure or myocar- dial ischemia at randomization. Treatment started 3-10 days after the infarct. After a mean observation time of 15 months, the risk of death was significantly reduced by 27% in the rampiril-treated patients. The effect of ramipril seemed related to the prevention of progression of heart failure. No effect was found on reinfarction, and sudden death was not mentioned.

In conclusion, in postinfarct patients with a left ventricular ejection fraction less than 40% or with clinical heart failure during the acute phase of the in- farction, and in a clinically stable situation without overt heart failure or myocardial ischemia at random- ization, ACE inhibitors prevented death primarily by prevention of the progression of heart failure. There might be a preventive effect on reinfarction but a lim- ited, if any, effect on sudden death. The effect was most pronounced in patients with the lowest ejection fractions, less than 32%.

Studies with Calcium Antagonists Heart failure Dihydropyridine calcium antagonists have been pro- posed as supplements to diuretics and digoxin due to their vasodilator properties in congestive heart fail- ure. The results have in general been disappointing, with no or an adverse effect of the calcium antagonists in patients with congestive heart failure [8,9]. New calcium antagonists, such as amlodipine and felodi- pine, are at present being tested in ongoing trials in patients with congestive heart failure [10].

Postinfarct studies Numerous studies with calcium antagonists during and after an acute myocardial infarction, examining the effect on survival and cardiovascular events, have been conducted. Several extensive reviews are avail- able [11-14]. The results may be summarized as fol- lows.

The dihydropyridine calcium antagonist nifedipine did not reduce cardiac death or cardiovascular events in either early or late intervention studies. On the contrary, a trend toward increased mortality was ob- served in nifedipine- versus placebo-treated patients [11]. This has been explained by activation of the sym- pathetic nervous system related to vasodilation and to a reduction of systemic blood pressure with a dete- rioration of coronary perfusion pressure [15]. The SPRINT study group also examined the effect of nifedipine compared with placebo on major events, that is, mortality or reinfarction, in relation to conges- tive heart failure prior to randomization in postinfarct patients. In patients with heart failure, the 1 year event rate in nifedipine-treated patients was 12% and in placebo-treated patients was 15% (NS); the corre- sponding figures in patients without heart failure were 8% and 7%, respectively [16]. Thus nifedipine treat- ment caused no harm in heart failure patients.

The benzothiazepine diltiazem has been tested in two post-myocardial infarction trials. In the non-Q- wave trial, 2 weeks of treatment with diltiazem pre- vented new infarcts but did not reduce mortality [17]. In the Multicenter Diltiazem Post Infarction Trial (MDPIT) [18], no difference was found in survival be-

ACE Inhibitors and Calcium Antagonists 505

tween diltiazem- and placebo-treated patients; a slight 10% nonsignificant reduction was observed in cardio- vascular events in diltiazem-treated patients. In the protocol of MDPIT, it was stated that analysis of death and cardiovascular events should be performed in relation to congestion on chest x-ray. This analysis showed a significant increase in cardiovascular events in patients with congestion (hazard ratio 1.41; 95% confidence limits 1.01-1.96) and a significant decrease in patients without congestion on chest x-ray (hazard ratio 0.77; 95% confidence limits 0.61-0.98), indicating a deleterious effect of diltiazem in patients with heart failure. This was further supported by the finding in patients with ejection fractions less than 40% that dil- tiazem significantly increased the risk of development of congestive heart failure by 21% compared with 12% in placebo-treated patients in MDPIT (p < 0.004) [19]. Thus, diltiazem might be considered contraindicated in postinfarct patients with severe congestion on a chest x-ray or an ejection fraction less than 40%. In patients without heart failure and in patients with non-Q-wave infarctions [20], diltiazem seems useful in the prevention of cardiovascular events.

Verapamil, a phenylalkylamine calcium antagonist, has been examined in the early Danish Verapamil In- farction Trial (DAVIT I) [21] and the late postinfarct study DAVIT II [22,23]. In DAVIT I, patients were treated from the time of admission during the follow- ing 6 months. After 6 months the mortality rate was 12.8% in verapamil-treated patients and 13.8% in pla- cebo-treated patients, an 8% nonsignificant reduction in mortality; the reinfarction rate was 7% versus 8.3% (NS). In DAVIT II patients were treated from the second week after admission and were followed for at least 12 months (mean 16 months). Verapami1360 rag/ day sigv.ificantly reduced major events, that is, first reinfarction or death, by 20% (hazard ratio 0.80; 95% confidence limits 0.64-0.99); the 18 month event rate was 18% in verapamil- versus 21.6% in placebo- treated patients. According to the protocol of DAVIT II it was decided a priori to analyze the end points in relation to the presence of congestive heart failure before randomization. In patients without congestive heart failure, verapamil significantly reduced mortal- ity (hazard ratio 0.64), major events (hazard ratio 0.70), and first reinfarctions (hazard ratio 0.67). In patients with congestive heart failure prior to ran- domization, the corresponding hazard ratio figures were 1.05, 1.00, and 0.98, which indicates that no dele- terious effect was found. The effect of verapamil is explained by prevention of sudden events, that is, re- infarction and sudden death [24], and an 18 month event rate of 15.3% in verapamil- and 18.3% in pla- cebo-treated patients (hazard ratio 0.78; p = 0.02). Thus, verapamil might be used for secondary preven- tion after an acute myocardial infarction [25].

In conclusion, in postinfarct patients verapamil showed an overall beneficial effect in the prevention

of cardiovascular events, with the effect being most pronounced in patients without congestive heart fail- ure during the acute phase of the myocardial infarct. Diltiazem might be used in postinfarct patients with- out congestive heart failure to prevent cardiovascular events. Nifedipine treatment did not influence sur- vival or cardiovascular events in postinfarct patients.

Calcium Antagonists and ACE Inhibitors in Various Trials

Calcium antagonists are prescribed to a large number of patients with a reduced ejection fraction or in clini- cal heart failure. In the SOLVD trial, 31% and 35%, in the SAVE trial 42%, and in the AIRE trial 16% of the patients with a reduced ejection fraction and clini- cal heart failure were treated with calcium antago- nists.

Limited information is available about the events in patients treated compared with those not treated with calcium antagonists. No information is available about the type of calcium antagonist used nor the indi- cation for use of a calcium antagonist.

In SAVE, the mortality rate in calcium antagonist- treated patients was 24.8% in the placebo group and 20.6% in captopril-treated patients, corresponding to a risk reduction of 19% (95% confidence limits, 7, 38). In patients not treated with calcium antagonists, the corresponding figures were 24.6% for placebo and 20.4% for captopril, with a risk reduction of 19% (95% confidence limits 2, 36) [26].

Less information is available from the AIRE study. The mortality rate was significantly reduced in pa- tients prescribed a calcium antagonist and given rami- pril when compared with placebo, with a relative hazard of 0.58. In patients not prescribed calcium an- tagonists, a significant beneficial effect of ramipril ver- sus placebo was also observed, with a relative hazard of 0.76 [7]. No information is available about the mor- tality rate in calcium antagonist- versus non-calcium antagonist-treated patients.

In the SOLVD trials, information is available about the effect of enalapril compared with placebo on myo- cardial infarction or hospitalization for angina pecto~ ris. In calcium antagonist-treated patients, the event rates were 36.1% for placebo and 29.7% for enalapril (21% reduction of risk ratio; 95% confidence limits 9, 31). In patients not receiving calcium antagonists the event rates were 19.7% versus 16.4% (22% reduction of risk ratio; 95% confidence limits 11, 32) [4].

It is not possible from these findings in the AIRE, SAVE, and SOLVD studies to determine if the combi- nation of treatment with an ACE inhibitor and a cal- cium antagonist has a harmful, beneficial, or no effect in patients with heart failure and/or a low ejection fraction with and without previous myocardial in- farction.

506 Hansen

Rationale for the Combination of Verapamil with an ACE Inhibitor Given the present knowledge of the effect of calcium antagonists on cardiovascular events in patients with ischemic heart disease, we think that a combination of verapamil and an ACE inhibitor could be promising because of the following:

1. Verapamil does not activate the sympathetic ner- vous system [27].

2. Verapamil prevented sudden death in patients with increased heart size (posthoc analysis of DAVIT II) [24], to the same degree in patients with (hazard ratio 0.74) and without heart failure (hazard ratio 0.75), and the results were significant using a treatment per protocol analysis (hazard ra- tio 0.63; 95% confidence limits 0.40-0.99) [23].

3. Verapamil apparently prevented the development of congestive heart failure in DAVIT II. After 1 year significantly fewer patients in the verapamil group (28%) compared with the placebo group (36%) were treated with diuretics (p < 0.005). After 1 year 44% of the verapamil- compared with 31% on the placebo-treated patients using diuretic treatment at randomization (about 40% of all pa- tients) had stopped diuretic treatment (p < 0.01). Thirteen percent of verapamil- and 15% (NS) of placebo-treated patients not treated with diuretics at randomization were using diuretic treatment after 1 year [12].

4. Verapamil prevented myocardial ischemia indi- cated by prevention of ischemia on Holter monitor- ing and of angina pectoris [28-30].

Verapamil has a major effect in patients with ischemic heart disease, in which ACE inhibitors have the least effect [14], which favors combined use in postinfarct patients.

The arguments used for testing the combination of verapamil and an ACE inhibitor are not immediately applicable to dihydropyridine calcium antagonists or diltiazem but do not exclude the possibility that these combinations might be useful. The major argument against diltiazem is that it provoked congestive heart failure during long-term therapy in patients with an ejection fraction less than 40% [19] and against dihy- dropyridines, that nifedipine increased cardiovascular events in heart failure studies [8,9].

Finally, it should be stressed that only by per- forming properly designed studies will it be possible to know whether the combination of calcium antago- nists and ACE inhibitors will improve cardioprotec- tion and thus reduce mortality and morbidity in post- infarct patients.

R e f e r e n c e s

1. The SOLVD Investigators. The effect of enalapril on sur- vival in patients with reduced left ventricular ejection frac-

tions and congestive heart failure. N Engl J Med 1991;325: 293-302.

2. The SOLVD Investigators. Effect of enaiapril on mortality and development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Meal 1992;327:685-691.

3. McKelvie RM, McConachie D, Yusuf S. Role of angiotensin converting enzyme inhibitors in patients with left ventricu- lar dysfunction and congestive heart failure. Eur Heart J 1994;15(Suppl B):9-13.

4. Yusuf S, Pepine CJ, Garces C, et ai. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992;340:1173-1178.

5. The CONSENSUS Trial Study Group. Effect of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-1435.

6. Pfeffer MA, Braunwaid E, Myoe LA, et ai. for the 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.

7. The Acute Infarction Ramipril Efficacy (AIRE) Study In- vestigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evi- dence of heart failure. Lancet 1993;342:821-828.

8. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahim- toola SH. A prospective, randomized, double-blind cross- over study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990;82:1954-1961.

9. Packer M. Calcium channel blockers in chronic heart failure. The risk of "physiologically rational" therapy. Circulation 1990;82:2254-2257.

10. Packer M. Calcium antagonists for congestive heart failure: Evolving concepts in bridge building. Cardiovasc Drugs Ther 1993;7:95-96.

11. Persson S. Calcium antagonists in secondary prevention after myocardial infarction. Drugs 1991;42(Suppl 2):54-60.

12. Hansen JF. Secondary prevention with calcium antagonists after an acute myocardial infarction. Drugs 1992;44(Suppl 1):33-43.

13. Hansen JF. Postinfarct prophylaxis by calcium antagonists. In: Opie LH, ed. Myocardial Protection by Calcium Antag- onists. New York: Authors' Publishing House/Wiley-Liss, 1994:98-111.

14. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina pectoris in light of the second Danish Verapamil Infarction Trial (DAVIT II) and other recent studies. Am J Cardiol 1991;67: 1295-1297.

15. Israeli SPRINT Study Group. Secondary Prevention Rein- farction Israeli Nifedipine Trial (SPRINT). A randomized intervention trial of nifedipine in patients with acute myo- cardial infarction. Eur Heart J 1988;9:354-364.

16. Mandelzweig L, Goldbourt U, Reicher-Reiss H, Behar S, Kaplinsky E, SPRINT Study Group. Nifedipine does not improve survival in AMI patients without heart failure. Cardiovasc Drugs Ther 1993;7:117-118.

17. Gibson RS, Boden WE, Theroux P, et al. Diltiazem and reinfarction in patients with non-Q-wave myocardial in- farction. Results of a double blind, randomized multicenter trial. N Engl J Med 1986;315:423-429.

18. Multicenter Diltiazem Postinfarct Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385-392.

ACE Inhibitor's and Calcium Antagonists 507

19. Goldstein RE, Boccuzzi SJ, Cruess D. Diltiazem increases late onset congestive heart failure in postinfarct patients with early reduction in ejection fraction. Circulation 1991; 83:52-60.

20. Gibson RS. Current status of calcium channel-blocking drugs after Q and non-Q-wave myocardial infarction. Circu- lation 1989;80(Suppl IV):109-119.

21. The Danish Study Group on Verapamil in Myocardial In- farction. Verapamil in myocardial infarction. Eur Heart J 1984;5:516-528.

22. The Danish Study Group on Verapamil in Myocardial In- farction. The effect of verapamil on mortality and major events after acute myocardial infarction. The Danish Vera- pamil Infarction Trial II--DAVIT II. Am J Cardiol 1990; 66:779-785.

23. The Danish Study Group on Verapamil in Myocardial In- farction. Secondary prevention with verapamil after myo- cardial infarction. Am J Cardiol 1990;66:331-40I.

24. Hanson JF. Verapamil prevents sudden death in patients with increased heart size after an acute myocardial in- farction. Cardiovasc Drugs Ther 1993;7:381-382.

25. Hansen JF. Review of postinfarct treatment with vera-

pamil: Combined experience of early and late intervention studies with verapamil in patients with acute myocardial infarction. Cardiovasc Drugs Thor 1994;8:543-547.

26. Moye LA; Pfeffer MA, Wun CC et al., SAVE Investigators. Uniformity of captopril benefit in the SAVE study: Sub- group analysis. Eur Heart J 1994;15(Suppl B):2-8.

27. Wallen NH, Held C, Rehnqvist N, Hjelmdahl P. Platelet aggregability in vivo is attenuated by verapamil but not by metoprolol in patients with stable angina pectoris. Am J Cardiol 1975;75:1-6.

28. Jespersen CM, Hanson JF, Mortensen LS, DAVIT Study Group. The prognostic significance of postinfarct angina pec- toris and the effect of verapamil on the incidence of angina pectoris and prognosis. Eur Heart J 1994;15:270-276.

29. Vaage-NiIsen M, Rasmussen V, Hollander NH, HansenJF, DAVIT Study Group. Prevalence of transient myocardial ischemia during the first year after a myocardial infarction. Effect of treatment with verapamfl. Eur Heart J 1992;13: 666-670.

30. Jespersen CM, DAVIT Study Group. Role of ischemia in post infarct heart failure. Cardiovasc D~gs Ther 1994;8: 823-828.