European Heart Journal (1999) 20, 867–871 Article No. euhj.1998.1393, available online at http://www.idealibrary.com on
Review Article Treatment of congestive heart failure Has the time come for decreased complexity? L. Ryde´n* and W. J. Remme† *Department of Cardiology, Karolinska Hospital, Stockholm, Sweden and †Sticares, Cardiovascular Research Foundation, Rotterdam, The Netherlands
Introduction The incidence of heart failure has increased in recent decades. In Europe alone the estimated number of patients is several millions[1]. Despite recent achievements in the treatment, as outlined in the Guidelines from the Task Force of the European Society of Cardiology[2], the prognosis is poor with a 50% overall mortality within 4 years after the diagnosis and a 50% mortality within 1 year for patients with severe heart failure. Therapeutic approaches to heart failure should be diversified and as much as possible directed towards the reason for cardiac malfunction as well as symptomatic relief. Most frequently it is based on pharmacological prescriptions against fluid retention, decreased cardiac output and increased preload. The standard treatment will be diuretics and ACE inhibitors, sometimes supplemented by digitalis and other vasodilators. As a shortterm measure this treatment may be supplemented by drugs with positive inotropic capacity[2]. The institution of ACE inhibitors, initiated by the results from the landmark CONSENSUS study[3], introduced new hope for physicians and their patients. Subsequent studies, conducted in less severe heart failure patients, were able to demonstrate a mortality reduction by early institution of ACE inhibition, as well as the potential to prevent or retard worsening of heart failure[4–6]. These and other studies confirmed the efficacy of ACE inhibitors. Despite these achievements the problem remains that survival is strikingly poor among Key Words: Congestive heart failure, pharmacological therapy, beta-blockers, ACE inhibitors, mortality, morbidity. Manuscript submitted 13 October 1998, and accepted 21 October 1998. Correspondence: L. Ryde´n MD FESC, Department of Cardiology, Karolinska Hospital, S-171 46 Stockholm, Sweden. 0195-668X/99/120867+05 $18.00/0
patients with severe and even with less severe heart failure. Although statistically highly significant, absolute mortality reduction is modest compared to the remaining mortality, even in the treatment arms of recent trials. Furthermore, worsening of heart failure, as indicated by the need for hospitalization, remains significant. Unfortunately, attempts to introduce positive inotropic agents into the therapeutic arsenal for congestive heart failure have been notoriously unsuccessful due to increased [7, 8] mortality .
Beta-blockers and heart failure One of the most promising developments in pharmacological heart failure treatment are the results obtained with beta-blockade. In the MDC study, Waagstein et al.[9] reported favourable effects of metoprolol, a beta-1-selective antagonist, on the combined end-point of cardiovascular morbidity and mortality in patients with dilated cardiomyopathy. The CIBIS I study, recruiting patients not only with idiopathic but also ischaemic cardiomyopathy[10] indicated a favourable effect of the beta-1-selective blocker bisoprolol on morbidity. These two trials suggested that beta-blockers have a favourable effect in heart failure patients, that a careful dose titration from a very small to a higher dose is needed during the institution of treatment and that it is not, at least so far, possible to predict which patients will become responders. Among suggested mechanisms for a beneficial outcome are a reduction in increased cardiac sympathetic tone, decreased heart rate, increased diastolic filling time and possibly also up-regulation of beta adrenergic receptors in the myocardium and a reduction of myocardial oxygen consumption. However, both the MDC and CIBIS 1 studies were not sufficiently powered to study the effect of beta-blockade on all-cause mortality. Very recently the CIBIS 2 study, which 1999 The European Society of Cardiology
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included over 2600 patients with NYHA class III-IV heart failure, was prematurely stopped after two interim analyses, in view of the favourable and highly significant effect when bisoprolol, compared to placebo, was added to conventional heart failure treatment. The risk reduction in overall mortality was 32% during the period of follow-up, regardless of the cause of heart failure, the decrease in sudden death amounted to 45%, while the need for heart failure hospitalization was reduced by 30% (reported at the HOT-line presentation, ESC annual congress, Vienna August 1998). In addition to beta-1-selective, other types of betablockers have demonstrated favourable effects in heart failure patients. Carvedilol combines non-selective betablockade with a relatively weak alpha-blockade and with antioxidant properties. The advantages compared with other beta-blockers may be the combination of beta-blockade and peripheral vasodilatation. This is considered to reduce afterload and to counteract negative inotropic effects and other possibly unfavourable effects of neurohormonal deactivation on the coronary and systemic vascular systems introduced by pure betablockade. The antioxidant properties of carvedilol may add value, for instance by beneficially affecting ventricular remodelling[11]. The clinical efficacy of carvedilol in heart failure has been tested in placebo-controlled trials. In the US phase 3 clinical trials programme, 696 patients were randomly assigned to carvedilol and 398 to placebo added to ACE inhibitor-based therapy. There was an overall reduction in hospitalization for cardiovascular reasons of 27% (CI:3–45%), and a 65% (CI: 39–80%) reduction in all-cause mortality among patients subjected to carvedilol, compared to those on placebo treatment[12]. Further support for a beneficial effect is obtained from a study in Australia/New Zealand, in which 415 patients with congestive heart failure, NYHA Class I-III, of ischaemic aetiology were recruited. Again, carvedilol or placebo was added to ACE inhibitors, loop diuretics and digitalis. Carvedilol resulted in a 26% (CI: 5–43%) reduction in the combined end-point, mortality and hospitalization[13].
Clinical trials and clinical practice Large, randomized clinical trials have significantly influenced our view on how heart failure should be treated. Indeed, they improved understanding of appropriate pharmacological therapy. By necessity, clinical trials of novel therapies had to add the test drug to currently accepted treatment. This introduces the possibility of unnecessary polypharmacy. Trial design may also have implications on the transfer of scientific achievements into clinical practice. It is known that the dosages of ACE inhibitors in clinical trials are considerably higher than those commonly used in practice[14]. One reason may be that a practitioner has to treat not only patients suitable for clinical trials but also other and possibly more fragile subjects. Another reason concerns tolerabilEur Heart J, Vol. 20, issue 12, June 1999
ity, in particular the risk for hypotension and renal side effects. Furthermore, it may be that it is not widely appreciated that low dosages may be less effective than high doses, causing the prescriptions to be lower than in the trials. This practice is, however, contradicted by recent ATLAS data, demonstrating that a high dose of lisinopril is significantly more efficient in reducing the combined end-point of mortality and hospitalization for heart failure than a low dosage[15]. Furthermore, in the MOCHA trial of carvedilol there were doserelated reductions in mortality and cardiovascular hospitalizations[16]. ACE inhibitors and beta-blockers carry a risk of hypotension as a side effect. For the practising physician, the combination of ACE inhibitors and betablockers may therefore be a less attractive combination, introducing the possibility that modern treatment will not be transferred into clinical practice despite evidence-based benefit. An obvious question is whether monotherapy with beta-blockers, at least in some heart failure patients, would be sufficient, thereby simplifying the therapy and its introduction in general practice. The question is relevant not the least since the use of ACE inhibitors includes a decrease of the sympathetic drive on the heart.
Left ventricular remodelling Great emphasis has been put on the fact that a remodelling process, characterized by myocardial restructuring causing progressive dilatation and a deterioration of left ventricular mechanical efficacy, is frequently observed in various clinical situations causing left ventricular strain and dysfunction. Remodelling is associated with poor prognosis, causing a successive deterioration of congestive heart failure and thereby adding to the impact of the disease that triggered the remodelling process. Experiences from a canine model of left ventricular dysfunction suggest that beta-1-selective blockade and ACE inhibition prevent the development of the remodelling process over 3 months of follow-up[17]. The effect of the beta-blocker carvedilol on left ventricular remodelling was carefully studied in the Australia/New Zealand study[18]. After only 6 months of treatment, left ventricular ejection fraction improved and left ventricular end-diastolic and end-systolic volumes reduced compared to the placebo group (Table 1). The changes observed at 6 months in the carvedilol group were maintained, while in the placebo group ventricular volumes continued to increase and left ventricular ejection fraction to decrease, causing the difference between the two groups to be even more apparent after 1 year of follow-up. Interestingly, the placebo group in this study were on ACE inhibitors, indicating that continued ACE inhibitor therapy was less effective than the combined treatment with an ACE inhibitor and carvedilol.
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Table 1 Left ventricular remodelling with carvedilol. Adapted from the Australia/ New Zealand Study[18] LVEF
Time
LVEDVI
LVESVI
Carvedilol
Placebo
Carvedilol
Placebo
Carvedilol
Placebo
28·6 +4·9* +5·5*
30·4 1·1 1·2
100·2 3·7** 6·0*
95·7 +4·4 +8·1
72·9 6·2*** 8·7***
68·2 +4·0 +6·6
Baseline (n=123) 6 months (n=97) 12 months (n=81)
P values: between treatment changes from baseline — *P<0·002 **P<0·007 ***P<0·0003. LVEF=left ventricular ejection fraction; LVEDVI=left ventricular end-diastolic volume index; LVESVI=left ventricular end- systolic volume index.
Table 2 Time
Baseline 4 months 12 months
Left ventricular remodelling with carvedilol. Adapted from Lowes et al.[19] LV Mass (g) Carvedilol
Placebo
304 272*† 242*
301 339
Sphericity index Carvedilol
LV thickness (cm)
Placebo
Carvedilol
Placebo
1·12 1·19
1·32 1·19* 1·12*
1·33 1·41
1·13 1·43*† 1·34
*P<0·05 vs baseline (carvedilol), †P<0·05 between treatment changes from baseline. LV=left ventricular.
Similar results were obtained by Lowes et al.[19]. These authors followed 27 patients on carvedilol and 17 on placebo during 4 months of blinded therapy, followed by open label carvedilol for a total of 12 months in all subjects. Carvedilol induced a reduction in left ventricular mass and wall thickness and improved the cardiac geometry. These beneficial effects, apparent after the initial period of treatment, were maintained during the remaining period of follow-up (Table 2). Several small studies with other beta-blockers, including beta-1-selective agents, have indicated that when added to ACE inhibition a moderate improvement in left ventricular ejection fraction is usually observed. Sympathetic over-activation leads either directly (cardiotoxicity) or indirectly (increasing heart rate, afterload and myocardial oxygen consumption) to further deterioration of the dysfunctioning heart and to further cardiac remodelling. Accordingly, inhibition of sympathetic activation by beta-blockade may prevent or retard remodelling. In addition, alpha-adrenergic blockade and antioxidant properties, features of carvedilol, may add significantly to this effect.
Beta-blockers or ACE inhibitors in heart failure Data from the study of left ventricular remodelling may support the hypothesis that a beta-blocker could be sufficient, even as monotherapy, in heart failure patients, at least if instituted at a relatively early stage before too much left ventricular remodelling has taken place. One may ask whether there is any evidence supporting
this assumption. Senor et al.[20] conducted a placebocontrolled study in 49 patients with left ventricular dysfunction following myocardial infarction. These patients were given carvedilol or placebo, but no ACE inhibitors. Preliminary data suggest that there was a significant increase in end-systolic and end-diastolic volume in the placebo, but not in the carvedilol group, while wall motion and site of infarct wall motion scores improved with carvedilol. There were also signs of a reduced number of cardiac events in the carvedilol-treated group. A breakdown of data from the US carvedilol studies[21] discloses sub-populations without ACE inhibitors. In Table 3 it can be seen that patients treated with carvedilol only demonstrated an improvement in all-cause mortality and left ventricular ejection fraction of a magnitude similar to those on the combination of carvedilol and ACE inhibitors. These data should, however, be interpreted with great caution as the numbers studied were small and the observations retrospective. However, they underline the interest shown in the testing of beta-blockers alone vs ACE inhibitors, and the two treatment modalities combined. Recently, a comparison of the beta-blocker metoprolol and the ACE inhibitor captopril was performed in a small number of patients. In this study the former drug had a more favourable haemodynamic profile than the latter[22].
Ongoing trials CARMEN (Carvedilol ACE inhibitor Remodelling Mild heart failure EvaluatioN) is the first study to Eur Heart J, Vol. 20, issue 12, June 1999
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Table 3 Effect of carvedilol on left ventricular ejection fraction and mortality in the presence and absence of an ACE-inhibitor in placebo-controlled clinical trials. Adapted from Gilbert et al.[21]
LVEF n= Baseline (%) Absolute Change (%) All-cause mortality n= mortality (%)
Carvedilol+ ACE inhibitor
Carvedilol alone
ACE inhibitor alone
Placebo
517 22 6·1
29 23 10·5
279 22 2·5
14 24 0·3
658 3·2
38 0
380 7·6
18 11
further test the hypothesis that beta-blockers alone will be sufficient treatment for congestive heart failure patients, without concomitant ACE inhibition. The study will recruit 450 patients with mild to moderate heart failure in which carvedilol alone is compared to enalapril alone, with respect to cardiac remodelling, i.e. left ventricular end-systolic volume index. In a third arm of the study, patients are treated with the two drugs combined, allowing for a comparison with enalapril alone. Secondary objectives include the comparison of the effect of the three treatment arms on other indices of left ventricular function and structure, on morbidity and mortality and on the safety and tolerability of the three treatment modalities.
Conclusion Pharmacological therapy of heart failure is still a matter of great concern. Despite achievements, including mortality reduction, longevity is still considerably reduced even for patients with modest heart failure. Improved therapy is a necessity for the future, not the least because of the great and increasing number of patients suffering from heart failure. As the number of pharmacological approaches to heart failure grows, thereby increasing the risk of unwanted and possibly unnecessary polypharmacy, the need for individualized, targeted therapies rises. Treatment instituted early in the course of heart failure and which aims to decrease left ventricular remodelling attracts interest since remodelling is associated with poor clinical outcome in terms of mortality and morbidity. At the same time it would be an advantage to establish therapies that are not too complex and without too many side effects, for example hypotension. Beta-blockers seem to have some of these capabilities. New studies should therefore be conducted following the hypothesis that it may be possible to reach similar or even better results with therapy based on beta-blockade alone, as compared to the current recommendation of combining it with ACE inhibition. Eur Heart J, Vol. 20, issue 12, June 1999
The authors wish to thank Marco Bobbio MD, Michel Komajda MD and Per Hildebrand MD for valuable criticism of the manuscript. This work was supported by a grant from the Swedish Heart and Lung Foundation.
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[18] Doughty RN, Whally GA, Gamble G et al. Left ventricular remodelling in patients with congestive heart failure due to ischemic heart disease. J am Coll Card 1997; 29: 1060–6. [19] Lowes D, Gill EA, Rodriguez-Larrain J et al. Carvedilol is associated with a reversal of remodelling in chronic heart failure. Circulation 1996; 94(8 Suppl 1): I-407, A 2371. [20] Senior R, Basu S, Lahiri A. Carvedilol prevents remodelling and improves prognosis in patients with left ventricular dysfunction following acute myocardial infarction. J Am Coll Card 1997; 27: 319A. [21] Gilbert EM, Colucci WS, Fowler WS et al. Carvedilol without ACE-inhibition in the treatment of patients with moderate to severe chronic heart failure. Circulation 1996; 94 (Suppl): I-663, A 3875. [22] Janson K, Karlberg KE, Nylander E et al. More favourable haemodynamic effects from metoprolol than from captopril in patients with dilated cardiomyopathy. Eur Heart J 1997; 18: 1115–21.
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