EDITORIAL COMMENT
Neurohormonal blockade in chronic heart failure
How much is enough? can there be too much?*
Barry M. Massie, MDa,*
* Cardiology Division, VA Hospital, San Francisco, California, USA
* Reprint requests and correspondence: Dr. Barry M. Massie, MD, Cardiology Division (111C), VA Hospital, 4150 Clement Street, San Francisco, California 94121, USA.
barry.massie{at}med.va.gov
For nearly 20 years, research studies into the pathophysiology of chronic heart failure (CHF) and its treatment have focused on the role of neurohormonal activation and its blockade (1,2). Initially, the increased activity of multiple neurohormonal systems in CHF was considered a potentially important compensatory response to the underlying hemodynamic abnormalities. Subsequently, the potentially deleterious consequences of neurohormonal activation and its association with a poorer prognosis became apparent. However, it was only with the recognition of the remarkable benefits of inhibition of the renin-angiotensin-aldosterone system and, subsequently, the adrenergic nervous system that the paradigm of neurohormonal activation and its downstream consequences of cytokine activation, apoptosis and myocardial remodeling became the dominant paradigm for understanding the mechanisms of progression of CHF and for developing new interventions to alter the natural history of this condition.
The pace of research in this area has been extraordinarily rapid, but few basic or clinical studies have examined the "dose-response" characteristics of either blockade of a single neurohormonal system or the cumulative effects of blocking multiple systems. Therefore, it has been assumed that higher doses of agents such as angiotensin-converting enzyme (ACE) inhibitors would be more effective than lower doses and that combination therapy with agents that produce more complete neurohormonal blockade would be associated with better outcomes. Indeed, the widespread use of ACE inhibitors in doses substantially below those found effective in clinical trials had been considered a target for quality improvement initiatives (3). Until relatively recently, few studies have contradicted these notions, and several observations provide indirect justification for the use of high-dose ACE inhibitors or combinations of neurohormonal antagonists. In particular, it is known that during chronic therapy with usual doses of ACE inhibitors, both angiotensin-II and aldosterone levels initially are lowered but subsequently "escape" to levels approaching pretreatment values (4–6). This may represent inadequate inhibition of ACE activity, alternative pathways for angiotensin-II generation, and/or the effect of nonangiotensin-II regulation of aldosterone secretion. Persistently elevated aldosterone levels, in particular, may play an important role in adverse cardiac remodeling (7). Furthermore, ACE inhibition has at best relatively minor long-term effects on plasma catecholamines (8,9).
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High- versus low-dose ACE inhibitor therapy
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The study reported by Tang et al. (10) in this issue of the Journal represents an ambitious effort to evaluate whether high or low doses of an ACE inhibitor produce greater neurohormonal suppression, changes in left ventricular structure and function, improvements in exercise tolerance, and clinical benefit. Seventy-five patients with ejection fractions <40% were randomized to enalapril 40 mg or 5 mg once daily and evaluated over a period of 30 weeks. At the end of the follow-up period there was greater suppression of serum ACE activity (and in a subgroup of 17 subjects, myocardial ACE activity) in the high-dose group, but no differences in measurements of angiotensin-II, aldosterone or catecholamines. There were only modest changes in New York Heart Association (NYHA) functional class, exercise tolerance and left ventricular function, with no intergroup differences. However, a composite clinical end point of death, hospitalizations, emergency room visits and need for sustained increases in diuretic dose occurred in fewer patients in the high-dose group (30% vs. 53%, p = 0.061). Perhaps the most clear and mechanistically important finding of this study is that high-dose therapy had no greater effect on the key neurohormonal measurements—angiotensin-II, aldosterone or catecholamines—than low-dose treatment. Unfortunately, the relatively small numbers of subjects, withdrawal of 25 of 75 patients, and limited period of follow-up preclude determination of whether there were differences in left ventricular size and clinical outcomes, both of which trended in favor of high-dose therapy. Thus, this study does not exclude the possibility that high doses of ACE inhibitors are superior to low doses, but it does suggest that differences are not likely to be dramatic.
This conclusion is consistent with the results of the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial (11). In that study, 3,164 patients with symptomatic heart failure and left ventricular ejection fraction  30% were randomized to a high (target dose 35 mg once daily) or low dose (2.5 or 5 mg once daily) lisinopril therapy. The high-dose group had a nonsignificant 8% lower risk of death, the primary end point (p = 0.128), but a significant 12% lower risk of death or hospitalization for any reason (p = 0.002) and a 24% reduction in heart failure hospitalizations (p = 0.002). In this much larger and longer study, the advantage of high-dose ACE inhibitor therapy was modest and would probably have been considerably smaller had the high dose been compared to the recommended doses of other ACE inhibitors (lisinopril 20 mg daily, enalapril 10 mg twice daily or captopril 50 mg three times daily).
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Are two neurohormonal antagonists better than one?
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The findings of a number of trials, involving well over 10,000 CHF patients, have clearly demonstrated that the addition of three different beta-blockers (carvedilol, bisoprolol and metoprolol) to ACE inhibitors reduce mortality by 30% to 35% and heart failure hospitalizations by a similar amount (12–15). Unfortunately, trials have not been conducted to establish that ACE inhibitors provide important additional benefit when added to beta-blockers, and such trials are unlikely to be done in symptomatic heart failure patients. However, one would expect significant additivity, and such has been the case in beta-blocked postmyocardial infarction patients with reduced ejection fractions (16). Thus, a combination of an ACE inhibitor and a beta-blocker is now the standard of care for most CHF patients (17,18).
Whether spironolactone, an aldosterone receptor blocker, could improve the outcomes of patients receiving typical doses of ACE inhibitors was addressed in patients with very severe CHF (NYHA functional class IV at entry or in the prior six months) in the Randomized Aldactone Longevity Evaluation Study (RALES) (19). This hypothesis was based upon the previously discussed escape of aldosterone during chronic ACE inhibition and the deleterious effect of this hormone on myocardial remodeling in animals (7,8). However, the magnitude of the benefit probably surprised even the investigators, with the trial being discontinued early as a result of a 30% reduction in mortality and a 35% reduction in heart failure hospitalizations in the spironolactone group.
The picture is much less clear when an angiotensin receptor blocker is added in patients receiving an ACE inhibitor. Again, benefit might be anticipated, because angiotensin-II levels remain elevated in many patients who are on ACE inhibitors. Furthermore, addition of an angiotensin receptor blocker has been associated with improvements in both hemodynamic measurements (20) and exercise tolerance (21). However, in a pilot study comparing candesartan in several doses either alone or in combination with enalapril or with enalapril alone, there was no sustained reduction on aldosterone or norepinephrine (22). Clinical events (death or the composite of death plus heart failure hospitalization) trended lower on enalapril alone compared to the combination, although the numbers are too small to reach any conclusions. The hypothesis that addition of an angiotensin receptor blocker to ACE inhibitor could improve outcomes was addressed in the Valsartan Heart Failure Trial (Val-HeFT) (23), which enrolled 5,010 patients with NYHA functional class II to IV CHF, left ventricular ejection fraction 40% and left ventricular dilation, of whom 93% were receiving ACE inhibitors. Two co-primary end points, mortality and the composite of mortality and morbidity (primarily hospitalization for worsening heart failure), were examined. Preliminary results of this trial indicated that the addition of valsartan has a neutral effect on mortality (relative risk [RR] 1.02, p = 0.80), but was associated with a modest benefit on the composite mortality and morbidity end point (RR 0.87, p = 0.009). However, in a prespecified subgroup analyses this benefit was greatest in the 7% of patients who were not taking ACE inhibitors and was no longer statistically significant among those who were on combination therapy. Thus, the combination of an angiotensin receptor blocker and ACE inhibitor seems to be at best marginally superior to an ACE inhibitor alone, although this issue is being addressed again in the ongoing Candesartan Cilexitil in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) and Valsartan in Acute Myocardial Infarction (VALIANT) trials (24,25).
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Are three neurohormonal antagonists better than two?
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Because the combination of ACE inhibitors and beta-blockers is now recommended for most CHF patients with systolic dysfunction, the relevant question has become whether adding a third neurohormonal antagonist is desirable. Again, the evidence is mixed. In RALES, 10% of the participants were receiving a beta-blocker as well as an ACE inhibitor (19). The mortality reduction in his subgroup was 58% compared to 28% in those who were not taking beta-blockers. The number of patients in this subgroup was small and the interaction was not statistically significant; nonetheless, this finding suggests that more neurohormonal antagonism may have something to offer. However, there are two important provisos. First, the patients entered into RALES had more severe heart failure as indicated by their recent NYHA functional class IV status and the 23% annual mortality rate in the placebo group, and they also required treatment with loop diuretics, usually in high doses. Thus, as a group they probably had marked neurohormonal activation. Second, one cannot assume that agents that block other hormones would have similar additivity.
Of the Val-HeFT subjects, 35% were on beta-blockers as well as ACE inhibitors, and there was a significant interaction between valsartan effect and background beta-blocker therapy (23). Although as noted above, valsartan was associated with a 13% reduction in morbidity and mortality overall, there was a 28% reduction in the patients who were not on beta-blockers and an 11% increase in those who were. Thus, in Val-HeFT, three neurohormonal antagonists were not better than two, but two appeared better than one.
Recent drug development has focused on new agents that modulate other neurohormonal systems or their potential downstream consequences such as cytokine activation, apoptosis and remodeling. In the current treatment milieu, most of these agents are being investigated in populations with nearly universal treatment with blockers of the renin-angiotensin system and a high proportion of beta-blocker therapy. So far, the results have not been very encouraging.
Two endothelin receptor antagonists, bosentan and enrasentan, both of which have mixed ET-1a and ET-1b activity, have been evaluated in phase II heart failure trials. Bosentan was evaluated in 368 patients with NYHA functional class IIIb or IV heart failure, all of whom were receiving an ACE inhibitor or angiotensin receptor blocker and 25% of whom were taking beta-blockers (26). Overall, bosentan had a neutral effect in clinical end points, but this appeared to reflect a higher incidence of early deterioration in the bosentan groups and a reduction in events in the latter half of the six-month follow-up period. Enrasentan was assessed in 419 patients with NYHA functional class II or III CHF on 5 to 10 mg of enalapril or the equivalent and, in many cases, beta-blockers (27). They were randomized to placebo or one of four doses of enrasentan. Although the numbers of subjects in each group were small, there was a strong trend toward less improvement and more deterioration in the enrasentan patients (p = 0.06). Finally, a large program evaluating the effect of the TNF-alpha binding protein etanercept was recently discontinued because of lack of benefit (27), again in a population in which patients were generally receiving both renin-angiotensin system antagonists and beta-blockers.
These results suggest that more neurohormonal antagonism may not necessarily lead to better outcomes. Clearly, it is too early to generalize, however, and until further information is available, these findings need to be considered to be specific to the agents utilized and the patient populations in which they were studied. Nonetheless, because the trends in several studies were toward worse outcomes with multiple neurohormonal antagonists, caution is warranted in both drug development and in the clinic. Indeed, excessive blockade of the adrenergic nervous system has been cited as a possible explanation for both the lesser benefit of bucindolol in the Beta-blocker Evaluation of Survival Trial (BEST) compared to other beta-blocker trials in heart failure patients (28) and in the early termination of the Moxonidine Congestive Heart Failure (MOXCON) trial for worse outcomes (29), although other potential explanations exist for both of these results.
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Is more neurohormonal antagonism necessary? Is it better?
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The results reviewed in this editorial have several important implications. First, it should be emphasized that the use of neurohormonal inhibitors represents the most important advance in the treatment of heart failure since the advent of diuretics. Both ACE inhibitors and beta-blockers are effective in improving survival, preventing progression of cardiac dysfunction and improving clinical status. Both should be used in patients with systolic dysfunction, unless not tolerated or otherwise contraindicated. The incremental benefit of the combination is likely to outweigh the incremental benefit of using higher doses of one.
Second, we lack adequate information to make definitive recommendations concerning doses of these agents. The study by Tang et al. (10) and the results of the ATLAS trial (11) suggest that there may be an advantage for higher doses of ACE inhibitors compared to low doses, but this advantage may be relatively modest. Thus, the use of what now can be considered moderate doses, those used in most clinical trials (enalapril 10 to 20 mg or captopril 75 to 150 mg or the equivalent) should be encouraged. The picture with beta-blockers is not much clearer. Although one study (30) has suggested that intermediate doses of a beta-blocker can be beneficial, other trials using relatively low doses (the first Cardiac Insufficiency Bisoprolol Study [CIBIS] and the Metroprolol in Dilated Cardiomyopathy [MDC]) did not demonstrate as impressive benefits as later trials using higher doses of the same agents (31,32). The present recommendation must be to use agents and doses that have improved survival—carvedilol 25 mg twice daily, metoprolol 150 to 200 mg daily or bisoprolol 10 mg daily.
Third, the addition of other neurohormonal antagonists in patients already receiving an ACE inhibitor (or an angiotensin receptor blocker in ACE-inhibitor-intolerant patients) and a beta-blocker needs to considered on a drug-by-drug basis and in relation to the characteristics of the individual patient. Spironolactone appears to be beneficial in patients with severe heart failure, but it may not be either effective or safe in those with less severe symptoms or lesser diuretic requirements. In contrast, there is no justification for adding an angiotensin receptor blocker to patients receiving both an ACE inhibitor and beta-blocker.
And finally, it is possible that the string of successes with neurohormonal antagonists may have run its course. Although the prognosis of heart failure patients remains poor and neurohormonal activation persists despite treatment with ACE inhibition, beta-blockers and spironolactone, the presumption that the addition of other antagonists will be effective cannot be taken for granted. Recent neutral or negative results may reflect the difficulty of producing additional blockade of relevant neurohormonal systems, the selection of mechanistically unimportant targets or an adverse effect of excessive blockade. Research in this area should and will continue, with agents such as endothelin antagonists, vasopressin antagonists and cytokine inhibitors. However, it is also important to explore other therapeutic avenues, such as drugs that improve myocardial energetics, oxygen-carrying capacity and myocardial contractility or relaxation by novel mechanisms, as well as devices that enhance myocardial performance or prevent arrhythmic death.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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High- versus low-dose ACE...
Are two neurohormonal...