Neurohormonal inhibition in heart failure, is there no limit?

Stein Ørna,* and Kenneth Dicksteinb

a Cardiology Division, Central Hospital in Rogaland, Stavanger, Norway
b University of Bergen, Central Hospital in Rogaland, Stavanger, Norway

* Corresponding author. Tel.: +00-47-51-51-80-00
E-mail address: orst{at}sir.no

E-mail address: trout{at}online.no

Received 4 July 2003; accepted 9 July 2003

See doi:10.1016/S1095-668X(03)00477-9for the article to which this editorial refers

The strategy supporting effective pharmacological treatment in heart failure patients stems from appreciation of the deleterious effects of chronic neurohormonal activation. Increasingly comprehensive treatment strategies that inhibit neurohormonal activation have evolved in an add-on fashion in the belief that the more complete the neurohormonal inhibition, the better. However, there is a downside to excessive neurohormonal inhibition, since an operational neurohormonal system is necessary to maintain homeostasis also in patients with heart failure. The aim of neurohormonal inhibition should not be to completely dismantle the neurohormonal system, but rather inhibit excessive activation, leaving autoregulatory functions and useful compensatory mechanisms intact.

The combination of diuretics, ACE inhibitors, ß-blockers and aldosterone antagonists is currently routine in the treatment of symptomatic heart failure patients. The role of angiotensin receptor blockers (ARBs), however, is unclear. There is sufficient data to support the use of ARBs when ACE inhibitors are not tolerated, but there is insufficient trial data to support the use of ARBs as an alternative to ACE inhibitors.1The potential role of ARBs as add-on therapy to ACE inhibitors and ß-blocker treatment is unresolved. In the Val-HeFT trial, patients already treated with ACE inhibitors did not have any mortality benefit of adding an ARB, although the combined co-primary end-point including morbidity was positive.2In patients treated with both ACE inhibitors and ß-blockers mortality was increased.

The ambitious study by McKelvie et al. in the current issue of the journal compares the effects of comprehensive neurohormonal inhibition with ARB, ACE inhibitors and ß-blockers on the surrogate end-points of selected neurohormones, left ventricular (LV) volumes and LV ejection fraction (LVEF).3In spite of a complicated study design and some major limitations, the study is interesting since there is little mechanistic data on this treatment combination. Furthermore, it is unlikely that a similar study will be repeated following the firm establishment of ß-blockers in the routine treatment of heart failure patients.

The study is based upon a cohort of patients (n=426) in the Randomised Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study (RESOLVD) that were considered eligible to receive ß-blocker treatment.4According to the original RESOLVD protocol, all patients were initially randomised to receive either candesartan, enalapril or the combination. After 19 weeks of treatment, patients were randomised to either metoprolol CR therapy or placebo in addition to original treatment assignment, and then followed for a total of 43 weeks. Patients were divided into four groups according to treatment: (1) ARB or ACE inhibitor as monotherapy, (2) ARB and ACE inhibitors as double therapy, (3) ß-blocker in double therapy with either ARB or ACE inhibitor or (4) ß-blocker in triple therapy with ARB and ACE inhibitor. LVEF, LV volumes, and neurohormones were measured at randomization and after 43 weeks.

The primary result was a significant improvement in LVEF when triple therapy was compared with any of the other treatment regimens. There was a non-significant improvement in LVEF when candesartan was added to captopril and when metoprolol was added to either treatment. There was no significant effect on pro-ANF, BNP, angiotensin II, aldosterone, norepinephrine or endothelin between the different treatment regimens. Importantly the discontinuation rate was higher among patients receiving a ß-blocker (13.9% in patients on ß-blocker and ARB or ACE inhibitor and 13.1% in patients on triple therapy) compared with those that did not receive a ß-blocker (3.4% in patients on ARB or ACE inhibitor and 5.1% in patients on the combination).

The findings are in accordance with other studies that have demonstrated modest improvements in LVEF in heart failure patients treated with ß-blockers on background therapy with and without ACE inhibitors.5However, the current study contrasts with the echo substudy in Val-HeFT, the only large scale study comparing the effect on LVEF of adding ARBs to ACE inhibitors and ß-blockers in heart failure patients. In Val-HeFT, there was no improvement in LVEF in patients receiving triple therapy. Do the results from the current study contradict the results of Val-Heft? The studies differ in several aspects. Most importantly, the patient population are not comparable. In Val-HeFT, patients were randomised to an ARB or placebo on top of existing stable heart failure treatment that included ACE inhibitors and ß-blockers. Background therapy in the Val-HeFT population may have been influenced by numerous factors including tolerance and response to the different treatment combinations. Remodelling benefits may already have been established with limited additional benefit by adding an ARB. Another important difference is the longer observation period on treatment in Val-HeFT.

The authors propose that the results of the current study may suggest improved survival in patients taking the combination of an ACE inhibitor, ARB and ß-blocker. There are no surrogate end-points that reliably predict survival. Large randomised mortality trials have taught us that seemingly apparent benefits of treatment in pilot and mechanistic studies do not necessarily translate into a mortality benefit when properly designed mortality trials have been conducted. The major limitation to mechanistic studies that require more than one observation time point, is that only patients that survive the observation period are included in the analysis. Obviously this is a different population than those originally randomised.

What are the clinical implications of the present study? The study demonstrates that the greatestimprovement in LV function in survivors with heart failure is achieved in patients receiving triple therapy. This is at the cost of substantially higher discontinuation rates comparing patients with and without ß-blockers. Discontinuation rates would probably be an even greater problem in routine clinical practice.

Of course, the study does not provide an answer to the most central question; will triple therapy be superior to double therapy in prolonging life and reducing morbidity? This is an issue that hopefully will be resolved by assessing the effect of triple therapy on patients in the CHARM6and VALIANT7trials. If these trials support the use of triple therapy we will face another challenge following the EPHESUS8and RALES9trials; what is the role of quadruple therapy (ACE inhibitor, ARB, ß-blocker and aldosterone antagonist)? What degree of neurohormonal inhibition will be efficacious and tolerated in patients with heart failure? Considering the multiple aetiologies in this heterogeneous population and the increasing complexity of different treatment alternatives, the importance of individually tailored therapy has become increasingly evident. The trick is to know who needs what?

References

  1. Maggioni A, Anand I, Gottlieb S et al. Effects of valsartan on morbidity and mortality in patients with heart failure not recieving angiotensin converting enzyme inhibitors. J Am Coll Cardiol. 2002;40:1414–1421.[CrossRef][Medline]
  2. Cohn JN, Tognoni G. for the Valsartan Heart Failure Trial Investigators. A randomised trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–1675.[Abstract/Free Full Text]
  3. McKelvie RS, Rouleau JL, White M et al. Comparative impact of enalapril, candesartan or metoprolol alone or in combination on remodelling in patients with congestive heart failure. Eur Heart J. 2003;24:1727–1734.[Abstract/Free Full Text]
  4. Tsuyuki RT, Yusuf S, Rouleau JL, for the RESOLVD pilot study investigators. Combination neurohormonal blockade with ACE inhibitors, angiotensin II antagonists and beta-blockers in patients with congestive heart failure: design of the Randomised Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot study. Can J Cardiol. 1997;13:1166–1174.[Medline]
  5. Remme WJ, Soler-Soler J, Ryden L, On behalf of the CARMEN investigators et al. Replacement of angiotensin converting enzyme inhibitor by carvedilol results in long-term reversed left ventricular remodelling in mild heart failure and is well tolerated: results of the CARMEN (Carvedilol Ace inhibitor remodelling in mild heart failure evaluation) study. J Am Coll Cardiol. 2003;41(supplement A): 204A.
  6. McMurray J, Ostergren J, Pfeffer M, On behalf of the CHARM committees and investigators et al. Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseløine characteristics of patients in the Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur J Heart Failure. 2003;5:261–270.[CrossRef][Medline]
  7. Pfeffer M, McMurray J, Leizorovicz A, for the VALIANT investigators et al. Valsartan in Acute Myocardial Infarction Trial (VALIANT): Rationale and design. Am Heart J. 2000;140:727–734.[CrossRef][Medline]
  8. Pitt B, Remme W, Zannad F, for the EPHESUS investigators et al. Eplenerone, a selective Aldosteron Blocker in patients with Left Ventricular Dysfunction after Myocardial Infarction. N Engl J Med. 2003;348:1309–1321.[Abstract/Free Full Text]
  9. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–717.[Abstract/Free Full Text]

Related articles in EHJ:

Comparative impact of enalapril, candesartan or metoprolol alone or in combination on ventricular remodelling in patients with congestive heart failure
Robert S. McKelvie, Jean-Lucien Rouleau, Michel White, Rizwan Afzal, James B. Young, Aldo P. Maggioni, Peter Held, and Salim Yusuf
EHJ 2003 24: 1727-1734. [Abstract] [Full Text]  




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