Major trials in the advancement of heart failure management

GVM Care & Research
Fondazione Ettore Sansavini per la Ricerca Scientifica
Health Science Foundation Onlus
Cotignola, ITALY

University of Bergen
Stavanger University Hospital

Major trials in the advancement of heart failure management

by F. Rashidi and K. Dickstein, Norway

The objective of this paper is to review the evidence provided by the major clinical trials that have yielded new advances in heart failure management. Heart failure is a major public health burden associated with high morbidity and mortality, frequent hospitalization, and substantial cost. Prevalence is increasing through the combined effects of an aging population and the efficacy of heart disease therapies, in particular the prolonged survival associated with coronary artery disease. The cornerstone of the pathophysiology of heart failure is the activation of key neurohormonal systems (reninangiotensin- aldosterone system and sympathetic nervous system). Landmark trials have established renin-angiotensin-aldosterone blockade using angiotensin- converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor blockers, along with sympathetic blockade using β-blockers, as the mainstays of current treatment, conferring significant morbidity and mortality benefit. Recently, the Systolic Heart failure treatment with If inhibitor ivabradine Trial (SHIFT) demonstrated that heart rate reduction with ivabradine added to adequate β-blockade improved clinical outcomes in patients with heart failure.

Medicographia. 2011;33:384-388 (see French abstract on page 388)

Heart failure is a common clinical syndrome dominated by signs and symptoms of fluid retention, even if many patients are asymptomatic. As the end stage of various cardiac conditions, it is associated with high morbidity and mortality, frequent hospitalization, and substantial socioeconomic cost. It affects an estimated 5 million Americans, with over 550 000 new patients being diagnosed annually,1 and a total of 15 million European patients, equivalent to 2% to 3% of the total population and 10% to 20% of the over-70s.2 Prevalence is increasing because of population aging and improved management of heart disease, in particular coronary artery disease.2-4

Heart failure can be divided into two types, depending on whether it is associated with systolic dysfunction (the more studied variant) or diastolic dysfunction. However, some consider the distinction arbitrary.5 Most trials have included only patients with left ventricular (LV) systolic dysfunction defined by an ejection fraction (EF) below 35% to 40%. Current drug therapy is based on our understanding of the pathophysiology behind heart failure progression. This review focuses on the drug management of heart failure as recommended in current guidelines2-4 on the basis of the evidence garnered from pivotal trials, and it includes prevention of acute decompensation that often requires hospitalization. We shall not be considering the lifestyle changes and dietary measures that are an integral part of heart failure management, nor the treatment of cardiac conditions leading to heart failure. Nor will our review encompass recently introduced nondrug approaches, such as implantable cardioverter defibrillators and cardiac resynchronization therapy using biventricular pacing.

Drug therapy remains the mainstay of management. Its key objectives are symptom relief, slowing of disease progression (even reversal of myocardial dysfunction, if possible), and prolongation of survival.

The management of heart failure patients is based on two main pathophysiological mechanisms: inhibition of the reninangiotensin- aldosterone system and inhibition of the sympathetic nervous system. Current guidelines recommend a number of medications that improve patient symptoms, including angiotensin-converting enzyme (ACE) inhibitors, β-blockers, diuretics, digoxin, angiotensin II receptor blockers (ARBs) (in patients who cannot tolerate ACE inhibitors), and vasodilators, such as nitrates.2-4 Among these, some medications have been shown to improve survival, such as ACE inhibitors, β-blockers, ARBs, and in some subsets of patients spironolactone and eplerenone.

Inhibition of the renin-angiotensin-aldosterone system

_ ACE inhibitors in heart failure and their effect on mortality
Several trials have shown ACE inhibitors to prolong survival in various disease stages ranging from severe heart failure to asymptomatic LV dysfunction.6-9

The COoperative North Scandinavian ENalapril SUrvival Study (CONSENSUS) investigated the effect of adding enalapril 40 mg to diuretics, digitalis, and spironolactone, but not β-blockers, in 253 patients with severe heart failure. Enalapril improved symptoms and life expectancy compared with placebo, but had no impact on sudden cardiac death.6

The Vasodilator-Heart Failure Trial II (V-HeFT-II) randomized 804 men with New York Heart Association (NYHA) class II and III heart failure to receive enalapril 20 mg (n=403) or hydralazine/ isosorbide dinitrate (n=401) for 2 years. Sudden death was 14% and mortality from progressive heart failure 12% in the enalapril group compared with 23% and 10% in the hydralazine/ isosorbide dinitrate group.7

The Studies Of Left Ventricular Dysfunction–Treatment (SOLVDTreatment) randomized 2569 patients with NYHA class II to III heart failure and EF <35% to enalapril 20 mg or placebo. After an average of 41 months, there were 16% fewer deaths in the enalapril group (P=0.0036), primarily deaths attributed to progressive heart failure, and 26% fewer hospitalizations (P<0.0001).8 SOLVD-Prevention randomized 4228 asymptomatic patients with EF ≤35% to enalapril 2.5 mg-20 mg or placebo. At an average of 37 months, total mortality was 8% lower in the enalapril group (nonsignificant [NS]) and there were fewer deaths and hospitalizations due to heart failure (P<0.001).9

_ Other trials
The Survival And Ventricular Enlargement (SAVE) trial with captopril,10 the Acute Infarction Ramipril Efficacy (AIRE) trial with ramipril,11 and the TRAndolapril Cardiac Evaluation (TRACE) trial with trandolapril12 all showed that ACE inhibition significantly improves survival and reduces morbidity and mortality due to major cardiovascular events in patients with heart failure and/or a low EF.

The above trials were consistent in showing that ACE inhibitors should be the basis for therapy, along with a diuretic and digoxin as necessary, in all patients with symptomatic LV dysfunction, unless contraindicated or not tolerated. However, they also showed, and clinical experience has confirmed, that potassium and creatinine levels need to be monitored in patients receiving ACE inhibitors.

Treatment may be associated with side effects such as hypotension and cough. ARBs are an alternative to ACE inhibitors for patients who cannot tolerate an ACE inhibitor.

_ Angiotensin II receptor blockers
ARBs are indicated mainly in patients in whom ACE inhibitors are contraindicated. The key trials in this regard include the Valsartan Heart Failure Trial (Val-HeFT), which showed that valsartan significantly reduced the combined end point of mortality and morbidity and improved the signs and symptoms of heart failure versus placebo13; the CHARM-Added trial (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity—in patients with LV dysfunction already taking ACE inhibitors), which revealed that candesartan (target dose 32 mg/day) significantly improved outcomes versus placebo in patients already receiving an ACE inhibitor or β-blocker14; the CHARM-Alternative trial (CHARM—in patients with LV dysfunction intolerant to ACE inhibitors), in which candesartan at the same target dose of 32 mg/day significantly reduced cardiovascular mortality and hospitalization for heart failure in patients unable to tolerate an ACE inhibitor15; and the VALIANT trial (VALsartan In Acute myocardial iNfarc- Tion), which found valsartan 160 mg to be as effective as captopril 150 mg in all-cause mortality in patients with myocardial infarction complicated by heart failure (the combination of valsartan plus captopril, however, provided no added survival benefit, serving only to increase the rate of adverse events).16

_ Aldosterone antagonists
Aldosterone antagonists are recommended in patients with NYHA class III or IV heart failure associated with systolic dysfunction in the absence of hyperkalemia and renal dysfunction.2 The recommendation is based on three placebo-controlled trials: the Randomized ALdactone Evaluation Study (RALES) in class III and IV heart failure patients with systolic dysfunction (EF ≥35%), which reported a 30% reduction in the relative risk (P<0.001) of all-cause mortality in the group taking spironolactone17; the Eplerenone Post-AMI Heart failure Efficacy and SUrvival Study (EPHESUS) in a total of 6632 patients with low EF (≤40%), which showed reductions in all-cause mortality (P=0.008) and the combined end point of cardiovascular mortality and hospitalization for cardiovascular events (P=0.002) over a mean follow-up of 16 months18; and, most recently, the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF), which confirmed the reductions observed in all-cause mortality (P=0.008) and cardiovascular mortality plus hospitalization for heart failure (P<0.001), only this time in patients with mild symptoms, over a median follow-up of 21 months (the trial was stopped prematurely according to prespecified rules).19

Inhibition of the sympathetic nervous system with β-blockers

The European and American guidelines recommend β-blockers in symptomatic heart failure unless contraindicated or not tolerated. As with ACE inhibition, the recommendations are based on a number of large-scale randomized trials.

_ US Carvedilol Heart Failure Trials Program
In 1996, the US Carvedilol Heart Failure Trials Program was the first to demonstrate the benefit of added β-blockade in heart failure, with reductions versus placebo of 65% in overall mortality and 38% in the combined risk of death or hospitalization (both P<0.001), leading the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion.20

The Cardiac Insufficiency Bisoprolol Study II (CIBIS II) randomized 2647 patients with class III to IV heart failure and EF ≤35% to bisoprolol 1.25-10 mg or placebo. The trial was stopped after the second interim analysis due to the lower overall mortality on bisoprolol (n=156 [12%] vs n=228 [17%] on placebo; P<0.0001), as well as significantly fewer sudden deaths and all-cause hospital admissions.21

In 2002, the CarvedilOl ProspEctive RaNdomIzed CUmulative Survival (COPERNICUS) trial reported reductions versus placebo of 27% (P<0.00002) in the combined risk of death or hospitalization for a cardiovascular cause and of 40% in the number of days in hospital for heart failure (P<0.0001) after a mean 10.4 months in 1156 patients with severe heart failure randomized to carvedilol (3.125-50 mg target dose).22

The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure (SENIORS) addressed the hitherto neglected topic of the safety and efficacy of &beta-blockade in patients aged 70 years or older with a broad range of EF values. Over a mean duration of 21 months, the primary outcome (a composite of all-causemortality or cardiovascular hospital admission) occurred in 31.1% of patients on nebivolol compared with 35.3% on placebo (P=0.039), leading the authors to conclude that β-blockade with nebivolol is safe and effective in elderly patients with heart failure.23

Heart rate reduction by sinus node inhibition

In 1986, the Norwegian cardiologist John Kjekshus tested the hypothesis that the degree of potential benefit of β-blockade after myocardial infarction depends quantitatively on the re duction in heart rate it achieves. Exhaustive and stringent review of acute and long-term intervention trials revealed a relation between the actual reduction in resting heart rate and the percentage reduction in mortality in each trial (r=0.60, P<0.05). Kjekshus also uncovered a near-similar relation between the reduction in resting heart rate and nonfatal reinfarction (r=0.59, P<0.05).24

These studies set the theoretical stage for the development of agents that would be devoid of the unwanted effects of &beta- and calcium blockade. They would lower heart rate while having little or no activity elsewhere in the body. First-in-class of these pure heart rate–lowering drugs was ivabradine, a specific inhibitor of the If current in the sinoatrial node.25

The recent Systolic Heart failure treatment with If inhibitor ivabradine Trial (SHIFT) randomized 6558 patients with moderate- to-severe heart failure and systolic dysfunction (EF ≤35%) to ivabradine or placebo.26 All patients received concomitant guideline therapy with ACE inhibitors, ARBs, β-blockers, aldosterone antagonists, and diuretics. The primary end point was a composite of cardiovascular death and hospitalization for worsening heart failure. Over a mean follow-up of 23 months, 793 patients in the ivabradine group (24%) had a primary end point event compared with 937 (29%) of those taking placebo (P<0.0001). The effects were driven mainly by fewer hospitalizations for worsening heart failure (P<0.0001) and fewer deaths due to heart failure (P=0.014). The hazard ratio for cardiovascular death or hospitalization for worsening heart failure was 18%lower than in the placebo group. Serious adverse events rates were also fewer in the active treatment group (P=0.025), leading the authors to conclude that ivabradine was effective and well tolerated and should have an important role to play in the treatment of heart failure in the future.


Insights into the fundamental mechanisms of heart failure, dominated by activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, have driven the major advances in drug therapy achieved in recent decades, namely the addition to therapy of ACE inhibitors, ARBs, and aldosterone inhibitors, on the one hand, and β-blockers on the other. More recently, a novel approach to reducing heart rate by sinus node inhibition with ivabradine has been shown to improve clinical outcomes and emphasizes the importance of achieving adequate heart rate reduction in patients with heart failure. _

1. American Heart Association. Heart Disease and Stroke Statistics: 2005 Update. Dallas, Tex: American Heart Association; 2005.
2. Dickstein K, Cohen-Solal A, Filippatos G, et al; Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of European Society of Cardiology. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-2442.
3. Swedberg K, Cleland J, Dargie H, et al; Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J. 2005;26:1115-1140.
4. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90.
5. Aurigemma GP, Gaasch WH. Clinical practice. Diastolic heart failure. N Engl J Med. 2004;351:1097-1105.
6. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435.
7. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine- isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303-310.
8. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302.
9. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685-691.
10. Pfeffer MA, Braunwald E, Moye LA, et al; SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327:669-677.
11. 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. Lancet. 1993;342:821-828.
12. Kober L, Torp-Pedersen C, Carlsen JE, et al; Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333:1670-1676.
13. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675.
14. McMurray JJ, Ostergren J, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771.
15. Granger CB, McMurray JJ, Yusuf S, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772-776.
16. Pfeffer MA, McMurray JJ, Velazquez EJ, et al; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906.
17. Pitt B, Zannad F, Remme WJ, et al; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717.
18. Pitt B, Remme W, Zannad F, et al; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.
19. Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011; 364:11-21.
20. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349-1355.
21. CIBIS II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13.
22. Packer M, Fowler MB, Roecker EB, et al; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194-2199.
23. Flather MD, Shibata MC, Coats AJ, et al; SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215-225.
24. Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F.
25. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757-1765.
26. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.

Keywords: angiotensin-converting enzyme inhibitor; angiotensin receptor blocker; _-blocker; diuretic; heart failure; ivabradine; systolic dysfunction