12 Congestive Heart Failure Studies Every Pharmacist Should Know, Part 2

Over the years, a number of landmark clinical studies on CHF have been published, shaping how we treat the disease today. This article is a continuation of 12 Congestive Heart Failure Studies Every Pharmacist Should Know, Part 1.

Congestive heart failure (CHF) affects an estimated 5.7 million individuals in the United States and costs the nation over $30 billion each year.

In the 1980s, CHF meant a poor prognosis due to limited treatment options; annual mortality exceeded 50% and one-third of all CHF patients were hospitalized each year. With the advent of new treatment options, CHF mortality has decreased, yet still about half of those who develop heart failure die within 5 years of diagnosis.

Over the years, a number of landmark clinical studies on CHF have been published, shaping how we treat the disease today. In part 1 of this article, we looked at 6 of those. Here are 6 more that every pharmacist should know:

7. CIBIS-II (1999)1

By the mid-1990s, ACE-inhibitors, diuretics, digoxin, and the combination of isosorbide dinitrate and hydralazine were commonly being used in the treatment of heart failure. There was some evidence that beta blockers may also be beneficial, from studies dating back to the mid-1970s and the original CIBIS study; however, their effect on mortality was unknown.

To examine their impact, researchers conducted a multicenter double-blind randomized-controlled trial in Europe. 2647 symptomatic patients in NYHA class III or IV with LVEF 35% or less and receiving standard therapy with diuretics and ACE-inhibitors were randomized to either bisoprolol or placebo daily. Patients were followed up for a mean of 1.3 years.

The study ended early because bisoprolol showed a significant mortality benefit. All-cause mortality was 34% lower with bisoprolol than placebo, and there were significantly fewer sudden deaths and hospitalizations for heart failure among patients treated with bisoprolol.


When added to standard therapy, bisoprolol resulted in reduced all-cause mortality and morbidity.

8. MERIT-HF (1999)2

This multicenter, double-blinded, parallel-group, placebo-controlled trial was conducted to investigate whether metoprolol extended release (XL), in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure.

Researchers enrolled 3991 patients with chronic heart failure in NYHA functional class II-IV and with LVEF of 40% or less. After a 2-week single-blind placebo run-in period, patients were assigned to metoprolol XL or placebo. Mean follow-up time was 1 year.

The study was stopped early after finding that all-cause mortality was 34% lower in the metoprolol XL group than in the placebo group. Additionally, there were fewer sudden deaths and deaths from worsening heart failure in the metoprolol XL group than with placebo.


When added to standard therapy, long-acting metoprolol resulted in reduced all-cause mortality and morbidity.

9. COPERNICUS (2002)3,4

While the role of certain beta-blockers in heart failure were solidified from the CIBIS-II and MERIT-HF studies, questions remained if carvedilol carried the same profile and whether benefit would be seen in those with more severe heart failure.

In the study, 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction less than 25% were randomized to either placebo or carvedilol for an average of 10.4 months.

The study showed that carvedilol reduced the risk of death by 35% compared to placebo. It also decreased the combined risk of death or hospitalization for a cardiovascular reason by 27% and the combined risk of death or hospitalization for heart failure by 31%. Patients in the carvedilol group spent 27% fewer days in the hospital for any reason and 40% fewer days in the hospital for heart failure.


In symptomatic CHF patients, the addition of carvedilol to conventional therapy reduces mortality and morbidity.

10. Val-HeFT (2001)5

After publication of several studies previously mentioned, ACE-inhibitors and beta blockers quickly became standard of care in HFrEF management by the end of the late 1990s. The role of angiotensin-receptor blockers (ARBs) in this condition hadn’t yet been defined.

Researchers randomly assigned a total of 5010 patients with heart failure of NYHA class II-IV and LVEF less than 40% to receive valsartan or placebo twice daily. At baseline 93% were taking an ACE inhibitor while only 35% were on a beta-blocker. The primary outcomes were mortality and the combined end point of mortality and morbidity. The overall mean duration of follow-up was 23 months.

Study results showed that overall mortality was similar among the two groups; however, the incidence of the combined endpoint was 13% lower with valsartan than with placebo. This was predominantly due to a lower number of patients hospitalized for heart failure in those taking valsartan. A subgroup analysis showed that among those receiving both an ACE-inhibitor and a beta blocker, valsartan had an adverse effect on mortality and was associated with a trend toward an increase in the combined end point of mortality and morbidity.


Addition of valsartan to standard therapy was not shown to improve survival but did reduce the incidence of a composite endpoint of morbidity and mortality. Combination with an ACE-inhibitor plus beta blocker was associated with significantly worse outcomes.

11. CHARM-Alternative (2003)6

The CHARM program was a collection of 3 studies comparing candesartan, an ARB, with placebo in patients with symptomatic heart failure. CHARM-alternative looked to determine whether use of an ARB could improve outcome in such patients not taking an ACE-inhibitor.

2028 patients with symptomatic heart failure and LVEF 40% or less who were not receiving ACE-inhibitors because of previous intolerance were randomly assigned to candesartan or placebo. Median follow-up was 33.7 months.

Candesartan was shown to be associated with a 20% reduction cardiovascular mortality and a 39% reduction in heart failure hospitalization. The medication was well tolerated throughout the study.


Use of candesartan in patients intolerant to ACE-inhibitors was well tolerated and reduced cardiovascular mortality and hospitalization for heart failure.

12. PARADIGM-HF (2014)7

This multinational, randomized, double-blind trial paved the way for the approval of Entresto, a combination of sacubitril and valsartan, the first approved agent in the angiotensin receptor-neprilysin inhibitor (ARNI) class.

PARADIGM-HF enrolled 8442 adult patients with symptomatic chronic heart failure defined as NYHA class II—IV and LVEF 40% or less. After an initial run-in period, patients were randomized to receive either Entresto or enalapril twice daily. At baseline, most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%) all of which were not altered throughout the trial. The median follow-up duration was 27 months, and patients were treated for up to 4.3 years.

The study demonstrated that Entresto was superior to enalapril in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, based on a time-to-event analysis, by 20%. Entresto was also shown to improve overall survival, which was driven by entirely by a lower incidence of cardiovascular mortality.

Although some experts have mixed opinions on the value of Entresto in clinical practice, the medication was endorsed in the most recent update of the US heart failure guidelines.


Among patients with HFrEF, treatment with Entresto was shown to reduce CV mortality or heart failure hospitalizations when compared to enalapril.


  • CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. The Lancet. 1999;353(9146):9-13.
  • Fagerberg B, et al. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure. The Lancet. 1999;353(9169):2001-2007.
  • Packer M, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure. Circulation. 2002;106(17):2194-2199.
  • Packer M, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;May 31;344(22):1651-1658.
  • Cohn JN, et al. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667-1675.
  • Granger CB, et al. 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. The Lancet. 2003;362(9386):772-776.
  • McMurray J, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371: 993-1004.