Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan - HEAAL — Presented at AHA 2009

Nov 17, 2009
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Trial Sponsor:
Merck
Date Presented:
01/01/2009
Date Published:
01/01/2009
Date Updated:
11/17/2009
Original Posted Date:
11/17/2009
References

Description:

The goal of this trial was to compare treatment with high-dose versus low-dose losartan among patients with heart failure.

Hypothesis:

High-dose losartan would be superior in reducing death or admission for heart failure.

Study Design

Study Design:

Patients Enrolled: 3,846
NYHA Class: II–69%, III–30%, IV–1%
Mean Follow Up: Median 4.7 years
Mean Patient Age: 66 years
Female: 30%
Mean Ejection Fraction: 33%

Patient Populations:

  • Patients with heart failure (New York Heart Association class II-IV)
  • Left ventricular ejection fraction 40% or less
  • Intolerance to ACE inhibitors
  • At least 18 years of age

Exclusions:

  • Pregnancy or lactation
  • Intolerance to angiotensin-receptor blockers
  • Systolic blood pressure <90 mm Hg
  • Significant valve disease
  • Active myocarditis or pericarditis
  • Planned heart transplantation
  • Percutaneous coronary intervention, coronary artery bypass grafting, myocardial infarction, unstable angina, or stroke/transient ischemic attack within the last 12 weeks
  • Renal artery stenosis
  • Contraindication to a vasodilator
  • Limited life span for a cause other than heart failure
  • Drug or alcohol abuse within the last 2 years
  • Participation in another investigational drug trial
  • Renal insufficiency
  • Hypo- or hyperkalemia
  • Liver disease
  • Anemia

Primary Endpoints:

  • Death or admission for heart failure causes

Secondary Endpoints:

  • Death or admission for cardiovascular causes
  • Change in severity of heart failure

Drug/Procedures Used:

Patients with heart failure and left ventricular ejection fraction 40% or less, were randomized to high-dose losartan (n = 1,927) versus low-dose losartan (n = 1,919).

Concomitant Medications:

At baseline, in the 150 mg losartan group, the use of antithrombotic/anticoagulant was 33%, antiarrhythmic 9%, beta-blocker 72%, diuretic 77%, aldosterone blocker 38%, and statin 39%.

The reason for angiotensin-converting enzyme (ACE) inhibitor intolerance was cough in 77%, gastrointestinal upset in 5%, rash in 3%, taste disturbance in 2%, hyperkalemia in 1%, and azotemia in 1%.

Principal Findings:

Overall, 3,846 patients were randomized. There was no difference in baseline characteristics between the groups. In the 150 mg losartan arm, the mean age was 66 years, 30% were women, 31% had a history of diabetes, and the mean left ventricular ejection fraction was 33%.

At a median of 4.7 years, the primary outcome, all-cause mortality or heart failure admission, was 11.1 per 100 patient-years in the 150 mg group versus 12.4 per 100 patient-years in the 50 mg group (p = 0.027). All-cause mortality or cardiovascular admission (per 100 patient-years) was 15.6 versus 17.0 (p = 0.068), all-cause mortality was 7.6 versus 8.2 (p = 0.24), heart failure admission was 6.0 versus 7.0 (p = 0.025), and cardiovascular admission was 11.5 versus 12.9 (p = 0.023), respectively for 150 mg versus 50 mg losartan.

Hyperkalemia (per 100 patient-years) was 2.79 versus 1.87 (p = 0.0004), hypotension was 2.92 versus 2.07 (p = 0.002), increased creatinine was 7.12 versus 4.73 (p < 0.0001), and angioedema was 0.08 versus 0 (p = 0.03), respectively for 150 mg versus 50 mg losartan.

Interpretation:

Among patients with heart failure due to left ventricular systolic dysfunction who are intolerant of ACE inhibitors, the use of high-dose losartan is beneficial. At a median of 4.7 years, 150 mg daily of losartan reduced all-cause mortality or heart failure admission. This outcome was driven by a reduction in heart failure admission. Hospital admission for cardiovascular reasons was also reduced by this regimen.

High-dose losartan resulted in more adverse events: hyperkalemia, hypotension, renal insufficiency, and angioedema. This study does not provide insight into high-dose angiotensin-receptor blocker therapy among patients who tolerate ACE inhibitors.

References:

Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009;374:1840-8.

Presented by Dr. Marvin Konstam at the American Heart Association Scientific Sessions, Orlando, FL, November 17, 2009.

Keywords: Angiotensin Receptor Antagonists, Losartan, Renal Insufficiency, Heart Failure, Hypotension, Stroke Volume, Hyperkalemia, Creatinine, Diabetes Mellitus


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