HEAL

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Konstam MA, et al. "Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure". The Lancet. 2009. 374(9704):1840-1848.
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Clinical Question

In patients with heart failure, does high-dose losartan reduce all-cause mortality or hospitalization for heart failure more effectively, as compared to low-dose losartan?

Bottom Line

In patients with heart failure, high-dose losartan reduces all-cause mortality and hospitalization for heart failure more effectively, as compared to low-dose losartan.

Major Points

The benefit of ACE inhibitors and angiotensin-receptor blockers (ARBs) in heart failure have been reported in many studies, including the CONSENSUS, Val-HeFT, and CHARM-Alternative trials.[1][2][3] The ELITE II did not observe any mortality benefit of losartan 50 mg over captopril in elderly heart-failure patients.[4] Therefore, the Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) trial studied the effect of high-dose losartan in patients with symptomatic heart failure (NYHA Class II-IV, LVEF), with the primary outcome being all-cause mortality or hospitalization for heart failure.[5]

Patients were randomized to receive high-dose (n=1,921) versus low-dose losartan (n=1,913). Patients who received high-dose losartan had a lower risk of the primary outcome (43% vs. 46% in placebo; HR 0·90; 95·5%CI 0·82-0·99; P=0·027). There were more cases of renal impairment, hypotension, and hyperkalemia in the high-dose group. However, these did not lead to significantly more withdrawal from treatment.

The HEAAL study was included in a Cochrane analysis of ARB in HFrEF (LVEF≤40%) published in 2012 (22 studies, n=17,900).[6] The authors concluded that ARBs do not reduce total mortality or morbidity significantly as compared to placebo or ACE inhibitors.

Guidelines

ACCF/AHA Guideline for the Management of Heart Failure (2013, adapted)[7]

  • ARBs are recommended for HFrEF with current or prior symptoms who are ACE inhibitor intolerant if not contraindicated (Class I; Level of Evidence: A)
  • ARBs are reasonable alternatives to ACE inhibitors as first-line therapy for HFrEF, especially if patients are already taking ARBs, unless contraindicated (Class IIa; Level of Evidence: A)
  • ARB may be considered in patients with HFrEF who are persistently symptomatic despite ACE inhibitor and beta-blocker treatment and whom an aldosterone antagonist is not indicated or tolerated (Class IIb; Level of Evidence: A)
  • Routine combination of ACE inhibitor, ARB, and aldosterone antagonist is potentially harmful for HFrEF. (Class III; Level of Evidence: C)

Design

  • Multicenter, double-blind, randomized, controlled trial
  • N=3,846
    • high-dose losartan (150 mg; n=1,927)
    • low-dose losartan (50 mg; n=1,919)
  • Setting: 255 centers in 30 countries
  • Enrollment: 2001-2005
  • Follow-up: median 4.7 years
  • Analysis: intention-to-treat
  • Primary outcomes: all-cause mortality or hospitalization for heart failure (HF)

Population

Inclusion Criteria

  • age ≥18 years
  • heart failure
    • NYHA class II-IV symptoms
    • LVEF ≤40%
    • optimal medical therapy for ≥2 months
  • intolerant to ACE inhibitor, due to cough, symptomatic hypotension, hyperkalemia, azotemia, taste disturbance, GI upset, or rash

Exclusion Criteria

  • intolerance to ARB
  • pregnancy or lactation
  • systolic BP <90 mm Hg
  • valvular heart disease causing hemodynamically significant stenosis
  • active myocarditis or pericarditis
  • heart transplant scheduled within 6 months
  • PCI, CABG, MI, unstable angina, CVA or TIA within previous 12 weeks
  • renal artery stenosis (documented or suspected)
  • contraindication to vasodilator
  • life-limiting illness, other than heart failure
  • loss of capacity
  • alcohol or drug use within the previous 2 years
  • participation in investigative drug trial within the last 4 weeks
  • serum creatinine >22 0μmol/L
  • serum potassium <3.5 mmol/L or >5.7 mmol/L
  • liver enzyme elevation >3x upper normal limit
  • Hb <6.2 mmol/L

Baseline Characteristics

From the high-dose losartan group (n=1,927)

  • Demographics: age 66·0 (56-73) years, males 70%, caucasian 60%
  • Heart failure:
    • NYHA Class II (69%), III (30%), IV (1%)
    • LVEF 33% (28-37)
  • Medical history:
    • IHD 64%; Hypertension 60%, DM 31%, hypercholesterolemia 52%; AF 28%
  • Clinical measurements: systolic BP 124 (110-140) mm Hg, diastolic BP 77 (70-80) mm Hg; heart rate 71 (64-80) beats/min; BMI 26·8 (24-30·1) kg/m²
  • Laboratory measurements: serum creatinine 97·2 (80·4-115·8) μmol/L; serum cholesterol 4·8 (4·1–5·6) μmol/L
  • Medications: ARB 77%, antiplatelet/anticoagulant 33%, statin 39%, beta-blockers 72%, aldosterone antagonist 38%, diuretics 77%, digoxin 42%, calcium-channel blocker 11%, salicylic acid and derivatives, alpha-blockers 2%

Interventions

  • Prior to randomization, ARB-naive patients received losartan titrated from 12.5 mg daily to 25 mg daily over 2 weeks. Patients already taking an ARB had their prescription discontinued.
  • Patients were randomized to high-dose losartan (150 mg; up-titrated from 50 mg daily over a 3-week period) or low-dose (50 mg) in 1:1 ratio with block randomisation

Outcomes

Comparisons are high-dose vs. low-dose losartan

Primary Outcome

All-cause mortality or hospitalization for HF
43% vs. 46% in placebo (HR 0·90; 95·5% CI 0·82-0·99; P=0·027)

Secondary Outcomes

All-cause mortality or hospital admission for CV reasons
15.6/100 pt-yrs vs. 17/100 pt-yrs (HR 0·92; 95% CI 0·85-1.01; P=0·068)
All-cause mortality
7.6/100 pt-yrs vs. 8.2/100 pt-yrs (HR 0·94; 99% CI 0·84-1.04; P=0·24)
Hospitalization for heart failure
6/100 pt-yrs vs. 7/100 pt-yrs (HR 0·87; 95% CI 0·76-0.98; P=0·025)
Hospitalization for CV reasons
11.5/100 pt-yrs vs. 12.9/100 pt-yrs (HR 0·89; 95% CI 0·81-0·99; P=0·023)

Subgroup Analysis

For the primary outcome

Hypertension: No difference

No hypertension: Favors high-dose losartan

P-value for interaction=0.01

There were no significant interactions with age, gender, race, systolic BP, heart rate, NYHA class, LVEF, history of IHD, AF, DM, ARB use at screening, aldosterone-antagonist, diuretic, beta-blocker, aspirin or statin use.

Adverse Events

Total events resulting in treatment discontinuation: 1.99/100 pt-yrs vs. 1.83/100 pt-yrs (P=0.44)

Hyperkalemia
2.79/100 pt-yrs vs. 1.87/100 pt-yrs (P=0·0004)
Resulting in treatment discontinuation: 0.12/100 pt-yrs vs. 0.05/100 pt-yrs (P=0.2)
Hypotension
2.92/100 pt-yrs vs. 2.07/100 pt-yrs (P=0·002)
Resulting in treatment discontinuation: 0.26/100 pt-yrs vs. 0.22/100 pt-yrs (P=0.65)
Renal impairment
7.12/100 pt-yrs vs.4.73/100 pt-yrs (P<0.0001)
Resulting in treatment discontinuation: 0.65/100 pt-yrs vs. 0.49/100 pt-yrs (P=0.22)
Angioedema
0.08/100 pt-yrs vs.0/100 pt-yrs (P=0.03)
Resulting in treatment discontinuation: 0.05/100 pt-yrs vs. 0/100 pt-yrs (P=0.12)

Criticisms

  • Hyperuricemia may predict poor prognosis in heart failure. Since losartan can decrease uric acid, it is unclear if some clinical benefit seen in this study may be related to this mechanism.[8]
  • Only ACE inhibitor-intolerant patients were included in this study. Hence it is unclear if the results can be applied to other HF patients.[9]

Funding

  • Merck & Co, Inc. Whitehouse Station, NJ, USA

Further Reading

  1. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure, results of the cooperative north Scandinavian enalapril survival study. The New England Journal of Medicine. 1987;316(23):1429-35.
  2. Cohn JN, et al. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. New England Journal of Medicine. 2001;345(23):1667-75
  3. 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
  4. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial – the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582–7
  5. 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(9704):1840-8.
  6. Heran BS, Musini VM, Bassett K, Taylor RS, Wright JM. Angiotensin receptor blockers for heart failure. Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No.: CD003040. DOI: 10.1002/14651858.CD003040.pub2
  7. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240-e327
  8. Kang SM, Oh J, Hong N. High-dose versus low-dose losartan in patients with heart failure. Lancet. 2010;375(9720):1079; author reply 1079-80
  9. McKelvie R. Randomised controlled trial: Compared with low-dose losartan, high-dose losartan decreases risk of death or hospital admission for heart failure in people with heart failure who are intolerant to ACE inhibitors. Evid Based Med. 2010;15(2):51-2