15 January 2010
The HEAAL study compared 50mg and 150mg daily doses of losartan in people with heart failure intolerant of ACE inhibitors. It suggested that the (unlicensed) higher dose reduced the relative risk of the combined outcome of all-cause death or admission for heart failure by about 10% over 4.7 years, mainly it would seem by reducing the rate of admissions. Current NICE guidance based on high quality evidence states that ACEs are first line agents for people with heart failure, not A2RAs. This study does not provide any evidence about whether A2RA therapy at a standard or higher dose is preferable to ACE inhibitor therapy, nor does it provide any additional information as to whether the combination of an A2RA plus an ACE inhibitor is preferable to either drug alone.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Practitioners should continue to follow NICE guidance on the management of heart failure and use ACE inhibitors as the cornerstone of drug therapy. ACE inhibitor doses should be titrated to the target doses established in clinical trials or, failing this, to the highest dose tolerated. A2RAs should be considered as an alternative to ACE inhibitors only in patients who cannot tolerate them, usually because of cough, and after other possible causes of cough (such as pulmonary oedema) have been excluded. If prescribers wish to increase the dose of losartan used on the basis of this study, they should note that a 150mg daily dose is not licensed for any indication.
What is the background to this?
The management of heart failure was discussed in a MeReC Bulletin in 2008. Treatment with an ACE inhibitor is the cornerstone of drug therapy, as this improves ventricular function and patients’ well-being, reduces hospitalisation for worsening heart failure, and increases survival. ACE inhibitors also improve symptoms, exercise tolerance and quality of life.
High doses of ACE inhibitors do not necessarily confer greater benefit than lower doses in terms of improving symptoms or life expectancy, but they do appear to reduce the risk of hospitalisation due to worsening heart failure. The NICE heart failure guideline recommends that ACE inhibitors should be titrated to the target doses established in clinical trials, such as ramipril 5mg twice daily or 10mg daily, or lisinopril 30mg to 35mg once a day. If this is not possible, the highest dose tolerated should be used. Some patients are not able to tolerate ACE inhibitors (but see below) and so may be prescribed an angiotensin-II receptor antagonist (A2RA). This study examined whether there was a similar difference in effectiveness between different doses of the A2RA, losartan.
The study recruited patients with NICE guidance on the management of heart failure who were intolerant of ACE inhibitors. They were randomised to receive 50mg or 150mg of losartan daily in double blind design. The analysis included 3,834 patients and took account of beta-blocker use.
What does this study claim?
Over a median of 4.7 years, patients taking 150mg losartan daily had a lower risk of the combined primary outcome of all-cause death or heart failure admission (11.1 vs 12.4 per 100 patient years of follow up, hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.82 to 0.99, P=0.027) compared with those taking 50mg losartan daily. There was no statistically significant difference in the major secondary outcome (all-cause death or cardiovascular admission; HR 0.92, 95%CI 0.85 to 1.01, P=0.068). With regard to other prespecified outcomes, there was a reduction in risk of heart failure admission (HR 0.87, 95%CI 0.76 to 0.98, P=0.025) and cardiovascular admission (HR 0.89, 95%CI 0.81 to 0.98, P=0.023) but not all-cause death (HR 0.94, 95%CI 0.84 to 1.04, P=0.24). Hyperkalaemia, hypotension, renal impairment and angiodema were all statistically significantly more common in the higher dose group, but there were no significant difference in rates of withdrawal due to these effects.
The results of this study suggest that patients with heart failure treated with losartan are more likely to do better if their treatment is titrated to 150mg daily. However, the usual maintenance dose for heart failure given in the losartan SPC is 50mg daily, and no dose greater than 100mg daily is licensed for any indication. Rates of adverse effects leading to discontinuation of treatment were similar in both groups. It should be noted that,about 77% of people had been taking an A2RA at baseline, and there was a titration period. Both of these factors may have selected for patients more tolerant of A2RAs, including at higher doses.
HEAAL was a large, well-conducted study but as the accompanying editorial points out, it is important to note what this study does not tell us. In particular, it provides no data on whether an A2RA at a higher dose is preferable to an ACE inhibitor, or whether the combination of an A2RA plus an ACE inhibitor is preferable to either drug alone.
A meta-analysis from 2008 found no significant difference in mortality or rates of hospital admission for heart failure between A2RAs and ACE inhibitors. In view of their substantial evidence base and generally good tolerability, and their lower cost to the NHS, ACE inhibitors are the first choice renin-angiotensin system drug. Some patients are not able to tolerate ACE inhibitors, usually due to cough. However, before switching to an A2RA, it is important to bear in mind that cough is common in patients with heart failure, and the differential diagnosis should be considered in a patient who develops a cough on an ACE. NICE heart failure guidance states that true ACE-inhibitor-induced cough rarely requires treatment discontinuation, and switching to an A2RA should be considered only if the cough is troublesome and persistent.
Konstam MA, 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;374:1840–48
Design: multi-centre double-blind RCT
Patients: 3,834 patients with NYHA class III or IV heart failure who were intolerant of ACE inhibitors. Investigators were encouraged to start beta-blocker therapy and titrate dosing to a maximum, whenever possible. Before randomisation, patients not already receiving an A2RA were titrated on to losartan from 12.5mg daily to 25mg daily over 2 weeks. For patients already receiving an A2RA, their prescription was discontinued, and investigators had the option of starting open-label losartan 25 mg daily for 1 week or randomly assigning the patient directly.
Intervention and comparison: 50mg or 150mg of losartan daily over a median of 4.7 years
Outcomes and results: Combined primary outcome (all-cause death or heart failure admission) 11.1 vs 12.4 per 100 patient years of follow up, HR 0.90, 95%CI 0.82 to 0.99, P=0.027). Main secondary outcome (all-cause death or cardiovascular admission) HR 0.92, 95%CI 0.85 to 1.01, P=0.068. Heart failure admission HR 0.87, 95%CI 0.76 to 0.98, P=0.025, cardiovascular admission HR 0.89, 95%CI 0.81 to 0.98, P=0.023, all-cause death HR 0.94, 95%CI 0.84 to 1.04, P=0.24. HR and P values were estimated from Cox models, with indicator variables for beta-blocker use, geographical region, and treatment group.
Hyperkalaemia, hypotension, renal impairment and angiodema were all statistically significantly more common in the higher dose group (rates per 100 patient years 2.79 vs 1.87, 2.92 vs 2.07, 7.12 vs 4.73, 0.08 vs 0.0, respectively), but there were no significant differences in rates of withdrawal due to these effects.
Merck & Co (known as Merck Sharp & Dohme Ltd in the UK), manufacturers of losartan
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