HEAAL: High-Dose Trumps Low-Dose ARB for Heart Failure in the ACE-Inhibitor Intolerant

November 18, 2009

November 17, 2009 (Orlando, Florida) — A 150-mg/day dosage of the angiotensin-receptor blocker (ARB) losartan (Cozaar, Merck) significantly cut the risk of death or heart-failure hospitalization over almost five years compared with a dosage of 50 mg/day in patients with systolic heart failure who couldn't tolerate ACE inhibitors, in a randomized trial published online today in the Lancet [1]. The benefit came at the cost of some renal function and hyperkalemia.

The findings, along with the results of other trials, "make a strong case for the value of incremental inhibition of the renin-angiotensin system," write the authors, led by Dr Marvin A Konstam (Tufts University, Boston, MA). "The present findings suggest that similar benefit could be achieved by increasing the dose of a particular agent, rather than by addition of an additional class of agent, although future studies are needed to directly test this hypothesis."

Publication of the group's report, from the Heart Failure End Point Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study, was timed to coincide with the study's presentation here at the American Heart Association (AHA) 2009 Scientific Sessions.

Losartan is approved for heart failure in some countries, but not the US, where the labeling indication is hypertension.

The clinical implication is that all patients on losartan today for heart failure need to be reevaluated and probably uptitrated to a higher dose level.

Although the potential adverse effects of high-dose ARB therapy should be recognized, observes Dr Henry Krum (Monash University, Melbourne, Australia) in an accompanying editorial [2], "in view of the small increment of serious adverse events in HEAAL (specifically in those patients who had to be withdrawn from therapy), these side effects seem a reasonable trade-off for the potential increased therapeutic benefit of the higher ARB dose."

Krum cautions against necessarily applying the HEAAL findings to patients who can take ACE inhibitors, as the trial "does not provide any information about whether a high-dose ARB is better than an ACE-inhibitor strategy." Nor, he continues, does it offer insights about whether "maximizing the dose of one [renin-angiotensin- ystem] RAS blocker is better than use of several agents" or whether it would be beneficial to add the 150-mg/day ARB to an ACE inhibitor.

As "positive outcomes with novel pharmacological therapies for chronic heart failure have been scarce," Krum observes, "it is somewhat ironic that HEAAL shows a definite beneficial effect comparing doses of a much older therapeutic strategy, that of RAS blockade, in addition to background contemporary practice for chronic heart failure (excepting ACE inhibitors)."

Chairing the discussion panel after Konstam's formal presentation of HEAAL, Dr Milton Packer (University of Texas Southwestern Medical Center) observed that "physicians now do not prescribe anywhere close to the target doses of ACE inhibitors used in any of the placebo-controlled trials. They certainly don't use the target dose of lisinopril used in ATLAS, they certainly don't use the target dose of losartan in HEAAL. They use low doses of both ACE inhibitors and angiotensin receptor blockers. So the question is, do the low doses they're using work at all on outcomes?"

Konstam replied, "Well, you know the answer to that: We don't know. . . . We're really talking about incremental inhibition of the renin-angiotensin system, and I think so far in the ranges that have been looked at, more seems to be better." But the appropriate dosages to aim for, he said, are the ones for which there is clinical trial evidence of benefit.

"There is a value with an incremental dose," observed panelist Dr Karl Swedberg (University of Gothenburg, Sweden). "I would encourage everyone to do what the guidelines state. The international guidelines are in harmony here. You should force-titrate according to the studies, and the [HEAAL] data support that."

Panel Exchange After the HEAAL Presentation

Packer: "A physician has a patient on a low dose of an ARB or a low dose of an ACE inhibitor. The patient has improved substantially on their current heart-failure regimen. They're [NHYA] class 2, they're happy. . . . The physician says it is reasonable to continue the low dose of ARB or ACE inhibitor. I want to know from each of you, is it reasonable to do that?"

Konstam: "No, and I think you've hit on the number-one take-home message here. If a clinician is using losartan to treat a patient with heart failure, he or she must know that if you uptitrate to 150 mg/day, you're going to get a better outcome."

Swedberg: "Clinically, it could be reasonable [to continue the low dose]. But remember that symptom improvement is not a surrogate for life prolongation. So there's no way around--if you want the best care for the patient, you should uptitrate the treatment."

Konstam et al randomized 3846 patients in 30 countries who had NYHA class 2–4 heart failure, an LVEF <40%, and intolerance of ACE inhibitors to receive losartan at either 150 mg/day (n=1921) or 50 mg/day (n=1913), with the daily dose for patients in the high-dose group uptitrated from 50 mg/day over three weeks. ACE-inhibitor intolerance was due to cough in 86% of cases.

Over a median follow-up of 4.7 years, the rates of death or heart-failure hospitalization--the primary end point--were 43% in the high-dose group and 46% in the low-dose group, a modest but significant benefit from the 150-mg/day dosage that was driven by a significant 13% reduction in risk of the latter component of the composite end point.

Hazard Ratio (HR) for End Points, High-Dose vs Low-Dose Losartan in HEAA

End point HR (95% CI) p
Death or heart failure hospitalization* 0.90 (0.82–0.99) 0.027
All-cause death 0.94 (0.84–1.04) 0.24
Heart failure hospitalization 0.87 (0.76–0.98) 0.025
CV hospitalization 0.89 (0.81–0.98) 0.023
*primary end point

Patients without a history of hypertension showed a greater treatment benefit from losartan at 150 mg/day than 50 mg/day compared with those with a history of hypertension: hazard ratio 0.77 (95% CI 0.67–0.90, p=0.01).

Mean systolic and diastolic pressures fell significantly in both treatment groups by six months, but heart rate did not.

At one year, mean serum potassium had risen by 0.02 mmol/L in the high-dose group and had dropped by 0.01 mmol/L in the low-dose group (p=0.03 for difference at one year). The estimated glomerular filtration rate had fallen in the two groups by 6.1 mL/min/1.73 m2 and 1.9 mL/min/1.73 m2, respectively (p<0.001).

Although the high-dose group experienced more renal dysfunction, hypotension, and hyperkalemia, these didn't lead to significantly more treatment discontinuations, Konstam et al report.

As the featured discussant following Konstam's HEAAL presentation, Swedberg said that the proportion of patients who dropped out of the study for one reason or another approached 30% in both groups. "That means that if there is [an outcomes] difference between the study groups, it is for sure an underestimate," he said. "The clinical implication is that all patients on losartan today [for heart failure] need to be reevaluated and probably uptitrated to a higher dose level."

To access presentation slides, click here .

HEAAL was funded by Merck. Konstam reports serving as an consultant to or receiving research grants from Merck. Disclosures for the other coauthors are in the report. Krum reports receiving payments for committee work (relating to clinical trials) from Pfizer and Novartis. Swedberg reports receiving research support from AstraZeneca, Merck, Novartis, and Servier, working as a consultant to Novartis, and receiving honoraria from AstraZeneca and Novartis.

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