CHICAGO – A year of losartan had no effect on left ventricular mass in patients with overt hypertrophic cardiomyopathy, compared with placebo, in the INHERIT trial.
The angiotensin receptor blocker did not alter any secondary endpoint, including maximal wall thickness, left ventricular fibrosis, diastolic function, and exercise capacity.
There also was no significant change in symptoms or resting left ventricular outflow tract (LVOT) gradient, Dr. Anna Axelsson reported at the American Heart Association scientific sessions.
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Dr. Anna Axelsson
Current therapies for hypertrophic cardiomyopathy (HCM) are palliative for symptoms only.
Losartan is known to reduce heart wall thickening in patients with hypertension, but is only used with caution in patients with HCM because of a suspicion of deleterious side effects.
INHERIT was initiated based on promising effects with angiotensin receptor blockade in animal and human studies, said Dr. Axelsson of Rigshospitalet, University of Copenhagen, and Harvard Medical School, Boston.
Losartan (Cozaar) has been shown to prevent the development of hypertrophy and fibrosis in HCM mice when started in the prehypertrophic phase. Candesartan (Atacand) use in humans was associated with regression of LV hypertrophy and improvement in LV function and exercise capacity in a small pilot study (J. Mol. Diagn. 2009;11:35-41).
INHERIT (Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy) evenly allocated 133 adults with overt HCM to daily losartan 100 mg or placebo for 12 months. LV mass was 108 g/m2 in the placebo group and 105 g/m2 in the losartan group, and 83% of patients had fibrosis.
Of the 124 patients completing the study, 93% were compliant (> 80%,) as assessed by pill count. Corroborating this was a significant decrease in blood pressure in the losartan group compared with the placebo group (P value = .001), Dr. Axelsson said.
At 12 months, both groups had a small decrease from baseline in LV mass, as assessed by magnetic resonance imaging or computed tomography, but the difference between groups was not statistically significant or clinically relevant (mean difference 1 g/m2), she said.
Adverse events were few, and comparable between the losartan and control groups. Sudden cardiac death occurred in two patients on placebo. One patient in each group had worsening of New York Heart Association class. Two controls and one losartan-treated patient had increases in LVOT gradient of at least 10 mm Hg. One patient discontinued losartan because of angioedema and two discontinued because of unspecified symptoms leading to withdrawal of consent.
“The observed safety suggests that losartan may be used for other indications in patients with obstructive physiology,” Dr. Axelsson said.
When asked whether clinicians can conclude that it’s safe to give patients with obstructive physiology a vasodilator, Dr. Axelsson said, “perhaps it shouldn’t be considered such a contraindication anymore, but it should still be done cautiously.”
Invited discussant Dr. Euan Ashley of Stanford (Calif.) University, said that only 15% of patients in the trial had an LVOT gradient of more than 30 mm Hg at baseline, “so to try and extrapolate that vasodilators are safe in older hypertrophics may be going too far.”
Patrice Wendling/Frontline Medical News
Dr. Euan Ashley
Finally, Dr. Axelsson said the overall results do not “close the door” to treatment with angiotensin receptor blockers in HCM, and that future trials may determine whether ARBs can prevent development of disease in preclinical or earlier stages of HCM.
The ongoing VANISH trial is evaluating valsartan (Diovan) in younger patients with early sarcomeric HCM. Also, the Liberty-HCM study will evaluate the effects of the investigational late sodium channel inhibitor, GS-6615, in patients aged 18-65 years, with symptomatic HCM.
INHERIT was funded by the Danish Heart Foundation and several other Danish research organizations. Dr. Axelsson holds stock with AstraZeneca.