PARALLAX meets one primary endpoint in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) affects approximately half of patients with heart failure. Prevalence is expected to rise with the ageing population and increased rates of risk factors such as hypertension, diabetes, obesity and atrial fibrillation. Patients are often highly symptomatic, with shortness of breath, reduced ability to exercise, impaired quality of life, and frequent rehospitalisations.

There is currently no approved therapy to reduce morbidity and mortality in patients with HFpEF. Treatment recommendations mainly focus on symptom relief with diuretics and treating comorbidities, typically with inhibitors of the renin-angiotensin system (RAS) including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).

The PARAGON-HF outcome trial suggested that sacubitril/valsartan may reduce heart failure hospitalisations in HFpEF patients compared to valsartan (an ARB). However, in daily practice, not all HFpEF patients receive an ARB. Many take an ACE inhibitor, and some no RAS inhibitor at all.

PARALLAX therefore tested the effects of sacubitril/valsartan versus optimal individualised background therapy, which could be the ACE inhibitor enalapril, the ARB valsartan, or placebo. The co-primary endpoints were chosen to assess heart failure severity and functional capacity: 1) change from baseline to 12 weeks in plasma N-terminal pro B-type natriuretic peptide (NT-proBNP); and 2) change in six-minute walk distance from baseline to 24 weeks.

A total of 2,572 HFpEF patients were randomly allocated to sacubitril/valsartan or their current RAS medication (enalapril, valsartan or placebo if they were not taking a RAS inhibitor). Patients in the trial had a mean age of 73 years and 51% were women. The mean left ventricular ejection fraction at baseline was 56%.

The trial met the first primary endpoint: after 12 weeks, patients treated with sacubitril/valsartan showed a highly significant 16.4% greater reduction in NT-proBNP than patients treated with optimal individualised medical therapy (p<0.0001).

The trial did not meet the second primary endpoint: at week 24, six-minute walk distance had improved in both groups compared to baseline (mean change was 9.7 m in the sacubitril/valsartan group and 12.2 m in the individualised medical therapy group), with no significant difference between groups (mean difference -2.5 m; 95% confidence interval -8.5 to 3.5 m; p=0.79).

Secondary endpoints included change from baseline to 24 weeks in quality of life (measured by the Kansas City Cardiomyopathy Questionnaire; KCCQ) and New York Heart Association (NYHA) functional class. Quality of life improved in both groups and was better with sacubitril/valsartan than the comparator at week 4 but there was no difference between groups at week 24. Changes in NYHA class were similar in both groups at week 24.

Overall, except for heart failure events, serious adverse events were reported in similar proportions of patients in both groups. Heart failure events (such as worsening heart failure requiring hospitalisation or not necessitating hospital admission) were the most common serious adverse events and occurred in more patients in the individualised medical therapy group than in the sacubitril/valsartan group. Based on this, a post hoc analysis showed that sacubitril/valsartan reduced the risk for heart failure hospitalisation by 50% (p=0.005). Patients in the sacubitril/valsartan group also had a significantly lower decline in renal function (estimated glomerular filtration rate; eGFR) at 24 weeks.

Principal investigator Professor Burkert Pieske from Charité University Medicine Berlin and the German Heart Centre, Berlin said: "The trial showed a consistent decline of the surrogate outcome marker NT-proBNP with sacubitril/valsartan, as compared to individual medical therapy."