Previously, the PARAGON-HF trial demonstrated a potential benefit of sacubitril/valsartan compared with valsartan in reducing HF hospitalisations in patients with HFpEF.1 However, the effects of sacubitril/valsartan compared with individualised medical therapy based on background renin-angiotensin-system inhibitor (RASi) therapy had not been studied. Furthermore, effects on functional capacity were unknown.
In PARALLAX, 2,572 patients with HFpEF were stratified according to their individual RASi treatment (angiotensin-converting enzyme inhibitor [ACEi], angiotensin receptor blocker [ARB], or neither ACEi nor ARB [ACEi/ARB naïve]) for comorbidities before being randomised to receive sacubitril/valsartan or the comparator agent (enalapril, valsartan or placebo, respectively). Co-primary endpoints were the change from baseline in plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) to 12 weeks and the change in the six-minute walk distance (6MWD) from baseline to 24 weeks.
The trial met its first primary endpoint. After 12 weeks, the reduction in NT-proBNP was 16.4% greater in patients treated with sacubitril/valsartan compared with individualised medical therapy (p<0.0001). However, there was no difference between groups for the second co-primary endpoint of improvement in 6MWD from baseline, with mean changes of 9.7 m with sacubitril/valsartan and 12.2 m with individualised medical therapy at week 24 (mean difference –2.5 m; 95% confidence interval –8.5 to 3.5; p=0.79). Quality of life improved in both groups; it was better with sacubitril/valsartan than the comparator at week 4, but there was no difference between groups at week 24.
Serious adverse events (SAEs) were reported in similar proportions of patients in both groups, with the exception of HF events – the most common SAEs – which occurred in more patients with individualised medical therapy than sacubitril/valsartan. In a post-hoc analysis, sacubitril/valsartan reduced the risk of HF hospitalisation by 50% (p=0.005). Patients in the sacubitril/valsartan group also had a significantly lower decline in renal function at 24 weeks than with individualised medical therapy. Does sacubitril/valsartan have a future in the treatment of HFpEF? Time (and further analyses) will tell.