A Putative Placebo Analysis of the Effects of Sacubitril/Valsartan in Heart Failure Across the Full Range of Ejection Fraction

Abstract

The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin-angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/ valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF).

Sex‐based differences in biomarkers, health status, and reverse cardiac remodelling in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan

“…Beyond those with HFrEF, benefit of S/V on remodelling may not be restricted to those with LVEF <40%. A recent imputed placebo analysis suggests treatment benefits of S/V on risk of adverse cardiovascular events up to an LVEF of 60%, 16 and in those with HF with preserved ejection fraction (HFpEF), women may benefit more from S/V than men. 17 Whether benefits of S/V in those with HFpEF indicate an effect on remodelling is not clear, however, the risk factors for remodelling differ substantially between HFrEF and HFpEF as does the biology; significant differences exist regarding location and pattern of cell death, microvascular changes, and fibrosis in both forms of HF.…”

Heart failure with preserved ejection fraction after the PARAGON-HF trial results: current knowledge and future directions

“…Sacubitril/valsartan was tested against an active comparator, valsartan, because most patients were receiving a renin-angiotensin system inhibitor before enrolment (96% had arterial hypertension) [2], which made a placebo-controlled trial impractical. And recently the putative placebo analysis was published [16] with data from the PARADIGM-HF and the PARAGON-HF trials (n = 13194) and also the CHARM-Preserved and the CHARM-Alternative trials (n = 5050) with candesartan. Compared to the putative placebo, sacubitril/valsartan was associated with a RR 0.54 (95%CI 0.45-0.65, P < 0.001) for the primary endpoint across the range of LVEF with attenuation above 60%, and also for first HF hospitalization RR 0.67 (95%CI 0.58-0.78), cardiovascular death RR 0.76 (95%CI 0.64-0.89) and all-cause of death RR 0.83 (95% CI 0.71-0.96), with P < 0.02 for all [16].…”

“…And recently the putative placebo analysis was published [16] with data from the PARADIGM-HF and the PARAGON-HF trials (n = 13194) and also the CHARM-Preserved and the CHARM-Alternative trials (n = 5050) with candesartan. Compared to the putative placebo, sacubitril/valsartan was associated with a RR 0.54 (95%CI 0.45-0.65, P < 0.001) for the primary endpoint across the range of LVEF with attenuation above 60%, and also for first HF hospitalization RR 0.67 (95%CI 0.58-0.78), cardiovascular death RR 0.76 (95%CI 0.64-0.89) and all-cause of death RR 0.83 (95% CI 0.71-0.96), with P < 0.02 for all [16]. The putative analysis supported the benefit of sacubitril/valsartan therapy across the range of LVEF up to 60%.…”

Angiotensin receptor–neprilysin inhibition in heart failure with preserved ejection fraction: lessons from PARAGON‐HF

“…While there is no clearly demonstrated standard of care for patients with HFpEF, valsartan, an angiotensin receptor blocker (ARB), was selected as a comparator instead of placebo in PARAGON-HF for several reasons. 21 First, nearly 90% of patients in PARAGON-HF were treated with an angiotensin-converting enzyme inhibitor (ACEi) or ARB before they were screened for inclusion in the trial. Unlike typical therapeutic scenarios when investigational therapies can be added on, the risk of angioedema would be excessive with concurrent use of a neprilysin inhibitor and ACEi.…”

“…In this analysis, there was a substantial and nominally significant benefit of sacubitril/valsartan on cardiovascular death and total HF hospitalizations up to a LVEF of approximately 60%. 21…”