Prevalent and incident anaemia in PARADIGM-HF and effect of sacubitril/valsartan

Abstract

Background Anaemia is common in patients with HFrEF and is associated with poor clinical outcomes. Although they reduce rates of mortality and heart failure hospitalization, renin-angiotensin (RAS) blockers lower haemoglobin and may induce anaemia. Concomitant neprilysin inhibition might ameliorate this effect of RAS blockers. Purpose We investigated the effect of sacubitril/valsartan compared with enalapril on clinical outcomes, according to anaemia status, and on haemoglobin levels in PARADIGM-HF. Methods Patient characteristics and clinical outcomes were compared between patients with and without anaemia (defined as haemoglobin <120 g/L in women and <130 g/L in men) at baseline. We investigated the effect of randomized treatment (sacubitril/valsartan or enalapril) on clinical outcomes according to anaemia status at screening. We also examined the effect of treatment on change in haemoglobin from baseline and on the incidence of anaemia. The primary endpoint in PARADIGM-HF was the composite of heart failure hospitalization or cardiovascular death. Results Of 8239 participants with a baseline haemoglobin measurement, 1677 (20.4%) were anaemic. Compared to those without anaemia, patients with anaemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement and worse clinical outcomes. Sacubitril/valsartan, compared to enalapril, reduced the risk of the primary endpoint similarly in patients with anaemia (HR 0.84, 95% CI 0.71–1.00) and without anaemia (HR 0.78, 95% CI 0.71–0.87), p-value for interaction=0.478. Between baseline and 12 months, haemoglobin decreased by 1.5 (95% CI 1.7 to 1.2) g/L with sacubitril/valsartan compared with 2.3 (2.6 to 2.0) g/L with enalapril group: mean difference 0.8 (95% CI 0.5 to 1.2) g/L, p<0.001. The between-treatment difference apparent by 12 months, persisted up to 36 months. Patients assigned to sacubitril/valsartan were less likely to develop new anaemia at 12 months [321 of 2806 (11.4%)] compared to patients randomized to enalapril [440 of 2384 (15.6%)], odds ratio 0.70 (95% CI 0.60–0.81), p<0.001. Conclusions Compared to enalapril, sacubitril/valsartan reduced mortality and hospitalization in HFrEF patients with and without anaemia. Haemoglobin decreased less with sacubitril/valsartan and the incidence of new anaemia was lower in the sacubitril/valsartan group compared with the enalapril group. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): PARADIGM-HF was funded by Novartis.

Prognostic Models Derived in PARADIGM-HF and Validated in ATMOSPHERE and the Swedish Heart Failure Registry to Predict Mortality and Morbidity in Chronic Heart Failure

“…The study design and main results of both PARADIGM-HF and ATMOSPHERE are published. [7][8][9][10] The inclusion and exclusion criteria of the 2 trials were almost identical and are described in eAppendix 1 in the Supplement. Briefly, patients were eligible at screening if they had NYHA class II through IV, LVEF of 35% or less (changed from ≤40% initially in PARADIGM-HF by amendment), had an elevated natriuretic peptide level (see eAppendix 1 in the Supplement for levels) and were receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), along with a β-blocker (unless contraindicated or not tolerated) and a mineralocorticoid receptor antagonist (MRA), if indicated.…”

“…[1][2][3][4] We used patient-level data (including natriuretic peptides) from the PARADIGM-HF trial to develop prognostic models for morbidity and mortality in contemporary patients with HF treated with evidence-based therapies for HF. 7,8 The models were validated using data from the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF) containing data on an unselected nationwide cohort. [9][10][11]…”

Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure

“…[5][6][7][8] The PARADIGM-HF study enrolled ambulatory patients with chronic HFrEF and patients with ADHF were excluded. 9,10 Patients randomized to receive sacubitril/valsartan vs enalapril had a greater reduction in NT-proBNP levels, and 48% vs 26% of patients had a reduction of more than 30% from baseline to 1 month after randomization. 5 The TRANSITION study that evaluated patients hospitalized for ADHF and receiving sacubitril/valsartan predischarge led to a 28% decrease in NT-proBNP levels by the time of discharge.…”

“…The magnitude of benefit is comparable with the findings from PARADIGM-HF in which within 30 days of randomization patients randomized to receive sacubitril/valsartan had a lower hazard for HF hospitalization compared with enalapril (HR, 0.60; 95% CI, 0.38-0.94). 10,11 Prior clinical trials and observational data suggest the hospital is a unique setting in which to initiate guideline-directed medical therapy and that in-hospital initiation is associated with short-term adherence, long-term persistence, and potentially improved postdischarge outcomes. 12,13 As such, HF guidelines recommend that evidence-based medications are instituted before hospital discharge.…”

Early Implementation of Sacubitril/Valsartan for Patients With Heart Failure

“…However, the S/V story remains consistent and the effect size of further reductions in clinical events (hazard ratio, 0.69; 95% CI, 0.49-0.97) that occurred within 4 weeks (weeks 8-12) during this open-label extension is convincing and validates the previous findings seen in multiple studies. The clinical benefit of S/V has now been described (1) across all spectrums of reduced ejection fraction (0.15-0.40), 5 (2) regardless of HF etiology (nonischemic vs ischemic), 6 or the (3) presence of background medical therapy for HF 7 among (4) stable outpatients with New York Heart Association functional classes II to III HF 8 and now among (5) inpatients with ADHF who have achieved hemodynamic stability. 3 Additionally, ADHF hospitalization and the worsening of HF that is treated in the out-patient setting represent this being a time to consider making the change to ARNI, as the benefit of S/V over angiotensinconverting enzyme inhibition is consistent across expanded composite end points (eg, worsening of HF, not just rehospitalization and death), reminding us that the global reduction in HF morbidity is also an important goal.…”