Dataset Information

Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study.

ABSTRACT:

Objectives

To determine efficacy and safety of sacubitril/valsartan compared with enalapril in Indian patients of PARADIGM-HF trial.

Methods

A randomized, double-blind, active-controlled, phase III sub-study (NCT01035255) was conducted between April 2010 and May 2014. Patients with chronic heart failure (HF), aged >18 years with left ventricular ejection fraction ?40% were randomized (1:1) to receive either sacubitril/valsartan 200 mg twice-daily or enalapril 10 mg twice-daily. The primary endpoint was to compare efficacy of sacubitril/valsartan to enalapril in delaying time-to-first occurrence of the composite endpoint (cardiovascular [CV] death or HF hospitalization).

Results

The trial was stopped after a median follow-up of 27 months, because the boundary for benefit with sacubitril/valsartan had crossed. Among 637 Indian patients in PARADIGM-HF (sacubitril/valsartan, n = 322 and enalapril, n = 315), the primary outcome, CV death, and the first hospitalization for HF occurred in 21.81% and 24.76% (HR 0.89; 95% CI, 0.646-1.231), 17.45% and 20.63% (HR 0.87; 95% CI, 0.605-1.236), and 7.48% and 9.52% (HR 0.78; 95% CI, 0.461-1.350) patients in the sacubitril/valsartan and enalapril group, respectively. The all-cause mortality (19.0% vs. 21.9%) and adverse events (78.4% vs. 82.2%) were comparatively lower in the sacubitril/valsartan than enalapril group. No significant difference was seen between the benefits of treatment in Indian and the total PARADIGM-HF cohort (p value for interaction >0.05).

Conclusion

Results support the use of sacubitril/valsartan in Indian patients with chronic HF with reduced ejection fraction with treatment benefits similar to global PARADIGM-HF cohort.

SUBMITTER: Jain AR

PROVIDER: S-EPMC7772612 | biostudies-literature | 2020 Nov-Dec

REPOSITORIES: biostudies-literature

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Publications

Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study.

Jain Anil Ranjeetmal AR Aggarwal Rakesh Kumar RK Rao Nanyam Srinivas NS Billa Gauri G Kumar Shankar S

Indian heart journal 20200928 6

<h4>Objectives</h4>To determine efficacy and safety of sacubitril/valsartan compared with enalapril in Indian patients of PARADIGM-HF trial.<h4>Methods</h4>A randomized, double-blind, active-controlled, phase III sub-study (NCT01035255) was conducted between April 2010 and May 2014. Patients with chronic heart failure (HF), aged >18 years with left ventricular ejection fraction ≤40% were randomized (1:1) to receive either sacubitril/valsartan 200 mg twice-daily or enalapril 10 mg twice-daily. Th ...[more]

PMID: 33357641

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Project description:ImportanceCompared with enalapril, sacubitril-valsartan reduces cardiovascular mortality and heart failure hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). These benefits may be related to effects on hemodynamics and cardiac remodeling.ObjectiveTo determine whether treatment of HFrEF with sacubitril-valsartan improves central aortic stiffness and cardiac remodeling compared with enalapril.Design, setting, and participantsRandomized, double-blind clinical trial of 464 participants with heart failure and ejection fraction of 40% or less enrolled across 85 US sites between August 17, 2016, and June 28, 2018. Follow-up was completed on January 26, 2019.InterventionsRandomization (1:1) to sacubitril-valsartan (n = 231; target dosage, 97/103 mg twice daily) vs enalapril (n = 233; target dosage, 10 mg twice daily) for 12 weeks.Main outcomes and measuresThe primary outcome was change from baseline to week 12 in aortic characteristic impedance (Zc), a measure of central aortic stiffness. Prespecified secondary outcomes included change from baseline to week 12 in N-terminal pro-B-type natriuretic peptide, ejection fraction, global longitudinal strain, mitral annular relaxation velocity, mitral E/e' ratio, left ventricular end-systolic and end-diastolic volume indexes (LVESVI and LVEDVI), left atrial volume index, and ventricular-vascular coupling ratio.ResultsOf 464 validly randomized participants (mean age, 67.3 [SD, 9.1] years; 23.5% women), 427 completed the study. At 12 weeks, Zc decreased from 223.8 to 218.9 dyne × s/cm5 in the sacubitril-valsartan group and increased from 213.2 to 214.4 dyne × s/cm5 in the enalapril group (treatment difference, -2.2 [95% CI, -17.6 to 13.2] dyne × s/cm5; P = .78). Of 9 prespecified secondary end points, no significant between-group difference in change from baseline was seen in 4, including left ventricular ejection fraction (34%-36% with sacubitril-valsartan vs 33 to 35% with enalapril; treatment difference, 0.6% [95% CI, -0.4% to 1.7%]; P = .24). However, greater reductions from baseline were seen with sacubitril-valsartan than with enalapril in all others, including left atrial volume (from 30.4 mL/m2 to 28.2 mL/m2 vs from 29.8 mL/m2 to 30.5 mL/m2; treatment difference, -2.8 mL/m2 [95% CI, -4.0 to -1.6 mL/m2]; P < .001), LVEDVI (from 75.1 mL/m2 to 70.3 mL/m2 vs from 79.1 mL/m2 to 75.6 mL/m2; treatment difference, -2.0 mL/m2 [95% CI, -3.7 to 0.3 mL/m2]; P = .02), LVESVI (from 50.8 mL/m2 to 46.3 mL/m2 vs from 54.1 to 50.6 mL/m2; treatment difference, -1.6 mL/m2 [95% CI, -3.1 to -0.03 mL/m2]; P = .045), and mitral E/e' ratio (from 13.8 to 12.3 vs from 13.4 to 13.8; treatment difference, -1.8 [95% CI, -2.8 to -0.8]; P = .001). Rates of adverse events including hypotension (1.7% vs 3.9%) were similar in both groups.Conclusions and relevanceTreatment of HFrEF with sacubitril-valsartan, compared with enalapril, did not significantly reduce central aortic stiffness. The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in HFrEF.Trial registrationClinicalTrials.gov Identifier: NCT02874794.

Project description:BackgroundCompared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP.MethodsWe analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP.FindingsAll-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP.InterpretationIn PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.

Project description:AimsThe PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction.Methods and resultsBoth PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61-0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75-0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43-1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P = 0.002).ConclusionIn pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.

Project description:BackgroundThe ratio of ucGMP (urinary cyclic guanosine monophosphate) to BNP (B-type natriuretic peptide) is thought to reflect the responsiveness of tissues to natriuretic peptides.MethodsWe examined the relationship between ucGMP/BNP ratio and clinical outcomes, the effect of sacubitril/valsartan, compared with enalapril, on the ucGMP/BNP ratio, and the efficacy of sacubitril/valsartan on clinical outcomes according to baseline ucGMP/BNP ratio in PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). ucGMP/BNP ratio was available at baseline (N=2031), 1 month (N=1959), and 8 months after randomization (N=1746). The primary outcome was a composite of heart failure hospitalization or cardiovascular death.ResultsCompared with the lowest tertile of baseline ucGMP/BNP ratio, patients in the higher tertiles had a lower risk of the primary outcome (tertile 1, reference; tertile 2, hazard ratio 0.57 [95% CI, 0.45-0.71]; tertile 3, hazard ratio, 0.54 [0.43-0.67]). Compared with baseline, the ucGMP/BNP ratio at 1 month and 8 months after randomization was higher with sacubitril/valsartan than with enalapril: ratio of geometric mean ratios at 1 month, 1.38 (95% CI, 1.27-1.51) and 8 months, 1.32 (95% CI, 1.20-1.45), and this difference was consistent across tertiles of ucGMP/BNP ratio at baseline (Pinteraction=0.19 and 0.91, respectively). The effect of sacubitril/valsartan, compared with enalapril, was consistent across tertiles of ucGMP/BNP ratio at baseline for all outcomes (Pinteraction ≥0.31).ConclusionsIn patients with heart failure and reduced ejection fraction, higher ucGMP/BNP ratio was associated with better outcomes. Sacubitril/valsartan increased the ucGMP/BNP ratio, compared with enalapril, and the effect of sacubitril/valsartan on clinical outcomes was not modified by baseline ucGMP/BNP ratio.RegistrationURL: https://www.Clinicaltrialsgov; Unique Identifier: NCT01035255.

Dataset Information

Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study.

Objectives

Methods

Results

Conclusion

Publications

Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study.

Similar Datasets

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