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John J V Mcmurray - One of the best experts on this subject based on the ideXlab platform.
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a putative placebo analysis of the effects of Sacubitril valsartan in heart failure across the full range of ejection fraction
European Heart Journal, 2020Co-Authors: Muthiah Vaduganathan, Brian Claggett, Milton Packer, Martin P Lefkowitz, Pardeep S Jhund, Jiri Widimský, Petar M Seferovic, Adel R Rizkala, John J V McmurrayAbstract:AIMS: 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). METHODS AND RESULTS: We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of Sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for Sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, Sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of Sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of Sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of Sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), 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 death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02. CONCLUSION: This putative placebo analysis reinforces the treatment benefits of Sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.
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systolic blood pressure in heart failure with preserved ejection fraction treated with Sacubitril valsartan
Journal of the American College of Cardiology, 2020Co-Authors: Senthil Selvaraj, Brian Claggett, Martin P Lefkowitz, Muthiah Vaduganathan, Michael Bohm, Stefan D Anker, Faiez Zannad, Burkert Pieske, Inder S Anand, John J V McmurrayAbstract:Abstract Background Guidelines recommend targeting systolic blood pressure (SBP) Objectives This study sought to determine the optimal achieved SBP and whether the treatment effects of Sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from Sacubitril/valsartan. Methods Using 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles ( Results Average age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, Sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p Conclusions Baseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of Sacubitril/valsartan, and the BP-lowering effects of Sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
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Sacubitril valsartan in asian patients with heart failure with reduced ejection fraction
Korean Circulation Journal, 2019Co-Authors: Pooja Dewan, Kieran F Docherty, John J V McmurrayAbstract:: The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (Sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with Sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, Sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of Sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF.
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Sacubitril/valsartan in Asian patients with heart failure with reduced ejection fraction
Korean Circulation Journal, 2019Co-Authors: Pooja Dewan, Kieran F Docherty, John J V McmurrayAbstract:: The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (Sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with Sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, Sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of Sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF.
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b type natriuretic peptide during treatment with Sacubitril valsartan the paradigm hf trial
Journal of the American College of Cardiology, 2019Co-Authors: Peder L Myhre, Brian Claggett, Milton Packer, Akshay S Desai, Michael R Zile, Karl Swedberg, Jean L Rouleau, Martin P Lefkowitz, Muthiah Vaduganathan, John J V McmurrayAbstract:Abstract Background Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in Sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with Sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with Sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of Sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with Sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of Sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of Sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
Brian Claggett - One of the best experts on this subject based on the ideXlab platform.
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effect of dapagliflozin in patients with hfref treated with Sacubitril valsartan the dapa hf trial
Jacc-Heart Failure, 2020Co-Authors: Scott D Solomon, Brian Claggett, Pardeep S Jhund, Pooja Dewan, Lars Kober, Mikhail Kosiborod, Felipe Martinez, Piotr Ponikowski, Marc S Sabatine, Silvio E InzucchiAbstract:Abstract Objectives This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking Sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial. Background Both the angiotensin receptor neprilysin-inhibitor Sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown. Methods DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking Sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to Sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by Sacubitril/valsartan group. Results A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with Sacubitril/valsartan at baseline. Patients prescribed Sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking Sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking Sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background Sacubitril/valsartan. Conclusions Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking Sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124 )
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a putative placebo analysis of the effects of Sacubitril valsartan in heart failure across the full range of ejection fraction
European Heart Journal, 2020Co-Authors: Muthiah Vaduganathan, Brian Claggett, Milton Packer, Martin P Lefkowitz, Pardeep S Jhund, Jiri Widimský, Petar M Seferovic, Adel R Rizkala, John J V McmurrayAbstract:AIMS: 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). METHODS AND RESULTS: We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of Sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for Sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, Sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of Sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of Sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of Sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), 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 death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02. CONCLUSION: This putative placebo analysis reinforces the treatment benefits of Sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.
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effects of Sacubitril valsartan on n terminal pro b type natriuretic peptide in heart failure with preserved ejection fraction
Jacc-Heart Failure, 2020Co-Authors: Jonathan W Cunningham, Brian Claggett, Milton Packer, Michael R Zile, Pardeep S Jhund, Muthiah Vaduganathan, Faiez Zannad, Inder S Anand, Stefan Janssens, Lars KoberAbstract:Abstract Objectives The authors sought to evaluate the prognostic significance of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to Sacubitril/valsartan, and the treatment effect of Sacubitril/valsartan on NT-proBNP overall and in key subgroups. Background Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). Methods In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to Sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and Sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. Results Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. Conclusions Baseline NT-proBNP predicted HF events but did not modify the Sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
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systolic blood pressure in heart failure with preserved ejection fraction treated with Sacubitril valsartan
Journal of the American College of Cardiology, 2020Co-Authors: Senthil Selvaraj, Brian Claggett, Martin P Lefkowitz, Muthiah Vaduganathan, Michael Bohm, Stefan D Anker, Faiez Zannad, Burkert Pieske, Inder S Anand, John J V McmurrayAbstract:Abstract Background Guidelines recommend targeting systolic blood pressure (SBP) Objectives This study sought to determine the optimal achieved SBP and whether the treatment effects of Sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from Sacubitril/valsartan. Methods Using 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles ( Results Average age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, Sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p Conclusions Baseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of Sacubitril/valsartan, and the BP-lowering effects of Sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
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effect of Sacubitril valsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction a randomized clinical trial
JAMA, 2019Co-Authors: Akshay S Desai, Scott D Solomon, Brian Claggett, Kevin Mccague, Ricardo Rocha, Amil M Shah, James C Fang, Joseph L Izzo, Cheryl A Abbas, Gary F MitchellAbstract:Importance Compared 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. Objective To determine whether treatment of HFrEF with Sacubitril-valsartan improves central aortic stiffness and cardiac remodeling compared with enalapril. Design, Setting, and Participants Randomized, 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. Interventions Randomization (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 Measures The 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. Results Of 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/cm5in the Sacubitril-valsartan group and increased from 213.2 to 214.4 dyne × s/cm5in 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/m2to 28.2 mL/m2vs from 29.8 mL/m2to 30.5 mL/m2; treatment difference, −2.8 mL/m2[95% CI, −4.0 to −1.6 mL/m2];P Conclusions and Relevance Treatment 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 Registration ClinicalTrials.gov Identifier:NCT02874794
Milton Packer - One of the best experts on this subject based on the ideXlab platform.
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a putative placebo analysis of the effects of Sacubitril valsartan in heart failure across the full range of ejection fraction
European Heart Journal, 2020Co-Authors: Muthiah Vaduganathan, Brian Claggett, Milton Packer, Martin P Lefkowitz, Pardeep S Jhund, Jiri Widimský, Petar M Seferovic, Adel R Rizkala, John J V McmurrayAbstract:AIMS: 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). METHODS AND RESULTS: We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of Sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for Sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, Sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of Sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of Sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of Sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), 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 death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02. CONCLUSION: This putative placebo analysis reinforces the treatment benefits of Sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.
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effects of Sacubitril valsartan on n terminal pro b type natriuretic peptide in heart failure with preserved ejection fraction
Jacc-Heart Failure, 2020Co-Authors: Jonathan W Cunningham, Brian Claggett, Milton Packer, Michael R Zile, Pardeep S Jhund, Muthiah Vaduganathan, Faiez Zannad, Inder S Anand, Stefan Janssens, Lars KoberAbstract:Abstract Objectives The authors sought to evaluate the prognostic significance of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to Sacubitril/valsartan, and the treatment effect of Sacubitril/valsartan on NT-proBNP overall and in key subgroups. Background Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). Methods In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to Sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and Sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. Results Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. Conclusions Baseline NT-proBNP predicted HF events but did not modify the Sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
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b type natriuretic peptide during treatment with Sacubitril valsartan the paradigm hf trial
Journal of the American College of Cardiology, 2019Co-Authors: Peder L Myhre, Brian Claggett, Milton Packer, Akshay S Desai, Michael R Zile, Karl Swedberg, Jean L Rouleau, Martin P Lefkowitz, Muthiah Vaduganathan, John J V McmurrayAbstract:Abstract Background Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in Sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with Sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with Sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of Sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with Sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of Sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of Sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
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reduced loop diuretic use in patients taking Sacubitril valsartan compared with enalapril the paradigm hf trial
European Journal of Heart Failure, 2019Co-Authors: Orly Vardeny, Brian Claggett, Milton Packer, Akshay S Desai, Michael R Zile, Karl Swedberg, Jean L Rouleau, Martin P Lefkowitz, Jessica Kachadourian, John J V McmurrayAbstract:Aims: To assess differences in diuretic dose requirements in patients treated with Sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM‐HF) trial. Methods and results: Overall, 8399 patients with New York Heart Association class II–IV heart failure and reduced LVEF were randomized to Sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for Sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with Sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post‐randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on‐treatment analysis. Conclusion: Treatment with Sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with Sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.
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effects of Sacubitril valsartan on biomarkers of extracellular matrix regulation in patients with hfref
Journal of the American College of Cardiology, 2019Co-Authors: Michael R Zile, Scott D Solomon, Brian Claggett, Milton Packer, Karl Swedberg, Martin P Lefkowitz, John J V Mcmurray, Margaret F. Prescott, Eileen Omeara, Jean L RouleauAbstract:Background Myocardial fibrosis is an important pathophysiological mechanism underlying the development of heart failure (HF). Given the biochemical targets of Sacubitril/valsartan, we hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered by Sacubitril/valsartan in comparison to enalapril. Objectives The purpose of this study was to examine the effects of Sacubitril/valsartan on biomarkers of ECM homeostasis and the association between the rate of primary composite outcome (cardiovascular death or HF hospitalization) and these biomarkers. Methods Biomarkers at baseline (n = 2,067) and both baseline and 8 months after randomization (n = 1,776) included aldosterone, soluble ST2 (sST2), tissue inhibitor of matrix metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-2, MMP-9, Galectin-3 (Gal-3), N-terminal propeptide of collagen I (PINP), and N-terminal propeptide of collagen III (PIIINP). The effects of Sacubitril/valsartan on biomarkers were compared with enalapril. Baseline biomarker values and changes from baseline to 8 months were related to primary outcome. Results At baseline, the profibrotic biomarkers aldosterone, sST2, TIMP-1, Gal-3, PINP, and PIIINP were higher, and biomarkers associated with collagen degradation, MMP-2 and -9, were lower than published referent control values. Eight months after randomization, aldosterone, sST2, TIMP-1, MMP-9, PINP, and PIIINP had decreased more in the Sacubitril/valsartan than enalapril group. At baseline, higher values of sST-2, TIMP-1, and PIIINP were associated with higher primary outcome rates. Changes from baseline to 8 months in sST-2 and TIMP-1 were associated with change in outcomes. Conclusions Biomarkers associated with profibrotic signaling are altered in HF with reduced ejection fraction, Sacubitril/valsartan significantly decreased many of these biomarkers, and these biomarkers have important prognostic value. These findings suggest that Sacubitril/valsartan may reduce profibrotic signaling, which may contribute to the improved outcomes. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF]; NCT01035255).
Michael R Zile - One of the best experts on this subject based on the ideXlab platform.
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effects of Sacubitril valsartan on n terminal pro b type natriuretic peptide in heart failure with preserved ejection fraction
Jacc-Heart Failure, 2020Co-Authors: Jonathan W Cunningham, Brian Claggett, Milton Packer, Michael R Zile, Pardeep S Jhund, Muthiah Vaduganathan, Faiez Zannad, Inder S Anand, Stefan Janssens, Lars KoberAbstract:Abstract Objectives The authors sought to evaluate the prognostic significance of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to Sacubitril/valsartan, and the treatment effect of Sacubitril/valsartan on NT-proBNP overall and in key subgroups. Background Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). Methods In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to Sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and Sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. Results Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. Conclusions Baseline NT-proBNP predicted HF events but did not modify the Sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
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b type natriuretic peptide during treatment with Sacubitril valsartan the paradigm hf trial
Journal of the American College of Cardiology, 2019Co-Authors: Peder L Myhre, Brian Claggett, Milton Packer, Akshay S Desai, Michael R Zile, Karl Swedberg, Jean L Rouleau, Martin P Lefkowitz, Muthiah Vaduganathan, John J V McmurrayAbstract:Abstract Background Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in Sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with Sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with Sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of Sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with Sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of Sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of Sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
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reduced loop diuretic use in patients taking Sacubitril valsartan compared with enalapril the paradigm hf trial
European Journal of Heart Failure, 2019Co-Authors: Orly Vardeny, Brian Claggett, Milton Packer, Akshay S Desai, Michael R Zile, Karl Swedberg, Jean L Rouleau, Martin P Lefkowitz, Jessica Kachadourian, John J V McmurrayAbstract:Aims: To assess differences in diuretic dose requirements in patients treated with Sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM‐HF) trial. Methods and results: Overall, 8399 patients with New York Heart Association class II–IV heart failure and reduced LVEF were randomized to Sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for Sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with Sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post‐randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on‐treatment analysis. Conclusion: Treatment with Sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with Sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.
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effects of Sacubitril valsartan on biomarkers of extracellular matrix regulation in patients with hfref
Journal of the American College of Cardiology, 2019Co-Authors: Michael R Zile, Scott D Solomon, Brian Claggett, Milton Packer, Karl Swedberg, Martin P Lefkowitz, John J V Mcmurray, Margaret F. Prescott, Eileen Omeara, Jean L RouleauAbstract:Background Myocardial fibrosis is an important pathophysiological mechanism underlying the development of heart failure (HF). Given the biochemical targets of Sacubitril/valsartan, we hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered by Sacubitril/valsartan in comparison to enalapril. Objectives The purpose of this study was to examine the effects of Sacubitril/valsartan on biomarkers of ECM homeostasis and the association between the rate of primary composite outcome (cardiovascular death or HF hospitalization) and these biomarkers. Methods Biomarkers at baseline (n = 2,067) and both baseline and 8 months after randomization (n = 1,776) included aldosterone, soluble ST2 (sST2), tissue inhibitor of matrix metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-2, MMP-9, Galectin-3 (Gal-3), N-terminal propeptide of collagen I (PINP), and N-terminal propeptide of collagen III (PIIINP). The effects of Sacubitril/valsartan on biomarkers were compared with enalapril. Baseline biomarker values and changes from baseline to 8 months were related to primary outcome. Results At baseline, the profibrotic biomarkers aldosterone, sST2, TIMP-1, Gal-3, PINP, and PIIINP were higher, and biomarkers associated with collagen degradation, MMP-2 and -9, were lower than published referent control values. Eight months after randomization, aldosterone, sST2, TIMP-1, MMP-9, PINP, and PIIINP had decreased more in the Sacubitril/valsartan than enalapril group. At baseline, higher values of sST-2, TIMP-1, and PIIINP were associated with higher primary outcome rates. Changes from baseline to 8 months in sST-2 and TIMP-1 were associated with change in outcomes. Conclusions Biomarkers associated with profibrotic signaling are altered in HF with reduced ejection fraction, Sacubitril/valsartan significantly decreased many of these biomarkers, and these biomarkers have important prognostic value. These findings suggest that Sacubitril/valsartan may reduce profibrotic signaling, which may contribute to the improved outcomes. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF]; NCT01035255).
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effects of Sacubitril valsartan on physical and social activity limitations in patients with heart failure a secondary analysis of the paradigm hf trial
JAMA Cardiology, 2018Co-Authors: Alvin Chandra, Brian Claggett, Milton Packer, Akshay S Desai, Michael R Zile, Karl Swedberg, Jean L Rouleau, Eldrin F LewisAbstract:Importance Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, Sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Objective To examine the effects of Sacubitril/valsartan on physical and social activities. Design, Setting, and Participants The PARADIGM-HF trial was a randomized, double-blind, active treatment–controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017. Interventions Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily. Main Outcomes and Measures Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of Sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied. Results At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving Sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50;P Conclusions and Relevance In patients with heart failure with reduced ejection fraction, Sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, Sacubitril/valsartan may improve limitations in common activities in these patients. Trial Registration clinicaltrials.gov Identifier:NCT01035255
Martin P Lefkowitz - One of the best experts on this subject based on the ideXlab platform.
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a putative placebo analysis of the effects of Sacubitril valsartan in heart failure across the full range of ejection fraction
European Heart Journal, 2020Co-Authors: Muthiah Vaduganathan, Brian Claggett, Milton Packer, Martin P Lefkowitz, Pardeep S Jhund, Jiri Widimský, Petar M Seferovic, Adel R Rizkala, John J V McmurrayAbstract:AIMS: 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). METHODS AND RESULTS: We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of Sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for Sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, Sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45-0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of Sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of Sacubitril/valsartan vs. putative placebo was 48% (95% CI 35-58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of Sacubitril/valsartan vs. putative placebo was 29% (95% CI 7-46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64-0.82), 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 death (RR 0.83, 95% CI 0.71-0.96); all P < 0.02. CONCLUSION: This putative placebo analysis reinforces the treatment benefits of Sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.
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systolic blood pressure in heart failure with preserved ejection fraction treated with Sacubitril valsartan
Journal of the American College of Cardiology, 2020Co-Authors: Senthil Selvaraj, Brian Claggett, Martin P Lefkowitz, Muthiah Vaduganathan, Michael Bohm, Stefan D Anker, Faiez Zannad, Burkert Pieske, Inder S Anand, John J V McmurrayAbstract:Abstract Background Guidelines recommend targeting systolic blood pressure (SBP) Objectives This study sought to determine the optimal achieved SBP and whether the treatment effects of Sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from Sacubitril/valsartan. Methods Using 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles ( Results Average age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, Sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p Conclusions Baseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of Sacubitril/valsartan, and the BP-lowering effects of Sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)
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b type natriuretic peptide during treatment with Sacubitril valsartan the paradigm hf trial
Journal of the American College of Cardiology, 2019Co-Authors: Peder L Myhre, Brian Claggett, Milton Packer, Akshay S Desai, Michael R Zile, Karl Swedberg, Jean L Rouleau, Martin P Lefkowitz, Muthiah Vaduganathan, John J V McmurrayAbstract:Abstract Background Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in Sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro–B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. Objectives The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with Sacubitril/valsartan. Methods BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with Sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. Results Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of Sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with Sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of Sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). Conclusions Circulating levels of BNP may increase meaningfully early after initiation of Sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255)
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reduced loop diuretic use in patients taking Sacubitril valsartan compared with enalapril the paradigm hf trial
European Journal of Heart Failure, 2019Co-Authors: Orly Vardeny, Brian Claggett, Milton Packer, Akshay S Desai, Michael R Zile, Karl Swedberg, Jean L Rouleau, Martin P Lefkowitz, Jessica Kachadourian, John J V McmurrayAbstract:Aims: To assess differences in diuretic dose requirements in patients treated with Sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM‐HF) trial. Methods and results: Overall, 8399 patients with New York Heart Association class II–IV heart failure and reduced LVEF were randomized to Sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for Sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with Sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post‐randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on‐treatment analysis. Conclusion: Treatment with Sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with Sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.
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effects of Sacubitril valsartan on biomarkers of extracellular matrix regulation in patients with hfref
Journal of the American College of Cardiology, 2019Co-Authors: Michael R Zile, Scott D Solomon, Brian Claggett, Milton Packer, Karl Swedberg, Martin P Lefkowitz, John J V Mcmurray, Margaret F. Prescott, Eileen Omeara, Jean L RouleauAbstract:Background Myocardial fibrosis is an important pathophysiological mechanism underlying the development of heart failure (HF). Given the biochemical targets of Sacubitril/valsartan, we hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered by Sacubitril/valsartan in comparison to enalapril. Objectives The purpose of this study was to examine the effects of Sacubitril/valsartan on biomarkers of ECM homeostasis and the association between the rate of primary composite outcome (cardiovascular death or HF hospitalization) and these biomarkers. Methods Biomarkers at baseline (n = 2,067) and both baseline and 8 months after randomization (n = 1,776) included aldosterone, soluble ST2 (sST2), tissue inhibitor of matrix metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-2, MMP-9, Galectin-3 (Gal-3), N-terminal propeptide of collagen I (PINP), and N-terminal propeptide of collagen III (PIIINP). The effects of Sacubitril/valsartan on biomarkers were compared with enalapril. Baseline biomarker values and changes from baseline to 8 months were related to primary outcome. Results At baseline, the profibrotic biomarkers aldosterone, sST2, TIMP-1, Gal-3, PINP, and PIIINP were higher, and biomarkers associated with collagen degradation, MMP-2 and -9, were lower than published referent control values. Eight months after randomization, aldosterone, sST2, TIMP-1, MMP-9, PINP, and PIIINP had decreased more in the Sacubitril/valsartan than enalapril group. At baseline, higher values of sST-2, TIMP-1, and PIIINP were associated with higher primary outcome rates. Changes from baseline to 8 months in sST-2 and TIMP-1 were associated with change in outcomes. Conclusions Biomarkers associated with profibrotic signaling are altered in HF with reduced ejection fraction, Sacubitril/valsartan significantly decreased many of these biomarkers, and these biomarkers have important prognostic value. These findings suggest that Sacubitril/valsartan may reduce profibrotic signaling, which may contribute to the improved outcomes. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF]; NCT01035255).
