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Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.
Mann, DL, Givertz, MM, Vader, JM, Starling, RC, Shah, P, McNulty, SE, Anstrom, KJ, Margulies, KB, Kiernan, MS, Mahr, C, et al
JAMA cardiology. 2022;(1):17-25
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Abstract
IMPORTANCE The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. OBJECTIVE To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. DESIGN, SETTING, AND PARTICIPANTS A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. INTERVENTION Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. MAIN OUTCOMES AND MEASURES The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. RESULTS Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns. CONCLUSIONS AND RELEVANCE The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02816736.
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Eligibility for sacubitril/valsartan in heart failure across the ejection fraction spectrum: real-world data from the Swedish Heart Failure Registry.
Savarese, G, Hage, C, Benson, L, Schrage, B, Thorvaldsen, T, Lundberg, A, Fudim, M, Linde, C, Dahlström, U, Rosano, GMC, et al
Journal of internal medicine. 2021;(3):369-384
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BACKGROUND Randomized controlled trials (RCT) generalizability may be limited due to strict patient selection. OBJECTIVE In a real-world heart failure (HF) population, we assessed eligibility for sacubitril/valsartan based on PARADIGM-HF (sacubitril/valsartan effective)/PARAGON-HF [sacubitril/valsartan effective in mildly reduced ejection fraction (EF)]. METHODS Outpatients from the Swedish HF Registry (SwedeHF) were analysed. In SwedeHF, EF is recorded as <30, 30-39, 40-49 and ≥50%. In PARAGON-HF, sacubitril/valsartan was effective with EF ≤ 57% (i.e. median). We defined reduced EF/PARADIGM-HF as EF < 40%, mildly reduced EF/PARAGON-HF ≤ median as EF 40-49%, and normal EF/PARAGON-HF > median as EF ≥ 50%. We assessed 2 scenarios: (i) criteria likely to influence treatment decisions (pragmatic scenario); (ii) all criteria (literal scenario). RESULTS Of 37 790 outpatients, 57% had EF < 40%, 24% EF 40-49% and 19% EF ≥ 50%. In the pragmatic scenario, 63% were eligible in EF < 50% (67% for EF < 40% and 52% for 40-49%) and 52% in EF ≥ 40% (52% for EF ≥ 50%). For the literal scenario, 32% were eligible in EF < 50% (38% of EF < 40%, 20% of EF 40-49%) and 22% in EF ≥ 40% (25% for EF ≥ 50%). Eligible vs. noneligible patients had more severe HF, more comorbidities and overall worse outcomes. CONCLUSION In a real-world HF outpatient cohort, 81% of patients had EF < 50%, with 63% eligible for sacubitril/valsartan based on pragmatic criteria and 32% eligible based on literal trial criteria. Similar eligibility was observed for EF 40-49% and ≥50%, suggesting that our estimates for EF < 50% may be reproduced whether or not a higher cut-off for EF is considered.
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The AWAKE-HF Study: Sacubitril/Valsartan Impact on Daily Physical Activity and Sleep in Heart Failure.
Khandwalla, RM, Grant, D, Birkeland, K, Heywood, JT, Fombu, E, Owens, RL, Steinhubl, SR, ,
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2021;(2):241-254
Abstract
BACKGROUND AWAKE-HF evaluated the effect of the initiation of sacubitril/valsartan versus enalapril on activity and sleep using actigraphy in patients who have heart failure with reduced ejection fraction (HFrEF). METHODS In this randomized, double-blind study, patients with HFrEF (n = 140) were randomly assigned to sacubitril/valsartan or enalapril for 8 weeks, followed by an 8-week open-label phase with sacubitril/valsartan. Primary endpoint was change from baseline in mean activity counts during the most active 30 min/day at week 8. The key secondary endpoint was change in mean nightly activity counts/minute from baseline to week 8. Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23) was an exploratory endpoint. RESULTS There were no detectable differences between groups in geometric mean ratio of activity counts during the most active 30 min/day at week 8 compared with baseline (0.9456 [sacubitril/valsartan:enalapril]; 95% confidence interval [CI] 0.8863-1.0088; P = 0.0895) or in mean change from baseline in activity during sleep (difference: 2.038 counts/min; 95% CI - 0.062 to 4.138; P = 0.0570). Change from baseline to week 8 in KCCQ-23 was 2.89 for sacubitril/valsartan and 4.19 for enalapril, both nonsignificant. CONCLUSIONS In AWAKE-HF, no detectable differences in activity and sleep were observed when comparing sacubitril/valsartan with enalapril in patients with HFrEF using a wearable biosensor. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT02970669.
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Comparison of the Efficacy and Safety of Sacubitril/Valsartan versus Ramipril in Patients With ST-Segment Elevation Myocardial Infarction.
Rezq, A, Saad, M, El Nozahi, M
The American journal of cardiology. 2021;:7-13
Abstract
The role of sacubitril and/or valsartan in patient with heart failure (HF) is established. Whether sacubitril and/or valsartan plays a role in improving outcomes in patients after ST-segment elevation myocardial infarction (STEMI) is unknown. The current study aims to comparing the efficacy and safety of sacubitril and/or valsartan versus ramipril in post-STEMI patients. Patients presenting with STEMI were randomized to receive either sacubitril and/or valsartan or ramipril after primary percutaneous coronary intervention. The main efficacy endpoint was major adverse cardiac events (MACE) at 30 days and 6 months, defined as a composite of cardiac death, myocardial infarction, and HF hospitalizations. Multiple secondary clinical safety and efficacy endpoints were examined. A total of 200 patients were randomized from January 2018 to March 2019, mean age 54.5±10.4, 87% men, 75% presented with anterior wall STEMI. Baseline clinical and echocardiographic characteristics were comparable between groups. The primary endpoint of MACE was similar with sacubitril/valsartan versus ramipril at 30 days (p = 0.18); however, at 6 months, sacubitril/valsartan was associated with significant reduction of MACE (p = 0.005), mainly driven by reduction in HF hospitalizations (18% vs 36%, OR 0.40, 95% 0.22 to 0.75; p = 0.004). At 6 months, LV ejection fraction was higher with sacubitril/valsartan (46.8±12.5% vs 42.09±13.8%; p = 0.012), with improved LV remodelling (LV end diastolic dimension 50.6±3.9 mm vs 53.2±2.7 mm, p = 0.047; and LV end systolic dimension 36.1±3.4 mm versus 39.9±6.3 mm, p = 0.001) compared with ramipril. No difference in other efficacy or safety clinical endpoints was observed. In conclusion, early initiation of sacubitril/valsartan may offer clinical benefit and improvement in myocardial remodelling in post-STEMI patients.
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Global Differences in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.
Tromp, J, Claggett, BL, Liu, J, Jackson, AM, Jhund, PS, Køber, L, Widimský, J, Boytsov, SA, Chopra, VK, Anand, IS, et al
Circulation. Heart failure. 2021;(4):e007901
Abstract
BACKGROUND Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial. METHODS We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region. RESULTS Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P>0.05). CONCLUSIONS Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
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A study of the sequential treatment of acute heart failure with sacubitril/valsartan by recombinant human brain natriuretic peptide: A randomized controlled trial.
Pang, Z, Pan, C, Yao, Z, Ren, Y, Tian, L, Cui, J, Liu, X, Zhang, L, Chen, Y
Medicine. 2021;(16):e25621
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This study aimed to investigate the effects of the basic treatment for heart failure and sequential treatment with rh-brain natriuretic peptide (rhBNP) alone or the combination of rhBNP and sacubitril/valsartan. Cardiac structure, pulmonary artery pressure, inflammation and oxidative stress in patients with acute heart failure were evaluated.Three hundred patients with acute heart failure were included. According to the random number table method, the patients were divided into 3 groups of 100 patients per group: the standard treatment group (treated with an angiotensin-converting enzyme inhibitor, β receptor blocker, and corticosteroid antagonist), rhBNP group (basic treatment combined with rhBNP) and sequential treatment group (basic treatment for heart failure combined with rhBNP followed by sacubitril/valsartan). The changes in NT-probrain natriuretic peptide (BNP) levels, cardiac troponin T (cTnT) levels, cardiac structure, pulmonary artery pressure, and the levels inflammatory factors and oxidative stress factors were compared among the 3 groups at 1, 4, 12, and 36 weeks after treatment.The sequential treatment group displayed superior outcomes than the standard treatment group and the rhBNP group in terms of left atrium diameter, left ventricular end diastolic volume, left ventricular ejection fraction, pulmonary artery pressure, NT-proBNP levels, and cTnT levels, which respond to damage to the heart structure and myocardium. This result may be related to the decreased levels of inflammatory factors and the correction of oxidative stress imbalance.Sacubitril/valsartan significantly reduce the serum levels of inflammatory factors in patients with acute heart failure while decreasing the levels of oxidizing factors and increasing the levels of antioxidant factors. These changes may be one of the explanations for the better cardiac structure and better pulmonary artery pressure observed in the sequential treatment group.
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Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial.
Cohen, JB, Hanff, TC, William, P, Sweitzer, N, Rosado-Santander, NR, Medina, C, Rodriguez-Mori, JE, Renna, N, Chang, TI, Corrales-Medina, V, et al
The Lancet. Respiratory medicine. 2021;(3):275-284
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BACKGROUND Biological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19. METHODS The REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009. FINDINGS Between March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; β-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups. INTERPRETATION Consistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19. FUNDING REPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.
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Efficacy and Safety of Sacubitril/Valsartan in High-Risk Patients in the PIONEER-HF Trial.
Berg, DD, Samsky, MD, Velazquez, EJ, Duffy, CI, Gurmu, Y, Braunwald, E, Morrow, DA, DeVore, AD
Circulation. Heart failure. 2021;(2):e007034
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BACKGROUND In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile. METHODS PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m2 (n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219). RESULTS The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (P interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (P interaction=NS for each). CONCLUSIONS In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.
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Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists.
Ambrosy, AP, Braunwald, E, Morrow, DA, DeVore, AD, McCague, K, Meng, X, Duffy, CI, Rocha, R, Velazquez, EJ, ,
Journal of the American College of Cardiology. 2020;(9):1034-1048
Abstract
BACKGROUND The PIONEER-HF (comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode) trial demonstrated the efficacy and safety of sacubitril/valsartan (S/V) in stabilized patients with acute decompensated heart failure (HF) and reduced ejection fraction. OBJECTIVES The study sought to determine whether and how prior HF history and treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) affected the results. METHODS The PIONEER-HF trial was a prospective, multicenter, double-blind, randomized clinical trial enrolling 881 patients with an ejection fraction ≤40%. Patients were randomly assigned 1:1 to in-hospital initiation of S/V (n = 440) versus enalapril (n = 441). Pre-specified subgroup analyses were performed based on prior HF history (i.e., de novo HF vs. worsening chronic HF) and treatment with an ACE inhibitor or ARB (i.e., ACE inhibitor or ARB-yes vs. ACE inhibitor or ARB-no) at admission. RESULTS At enrollment, 303 (34%) patients presented with de novo HF and 576 (66%) patients with worsening chronic HF. A total of 421 (48%) patients had been treated with an ACE inhibitor or ARB, while 458 (52%) had not been treated with an ACE inhibitor or ARB. N-terminal pro-B-type natriuretic peptide declined significantly in all 4 subgroups (p < 0.001), with greater decreases in the S/V versus the enalapril arm (p < 0.001). There was no interaction between prior HF history (p = 0.350) or ACE inhibitor or ARB treatment (p = 0.880) and the effect of S/V versus enalapril on cardiovascular death or rehospitalization for HF. The incidences of adverse events were comparable between S/V and enalapril across all 4 subgroups. CONCLUSIONS Among patients admitted for acute decompensated HF, S/V was safe and well tolerated, led to a significantly greater reduction in N-terminal pro-B-type natriuretic peptide, and improved clinical outcomes compared with enalapril irrespective of previous HF history or ACE inhibitor or ARB treatment. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).
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Comparative Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Response to a Physical Activity Intervention in Older Adults: Results From the Lifestyle Interventions and Independence for Elders Study.
Brown, JD, Smith, SM, Strotmeyer, ES, Kritchevsky, SB, Gill, TM, Blair, SN, Fielding, RA, Buford, TW, Pahor, M, Manini, TM
The journals of gerontology. Series A, Biological sciences and medical sciences. 2020;(5):1010-1016
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BACKGROUND Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) may protect against aging-related decline. This study directly compared ACEis and ARBs on associations with risk of mobility disability in older adults when combined with a physical activity intervention. METHODS This was a secondary analysis of the Lifestyle Interventions and Independence for Elders (LIFE) trial. Participants aged 70-89 years were randomized to a physical activity or health education intervention. Outcomes included incident and persistent major mobility disability, injurious falls, short physical performance battery, and gait speed. For this analysis, only participants who reported ACEi or ARB use at baseline were included. Baseline differences between ACEi and ARB groups were adjusted for using inverse probability of treatment weights. Weighted Cox proportional hazard models and analysis of covariance models were used to evaluate the independent effects of medications and interaction effects with the intervention on each outcome. RESULTS Of 1,635 participants in the Lifestyle Interventions and Independence for Elders study, 796 used either an ACEi (496, 62.3%) or ARB (300, 37.7%). Compared with ACEi users, ARB users had 28% lower risk (hazard ratio [HR] = 0.72 [0.60-0.85]) of incident major mobility disability and 35% (HR = 0.65 [0.52-0.82]) lower risk of persistent major mobility disability whereas no interaction between medication use and intervention was observed. Risk of injurious falls and changes in short physical performance battery or gait speed were not different between ARB and ACEi users. CONCLUSIONS These results suggest that ARBs may protect from major mobility disability by other mechanisms than improving physical performance.