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Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation.
Patel, SM, Braunwald, E, Steffel, J, Boriani, G, Palazzolo, MG, Antman, EM, Bohula, EA, Carnicelli, AP, Connolly, SJ, Eikelboom, JW, et al
Circulation. 2024;(12):932-943
Abstract
BACKGROUND The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. METHODS We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m2. RESULTS Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m2, and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HRadj], 0.80 [95% CI, 0.73-0.88]; P<0.001), with a generally consistent effect across BMI (Ptrend across HRs, 0.48). NOACs also reduced major bleeding overall (HRadj, 0.88 [95% CI, 0.82-0.94]; P<0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [Ptrend], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HRadj, 0.91 [95% CI, 0.87-0.95]; P<0.001; death, HRadj, 0.91 [95% CI, 0.86-0.97]; P=0.003), these benefits were attenuated at higher BMI (Ptrend, 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW. CONCLUSIONS The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.
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Gliflozins in the Management of Cardiovascular Disease.
Braunwald, E
The New England journal of medicine. 2022;(21):2024-2034
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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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The Effects of Angiotensin Receptor-Neprilysin Inhibition on Major Coronary Events in Patients With Acute Myocardial Infarction: Insights From the PARADISE-MI Trial.
Mehran, R, Steg, PG, Pfeffer, MA, Jering, K, Claggett, B, Lewis, EF, Granger, C, Køber, L, Maggioni, A, Mann, DL, et al
Circulation. 2022;(23):1749-1757
Abstract
BACKGROUND In patients who survive an acute myocardial infarction (AMI), angiotensin-converting enzyme inhibitors decrease the risk of subsequent major cardiovascular events. Whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan reduce major coronary events more effectively than angiotensin-converting enzyme inhibitors in high-risk patients with recent AMI remains unknown. We aimed to compare the effects of sacubitril/valsartan on coronary outcomes in patients with AMI. METHODS We conducted a prespecified analysis of the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI), which compared sacubitril/valsartan (97/103 mg twice daily) with ramipril (5 mg twice daily) for reducing heart failure events after myocardial infarction in 5661 patients with AMI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. In the present analysis, the prespecified composite coronary outcome was the first occurrence of death from coronary heart disease, nonfatal myocardial infarction, hospitalization for angina, or postrandomization coronary revascularization. RESULTS Patients were randomly assigned at a median of 4.4 [3.0-5.8] days after index AMI (ST-segment-elevation myocardial infarction 76%, non-ST-segment-elevation myocardial infarction 24%), by which time 89% of patients had undergone coronary reperfusion. Compared with ramipril, sacubitril/valsartan decreased the risk of coronary outcomes (hazard ratio, 0.86 [95% CI, 0.74-0.99], P=0.04) over a median follow-up of 22 months. Rates of the components of the composite outcomes were lower in patients on sacubitril/valsartan but were not individually significantly different. CONCLUSIONS In survivors of an AMI with left ventricular systolic dysfunction and pulmonary congestion, sacubitril/valsartan-compared with ramipril-reduced the risk of a prespecified major coronary composite outcome. Dedicated studies are necessary to confirm this finding and elucidate its mechanism. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT02924727.
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Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure: Analysis of the LIFE Trial Run-In.
Vader, JM, Givertz, MM, Starling, RC, McNulty, SE, Anstrom, KJ, Desvigne-Nickens, P, Hernandez, AF, Braunwald, E, Mann, DL, ,
JACC. Heart failure. 2022;(7):449-456
Abstract
BACKGROUND The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction. OBJECTIVES The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction. METHODS In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan. RESULTS Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance. CONCLUSIONS Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors. (EntrestoTM [LCZ696] in Advanced Heart Failure [LIFE Study] [HFN-LIFE] NCT02816736).
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Patients with diabetes mellitus and atrial fibrillation treated with non-vitamin K antagonist oral anticoagulants: meta-analysis of eight outcomes in 58 634 patients across four randomized controlled trials.
Plitt, A, Zelniker, TA, Park, JG, McGuire, DK, Ruff, CT, Antman, EM, Braunwald, E, Giugliano, RP
European heart journal. Cardiovascular pharmacotherapy. 2021;(FI1):f40-f49
Abstract
AIMS: Concomitant atrial fibrillation (AF) and diabetes mellitus (DM) increases the risk of stroke and systemic embolic events (SEE). This meta-analysis assessed the benefit/risk balance of non-vitamin K antagonist oral anticoagulants (NOACs) vs. warfarin, and explored whether there was effect modification by DM or heterogeneity in outcomes between NOACs in patients with and without DM. METHODS AND RESULTS We performed a meta-analysis of 58 634 patients from four Phase 3 trials of NOAC vs. warfarin in patients with AF, comparing the primary outcomes of efficacy and safety and six other secondary outcomes in patients stratified by the presence of DM. Interaction testing was used to assess for heterogeneity of treatment effects. A meta-regression was performed to evaluate the influence of baseline characteristics. NOACs reduced the risk of stroke/SEE in 18 134 patients with DM [hazard ratio (HR) 0.80; 95% confidence interval (CI) (0.69-0.93), I2 3.90] to a similar degree as in 40 500 patients without DM [HR 0.82; 95% CI (0.74-0.91), I2 16.33; P-int 0.81]. There was no effect modification of DM on the relative reduction with NOACs vs. warfarin in major bleeding (DM: 0.95, 95% CI 0.75-1.20, I2 43.83; no DM: 0.83, 95% CI 0.55-1.24; I2 87.90; P-int 0.37). Intracranial haemorrhage (HRs 0.51 and 0.47, P-int 0.70) and cardiovascular death (HRs 0.87 and 0.90, P-int 0.70) were significantly reduced by NOACs in the presence or absence of DM. CONCLUSION Non-vitamin K antagonist oral anticoagulants are more effective and safer than warfarin in AF patients with or without DM. Absent contraindications, NOACs should be the anticoagulation treatment choice in patients with diabetes.
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Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction.
Pfeffer, MA, Claggett, B, Lewis, EF, Granger, CB, Køber, L, Maggioni, AP, Mann, DL, McMurray, JJV, Rouleau, JL, Solomon, SD, et al
The New England journal of medicine. 2021;(20):1845-1855
Abstract
BACKGROUND In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. METHODS We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. RESULTS A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. CONCLUSIONS Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).
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Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT.
Oyama, K, Giugliano, RP, Blazing, MA, Park, JG, Tershakovec, AM, Sabatine, MS, Cannon, CP, Braunwald, E
Journal of the American College of Cardiology. 2021;(15):1499-1507
Abstract
BACKGROUND The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL despite maximally tolerated statin. OBJECTIVES The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS). METHODS IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke. RESULTS Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints. CONCLUSIONS Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).
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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).