Eugene Braunwald’s research while affiliated with University of Massachusetts Boston and other places

Aims The temporal changes in clinical profiles and outcomes of high‐risk myocardial infarction survivors enrolled in clinical trials are poorly described. This study compares mortality rates, baseline characteristics, and the prognostic impact of therapies among participants of the VALIANT and PARADISE‐MI trials. Methods and results Exclusively VALIANT participants who matched the inclusion criteria of the PARADISE‐MI trial were included in the analysis. Risk of death was compared between trials using Cox regression models. The impact of baseline characteristics and therapies on mortality was estimated by the magnitude reduction of β coefficients using Cox proportional hazards regression models. A total of 9617 VALIANT participants matched the inclusion criteria of the PARADISE‐MI trial ( n = 5661). All‐cause mortality in PARADISE‐MI was less than half that in VALIANT (4.2 vs 9.9 per 100 patient‐years; hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.37–0.46). This difference was reduced after adjustment for clinical variables but remained substantial (adjusted HR 0.68, 95% CI 0.58–0.80). The most important mediator of this reduction related to covariate adjustment was the use of percutaneous coronary intervention (PCI), accounting for almost half of the attenuation observed. Similar results were found for cardiovascular (CV) death, while no between‐trial significant differences were found in the non‐CV mortality risk. Conclusions Cardiovascular mortality following high‐risk myocardial infarction has significantly declined over time, while the risk for non‐CV death has remained unchanged. This improvement is partially attributable to advancements in CV care, particularly the use of PCI. Continued efforts to implement guidelines and standardize the quality of care are needed to sustain this positive trend.

Background: Prior data suggest the MI risk may be higher with paroxysmal AF (PAF) vs. non-paroxysmal AF (non-PAF). Proposed mechanisms include tachycardia-induced oxidative stress (via LOX-1) with microvascular flow abnormalities, ischemia downstream of a fixed coronary obstruction, and plaque rupture. Methods: We compared MI rates in pts with PAF vs. non-PAF in COMBINE AF, a patient-level metanalysis of 4 RCTS of DOACs vs warfarin (ARISTOTLE, ENGAGE AF-TIMI 48, RE-LY,ROCKET AF). Secondary endpoints were ischemic stroke and CV death. Cox proportional-hazards models stratified by trial and adjusted for elements of the CHADS-VASc score were constructed. Sensitivity analyses were performed across subgroups, omitting pts on lower-dose DOAC regimens, and accounting for competing risk of death. Results: Of 71,466 pts, 16,609 (23%) had PAF at enrollment. Pts with PAF vs non-PAF were similar age (median 72 vs 72. P=0.15), but more likely women (43 vs 36%), with prior CAD (35 vs 31%), and on aspirin (41 vs 32%); but less likely Asian race (12 vs 15%) or with CHADS-VASc score > 4 (59 vs 60%), p < 0.002 for each. During >160,000 pt-yrs of follow-up, 1033 MIs occurred: 277 (1.67%) in pts with PAF vs 766 (1.40%) in pts with non-PAF, corresponding to rates of 0.81% and 0.70% per pt-year. The HR adj for MI with PAF vs non--paroxysmal AF was 1.17 [1.02-1.35], p=0.028 (Fig). Ischemic stroke occurred in 364 (2.19%) vs 1425 (2.60%) pts with PAF vs non--paroxysmal AF (HR adj 0.81 [0.72-0.91], p<0.001). CV death occurred in 625 (3.77%) pts with PAF vs 3027 (5.52%) with non-paroxysmal AF (HR adj 0.75 [0.68-0.81], p<0.001). No significant effect modification of pt characteristics on MI risk by AF pattern were present, although a trend was seen for higher MI risk with PAF vs non-PAF in pts with prior CAD (HR 1.34 [1.12-1.59]) vs no prior CAD (HR 0.96 [0.76-1.22]), P INT 0.06. Results were consistent across trials, by anticoagulant, excluding lower dose DOACs, and accounting for competing mortality risk. Conclusions: This individual patient-level metanalysis of 71,466 pts from COMBINE AF shows that the adjusted risk of MI is higher in pts with PAF than non--paroxysmal AF, while the adjusted risks of ischemic stroke and CV death were lower in pts with PAF.

Background: The ability of polygenic risk scores (PRS) to predict heart failure (HF) beyond classic risk factors is unclear. Aims: To evaluate the risk of a HF PRS with incident hospitalization for HF (HHF) in patients with established cardiovascular disease. Methods: We analyzed a 59 SNP HF PRS (HERMES collaboration, Henry et al) in genotyped patients from six multinational TIMI randomized controlled trials (DECLARE, ENGAGE AF, FOURIER, PEGASUS, SAVOR, SOLID). Patients were stratified to low (quintile, Q1), intermediate (Q2-Q4), or high (Q5) genetic risk. We investigated the association of the HF PRS with incident HHF (median of 2.5 years) i) stratified by prior HF, and ii) across NTproBNP concentrations at baseline, using Cox-proportional hazard models. Results are reported as HR [95% CI], per 1-SD or with Q1 as a reference, and adjusted for ancestry (principal components 1-5), age, sex, trial, BMI, smoking, systolic BP, prior CAD, DM, AF, and eGFR. Results: In 59,906 pts (median age 66 years; 71% male; 26% prior HF), the HF PRS was associated with incident HHF (HR adj per 1-SD 1.08 [1.03, 1.13], p<0.001). Compared to low genetic risk pts, the HR adj for HHF was 1.12 [1.00, 1.26] in intermediate and 1.17 [1.02, 1.35] in high-risk pts. There were significant interactions between the HF PRS and prior HF (P int 0.001), and NTproBNP (P int 0.038), respectively. In pts without prior HF (Fig A), compared to low-risk pts, the risk was increased in high- (HR adj 1.56 [1.25, 1.94], p<0.001) and intermediate-risk pts (HR adj 1.27 [1.05, 1.54], p=0.013). In contrast, there was no significant association in pts with known HF at baseline ( Fig B ). Similarly, the HF PRS was significantly associated with HHF in pts with low but not elevated NTproBNP at baseline ( Fig C ). Conclusion: Our study confirms the role of polygenic risk for HF and demonstrates that a 59 SNP PRS can identify pts at increased risk of future HF events beyond traditional clinical factors, specifically in patients without established HF or elevated NTproBNP. These findings suggest a potential application of a HF PRS for screening and early identification of pts at increased risk for HF.

Importance Sudden death is a leading cause of death after acute myocardial infarction (AMI). The Prospective ARNi vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) and Valsartan in Acute Myocardial Infarction (VALIANT) trials enrolled patients with pulmonary congestion and/or left ventricular dysfunction after AMI. Whether the prognosis in such patients has changed over time has not been examined. Objective To compare the rate of sudden death/resuscitated cardiac arrest (RCA) after AMI in the PARADISE-MI and VALIANT trials. Design, Setting, and Participants This was a secondary analysis of multicenter randomized clinical trials enrolling patients after AMI. In the primary analysis, the VALIANT cohort was restricted to patients with “PARADISE-MI–like” characteristics (eg, at least 1 augmenting risk factor and no history of heart failure). The baseline characteristics of people in both trials were compared. The VALIANT trial enrolled from December 1998 to June 2001, and the PARADISE-MI trial enrolled between December 2016, and March 2020. The median follow-up in the VALIANT and PARADISE-MI trials was 24.7 and 22 months, respectively. People with AMI, complicated by pulmonary congestion and/or left ventricular dysfunction, were included in the analysis. Exposure Sudden death after AMI. Results A total of 5661 patients were included in the PARADISE-MI cohort (mean [SD] age, 63.7 [11.5] years; 4298 male [75.9%]), 9617 were included in the VALIANT (PARADISE-MI–like) cohort (mean [SD] age, 66.1 [11.5] years; 6504 male [67.6%]), and 14 703 patients were included in the VALIANT (total) cohort (mean [SD] age, 64.8 [11.8] years; 10 133 male [68.9%]). In the PARADISE-MI–like cohort of the VALIANT trial, 707 of 9617 participants (7.4%) experienced sudden death/RCA. A total of 148 of 5661 people (2.6%) in the PARADISE-MI trial experienced sudden death/RCA. Sudden death rates were highest in the first month after infarction in both trials: 19.3 (95% CI, 16.4-22.6) per 100 person-years in the VALIANT trial and 9.5 (95% CI, 7.0-12.7) per 100 person-years in the PARADISE-MI trial, and these rates declined steadily thereafter. Compared with the VALIANT cohort, people in the PARADISE-MI trial were more often treated with percutaneous coronary intervention for their qualifying AMI and received a β-blocker, statin, and mineralocorticoid receptor antagonist more frequently. Conclusions and Relevance After AMI, the risk of sudden death/RCA was highest in the first month, declining rapidly thereafter. Results revealed that compared with counterparts from 20 years ago, the rate of sudden death/RCA in patients with a reduced left ventricular ejection fraction and/or pulmonary congestion was 2- to 3-fold lower in people receiving contemporary management. Interventions to further protect people in the highest risk first month after infarction are needed. Trial Registration ClinicalTrials.gov Identifier: NCT02924727

Importance In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data. Objective To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin. Design, Setting, and Participants The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023. Interventions Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin. Main Outcomes and Measures Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component. Results The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable. Conclusions and Relevance In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria. Trial Registration ClinicalTrials.gov Identifier: NCT00781391

BACKGROUND Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events. METHODS ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization. RESULTS 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05–1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05–1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use. CONCLUSIONS In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00781391.