Abstract Background Hierarchical composite outcomes, analyzed using the win ratio, are increasingly used in randomized clinical trials (RCTs). However, methods for covariate adjustment in this context are underdeveloped, despite evidence that adjusting for prognostic variables can increase statistical power. Objectives Introducing a new covariate adjustment method for hierarchical outcomes using ordinal logistic regression, comparing it with existing approaches, and assessing whether adjustment improves power in randomized trials with hierarchical outcomes. Methods We developed an ordinal regression-based method for covariate adjustment of the win ratio and compared it with three alternatives: probability index models, inverse probability weighting, and a randomization-based estimator. Methods were applied to the EMPEROR-Preserved rial and tested through extensive simulations involving two common hierarchical outcome structures: time-to-event composites, and composites combining time-to-event with quantitative measures. Simulations assessed impacts on estimates, standard errors, and power across prognostic and non-prognostic settings. Results In RCT data and simulations, covariate adjustment consistently increased power when adjusting for prognostic baseline variables. Gains were comparable to or greater than those in conventional Cox models, with no power loss for non-prognostic covariates. Our ordinal approach performed similarly to existing methods while providing interpretable covariate effect estimates. Adjusting for baseline values of quantitative components yielded power gains according to the baseline-to-follow-up correlation. Conclusions Covariate adjustment for prognostic variables meaningfully improves efficiency in win ratio analyses for hierarchical outcomes. Our ordinal method is easily implemented and facilitates covariate effect interpretation. We recommend the broader adoption of covariate adjustment and our ordinal method in randomized trials using hierarchical outcomes.

BACKGROUND:The SPYRAL HTN-ON MED (Global Clinical Study of Renal Denervation With the Symplicity Spyral Multielectrode Renal Denervation System in Patients With Uncontrolled Hypertension on Standard Medical Therapy) trial showed that radiofrequency renal denervation (RDN) using the Symplicity Spyral catheter yielded significant blood pressure (BP) reductions at 6 and 24 months compared with sham control in patients with hypertension on antihypertensive medications. In this prespecified analysis through the final follow-up, we evaluate the durability of BP reductions, antihypertensive medication use, and safety through 3 years. METHODS:SPYRAL HTN-ON MED is a global, randomized, sham-controlled trial enrolling patients with uncontrolled hypertension. Patients were prescribed 1 to 3 antihypertensive medications and randomized to RDN or a sham procedure. After 6 months, patients were unblinded, and sham patients could cross over to RDN. Crossover patients' values for BP and antihypertensive medications were imputed to 36 months using their last observation before crossover to RDN carried forward. Statistical analyses, including imputation, were exploratory and conducted on the intention-to-treat population. RESULTS:After 6 months, 74% of sham patients crossed over to undergo RDN. Patients undergoing RDN had statistically significant 24-hour ambulatory systolic BP reductions (treatment difference, -4.7 mm Hg; P=0.0028) and office systolic BP reductions (difference, -7.5 mm Hg; P=0.0002) compared with the sham control group through 36 months. At 36 months, the antihypertensive medication burden was balanced between groups (RDN, 5.2±5.0 versus 5.5±9.9; P=0.63). Crossover patients had significantly better office BP control after RDN. Clinical adverse events were rare. CONCLUSIONS:Compared with sham patients through 3 years, patients undergoing RDN had significantly greater 24-hour ambulatory and office BP reductions, with a similar medication burden. RDN maintained a durable safety profile through 3 years. REGISTRATION:URL: https://clinicaltrials.gov/study; Unique identifier: NCT02439775.

BACKGROUND AND AIMS:Recent trials have challenged the guideline recommendation of beta-blockers for post-myocardial infarction (MI) patients without reduced left ventricular ejection fraction (LVEF). Whether these recent findings apply equally to women and men remains unknown. METHODS:Using data from REBOOT (tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion), the largest randomized trial evaluating the effect of beta-blockers after acute MI with LVEF > 40%, a pre-specified sex-specific subgroup analysis was performed. A total of 8438 out of the 8505 randomized patients comprised the intention-to-treat population. RESULTS:Among 8438 patients, 1627 were women, who were older, had more comorbidities, and received fewer guideline-based therapies than men. Over a median follow-up of 3.7 years, women had overall higher rates of the primary composite outcome (death, MI, or heart failure hospitalization) than men. The incidence rate of the primary endpoint in women was 30.4 and 21.0/1000 patient-years in the beta-blocker group and no beta-blocker group, respectively (hazard ratio 1.45, 95% confidence interval 1.04-2.03). No significant differences were observed in men (hazard ratio .94, 95% confidence interval .79-1.13; P for interaction = .026). The excess risk in women was mainly driven by increased mortality and was most evident among those with preserved LVEF (P for interaction = .030) and those receiving higher beta-blocker doses (P for interaction = .045). CONCLUSIONS:In the REBOOT trial of MI patients managed according to contemporary standards, beta-blocker therapy was associated with evidence of harm in women-particularly those with preserved LVEF and receiving higher doses-an effect not observed in men.

AIMS:Current guidelines recommend beta-blocker therapy after myocardial infarction (MI) regardless of left ventricular ejection fraction (LVEF). However, recent trials question their benefit in patients with preserved LVEF. No study has yet compared beta-blocker effects during the acute coronary syndrome (ACS) phase (≤1 year post-MI) vs. the chronic coronary syndrome (CCS) phase (>1 year). METHODS AND RESULTS:In this pre-specified landmark analysis of the REBOOT trial, we evaluated the effect of beta-blocker therapy on outcomes in two post-MI phases: the ACS period (first year; cohort 1, n = 8438) and the CCS period (>1 year, event-free patients with follow-up; cohort 2, n = 7783). The primary endpoint was all-cause death, nonfatal reinfarction, or heart failure hospitalization; secondary endpoints included individual and additional cardiovascular events. Among 623 primary outcome events, 238 occurred in the first year (28.9/1000 patient-years) and 385 thereafter (19.3/1000 patient-years). Secondary prevention use was generally high, but patients with early events had lower prescription rates than those with late events or no events. Beta-blockers were not associated with lower risk of the primary or component outcomes in either phase. A nonsignificant trend towards benefit of beta-blockers appeared during the first year in patients with mildly reduced LVEF (41-49%), whereas in the CCS phase, higher beta-blocker doses were associated with worse outcomes. CONCLUSION:In invasively treated MI patients with LVEF >40%, beta-blockers did not reduce adverse outcomes in either the ACS or CCS phases. These findings challenge their routine use in this population and support reconsidering current guidelines. Long-term beta-blocker users after MI may be candidates for deprescription.

INTRODUCTION AND OBJECTIVES:Recent trials have questioned the clinical benefit of beta-blockers in post-myocardial infarction (MI) patients with preserved left ventricular ejection fraction (LVEF). However, differences in pathophysiology and risk profile between MI with and without ST-segment elevation (STEMI and NSTEMI) may influence the effect of beta-blockers. METHODS:In this prespecified subgroup analysis of the REBOOT trial, which randomized invasively managed MI patients with LVEF> 40% to beta-blockers or control, we evaluated differences in long-term effects of the intervention between STEMI (n=4296) and NSTEMI (n=4142). The primary endpoint was a composite of all-cause death, reinfarction, or heart failure hospitalization over a median follow-up of 3.7 years. RESULTS:The primary endpoint and its components occurred more frequently in NSTEMI than in STEMI. A significant interaction between MI type and beta-blocker allocation was observed (P=.027). Among STEMI patients, beta-blockers were associated with a higher incidence of the primary endpoint (HR, 1.27; 95%CI, 1.00-1.62), whereas NSTEMI patients assigned to beta-blockers showed no effect (HR, 0.89; 95%CI, 0.72-1.10). Notably, NSTEMI patients with mildly reduced LVEF (40% to 50%) on beta-blockers experienced significantly fewer events than controls. CONCLUSIONS:The absence of clear clinical benefit from beta-blockers in invasively managed MI patients with preserved LVEF was consistent across STEMI and NSTEMI. The observed interaction by infarct type is exploratory and should not be interpreted as definitive evidence of harm associated with beta-blocker therapy in patients with STEMI and preserved LVEF. NSTEMI patients with mildly reduced LVEF may benefit from beta-blockers, warranting further investigation. (ClinicalTrials.gov: NCT03596385).

Subclinical atherosclerosis (SA) burden and progression are independently associated with all-cause mortality. However, monitoring SA progression requires reliable and cost-effective biomarkers. While leukocyte telomere length (LTL) attrition has been linked to cardiovascular disease and mortality, it remains uncertain whether changes in LTL over time can predict SA progression. In this study, we conducted a longitudinal study to assess whether accelerated LTL attrition is associated with SA progression over a 6-year period in healthy middle-aged individuals. LTL was measured by high-throughput quantitative fluorescence in-situ hybridization in peripheral-blood leukocyte samples obtained 6 years apart from a sub-cohort of 1068 Progression of Early Subclinical Atherosclerosis (PESA)-study participants. SA was assessed by 3D vascular ultrasound in the carotid and femoral territories. Associations were evaluated using linear and logistic regression models. LTL parameters at baseline and after 6 years showed a positive correlation, but no significant associations were found between changes in LTL and changes in plaque volume over 6 years, either in the total sample or when stratified by sex. Likewise, no significant associations were found between LTL changes and the odds of SA progression over a 6-year period. Similar results were found when considering short telomere load changes. These findings suggest limited utility of LTL dynamics as an early biomarker for SA progression in healthy middle-aged individuals.

AbstractThe win ratio is a method for analyzing a clinical hierarchy of outcomes. It is most commonly applied to randomized clinical trials to evaluate the superiority of an intervention versus the standard of care. Once an intervention is approved, a noninferiority trial may be used to assess whether or not an alternative intervention is as effective. The authors explain how to select an appropriate noninferiority margin in terms of the win ratio, while emphasizing the importance of translating it into familiar metrics (e.g., rate ratios, differences in means) for easier interpretation. This framework is illustrated with a worked example of a hypothetical trial. The authors provide practical guidance on how the win ratio could be effectively used in future noninferiority trials.

BACKGROUND AND AIMS:Randomized trials demonstrated that in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) direct oral anticoagulants (DOAC) and a P2Y12 inhibitor reduce bleeding compared with vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT) with no increase in ischemic risk; however, important gaps in knowledge remain, limiting certainty and generalizability of these findings. METHODS:In this patient-level meta-analysis of randomized trials evaluating antithrombotic strategies in patients with AF undergoing PCI, Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios and 95% confidence intervals (HR, 95%CI). The primary efficacy and safety outcomes were the composite of cardiovascular death, myocardial infarction, or stroke, and TIMI major bleeding, respectively. The study was registered in PROSPERO (CRD420251130025). RESULTS:Six trials (10,634 patients) comparing DOAC plus P2Y12 inhibitor (4,083), VKA plus single antiplatelet therapy (SAPT, 1,247), VKA plus DAPT (3,715), and DOAC plus DAPT (1,589) were included. The transition from DAPT to SAPT was recommended at 1 (1-3) and 3 (1-7) days in the DOAC plus P2Y12 inhibitor and VKA plus SAPT groups, respectively. At 1 year, the risk of the primary efficacy outcome did not differ across the antithrombotic strategies (reference group: VKA plus DAPT; DOAC plus P2Y12 inhibitor: HR 1.16, 95%CI 0.97-1.41; VKA plus SAPT: 1.14, 0.85-1.54, DOAC plus DAPT: 0.99, 0.75-1.30), without any statistically significant interaction between treatment effects and all prespecified subgroups, including age, sex, bleeding risk, and thrombotic risk. However, 14-day landmark analysis showed an increased risk of myocardial infarction and definite/probable stent thrombosis in patients receiving DOAC plus P2Y12 inhibitor or VKA plus SAPT in the early phase after PCI. DOAC plus P2Y12 inhibitor reduced the risk of the primary safety outcome compared with VKA plus DAPT (0.48, 0.38- 0.65) and VKA plus SAPT (0.62, 0.40-0.97); only a borderline reduction was observed compared to DOAC plus DAPT (0.66, 0.44-1.01). DOAC plus P2Y12 inhibitor reduced intracranial hemorrhage compared with VKA plus DAPT (0.21, 0.07-0.64). CONCLUSIONS:In patients with AF undergoing PCI, the risk of cardiovascular death, myocardial infarction, or stroke did not significantly differ according to whether patients received a DOAC or VKA, whereas a modest increase in risk with single compared with dual antiplatelet therapy cannot be excluded, given the higher risk of early coronary events. DOACs compared with VKAs reduced the risk of bleeding across all severity grades, including intracranial hemorrhage, whereas omission of a second antiplatelet agent reduced the risk of TIMI major or minor bleeding.

BACKGROUND:Limited data are available regarding the relative rates, etiology, and long-term prognostic implications of spontaneous myocardial infarction (MI) after percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery for left main coronary artery disease (LMCAD). METHODS:MIs after PCI and CABG for LMCAD were adjudicated from the EXCEL trial (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization). Cox proportional hazards regression was performed to assess the association between spontaneous (and procedural) MI and cardiovascular and all-cause mortality at 5 years. RESULTS:Among 1882 patients who underwent LMCAD revascularization, spontaneous MI during 5-year follow-up occurred in 60 (6.8%) patients after PCI and in 29 (3.4%) patients after CABG (adjusted hazard ratio [adjHR], 2.01; 95 CI, 1.29-3.15; P=0.002). By multivariable analysis, spontaneous MI (as a time-adjusted covariate) was a strong independent predictor of subsequent cardiovascular mortality (adjHR, 9.39; 95% CI, 5.22-16.87) and all-cause mortality (adjHR, 4.77; 95% CI, 2.92-7.80) within 5 years, with consistent effects after PCI and CABG (Pinteraction=0.60 and 0.78, respectively). In the same models, procedural MI as defined by extensive myonecrosis was associated with 5-year cardiovascular (adjHR, 3.02; 95% CI, 1.64-5.56) and all-cause mortality (adjHR, 2.38; 95% CI, 1.48-3.80), with consistent effects after PCI and CABG (Pinteraction=0.23 and 0.34, respectively). CONCLUSIONS:In the EXCEL trial, spontaneous MI occurred relatively infrequently within 5 years after LMCAD revascularization but at a higher rate after PCI compared with CABG. Spontaneous MI after revascularization was strongly related to subsequent cardiovascular and all-cause mortality, consistently after PCI and CABG, and was more strongly associated with mortality than was large procedural MI. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01205776.

Background The benefit of an implantable cardioverter-defibrillator (ICD) in patients with heart failure with reduced ejection fraction on foundational therapy that includes a sodium-glucose cotransporter 2 inhibitor is unknown. Objectives This study aims to evaluate the impact of an ICD among participants enrolled in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction). Methods Propensity score matching was used to compare outcomes in patients with and without an ICD in the placebo and empagliflozin arms of the EMPEROR-Reduced trial. Time-to-event curves and Cox regression analysis were used to evaluate the risk of the primary endpoint of sudden cardiac death (SCD). Results A total of 1,674 patients were included in the analysis of whom 837 (429 on placebo and 408 on empagliflozin) with an ICD at baseline were matched to 837 (424 on placebo and 413 on empagliflozin) without an ICD. Background therapy included an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor blocker-neprilysin inhibitor (≥88%); beta-blockers (≥94%), and mineralocorticoid receptor antagonists (≥65%). Cox regression analysis showed ICD vs non-ICD treatment was associated with a lower risk of SCD in both the empagliflozin (HR: 0.59; 95% CI: 0.26-1.3) and placebo arms of the trial (HR: 0.31; 95% CI: 0.13-0.74), treatment-by-ICD interaction P = 0.30. Conclusions In patients with heart failure with reduced ejection fraction enrolled in EMPEROR-Reduced, those with an ICD (vs non-ICD) experienced a lower risk of SCD regardless of empagliflozin treatment.

Extension follow-up trials are essential for understanding the long-term safety and efficacy of cardiovascular interventions. Whereas primary randomized trials primarily capture short-term outcomes, extended observation may reveal delayed benefits or harms that are highly relevant to clinical decision-making. However, methodologic standards for extension trials remain poorly defined, leading to inconsistent design, analysis, and reporting. This scientific statement outlines best practices for cardiovascular trial extensions, addressing outcome selection, duration and completeness of follow-up, and analytic strategies suited to evolving treatment effects. Practical considerations, including strategies for participant retention, reconsent, data continuity, and resource allocation, are also discussed.

Introducción y objetivos Ensayos recientes han cuestionado el beneficio clínico de los bloqueadores beta en pacientes tras un infarto agudo de miocardio (IAM) con fracción de eyección del ventrículo izquierdo (FEVI) conservada. Las diferencias en la fisiopatología y el perfil de riesgo entre un IAM con y sin elevación del ST (IAMCEST e IAMSEST) podrían influir en su efecto. Métodos En este análisis de subgrupos preespecificado del ensayo REBOOT, en el que se aleatorizó a pacientes con IAM tratados de forma invasiva y con una FEVI> 40% a recibir bloqueadores beta o tratamiento de control, se evaluó las diferencias en los efectos a largo plazo de la intervención entre los pacientes con IAMCEST (n=4.296) y los pacientes con IAMSEST (n=4.142). El objetivo principal primario fue un compuesto de muerte por cualquier causa, reinfarto u hospitalización por insuficiencia cardiaca durante un seguimiento mediano de 3,7 años. Resultados El objetivo principal y sus componentes se dieron más frecuentemente en el IAMSEST que en el IAMCEST. Se observó una interacción significativa entre el tipo de IAM y la asignación a bloqueadores beta (p = 0,027). En el IAMCEST, los bloqueadores beta se asociaron con una mayor incidencia del objetivo principal (HR=1,27; IC95%, 1,00-1,62), mientras que, en el IAMSEST, no se dieron diferencias (HR=0,89; IC95%, 0,72-1,10). Pacientes con IAMSEST y FEVI intermedia (40-50%) tratados con bloqueadores beta presentaron significativamente menos episodios que los controles. Conclusiones La ausencia de beneficio de los bloqueadores beta en el IAM tratados invasivamente con FEVI conservada es consistente en IAMCEST e IAMSEST. La interacción observada por tipo de infarto es exploratoria y no debe interpretarse como una señal definitiva de daño asociado al uso de bloqueadores beta en el IAMCEST. Pacientes con IAMSEST y FEVI parecen beneficiarse de bloqueadores beta, pero se requiere de investigación adicional en estudios adecuados. (ClinicalTrials.gov: NCT03596385)

Background Magnesium plays a central role in maintaining cellular homeostasis. Limited data exist on the clinical implications of magnesium derangements and the influence of sodium-glucose cotransporter 2 inhibitors on magnesium levels in heart failure with mildly reduced or preserved ejection fraction. Objectives Using the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) population, the authors aimed to study the association of serum magnesium with outcomes, assess the impact of empagliflozin on serum magnesium levels, and explore the influence of serum magnesium on the effect of empagliflozin on the study outcomes. Methods Patients with heart failure with mildly reduced or preserved ejection fraction were randomized to receive placebo or empagliflozin 10 mg daily. Laboratory results were available at baseline; week 4; weeks 12, 32, and 52; and every 24 weeks thereafter. The median follow-up time was 26.2 months. The primary outcome was a composite of cardiovascular death or heart failure hospitalization. Results A total of 5,988 patients were included. The mean serum magnesium levels at baseline were 0.82 ± 0.11 mmol/L. The corresponding magnesium quintiles were as follows: Q1 = 0.67 ± 0.07 mmol/L (n = 1,291), Q2 = 0.78 ± 0.02 (n = 1,189), Q3 = 0.83 ± 0.01 (n = 1,378), Q4 = 0.88 ± 0.01 (n = 1,078), and Q5 = 0.96 ± 0.05 (n = 1,052). Patients with higher magnesium levels were older, had lower estimated glomerular filtration rate, and higher prevalence of atrial fibrillation. Conversely, patients with lower serum magnesium had diabetes and used thiazide-type diuretic agents more frequently. Placebo-treated patients experienced a higher risk of primary outcome events with higher magnesium levels (Q5). Empagliflozin (vs placebo) was associated with a more pronounced reduction of primary outcome events at higher baseline magnesium levels: Q1, HR: 1.05 [95% CI: 0.77-1.39]; Q2, HR: 0.85 [95% CI: 0.63-1.14]; Q3, HR: 0.88 [95% CI: 0.66-1.17]; Q4, HR: 0.62 [95% CI: 0.45-0.86]; Q5, HR: 0.60 [95% CI: 0.45-0.79]; interaction P-trend = 0.030. At week 4, empagliflozin had increased magnesium levels by 0.05 mmol/L, reaching a steady state thereafter. Conclusions In EMPEROR-Preserved, higher serum magnesium levels were associated with a higher risk of primary outcome events among patients treated with placebo but not among patients treated with empagliflozin who experienced pronounced benefit. (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction [EMPEROR-Preserved]; NCT03057951)

BACKGROUND:Current guideline recommendations for the use of beta-blockers after myocardial infarction without reduced ejection fraction are based on trials conducted before routine reperfusion, invasive care, complete revascularization, and contemporary pharmacologic therapies became standard practice. METHODS:We conducted an open-label, randomized trial in Spain and Italy to evaluate the effect of beta-blocker therapy, as compared with no beta-blocker therapy, in patients with acute myocardial infarction (with or without ST-segment elevation) and a left ventricular ejection fraction above 40%. The primary outcome was a composite of death from any cause, reinfarction, or hospitalization for heart failure. RESULTS:In total, 4243 patients were randomly assigned to receive beta-blocker therapy and 4262 to receive no beta-blocker therapy; after exclusions, 8438 patients were included in the main analysis. During a median follow-up of 3.7 years, a primary-outcome event occurred in 316 patients (22.5 events per 1000 patient-years) in the beta-blocker group and in 307 patients (21.7 events per 1000 patient-years) in the no-beta-blocker group (hazard ratio, 1.04; 95% confidence interval [CI], 0.89 to 1.22; P = 0.63). Death from any cause occurred in 161 patients and 153 patients, respectively (11.2 vs. 10.5 events per 1000 patient-years; hazard ratio, 1.06; 95% CI, 0.85 to 1.33); reinfarction in 143 patients and 143 patients (10.2 vs. 10.1 events per 1000 patient-years; hazard ratio, 1.01; 95% CI, 0.80 to 1.27); and hospitalization for heart failure in 39 patients and 44 patients (2.7 vs. 3.0 events per 1000 patient-years; hazard ratio, 0.89; 95% CI, 0.58 to 1.38). No apparent between-group differences in safety outcomes were noted. CONCLUSIONS:Among patients discharged after invasive care for a myocardial infarction with a left ventricular ejection fraction above 40%, beta-blocker therapy appeared to have no effect on the incidence of death from any cause, reinfarction, or hospitalization for heart failure. (Funded by Centro Nacional de Investigaciones Cardiovasculares Carlos III and others; ClinicalTrials.gov number, NCT03596385; EudraCT number, 2017-002485-40.).

BACKGROUND:Current guidelines recommend beta blockers after myocardial infarction (MI) regardless of left ventricular ejection fraction (LVEF), aiming to reduce reinfarction and ventricular arrhythmias. However, recent trials have challenged this practice in patients without reduced LVEF. Whether beta blocker withdrawal in these patients increases short-term or recurrent ischaemic events remains uncertain. AIMS:We aimed to evaluate the short-term ischaemic safety of beta blocker withholding or withdrawal at hospital discharge in patients with MI and LVEF >40% and to determine the effect of beta blocker therapy on a broad composite ischaemic endpoint. METHODS:This is a post hoc analysis of the REBOOT trial, in which patients with MI and LVEF >40% were randomised to beta blocker therapy or no beta blocker at discharge. The incidence of short-term (3-month) and recurrent ischaemic events (a composite of cardiac death, reinfarction, sustained ventricular tachycardia/fibrillation, resuscitated cardiac arrest, or unplanned revascularisation) was assessed overall and according to prior beta blocker use. RESULTS:From the 8,438 patients in the intention-to-treat population of the trial, information regarding beta blocker history was available for 8,401. Of these, 12.1% were on chronic beta blocker therapy before MI. Overall, withholding or withdrawing beta blockers was not associated with increased short-term ischaemic risk (hazard ratio [HR] 1.13, 95% confidence interval [CI]: 0.74-1.72). Over a median follow-up of 3.7 years, there were no differences in recurrent ischaemic events between groups (HR 0.98, 95% CI: 0.82-1.16), nor significant interactions with prior beta blocker therapy. In patients who were on a beta blocker before the index MI, randomisation to no beta blocker (withdrawal) was not associated with an increased risk of ischaemic events during trial follow-up (composite ischaemic endpoint HR 0.93, 95% CI: 0.64-1.34). CONCLUSIONS:In patients with MI and LVEF >40%, beta blocker withholding or withdrawal at discharge was not associated with increased short-term or recurrent ischaemic events, supporting the safety of this strategy in contemporary clinical practice.