Showing papers by "Elliott M. Antman published in 2018"
TL;DR: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed in collaboration with EACTS is described in this paper.
Abstract: 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS : The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).
1,954 citations
1,540 citations
TL;DR: In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.
Abstract: Background Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse. Methods and Results The ENGAGE AF - TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230-771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78-3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07-2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83-1.42). Relative outcomes with higher-dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism ( HR , 0.60 [95% CI, 0.31-1.15] for malignancy versus HR , 0.89 [95% CI, 0.76-1.05] for no malignancy; interaction P=0.25) and major bleeding ( HR , 0.98 [95% CI, 0.69-1.40] for malignancy versus HR , 0.79 [95% CI, 0.69-1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher-dose edoxaban versus warfarin in patients with malignancy ( HR , 0.54; 95% CI, 0.31-0.93) compared with no malignancy ( HR , 1.02; 95% CI, 0.88-1.18; interaction P=0.026). Conclusions In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.
94 citations
87 citations
TL;DR: The correlation between dose, trough edoxaban level, and the risk of GIB risk suggests GIB is exposure-related, whereas surgery required to manage bleeding was less frequent with HD-ER and warfarin.
Abstract: Background: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction) compared higher-dose edoxaban regimen (HD-ER) and lower-dose edoxaban regimen with well-managed warfarin in 21 105 patients with atrial fibrillation. The risk factors and clinical impact of gastrointestinal bleeding (GIB) in this trial have not been described in detail. Methods and Results: This analysis was undertaken to identify risk factors for major GIB (MGIB) and compare the severity and outcomes of GIB with edoxaban and warfarin. During 2.8 years mean follow-up, there were 579 MGIB (1.22% per year), of which 63 were life-threatening or fatal (0.13% per year). Male sex, increased age, prior GIB, concomitant aspirin, lower baseline hemoglobin, renal dysfunction, and higher HAS-BLED and CHADS 2 scores were independently associated with the risk of MGIB. Whereas the annual rate of MGIB was higher with HD-ER than with warfarin (1.53% and 1.25%, respectively; hazard ratio, 1.23; 95% confidence interval, 1.02–1.48; P =0.033), the annual rates of life-threatening or fatal GIB were similar (0.15% and 0.18%, respectively). Several indicators of more severe GIB, including hemodynamic instability, hospitalization, ≥ 4 U transfusion, and hemoglobin loss ≥5 g/dL, were similar with HD-ER and warfarin, whereas surgery required to manage bleeding was less frequent with HD-ER. Lower-dose edoxaban regimen, which achieved 50% lower trough edoxaban levels, was associated with significantly less MGIB than warfarin. Conclusions: MGIB occurred more frequently with HD-ER than warfarin. The rates of life-threatening or fatal GIB were low and similar with both HD-ER and warfarin. Clinical outcomes were generally favorable. The correlation between dose, trough edoxaban level, and the risk of GIB risk suggests GIB is exposure-related. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.
33 citations
TL;DR: The extent of inhibition of endogenous FXa activity is influenced by edoxaban dosing and clinical characteristics, and it is associated with both antithrombotic benefit and risk of bleeding.
Abstract: Background: We previously reported exogenous antifactor Xa (FXa) activity as a pharmacokinetic surrogate marker for edoxaban plasma concentrations. Inhibition of endogenous FXa activity is a more b...
29 citations
TL;DR: Sudden death represents the largest proportion of CV deaths after 30 days among patients enrolled in CV clinical trials with NSTE-ACS, and further investigations aimed at defining the epidemiology of SD and developing specific therapies and management approaches to reduce SD may be critical to reducing late mortality.
Abstract: Aims Although presenting features and early sequelae of non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are well described, less is known about longer-term risks and modes of death. The purpose of this study was to characterize modes of death following NSTE-ACS in clinical trial populations. Methods and results We evaluated 66 252 patients with NSTE-ACS enrolled in 14 Thrombolysis in Myocardial Infarction (TIMI) trials, examining baseline characteristics and modes and timing of death. Of the 66 252 patients followed for a median of 372 (interquartile range 218-521) days, 3147 (4.8%) died by the time of last follow-up. Of the 2606 patients (82.8%) with known modes of death, 75.1% were related to a cardiovascular (CV) event, 3.0% were related to a bleeding event (including intracranial haemorrhage), and 21.8% were related to a non-CV/non-bleeding event. The most common modes of CV death were sudden death (SD) and recurrent myocardial infarction (MI) (36.4% and 23.4%, respectively, of CV deaths). The proportion of CV deaths related to recurrent MI was higher in the first 30 days than it was after 30 days following NSTE-ACS (30.6% vs. 18.7%), whereas the proportion of SD was lower in the first 30 days than after 30 days (21.6% vs. 46.2%). Conclusion Sudden death represents the largest proportion of CV deaths after 30 days among patients enrolled in CV clinical trials with NSTE-ACS. Further investigations aimed at defining the epidemiology of SD and developing specific therapies and management approaches to reduce SD following NSTE-ACS may be critical to reducing late mortality.
28 citations
TL;DR: In patients requiring surgery/procedure in ENGAGE AF-TIMI 48, peri-operative rates of SSE, MB and death were not significantly different in patients who received edoxaban or warfarin.
Abstract: Background Peri-operative management of anticoagulated patients with atrial fibrillation (AF) is challenging. To gain information on the peri-operative management of edoxaban, we compared outcomes in patients on warfarin or edoxaban enrolled in ENGAGE AF-TIMI 48 who underwent a surgery or invasive procedure. Methods Data from patients undergoing their first surgery/procedure were analysed and results compared by anticoagulant (warfarin vs. higher- or lower-dose edoxaban regimen [HDER and LDER, respectively]). Patients were classified by procedural management: anticoagulant interrupted (last dose 4–10 days pre-procedure) or anticoagulant continued (last dose ≤ 3 days pre-procedure). Stroke/systemic embolism (SSE), major bleeding (MB), MB or clinically relevant non-MB (CRNMB) and death were assessed from 7 days pre- until 30 days post-procedure. The chi-square test was used to compare outcomes across treatment groups. Results A total of 7,193 patients (34%) underwent surgery/procedure: 3,116 had anticoagulant interrupted, 4,077 had anticoagulant continued. Among patients on warfarin, HDER and LDER who had anticoagulant interrupted, rates of SSE were 0.6, 0.5 and 0.9% (p = 0.53), rates of MB were 1.0, 1.2 and 1.1% (p = 0.94) and rates of MB or CRNMB were 3.9, 4.2 and 3.6% (p = 0.78); among patients on warfarin, HDER and LDER who had anticoagulant continued, rates of SSE were 1.1, 0.7 and 0.9% (p = 0.51), rates of MB were 3.6, 2.6 and 2.4% (p = 0.13) and rates of MB or CRNMB were 8.5, 7.9 and 6.6% (p = 0.17). Conclusion In patients requiring surgery/procedure in ENGAGE AF-TIMI 48, peri-operative rates of SSE, MB and death were not significantly different in patients who received edoxaban or warfarin.
19 citations
TL;DR: Interruption of study drug was frequent in patients with AF and was associated with a substantial risk of major cardiac and cerebrovascular events over the ensuing 30 days, particularly high in patients who interrupted as a result of an adverse event.
15 citations
TL;DR: After multivariable adjustment, LatAm subjects with atrial fibrillation had higher rates of intracranial hemorrhage and death than nLAS, and outcomes with higher-dose edoxaban versus warfarin were at least as favorable in Lat am subjects as in nLas, with an even greater reduction in hemorrhagic stroke seen in LatAm.
10 citations
TL;DR: In this paper, the authors proposed a factorial randomization approach to evaluate potential drug-drug interactions in clinical trials, which is not always practical or even possible to randomize subjects prospectively to multiple drugs.
TL;DR: The earliest biomarkers introduced to diagnose myocardial infarction such as aspartate aminotransferase (AST) and lactic dehydrogenase (LDH) lacked cardiac specificity and were replaced by creatine kinase (CK), the CK‐MB isoenzyme, and ultimately the cardiac‐specific troponins (cTnT and cTnI).
Abstract: The earliest biomarkers introduced to diagnose myocardial infarction (MI) such as aspartate aminotransferase (AST) and lactic dehydrogenase (LDH) lacked cardiac specificity and were replaced by creatine kinase (CK), the CK-MB isoenzyme, and ultimately the cardiac-specific troponins (cTnT and cTnI). This has opened up the possibilities of ruling out MI more rapidly and also identifying patients with a chronic elevation of cTn and a poor prognosis in a range of cardiac conditions.
TL;DR: El texto completo y el documento complementario de casos clinicos de la presente actualizacion se encuentran disponibles en: www.escardio.org/Guidelines/Clinical-Practice-Guidelines /2017-focused-update-on-dual-antiplatelet-therapy-dapt.
Abstract: El texto completo y el documento complementario de casos clinicos de la presente actualizacion se encuentran disponibles en: www.escardio.org/Guidelines/Clinical-Practice-Guidelines/2017-focused-update-on-dual-antiplatelet-therapy-dapt .
TL;DR: A trial of patients with acute myocardial infarction reported significant attenuation of adverse left ventricular remodeling and noninfarct myocardIAL fibrosis after 6 months.
TL;DR: There is strong biological plausibility that treatments tracked in SWEDEHEART are in the causal pathway for improvements in outcome, and standardized incidence ratios for events and regression analyses adjusting for demographic changes over time showed improvements in cardiovascular outcomes in association with greater use of guideline-recommended treatments.
Abstract: Clinical trials over the last several decades provide a roadmap for managing an acute coronary syndrome (ACS). Clinical practice guidelines from professional societies codified the findings of such trials into recommendations for management of the patient with an ACS event. It is of interest to evaluate the long-term impact of ACS management strategies with particular attention to the changes brought about by serial expansion of the ACS therapeutic armamentarium. Longitudinal assessments of therapies for ACS cannot be derived from clinical trials, which by definition are confined to a particular era in time. Instead, observational data must be used, and it would be desirable if the source of those data is comprehensive and stable over time. The Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) is an ideal registry to conduct such analyses. All 72 hospitals in Sweden providing care for patients with cardiac diseases participate in SWEDEHEART and data can be linked to national patient registries and compared with general population statistics in Sweden. Using a sophisticated epidemiological approach, Szummer et al. previously reported improved outcomes in 105 674 patients with ST-elevation myocardial infarction (STEMI) tracked in SWEDEHEART between 1995 and 2014. The 20-year interval was divided into 2-year blocks and the percentages of STEMI patients receiving key treatments [beta-blockers, reperfusion, angiotensinconverting enzyme inhibitors/angiotensin receptor blockers (ACEI/ ARBs), statins, coronary angiography, primary percutaneous corronary intervention (PCI), and in-hospital coronary artery bypass graft (CABG)] were plotted. Total mortality and cardiovascular deaths decreased over time, roughly paralleling the time course of increased use of evidence-based treatments. Standardized incidence ratios for events compared with the general population and regression analyses adjusting for demographic changes over time also showed improvements in cardiovascular outcomes in association with greater use of guideline-recommended treatments. Szummer et al. present in the current issue of the European Heart Journal an analysis of 20-year outcomes in 205 693 cases of non ST-elevation MI (NSTEMI) in SWEDEHEART. This required additional adjustments, accounting for the shift in biomarkers used to diagnose MI from creatine kinase (CK)-MB (89.6% in 1995–1996) to cardiac-specific troponins (99% in 2013–2014). Aspirin and betablockers were generally in broad use already in the mid-1990s, but ACEIs/ARBs, statins, PCI, coronary angiography, and dual antiplatelet therapy showed progressive dramatic increases in use over the 2-year blocks through 2013–2014. Tracking with the increases in use of recommended treatments were significant reductions in crude in-hospital and 1-year total and cardiovascular deaths. Standardized in-hospital and 1-year rates of death/MI also showed progressive significant declines over time. Additional analyses that support the association between greater use of guideline treatments and improvements in outcomes after NSTEMI include regression analyses adjusting for age and gender, baseline characteristics, and in-hospital angiography/PCI. Standardized incidence rate ratios compared with the general population showed that the risk of death was 5.5 times higher in NSTEMI patients in 1995–1996 and declined to 3.03 times higher in 2013–2014. What are we to make of these impressive findings? It is gratifying to see translation of the results of clinical trials into practice. While we cannot assign causation between the significant trends in increasing use of effective treatments and progressive improvement in outcomes, there is strong biological plausibility that treatments tracked in SWEDEHEART are in the causal pathway for improvements in outcome. Enhancing flow in compromised coronary arteries, maintaining patency with stents and combination antithrombotics, and unloading a damaged left ventricle with ACEI/ARB treatments have all been shown to reduce morbidity and mortality from an ACS event. Evidence supporting the treatments tracked in SWEDEHEART was