Showing papers by "Eugene Braunwald published in 2016"

Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis

Abstract: Importance The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. Objective To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. Data Sources and Study Selection The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included. Data Extraction and Synthesis Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression. Main Outcomes and Measures The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level. Results A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84;P Conclusions and Relevance In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.

Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial

Abstract: Importance Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure, irrespective of type 2 diabetes status. Objective To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure. Design, Setting, and Participants Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized. Patients were enrolled between August 2013 and March 2015 at 24 US sites. Interventions The GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days. Main Outcomes and Measures The primary end point was a global rank score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. Higher values indicate better health (stability). Exploratory secondary outcomes included primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events. Results Among the 300 patients who were randomized (median age, 61 years [interquartile range {IQR}, 52-68 years]; 64 [21%] women; 178 [59%] with type 2 diabetes; median LVEF of 25% [IQR, 19%-33%]; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [IQR, 1054-4235 pg/mL]), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs 16 [11%] in the placebo group; hazard ratio, 1.10 [95% CI, 0.57-2.14]; P = .78) or rehospitalizations for heart failure (63 [41%] vs 50 [34%], respectively; hazard ratio, 1.30 [95% CI, 0.89-1.88]; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 [1%] vs 4 [3%], respectively). Conclusions and Relevance Among patients recently hospitalized with heart failure and reduced LVEF, the use of liraglutide did not lead to greater posthospitalization clinical stability. These findings do not support the use of liraglutide in this clinical situation. Trial Registration clinicaltrials.gov Identifier:NCT01800968

Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial.

Abstract: Background:Edoxaban, an oral factor Xa inhibitor with 50% renal clearance, was noninferior to well-managed warfarin for stroke or systemic embolism (S/SE) prevention and reduced bleeding in patient...

Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF–TIMI 48 Trial

Abstract: Background Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF‐TIMI 48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age. Methods and Results Twenty‐one thousand one‐hundred and five patients enrolled in the ENGAGE AF‐TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P <0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups ( P trend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with edoxaban versus warfarin (hazard ratio 0.83 [0.66–1.04]), while major bleeding was significantly reduced with edoxaban (hazard ratio 0.83 [0.70–0.99]). The absolute risk difference in major bleeding (−82 events/10 000 pt‐yrs) and in intracranial hemorrhage (−73 events/10 000 pt‐yrs) both favored edoxaban over warfarin in older patients. Conclusions Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients. Clinical Trial Registration URL: . Unique identifier: NCT00781391.

Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease: Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50).

Abstract: Background Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a morbid event that may result in limb loss. We investigated the causes, sequelae, and predictors of ALI in a contemporary population with symptomatic PAD and whether protease-activated receptor 1 antagonism with vorapaxar reduced ALI overall and by type. Methods and results The Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients, including 3787 with symptomatic PAD. ALI was a prespecified adjudicated end point using a formal definition. A total of 150 ALI events occurred in 108 patients during follow-up (placebo 3-year rate, 3.9%; 1.3% annualized). For patients with symptomatic PAD, previous peripheral revascularization, smoking, and the ankle-brachial index were predictive of ALI. The majority of ALI events occurred as a result of surgical graft thrombosis (56%), followed by native vessel in situ thrombosis (27%). Stent thrombosis and thromboembolism caused ALI in 13% and 5%, respectively. Amputation occurred in 17.6% presenting with ALI. Vorapaxar reduced first ALI events by 41% (hazard ratio, 0.58; 95% confidence interval, 0.39-0.86; P=0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59; 95% confidence interval, 0.38-0.93; P=0.022). The efficacy of vorapaxar was consistent across types of ALI. Conclusions In selected patients with symptomatic PAD and without atrial fibrillation, ALI occurs at a rate of 1.3%/y, is most frequently caused by acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, and often results in limb loss. Vorapaxar reduces ALI in patients with symptomatic PAD with consistency across type, including PAD resulting from surgical graft thrombosis and in-situ thrombosis. Clinical trial registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.

Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54

Abstract: Aims Ticagrelor reduced major adverse cardiovascular event (MACE) by 15–16% in patients with prior myocardial infarction (MI) in PEGASUS-TIMI 54. We hypothesized that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and may derive particular benefit from continuation or reinitiation of therapy. Methods and results Patients in PEGASUS-TIMI 54 were categorized by time from last P2Y12 inhibitor (days: ≤30, >30–360, >360). The risk of MACE and the efficacy of ticagrelor were compared across categories. In the placebo arm, patients who more recently stopped P2Y12 inhibitor therapy had a greater number of risk factors but still had a higher risk of MACE after multivariable adjustment [≤30 days, hazard ratio (HR)adj 1.47, 95% confidence interval (CI) 1.12–1.93, P = 0.0051; 30 days–1 year, HRadj 1.28, 95% CI 0.98–1.67, P = 0.073] compared with those who stopped >1 year prior ( P -trend = 0.0097). The benefit of ticagrelor depended on the time from last dose, with HRs (95% CI) for ticagrelor (pooled doses) vs. placebo of 0.73 (0.61–0.87), 0.86 (0.71–1.04), and 1.01 (0.80–1.27), respectively, by category ( P -trend for interaction < 0.001). The benefit in those ≤30 days of stopping was similar regardless of time from MI (<2 years, HR 0.73, 95% CI 0.60–0.89 vs. ≥2 years, HR 0.71, 95% CI 0.50–1.00). Conclusion The benefit of ticagrelor for long-term secondary prevention in patients with prior MI and at least one additional risk factor appeared more marked in patients continuing on or re-starting after only a brief interruption of P2Y12 inhibition, when compared with patients who had proved themselves stable more than 2 years from their MI and off P2Y12 inhibitor therapy for more than a year. The increase in bleeding events with ticagrelor was similar regardless of this time interval. For clinicians considering a strategy of prolonged P2Y12 inhibitor therapy in high-risk patients, these data suggest greater benefit in the continuation of such therapy without interruption after MI, rather than re-initiating such therapy in patients who have remained stable for an extended period. Future analyses may help to clarify further the profile of post-MI patients most likely to benefit from uninterrupted dual antiplatelet therapy. Clinical Trial Registration Information [NCT01225562][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01225562&atom=%2Fehj%2F37%2F14%2F1133.atom

Atherothrombotic Risk Stratification and the Efficacy and Safety of Vorapaxar in Patients With Stable Ischemic Heart Disease and Previous Myocardial Infarction.

Abstract: Background —Patients with stable ischemic heart disease and prior MI vary in their risk for recurrent CV events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventative therapy such as treatment with vorapaxar. Methods —We identified independent clinical indicators of atherothrombotic risk among 8,598 stable, placebo-treated patients with a prior MI followed for 2.5 years (median) in TRA 2°P-TIMI 50. The efficacy and safety of vorapaxar was assessed by baseline risk among patients with prior MI without prior stroke or TIA for whom there is a clinical indication for vorapaxar. Endpoints were CV death, MI, or ischemic stroke (CVD/MI/iCVA) and GUSTO severe bleeding. Results —The 9 independent risk predictors were age, diabetes, hypertension, smoking, peripheral arterial disease, prior stroke, prior coronary bypass-grafting, heart failure, and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rate of CVD/MI/iCVA and the individual components (p-trend<0.001 for all). High-risk patients (≥3 risk indicators; 20% of population) had a 3.2% absolute risk reduction (ARR) in CVD/MI/iCVA with vorapaxar and intermediate-risk (1-2; 61%) had a 2.1% ARR (p<0.001 each), translating to a number-needed-to-treat of 31 and 48. Bleeding increased across risk groups (p-trend<0.01); however, net clinical outcome was increasingly favorable with vorapaxar across risk groups. Fatal bleeding or intracranial hemorrhage was 0.9% with both treatments in high-risk patients. Conclusions —Stratification of baseline atherothrombotic risk can assist with therapeutic decision-making regarding vorapaxar use for secondary prevention after MI. Clinical Trial Registration —http://www.clinicaltrials.gov; [NCT00526474][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00526474&atom=%2Fcirculationaha%2Fearly%2F2016%2F07%2F20%2FCIRCULATIONAHA.115.019861.atom

Updates on Acute Coronary Syndrome: A Review

Abstract: Importance Acute coronary syndrome (ACS), the acute manifestation of ischemic heart disease, remains a major cause of morbidity and mortality worldwide and is responsible for more than 1 million hospital admissions in the United States annually. Considerable research is being conducted in the field. This review provides a contemporary overview of key new findings on the pathophysiology, diagnosis, treatment, and prognosis of ACS. Observations While plaque rupture is the most frequent cause of coronary thrombosis, studies with optical coherence tomography demonstrate that superficial plaque erosion is more common than previously thought. High-sensitivity troponin assays (not yet available in the United States) and cardiac computed tomographic angiography are being increasingly used in diagnosis and risk stratification of patients with suspected ACS. New data from long-term dual antiplatelet therapy studies and investigations of anticoagulants provide important insights into the balance between ischemic and bleeding risks. The added benefit of percutaneous coronary intervention in non–infarct-related arteries in patients with ST-segment elevation myocardial infarction has been demonstrated in randomized trials, and the radial approach has become the standard of care in patients with ACS undergoing angiography. Promising old and new adjunctive therapies, such as pretreatment with β-blockers, ezetimibe, and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, are discussed. New guidelines on the management of non–ST-segment elevation ACS were published in the last 2 years, as well as scientific documents on ACS in understudied populations, such as women and patients with renal dysfunction. Conclusions and Relevance Substantial progress in the prevention, diagnosis, and management of patients with ACS has been accomplished in recent years. Despite optimal pharmacological and invasive therapies, the burden of recurrent ischemic events and mortality remains high, and future research is ongoing to prevent and improve the outcome of patients with ACS.

Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF‐TIMI48 Trial

Abstract: Background We studied the concomitant use of single antiplatelet therapy (SAPT) on the efficacy and safety of the anti‐Xa agent edoxaban in patients with atrial fibrillation (AF). Methods and Results ENGAGE AF‐TIMI 48 was a randomized trial that compared 2 dose regimens of edoxaban with warfarin. We studied both the approved high‐dose edoxaban regimen (HDER; 60 mg daily reduced by one half in patients with anticipated increased drug exposure), as well as a lower‐dose edoxaban regimen (LDER; 30 mg daily, also reduced by one half in patients with anticipated increased drug regimen). SAPT (aspirin in 92.5%) was administered at the discretion of the treating physician. Cox proportional hazard regressions stratified by SAPT at 3 months with treatment as a covariate were performed. The 4912 patients who received SAPT were more frequently male, with histories of coronary artery disease and diabetes, and had higher CHADS2Vasc and HAS BLED scores than did the 14 977 patients not receiving SAPT. When compared to patients not receiving SAPT, those receiving SAPT had a higher incidence of major bleeding; (adjusted hazard ratio [HRadj]=1.46; 95% CI, 1.27–1.67, P <0.001). SAPT did not alter the relative efficacy of edoxaban compared to warfarin in preventing stroke or systemic embolic events (SEEs): edoxaban versus warfarin without SAPT, hazard ratio (HRadj for HDER)=0.94; (95% CI: 0.77–1.15) with SAPT, HRadj=0.70 (95% CI: 0.50–0.98), P interaction ( P int)=0.14. (HRadj for LDER versus warfarin without SAPT=1.19 (95% CI 0.99–1.43) With SAPT, 1.03 (95% CI, 0.76–1.39) P int=0.42. Major bleeding was lower with edoxaban than warfarin both without SAPT, HRadj for HDER=0.80 (95% CI, 0.68–0.95), and with SAPT, HRadj=0.82 (95% CI, 0.65–1.03; P int=0.91). For LDER without SAPT (HRadj=0.56 [95% CI 0.46–0.67]) and with SAPT (HRadj=0.51 [95% CI 0.39–0.66]). Conclusions Patients with AF who were selected by their physicians to receive SAPT in addition to an anticoagulant had a similar risk of stroke/SEE and higher rates of bleeding than those not receiving SAPT. Edoxaban exhibited similar relative efficacy and reduced bleeding compared to warfarin, with or without concomitant SAPT. Clinical Trial Registration URL: . Unique identifier: NCT00781391.

Long-term Tolerability of Ticagrelor for the Secondary Prevention of Major Adverse Cardiovascular Events: A Secondary Analysis of the PEGASUS-TIMI 54 Trial.

Abstract: Importance In the PEGASUS-TIMI 54 trial, treatment with ticagrelor reduced the incidence of cardiovascular death, myocardial infarction, or stroke by 15% to 16% among stable patients compared with placebo. However, more patients prematurely discontinued treatment with ticagrelor than with placebo. Objective To investigate the reasons and timing of discontinuation of treatment with ticagrelor among stable patients prior myocardial infarction. Design, Setting, and Participants In the PEGASUS-TIMI 54 trial, 21 162 stable outpatients with prior myocardial infarction were randomly assigned to 90 mg of ticagrelor twice daily, 60 mg of ticagrelor twice daily, or placebo, with all of the patients receiving a low dose of aspirin. These participants were followed up for a median of 33 months (study start date: October 2010; completion date: December 2014). Discontinuation of treatment was evaluated by treatment arm, cause, and timing. This analysis was initiated in May 2015. Main Outcome and Measure Discontinuation of treatment. Results Over 33 months, 32%, 29%, and 21% of patients receiving 90 mg of ticagrelor, 60 mg of ticagrelor, and placebo, respectively, discontinued treatment ( P P P P Conclusions and Relevance When initiated among stable patients with prior myocardial infarction, discontinuation of treatment with ticagrelor was driven primarily by nonserious adverse events occurring primarily early after randomization. For patients completing 1 year of treatment, the subsequent discontinuation rate was low. These data demonstrate how adverse events considered “nonserious” by traditional trial criteria may have an effect on quality of life and, thus, may precipitate the discontinuation of treatments and underscore the need for patient education and counseling on the timing and nature of adverse effects with the aim of improving adherence when appropriate. Trial Registration clinicaltrials.gov Identifier:NCT01225562

Outcomes With Edoxaban Versus Warfarin in Patients With Previous Cerebrovascular Events: Findings From ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48).

Abstract: Background and Purpose— Patients with atrial fibrillation and previous ischemic stroke (IS)/transient ischemic attack (TIA) are at high risk of recurrent cerebrovascular events despite anticoagulation. In this prespecified subgroup analysis, we compared warfarin with edoxaban in patients with versus without previous IS/TIA. Methods— ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind trial of 21 105 patients with atrial fibrillation randomized to warfarin (international normalized ratio, 2.0–3.0; median time-in-therapeutic range, 68.4%) versus once-daily edoxaban (higher-dose edoxaban regimen [HDER], 60/30 mg; lower-dose edoxaban regimen, 30/15 mg) with 2.8-year median follow-up. Primary end points included all stroke/systemic embolic events (efficacy) and major bleeding (safety). Because only HDER is approved, we focused on the comparison of HDER versus warfarin. Results— Of 5973 (28.3%) patients with previous IS/TIA, 67% had CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack) >3 and 36% were ≥75 years. Compared with 15 132 without previous IS/TIA, patients with previous IS/TIA were at higher risk of both thromboembolism and bleeding (stroke/systemic embolic events 2.83% versus 1.42% per year; P <0.001; major bleeding 3.03% versus 2.64% per year; P <0.001; intracranial hemorrhage, 0.70% versus 0.40% per year; P <0.001). Among patients with previous IS/TIA, annualized intracranial hemorrhage rates were lower with HDER than with warfarin (0.62% versus 1.09%; absolute risk difference, 47 [8–85] per 10 000 patient-years; hazard ratio, 0.57; 95% confidence interval, 0.36–0.92; P =0.02). No treatment subgroup interactions were found for primary efficacy ( P =0.86) or for intracranial hemorrhage ( P =0.28). Conclusions— Patients with atrial fibrillation with previous IS/TIA are at high risk of recurrent thromboembolism and bleeding. HDER is at least as effective and is safer than warfarin, regardless of the presence or the absence of previous IS or TIA. Clinical Trial Registration— URL: . Unique identifier: [NCT00781391][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00781391&atom=%2Fstrokeaha%2F47%2F8%2F2075.atom

Prognostic Implications of Biomarker Assessments in Patients With Type 2 Diabetes at High Cardiovascular Risk: A Secondary Analysis of a Randomized Clinical Trial.

Abstract: Importance Cardiac biomarkers provide insights into pathophysiologic processes and offer an attractive strategy for the assessment of cardiovascular risk. Objective To assess the incremental prognostic value of biomarkers that reflect different pathophysiologic processes in patients with type 2 diabetes. Design, Setting, and Participants The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 is a randomized, double-blind, placebo-controlled clinical trial that evaluated the safety of saxagliptin vs placebo in 16 492 outpatients with type 2 diabetes with overt cardiovascular disease (CVD) or multiple risk factors. In this secondary analysis, widely used biomarkers were evaluated to ascertain whether they would provide incremental prognostic value in the risk stratification. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years). The study was performed from May 10, 2010, to June 15, 2013. Interventions Randomization to saxagliptin vs placebo in addition to standard care. Main Outcomes and Measures Concentrations of high-sensitivity troponin T, N-terminal pro–B-type natriuretic peptide, and high-sensitivity C-reactive protein were analyzed continuously and by established cut points. Cardiovascular death, myocardial infarction, ischemic stroke, and hospitalization for heart failure (HF) were adjudicated by a blinded events committee. Results Of the 16 492 patients, 5455 (33.1%) were female and 11 037 (66.9%) were male. Mean (SD) age was 65.0 (8.5) years (range, 39-99 years). Baseline biomarkers were measured in 12 310 patients. Elevated levels of each biomarker were associated significantly with increased risk for all cardiovascular end points. When added to clinical variables, biomarkers significantly improved the discrimination and appropriate reclassification of risk. Elevated high-sensitivity troponin T was associated with an increased risk of cardiovascular death (adjusted hazard ratio [AHR], 3.07; 95% CI, 2.35-4.02; P P P P P P P P Conclusions and Relevance A substantial proportion of patients with stable type 2 diabetes with established CVD or multiple clinical risk factors have evidence of ongoing myocardial injury, hemodynamic stress, or systemic inflammation. Biomarker risk stratification thus challenges the traditional differentiation between primary and secondary prevention based simply on clinical history. Strategies to improve risk stratification in patients with type 2 diabetes, with or without CVD, should consider incorporation of biomarker data into standard risk algorithms. Trial Registration clinicaltrials.gov Identifier:NCT01107886

Efficacy and safety of edoxaban compared with warfarin in patients with atrial fibrillation and heart failure: insights from ENGAGE AF-TIMI 48.

Abstract: Aims In the ENGAGE AF-TIMI 48 trial, edoxaban, a factor Xa inhibitor, was not found to be inferior to warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with atrial fibrillation (AF) and was associated with significantly less bleeding. The higher-dose edoxaban regimen (HDER; 60 mg dose-reduced to 30 mg once daily) has been approved in various countries in Europe, the USA, and Japan. Among patients treated with vitamin K antagonists (VKAs), symptomatic heart failure (HF) is an independent risk factor for lower time-in-therapeutic range, which reduces the efficacy and safety of VKA therapy. We evaluated the efficacy and safety of edoxaban compared with warfarin across the spectrum of HF severity in the ENGAGE AF-TIMI 48 trial. Methods and results Of 14 071 patients randomized to well-controlled warfarin or the HDER, 5926 (42%) had no history of HF, 6344 (45%) were in New York Heart Association (NYHA) class I–II, and 1801 (13%) were in NYHA class III–IV. The efficacy of edoxaban compared with warfarin in preventing stroke/SEE was similar in patients without and with HF regardless of the severity of HF; [HDER vs. warfarin: No-HF: hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.69–1.11; NYHA class I–II: HR 0.88, 95% CI 0.69–1.12; NYHA class III–IV: HR 0.83, 95% CI 0.55–1.25; Pinteraction = 0.97]. Compared with warfarin, HDER was consistently associated with lower risk of major bleeding (No-HF: HR 0.82, 95% CI 0.68–0.99; NYHA class I–II: HR 0.79, 95% CI 0.65–0.96; NYHA class III–IV: HR 0.79, 95% CI 0.54–1.17; Pinteraction = 0.96). Conclusion The relative efficacy and safety of HDER compared with well-managed warfarin in AF patients with HF were similar to those without HF.

Cardiovascular Biomarker Score and Clinical Outcomes in Patients With Atrial Fibrillation: A Subanalysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial.

Abstract: Importance Treatment decisions in atrial fibrillation (AF) are based on clinical assessment of risk. The CHA 2 DS 2 -VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes mellitus, and stroke, transient ischemic attack or thromboembolism [2 points]–vascular disease, and sex category [female]) risk score is pragmatic and widely used but has only moderate discrimination. Objective To develop and test a cardiovascular biomarker score for indication of risk in patients with AF. Design, Setting, and Participants The ENGAGE AF-TIMI 48 trial was a randomized, double-blind, double-dummy clinical trial comparing 2 once-daily edoxaban dose regimens with warfarin in 21 105 patients with AF at moderate to high risk of stroke. This prespecified subanalysis was performed in 4880 patients enrolled at randomization in the biomarker substudy. Cardiac troponin I, N-terminal pro-B-type natriuretic peptide, andd-dimer levels were measured at baseline. A multimarker risk score was developed to determine the probability of stroke, systemic embolic events, or death by assigning tiered points for higher concentrations of the biomarkers. Main Outcomes and Measures Risk score and clinical outcomes based on cardiac troponin I, N-terminal pro-B-type natriuretic peptide, andd-dimer levels at baseline. Results Of the 5002 patients enrolled in the biomarker substudy of the ENGAGE AF-TIMI 48 trial, 4880 patients (97.6%) had all 3 biomarkers available at randomization (1820 [37.3%] were women; median [interquartile range] age, 71 [64-77] years). After adjustment for the CHA 2 DS 2 -VASc score, each biomarker was associated with a 2.8-fold to 4.2-fold gradient of risk comparing the highest vs lowest concentrations across groups of increasing concentrations ( P 2 DS 2 -VASc score. When added to the CHA 2 DS 2 -VASc score, the biomarker score significantly enhanced prognostic accuracy by improving the C statistic from 0.586 (95% CI, 0.565-0.607) to 0.708 (95% CI, 0.688-0.728) ( P P Conclusions and Relevance A prototype multimarker risk score significantly enhanced risk assessment for stroke, systemic embolic events, or death compared with traditional clinical risk stratification. Incorporation of biomarkers into clinical decision making to define therapeutic management in AF warrants consideration. Trial Registration clinicaltrials.gov Identifier:NCT00781391

The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial.

Abstract: Aims To examine the efficacy and safety of ezetimibe added to statin in patients with prior coronary artery bypass graft surgery (CABG) following hospitalization for an acute coronary syndrome (ACS). Methods and results In the IMPROVE-IT trial, post-ACS patients with mean low density lipoprotein cholesterol (LDL-C) of 93.8 mg/dL at presentation were randomized to simvastatin/ezetimibe or simvastatin/placebo. The primary endpoint was cardiovascular death, major coronary event or stroke, and the median follow-up was 6 years. Efficacy and safety endpoints were examined by prior CABG status. Among 18 134 patients, 1684 (9.3%) had a prior CABG (median age 69 years, 82% male). During the trial, the median time-weighted LDL-C level was 55.0 mg/dL with simvastatin/ezetimibe vs. 69.9 mg/dL with simvastatin/placebo in patients with prior CABG ( P < 0.001), and it was 53.6 mg/dL vs. 69.5 mg/dL, respectively, in patients without prior CABG ( P < 0.001). The rate of the primary endpoint was higher in patients with vs. without prior CABG [56% vs. 32%, adj. hazard ratio 1.45, 95% confidence interval (CI) 1.33–1.58]. Patients with prior CABG receiving simvastatin/ezetimibe had an 8.8% (95% CI 3.1–14.6%) lower absolute risk over simvastatin/placebo in the primary endpoint, whereas patients without prior CABG had a 1.3% (95% CI 0–2.6%) lower absolute risk ( P -interaction = 0.02). There were no between-group significant differences in safety endpoints. Conclusion The clinical benefit of adding ezetimibe to statin appears to be enhanced in patients with prior CABG, supporting the use of intensive lipid lowering therapy in these high-risk patients following ACS.

Sudden Cardiac Death in Patients With Atrial Fibrillation: Insights From the ENGAGE AF-TIMI 48 Trial.

Abstract: Background Recent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation. Methods and Results SCD was defined as witnessed death ≤60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient‐years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction ( P <0.001 for each). Additional significant baseline predictors of SCD, but not of other causes of death, included male sex, electrocardiographic left ventricular hypertrophy, higher heart rate, nonuse of beta blockers, and use of digitalis. The latter was associated with SCD in patients with or without heart failure (adjusted hazard ratio 1.55 [95% CI 1.29–1.86] and 1.56 [95% CI 1.14–2.11], respectively; P interaction=0.73). The rate of SCD was numerically but not statistically lower with edoxaban (1.20% per year with lower dose edoxaban; 1.28% per year with higher dose edoxaban) compared with warfarin (1.40% per year). Conclusion SCD is the most common cause of cardiovascular death in patients with atrial fibrillation and has several distinct predictors, some of which are modifiable. These findings may be considered in planning research and treatment strategies for patients with atrial fibrillation. Clinical Trial Registration URL: . Unique identifier: NCT00781391.

Sharing Data from Cardiovascular Clinical Trials--A Proposal.

Abstract: n engl j med 375;5 nejm.org August 4, 2016 portunity to conduct confirmatory analyses before publication of an article, thereby advancing the ICMJE’s stated goal of increasing “confidence and trust in the conclusions drawn from clinical trials.” Finally, persons who were not involved in an investigator-initiated trial but want access to the data should financially compensate the original investigators for their efforts and investments in the trial and the costs of making the data available.

Oral Iron Therapy for Heart Failure With Reduced Ejection Fraction: Design and Rationale for Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure

Abstract: Iron deficiency is present in ≈50% of patients with heart failure and is an independent predictor of mortality. Despite growing recognition of the functional and prognostic significance of iron deficiency, randomized multicenter trials exploring the use of oral iron supplementation in heart failure, a therapy that is inexpensive, readily available, and safe, have not been performed. Moreover, patient characteristics that influence responsiveness to oral iron in patients with heart failure have not been defined. Although results of intravenous iron repletion trials have been promising, regularly treating patients with intravenous iron products is both expensive and poses logistical challenges for outpatients. Herein, we describe the rationale for the Oral Iron Repletion effects on Oxygen Uptake in Heart Failure (IRONOUT HF) trial. This National Institute of Health-sponsored trial will investigate oral iron polysaccharide compared with matching placebo with the primary end point of change in exercise capacity as measured by peak oxygen consumption at baseline and at 16 weeks. Clinical Trial Registration— URL: . Unique identifier: [NCT02188784][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02188784&atom=%2Fcirchf%2F9%2F5%2Fe000345.atom

Prevalence, Profile, and Prognosis of Severe Obesity in Contemporary Hospitalized Heart Failure Trial Populations

Abstract: Objectives This study evaluated the prevalence, profile, and prognosis of severe obesity in a large contemporary acute heart failure (AHF) population. Background Better prognosis has been reported for obese heart failure (HF) patients than nonobese HF patients, but in other cardiovascular populations, this effect has not been demonstrated for severely obese patients. Methods A cohort of 795 participants with body mass index (BMI) measured at time of admission and complete follow-up were identified from enrollment in 3 contemporary AHF trials (DOSE [Diuretic Strategies Optimization Evaluation], CARRESS-HF [Cardiorenal Rescue Study in Acute Decompensated Heart Failure], and ROSE [Renal Optimization Strategies Evaluation in Acute Heart Failure]). Patients were divided into 4 BMI categories according to standard World Health Organization criteria, as follows: normal weight: 18.5 to 25 kg/m 2 [n = 128]; overweight: 25 to 29.9 kg/m 2 [n = 209]; mild-to-moderate obese: 30 to 39.9 kg/m 2 [n = 301]; and severely obese: ≥40 kg/m 2 [n = 157]). The relationship between BMI and 60-day composite outcome (death, rehospitalization, or unscheduled provider visit) was investigated. Results Patients with severe obesity (19.7%) were younger, more often female, hypertensive, diabetic, and more likely to have higher blood pressures and left ventricular ejection fraction, and lower N-terminal pro-B-type natriuretic peptide and troponin I levels than other BMI category patients. Following admission for AHF, patients with normal weight showed the highest risk of 60-day composite outcome, followed by patients who were severely obese. Overweight and mild-moderately obese patients showed lowest risk. Conclusions Nearly one-fifth of AHF patients enrolled in contemporary randomized clinical trials are severely obese. A U-shaped curve for short-term prognosis according to BMI is seen in AHF. These findings may help to better inform both HF clinical care and future clinical trial planning.

Prevention of Stroke with Ticagrelor in Patients with Prior Myocardial Infarction: Insights from PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54).

Abstract: BACKGROUND: In the PEGASUS-TIMI 54 trial (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54), ticagrelor reduced the risk of major adverse cardiovascular events when added to low-dose aspirin in stable patients with prior myocardial infarction, resulting in the approval of ticagrelor 60 mg twice daily for long-term secondary prevention. We investigated the incidence of stroke, outcomes after stroke, and the efficacy of ticagrelor focusing on the approved 60 mg twice daily dose for reducing stroke in this population. METHODS: Patients were followed for a median of 33 months. Stroke events were adjudicated by a central committee. Data from similar trials were combined using meta-analysis. RESULTS: Of 14 112 patients randomly assigned to placebo or ticagrelor 60 mg, 213 experienced a stroke; 85% of these strokes were ischemic. A total of 18% of strokes were fatal and another 15% led to either moderate or severe disability at 30 days. Ticagrelor significantly reduced the risk of stroke (hazard ratio, 0.75; 95% confidence interval, 0.57-0.98; P=0.034), driven by a reduction in ischemic stroke (hazard ratio, 0.76; 95% confidence interval, 0.56-1.02). Hemorrhagic stroke occurred in 9 patients on placebo and 8 patients on ticagrelor. A meta-analysis across 4 placebo-controlled trials of more intensive antiplatelet therapy in 44 816 patients with coronary disease confirmed a marked reduction in ischemic stroke (hazard ratio, 0.66; 95% confidence interval, 0.54-0.81; P=0.0001). CONCLUSIONS: High-risk patients with prior myocardial infarction are at risk for stroke, approximately one-third of which are fatal or lead to moderate-to-severe disability. The addition of ticagrelor 60 mg twice daily significantly reduced this risk without an excess of hemorrhagic stroke but with more major bleeding. In high-risk patients with coronary disease, more intensive antiplatelet therapy should be considered not only to reduce the risk of coronary events, but also of stroke.

Peripheral Revascularization in Patients With Peripheral Artery Disease With Vorapaxar: Insights From the TRA 2°P-TIMI 50 Trial.

Abstract: Objectives The aim of this study was to determine whether the reduction in peripheral revascularization with vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both Background The protease-activated receptor–1 antagonist vorapaxar reduces peripheral revascularization in patients with PAD Methods The TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to vorapaxar or placebo on a background of standard therapy A total of 5,845 patients had a known history of PAD at randomization Peripheral revascularization procedures reported by the site were a pre-specified outcome We explored whether the benefit of vorapaxar was consistent across indication and type of procedure Results Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 25 years (median) More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%) Vorapaxar significantly reduced peripheral revascularization (193% for placebo, 154% for vorapaxar; hazard ratio: 082; 95% confidence interval: 072 to 093; p = 0003), with a consistent pattern of efficacy across indication Conclusions Vorapaxar reduces peripheral revascularization in patients with PAD This benefit of vorapaxar is directionally consistent across type of procedure and indication (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P - TIMI 50] [P04737]; NCT00526474)

The Prognostic Significance of Cardiac Structure and Function in Atrial Fibrillation: The ENGAGE AF–TIMI 48 Echocardiographic Substudy

Abstract: Background Atrial fibrillation (AF) is associated with increased risk for thromboembolism and death; however, the relationships between cardiac structure and function and adverse outcomes among individuals with AF are incompletely understood. Methods The Effective Anticoagulation with Factor Xa Next Generation in AF–Thrombolysis in Myocardial Infarction 48 study tested the once-daily oral factor Xa inhibitor edoxaban in comparison with warfarin for the prevention of stroke (ischemic or hemorrhagic) or systemic embolism in 21,105 subjects with nonvalvular AF and increased risk for thromboembolic events (CHADS 2 score ≥ 2). In a prospective substudy of 971 subjects who underwent transthoracic echocardiography at baseline, Cox proportional hazards models were used to evaluate associations between cardiac structure and function and the risks for death and thromboembolism (ischemic stroke, transient ischemic attack, or systemic embolism). Results Over a median follow-up period of 2.5 years, 89 deaths (9.2%) and 48 incident thromboembolic events (4.9%) occurred in 971 subjects. In models adjusted for CHADS 2 score, aspirin use, and randomized treatment, larger left ventricular (LV) end-diastolic volume index (hazard ratio per 1 SD [12.9 mL/m 2 ], 1.49; 95% CI, 1.16–1.91) and higher LV filling pressures measured by E/e′ ratio (hazard ratio per 1 SD [4.6], 1.32; 95% CI, 1.08–1.61) were independently associated with increased risks for death. E/e′ ratio > 13 significantly improved the prediction of death beyond clinical factors alone. No features of cardiac structure and function were independently associated with thromboembolism in this population. Findings were similar when adjusted for CHA 2 DS 2 -VASc score in place of CHADS 2 score. Conclusions In a contemporary population of patients with AF at increased risk for thromboembolic events, larger LV size and higher filling pressures were significantly associated with increased risk for death, but neither left atrial nor LV measures were associated with thromboembolic risk. LV size and filling pressures may help identify patients with AF at increased risk for death.