Showing papers by "Eugene Braunwald published in 2018"
TL;DR: Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity.
Abstract: Importance There are few effective treatments for heart failure with preserved ejection fraction (HFpEF). Short-term administration of inorganic nitrite or nitrate preparations has been shown to enhance nitric oxide signaling, which may improve aerobic capacity in HFpEF. Objective To determine the effect of 4 weeks’ administration of inhaled, nebulized inorganic nitrite on exercise capacity in HFpEF. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled, 2-treatment, crossover trial of 105 patients with HFpEF. Participants were enrolled from July 22, 2016, to September 12, 2017, at 17 US sites, with final date of follow-up of January 2, 2018. Interventions Inorganic nitrite or placebo administered via micronebulizer device. During each 6-week phase of the crossover study, participants received no study drug for 2 weeks (baseline/washout) followed by study drug (nitrite or placebo) at 46 mg 3 times a day for 1 week followed by 80 mg 3 times a day for 3 weeks. Main Outcomes and Measures The primary end point was peak oxygen consumption (mL/kg/min). Secondary end points included daily activity levels assessed by accelerometry, health status as assessed by the Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores reflecting better quality of life), functional class, cardiac filling pressures assessed by echocardiography, N-terminal fragment of the prohormone brain natriuretic peptide levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks. Results Among 105 patients who were randomized (median age, 68 years; 56% women), 98 (93%) completed the trial. During the nitrite phase, there was no significant difference in mean peak oxygen consumption as compared with the placebo phase (13.5 vs 13.7 mL/kg/min; difference, −0.20 [95% CI, −0.56 to 0.16];P = .27). There were no significant between–treatment phase differences in daily activity levels (5497 vs 5503 accelerometry units; difference, −15 [95% CI, −264 to 234];P = .91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs 61.9; difference, 1.1 [95% CI, −1.4 to 3.5];P = .39), functional class (2.5 vs 2.5; difference, 0.1 [95% CI, −0.1 to 0.2];P = .43), echocardiographic E/e′ ratio (16.4 vs 16.6; difference, 0.1 [95% CI, −1.2 to 1.3];P = .93), or N-terminal fragment of the prohormone brain natriuretic peptide levels (520 vs 533 pg/mL; difference, 11 [95% CI, −53 to 75];P = .74). Worsening heart failure occurred in 3 participants (2.9%) during the nitrite phase and 8 (7.6%) during the placebo phase. Conclusions and Relevance Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity. Trial Registration ClinicalTrials.gov Identifier:NCT02742129
184 citations
TL;DR: Selective use of bedside ultrasound (or insonation) can be one such strategy that could be incorporated as the fifth component of the physical examination.
Abstract: Inspection, palpation, percussion, and auscultation have been the 4 pillars of clinical bedside medicine. Although these basic methods of physical examination have served us well, traditional bedside examination, for a number of reasons including diminishing interest and expertise, performs well less than what is required of a modern diagnostic strategy. Improving the performance of physical examination is vital given that it is crucial to guide diagnostic possibilities and further testing. Current efforts at improving physical examination skills during medical training have not been very successful, and incorporating appropriate technology at the bedside might improve its performance. Selective use of bedside ultrasound (or insonation) can be one such strategy that could be incorporated as the fifth component of the physical examination. Seeing pathology through imaging might improve interest in physical examination among trainees, and permit appropriate downstream testing and possibly superior decision making. Current ultrasound technology makes this feasible, and further miniaturization of ultrasound devices and reduced cost will allow for routine use at the bedside. It is time to have a wider debate and a possible consensus about updates required to enhance current paradigms of physical examination.
173 citations
TL;DR: Known and possible mechanisms that contribute to the salutary effects of SGLT2is are summarized and the interplay between cardiac and renal function, as well as safety issues associated with this class of drugs are discussed.
172 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
TL;DR: The benefit of ezetimibe is consistent in patients with and without polyvascular disease and type 2 diabetes; however, by nature of their higher risk patients with one, or especially both, of these diseases might derive the greatest absolute benefits.
85 citations
TL;DR: The PIONEER‐HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in‐hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF.
60 citations
TL;DR: A comprehensive review of the use of cell therapy for cardiac regeneration can be found in the Compendium by Banarjee, Bolli, and Hare as mentioned in this paper, where important observations have led to more questions and challenges.
Abstract: Although pioneering preclinical research on the use of cell therapy for cardiac regeneration was conducted in the last quarter of the 20th century,1,2 a preponderance of advances have occurred in the 21st century, making this a relatively young field. In the first important clinical trial of cardiac cell therapy, begun in 2001, Menasche et al3 implanted autologous skeletal myoblasts into postinfarct scar at the time of coronary artery bypass surgery. Although the transplanted cells remained viable and exhibited contraction, they formed the nidus for serious ventricular tachyarrhythmias, which led to premature discontinuation of the trial. Despite this outcome, the trial energized the field, accelerating both preclinical and clinical research, albeit not with skeletal myoblasts. The extensive progress in cardiac regeneration is reviewed in this Compendium, and as occurs frequently in science, important observations have led to more questions and challenges (Table).
View this table:
Table.
Important Challenges to Cell Therapy for Cardiac Regeneration
Many cell types have been evaluated as candidates for cardiac regeneration. Among the earliest clinical trials, Zeiher’s group infused autologous bone marrow-derived progenitor cells into the coronary arteries of patients with acute,4 as well as healed myocardial infarction (MI)5 and reported improvements in left ventricular (LV) function. However, these results have not been fully confirmed by later studies, as pointed out in the review in the Compendium by Banarjee, Bolli, and Hare.6
Pittenger et al7 were among the first to direct attention to bone marrow-derived (stromal) mesenchymal stem cells (MSCs), emphasizing that these cells proliferated extensively in culture and suggesting that they could be attractive candidates for transplantation. In 2004, Chen et al8 reported that intracoronary infusion of autologous bone marrow-derived MSCs improved cardiac function. Zimmet and Hare pointed out that MSCs lack histocompatibility type II markers and elude rejection by …
56 citations
TL;DR: Patients with prior myocardial infarction and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD.
55 citations
TL;DR: During the late 1950s and most of the 1960s, Dr John Ross and I led the busy clinical cardiology program then existing at the Clinical Center of the National Institutes of Health, where the assessment and surgical treatment of severe aortic stenosis in adults were both undergoing rapid changes.
Abstract: During the late 1950s and most of the 1960s, Dr John Ross and I led the busy clinical cardiology program then existing at the Clinical Center of the National Institutes of Health. During this period, the assessment and surgical treatment of severe aortic stenosis (AS) in adults, predominantly rheumatic in origin, were both undergoing rapid changes. In the 1950s, before open heart surgery and left-sided heart catheterization were available, after thoracotomy dilators were inserted through a ventriculotomy, and severely obstructed aortic valves were "blindly" opened. 1 The selection of patients for this operation was difficult. Dr Paul Wood, Director of the National Heart Institute in London, who was considered by many to be the world9s leading clinical cardiologist of the era,
wrote: "At the present time aortic valvotomy is too hazardous and too crude an operation to advise when it is most desirable (just before the onset of symptoms) and frequently too late when impending disaster makes it imperative." 2
35 citations
TL;DR: In patients stabilized after ACS, elevated FGF-23 concentrations may be associated with recurrent major CV events and all-cause mortality, providing information independent of established clinical risk factors and cardiorenal biomarkers.
Abstract: Importance Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with myocardial fibrosis and renin-angiotensin system upregulation, potentially providing prognostic information distinct from standard cardiovascular (CV) biomarkers. Objective To evaluate the association of FGF-23 with recurrent CV events in patients after an acute coronary syndrome (ACS). Design, Setting, and Participants C-terminal FGF-23 was measured in plasma samples using an established enzyme-linked immunosorbent assay system for 4947 patients within 30 days of ACS (median, 14 days) and with 1 additional CV risk factor in the Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) trial of the lipoprotein-associated phospholipase A 2 inhibitor darapladib vs placebo performed from December 1, 2009, to April 24, 2014 (median follow-up, 2.5 years). Analyses were adjusted for clinical risk factors, renal function, and established cardiorenal biomarkers. This secondary analysis was performed from September 25, 2014, to October 1, 2017. Exposure The FGF-23 concentration at baseline. Main Outcomes and Measures The primary end point for this post hoc analysis was the composite of CV death or hospitalization for heart failure. Results In this study, baseline FGF-23 concentrations were available for 4947 patients (median age, 64.0 years; interquartile range, 59.0-71.0 years; 1276 [25.8%] female). Patients with higher FGF-23 concentrations were older and more likely female, with a greater proportion of hypertension, diabetes, and previous myocardial infarction. After multivariable adjustment for baseline clinical characteristics and established biomarkers (high-sensitivity troponin I, brain-type natriuretic peptide, and high-sensitivity C-reactive protein), FGF-23 concentration in the top quartile was independently associated with an increased risk of CV death or heart failure hospitalization (adjusted hazard ratio [HR], 2.35; 95% CI, 1.82-3.02; P P P P = .67) compared with men (HR, 3.11; 95% CI, 2.29-4.22; P P Conclusions and Relevance In patients stabilized after ACS, elevated FGF-23 concentrations may be associated with recurrent major CV events and all-cause mortality, providing information independent of established clinical risk factors and cardiorenal biomarkers. A potential sex difference in these findings deserves further study.
33 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.
TL;DR: Cys‐C is associated with the risk of adverse outcomes in patients after acute coronary syndrome, independent of established and novel biomarkers of the cardiorenal axis.
Abstract: Background Cystatin C (Cys‐C) is a marker of renal function that has shown prognostic value for cardiovascular risk stratification across different patient populations. The incremental value of Cys...
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...
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.
TL;DR: High‐sensitivity troponin I levels are commonly elevated among both hospitalized and ambulatory patients with HFpEF and are associated with worse cardiac structure and increased risk of adverse events.
Abstract: Background We sought to study the prevalence of high‐sensitivity troponin and its association with cardiac structure and outcomes in ambulatory and hospitalized patients with heart failure with a p...
TL;DR: This study will compare ART-treated virally suppressed HIV-infected individuals with and without DD and HIV- individuals with DD regarding systemic inflammation, myocardial stress, and subclinicalMyocardial necrosis as indicated by circulating biomarkers.
Duke University1, Durham University2, Beth Israel Deaconess Medical Center3, Brigham and Women's Hospital4, University of Alberta5, Katholieke Universiteit Leuven6, University of Paris7, University of Kentucky8, Uppsala University9, Flinders University10, Stanford University11, Auckland City Hospital12
TL;DR: The third universal definition of MI and the SCAI definition were both associated with significant risk for mortality at 1 year and suboptimal concordance was observed between ACL and local investigators in identifying patients with PCI complications detected on angiography.
Abstract: Objectives In 13,038 patients with non–ST-segment elevation acute coronary syndrome undergoing index percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) and TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trials, the relationship between PCI-related myocardial infarction (MI) and 1-year mortality was assessed. Background The definition of PCI-related MI is controversial. The third universal definition of PCI-related MI requires cardiac troponin >5 times the 99th percentile of the normal reference limit from a stable or falling baseline and PCI-related clinical or angiographic complications. The definition from the Society for Cardiovascular Angiography and Interventions (SCAI) requires creatine kinase–MB elevation >10 times the upper limit of normal (or 5 times if new electrocardiographic Q waves are present). Implications of these definitions on prognosis, prevalence, and implementation are not established. Methods In our cohort of patients undergoing PCI, PCI-related MIs were classified using the third universal type 4a MI definition and SCAI criteria. In the subgroup of patients included in the angiographic core laboratory (ACL) substudy of EARLY ACS (n = 1,401) local investigator– versus ACL-reported angiographic complications were compared. Results Altogether, 2.0% of patients met third universal definition of PCI-related MI criteria, and 1.2% met SCAI criteria. One-year mortality was 3.3% with the third universal definition (hazard ratio: 1.96; 95% confidence interval: 1.24 to 3.10) and 5.3% with SCAI criteria (hazard ratio: 2.79; 95% confidence interval: 1.69 to 4.58; p Conclusions The third universal definition of MI and the SCAI definition were both associated with significant risk for mortality at 1 year. Suboptimal concordance was observed between ACL and local investigators in identifying patients with PCI complications detected on angiography. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRA·CER] [Study P04736]; NCT00527943; EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome [Study P03684AM2]; NCT00089895)
TL;DR: After acute coronary syndrome, diabetes is a strong and independent predictor of adverse outcomes and assessment of the metabolic syndrome provides only marginal incremental value once the presence or absence of diabetes is established.
Abstract: BackgroundThe incremental prognostic value of assessing the metabolic syndrome has been disputed. Little is known regarding its prognostic value in patients after an acute coronary syndrome.Design ...
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.
TL;DR: In ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding.
Abstract: Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study.
TL;DR: Elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban wasassociated with lower D-Dimer levels compared with placebo after the first dose.
Abstract: D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.
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.
TL;DR: Both fatal or irreversible ischemia and bleeding are clinically significant events that can be compared to assess the net clinical outcomes associated with therapy, and Rivaroxaban therapy at an oral dose of 2.5 mg twice daily in patients treated with aspirin and clopidogrel is associated with a net reduction in fatal or reversible events.
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.
TL;DR: Ticagrelor as mentioned in this paper reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUS-TIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Compared to Placebo on a Background of Aspirin).
Abstract: Background Ticagrelor reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUS-TIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). MI can occur in diverse settings and with varying severity; therefore, understanding the types and sizes of MI events prevented is of clinical importance. Methods and Results MIs were adjudicated by a blinded clinical events committee and categorized by subtype and fold elevation of peak cardiac troponin over the upper limit of normal. A total of 1042 MIs occurred in 898 of the 21 162 randomized patients over a median follow-up of 33 months. The majority of the MIs (76%) were spontaneous (Type 1), with demand MI (Type 2) and stent thrombosis (Type 4b) accounting for 13% and 9%, respectively; sudden death (Type 3), percutaneous coronary intervention-related (Type 4a) and coronary artery bypass graft-related (Type 5) each accounted for <1%. Half of MIs (520, 50%) had a peak troponin ≥10x upper limit of normal and 21% of MIs (220) had a peak troponin ≥100× upper limit of normal. A total of 21% (224) were ST-segment-elevation MI STEMI. Overall ticagrelor reduced MI (4.47% versus 5.25%, hazard ratio 0.83, 95% confidence interval 0.72-0.95, P=0.0055). The benefit was consistent among the subtypes, including a 31% reduction in MIs with a peak troponin ≥100× upper limit of normal (hazard ratio 0.69, 95% confidence interval 0.53-0.92, P=0.0096) and a 40% reduction in ST-segment elevation MI (hazard ratio 0.60, 95% confidence interval 0.46-0.78, P=0.0002). Conclusions In stable outpatients with prior MI, the majority of recurrent MIs are spontaneous and associated with a high biomarker elevation. Ticagrelor reduces the MI consistently among subtypes and sizes including large MIs and ST-segment elevation MI. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01225562.
TL;DR: The author continued Cournand's work on heart failure by developing techniques to measure ventricular function in patients and to describe the neurohumoral changes that occur in human heart failure.
Abstract: In 1954–1955, the author served as a research fellow in the cardiopulmonary laboratory led by Andre Cournand at Bellevue Hospital in New York. Cournand was a pulmonary physiologist and a professor of medicine at Columbia University. In his quest to obtain mixed venous blood to calculate pulmonary blood flow, he catheterized the right atrium, right ventricle, and pulmonary artery in patients and also measured the pressures in these chambers. Cournand and his collaborators soon appreciated the enormous potential of cardiac catheterization in deepening the understanding of cardiovascular pathophysiology. After a series of groundbreaking studies, Cournand and his coworker Dickinson Richards, as well as German physician Werner Forssmann, were awarded a Nobel Prize in 1956. Cournand’s laboratory, his work habits, and his rigorous approach to science are described, as well as the stimulation the author received during the author’s fellowship. As a result, the author went on to extend to the left side of the hear...
TL;DR: Persistent elevation of thrombin following brain ischemia may account, at least in part, for the adverse sequelae among patients who sustain a stroke.
TL;DR: Patients hospitalized for ACS with pre-existing or de novo HF were older and had a greater burden of medical co-morbidities, and HF was independently associated with increased risk of long-term morbidity and mortality with the pre- existing HF cohort demonstrating the highest overall risk.
Abstract: The natural history of patients hospitalized for acute coronary syndrome (ACS) with pre-existing versus (vs) de novo heart failure (HF) has not been previously reported over an extended duration of follow-up. The IMPROVE-IT trial enrolled 18,144 patients hospitalized for ACS and randomized them to combination simvastatin (40 mg)/ezetimibe (10 mg) vs simvastatin (40 mg). Subjects were divided into 3 groups: pre-existing HF (i.e., defined by past medical history), de novo HF (i.e., defined by Killip class II or greater during index admission), and no HF. The final analytical cohort included 14,792 patients (82%) with HF status recorded at baseline. In total, 790 patients (5.3%) reported a pre-existing diagnosis of HF and 1374 patients (9.3%) experienced de novo HF. Patients with pre-existing or de novo HF were older, more likely to be woman, and had a greater prevalence of atrial fibrillation and diabetes mellitus. The incidences of death/HF-hospitalizations at 5 years were 32%/20% for pre-existing HF, 18%/7% for de novo HF, and 8%/3% for no HF. After adjusting for potential confounders, a history of pre-existing or de novo HF was independently associated with increased risk of death (pre-existing HF: hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.68 to 2.22, p < 0.001; de novo HF: HR 1.51, 95% CI 1.33 to 1.72, p < 0.001) and hospitalizations for HF (pre-existing HF: HR 2.96, 95% CI 2.36 to 3.71, p < 0.001; de novo HF: HR 1.88, 95% CI 1.49 to 2.38, p < 0.001). There was no interaction among baseline HF status (i.e., pre-existing or de novo), lipid lowering therapy (i.e., simvastatin/ezetimibe vs simvastatin alone), and clinical outcomes. In conclusion, patients hospitalized for ACS with pre-existing or de novo HF were older and had a greater burden of medical co-morbidities. In conclusion, HF was independently associated with increased risk of long-term morbidity and mortality with the pre-existing HF cohort demonstrating the highest overall risk.
TL;DR: Patients with peripheral artery disease are most suitable for prolongation of therapy with ticagrelor beyond 1 year following a myocardial infarction, from a clinical and health economic perspective.