Showing papers by "Eugene Braunwald published in 2017"
TL;DR: The results do not support use of oral iron supplementation in patients with HFrEF and iron deficiency, and high-dose oral iron did not improve exercise capacity over 16 weeks.
Abstract: Importance Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. Objective To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. Design, Setting, and Participants Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF ( Interventions Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. Main Outcomes and Measures The primary end point was a change in peak oxygen uptake (Vo 2 ) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). Results Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak Vo 2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak Vo 2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs −2 mL/min; difference, 21 mL/min [95% CI, −34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (−13 m; 95% CI, −32 to 6 m), NT-proBNP levels (159; 95% CI, −280 to 599 pg/mL), or KCCQ score (1; 95% CI, −2.4 to 4.4), all P > .05. Conclusions and Relevance Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. Trial Registration clinicaltrials.govIdentifier:NCT02188784
287 citations
TL;DR: In IMPROVE-IT the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk non-diabetics.
Abstract: Background —Ezetimibe, when added to simvastatin, reduces cardiovascular events following acute coronary syndrome (ACS); we explored outcomes stratified by diabetes mellitus (DM). Methods —In IMPROVE-IT, 18,144 patients post ACS with LDL-C 50-125 mg/dL were randomized to ezetimibe/simvastatin-40mg (E/S) or placebo/simvastatin-40mg (P/S). The primary composite endpoint was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup. Results —The 4933 (27%) patients with DM were more often older, female, with prior MI and revascularization, and presented more frequently with non-ST segment elevation ACS compared to non-DM (each p interaction =0.02). The largest relative reductions in DM patients were in MI (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients ≥75 years had a 20% relative reduction in the primary endpoint regardless of DM (P interaction =0.91), while patients interaction =0.011). When stratified by the TIMI risk score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among non-diabetics, patients with a high risk score experienced a significant 18% relative reduction in the composite of cardiovascular death, MI, and ischemic stroke with E/S compared to P/S, whereas non-diabetics at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin (P interaction 0.034). Conclusions —In IMPROVE-IT the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk non-diabetics. Clinical Trial Registration —URL: https://clinicaltrials.gov Unique Identifier: NCT00202878
267 citations
TL;DR: Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR, and the beneficial effect of saxagLIptin on albuminuria could not be explained by its effect on glycemic control.
Abstract: OBJECTIVE Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy. RESEARCH DESIGN AND METHODS We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial. RESULTS At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] 300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P 50 mL/min/body surface area per 1.73 m2 (BSA), −105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and −245.2 mg/g (P = 0.086) for eGFR 6.0 mg/dL, were similar as well. CONCLUSIONS Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control.
206 citations
TL;DR: Adding treatment with high-dose spironolactone to usual care for patients with AHF for 96 hours was well tolerated but did not improve the primary or secondary efficacy end points.
Abstract: Importance Persistent congestion is associated with worse outcomes in acute heart failure (AHF). Mineralocorticoid receptor antagonists administered at high doses may relieve congestion, overcome diuretic resistance, and mitigate the effects of adverse neurohormonal activation in AHF. Objective To assess the effect of high-dose spironolactone and usual care on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared with usual care alone. Design, Setting, and Participants This double-blind and placebo (or low-dose)-controlled randomized clinical trial was conducted in 22 US acute care hospitals among patients with AHF who were previously receiving no or low-dose (12.5 mg or 25 mg daily) spironolactone and had NT-proBNP levels of 1000 pg/mL or more or B-type natriuretic peptide levels of 250 pg/mL or more, regardless of ejection fraction. Interventions High-dose spironolactone (100 mg) vs placebo or 25 mg spironolactone (usual care) daily for 96 hours Main Outcomes and Measures The primary end point was the change in NT-proBNP levels from baseline to 96 hours. Secondary end points included the clinical congestion score, dyspnea assessment, net urine output, and net weight change. Safety end points included hyperkalemia and changes in renal function. Results A total of 360 patients were randomized, of whom the median age was 65 years, 129 (36%) were women, 200 (55.5%) were white, 151 (42%) were black, 8 (2%) were Hispanic or Latino, 9 (2.5%) were of other race/ethnicity, and the median left ventricular ejection fraction was 34%. Baseline median (interquartile range) NT-proBNP levels were 4601 (2697-9596) pg/mL among the group treated with high-dose spironolactone and 3753 (1968-7633) pg/mL among the group who received usual care. There was no significant difference in the log NT-proBNP reduction between the 2 groups (−0.55 [95% CI, −0.92 to −0.18] with high-dose spironolactone and −0.49 [95% CI, −0.98 to −0.14] with usual care, P = .57). None of the secondary end point or day-30 all-cause mortality or heart failure hospitalization rate differed between the 2 groups. The changes in serum potassium and estimated glomerular filtration rate at 24, 48, 72, and 96 hours. were similar between the 2 groups. Conclusions and Relevance Adding treatment with high-dose spironolactone to usual care for patients with AHF for 96 hours was well tolerated but did not improve the primary or secondary efficacy end points. Trial Registration clinicaltrials.gov Identifier:NCT02235077
171 citations
TL;DR: The hypothesis that atherothrombotic risk stratification may be useful to identify post-ACS patients who have the greatest potential for benefit from the addition of ezetimibe to statin therapy is tested.
147 citations
TL;DR: Analysis of outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial provided reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-Cs.
Abstract: Importance In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, intensive low-density lipoprotein cholesterol (LDL-C)–reducing therapy with ezetimibe/simvastatin compared with simvastatin alone was associated with a significant reduction in cardiovascular events in 18 144 patients after acute coronary syndrome. The safety of very low LDL-C levels over the long-term is unknown. Objective To assess the safety and clinical efficacy of achieving a very low ( Design, Setting, and Participants This prespecified analysis compared outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial and adjusted for baseline characteristics during 6 years’ median follow-up. Patients were enrolled from October 26, 2005, to July 8, 2010, and the data analysis was conducted from December 2014 to February 2017. Main Outcomes and Measures Safety end points included adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death. Efficacy events were as specified in the overall trial. Results Among the 15 281 patients included in the study, 11 645 (76.2%) were men and the median age was 63 years (interquartile range, 56.6-70.7 years). In these patients without an event in the first month, the achieved LDL-C values at 1 month were less than 30 mg/dL, 30 to 49 mg/dL, 50 to 69 mg/dL, and 70 mg/dL or greater in 6.4%, 31%, 36%, and 26% of patients, respectively. Patients with LDL-C values less than 30 mg/dL (median, 25 mg/dL; interquartile range, 21-27 mg/dL) at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a first myocardial infarction. After multivariate adjustment, there was no significant association between the achieved LDL-C level and any of the 9 prespecified safety events. The adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was significantly lower in patients achieving an LDL-C level less than 30 mg/dL at 1 month (adjusted hazard ratio, 0.79; 95% CI, 0.69-0.91; P = .001) compared with 70 mg/dL or greater. Conclusions and Relevance Patients achieving an LDL-C level less than 30 mg/dL at 1 month had a similar safety profile (and numerically the lowest rate of cardiovascular events) over a 6-year period compared with patients achieving higher LDL-C concentrations. These data provide reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-C levels. Trial Registration clinicaltrials.gov Identifier:NCT00202878
136 citations
TL;DR: Patients with paroxysmal AF suffered fewer thromboembolic events and deaths compared with those with persistent and permanent AF, and the efficacy and safety profile of edoxaban as compared with warfarin was consistent across the 3 patterns of AF.
Abstract: Background— Whether the pattern of atrial fibrillation (AF) modifies the risk/benefit of anticoagulation is controversial. In ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48), the factor Xa inhibitor edoxaban was noninferior to warfarin in preventing stroke or systemic embolic events and significantly reduced bleeding and cardiovascular mortality. However, detailed analyses by AF pattern have not been reported. Methods and Results— The 21 105 patients were categorized as having paroxysmal ( P -adj =0.015) and permanent AF (1.95%/year; P -adj =0.004). Overall, all-cause mortality also was lower with paroxysmal (3.0%/year) compared with persistent (4.4%/year; P -adj P -adj Conclusions— In ENGAGE AF-TIMI 48 trial, patients with paroxysmal AF suffered fewer thromboembolic events and deaths compared with those with persistent and permanent AF. The efficacy and safety profile of edoxaban as compared with warfarin was consistent across the 3 patterns of AF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
126 citations
TL;DR: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke.
Abstract: Background —Patients who experience an acute coronary syndrome (ACS) are at heightened risk of recurrent ischemic events, including stroke Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after ACS We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT, with a focus on patients with a stroke prior to randomization Methods —Post-ACS patients were randomized to placebo/simvastatin or ezetimibe/simvastatin and followed for a median of 6 years Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the endpoints of stroke of any etiology, stroke subtypes, and the primary trial endpoint at 7 years Results —Of 18,144 patients, 641 (35%) experienced at least one stroke; most were ischemic (527, 82%) Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes, MI, and renal dysfunction There was a non-significant reduction in the first event of stroke of any etiology (42% vs 48%; HR 086, 073-100; p=0052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (34% vs 41%; HR 079, 067-094; p=0008) and a non-significant increase in hemorrhagic stroke (08% vs 06%; HR 138, 093-204; p=011) Evaluating total events, including the first stroke and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR 083, 070-098; p=0029) and ischemic stroke (HR 076, 063-091; p=0003) Patients who had experienced a stroke prior to randomization were at higher risk of recurrence and demonstrated an absolute risk reduction of 86% for stroke of any etiology (102% vs 188%; NNT=12; HR 060, 038-095; p=0030) and 76% for ischemic stroke (87% vs 163%; NNT=13; HR 052, 031-086; p=0011) with ezetimibe added to simvastatin therapy Conclusions —The addition of ezetimibe to simvastatin in patients stabilized after ACS reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke Clinical Trial Registration —URL: http://wwwclinicaltrialsgov Unique Identifier: NCT00202878
98 citations
TL;DR: The presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF.
92 citations
TL;DR: In this compendium, some of the most important advances in this field are reviewed and scientific opportunities to enhance further collaborative research to accelerate progress are identified.
Abstract: The nonischemic cardiomyopathies are a diverse group of cardiac disorders that frequently cause heart failure and death and are now recognized with increasing frequency. There has been substantial progress in the clinical recognition and understanding of the natural history of these conditions. Well-established and new techniques of cardiac imaging are also helpful in this regard. Basic scientists are elucidating the pathogenesis and pathobiology of individual cardiomyopathies. In this compendium, some of the most important advances in this field are reviewed. Scientific opportunities to enhance further collaborative research to accelerate progress are identified.
87 citations
TL;DR: In patients after ACS, IL‐6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers, lending support to the concept of IL‐ 6 as a potential therapeutic target in patients with unstable ischemic heart disease.
Abstract: BackgroundInterleukin‐6 (IL‐6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome (ACS). We aimed to evaluate the prognostic implications of IL‐6 post‐ACS. Meth...
TL;DR: In patients with type 2 diabetes, UACR was independently associated with increased risk for a spectrum of adverse cardiovascular outcomes, however, the incremental cardiovascular prognostic value of UacR was minimal when evaluated together with contemporary cardiac biomarkers.
Abstract: Importance An elevated level of urinary albumin to creatinine ratio (UACR) is a marker of renal dysfunction and predictor of kidney failure/death in patients with type 2 diabetes. The prognostic use of UACR in established cardiac biomarkers is not well described. Objective To evaluate whether UACR offers incremental prognostic benefit beyond risk factors and established plasma cardiovascular biomarkers. Design, Setting, and Participants The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 study was performed from May 2010 to May 2013 and evaluated the safety of saxagliptin vs placebo in patients with type 2 diabetes with overt cardiovascular disease or multiple risk factors. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years). Interventions Patients were randomized to saxagliptin vs placebo plus standard care. Main Outcomes and Measures Baseline UACR was measured in 15 760 patients (95.6% of the trial population) and categorized into thresholds. Results Of 15 760 patients, 5205 were female (33.0%). The distribution of UARC categories were: 5805 patients (36.8%) less than 10 mg/g, 3891 patients (24.7%) at 10 to 30 mg/g, 4426 patients (28.1%) at 30 to 300 mg/g, and 1638 patients (10.4%) at more than 300 mg/g. When evaluated without cardiac biomarkers, there was a stepwise increase with each higher UACR category in the incidence of the primary composite end point (cardiovascular death, myocardial infarction, or ischemic stroke) (3.9%, 6.9%, 9.2%, and 14.3%); cardiovascular death (1.4%, 2.6%, 4.1%, and 6.9%); and hospitalization for heart failure (1.5%, 2.5%, 4.0%, and 8.3%) (adjustedP Conclusions and Relevance In patients with type 2 diabetes, UACR was independently associated with increased risk for a spectrum of adverse cardiovascular outcomes. However, the incremental cardiovascular prognostic value of UACR was minimal when evaluated together with contemporary cardiac biomarkers. Trial Registration clinicaltrials.gov Identifier:NCT01107886
TL;DR: The efficacy of low-dose ticagrelor is consistent over time with a trend toward less excess bleeding, and patients with a history of MI remain at persistent high risk for CVD, MI, and stroke as late as 5 years after MI.
TL;DR: In HFpEF, sST2 levels were associated with proinflammatory comorbidities, right ventricular pressure overload and dysfunction, and systemic congestion but not with left ventricular geometry or function, suggesting that ST2 may be a marker of systemic inflammation inHFpEF and potentially of extracardiac origin.
Abstract: BackgroundSoluble ST2 is a biomarker that is elevated in certain systemic inflammatory diseases. Comorbidity‐driven microvascular inflammation is postulated to play a key role in heart failure with...
TL;DR: It is demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipid‐lowering therapy to optimize cardiovascular outcomes.
Abstract: BackgroundIMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in pat...
TL;DR: The rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, is presented.
Abstract: Approximately half of patients with heart failure have preserved ejection fraction. There is no proven treatment that improves outcome. The pathophysiology of heart failure with preserved ejection fraction is complex and includes left ventricular systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide (NO)-cGMP bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidosis conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when left ventricular filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the National Heart, Lung, and Blood Institute–sponsored Heart Failure Clinical Research Network.
Clinical Trial Registration URL: . Unique identifier: [NCT02742129][1].
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02742129&atom=%2Fcirchf%2F10%2F5%2Fe003862.atom
TL;DR: In randomized trials, the efficacy and safety of the potent P2Y12 inhibitors were comparable between men and women, and sex should not influence patient selection for the administration of potent P3y12 inhibitors.
TL;DR: Daily activity is a measure of HF-related and global functional status in HF with preserved ejection fraction and as compared with intermittently assessed standard HF assessments, change in daily activity may provide unique information about the impact of HF interventions on functional status.
Abstract: Background—Daily physical activity assessed by accelerometers represents a novel method to assess the impact of interventions on heart failure (HF) patients’ functional status. We hypothesized that...
TL;DR: The VANISH trial is testing the safety and feasibility of disease‐modifying therapy with an ARB in genotyped HCM patients with early disease, and those at risk for its development.
TL;DR: In VKA naive patients with AF, the TIMI-AF score can assist in the prediction of a poor composite outcome and guide selection of anticoagulant therapy by identifying a differential clinical benefit with a NOAC or VKA.
Abstract: Aims The choice between initiating a non-vitamin K antagonist oral anticoagulant (NOAC) and a vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) may be challenging. To assist in this decision, we developed a risk score to identify patients for whom a therapeutic benefit of NOACs over VKA is predicted.
Methods and results ENGAGE AF-TIMI 48 was a randomized clinical trial of edoxaban vs. warfarin in 21 105 patients with AF. Cox proportional hazard models identified factors associated with a serious net clinical outcome (NCO) of disabling stroke, life-threatening bleeding, and all-cause mortality in VKA naive patients from the warfarin arm. These were used to develop an integer risk score. Performance was assessed by C-indices and validation by bootstrapping. Kaplan–Meier analyses were stratified by three score categories and treatment arm. Over a median of 2.7 years, 457 NCO events occurred in 2898 patients with a total person-time of 7549.5 years (6.05%/year). The risk prediction model (C = 0.693) for the NCO was translated into a 17-point integer score, with annualized event rates for the low, intermediate, and high-risk categories in the warfarin arm of 3.5%, 9.9%, and 20.8%, respectively. Therapeutic benefit of higher- and lower-dose edoxaban over warfarin was demonstrated in the high- and intermediate-risk, with equal benefit in the low-risk categories ( P -interaction 0.008 and 0.014, respectively).
Conclusion In VKA naive patients with AF, the TIMI-AF score can assist in the prediction of a poor composite outcome and guide selection of anticoagulant therapy by identifying a differential clinical benefit with a NOAC or VKA.
TL;DR: The association between digoxin use and worse clinical outcomes highlights the need to examineDigoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial.
Abstract: BackgroundDigoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association wi...
TL;DR: For patients with a history of MI >1 year previously, long-term treatment with ticagrelor 60 mg + low-dose ASA yields a cost-effectiveness ratio suggesting intermediate value based on current guidelines, which appears to provide higher value for patients in several recognized high-risk subgroups.
TL;DR: The data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with Atherosclerosis.
Abstract: Background —Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and whether more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. Methods —TRA2P-TIMI 50 (vorapaxar) and PEGASUS-TIMI 54 (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials. Results —Of 47,611 patients with stable vascular disease followed for three years in both studies there were 343 VTE events in 301 patients (KM rate at 3 years 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease and malignancy. The burden of atherosclerosis manifested as increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for one, 1.53% for two and 2.45% for three territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (HR 0.71, 95% CI 0.56-0.89; p=0.003). Conclusions —The rate of VTE in patients with atherosclerosis is ~0.3% per year while on treatment with at least one antiplatelet agent with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk and support inclusion of VTE as a prospective endpoint in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. Clinical Trial Registration —URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01225562.
TL;DR: In stable patients with established atherosclerosis, hs-TnI concentrations effectively stratified the risk of new or recurrent cardiovascular (CV) events, in particular CV death and MI.
Abstract: BACKGROUND: Cardiac troponin I, measured with a high-sensitivity assay (hs-TnI), is well-established for risk prediction in acute coronary syndromes. However, its prognostic role in stable atherosclerotic disease, particularly for future myocardial infarction (MI), is less well defined.
METHODS: We measured hs-TnI (Abbott ARCHITECT) in 15833 patients with prior MI, ischemic stroke, or peripheral arterial disease from the placebo-controlled Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)–Thrombolysis in Myocardial Infarction (TIMI) 50 trial of the platelet inhibitor vorapaxar, excluding patients with recent MI (<30 days). hs-TnI was categorized into 5 groups based on the detection limit (1.9 ng/L), 99th percentile reference limit (26 ng/L), and tertiles in between (1.9–26 ng/L), as well as sex-specific reference limits.
RESULTS: Higher hs-TnI concentration was associated with older age, male sex, and increased atherosclerosis burden. hs-TnI identified a graded 3-year risk of cardiovascular death, MI, or stroke from 5.0% to 18.6% ( P 26 ng/L vs 26 ng/L vs 0.3% with hs-TnI <1.9 ng/L; P interaction = 0.82).
CONCLUSIONS: In stable patients with established atherosclerosis, hs-TnI concentrations effectively stratified the risk of new or recurrent cardiovascular (CV) events, in particular CV death and MI. High-risk patients with prior MI identified by increased hs-TnI had a substantial absolute improvement in net clinical outcome with vorapaxar.
TL;DR: The expanded TRS 2°P provides a practical and well-calibrated risk prediction tool for patients with type 2 diabetes and elevated cardiovascular (CV) risk.
Abstract: OBJECTIVE Improved risk assessment for patients with type 2 diabetes and elevated cardiovascular (CV) risk is needed. The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P) predicts a gradient of risk in patients with prior myocardial infarction (MI) but has not been evaluated in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS CV event rates were compared by baseline TRS 2°P in 16,488 patients enrolled in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) with type 2 diabetes and high CV risk or established CV disease. Calibration was tested in the diabetes cohort from the REACH (REduction of Atherothrombosis for Continued Health) Registry. RESULTS TRS 2°P revealed a robust risk gradient for the composite of CV death, MI, and ischemic stroke in the full trial population, with 2-year event rates of 0.9% in the lowest- and 19.8% in the highest-risk groups ( P trend P trend P = 0.78). CONCLUSIONS The expanded TRS 2°P provides a practical and well-calibrated risk prediction tool for patients with type 2 diabetes.
TL;DR: This recognition closes a significant gap in understanding the natural history of hypertrophic cardiomyopathy, also underscoring that the disease is not uniformly grim but instead consistent with extended longevity, thereby providing many patients with a measure of reassurance.
TL;DR: Among post‐ACS patients enrolled in a long‐term clinical trial, the relative incidence of cardiovascular and noncardiovascular death differed based on type of ACS presentation and sex, but not age, which should inform the design of future cardiovascular outcomes trials.
Abstract: Background Understanding the relative risk of cardiovascular versus noncardiovascular death is important for designing clinical trials. These risks may differ depending on patient age, sex, and type of acute coronary syndrome (ACS). Methods and Results IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized controlled trial of simvastatin plus either ezetimibe or placebo following stabilized ACS. Cause of death was adjudicated by an independent committee. We compared the cumulative incidence of cardiovascular and noncardiovascular death for patients with unstable angina/non‐ST‐segment elevation myocardial infarction (UA/NSTEMI) and ST‐segment elevation myocardial infarction (STEMI), in those Conclusions Among post‐ACS patients enrolled in a long‐term clinical trial, the relative incidence of cardiovascular and noncardiovascular death differed based on type of ACS presentation and sex, but not age. These findings further delineate long‐term prognosis after ACS and should inform the design of future cardiovascular outcomes trials.
TL;DR: It has been known for more than a century that coronary-artery thrombosis is the most common precipitant of acute myocardial infarction and that atherosclerotic plaques in the coronary arteries are often responsible for angina pectoris.
Abstract: It has been known for more than a century that coronary-artery thrombosis is the most common precipitant of acute myocardial infarction and that atherosclerotic plaques in the coronary arteries are often responsible for angina pectoris. When anticoagulants and antiplatelet agents became available, clinical investigators rushed to study their efficacy and safety in patients with coronary artery disease. Attention was focused on two large populations — patients with acute coronary syndromes and those with stable ischemic disease, many of whom had previously had an acute event. Hundreds of trials, registries, and systematic analyses on the benefits and risks of individual and . . .
TL;DR: Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high‐potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events.
Abstract: BackgroundHigh‐potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high‐potency statins after ...
TL;DR: In patients with a prior CABG, vorapaxar significantly reduced the risk of recurrent major cardiovascular events, and bleeding risk appeared similar to that seen in the overall trial population.
Abstract: Background:Vorapaxar is a first-in-class protease-activated receptor-1 antagonist indicated for the reduction of cardiovascular death, myocardial infarction, and stroke in stable patients with prio...