Apixaban vs. standard of care after transcatheter aortic valve implantation: the ATLANTIS trial.

AIMS: The respective roles of oral anticoagulation or antiplatelet therapy following transcatheter aortic valve implantation (TAVI) remain debated. ATLANTIS is an international, randomized, open-label, superiority trial comparing apixaban to the standard of care. METHODS AND RESULTS: After successful TAVI, 1500 patients were randomized (1:1) to receive apixaban 5 mg (2.5 mg if impaired renal function or concomitant antiplatelet therapy) (n = 749) twice daily, or standard of care (n = 751). Randomization was stratified by the need for chronic anticoagulation therapy. Standard-of-care patients received a vitamin K antagonist (VKA) (Stratum 1) or antiplatelet therapy (Stratum 2) if there was an indication for anticoagulation or not, respectively. The primary endpoint was the composite of death, myocardial infarction, stroke or transient ischaemic attack, systemic embolism, intracardiac or bioprosthesis thrombosis, deep vein thrombosis or pulmonary embolism, and life-threatening, disabling, or major bleeding over 1-year follow-up. The primary safety endpoint was major, disabling, or life-threatening bleeding. The primary outcome occurred in 138 (18.4%) and 151 (20.1%) patients receiving apixaban or standard of care, respectively [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.73-1.16] and there was no evidence of interaction between treatment and stratum (Pinteraction = 0.57). The primary safety endpoint was similar in both groups (HR 1.02; 95% CI 0.72-1.44). In Stratum 1 (n = 451), an exploratory analysis showed no difference for all endpoints between apixaban and VKA. In Stratum 2 (n = 1049), the primary outcome and primary safety endpoint did not differ, but obstructive valve thrombosis was reduced with apixaban vs. antiplatelet therapy (HR 0.19; 95% CI 0.08-0.46), while a signal of higher non-cardiovascular mortality was observed with apixaban. CONCLUSION: After TAVI, apixaban was not superior to the standard of care, irrespective of an indication for oral anticoagulation.

Prevalence, characteristics and outcome of cardiac manifestations in critically-ill antiphospholipid syndrome patients.

AIMS: Antiphospholipid syndrome (APS) is a rare autoimmune disease defined by thrombotic events occurring in patients with persistent antiphospholipid antibodies. Cardiac manifestations in critically-ill APS patients are poorly investigated. We conducted a study to assess the prevalence, the characteristics and the prognosis of cardiac manifestations in thrombotic APS patients admitted to intensive care unit (ICU). METHODS AND RESULTS: A French, national, multicentre, retrospective study, conducted, from January 2000 to September 2018, including all APS patients admitted to 24 participating centres' ICUs with any new thrombotic (arterial, venous or microvascular) manifestation. Cardiac manifestations were defined as any new cardiac abnormalities relying on clinical examination, cardiac biomarkers, echocardiography, cardiac magnetic resonance (CMR) and coronarography. One hundred and thirty-six patients (female 72%) were included. Mean age at ICU admission was 46 ± 15years. Cardiac manifestations were present in 71 patients (53%). In patients with cardiac involvement, median left ventricular ejection fraction (LVEF) was 40% [28-55], troponin was elevated in 93% patients, coronary angiogram (n = 19, 27%) disclosing a coronary obstruction in 21%. CMR (n = 21) was abnormal in all cases, with late gadolinium enhancement in 62% of cases. Cardiac manifestations were associated with a non-significant increase of mortality (32% vs. 19%, p = 0.08). After 1-year follow-up, median LVEF was 57% [44-60] in patients with cardiac involvement. CONCLUSION: Cardiac involvement is frequent in critically-ill thrombotic APS patients and may be associated to more severe outcome. Increased awareness on this rare cause of myocardial infarction with or without obstructive coronary artery is urgently needed.

Clinical manifestations and outcomes of coronavirus disease-19 in heart transplant recipients: a multicentre case series with a systematic review and meta-analysis.

Available data on clinical presentation and mortality of coronavirus disease-2019 (COVID-19) in heart transplant (HT) recipients remain limited. We report a case series of laboratory-confirmed COVID-19 in 39 HT recipients from 3 French heart transplant centres (mean age 54.4 ± 14.8 years; 66.7% males). Hospital admission was required for 35 (89.7%) cases including 14/39 (35.9%) cases being admitted in intensive care unit. Immunosuppressive medications were reduced or discontinued in 74.4% of the patients. After a median follow-up of 54 (19-80) days, death and death or need for mechanical ventilation occurred in 25.6% and 33.3% of patients, respectively. Elevated C-reactive protein and lung involvement ≥50% on chest computed tomography (CT) at admission were associated with an increased risk of death or need for mechanical ventilation. Mortality rate from March to June in the entire 3-centre HT recipient cohort was 56% higher in 2020 compared to the time-matched 2019 cohort (2% vs. 1.28%, P = 0.15). In a meta-analysis including 4 studies, pre-existing diabetes mellitus (OR 3.60, 95% CI 1.43-9.06, I2  = 0%, P = 0.006) and chronic kidney disease stage III or higher (OR 3.79, 95% CI 1.39-10.31, I2  = 0%, P = 0.009) were associated with increased mortality. These findings highlight the aggressive clinical course of COVID-19 in HT recipients.

Radial versus femoral artery access for percutaneous coronary artery intervention in patients with acute myocardial infarction and multivessel disease complicated by cardiogenic shock: Subanalysis from the CULPRIT-SHOCK trial.

BACKGROUND: The use and impact of transradial artery access (TRA) compared to transfemoral artery access (TFA) in patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) complicated by cardiogenic shock (CS) remain unclear. METHODS: This is a post hoc analysis of the CULPRIT-SHOCK trial where patients presenting with MI and multivessel disease complicated by CS were randomized to a strategy of culprit-lesion-only or immediate multivessel PCI. Arterial access was left at operator's discretion. Adjudicated outcomes of interest were the composite of death or renal replacement therapy (RRT) at 30 days and 1 year. Multivariate logistic models were used to assess the association between the arterial access and outcomes. RESULTS: Among the 673 analyzed patients, TRA and TFA were successfully performed in 118 (17.5%) and 555 (82.5%) patients, respectively. Compared to TFA, TRA was associated with a lower 30-day rate of death or RRT (37.3% vs 53.2%, adjusted odds ratio [aOR]: 0.57; 95% confidence interval [CI] 0.34-0.96), a lower 30-day rate of death (34.7% vs 49.7%; aOR: 0.56; 95% CI 0.33-0.96), and a lower 30-day rate of RRT (5.9% vs 15.9%; aOR: 0.40; 95% CI 0.16-0.97). No significant differences were observed regarding the 30-day risks of type 3 or 5 Bleeding Academic Research Consortium bleeding and stroke. The observed reduction of death or RRT and death with TRA was no longer significant at 1 year (44.9% vs 57.8%; aOR: 0.85; 95% CI 0.50-1.45 and 42.4% vs 55.5%, aOR: 0.78; 95% CI 0.46-1.32, respectively). CONCLUSIONS: In patients undergoing PCI for acute MI complicated by CS, TRA may be associated with improved early outcomes, although the reason for this finding needs further research.

Machine learning versus traditional risk stratification methods in acute coronary syndrome: a pooled randomized clinical trial analysis.

Traditional statistical models allow population based inferences and comparisons. Machine learning (ML) explores datasets to develop algorithms that do not assume linear relationships between variables and outcomes and that may account for higher order interactions to make individualized outcome predictions. To evaluate the performance of machine learning models compared to traditional risk stratification methods for the prediction of major adverse cardiovascular events (MACE) and bleeding in patients with acute coronary syndrome (ACS) that are treated with antithrombotic therapy. Data on 24,178 ACS patients were pooled from four randomized controlled trials. The super learner ensemble algorithm selected weights for 23 machine learning models and was compared to traditional models. The efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. The safety endpoint was a composite of TIMI major and minor bleeding or bleeding requiring medical attention. For the MACE outcome, the super learner model produced a higher c-statistic (0.734) than logistic regression (0.714), the TIMI risk score (0.489), and a new cardiovascular risk score developed in the dataset (0.644). For the bleeding outcome, the super learner demonstrated a similar c-statistic as the logistic regression model (0.670 vs. 0.671). The machine learning risk estimates were highly calibrated with observed efficacy and bleeding outcomes (Hosmer-Lemeshow p value = 0.692 and 0.970, respectively). The super learner algorithm was highly calibrated on both efficacy and safety outcomes and produced the highest c-statistic for prediction of MACE compared to traditional risk stratification methods. This analysis demonstrates a contemporary application of machine learning to guide patient-level antithrombotic therapy treatment decisions.Clinical Trial Registration ATLAS ACS-2 TIMI 46: https://clinicaltrials.gov/ct2/show/NCT00402597. Unique Identifier: NCT00402597. ATLAS ACS-2 TIMI 51: https://clinicaltrials.gov/ct2/show/NCT00809965. Unique Identifier: NCT00809965. GEMINI ACS-1: https://clinicaltrials.gov/ct2/show/NCT02293395. Unique Identifier: NCT02293395. PIONEER-AF PCI: https://clinicaltrials.gov/ct2/show/NCT01830543. Unique Identifier: NCT01830543.

The CSL112-2001 trial: Safety and tolerability of multiple doses of CSL112 (apolipoprotein A-I [human]), an intravenous formulation of plasma-derived apolipoprotein A-I, among subjects with moderate renal impairment after acute myocardial infarction.

BACKGROUND: CSL112 (apolipoprotein A-I [human]) is a plasma-derived apolipoprotein A-I developed for early reduction of cardiovascular risk following an acute myocardial infarction (AMI). The safety of CSL112 among AMI subjects with moderate, stage 3 chronic kidney disease (CKD) is unknown. METHODS: CSL112_2001, a multicenter, placebo-controlled, parallel-group, double-blind, randomized phase 2 trial, enrolled patients with moderate CKD within 7 days following AMI. Enrollment was stratified on the basis of estimated glomerular filtration rate and presence of diabetes requiring treatment. Patients were randomized in a 2:1 ratio to receive 4 weekly infusions of CSL112 6 g or placebo. The co-primary safety end points were renal serious adverse events (SAEs) and acute kidney injury, defined as an increase ≥26.5 µmol/L in baseline serum creatinine for more than 24 hours, during the treatment period. RESULTS: A total of 83 patients were randomized (55 CSL112 vs 28 placebo). No increase in renal SAEs was observed in the CSL112 group compared with placebo (CSL112 = 1 [1.9%], placebo = 4 [14.3%]). Similarly, no increase in acute kidney injury events was observed (CSL112 = 2 [4.0%], placebo = 4 [14.3%]). Rates of other SAEs were similar between groups. CSL112 administration resulted in increases in ApoA-I and cholesterol efflux similar to those observed in patients with AMI and normal renal function or stage 2 CKD enrolled in the ApoA-I Event Reducing in Ischemic Syndromes I trial. CONCLUSIONS: These results demonstrate the acceptable safety of the 6-g dose of CSL112 among AMI subjects with moderate stage 3 CKD and support inclusion of these patients in a phase 3 cardiovascular outcomes trial powered to assess efficacy.

Modulation of cholesterol efflux capacity in patients with myocardial infarction.

PURPOSE OF REVIEW: Epidemiologic studies consistently demonstrated that patients with coronary artery disease (CAD) and low HDL cholesterol (HDL-C) are more likely to develop major adverse cardiovascular events as compared with those with normal or high HDL. However, several large randomized trials failed to demonstrate that a substantial, pharmacological-based, increase of HDL-C concentrations results in a clinically significant reduction of ischemic outcomes. This has been largely attributed to the fact that, although these drugs are able to raise the HDL-C concentration, they have no effect on HDL-C atheroprotective function. Subsequently, the 'HDL hypothesis' evolved, and the focus shifted from raising the concentration of HDL-C to raising the reverse cholesterol transport (RCT) function by increasing patients cholesterol efflux capacity (CEC) instead. Indeed, new data suggest that HDL-C metabolism and the ability of the HDL molecule to transport cholesterol from the atherosclerotic plaque to the liver, measured by the CEC, is more important than steady-state HDL-C levels. Modulation of the CEC has become, therefore, a promising therapeutic target in CAD patients. This article reviews the current data on the 'cholesterol efflux hypothesis' and discuss its ability to be modulated has a potential therapeutic target. RECENT FINDINGS: Recent data have demonstrated that impaired serum CEC was associated with increased mortality after a myocardial infarction (MI). Thus, therapeutic intervention aiming to improve CEC and RCT may reduce the risk of recurrent events. Early phase clinical studies targeting CEC showed promising results and a megatrial is ongoing testing the hypothesis that an improved RCT trough a modulation of the CEC can modify patient's prognosis after an acute MI. SUMMARY: The 'cholesterol efflux hypothesis' is now supported by several clinical studies and is being tested with a therapeutic candidate in a megatrial enrolling high-risk patient with MI.

Pre-hospital administration of ticagrelor in diabetic patients with ST-elevation myocardial infarction undergoing primary angioplasty: A sub-analysis of the ATLANTIC trial.

OBJECTIVE: We investigated, in the contemporary era of ST-elevation myocardial infarction (STEMI) treatment, the influence of diabetes mellitus (DM) on cardiovascular outcomes, and whether pre-hospital administration of ticagrelor may affect these outcomes in a subgroup of STEMI patients with DM. BACKGROUND: DM patients have high platelet reactivity and a prothrombotic condition which highlight the importance of an effective antithrombotic regimen in this high-risk population. METHODS: In toal 1,630 STEMI patients enrolled in the ATLANTIC trial who underwent primary percutaneous coronary intervention (PCI) were included. Multivariate analysis was used to explore the association of DM with outcomes and potential treatment-by-diabetes interaction was tested. RESULTS: A total of 214/1,630 (13.1%) patients had DM. DM was an independent predictor of poor myocardial reperfusion as reflected by less frequent ST-segment elevation resolution (≥70%) after PCI (OR 0.59, 95% CI 0.43-0.82, P < 0.01) and was an independent predictor of the composite 30-day outcomes of death/new myocardial infarction (MI)/urgent revascularization/definite stent thrombosis (ST) (OR 2.80, 95% CI 1.62-4.85, P < 0.01), new MI or definite acute ST (OR 2.46, 95% CI 1.08-5.61, P = 0.03), and definite ST (OR 10.00, 95% CI 3.54-28.22, P < 0.01). No significant interaction between pre-hospital ticagrelor vs in-hospital ticagrelor administration and DM was present for the clinical, electrocardiographic and angiographic outcomes as well as for thrombolysis in myocardial infarction major bleeding. CONCLUSIONS: DM remains independently associated with poor myocardial reperfusion and worse 30-day clinical outcomes. No significant interaction was found between pre-hospital vs in-hospital ticagrelor administration and DM status. Further approaches for the treatment of DM patients are needed. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01347580.

Most Promising Therapies in Interventional Cardiology.

PURPOSE OF REVIEW: The last 40 years of clinical research in interventional cardiology were extraordinarily innovative. This article will review the most promising up and coming interventional cardiovascular therapies, with a primary focus on the treatment of coronary artery disease. RECENT FINDINGS: From the first stent, to the first transcatheter aortic valve implantation (TAVI), and the left appendage closure technique, percutaneous interventions revolutionized the treatment of multiple diseases and dramatically improved the prognosis of many patients. While these advances have decreased the risk of mortality in some patients (such as ST-elevation myocardial infarction), 15% of acute coronary syndrome (ACS) patients still experience recurrent ischemic events within the first year, challenging us to develop new pharmaceutical targets and new devices. The continued emergence of data supporting inflammation as a risk factor and pharmacologic target as well as data supporting the importance of cholesterol efflux have identified novel therapeutic targets that may play a major role in the improvement of prognosis of patients with coronary artery disease. In addition, novel medical devices are being developed to allow even earlier detection of acute cardiac events and to support high-risk percutaneous coronary interventions. Advances in computing and the ability to analyze large datasets will allow us to use artificial intelligence to augment the clinician patient experience, both in and out of the catheterization laboratory, with live procedural guidance as well as pre- and post-operative prognostication tools.

Periprocedural myocardial infarction and injury in elective coronary stenting.

Aims: To assess the incidence, risk factors and prognosis of periprocedural myocardial infarction (MI) and myocardial injury in patients undergoing elective percutaneous coronary intervention (PCI). Methods and results: We included all consecutive patients who underwent elective PCI with a negative troponin level at admission from 1 January 2014 to 31 December 2015. The primary endpoint was defined as the composite of periprocedural MI (Type 4a MI), stent thrombosis (Type 4b MI), and myocardial injury according to the Third universal definition of MI. Multivariable analysis was performed to identify independent predictors of periprocedural MI and myocardial injury and its relation to 30-day and 1-year clinical outcome. Of the 1390 elective PCI patients, the primary endpoint occurred in 28.7% of patients, including 7.0% of Type 4a MI, 0.14% of Type 4b MI, and 21.6% of myocardial injury. Independent risk factors for the occurrence of the primary endpoint were left main PCI, total stent length >30 mm, multiple stenting, chronic kidney disease (estimated glomerular filtration rate <60 mL/min) and age >75 years. At 30 days, patients with periprocedural MI and myocardial injury had a higher rate of cardiovascular events [5.5% vs. 1.2%, adjusted hazard ratio (adjHR) = 3.8, 95% confidence interval (CI) 1.9-6.9; P < 0.001] mainly driven by ischaemic events (3.2% vs. 0.6%, HR 5.9, 95% CI 2.9-20; P < 0.0001). At 1-year, the risk of ischemic events remained higher in the periprocedural MI and myocardial injury group (adjHR = 1.7, 95% CI 1.1-2.6; P = 0.004). Conclusions: Periprocedural MI and injury are frequent complications of elective PCI associated with an increased rate of cardiovascular events at 30 days and 1 year.

Safety and efficacy of non-vitamin K oral anticoagulant for atrial fibrillation patients after percutaneous coronary intervention: A bivariate analysis of the PIONEER AF-PCI and RE-DUAL PCI trial.

BACKGROUND: The tradeoff in safety versus efficacy in substituting a non-vitamin K antagonist oral anticoagulant for a vitamin K antagonist (VKA) in the stented atrial fibrillation patient has not been quantitatively evaluated. METHODS: Based on summary data from the PIONEER AF-PCI and RE-DUAL PCI trials, 4 antithrombotic regimens were compared with VKA-based triple therapy: (1) rivaroxaban (riva) 15 mg daily + P2Y12 inhibitor, (2) riva 2.5 mg twice daily + P2Y12 inhibitor + aspirin, (3) dabigatran (dabi) 110 mg twice daily + P2Y12 inhibitor, and (4) dabi 150 mg twice daily + P2Y12 inhibitor. A bivariate model with a noninferiority margin of 1.38 was used to simultaneously assess safety and efficacy. The safety end point was major or clinically relevant nonmajor bleeding by International Society on Thrombosis and Haemostasis definitions. The efficacy end point was a thromboembolic event (myocardial infarction, stroke, or systemic embolism), death, or urgent revascularization. The bivariate outcome, a measure of risk difference in the net clinical outcome, was compared between antithrombotic regimens. RESULTS: All 4 non-vitamin K antagonist oral anticoagulant regimens were superior in bleeding and noninferior in efficacy compared with triple therapy with VKA. Riva 15 mg daily and 2.5 mg twice daily were associated with bivariate combined risk reductions of 5.6% (2.3%-8.8%) and 5.5% (2.1%-8.7%), respectively, and dabi 110 mg twice daily and 150 mg twice daily reduced the bivariate risk by 3.8% (0.5%-7.0%) and 6.3% (2.4%-9.8%), respectively. CONCLUSIONS: A bivariate analysis that simultaneously characterizes both risk and benefit demonstrates that riva- and dabi-based regimens were both favorable over VKA plus dual antiplatelet therapy among patients with atrial fibrillation undergoing PCI.

Symptomatic event reduction with extended-duration betrixaban in acute medically ill hospitalized patients.

BACKGROUND: Approximately 15%-30% of patients in trials of medical thromboprophylaxis will have missing compression ultrasound (CUS) data. The goal of the present analysis was to perform analyses to minimize missing data. METHODS: The APEX trial randomized 7,513 acutely medically ill hospitalized patients to thromboprophylaxis with either betrixaban for 35-42 days or enoxaparin for 6-14 days. A modified intent-to-treat (mITT) analysis was performed and included all subjects administered study drug, irrespective of CUS performance, and an analysis of symptomatic events which do not require performance of a CUS (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, and venous thromboembolism (VTE)-related mortality). RESULTS: In the mITT population, betrixaban significantly reduced the primary end point (which included both symptomatic and CUS events) (165 [4.4%] vs 223 [6.0%]; relative risk = 0.75; 95% CI 0.61-0.91; P = .003; absolute risk reduction [ARR] = 1.6%; number needed to treat [NNT] = 63). Betrixaban also reduced symptomatic VTE through day 42 (35 [1.28%] vs 54 [1.88%], hazard ratio [HR] = 0.65; 95% CI 0.42-0.99; P = .044; ARR = 0.6%; NNT=167) as well as through day 77 (37 [1.02%] vs 67 [1.89%]; HR= 0.55; 95% CI 0.37-0.83; P = .003; ARR = 0.87%; NNT=115) as well as the individual end point of nonfatal pulmonary embolism (9 [0.25%] vs 20 [0.55%]; HR= 0.45; 95% CI 0.21-0.99; P = .041; ARR = 0.30%; NNT=334). On an "as-treated" basis, 80 mg of betrixaban reduced VTE-related mortality through day 77 (10 [0.34%] vs. 22 [0.79%]; HR=0.46; 95% CI 0.22-0.96; P = .035; ARR = 0.45%; NNT=223). CONCLUSION: In an mITT analysis of all patients administered study drug, extended-duration betrixaban reduced the primary end point as well as symptomatic events. In an as-treated analysis, 80 mg of betrixaban reduced VTE-related death.

Non-invasive differentiation of idiopathic inflammatory myopathy with cardiac involvement from acute viral myocarditis using cardiovascular magnetic resonance imaging T1 and T2 mapping.

BACKGROUND: Idiopathic inflammatory myopathy (IIM) is a group of autoimmune diseases with systemic myositis which may involve the myocardium. Cardiac involvement in IIM, although often subclinical, may mimic clinical manifestations of acute viral myocarditis (AVM). Our aim was to investigate the usefulness of the combined analysis of cardiovascular magnetic resonance (CMR) T1 and T2 mapping parameters measured both in the myocardium and in the thoracic skeletal muscles to differentiate AVM from IIM cardiac involvement. METHODS: Sixty subjects were included in this retrospective study (36 male, age 45 ± 16 years): twenty patients with AVM, twenty patients with IIM and cardiac involvement and twenty healthy controls. Study participants underwent CMR imaging with modified Look-Locker inversion-recovery (MOLLI) T1 mapping and 3-point balanced steady-state-free precession T2 mapping. Relaxation times were quantified after endocardial and epicardial delineation on basal and medial short-axis slices, as well as in different thoracic skeletal muscle groups present in the CMR field-of-view. ROC-Analysis was performed to assess the ability of mapping indices to discriminate the study groups. RESULTS: Mapping parameters in the thoracic skeletal muscles were able to discriminate between AVM and IIM patients. Best skeletal muscle parameters to identify IIM from AVM patients were reduced post-contrast T1 and increased extracellular volume (ECV), resulting in an area under the ROC curve (AUC) of 0.95 for post-contrast T1 and 0.96 for ECV. Conversely, myocardial mapping parameters did not discriminate IIM from AVM patients but increased native T1 (AUC 0.89 for AVM; 0.84 for IIM) and increased T2 (AUC 0.82 for AVM; 0.88 for IIM) could differentiate both patient groups from healthy controls. CONCLUSION: CMR myocardial mapping detects cardiac inflammation in AVM and IIM compared to normal myocardium in healthy controls but does not differentiate IIM from AVM. However, thoracic skeletal muscle mapping was able to accurately discern IIM from AVM.

Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial.

Hospitalized acute medically ill patients with a history of venous thromboembolism (VTE) are at increased risk for recurrent VTE. We characterized the efficacy and safety of betrixaban for prevention of recurrent VTE in these high risk patients. The APEX trial randomized 7513 acutely ill hospitalized medical patients at risk for developing VTE to receive either betrixaban for 35-42 days or enoxaparin for 10 ± 4 days to prevent VTE. This exploratory post-hoc analysis assessed the efficacy and safety of betrixaban versus enoxaparin among subjects with and without prior VTE. Time-to-multiple symptomatic VTE events was also calculated. Approximately 8% of subjects in both arms had prior VTE, which was associated with a fourfold increase in adjusted risk of VTE [MV OR 4.03, 95% CI 3.06-5.30, p < 0.001]. Betrixaban reduced VTE compared with enoxaparin among subjects with prior VTE [32 (10.4%) vs. 55 (18.9%), RR 0.57, 95% CI 0.38-0.86, p = 0.006, ARR 8.5%, NNT 12] and without prior VTE [133 (3.9%) vs. 168 (4.9%), RR 0.79, 95% CI 0.64-0.99, p = 0.042, ARR 1.0%, NNT 100] (interaction p > 0.05). Additionally, four subjects in the enoxaparin arm and one subject in the betrixaban arm experienced a recurrent VTE. Compared with enoxaparin, betrixaban use was associated with reduction of recurrent VTE events through the active treatment period [36 vs. 57, HR 0.63, 95% CI 0.41-0.97, p = 0.045] and through the end of study [38 vs. 71, HR 0.54, 95% CI 0.36-0.81, p = 0.004]. Prior VTE is associated with a fourfold increase in the risk of VTE among hospitalized medically ill patients. Only 12 such patients would need to be treated with betrixaban versus enoxaparin to prevent an additional VTE endpoint. Betrixaban reduced not only the first but also all recurrent VTE events in a time-to-any-event analysis. TRIAL REGISTRATION: http://www.clinicaltrials.gov , Unique identifier: NCT01583218.

Total bleeding with rivaroxaban versus warfarin in patients with atrial fibrillation receiving antiplatelet therapy after percutaneous coronary intervention.

Among atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI), rivaroxaban with background antiplatelet therapy significantly reduced the first occurrence of bleeding compared to triple therapy with warfarin. This study hypothesized that total bleeding events, including those beyond the first event, would be reduced with rivaroxaban-based regimens. In the PIONEER AF-PCI trial, 2099 patients in the modified intention-to-treat population were randomized to three groups and followed for 12 months: (1) rivaroxaban 15 mg once daily plus a P2Y12 inhibitor (N = 696); (2) rivaroxaban 2.5 mg twice daily plus dual antiplatelet therapy (DAPT) (N = 706); and (3) dose-adjusted warfarin plus DAPT (N = 697). Descriptive statistics for the number of subjects who experienced one or more bleeding events were calculated. The total number of bleeding events was compared across treatment groups using the Wei, Lin, and Weissfeld method. A total of 514 and 439 events of clinically significant bleeding and bleeding requiring medical attention occurred throughout the study. Compared to triple therapy with warfarin, rivaroxaban-based regimen was associated with a reduction in total events of clinically significant bleeding (Group 1 vs. Group 3: HR 0.64 [95% CI 0.49-0.85], p < 0.001, NNT = 11; Group 2 vs. Group 3: HR 0.62 [95% CI 0.48-0.80], p < 0.001, NNT = 10). Similarly, rivaroxaban reduced the total bleeding events requiring medical attention (Group 1 vs. Group 3: HR 0.66 [95% CI 0.49-0.89], p < 0.001, NNT = 14; Group 2 vs. Group 3: HR 0.64 [95% CI 0.48-0.85], p = 0.002, NNT = 13). Rivaroxaban-based regimen reduced the total bleeding events compared with VKA-based triple therapy in stented AF patients. One clinically significant bleeding event could be prevented with rivaroxaban use for every 10-11 patients treated, and one bleeding requiring medical attention could be prevented with rivaroxaban for every 13-14 patients treated. These data provide evidence that total bleeding events, including those beyond the first event, are reduced with rivaroxaban-based antithrombotic regimens. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01830543 (PIONEER AF-PCI).

Platelet reactivity in human immunodeficiency virus infected patients on dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV study.

AIM: To explore platelet reactivity on dual antiplatelet therapy (DAPT) of acute coronary syndrome (ACS) patients infected with HIV. METHODS AND RESULTS: Acute coronary syndrome patients infected with HIV (n = 80) were matched to ACS patients without HIV (n = 160) on age, sex, diabetes, and DAPT (aspirin 100%, clopidogrel 68%, prasugrel 31%, ticagrelor 1%). Platelet reactivity was evaluated after ACS (>30 days) by measuring residual platelet aggregation (RPA) to aspirin and to P2Y12 inhibitors with light transmission aggregometry (LTA), VerifyNow aspirin assay (ARU), and P2Y12 assay (PRU) and with the VASP platelet reactivity index (VASP-PRI). Proportion of patients with high residual platelet reactivity (HPR) was evaluated. HIV-infected ACS patients had higher levels of platelet reactivity in response to P2Y12 inhibitors (RPA: 23.8 ± 2.7% vs. 15.3 ± 1.3%; P = 0.001; PRU: 132 ± 10 vs. 107.4 ± 6.6; P = 0.04; and VASP-PRI: 45.2 ± 2.6% vs. 32.0 ± 2.0%; P < 0.001) and to aspirin (RPA: 3.6 ± 1.5% vs. 0.4 ± 0.1%; P = 0.004 and ARU: 442 ± 11 vs. 407 ± 5; P = 0.002) compared with non-HIV. HIV-infection was independently associated with increased platelet reactivity regardless of the test used (RPA: P = 0.005; PRU: P < 0.001 and VASP-PRI: P < 0.001) and a higher proportion of HPR (OR = 7.6; P < 0.001; OR = 2.06; P = 0.06; OR = 2.91; P = 0.004, respectively) in response to P2Y12 inhibitors. Similar results were found with aspirin. Protease inhibitors use was associated with increased platelet reactivity and higher rate of HPR. CONCLUSIONS: Acute coronary syndrome patients infected with HIV have increased levels of platelet reactivity and higher prevalence of HPR to P2Y12 inhibitors and aspirin than non-HIV patients. These results could provide potential explanations for the observed increase risk of recurrent ischemic events in the HIV-infected population.

EURObservational Research Programme: the Chronic Ischaemic Cardiovascular Disease Registry: Pilot phase (CICD-PILOT).

AIMS: Chronic ischaemic cardiovascular disease (CICD) is a major cause of mortality and morbidity worldwide. The primary objective of the CICD-Pilot registry was to describe the clinical characteristics and management modalities across Europe in a broad spectrum of patients with CICD. METHODS AND RESULTS: The CICD-Pilot registry is an international prospective observational longitudinal registry, conducted in 100 centres from 10 countries selected to reflect the diversity of health systems and care attitudes across Europe. From April 2013 to December 2014, 2420 consecutive CICD patients with non-ST-elevation acute coronary syndrome (n = 755) and chronic stable coronary artery disease (n = 1464), of whom 933 (63.7%) were planned for elective coronary intervention, or with peripheral artery disease (PAD) (n = 201), were enrolled (30.5% female patients). Mean age was 66.6 ± 10.9 years. The following risk factors were reported: smoking 54.6%, diabetes mellitus 29.2%, hypertension 82.6%, and hypercholesterolaemia 74.1%. Assessment of cardiac function was made in 69.5% and an exercise stress test in 21.2% during/within 1 year preceding admission. New stress imaging modalities were applied in a minority of patients. A marked increase was observed at discharge in the rate of prescription of angiotensin-converting enzyme-inhibitors/angiotensin receptor blockers (82.8%), beta-blockers (80.2%), statins (92.7%), aspirin (90.3%), and clopidogrel (66.8%). Marked differences in clinical profile and treatment modalities were observed across the four cohorts. CONCLUSION: The CICD-Pilot registry suggests that implementation of guideline-recommended therapies has improved since the previous surveys but that important heterogeneity exists in the clinical profile and treatment modalities in the different cohorts of patients enrolled with a broad spectrum of CICDs.