Higher Incidence Of Major Bleeding Research Articles

Efficacy and Safety of Tinzaparin in CAT Patients with Metastatic Disease

Introduction Venous thromboembolism (VTE) frequently complicates the course of active cancer with a significant impact on morbidity and mortality. The results of CATCH trial for treatment of cancer-associated thrombosis (CAT) have been reported and included patients with and without metastatic disease. As metastatic disease is known to be associated with a higher risk of recurrent VTE and bleeding, we performed these post hoc analyses to assess the recurrent VTE (rVTE), recurrent deep vein thrombosis (rDVT), and bleeding events (major bleeding (MB), clinically relevant (CRB) and clinically relevant non-major (CRNMB)) in patients with CAT with metastatic disease. Risk factors associated with rVTE, rDVT and CRB were also explored. Method CATCH (ClinicalTrials.govNCT01130025; Lee A et al. JAMA 2015) was a Phase III, multinational, randomized, active-controlled, open-label trial. Patients with solid tumor cancer and haematological malignancies were included. Patients were randomized to receive therapeutic dosing of tinzaparin (175 U/kg OD) vs warfarin (INR target 2.0 - 3.0). Treatment was given for up to 6 months. The primary efficacy outcome was the composite of symptomatic DVT, symptomatic nonfatal pulmonary embolism (PE), fatal PE, incidental proximal DVT and incidental proximal PE. All cumulative incidence VTE and MB outcome were objectively documented and centrally adjudicated in a treatment-blinded fashion. Patients who had known metastatic solid tumor at presentation were included in these analysis. The regression model compared the two treatment groups adjusting for competing risks and geographical region and history of VTE. Results Among the CATCH study population, 55% had metastatic disease. Of these patients, 247 and 245 received tinzaparin and warfarin, respectively, with no significant differences in patient characteristics between treatment groups. Patients with metastatic disease had a higher incidence of rVTE (10.2% vs 7.0%) and symptomatic non-fatal rDVT (5.5% vs 2.9%) compared to patients without metastatic disease. Patients with metastatic disease also had a higher incidence of MB (2.8% vs 1.9%), CRB (17.7%% vs 11.8%) and CRNMB (15.0% vs 10.5%) compared to patients without metastatic disease. rVTE occurred in significantly fewer patients assigned to tinzaparin (6.8%) versus warfarin (14.4%) (HR 0.45; 95%CI 0.25-0.80; p=0.007). rDVT also occurred significantly less frequently in patients assigned to tinzaparin (3.0%) versus warfarin (8.4%) (HR 0.34; 95%CI 0.15-0.81; p=0.015). 96% of rVTE were symptomatic. There was no significant difference in MB between tinzaparin- and warfarin-treated patients (4.0% vs 1.6%; HR 2.17; 95%CI 0.71-6.65; p=0.177), but tinzaparin was associated with significantly lower risk of CRB (15.8% vs 19.6%; HR 0.63; 95%CI 0.41-0.97; p=0.037) and CRNMB (12.1% vs 18.0%; HR 0.53; 95%CI 0.33-0.84; p=0.008). Factors associated with rVTE in patients with metastatic disease included central venous catheterization (HR 0.10; 95%CI 0.01-0.79; p=0.029), venous compression from mass or adenopathy (HR 3.99; 95%CI 2.14-7.43; p<0.001), and hepatobiliary cancer (HR 4.07; 95%CI 1.65-10.0; p=0.002). The latter two were also significant risk factors for rDVT. Age > 75 (HR 2.56; 95%CI 1.43-4.60; p=0.002) and known intracranial pathology (HR 2.24; 95%CI 1.07-4.66; p=0.031) were found to be significant risk factors for CRB. Conclusion CAT patients with metastatic diseases have higher risks of rVTE and bleeding compared with patients without metastases. Amongst CAT patients with metastatic solid tumors, treatment with tinzaparin was associated with significantly lower risk of rVTE and rDVT and significantly lower risk of CRB and CRNMB compared with warfarin. Tinzaparin offers a favourable risk-benefit profile in treatment of CAT in patients with metastatic solid tumors. Disclosures Lee: Pfizer: Consultancy, Honoraria; BMS: Research Funding; LEO Pharma A/S: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Other: Advisory board, steering committee. Bauersachs:Aspen: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; LEO Pharma A/S: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Turpin:LEO Pharma Canada: Current Employment. Hansen:LEO Pharma A/S: Current Employment. Khorana:Leo Pharma: Honoraria; Merck: Research Funding; Array: Other: Research funding (to institution); Leap: Research Funding; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Medscape: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Sanofi: Honoraria.

Oral anticoagulant monotherapy compared to oral anticoagulant plus single anti-platelet therapy in stable ischemic heart disease with atrial fibrillation: a meta-analysis

Abstract Introduction Evidence for antithrombotic therapy regimen in patients with concurrent stable ischemic heart disease (SIHD) and atrial fibrillation (AF) is not well established. The ideal regimen needs to been balanced to prevent thrombotic and embolic events, without increasing the risk of bleeding tendencies. Two randomized control trials have been published studying oral anticoagulant monotherapy (OAC) as compared to oral anticoagulant plus single antiplatelet therapy (OAC+SAPT), of which one trial was terminated prematurely and was underpowered. Purpose We performed a meta-analysis of RCTs and observational studies comparing OAC monotherapy to OAC+ SAPT in SIDH patients with AF. Methods We performed a systematic search of the PubMed, EMBASE and Cochrane databases to identify relevant articles. The database search was performed from the inception of the databases to January 2020. Inclusion criteria were RCTs and observation studies comparing OAC to OAC+SAPT in SIDH patients with AF and reporting time to event outcomes of major bleeding or cardiovascular mortality. The definition of major bleeding as per the definition provided by individual studies. Two authors independently performed data extraction to check for reproducibility. We used inverse variance method with random effect model to calculate hazard ratio (HR) with 95% confidence interval (CI). Statistical heterogeneity was calculated using Higgins I2 statistics. All statistical analysis was performed using RevMan Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Results Seven studies (2 RCTs and 5 observational studies) were included in the final analysis. OAC+ SAPT as compared to OAC monotherapy in patients with SIHD and AF was associated with a higher incidence of major bleeding [HR: 1.59, 95% CI: 1.36–1.85, P value<0.05, I2: 0%] [Figure 1, Panel A]. OAC+SPT as compared to OAC monotherapy was associated with similar incidence of cardiovascular mortality [HR: 1.07, 95% CI: 0.86–1.33, P value= 0.55, I2: 32%] [Figure 1, Panel B]. There was no statistical heterogeneity associated with either pooled estimates. Conclusion OAC monotherapy as compared to OAC+SAPT in patients with SIHD and AF was associated with a lower incidence of major bleeding and similar incidence of cardiovascular mortality. Figure 1 Funding Acknowledgement Type of funding source: None

Prevalence of type 2 diabetes with stable coronary artery disease but without prior myocardial infarction or stroke and THEMIS-like patients from the SNDS French nationwide claims database

Abstract Background The THEMIS randomized controlled trial showed that patients with stable coronary artery disease and type 2 diabetes mellitus (CAD-T2DM), without prior myocardial infarction (MI) or stroke, and who received ticagrelor plus aspirin, had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. The number of patients concerned and their characteristics in current practice are not well known. Purpose To assess the characteristics of CAD-T2DM adults (≥18 years) without prior MI-stroke, and more specifically, of THEMIS-like patients in a real world setting. Methods Cohort within the main scheme of the SNDS (Système National des Données de Santé), the French nationwide claims database, representing about 86% of 66 million people. All CAD-T2DM prevalent patients without prior MI-stroke were identified on January 1st, 2014 (index date) based on a 5-year database history, and followed for two years. The THEMIS-like population included CAD-T2DM patients without prior MI-stroke ≥50 years at index date without renal failure with dialysis, cirrhosis or liver cancer history, as well as no intracranial and gastro-intestinal bleeding for the last 6 months, or anticoagulant or antiplatelet agent 2 months before and after index date. Study prevalence was standardized for the European population for 1,000 adults (‰) using sex and 5-year age classes from Eurostat statistics. Results From the 359,595 CAD-T2DM patients identified in the database, 71.8% had no prior MI-stroke (n=258,260), including 24.9% of THEMIS-like patients (n=64,334). CAD-T2DM without prior MI-stroke and THEMIS-like patients had the same mean age of 72 years, with 68% and 66% men, 26% and 25% with more than 4-year CAD and T2DM history, 79% and 76% of hypertension, 28% and 19% of revascularisation procedure, 19% and 11% of peripheral arterial disease, 16% and 9% of heart failure, and 39% and 32% of diabetes complications, respectively. The table below presents prevalence estimation per 1,000 European adults with differences according to both populations, as well as sex and age-classes. Conclusions The two populations had similar characteristics, although noting some differences in comorbidities. The THEMIS-like prevalence was estimated to 1.50‰ European adults, representing about a quarter of CAD-T2DM patients without prior MI-stroke. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Study performed with unconditional funding from AstraZeneca

Real world risk of major outcomes for type 2 diabetes with stable coronary artery disease without prior MI or stroke and THEMIS-like patients using the SNDS French nationwide claims database

Abstract Background The THEMIS randomized controlled trial showed that patients with stable coronary artery disease and type 2 diabetes mellitus (CAD-T2DM), without a history of myocardial infarction (MI) or stroke, and who received ticagrelor plus aspirin, had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. After 3 years of follow-up, the incidence of major outcomes in the placebo arm was 1.8% for ischemic stroke, 3.3% for MI, 4.9% for all-cause death, 9.2% for a composite of all-cause-death, MI or stroke, and 0.38 per 100 patients-years for TIMI major bleedings. The risk of these outcomes is not well known in current practice. Purpose To estimate the incidence of major outcomes for CAD-T2DM patients without prior MI-stroke and more specifically for THEMIS-like patients in a real world setting. Methods Cohort within the main scheme of the SNDS (Système National des Données de Santé), the French nationwide claims database, representing about 86% of 66 million people. All CAD-T2DM prevalent patients without prior MI-stroke were identified on January 1st, 2014 (inclusion date), based on a 5-year database history, and followed for two years. The THEMIS-like population included CAD-T2DM patients without prior MI-stroke ≥50 years at inclusion date without renal failure with dialysis, cirrhosis or liver cancer history, as well as no intracranial and gastro-intestinal bleeding for the last 6 months, or anticoagulant or antiplatelet agent 2 months before and after inclusion date. The Kaplan-Meier method was used to estimate the 2-year cumulative incidence of all-cause death and a composite of all-cause death, MI and stroke, and the cumulative incidence function, taking into account death as competing risk for other clinical outcomes. Results From 258,260 CAD-T2DM patients without prior MI-stroke, 64,334 were included in the THEMIS-like population (24.9%) with the same median age of 72 years, with 68.3% and 65.7% men, respectively. The 2-year cumulative incidence for the CAD-T2DM without prior MI-stroke and THEMIS-like populations was 1.7% and 1.5% for ischemic stroke, 1.7% and 1.3% for MI, 9.5% and 5.3% for heart failure, 4.9% and 3.2% for major bleeding, 13.6% and 9.7% for all-cause death, and 16.2% and 12.0% for the composite outcome, respectively. Conclusions In current practice, the median age of the THEMIS-like population was 6 years older than in the THEMIS trial (i.e. 66 years), with an observed risk after 2 years of follow-up, about double for the composite outcome, triple for deaths and quadruple for major bleedings than those of the placebo arm of the trial (estimation after 2 years of follow-up in the THEMIS trial placebo arm assuming constant risk across time according to Kaplan-Meier graph). Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Study performed with unconditional funding from AstraZeneca

Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation

BackgroundImplementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding.MethodsWe conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis.ResultsA total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P=0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36).ConclusionsIn very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.)

Relationship between the nutritional status and safety and efficacy outcomes in atrial fibrillation patients aged 80 years and over receiving oral anticoagulants

BackgroundMalnutrition has been reported to be associated with worse clinical outcomes in various cardiovascular diseases. We aimed to investigate the clinical significance of the nutritional status in atrial fibrillation (AF) patients aged 80 years and over receiving oral anticoagulants (OACs), focusing on the difference between direct OACs (DOACs) and warfarin treatment. MethodsThis was a retrospective and observational study. We enrolled 332 consecutive AF patients aged 80 years and over who were treated with OACs: DOACs (n = 256) and warfarin (n = 76). A controlling nutritional status (CONUT) score was used to evaluate the nutritional status. The enrolled patients were divided into two groups based on the CONUT score: CONUT score <5 (n = 239) and CONUT score ≥5 (n = 93) groups. We investigated the relationship between the nutritional status and clinical outcomes. ResultsThe CONUT score ≥5 group had significantly higher incidence of major bleeding (MB) compared to the CONUT score <5 group (4.6/100 person-years vs. 0.7/100 person-years, p < 0.01). On Cox hazard analysis, CONUT score ≥5 group was significantly associated with increased MB compared with the CONUT score <5 group (hazard ratio: 5.80, 95% confidence interval: 1.44–23.33, p = 0.013). In the DOAC group, the incidence of MB did not differ between the CONUT score ≥5 and CONUT score <5 groups (p = 0.54). In the warfarin group, MB occurred more frequently in the CONUT score ≥5 group than CONUT score <5 group (p < 0.01). There was no significant difference in the incidence of thromboembolic events between the CONUT score ≥5 and CONUT score <5 groups in both the DOAC and warfarin groups. ConclusionsThe prognostic values of the nutritional status based on the CONUT score for MB differed between AF patients aged 80 years and over receiving DOACs and those receiving warfarin. It may be favorable to use DOACs to avoid bleeding events in those with malnutrition.

Novel insights into clinical characteristics and in-hospital outcomes of patients undergoing percutaneous coronary intervention in Vietnam.

Little is known about percutaneous coronary intervention (PCI) practices and outcomes in low-and middle-income nations, despite its rapid uptake across Asia. For the first time, we report on clinical characteristics and in-hospital outcomes for patients undergoing PCI at a leading cardiac centre in Vietnam. Information on characteristics, treatments, and outcomes of patients undergoing PCI was collected into the first PCI registry through direct interviews using a standardised form, medical record abstraction, and reading PCI imaging data on secured disks. Subgroup analysis was also conducted to explore gender differences. Between September 2017 and May 2018, 1022 patients undergoing PCI were recruited from a total of 1041 procedures. The mean age was 68.3years and two thirds were male. While 54.4% of patients presented with acute coronary syndromes, the rate of ST-elevation myocardial infarction was 14.5%. The majority of lesions were classified as type B2 and C and the radial artery was the most common access location for PCI (79.2%). The use of drug-eluting stents was universal and the angiographic success rate was 99.4%. Cardiac complications following PCI were rare with the exception of major bleeding (2.0%). Female patients were older with relatively more comorbidities and a higher incidence of major bleeding than males (p<0.05). Findings of this study provide an opportunity to benchmark current PCI practices in Vietnam, identify possible care gaps and potentially inform the adoption of treatment guidelines as well as use of prevention strategies.

Effect of Temporary Interruption of Warfarin Due to an Intervention on Downstream Time in Therapeutic Range in Patients With Atrial Fibrillation (from ORBIT AF)

The aim of this study was to quantify time in therapeutic range (TTR) before and after a temporary interruption of warfarin due to an intervention in the Outcomes Registry for Better Informed Treatment of atrial fibrillation (AF). AF patients on warfarin who had a temporary interruption followed by resumption were identified. A nonparametric method for estimating survival functions for interval censored data was used to examine the first therapeutic International Normalized Ratio (INR) after interruption. TTR was compared using Wilcoxon signed rank test. Cox proportional hazards model was used to investigate the association between TTR in the first 3 months after interruption and subsequent outcomes at 3 to 9 months. Of 9,749 AF patients, 71% were on warfarin. Over a median (IQR) follow-up of 2.6 (1.8 to 3.1) y, 33% of patients had a total of 3,022 temporary interruptions. The first therapeutic INR was recorded within 1 week in 35.0% (95% confidence interval 32.6% to 37.4%), 2 weeks in 54.6% (52.2% to 57.0%), 30 days in 70.0% (67.9% to 72.1%) and 90 days in 91.3% (90.0% to 92.5%) of patients. Compared with pre-interruption, TTR 3 months after interruption was significantly lower (61.1% [36.6% to 85.0%] vs 67.6% [50.0% to 81.3%], p <0.0001). A 10 unit increment in the TTR in the first 3 months after interruption was associated with a lower risk of major bleeding [Hazard ratio 0.91 (0.85 to 0.97), p = 0.005]. This association was noted in patients who received bridging anticoagulation, but not in those who did not. In conclusion, temporary interruption of warfarin is common, and nearly half of these patients had subtherapeutic INR after 2 weeks. Lower TTR in the first 3 months after interruption was associated with higher incidence of major bleeding in patients who received bridging anticoagulation.

Prevención de trombosis protésica por anticoagulación luego de sustitución valvular aórtica con bioprótesis. Metaanálisis

Background: increased risk of thrombosis and clinical events has been reported in patients receiving bioprostheses after aortic valve replacement or transcatheter aortic valve implant.Objective: to assess whether the use of anticoagulation for at least 90 days decreases and / or prevents occurrence of thrombo-embolic or subclinical thrombosis in patients with biological aortic valve replacement. To evaluate the incidence of bleeding and mortality associated with this strategy.|Methods: we searched articles in databases: PubMed, Central Cochrane, Cochrane Library and SciELO. The terms used were: “Anticoagulation AND aortic bioprosthesis” and “Anticoagulation AND TAVI OR TAVR”. Inclusion and exclusion criteria were established, performing the analysis of clinical and subclinical events separately. The statistic used was odds ratio (OR). A randomized effects model was used to calculate the statistic and its 95% confidence interval (CI).The meta-analysis results were presented as a forest diagram. We consider p <0.05 significant.Results: 233 articles were identified; selecting 8 for clinical thrombosis and 5 for subclinical thrombosis. There was no significant difference in the incidence of embolic events with the use of oral anticoagulation (OR = 1.01; 95% CI: 0.63-1.61;p = 0.98) or short-term mortality (OR = 1.10; 95% CI: 0.77-1.56;p = 0.61). A higher incidence of major bleeding was demonstrated in patients receiving oral anticoagulation (OR = 1.60; 95% CI: 1.04-2.48; p = 0.03). The risk of subclinical prosthetic thrombosis was higher in patients who did not receive oral anticoagulation (OR = 5.52; 95% CI: 3.37-9.05; p = 0.001).Conclusions: oral anticoagulation is associated with a lower risk of subclinical prosthetic thrombosis, increasing the risk of bleeding. Between the groups compared, there is no difference in mortality or embolic phenomena at medium term.

517 Novel Insights into Clinical Characteristics and In-Hospital Outcomes of Patients Undergoing Percutaneous Coronary Intervention in Vietnam

Despite the rapid uptake of percutaneous coronary intervention (PCI) in Asia, little is known about patient characteristics and outcomes following the procedure in low-and middle-income nations. To report on the clinical characteristics and in-hospital outcomes for patients undergoing PCI in Vietnam. 1,022 patients undergoing PCI were recruited from September 2017 to May 2018 in the first PCI registry established in the Vietnam National Heart Institute. Patients were categorized in male (n=696) and female (n=326) groups and analysed. The mean age was 68.3±10.3 years and two thirds were male. Diabetes, hyperlipidemia, hypertension and current smoking were observed in 27.3%, 29.9%, 67.2% and 25.5% of patients, respectively. While 54.4% of patients presented with acute coronary syndromes, the rate of ST-elevation myocardial infarction was 14.5%. The majority of lesions were classified as type B2 and C and the radial artery was the most common access location for PCI. The mean number of stents per patient was 1.5±0.71. The use of drug-eluting stents was universal and the angiographic success rate was 99.4%. Cardiac complications following PCI were rare with the exception of major bleeding (2.0%). Female patients were older with relatively more comorbidities and a higher incidence of major bleeding than males (p<0.05). Findings of this study provide an opportunity to benchmark current PCI practices in Vietnam, identify possible care gaps and potentially inform the adoption of treatment guidelines as well as use of prevention strategies.

Ventricular arrhythmias in patients with biventricular assist devices.

Ventricular arrhythmias (VAs) are common in patients after left ventricular assist device (LVAD) implant and are associated with worse outcomes. However, the prevalence and impact of VA in patients with durable biventricular assist device (BIVAD) is unknown. We performed a retrospective cohort study of patients with BIVADs to evaluate the prevalence of VA and their clinical outcomes. Consecutive patients who received a BIVAD between June 2014 and July 2017 at our medical center were included. The prevalence of VA, defined as sustained ventricular tachycardia or fibrillation requiring defibrillation or ICD therapy, was compared between BIVAD patients and a propensity-matched population of patients with LVAD from our center. The occurrence of adverse clinical events was compared between BIVAD patients with and without VA. Of the 13 patients with BIVADs, 6 patients (46%) experienced clinically significant VA, similar to a propensity-matched LVAD population (38%, p = 1.00). There were no differences in baseline characteristics between the two cohorts, except patients in the non-VA group who had worse hemodynamics (mitral regurgitation and right-sided indices), had less history of VA, and were younger. BIVAD patients with VA had a higher incidence of major bleeding (MR 3.05 (1.07-8.66), p = 0.036) and worse composite outcomes (log-rank test, p = 0.046). The presence of VA was associated with worse outcomes in both LVAD and BIVAD groups. Ventricular arrhythmias are common in patients with BIVADs and are associated with worse outcomes. Future work should assess whether therapies such as ablation improve the outcome of BIVAD patients with VA.

Ticagrelor in Patients with Stable Coronary Disease and Diabetes

BackgroundPatients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear.MethodsIn this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.ResultsA total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P=0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P=0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P=0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02).ConclusionsIn patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.)

Anticoagulation with Vitamin K Antagonists Versus Antiplatelet Therapy After Surgical Bioprosthetic Valve Implantation in the Prevention of Thromboembolism: A Meta-Analysis of Randomized Controlled Trials

BACKGROUND: The optimum medical therapy in the first three months after surgical bioprosthetic valve implantation (BVI) remains controversial. Current guidelines of the American College of Cardiology recommend either anticoagulation with vitamin K antagonists (VKA) (level IIa) or antiplatelet (AP) using aspirin (level IIa) after surgery, which is based on non-randomized studies. Hence, we performed a meta-analysis of randomized controlled trials (RCT) comparing the efficacy and safety of VKA vs AP therapy early after surgical BVI. METHODS: An extensive search of PubMed, Medline, Cochrane and Ovid was performed for RCTs comparing VKA vs AP therapy among adult patients who underwent surgical BVI. Outcome measures for thromboembolism, all-cause mortality and major bleeding were extracted and analyzed using a random effect model via Review Manager V5.3. RESULTS: Three RCTs with 590 patients were included. There were no differences in the rates of thromboembolic events (5% vs 6.8%; p=0.37) or all-cause mortality (4.7% vs 5.8% p=0.64) between the VKA vs AP groups There was a higher incidence of major bleeding in the VKA group (6% vs 2.4%), which was statistically significant (OR 2.63 (95% CI 1.08–6.43; p=0.03)). CONCLUSION: Vitamin K antagonist and AP therapies have similar rates of thromboembolic events and all-cause mortality in the first three months among patients post-surgical BVI. However, VKAs have a significantly higher incidence of major bleeding, which suggests that AP therapy may be the preferable strategy for anticoagulation in BVI post-surgery. KEYWORDS: Prosthetic heart valve, Anticoagulation, Antiplatelet therapy, Bioprosthetic Valve Implantation

Bleeding in Patients Treated With Ticagrelor or Clopidogrel Before Coronary Artery Bypass Grafting

We evaluated perioperative bleeding after coronary artery bypass grafting (CABG) in patients preoperatively treated with ticagrelor or clopidogrel, stratified by discontinuation of these P2Y12 inhibitors. All patients from the prospective, European Multicenter Registry on Coronary Artery Bypass Grafting (E-CABG) treated with ticagrelor or clopidogrel undergoing isolated primary CABG were eligible. The primary outcome measure was severe or massive bleeding defined according to the Universal Definition of Perioperative Bleeding, stratified by P2Y12 inhibitor discontinuation. Secondary outcome measures included four additional definitions of major bleeding. Propensity score matching was performed to adjust for differences in preoperative and perioperative covariates. Of 2,311 patients who were included, 1,293 (55.9%) received clopidogrel and 1,018 (44.1%) ticagrelor preoperatively. Mean time between discontinuation and the operation was 4.5 ± 3.2 days for clopidogrel and 4.9 ± 3.0 days for ticagrelor. In the propensity score-matched cohort, ticagrelor-treated patients had a higher incidence of major bleeding according to Universal Definition of Perioperative Bleeding when ticagrelor was discontinued 0 to 2 days compared with 3 days before the operation (16.0% vs 2.7%, p= 0.003). Clopidogrel-treated patients had a higher incidence of major bleeding according to the Universal Definition of Perioperative Bleeding when clopidogrel was discontinued 0 to 3 days compared with 4 to 5 days before the operation (15.6% vs 8.3%, p= 0.031). In patients receiving ticagrelor 2 days before CABG and in those receiving clopidogrel 3 days before CABG, there was an increased rate of severe bleeding. Postponing nonemergent CABG for at least 3 days after discontinuation of ticagrelor and 4 days after clopidogrel should be considered.

Cardiology update – Third quarter

In continuation of previous updates this article contains some recent trials which includes CAPTURE study that showed benefits of carotid filter in stroke prevention,THEMIS study showed that in stable CAD patients ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than aspirin alone, AMBER study concluded that potassium binder patiromer enabled more patients to continue treatment with spironolactone with less hyperkalaemia.

A cost-effectiveness and safety analysis of dual antiplatelet therapy comparing aspirin–clopidogrel to aspirin–ticagrelor in patients with acute coronary syndrome

Background: Dual antiplatelet therapy (DAPT) using either an aspirin–clopidogrel (A–C) combination or aspirin–ticagrelor (A–T) combination has become the standard therapy for acute coronary syndrome (ACS). Ticagrelor shows better pharmacokinetic profiles but is more expensive. This study aimed to compare cost-effectiveness and safety profiles of A–C versus A–T in patients with ACS.Methods: This was a retrospective cohort study of ACS patient at the Cipto Mangunkusumo Hospital between 2014 and 2016. ACS patients treated for the first time with A–T or A–C were included. Occurrence of major adverse cardiovascular events (MACE) within 3, 6, 9, and 12 months were used as effectiveness outcomes, while safety outcomes were measured based on the incidence of adverse drug reactions (major and minor bleeding, dyspnea, and hyperuricemia). Cost-effectiveness analysis was presented as incremental cost-effectiveness ratio (ICER).Results: Data records obtained from 123 ACS patients treated with A–C and 57 ACS patients treated with A–T were evaluated. Within the first three months, the MACE rate was 15.8% in the A–T group and 31.7% in the A–C group (RR: 0.498, 95% CI: 0.259–0.957, p=0.039). There was no statistically significant difference observed in the number of MACE between groups after 6, 9, and 12 months. The A–T group had a higher incidence of major bleeding (melena) than the A–C group (5.3% vs 1.62%, p=0.681), especially in geriatric patients. Minor bleeding was observed in three patients of the A–C group, but in none of the patients in the A–T group. The cost of ICER was IDR 279,438, indicating the additional cost needed for avoiding MACE within 3 months, if A–T was used.Conclusion: The aspirin–ticagrelor combination is a clinically superior and cost-effective option for MACE prevention among ACS patients, especially during the first three months of DAPT, with a slight but not significantly higher major bleeding risk when compared to the aspirin–clopidogrel combination.

Recurrent Venous Thromboembolism (VTE), Major Bleeding (MB), and Associated Cost of Treatment with Low Molecular Weight Heparin (LMWH) or Direct Oral Anticoagulant (DOAC) in High Risk Patients with Gastrointestinal (GI) Malignancies: Retrospective Real-World Analysis at a Comprehensive Cancer Center

Introduction:Cancer patients who experienced a venous thromboembolism (VTE) are at high risk for poor clinical outcomes; hence VTE recurrence prevention is salient. Low molecular weight heparin (LMWH) has been the preferred treatment for cancer-related VTE; however, direct oral anticoagulants (DOACs) have been prescribed empirically in cancer due to patient convenience. Although the recent HOKUSAI and SELECT-D trials have confirmed the non-inferiority of DOACs to LMWH in the management of recurrent VTE in cancer patients, there remain a continued safety concern for major bleeds (MB). Recurrent VTE and MB complications during anticoagulation treatment of GI cancer (GICA) patients are increased as compared to other cancer types. The incremental health care costs associated with VTE recurrences and MB episodes are significant and steadily increasing. In this retrospective analysis, we aimed (1) to evaluate for differences in the VTE recurrence rate and MB events based on anticoagulation therapy (LMWH or DOAC) prescribed with a prior VTE and (2) to calculate the associated healthcare costs for six months of treatment.Methods:We reviewed the medical records of patients with biopsy-proven GICA and imaging documented VTE treated with DOAC or LMWH from November 2013 to February 2017. Patients were excluded if anticoagulation was given for another treatment indication or cancer diagnosis. Adverse events of recurrent VTE and MB criteria were defined per the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Costs of LMWH and DOAC t was sourced from Medicare Reimbursement 2018. Hospital admission and adjusted 6-month ambulatory cots were sourced from Economic Evaluations of Anticoagulation Outcomes in the U.S. by Amin et al 2015. Costs were inflation-adjusted to 2018 cost levels using the Medical Care component of the Consumer Price Index. The Chi-squared test was used for overall and the Fisher exact test for pairwise comparisons of the proportions of patients experiencing VTE and MB events.Results:Our analysis included 106 patients on enoxaparin (N=40), rivaroxaban (N=37) and apixaban (N=29). Recurrent VTE outcomes at 6 months were 3 (7.5%) for enoxaparin, 1 (2.7%) for rivaroxaban, and 2 (6.8%), for apixaban (all p=n.s.) (Table 1). Major bleeding events at 6 months were 2 (5%) for enoxaparin, 2 (6.8%) for apixaban, and a significantly higher 8 (21.6%) for rivaroxaban (overall p=0.048; v. LMWH pairwise p=0.042; all other p=n.s.). The estimated composite costs associated with the observed recurrent VTE event rates were $173,130 for enoxaparin, $57,710 for rivaroxaban, and $115,420 for apixaban. The estimated composite costs associated with the observed MB event rates were $117,146 for enoxaparin and apixaban, versus $468,558 for rivaroxaban. The estimated total 6-months healthcare costs for recurrent VTE, MB and prescriptions were $293,784 for enoxaparin, $529,336 for rivaroxaban, and $235,634 for apixaban.Conclusion:Our real-world retrospective analysis corroborates a non-inferiority of DOACs to LMWH in preventing recurrent VTE in GICA patients at 6 months but a higher incidence of MB in rivaroxaban v. LMWH treated patients. The higher MB rate for rivaroxaban mainly accounts for the higher overall costs of this DOAC v. LMWH and apixaban. In absolute total costs, apixaban prevails over LMWH and rivaroxaban, and LMWH prevails over rivaroxaban in cost-efficiency in this analysis of anticoagulation in selected high-risk GICA patients. Rivaroxaban significantly increases medical costs, mainly driven by the total number of major bleed adverse events in GICA patients, confirming previously published evidence. The subpopulation of GICA patients at high risk of VTE/MB warrants an additional prospective clinical trial for primary safety major bleed outcomes of DOACs with an accompanying cost-effectiveness analysis. This may eventually reduce the healthcare economic burden. DisclosuresAbraham:Sandoz: Consultancy.

Safety and efficacy of rivaroxaban compared with warfarin in patients undergoing peripheral arterial procedures

ObjectiveRivaroxaban is a United States Food and Drug Administration-approved oral anticoagulant for venous thromboembolic disease; however, there is no information regarding the safety and its efficacy to support its use in patients after open or endovascular arterial interventions. We report the safety and efficacy of rivaroxaban vs warfarin in patients undergoing peripheral arterial interventions. MethodsThis single-institution retrospective study analyzed all sequential patients from December 2012 to August 2014 (21 months) who were prescribed rivaroxaban or warfarin after a peripheral arterial procedure. Our study population was then compared using American College of Chest Physicians guidelines with patients then stratified as low, medium, or high risk for bleeding complications. Statistical analyses were performed using the Student t-test and χ2 test to compare demographics, readmissions because of bleeding, and the need for secondary interventions. Logistic regression models were used for analysis of variables associated with bleeding complications and secondary interventions. The Fisher exact test was used for power analysis. ResultsThere were 44 patients in the rivaroxaban group and 50 patients in the warfarin group. Differences between demographics and risk factors for bleeding between groups or reintervention rate were not statistically significant (P = .297). However, subgroup evaluation of the safety profile suggests that patients who were aged ≤65 years and on warfarin had an overall higher incidence of major bleeding (P = .020). Patients who were aged >65 years, undergoing open operation, had a significant risk for reintervention (P = .047) when they received rivaroxaban. ConclusionsReal-world experience using rivaroxaban and warfarin in patients after peripheral arterial procedures suggests a comparable safety and efficacy profile. Subgroup analysis of those requiring an open operation demonstrated a decreased bleeding risk when rivaroxaban was used (in those aged <65 years) but an increased risk for secondary interventions. Further studies with a larger cohort are required to validate our results.

Asymptomatic Lower Extremity Deep Vein Thrombosis - Clinical Characteristics, Management Strategies, and Long-Term Outcomes.

The prognosis of asymptomatic deep vein thrombosis (DVT) is uncertain and there is no consensus on the necessity of detection and treatment.Methods and Results:We retrospectively evaluated 300 patients with asymptomatic lower extremity DVT screened from 4,514 consecutive patients on ultrasound at Kyoto University Hospital between January 2010 and September 2015. The subjects had concomitant active cancer in 40%, unprovoked DVT in 59%, and distal DVT in 70%. The cumulative 5-year incidences of symptomatic recurrent venous thromboembolism (VTE); major bleeding; and all-cause death were 14.5%, 16.6%, and 34.1%, respectively. Among 232 patients (77%) with prolonged anticoagulant therapy, anticoagulants were discontinued in 48.4% at 1 year. Anticoagulant therapy was associated with a significantly higher incidence of major bleeding compared with the non-anticoagulant group (20.5% vs. 1.5%, P=0.01) with no significant effect on the incidence of VTE. In patients with active cancer, the favorable effect of anticoagulants relative to no anticoagulants for VTE was significant (HR, 0.22; 95% CI: 0.05-0.95). Prolonged anticoagulants therapy was implemented in the majority of patients with asymptomatic DVT, but was associated with a significantly higher risk for major bleeding. On subgroup analysis in patients with active cancer, however, there appeared to be a benefit of prolonged anticoagulant therapy in decreasing the rate of symptomatic recurrent VTE.

Improved outcomes from extracorporeal membrane oxygenation versus ventricular assist device temporary support of primary graft dysfunction in heart transplant

Primary graft dysfunction (PGD) is one of the most common causes of early death after orthotopic heart transplantation. Mechanical circulatory support devices are required for severe forms of PGD. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) and temporary ventricular assist device (VAD) support have both been reported to be useful for severe PGD. Between January 2007 and December 2015, 597 patients received a heart transplant at our center. Of those, severe PGD developed in 44 patients (7.4%), and they received a continuous-flow external VAD (n = 17) or VA-ECMO (n = 27) support within 24 hours after transplant. We compared early and late outcomes between groups. Baseline characteristics were similar between groups. Implantation of the temporary VAD required longer cardiopulmonary bypass time compared with VA-ECMO (323 ± 86 minutes vs 216 ± 65 minutes, p < 0.0001). Patients who received a VAD were more likely to have longer support time (14 ± 17 days vs 5.2 ± 3.9 days, p = 0.011), a higher incidence of major bleeding requiring chest reexploration (77% vs 30%, p = 0.0047), and a higher incidence of renal failure requiring renal replacement therapy (53% vs 11%, p = 0.0045) after surgery. Overall hospital mortality was 27%. In-hospital mortality for VAD and VA-ECMO patients were 41% and 19%, respectively (p = 0.16). Ten patients (59%) were weaned from VAD support, and 24 (89%) were weaned from VA-ECMO support after adequate graft function recovery (p = 0.03). The 3-year post-transplant survival was 41% in the VAD group and 66% in the VA-ECMO group (p = 0.13). For severe PGD, support with VA-ECMO appears to result in better clinical outcomes compared with VAD.