Reduction In Thrombotic Events Research Articles

Effectiveness and safety of rivaroxaban for anticoagulation therapy in COVID-19: A meta-analysis of randomized controlled trials.

To evaluate the effectiveness and safety of rivaroxaban anticoagulation in COVID-19 patients. PubMed, Embase, Cochrane Library electronic databases, and ClinicalTrials.gov were searched to identify all relevant randomized controlled trial studies from December 2019 to July 2023. A total of 6 randomized controlled trials, which included a total of 3323 patients, were considered for evaluation. Overall, short-term all-cause mortality and hospitalization rates were not significantly different between the rivaroxaban and control groups. Thrombotic events were significantly reduced in the rivaroxaban prophylaxis group compared to the placebo control group. However, the reduction in thrombotic events was not significantly different between rivaroxaban therapy and heparin or low-molecular-weight heparin (LMWH). Rivaroxaban prophylaxis and the therapeutic dose may be associated with a higher rate of overall bleeding rate, but major bleeding rates did not differ substantially. Rivaroxaban may reduce thrombotic events in COVID-19 patients, but it does not appear to have an advantage over heparin or LMWH, and it may increase the risk of bleeding.INPLASY Reg. No.: INPLASY 202370097.

Factor XI inhibition in patients with acute coronary syndrome.

A hypercoagulable condition is typical of patients with acute coronary syndrome and is a determining factor in the genesis of recurrent ischaemic events. Modern pharmacological therapies consisting of antiplatelets and anticoagulants derive their rationale for use on the pathophysiological mechanisms most commonly associated with myocardial infarction (MI); they have contributed to reducing the ischaemic risk of these patients, but left ample room for improvement. In particular, trials that have studied the association of an anticoagulant with antiplatelet drugs have provided promising results in terms of efficacy, but highlighted a significant bleeding risk. Evidence derived from experimental animal and epidemiological studies has shown how factor XI (FXI) deficiency is associated with a reduction in thrombotic events but with modest bleeding. These data added to the role that FXI plays in the coagulation cascade constituted an incipit for the pharmacological attempt to decouple thrombosis from haemostasis by means of the inhibition of this factor. The theoretical assumption that FXI inhibitor drugs may be able to reduce the ischaemic risk without significantly increasing the haemorrhagic risk makes these compounds a potential therapeutic aid for patients in secondary prevention after acute MI. To date, on these patients, we only have data from a Phase 2 trial, PACIFIC-AMI (Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2 433 334 in Patients Following an Acute Heart Attack). In this study, the primary endpoint-represented by the Bleeding Academic Research Consortium (BARC) composite of Type 2, 3, or 5 bleeding-showed no significant differences between the various doses of asundexian tested (10, 20, and 50 mg quoque die), and between these and placebo (asundexian all doses vs. placebo: hazard ratio, 0.98; 90% confidence interval, 0.71-1.35). The data on efficacy, however, showed neutral results, but it should be noted that the study did not have the adequate statistical power to evaluate this outcome. Valuable information could, therefore, derive in the future from the ongoing Phase 3 trial with milvexian, LIBREXIA-ACS (A Study of Milvexian in Participants After a Recent Acute Coronary Syndrome) and from any future studies that could be started by testing different molecules.

Superiority of bivalirudin over heparin anticoagulation therapy for extracorporeal membrane oxygenation? Too early to draw conclusions

BackgroundWe aimed to compare the efficacy and safety of bivalirudin versus heparin as the anticoagulant in patients undergoing extracorporeal membrane oxygenation (ECMO). MethodsWe conducted a search in PubMed, Embase and the Cochrane Library for all the studies in which bivalirudin was compared to heparin as the anticoagulant for ECMO. Efficacy outcomes were defined as the time to reach therapeutic levels, time within therapeutic range (TTR), thrombotic events, circuit thrombosis, circuit exchanges. Safety outcomes were reported as heparin-induced thrombocytopenia (HIT), major bleeding events, minor bleeding events. Other outcomes included hospital length of stay (LOS), ICU LOS, mortality, 30-day mortality and in-hospital mortality. ResultsTen studies with 1091 patients were included for meta-analysis. A significant reduction in thrombotic events [OR 0.51, 95%CI 0.36,0.73, p = 0.0002, I2 = 0%], major bleeding events [OR 0.31, 95%CI 0.10,0.92, p = 0.04, I2 = 75%] and in-hospital mortality [OR 0.63, 95%CI 0.44,0.89, p = 0.009, I2 = 0%] treated with bivalirudin were found compared with heparin. There were no significant differences between groups regarding the time to reach therapeutic levels [MD 3.53, 95%CI −4.02,11.09, p = 0.36, I2 = 49%], TTR [MD 8.64, 95%CI −1.72,18.65, p = 0.10, I2 = 77%], circuit exchanges [OR 0.92, 95%CI 0.27,3.12, p = 0.90, I2 = 38%], HIT [OR 0.25, 95%CI 0.02,2.52, p = 0.24, I2 = 0%], minor bleeding events [OR 0.93, 95%CI 0.38,2.29, p = 0.87, I2 = 0%], hospital LOS [MD −2.93, 95%CI -9.01,3.15, p = 0.34, I2 = 45%], ICU LOS [MD −4.22, 95%CI -10.07,1.62, p = 0.16, I2 = 0%], mortality [OR 1.84, 95%CI 0.58,5.85, p = 0.30, I2 = 60%] and 30-day mortality [OR 0.75, 95%CI 0.38,1.48, p = 0.41, I2 = 0%]. ConclusionBivalirudin probably be a potential choice for ECMO anticoagulation. However, based on the included studies’ limitation, the superiority of bivalirudin over heparin for anticoagulation in the ECMO population still require further prospective randomized controlled studies before a definite conclusion.

Historical Review and Future of Cardiac Xenotransplantation.

Along with the development of immunosuppressive drugs, major advances on xenotransplantation were achieved by understanding the immunobiology of xenograft rejection. Most importantly, three predominant carbohydrate antigens on porcine endothelial cells were key elements provoking hyperacute rejection: α1,3-galactose, SDa blood group antigen, and N-glycolylneuraminic acid. Preformed antibodies binding to the porcine major xenoantigen causes complement activation and endothelial cell activation, leading to xenograft injury and intravascular thrombosis. Recent advances in genetic engineering enabled knock-outs of these major xenoantigens, thus producing xenografts with less hyperacute rejection rates. Another milestone in the history of xenotransplantation was the development of co-stimulation blockaded strategy. Unlike allotransplantation, xenotransplantation requires blockade of CD40-CD40L pathway to prevent T-cell dependent B-cell activation and antibody production. In 2010s, advanced genetic engineering of xenograft by inducing the expression of multiple human transgenes became available. So-called 'multi-gene' xenografts expressing human transgenes such as thrombomodulin and endothelial protein C receptor were introduced, which resulted in the reduction of thrombotic events and improvement of xenograft survival. Still, there are many limitations to clinical translation of cardiac xenotransplantation. Along with technical challenges, zoonotic infection and physiological discordances are major obstacles. Social barriers including healthcare costs also need to be addressed. Although there are several remaining obstacles to overcome, xenotransplantation would surely become the novel option for millions of patients with end-stage heart failure who have limited options to traditional therapeutics.

Dual therapy with oral anticoagulation and single antiplatelet agent versus monotherapy with oral anticoagulation alone in patients with atrial fibrillation and stable ischemic heart disease: a systematic review and meta-analysis.

In patients with atrial fibrillation (AF) and stable ischemic heart disease, recent guidelines recommend oral anticoagulant (OAC) monotherapy in preference to OAC + single antiplatelet agent (SAPT) dual therapy. However, these data are based on the results of only two randomized controlled trials (RCTs) and a relatively small group of patients. Thus, the safety and efficacy of this approach may be underpowered to detect a significant difference. We hypothesized that OAC monotherapy will have a reduced risk of bleeding, but similar all-cause mortality and ischemic outcomes as compared to dual therapy (OAC + SAPT). A systematic search of PubMed/MEDLINE, EMBASE, and Scopus was conducted. Safety outcomes included total bleeding, major bleeding, and others. Efficacy outcomes included all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, and major adverse cardiovascular events (MACE). RCTs and observational studies were pooled separately (study design stratified meta-analysis). Subgroup analyses were performed for vitamin K antagonists and direct oral anticoagulants (DOACs). Pooled risk ratios (RR) with corresponding 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method. Meta-analysis of 2 RCTs comprising a total of 2905 patients showed that dual therapy (OAC + SAPT) vs. OAC monotherapy was associated with a statistically significant increase in major bleeding (RR 1.51; 95% CI [1.10, 2.06]). There was no significant reduction in MACE (RR 1.10; [0.71, 1.72]), stroke (RR 1.29; [0.85, 1.95]), myocardial infarction (RR 0.57; [0.28, 1.16]), cardiovascular mortality (RR 1.22; [0.63, 2.35]), or all-cause mortality (RR 1.18 [0.52, 2.68]). Meta-analysis of 20 observational studies comprising 47,451 patients showed that dual therapy (OAC + SAPT) vs. OAC monotherapy was associated with a statistically significant higher total bleeding (RR 1.50; [1.20, 1.88]), major bleeding (RR = 1.49; [1.38, 1.61]), gastrointestinal bleeding (RR = 1.62; [1.15, 2.28]), and myocardial infarction (RR = 1.15; [1.05, 1.26]), without significantly lower MACE (RR 1.10; [0.97, 1.24]), stroke (RR 0.93; [0.73, 1.19]), cardiovascular mortality (RR 1.11; [0.95, 1.29]), or all-cause mortality (RR 0.93; [0.78, 1.11]). Subgroup analysis showed similar results for both vitamin K antagonists and DOACs, except a statistically significant higher intracranial bleeding with vitamin K antagonist + SAPT vs. vitamin K antagonist monotherapy (RR 1.89; [1.36-2.63]). In patients with AF and stable ischemic heart disease, OAC + SAPT as compared to OAC monotherapy is associated with a significant increase in bleeding events without a significant reduction in thrombotic events, cardiovascular mortality, and all-cause mortality.

Use of anticoagulants in patients with COVID-19: a living systematic review and meta-analysis.

ABSTRACTObjective:To answer questions related to the use of anticoagulants in the treatment of COVID-19 patients. Methods:This was a systematic review and meta-analysis of phase 3 randomized controlled trials comparing the use of anticoagulants in non-hospitalized and hospitalized COVID-19 patients. We searched the following databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to January 22, 2022. The risk of bias was assessed by the Cochrane risk-of-bias tool, and the quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation system. Results:A total of 401 studies were initially selected. Of those, 9 met the inclusion criteria and were therefore analyzed (a total of 6,004 patients being analyzed). In non-hospitalized COVID-19 patients, no significant difference was found between post-discharge prophylactic anticoagulation and no intervention regarding venous thromboembolism or bleeding at 30 days. In hospitalized COVID-19 patients, full anticoagulation resulted in a slight reduction in thrombotic events at 30 days (risk difference, −0.03; 95% CI, −0.06 to −0.00; p = 0.04; I2 = 78%), the quality of evidence being moderate. However, no significant difference was found between full anticoagulation and no intervention regarding the risk of major bleeding, the quality of evidence being very low. No significant difference was found between intermediate- and standard-dose prophylactic anticoagulation (risk difference, −0.01; 95% CI, −0.07 to 0.06; p = 0.81; I2 = 0%), the quality of evidence being very low. Conclusions:Therapeutic anticoagulation appears to have no effect on mortality in COVID-19 patients, resulting in a slight reduction in venous thromboembolism in hospitalized patients.

Thromboinflammation in cardiovascular disease: lessons learned for the management of hypertension, heart failure, and aortic valve stenosis.

Thromboinflammation has emerged as a new term to describe the interconnection between the simultaneous activation of the coagulation and the immune system. It is the flipside of immunothrombosis, an evolutionary highly conserved mechanism of innate immunity that has developed to allow trapping and compartimentalization of invaded pathogens and to improve host defence. In contrast to immunothrombosis, it occurs in the absence of a pathogen, but is triggered mainly by endothelial dysfunction. This may lead to release of pro-inflammatory cytokines as well as chemokines and adhesion molecules, activation of myeloid cells, decryption of tissue factor on the surface of neutrophils and monocytes, release of von Willebrand factor (vWF) from platelets and endothelial cell Weibel–Palade bodies, and netting of neutrophils with consecutive activation of the contact phase of the coagulation cascade and FXa/thrombin activation, implying both thrombin propagation via the FXI feedback activation and increased fibrin deposition.1 In cardiovascular diseases (CVDs), paradigmatic conditions of thromboinflammation are endothelial erosion as a mechanism of acute coronary syndrome in the absence of plaque rupture [Type II myocardial infarction (MI)],2 deep vein thrombosis induced by low flow,3 and atherogenesis propelled by a chronically activated coagulation cascade.4 In some indications, recent advances in pharmacotherapy were successful in ameliorating the disease burden evoked by thromboinflammation. For example, long-term FXa inhibition can reduce thrombosis-associated morbidity and mortality in cancer, when administered for primary prevention of venous thromboembolism in selected patients,5 and low-dose rivaroxaban in addition to aspirin can lower major adverse cardiovascular events and all-cause mortality in patients with coronary artery disease who had an MI in the past.6 These findings of the COMPASS trial merit special consideration, because one-fourth of the anticoagulant dose of rivaroxaban was efficient for reaching this endpoint including reduction in thrombotic events, which has been attributed to vascular protection mediated through protease-activated receptor inhibition instead of reducing thrombin and fibrin formation in this population of non-atrial fibrillation patiens. The identification of the thrombin-FXI feedback amplification loop for thrombin propagation holds promise to avoid blood clotting without abolishing haemostasis and has sparked the development of novel FXI(a) inhibitors for safer anticoagulation7 that seamlessly align into the concept of thromboinflammation (Figure 1).

Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

SummaryBackgroundAspirin has been proposed as a treatment for COVID-19 on the basis of its anti-thrombotic properties. We aimed to evaluate the efficacy and safety of aspirin in patients admitted to hospital with COVID-19.MethodsIn this randomised, controlled, open-label, platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. The trial took place at 177 hospitals in the UK, two hospitals in Indonesia, and two hospitals in Nepal. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care plus 150 mg aspirin once per day until discharge or usual standard of care alone using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28 day mortality. All analyses were done by intention to treat. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).FindingsBetween Nov 1, 2020, and March 21, 2021, 14 892 (66%) of 22 560 patients enrolled into the RECOVERY trial were eligible to be randomly allocated to aspirin. 7351 patients were randomly allocated (1:1) to receive aspirin and 7541 patients to receive usual care alone. Overall, 1222 (17%) of 7351 patients allocated to aspirin and 1299 (17%) of 7541 patients allocated to usual care died within 28 days (rate ratio 0·96, 95% CI 0·89–1·04; p=0·35). Consistent results were seen in all prespecified subgroups of patients. Patients allocated to aspirin had a slightly shorter duration of hospitalisation (median 8 days, IQR 5 to >28, vs 9 days, IQR 5 to >28) and a higher proportion were discharged from hospital alive within 28 days (75% vs 74%; rate ratio 1·06, 95% CI 1·02–1·10; p=0·0062). Among patients not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs 22%; risk ratio 0·96, 95% CI 0·90–1·03; p=0·23). Aspirin use was associated with a reduction in thrombotic events (4·6% vs 5·3%; absolute reduction 0·6%, SE 0·4%) and an increase in major bleeding events (1·6% vs 1·0%; absolute increase 0·6%, SE 0·2%).InterpretationIn patients hospitalised with COVID-19, aspirin was not associated with reductions in 28 day mortality or in the risk of progressing to invasive mechanical ventilation or death, but was associated with a small increase in the rate of being discharged alive within 28 days.FundingUK Research and Innovation (Medical Research Council), National Institute of Health Research, and the Wellcome Trust through the COVID-19 Therapeutics Accelerator.

Efficacy and safety of glycoprotein IIb/IIIa inhibitors in addition to P2Y12 inhibitors in ST-segment elevation myocardial infarction: A subanalysis of the POPular Genetics trial.

Glycoprotein IIb/IIIa inhibitors (GPI) are still used in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI), although discussion about its clinical benefit is ongoing. GPI use was analyzed in this subanalysis of the POPular Genetics trial, which randomized STEMI patients to CYP2C19 genotype-guided treatment (clopidogrel or ticagrelor) or standard treatment with ticagrelor/prasugrel. The composite thrombotic endpoint consisted of cardiovascular death, myocardial infarction (MI), definite stent thrombosis, and stroke at 30 days. The combined bleeding endpoint consisted of Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding at 30 days. Univariable and multivariable analyses in addition to a propensity score-matched (PSM) analysis were conducted. In total, 2378 patients, of whom 1033 received GPI and 1345 did not, were included. In multivariable analysis, GPI administration was associated with fewer thrombotic events (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.09-0.55) and MIs (HR 0.24, 95% CI 0.08-0.73). Furthermore, GPI administration was associated with an increase in bleedings (HR 2.02, 95% CI 1.27-3.19), driven by minor bleedings (HR 2.32, 95% CI 1.43-3.76), without a significant difference in major bleedings (HR 0.69, 95% CI 0.19-2.57). In the PSM analysis, no significant association was found. In STEMI patients undergoing primary PCI, GPI administration was associated with a reduction in thrombotic events at a cost of an increase in (mostly minor) bleedings in multivariable analysis, while propensity score analysis did not show significant associations.

Risk of Thromboembolic Disease and Hemorrhage in Patients with Multiform Glioblastoma

Introduction: Glioblastoma Multiforme (GBM) is the most frequent malignant brain tumor, with an aggressive course and a short life expectancy despite standard treatment (chemotherapy and radiotherapy). The possibility of the development of Thrombotic Events (VTE) with this type of cancer is frequent. We designed this study to determine the risk of presenting VTE and hemorrhagic events in patients affected by GBM. Methods: Observational retrospective study of patients with GBM diagnosis at the General University Hospital of Ciudad Real between 2012 and 2015. The demographic characteristics of patients were studied, predictive models were compared, and a survival analysis was performed. Results: 77 patients were studied, 42 (55.3%)/34 (44.7%), men and women respectively, with an average age of 66.42 years. 13 (16.9%) presented VTE; of which 10 (61.54%) in the form of Deep Venous Thrombosis (DVT), 3 (23.08%) Pulmonary Embolism (PE) and 2 (15.38%) mixed events. The quality of life according to the performance status ECOG scale at the moment of diagnosis was 1 in 42 (15.38%) patients, and at the time of VTE, 5 (41.7%) had a value of 2, and 4 (33.3.3 %) registered 3. In the group that developed VTE according to the predictive model of risk for thrombosis in Khorana 5 (38.5%) had low risk and 8 (61.5%) intermediate; on the ASCO 2013 modified scale 5 (38.5%) had an Intermediate risk and 8 (61.5%) high. With a median, 1 year follow-up, 64 (84.2%) patients died, with an average time after the diagnosis of 279.09 days (216.6-341.6) (SE 31,8). 2 (2.6%) of the patients presented a greater haemorrhagic event and 7 (7.9%) cerebral haemorrhage, of which 4 (44.4%) had prophylactic Low Molecular Weight Heparins (LMWHs). In the survival analysis of Kaplan Meyer, patients who received prophylactic treatment with LMWHs had a higher survival rate with an average of 298.5 days compared to 239.3 of those who did not (p >0.05). There were no significant variables in the multivariate analysis for thrombotic or haemorrhagic events. Conclusion and Discussion: The demographic and clinical characteristics of our patients were similar to those reported in other international publications. The predictive scale of Khorana was not validated in our study, in contrast, the modified ASCO 2013 scale was closer to our results. The creation of a precise predictive model would help to delineate the benefit of prophylactic anticoagulation in high-risk patients. Long-term prophylaxis with LMWHs has demonstrated a reduction of thrombotic events without significantly increasing the fatal haemorrhagic episodes, also demonstrating greater long-term survival, independent of thrombotic events. Randomized prospective studies are needed to demonstrate its benefits.

P2Y12 Inhibitor Monotherapy After a Short Dual Antiplatelet Therapy Versus Standard-Term Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention: A Contemporary Meta-Analysis.

Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) reduces the incidence of thrombotic events but increases the risk of bleeding, which is associated with a substantial and durable risk of death and could offset the benefits of a reduction in thrombotic events. P2Y12 inhibitor monotherapy after short-term DAPT could be an option to reduce the risk of bleeding. We carried out a meta-analysis comparing P2Y12 inhibitor monotherapy after short-term DAPT with standard-term DAPT in patients undergoing PCI. We searched the PubMed and EMBASE databases through 11 April 2020. Two authors independently reviewed and selected eligible trials. The DerSimonian-Laird method with the binary random-effects model was used to calculate the relativerisk (RR) with 95% confidence interval (CI). Five trials involving 23,762 patients were included in the final analyses; four were open-label trials, while the TWILIGHT trial was double-blinded. Ticagrelor was used in three trials, and the other two trials included several P2Y12 inhibitors. P2Y12 inhibitor monotherapy after short-term DAPT significantly reduced the bleeding events, defined as Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding and Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, by 39% (RR 0.61, 95% CI 0.38-0.99; p = 0.045) and 46% (RR 0.56, 95% CI 0.42-0.73; p < 0.001), respectively. A significant reduction in cardiovascular death was associated with P2Y12 inhibitor monotherapy after short-term DAPT (RR 0.75, 95% CI 0.58-0.98; p = 0.037; I2 = 0). No significant difference in all-cause mortality, myocardial infarction, stroke, or definite or probable stent thrombosis was observed. This meta-analysis showed a significantly lowered risk of major bleeding and similar benefits of P2Y12 inhibitor monotherapy after short-term DAPT compared with standard-term DAPT in patients undergoing PCI.

P2Y12 INHIBITOR MONOTHERAPY AFTER A SHORT DUAL ANTIPLATELET THERAPY VS. 12-MONTH DUAL ANTIPLATELET THERAPY IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: A META-ANALYSIS

Dual Antiplatelet Therapy (DAPT) after PCI reduces the incidence of thrombotic events but increases the risk of bleeding, which is associated with a substantial and durable risk of death and could offset the benefits of a reduction in thrombotic events. P2Y12 inhibitor monotherapy after a short DAPT

A Multi-Center Quality Improvement Intervention to Reduce the Inappropriate Use of Aspirin Among Patients Anticoagulated with Warfarin for Atrial Fibrillation or Venous Thromboembolism

Introduction: For warfarin-treated patients with atrial fibrillation (AF) or venous thromboembolism (VTE), concomitant use of aspirin and warfarin increases the risk of major bleeding 1.5-1.8 fold without an apparent reduction in thrombotic events when there is no clear indication for combination therapy. As a result, each of six anticoagulation clinics in the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) consortium implemented a common intervention between late 2017 and mid 2018 aiming to reduce inappropriate aspirin use. The intervention consisted of a screening process to identify possible inappropriate aspirin use and then contacting the patient's provider to discuss the need for ongoing aspirin therapy. Site-level implementation variation included the personnel carrying out the intervention, the use of technology, and the means of provider communication. Treatment decisions were deferred to the treating provider but facilitated by the anticoagulation clinic staff. We sought to assess the impact of this intervention on the rate of inappropriate aspirin use over time and compare patient characteristics based on aspirin use post intervention. Methods: First, we compared the overall rate of inappropriate aspirin use among the six center MAQI2 anticoagulation clinic cohort immediately before and after the intervention. All patients in MAQI2 were treated with warfarin. Then, we identified a sub-cohort of warfarin-treated patients with AF and/or VTE enrolled between January 2010 to June 2019. Within that sub-cohort, we assessed aspirin use pre and post the site-specific date of implementation of the intervention. Patients with a potential indication for aspirin use were excluded (e.g., any history of coronary artery disease, myocardial infarction, percutaneous coronary intervention, mechanical heart valve replacement, left ventricular assist device placement, peripheral arterial disease, or coronary artery bypass grafting). Each site was able to further restrict who was targeted for intervention (for example, excluding patients with a history of antiphospholipid syndrome or stroke). Using site specific definitions for inappropriate aspirin use we identified four groups at the end of the study period: 1) patients not on aspirin, 2) aspirin-using patients without an apparent indication who stopped aspirin following implementation, 3) aspirin-using patients without an apparent indication who remained on aspirin following implementation, and 4) aspirin-using patients who developed an indication for aspirin during the study period. To assess inappropriate aspirin use in our cohort, the characteristics of the first three groups were compared. Results: Between August 2017 and May 2019, a total of 3,766 warfarin-treated patients enrolled in MAQI2. Following implementation, inappropriate aspirin use was reduced by 34% (from 27.9% [401/1437] to 18.5% [251/1356]). A sub-cohort of 1,007 patients who met the inclusion criteria had clinical follow-up pre and post intervention and were followed for an average of 40.1 months from enrollment to their first follow-up post-intervention. Of this sub-cohort, 226 (22.4%) were inappropriately on aspirin, with 50 (22.1%) stopping aspirin. A small number of patients 37 (3.7%) developed an indication for aspirin (e.g., myocardial infarction) during the study period and were removed from this analysis. As compared to patients not taking aspirin, patients on inappropriate aspirin were more often taking warfarin for AF, had congestive heart failure, chronic kidney disease, diabetes mellitus, hypertension, and had a higher Charlson Comorbidity index; they were less likely to have VTE or a history of VTE. As compared to patients continuing on aspirin following implementation, patients stopping inappropriate aspirin were more likely to have chronic kidney disease (p=0.02) or a history of falls (p=0.03). Conclusion: Among warfarin-treated patients with AF or VTE, inappropriate aspirin usage can be identified and significantly reduced using a simple intervention in the anticoagulation clinic. Patients at higher risk of bleeding may be more likely to have their aspirin discontinued. Further studies are needed to see if reducing inappropriate aspirin usage translates to improved clinical outcomes and to determine the reasons for patient persistence on inappropriate aspirin. Disclosures Kaatz: Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Portola: Honoraria. Kline-Rogers:AC Forum: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; QUANTUM-AF: Membership on an entity's Board of Directors or advisory committees. Sood:Bayer: Research Funding. Froehlich:Blue Cross Blue Shield of Michigan: Research Funding; Novartis: Honoraria; Boehringer-Ingelheim: Honoraria; Fibromuscular Dysplasia Society: Research Funding; Merck: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Barnes:Portola: Honoraria; Pfizer/Bristol Myers Squib: Research Funding; Pfizer: Honoraria; AMAG Pharmaceuticals: Honoraria; Bristol Myers Squib: Honoraria; Blue Cross Blue Shield of Michigan: Research Funding; Janssen: Honoraria.

Tailored P2Y12 inhibitor treatment in patients undergoing non-urgent PCI-the POPular Risk Score study.

The POPular Risk Score was developed for the selective intensification of P2Y12 inhibitor treatment with prasugrel instead of clopidogrel in patients undergoing non-urgent percutaneous coronary intervention (PCI) with stent implantation. This score is based on platelet reactivity (VerifyNow P2Y12 assay), CYP2C19 genotyping, and clinical risk factors. Our aim was to determine if the use of this score in clinical practice is associated with a reduction in thrombotic events without increasing bleeding events. In a single-center prospective cohort study, patients with a high risk score were treated with prasugrel and patients with a low risk score with clopidogrel. The risk score-guided cohort was compared with a historic cohort of clopidogrel-treated patients. The endpoint consisted of all-cause death, myocardial infarction, stroke, or stent thrombosis during 1year of follow-up. TIMI major and minor bleeding events were also analyzed. The guided cohort contained 1127 patients, 26.9% of whom were switched to prasugrel according to the POPular Risk Score. The historic cohort contained 893 patients. The incidence of the combined thrombotic endpoint was significantly lower in the guided cohort as compared with the historic cohort (8.4% versus 3.7%, p < 0.001). This strategy was safe with respect to bleeding (4.0% versus 1.3%, p < 0.001, for TIMI major or minor bleeding). Results were comparable after multivariate and propensity score matched and weighted analysis. Selective intensification of P2Y12 inhibitor treatment after non-urgent PCI based on the POPular Risk Score is associated with a reduction in thrombotic events without an increase in bleeding events.

Clinical effects with inhibition of multiple coagulative pathways in patients admitted for acute coronary syndrome.

Platelets and the coagulation cascade play key roles in initiation, amplification, and perpetuation of acute coronary syndromes (ACS). In the past few years, there has been great progress in ACS antithrombotic treatment with the introduction of novel anticoagulants (fondaparinux and bivalirudin), more potent P2Y12 inhibitors (prasugrel and ticagrelor) and protease-activated receptor antagonists (vorapaxar). Nonetheless, patients with ACS frequently have recurrent ischemic events despite the use of currently recommended dual antiplatelet therapy, revascularization procedures as appropriate, and other evidence-based secondary preventive measures. This is the rationale beyond intensification of antiplatelet therapy. However, the major downside of intensive antithrombotic therapy is bleeding. When treating ACS patients, clinicians should find the adequate balance between the reduction of thrombotic events by effective drug treatment and the induction of bleeding that is linked to the use of potent or multiple antithrombotic agents. Numerous antithrombotic cocktails including oral anticoagulants with or without aspirin have been tested in large clinical trials with the goal of further reduction of ischemia and bleeding risk. The aim of this review is to discuss clinical outcomes resulting from inhibition of multiple coagulative pathways in patients with ACS in light of evidence from large randomized controlled clinical trials.

Abstract P273: Treatment Patterns Among Vorapaxar New Users in a US Outpatient Clinical Setting

Introduction: Vorapaxar is a once daily oral protease-activated receptor-1 (PAR-1) antagonist for the reduction of thrombotic events in patients with a history of myocardial infarction or peripheral arterial disease. Efficacy and safety was evaluated in a large randomized clinical trial (TRA 2°P TIMI 50), with a median follow-up of 30 months. This is the first descriptive study of vorapaxar treatment patterns in routine clinical practice. Objectives: To evaluate medication adherence and persistence among vorapaxar new users. Methods: Vorapaxar new users ≥18 years of age were identified with an index prescription date between June 2014 and October 2015 with ≥1 years of follow-up through October 2016. The qualifying prescription was identified from Symphony Health’s US outpatient pharmacy claims linked to private practitioner claims and hospital data. Baseline characteristics were assessed using a 1-year look-back prior to the index prescription date. Adherence was defined as a medication possession ratio (MPR) ≥80%, and persistence was defined allowing for up to a 7-day gap in days supply. Sensitivity analysis with 15-day gap to define persistence was performed. Results: The 529 vorapaxar new users included in the analysis were predominantly male (67%), 11% African American and 70% Caucasian, and had a mean (SD) age of 65.2 (10.5) years. At the end of 3, 6, and 12 months, 61%, 45%, and 32%, respectively, of new users were adherent on vorapaxar. A majority (68%) of vorapaxar users were persistent at 3 months, 48% at 6 months, and 29% at 12 months. An additional 10% restarted therapy by the end of the first year after a period of supply interruption. Results of the sensitivity analysis for persistence using 15-day allowable gap were within 1-2% of primary analysis. The median (IQR) time to discontinuation of therapy during the first year was 2.6 (1.2-6.1) months. During the first year, a median (IQR) of 5 (3-9) prescriptions per patient were filled- majority 30 day fills. Conclusions: Medication adherence and persistence of use decreased over time. One-third of patients were adherent and/or persistent at one year. Further research is warranted to understand treatment pattern differences by indication of use and factors affecting adherence and discontinuation.

Abstract P274: Cross-sectional Analysis of Baseline Characteristics for New Users of Vorapaxar (PAR-1 Antagonist) and P2Y 12 Inhibitors

Introduction: Vorapaxar is indicated for the reduction of thrombotic events in patients with a prior myocardial infarction (MI) or peripheral arterial disease (PAD), and contraindicated in patients with a prior stroke, transient ischemic attack (TIA), or intracranial hemorrhage (ICH). This is the first descriptive study of vorapaxar in US clinical practice. Objectives: Main objective was to describe baseline characteristics of vorapaxar new users. For context, P2Y 12 new users were also examined, with indications summarized in Table 1. Methods: Cross-sectional analysis of vorapaxar new users ≥18 years with ≥1 prescription between June 2014 - June 2016 identified in Symphony Health’s outpatient pharmacy claims database linked to private practitioner claims and hospital data. Concomitant clopidogrel use was defined with overlapping days of supply. Medical history was defined using a 1-year baseline period. Results: The analysis included 1,362 vorapaxar (44% with clopidogrel), 975,023 clopidogrel, 133,724 ticagrelor, and 98,101 prasugrel new users (Table 1). Most ticagrelor (87%) and prasugrel (85%) users had evidence of coronary artery disease (CAD) compared with 52% of clopidogrel and 58% of vorapaxar users. In contrast, &lt;1% of ticagrelor and prasugrel users had PAD but no CAD vs. 6% of clopidogrel and 15% of vorapaxar users. The proportion of vorapaxar users (44%) with PAD, alone or with CAD, was 3-5 times larger than P2Y 12 users. PAD was more prevalent for vorapaxar with (50%) vs. without (39%) clopidogrel. Contraindications were infrequent for vorapaxar users - no ICH, &lt;4% with stroke or TIA. Median time from recent MI to therapy start was 6 months for vorapaxar vs. 3 days for ticagrelor and prasugrel and 7 days for clopidogrel. Vorapaxar users were mostly male and on average ~65 years old. Conclusions: The majority of vorapaxar new users had a history of CAD and/or PAD, with PAD prevalence more than twice that of P2Y 12 new users. Contraindications were infrequent.

The optimal discontinuation of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention with drug-eluting stents: A meta-analysis of randomized trials

BackgroundCurrent guidelines recommend prolonged dual antiplatelet therapy (DAPT) for patients with drug-eluting stents (DES) implantation. Nevertheless, optimal discontinuation of DAPT remains a controversy. We performed a meta-analysis of all randomized controlled trials (RCTs) that evaluate optimal discontinuation of DAPT in patients undergoing percutaneous coronary intervention (PCI) with DES. MethodsWe searched electronic databases including PubMed, Cochrane Library, EMBASE and ClinicalTrials.gov from database RCTs that reported different modes of discontinuation of DAPT in patients with DES. The primary endpoints were all-cause death, cardiovascular death, myocardial infarction (MI) and probably or definite stent thrombosis (ST). Secondary endpoints were repeat revascularization, stroke, major bleeding and net adverse clinical events (NACE). ResultsWe included 13 RCTs meeting the criteria with a total of 36,749 patients. No significant difference was observed in all-cause death (RR [95% CI]=0.87 [0.75, 1.01], P=0.07, I2=0%), cardiovascular death (RR [95% CI]=0.97 [0.79, 1.19], P=0.76, I2=0%), repeat revascularization (RR [95% CI]=1.07 [0.92, 1.25], P=0.36, I2=0%), and stroke (RR [95% CI]=1.01 [0.80, 1.28], P=0.94, I2=0%). Compared with shorter DAPT, longer DAPT was associated with a significant reduction in MI (RR [95% CI]=1.46 [1.26, 1.69], P<0.00001, I2=28%) and ST (RR [95% CI]=1.93 [1.45, 2.58], P<0.00001, I2=32%), and a significant increase in major bleeding (RR [95% CI]=0.60 [0.49, 0.74], P<0.00001, I2=0%). However, there was no difference in NACE (RR [95% CI]=1.03 [0.91, 1.17], P=0.63, I2=0%). In subgroup analyses based on stent type, we demonstrated that longer DAPT was associated with a significant reduction in thrombotic events (MI and ST) after first-generation DES implantation (RR [95% CI]=2.58 [1.85, 3.58], I2=0%) and everolimus-eluting stents (EES, RR [95% CI]=1.54 [1.12, 2.11], I2=0%). Conversely, there was no difference in thrombotic events in patients with zotarolimus-eluting stents (ZES, RR [95% CI]=1.17 [0.83, 1.63], I2=75%) and biodegradable polymer DES (BP-DES, RR [95% CI]=1.15 [0.74, 1.79]). Conclusions1) Compared with shorter DAPT, longer DAPT was associated with a significant reduction in thrombotic events (MI and ST) and a higher rate of major bleeding. 2) By the assessment of the trade-off between thrombotic and hemorrhagic events, shorter DAPT was non-inferior to longer DAPT. 3) The benefit of longer DAPT was significant in patients with first-generation DES and EES and weakened with other second-generation DES (ZES and BP-DES).

Antithrombotic therapy for acute coronary syndrome: Past, present and future.

Plaque erosions and ruptures are the histopathological hallmarks of arterial thrombus formation in the coronary arteries. The clinical condition associated with this process is usually referred to as acute coronary syndrome (ACS). Importantly, both blood platelets and the coagulation cascade are key players for initiation, amplification and perpetuation of ACS. There has been great progress in ACS treatment in recent decades, both at the technical level of (percutaneous) revascularisation and at the level of antithrombotic treatment. Numerous trials have led to significant advancements in the development of effective anticoagulant and antiplatelet drugs. The large number of randomised controlled clinical trials (RCTs) and the huge number of patients enrolled in these RCTs, with mega trials including >10,000 patients, is unique in the history of medical research and also reflects the exceptional efforts associated with these huge research activities. The crucial issue, however, with respect to optimising treatment, relates to finding the delicate balance between the reduction of thrombotic events by effective drug treatment and the induction of bleeding that is linked to the use of potent or multiple antithrombotic agents. Interestingly, there is a gap in modern days between current guideline recommendations favouring potent platelet inhibition in ACS and the utilization of the respective drugs in clinical practice. In this review, we will summarise and discuss the past, present and future antithrombotic treatment for ACS patients with a focus on the development of optimised antiplatelet treatment strategies and their utilisation in the real world.

Outcomes following routine antithrombin III replacement during neonatal extracorporeal membrane oxygenation

BackgroundWe sought to examine the effect of routine antithrombin III (AT3) infusion on hemorrhagic and thrombotic complications, blood product utilization, and circuit lifespan in neonatal extracorporeal membrane oxygenation (ECMO). MethodsWe performed a retrospective cohort study of 162 infants placed on ECMO for hypoxic respiratory failure. Infants requiring ECMO for primary cardiac support were excluded. Demographic data, time on ECMO, blood product usage, coagulation profile, and complications were compared between 90 control patients and 72 patients treated with AT3. ResultsInfants receiving AT3 during ECMO had less thrombotic and similar bleeding complications as compared to infants receiving standard anticoagulation therapy. Total blood product infusion during ECMO was decreased (54.7±20.1 vs. 67.4±34.9mL/kg per day, p=0.001) in infants receiving AT3 during ECMO. Tighter control of activated clotting time and higher serum heparin anti-Xa levels were observed in the AT3 cohort during the first days of ECMO support. 1st ECMO circuit lifespan did not differ between groups. ConclusionsRoutine administration of AT3 in neonates receiving ECMO therapy was associated with tighter control of anticoagulation and a reduction in thrombotic events without increasing unwanted bleeding. However, circuit lifespan was unaffected. Level of evidenceLevel III.