Risk Of Major Bleeding Events Research Articles

Influence of Baseline Platelet Count on Outcomes in Patients With Venous Thromboembolism (from the COMMAND VTE Registry)

The influence of thrombocytopenia on the long-term clinical outcomes has not been thoroughly evaluated in patients with venous thromboembolism (VTE). This study sought to elucidate association of baseline thrombocytopenia with bleeding, recurrent VTE, and mortality risk. We evaluated the influence of baseline thrombocytopenia among 3,012 patients whose baseline platelet counts were available in the COMMAND VTE Registry in Japan with a median follow-up period of 1,219 days. Baseline thrombocytopenia was classified as follows: mild: 100,000 to 150,000/μl; moderate: 50,000 to 99,999/μl; and severe: <50,000/μl. The primary outcome measurement was International Society of Thrombosis and Hemostasis major bleeding, and the secondary outcome measurements were recurrent VTE and all-cause death. There were 167 patients (5.5%) with moderate or severe thrombocytopenia (moderate: 144 patients and severe: 23 patients), 523 patients (17.4%) with mild thrombocytopenia, and 2,322 patients (77.1%) without thrombocytopenia. The cumulative 5-year incidence of major bleeding was markedly higher in patients with moderate or severe thrombocytopenia (moderate or severe 29.4% vs mild: 14.1% vs no thrombocytopenia: 10.6%, p <0.001). After adjusting the confounders, the risk of or thrombocytopenia relative to no thrombocytopenia for major bleeding remained significant (adjusted hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.43 to 3.13, p <0.001). The excess risk of moderate or severe thrombocytopenia relative to no thrombocytopenia was also significant for mortality (adjusted HR 1.54, 95% CI 1.18 to 1.97, p = 0.002), but the risk was neutral for recurrent VTE (adjusted HR 1.05, 95% CI 0.55 to 1.81, p = 0.87). In conclusion, VTE patients with baseline moderate or severe thrombocytopenia had higher risk for major bleeding events and mortality without significant excess risk for recurrent VTE events.

Low-Molecular-Weight Heparin for the Prevention of Venous Thromboembolism in Patients Undergoing Knee Arthroscopic Surgery and Anterior Cruciate Ligament Reconstruction: A Meta-analysis of Randomized Controlled Trials

Background: Low-molecular-weight heparin (LMWH) thromboprophylaxis is widely used for reducing the risk of thrombosis after major orthopaedic surgery. However, the effect and safety on knee arthroscopic surgery are still controversial. Purpose: To assess the efficacy and safety of LMWH for the prevention of symptomatic venous thromboembolism (VTE) after knee arthroscopic surgery and anterior cruciate ligament reconstruction (ACLR) by conducting a meta-analysis of randomized controlled trials (RCTs). Study Design: Meta-analysis. Methods: The authors searched the electronic databases of MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Web of Science for all studies from inception to June 30, 2017. All selected studies were categorized into 2 subgroups: simple knee arthroscopic surgery and ACLR. The primary effect and safety endpoint were the incidence of major VTE and major bleeding events (BEs), respectively. The secondary effect and safety endpoint were the incidence of all VTE and all BEs, respectively. Relative risks (RRs) with 95% CIs were calculated using Review Manager 5.3. Results: Eight RCTs with 4113 patients were included. For patients undergoing simple knee arthroscopic surgery, LMWH prophylaxis did not bring a significant reduction in the risk of major VTE (RR, 1.00 [95% CI, 0.37-2.67]; P > .99) and all VTE (RR, 0.63 [95% CI, 0.31-1.29]; P = .21) and did not increase the risk of major BEs (RR, 0.98 [95% CI, 0.06-15.72]; P = .99) but did have a higher risk of all BEs (RR, 1.64 [95% CI, 1.18-2.28]; P = .003) in comparison with non-LMWH prophylaxis. For patients undergoing ACLR, LMWH prophylaxis was associated with a significantly lower rate of major VTE (RR, 0.23 [95% CI, 0.12-0.43]; P < .001) and all VTE (RR, 0.22 [95% CI, 0.06-0.73]; P = .01) but no increase in major BEs (RR, 1.80 [95% CI, 0.19-17.25]; P = .61) and all BEs (RR, 1.12 [95% CI, 0.72-1.74]; P = .61) in comparison with non-LMWH prophylaxis. Conclusion: Compared with non-LMWH treatment, LMWH had no significant efficacy in preventing VTE in patients undergoing simple knee arthroscopic surgery but increased the risk of BEs. However, LMWH had significant efficacy in preventing VTE for patients mainly undergoing ACLR and did not increase the risk of BEs.

Mechanical Versus Bioprosthetic Aortic Valve Replacement in Patients Aged 50 Years and Younger

This study evaluated outcomes in younger patients, specifically aged 50 years and younger, after mechanical aortic valve replacement (mAVR) and bioprosthetic AVR (bAVR). From 1994 to 2016, 643 patients underwent AVR (411 mAVR and 232 bAVR) at age 50 or younger. Concomitant coronary artery bypass grafting and mitral valve procedures were also included. Propensity score-matching methods resulted in 170 evenly matched patient pairs. Primary end points were operative mortality and long-term survival. Secondary end points were stroke, major bleeding, and redo AVR. Median observation time was 8.1 years (range, 0 to 23.6 years). Overall, mean age was 41.9 years, and 29.3% were women, with an increasing trend toward use of bAVR. Mean age in the matched patients was 43.3 years for both cohorts (p= 0.68). Operative mortality, stroke, atrial fibrillation, reoperation for bleeding, and readmission rates within 30 days were all similar between the two groups. bAVR patients were at higher risk for redo AVR (13% vs 1.6%, p < 0.001), and mAVR patients were at higher risk for major bleeding events (8.5% vs 2.2%, p= 0.006). However, when adjusted, there were no differences in midterm and long-term survival between unmatched and matched cohorts. The increased risk of reoperation for bAVR and major bleeding incidents for mAVR was not reflected in midterm and long-term survival differences between the two groups. Our results suggest that bAVR may be an acceptable prosthesis choice for some patients aged 50 years and younger, although the results should be taken with caution.

Annual Risk of Major Bleeding Among Persons Without Cardiovascular Disease Not Receiving Antiplatelet Therapy

A decision to initiate aspirin therapy for primary prevention of cardiovascular disease (CVD) requires consideration of both treatment benefits and harms. The most significant harm associated with aspirin is major bleeding, yet there is a paucity of data on bleeding risk in suitable community populations. To determine the risk of major bleeding among people without CVD who are not receiving antiplatelet therapy. Prospective cohort study of 359 166 individuals aged 30 to 79 years receiving primary care in New Zealand who had CVD risk assessment between 2002 and 2015. Participants were censored at the earliest date on which they had a first major bleeding event, died, or met any baseline cohort exclusion criteria or the study end date of December 31, 2015. Analyses were repeated after excluding people with medical conditions associated with increased bleeding risk (non-high-risk cohort; n=305 057) and after further excluding people receiving other medications associated with increased bleeding risk (nonmedication cohort; n=240 254). Sex and age group in 10-year bands from 30 to 79 years. Risk of a major bleeding event (hospitalization or death associated with bleeding); nonfatal gastrointestinal tract bleeding; and gastrointestinal tract bleeding-related case fatality. Mean participant age was 54 years (SD, 10 years), 44% were women, and 57% were European. Among the 359 166 individuals in the baseline cohort, 3976 had a major bleeding event during 1 281 896 person-years of follow-up. Most had gastrointestinal (GI) bleeding (n=2910 [73%]). There were 274 fatal bleeding events (7%), of which 153 were intracerebral. The risk of a nonfatal GI bleeding event per 1000 person-years was 2.19 (95% CI, 2.11-2.27), 1.77 (95% CI, 1.69-1.85) and 1.61 (95% CI, 1.52-1.69), in the baseline, non-high-risk, and nonmedication cohorts, respectively. Case fatality associated with GI bleeding was 3.4% (95% CI, 2.2%-4.1%), 4.0% (95% CI, 3.2%-5.1%), and 4.6% (95% CI, 3.6%-6.0%) in the baseline, non-high-risk, and nonmedication cohorts, respectively. In a population not receiving antiplatelet therapy, the annual risk of major bleeding events and nonfatal major bleeding was estimated. These findings could inform population-level guidelines for primary prevention of CVD.

Calculation of HAS-BLED Score Is Useful for Early Identification of Venous Thromboembolism Patients at High Risk for Major Bleeding Events: A Prospective Outpatients Cohort Study

The aim of this study was prospective evaluation of the performance of the HAS-BLED score in predicting major bleeding complications in a real-world outpatient cohort, during long-term anticoagulation for venous thromboembolism (VTE), treated with a broad spectrum of anticoagulants. We analyzed 111 outpatients objectively diagnosed with VTE and treated long-term with various anticoagulants. Patients were grouped in three cohorts based on the anticoagulant regimen. Calculation of the HAS-BLED score and documentation of bleeding events were performed every 6 months for 1 year. Patients with a HAS-BLED score ≥ 3 had an increased risk for major bleeding events (odds ratio [OR]: 13.05, 95% confidence interval [CI]: 0.96-692.58, p = 0.028) and a trend to higher risk for minor bleeding events as well (OR: 2.25, 95% CI: 0.87-5.85, p = 0.091) when compared with patients with a HAS-BLED score < 3.This indicates that a HAS-BLED score ≥ 3 allows for identification of patients with VTE on long-term anticoagulation at an increased risk for major bleeding events, irrespective of the anticoagulant agent used.

Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease.

Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation (AF), which is more prevalent among CKD patients than the general population. AF causes stroke or systemic embolism, leading to increased mortality. The conventional antithrombotic prophylaxis agent warfarin is often prescribed for the prevention of stroke, but risk of bleeding necessitates regular therapeutic monitoring. Recently developed direct oral anticoagulants (DOAC) are expected to be useful as alternatives to warfarin. To assess the efficacy and safety of DOAC including apixaban, dabigatran, edoxaban, and rivaroxaban versus warfarin among AF patients with CKD. We searched the Cochrane Kidney and Transplant Specialised Register (up to 1 August 2017) through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. We included all randomised controlled trials (RCTs) which directly compared the efficacy and safety of direct oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) with dose-adjusted warfarin for preventing stroke and systemic embolic events in non-valvular AF patients with CKD, defined as creatinine clearance (CrCl) or eGFR between 15 and 60 mL/min (CKD stage G3 and G4). Two review authors independently selected studies, assessed quality, and extracted data. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for the association between anticoagulant therapy and all strokes and systemic embolic events as the primary efficacy outcome and major bleeding events as the primary safety outcome. Confidence in the evidence was assessing using GRADE. Our review included 12,545 AF participants with CKD from five studies. All participants were randomised to either DOAC (apixaban, dabigatran, edoxaban, and rivaroxaban) or dose-adjusted warfarin. Four studies used a central, interactive, automated response system for allocation concealment while the other did not specify concealment methods. Four studies were blinded while the other was partially open-label. However, given that all studies involved blinded evaluation of outcome events, we considered the risk of bias to be low. We were unable to create funnel plots due to the small number of studies, thwarting assessment of publication bias. Study duration ranged from 1.8 to 2.8 years. The large majority of participants included in this study were CKD stage G3 (12,155), and a small number were stage G4 (390). Of 12,545 participants from five studies, a total of 321 cases (2.56%) of the primary efficacy outcome occurred per year. Further, of 12,521 participants from five studies, a total of 617 cases (4.93%) of the primary safety outcome occurred per year. DOAC appeared to probably reduce the incidence of stroke and systemic embolism events (5 studies, 12,545 participants: RR 0.81, 95% CI 0.65 to 1.00; moderate certainty evidence) and to slightly reduce the incidence of major bleeding events (5 studies, 12,521 participants: RR 0.79, 95% CI 0.59 to 1.04; low certainty evidence) in comparison with warfarin. Our findings indicate that DOAC are as likely as warfarin to prevent all strokes and systemic embolic events without increasing risk of major bleeding events among AF patients with kidney impairment. These findings should encourage physicians to prescribe DOAC in AF patients with CKD without fear of bleeding. The major limitation is that the results of this study chiefly reflect CKD stage G3. Application of the results to CKD stage G4 patients requires additional investigation. Furthermore, we could not assess CKD stage G5 patients. Future reviews should assess participants at more advanced CKD stages. Additionally, we could not conduct detailed analyses of subgroups and sensitivity analyses due to lack of data.

Abstract 36: Factor XII RNAi-based Therapeutic as a Prophylactic Anti-thrombotic Therapy

Introduction: Current anticoagulants effectively prevent thromboembolic (TBE) events, but unmet medical need remains due to elevated risk of major bleeding events, particularly where Factor Xa inhibitors are contraindicated. Factor XII (F12) zymogen initiates the intrinsic coagulation pathway through both autocleavage and Factor XI cleavage. F12 deficient mice show protection from induced thrombosis without increased bleeding risk. F12 deficiency in humans is not associated with increased bleeding risk, suggesting F12 is not essential for hemostasis. Methods: Hepatocyte-targeted RNA interference (RNAi) triggers for reducing liver F12 expression were developed for subcutaneous (SQ) administration. Specific rodent/human/non-human primate (NHP) cross-reactive RNAi triggers were designed in silico and screened for knockdown activity in vitro and in wild-type mice. Structure activity relationship (SAR) studies of active RNAi triggers identified optimal modifications for lead identification. Candidate RNAi triggers were evaluated for activity and safety in NHPs. In addition, candidate RNAi triggers were evaluated for activity in two rodent models of thrombosis and bleeding risk. Results: F12 RNAi triggers exhibited significant and sustained knockdown of serum F12 levels in both mice and NHPs. SAR studies enabled identification of a candidate lead molecule that demonstrated &gt;95% knockdown after a single 1 mg/kg dose in mice. Evaluation of two SQ doses of this RNAi trigger in NHPs demonstrated &gt;93% knockdown of serum F12 levels at nadir with durable knockdown of &gt;90% for over 5 weeks after the final dose. Concomitant increases in coagulation biomarker aPTT were observed, consistent with functional F12 depletion. Both arteriovenous shunt studies in rats and FeCl 3 -induced TBE studies in mice exhibited prevention of clot formation after F12 knockdown. Importantly, F12 knockdown did not increase bleeding times in explicit hemostasis studies in mice. Conclusions: Development of a SQ-administered F12-specific RNAi trigger offers potential for a novel, infrequently dosed prophylactic treatment for TBE without increased bleeding risk. Administration by medical personnel would eliminate adherence concerns inherent to current therapies.

Abstract TP408: Temporal Relationship of AF and Oral Anticoagulation to Major Bleeding Events in Patients with Cardiovascular Implantable Electronic Devices

Introduction: After diagnosis of atrial fibrillation (AF), oral anticoagulation (OAC) is taken daily and may increase risk of bleeding, even during AF-free periods. We explored temporal discordance between AF and major bleeding events (MBE) in patients with cardiovascular implantable electronic devices (CIED). Methods: We linked Veterans Administration (VA) and Medicare data to CIED remote monitoring data. Analyses were restricted to Medtronic cardiac rhythm devices with atrial leads, which provide a daily, continuous measure of AF burden. We identified the earliest date of monitoring and searched for a subsequent MBE (including but not limited to intracranial hemorrhaging, gastrointestinal bleeds, and vascular bleeds) from 2004 to 2015. We restricted analysis to patients with &lt;75% coverage of remote monitoring in the 90 days before and after MBE and with OAC prescription and pill coverage in the 90 days prior and on day of MBE. Patients were categorized into 4 groups based on the presence of AF ≥ 6 minutes on any of the 90 days on or prior to MBE and 90 days after MBE: NO/NO, NO/YES, YES/NO, YES/YES. Results: There were 189 patients meeting inclusion criteria (69±9.4 years, CHA 2 DS 2 -VASc 4.3±1.4). Of these, 99 (52%) of patients had no AF≥ 6 min in the 90 days on or before MBE (NO/NO). Among all patients, there were 3 ischemic strokes, 2 ICH, 33 MBE, and 83 deaths following the index MBE. Across all categories, the risk of recurrent MBE and death was substantially higher than stroke or ICH and only 7% with no AF pre had AF post (NO/YES). (TABLE) Conclusion: Among CIED patients on OAC, most did not have AF at the time of MBE. Risk of MBE and death was substantially higher than stroke or ICH and call into question rationale to remain on indefinite OAC. Long-term AF monitoring may prove useful and requires evaluation.

Stroke risk reduction outweighed bleeding risk increase from vitamin K antagonist treatment among nonvalvular atrial fibrillation patients with high stroke risk and low bleeding risk

Objective: Warfarin is widely used for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We compared the rates of stroke and major bleeding in NVAF patients with a high stroke risk and low bleeding risk profile during warfarin treated (W+) and warfarin untreated (W−) periods.Method: Insurance claims from six commercial, Medicaid or Medicare databases were analyzed from 2000 to 2014. NVAF patients treated with warfarin, with a CHADS2/CHA2DS2-VASc score ≥2, and an ATRIA score ≤3 at baseline were identified. Incidence rate ratios (IRRs) of stroke and major bleeding were calculated for W + versus W− episodes of person-time, as well as for first 30 days versus beyond 30 days of W + episodes.Results: Among 316,145 patients, anticoagulant prophylaxis with warfarin significantly reduced stroke risk, with IRRs ranging from 0.48 (95% CI: 0.46–0.51) to 0.80 (95% CI: 0.70–0.91), and increased major bleeding risk, with IRRs ranging from 1.13 (95% CI: 1.10–1.15) to 1.95 (95% CI: 1.10–3.45). Stroke and major bleeding rates were higher during the first 30 days of W + than beyond.Conclusion: In NVAF patients at high risk for stroke and low risk for bleeding, our data confirm the effectiveness of anticoagulation for stroke prevention. The decrease in stroke risk of anticoagulation may outweigh the risk of major bleeding events, particularly among elderly patients. Potential risks of warfarin during initiation warrant attention, especially among patients who stop and start therapy repeatedly.

Clinical Impact and Course of Anticoagulant-Related Major Bleeding in Cancer Patients

BackgroundVenous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is a frequent complication in cancer patients. During anticoagulant treatment for VTE, the risk of major bleeding events (MBE) is 2- to 6-fold higher in cancer patients than in those without cancer. It is unknown whether the clinical presentation and course of anticoagulant-related MBE in cancer patients differ from patients without cancer.MethodsIndividual patient data from 4 randomized controlled phase III trials in which factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) were compared with vitamin K antagonists for the treatment of VTE were used for the present analysis. The severity of the clinical presentation and clinical course of anticoagulant-related MBE were compared between patients with and without cancer. Using predefined criteria, the severity of the clinical presentation and course of MBE were classified into four categories by independent adjudicators, who were blinded to treatment allocation. Category 1 indicates a mild clinical presentation or course, while category 4 indicates a severe presentation or course (Table 1). A one-stage meta-analysis was used to estimate crude odds ratios (ORs) and ORs adjusted for age, sex, and type of anticoagulant treatment with 95% confidence intervals (CIs) for the effect of cancer on the severity of the clinical presentation and course. For this analysis categories 3 and 4 were combined. We also explored the cause and site of bleeding in these patients.ResultsThe study group comprised 290 patients with MBE, of whom 50 (17%) had active cancer or were diagnosed with cancer during follow-up. The clinical presentation was judged to be severe (category 3 or 4) in 38% of patients with cancer and 44% of patients without cancer (adjusted OR 0.90, 95% CI 0.47-1.72). Clinical course was judged to be severe in 20% and 25% of patients with and without cancer, respectively (adjusted OR 0.75, 95% CI 0.35-1.61) (Table 2). The bleeding pattern varied significantly between the two groups (p=0.002); cancer patients more often had gastrointestinal (52% vs. 35%) and vaginal (14% vs. 6%) MBE, whereas intracranial (19% vs. 6% and retroperitoneal (5% vs. 0%) MBE occurred more often in patients without cancer (Table 3). MBE was related to the tumor site in 40% of cancer patients.ConclusionThe findings of the present study indicate that the clinical presentation and course of anticoagulant-related MBE are not more severe in cancer patients than in patients without cancer, which is reassuring for physicians who treat cancer-associated VTE. [Display omitted] [Display omitted] [Display omitted] DisclosuresEerenberg:Sanquin: Consultancy; CSL Behring: Consultancy; Baxter: Consultancy. Middeldorp:Aspen: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Bayer: Consultancy; Sanquin: Consultancy; GSK: Consultancy, Honoraria; BMS/Pfizer: Consultancy, Honoraria. Cohen:Takeda: Consultancy; Leo Pharma: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Department of Health: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Medscape: Speakers Bureau; UK Government Health Select Committee: Membership on an entity’s Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Speakers Bureau; Colation to Prevent Venous Thromboembolism: Other: Founder; NHS: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Aspen: Consultancy, Speakers Bureau; ONO: Consultancy, Honoraria; XO1: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Lifeblood: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the second update of a review first published in February 2012. To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016. Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants. We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. One large trial of 3212 participants found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau2 = 0.00%) with a non-statistically significant 44% higher risk of major bleeding events (RR 1.44, 95% CI 0.98 to 2.11). In participants with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). Major bleeding was observed in none of the participants treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis but did not report on VTE or major bleeding. When compared with placebo, warfarin was associated with a non-statistically significant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE or on major bleeding when compared with no antithrombin. The direct oral factor Xa inhibitor apixaban was evaluated in a phase II dose-finding study that suggested a low rate of major bleeding (2.1% versus 3.4%) and symptomatic VTE (1.1% versus 13.8%) in comparison with placebo. In this second update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin, which is not commercially available, significantly reduced the incidence of symptomatic VTE. The risk of major bleeding associated with LMWH, while not reaching statistical significance, suggest caution and mandate additional studies to determine the risk-to-benefit ratio of LMWH in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.

Relationship of Platelet Reactivity With Bleeding Outcomes During Long-Term Treatment With Dual Antiplatelet Therapy for Medically Managed Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

BackgroundThe relationship between “on‐treatment” low platelet reactivity and longitudinal risks of major bleeding dual antiplatelet therapy following acute coronary syndromes remains uncertain, especially for patients who do not undergo percutaneous coronary intervention.Methods and ResultsWe analyzed 2428 medically managed acute coronary syndromes patients from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial who had serial platelet reactivity measurements (P2Y12 reaction units; PRUs) and were randomized to aspirin+prasugrel versus aspirin+clopidogrel for up to 30 months. Contal's method was used to determine whether a cut point for steady‐state PRU values could distinguish high versus low bleeding risk using 2‐level composites: Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe/life‐threatening or moderate bleeding unrelated to coronary artery bypass grafting (CABG) and non‐CABG Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding. Exploratory analyses used 3‐level composites that incorporated mild and minimal GUSTO and TIMI events. Continuous measures of PRUs (per 10‐unit decrease) were not independently associated with the 2‐level GUSTO (adjusted hazard ratio [HR], 1.01; 95% CI, 0.96–1.06) or TIMI composites (1.02; 0.98–1.07). Furthermore, no PRU cut point could significantly distinguish bleeding risk using the 2‐level composites. However, the PRU cut point of 75 differentiated bleeding risk with the 3‐level composites of GUSTO (26.5% vs 12.6%; adjusted HR, 2.28; 95% CI, 1.77–2.94; P<0.001) and TIMI bleeding events (25.9% vs 12.2%; adjusted HR, 2.30; 95% CI, 1.78–2.97; P<0.001).ConclusionsAmong medically managed non‐ST‐segment elevation acute coronary syndromes patients receiving prolonged dual antiplatelet therapy, PRU values were not significantly associated with the long‐term risk of major bleeding events, suggesting that low on‐treatment platelet reactivity does not independently predict serious bleeding risk.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00699998.

The effect of in-hospital acquired thrombocytopenia on the outcome of patients with acute coronary syndromes: A systematic review and meta-analysis

BackgroundIn-hospital acquired thrombocytopenia (TP) is relatively common among patients hospitalized with acute coronary syndromes (ACS). However, its effect on short-term and long-term outcomes has yet to be reviewed systematically. MethodsWe conducted a systematic review and meta-analysis of clinical studies assessing the relationship between new-onset in-hospital TP and adverse outcomes among ACS patients. MEDLINE, Scopus and the Cochrane Library were searched for eligible studies published before March 20, 2016. ResultsTen studies reporting on a total of 142,161 ACS patients were identified. 8133 patients showed evidence of new-onset TP during the course of their hospitalization. Compared with patients with normal platelet counts, patients with new-onset TP had a prolonged in-hospital stay, significantly higher risk of both short-term mortality (<30days) (Odds ratio (OR) [95% confidence interval (CI)]: 5.58 [3.63–8.57]) and late death (6months to 1year) (OR [95% CI]: 3.45 [2.35–5.07]), as well as a significantly higher risk of major bleeding events in the first 30days (OR [95% CI]: 6.93 [5.13–9.38]). In addition, risk for other secondary cardiovascular endpoints, including recurrent myocardial infarction, stroke, in-hospital heart failure, stent thrombosis and unplanned revascularization was also significantly higher in the TP versus the no TP group. ConclusionsDevelopment of TP during the in-hospital management of ACS patients is a significant predictor of both short- and long-term adverse events, including mortality. In the light of this evidence, clinicians should be cautious and closely monitor abnormal platelet counts that present early following an ACS.

Bleeding Risk with Long-Term Low-Dose Aspirin: A Systematic Review of Observational Studies.

BackgroundLow-dose aspirin has proven effectiveness in secondary and primary prevention of cardiovascular events, but is also associated with an increased risk of major bleeding events. For primary prevention, this absolute risk must be carefully weighed against the benefits of aspirin; such assessments are currently limited by a lack of data from general populations.MethodsSystematic searches of Medline and Embase were conducted to identify observational studies published between 1946 and 4 March 2015 that reported the risks of gastrointestinal (GI) bleeding or intracranial hemorrhage (ICH) with long-term, low-dose aspirin (75–325 mg/day). Pooled estimates of the relative risk (RR) for bleeding events with aspirin versus non-use were calculated using random-effects models, based on reported estimates of RR (including odds ratios, hazard ratios, incidence rate ratios and standardized incidence ratios) in 39 articles.FindingsThe incidence of GI bleeding with low-dose aspirin was 0.48–3.64 cases per 1000 person-years, and the overall pooled estimate of the RR with low-dose aspirin was 1.4 (95% confidence interval [CI]: 1.2–1.7). For upper and lower GI bleeding, the RRs with low-dose aspirin were 2.3 (2.0–2.6) and 1.8 (1.1–3.0), respectively. Neither aspirin dose nor duration of use had consistent effects on RRs for upper GI bleeding. The estimated RR for ICH with low-dose aspirin was 1.4 (1.2–1.7) overall. Aspirin was associated with increased bleeding risks when combined with non-steroidal anti-inflammatory drugs, clopidogrel and selective serotonin reuptake inhibitors compared with monotherapy. By contrast, concomitant use of proton pump inhibitors decreased upper GI bleeding risks relative to aspirin monotherapy.ConclusionsThe risks of major bleeding with low-dose aspirin in real-world settings are of a similar magnitude to those reported in randomized trials. These data will help inform clinical judgements regarding the use of low-dose aspirin in prevention of cardiovascular events.

Aspirin and cardiovascular primary prevention in non-endstage chronic kidney disease: A meta-analysis

Background and aimsChronic kidney disease is a strong independent predictor of cardiovascular disease. No published meta-analyses on the use of aspirin for the primary prevention of cardiovascular disease in chronic kidney disease exist. We therefore performed a systematic review and meta-analysis of this subject. MethodsWe used a pre-defined and registered protocol (PROSPERO identification CRD42014008860). We searched Medline and Embase between 1996 and July 2015. Inclusion criteria were adult subjects with non-endstage chronic kidney disease (CKD) and no history of cardiovascular disease. The co-primary outcomes were major cardiovascular events and all-cause mortality. Secondary outcomes included bleeding-related events. We used a random effects model to pool data. ResultsThree trials were identified and two of these provided previously unpublished data. The studies included 4468 participants and 16,740 person-years of follow-up. There were no statistically significant reductions in the risk of major cardiovascular events (RR 0.92, 95% CI 0.49 to 1.73, p = 0.79, I2 71%) or mortality (RR 0.74, 95% CI 0.55 to 1.00, p = 0.05, I2 0%) with aspirin compared to the control group. Major bleeding events were increased with aspirin though (RR 1.98, 95% CI 1.11 to 3.52, p = 0.02, I2 0%). ConclusionsThere is no clear benefit of aspirin for the primary prevention of cardiovascular events in CKD and no statistically significant reduction in mortality. Aspirin is likely to increase the risk of major bleeding events. Currently, insufficient randomised control trial data exists to recommend universal use or avoidance of aspirin for primary prevention of cardiovascular events in CKD.

Efficacy and safety of oral direct factor Xa inhibitors versus warfarin in patients with atrial fibrillation: a meta-analysis of randomized controlled trials

Objective Oral direct factor Xa inhibitors, a new class of anticoagulants, have emerged as an alternative to warfarin in patients with atrial fibrillation (AF). We aimed to assess the effects of oral direct factor Xa inhibitors versus warfarin on ischaemic and bleeding outcomes.Methods and results We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials comparing oral direct factor Xa inhibitors with warfarin in patients with AF. The primary efficacy outcome was the composite end point of strokes and other systemic embolic events. The primary safety outcome was major bleeding. We calculated pooled relative risks (RRs) and 95% Cis using randomeffects model. We included 9 trials involving 57,497 patients. Compared with warfarin, oral direct factor Xa inhibitors were associated with an 18% reduction in strokes and other systemic embolic events (RR: 0.82; 95% CI: 0.69-0.99; P= 0.04), mainly driven by a reduction in haemorrhagic stroke (RR: 0.49; 95% CI: 0.40-0.60; P < 0.00001). Oral direct factor Xa inhibitors also significantly reduced all-cause mortality (RR: 0.89; 95% CI: 0.84-0.95; P= 0.0002) and intracranial haemorrhage (RR: 0.47; 95% CI: 0.37-0.59; P < 0.00001). Oral direct factor Xa inhibitors lowered the risk of major bleeding events by 25% compared with warfarin (RR: 0.75; 95% CI: 0.58-0.97; P= 0.03).Conclusions In patients with AF, oral direct factor Xa inhibitors conferred favourable benefit and risk profiles, with significant reductions in strokes and systemic embolic events, haemorrhagic stroke, mortality, major bleeding, and intracranial haemorrhage when compared with warfarin.

TCT-218 Balancing The Risk Between Myocardial Infarction and Clinically Significant Bleeding With Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation

Longer DAPT (> 12 months) after drug-eluting stent (DES) implantation is associated with a lower risk of myocardial infarction (MI) counterbalanced by a higher risk of major bleeding events. We sought to simulate the therapeutic risks and benefits of longer versus short DAPT durations after PCI

Interethnic variability of CYP4F2 (V433M) in admixed population of Roma and Hungarians

AimsPharmacogenetic based dosing recommendations are provided in FDA-approved warfarin label for Caucasians. Evidence of notable difference in dosing algorithms of under-represented populations forced us to explore the genetic variability of CYP4F2 gene in Roma and Hungarian populations. Patients and methods484 Roma, 493 Hungarian untreated subjects were genotyped for the CYP4F2*3 (rs2108622) variant by PCR-RFLP assay. Results and discussionWe firstly report, that frequencies of the CYP4F2 rs2108622 GG, GA, AA genotypes and A allele in the Roma population were 46.5%, 42.6%, 10.9% and 32.2%; in Hungarians 50.1%, 42.2%, 7.7% and 22.8%, respectively. Bearing of two minor alleles of CYP4F2 missense variant (AA genotype) modestly explains inter-ethnic differences of studied populations (p<0.08). CYP4F2*3 (V433M) risk allele frequency of Roma (0.32) was in higher range, and of Hungarians (0.23) in lower range, as compared with other world populations. ConclusionsRoma have an elevated chance for higher mean warfarin dose, besides a decreased risk of major bleeding events in long-term warfarin use.

Safety of the direct-acting anticoagulants in patients with atrial fibrillation: a meta-analysis

IntroductionAtrial fibrillation (AF) is known as one of the independent risk factors for stroke and might significantly increase its risk. Nowadays, direct-acting oral anticoagulants (DOACs) have been developed and demonstrated a more promising option to warfarin, the conclusion for safety is heterogeneous in different studies. It indicates the importance of comprehensive comparison of safety between DOACs and warfarin. Material and MethodsFour studies including ARISTOTLE, ENGAGE AF-TIMI 48, RE-LY and ROCKET-AF were included in the meta-analysis to perform separate meta-analyses for high-dose regimen, low-dose regimen and their combination. The events included major bleeding, intracranial haemorrhage, gastrointestinal bleeding, non-major clinically relevant and minor bleeding. ResultsRegardless of high dose or low dose regimen, DOACs were associated with lower risk of intracranial haemorrhage but due to no significant association for gastrointestinal bleeding, the overall effect measured by the major bleeding was also insignificant (High dose: RR=0.86, 95% CI 0.73 to 1.01; Low dose: RR=0.63, 95% CI 0.38 to 1.04). However, the combined result of high-dose and low-dose regimens showed DOACs were associated with lower risk of major bleeding events (RR=0.77, 95% CI 0.63 to 0.95). ConclusionsMeta-analyses have showed the comparative safety of the direct-acting oral anticoagulants than warfarin in most endpoints and even better in intracranial haemorrhage. Therefore, without the need of INR monitoring, DOACs demonstrated promising alternatives to warfarin in prevention of stroke in patients with AF.

Efficacy of Therapeutic Dose Versus Prophylactic Dose of Anticoagulants in the Primary Prevention of Thrombotic Events in Ambulatory Patients with Solid Malignancies Receiving Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Vascular thromboembolism (VTE) is a recognized complication of cancer. Clinical trials have demonstrated varying degrees of efficacy of antithrombotic agents in preventing VTE in patients suffering from cancer. Benefit of anticoagulants was found to be more pronounced among patients who are at a higher risk for VTE such as patients with advanced cancer and patients undergoing chemotherapy and/or radiotherapy. However, the optimal dose of anticoagulants used in these settings remains unknown. Therefore, we have performed a systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate the efficacy of different dosing of anticoagulants in the primary prevention of VTE among patients with advanced solid malignancies receiving chemotherapy.Methods: We undertook an extensive electronic database search using PUBMED and EMBASE databases for eligible studies. RCTs, involving patients with advanced solid malignancies receiving chemotherapy, which reported VTE rates as a primary or secondary outcome were included. RCTs that had a mixed population of patients such as all stages of cancer, solid and hematologic cancers, and chemotherapy and non-chemotherapy patients were excluded. The primary outcomes in this analysis were all reported VTE events and major bleeds. The secondary outcome was overall mortality rate. We used Comprehensive Meta-analysis Version 2 (Biostat, Englewood NJ) to estimate the pooled event-based risk ratio (RR) and risk difference (RD) with 95% confidence interval (CI) by using Mantel-Haenszel method. Random effects model was applied because of heterogeneity among the studies.Results: Eight RCTs comprising 6,492 patients (5 RCTs using prophylactic dose (n = 5,556), 1 RCT using semi-therapeutic dose (n = 312), 2 RCTs using therapeutic dose (n = 624)) are eligible for analysis. The duration of thromboprophylaxis ranged from 6 weeks to 6 months. The crude VTE rates were 2.65% and 5.66% in thromboprophylaxis and control groups, respectively, with an overall RR of 0.48 (CI = 0.36 – 0.64). RRs for VTE in patients receiving prophylactic, semi-therapeutic and therapeutic doses of anticoagulants were 0.48 (CI = 0.33 – 0.68), 0.35 (CI = 0.16 – 0.75) and 0.62 (CI = 0.33 – 1.16), respectively. The RRs of these subgroups were not significantly different from one another (p = 0.518). The overall RD was -0.024 (CI = -0.033 – -0.016), suggesting an estimated number needed to treat (NNT) of 42 (CI = 30 – 63) to prevent one VTE event. RRs for major bleeding across different antithrombotic doses were not statistically different (p = 0.44) with RRs of 1.1 (CI = 0.69 – 1.75), 0.63 (CI = 0.29 – 1.37) and 1.16 (CI = 0.52 – 2.58) for prophylactic, semi-therapeutic and therapeutic doses, respectively. The overall RR for major bleeding was 0.99 (CI = 0.69 – 1.41). There was no difference in mortality rate between thromboprophylaxis and control groups (RR = 0.98, CI = 0.92 – 1.04, p = 0.42). However, there was a nonsignificant trend towards improvement in mortality in the therapeutic dose subgroup (RR = 0.9, CI = 0.78 – 1.05, p = 0.17).Conclusions: Our meta-analysis demonstrated that, among patients with advanced solid malignancies receiving chemotherapy, primary thromboprophylaxis with anticoagulants significantly reduced VTE events without an increase in major bleeding events compared to control, even though an overall survival benefit was not observed. The benefit in VTE reduction, the risk of major bleeding events and the incidence of overall mortality were similar among the three dosing regimens. However, it was noted that there was a nonsignificant trend towards survival advantage in the therapeutic dose subgroup. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.