Clinically Relevant Non-major Bleeding Events Research Articles

Efficacy and Safety of Extended Duration Postoperative Thromboprophylaxis with Low-Molecular-Weight-Heparin Among Subgroups of Patients Undergoing Surgical Resection of Colorectal Cancer: A Post-Hoc Analysis of the Periop-01 Trial

Background: Clinical practice guidelines suggest the use of extended duration of postoperative thromboprophylaxis to prevent venous thromboembolic (VTE) complications after any cancer-related major abdominal or pelvic surgeries. However, recent trials including patients undergoing surgical resection of colorectal cancer have reported relatively low rates of symptomatic VTE. Hence, the risk and benefits of extended postoperative thromboprophylaxis need to be carefully assessed in this patient population. We sought to determine the impact of extended duration thromboprophylaxis with low-molecular-weight-heparin on VTE and bleeding events among different subgroups of patients undergoing surgical resection of localized colorectal cancer. Methods: This is a pre-planned post-hoc analysis of the PERIOP-01 randomized controlled trial which compared extended (up to 6 weeks) to standard duration (in hospital only) of perioperative thromboprophylaxis with tinzaparin (4500 IU SC daily) in patients undergoing surgical resection of localized colorectal cancer. Subgroup analyses were performed based on different baseline characteristics. The primary efficacy and safety outcomes were objectively documented major VTE and combination of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) events, respectively. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using the Cox proportional hazards model to compare the treatment effect accounting for clustering at study center level. Results: A total of 614 patients were randomized in the PERIOP-01 trial (307 in the extended and 307 in the standard duration thromboprophylaxis groups). Overall, the mean age of the participants was 61 years, 41% of them were women, and most patients were white (90%). Type of primary cancer was well-balanced with 311 patients having rectal cancer (51%), whereas 303 (49%) had primary colon cancer. During the study period, major VTE events occurred in 2% and 1% of the extended- and standard-duration prophylaxis groups, respectively (P=0.8). Combination of MB and CRNMB events occurred in 3% of each group. No specific characteristics were found to be associated with a decreased risk of major VTE among patients on extended duration thromboprophylaxis (Figure 1). Patients with colon cancer resection receiving extended thromboprophylaxis were at an increased risk of bleeding complication compared to patients with rectal cancer (HR 2.57, 95%CI 1.25-5.3) (Figure 1). Other characteristics that may be associated with an increased risk of bleeding among patient on extended thromboprophylaxis included age >= 75 (HR 2.37, 95%CI 0.47-11.98) and male sex (HR 2.13, 95%CI 0.2-23.17), although these characteristics were not statistically significant. Conclusions: In the PERIOP-01 trial, extended thromboprophylaxis didn't reduce the risk of major VTE in any subgroups of patients. On the other hand, extended duration of thromboprophylaxis may be associated with an increased bleeding risk among male, elderly patients, and those with colon cancer.

Comparative Bleeding Risk in Patients with Atrial Fibrillation with Cancer versus Without Cancer from Nationwide Prospective Cohort.

Comparison of the bleeding risk for long-term oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (AF) with and without cancers has been inconsistent. This study aimed to clarify the differences in the bleeding risk in patients with AF with cancers and those without cancers during the long-term OAC.The CODE-AF prospective registry enrolled 5,902 consecutive patients treated for AF at 10 tertiary referral centers in Korea. Of the enrolled patients, 464 (7.8%) were diagnosed with cancers and were followed for all stroke and bleeding events (net composite events).The age, CHA2DS2-VASC, and HAS-BLED scores were similar between AF patients with and without cancers. Male population greatly comprised patients with AF with cancers. They were equally prescribed with direct OAC compared to those without cancers. The incidence rate for clinically relevant nonmajor (CRNM) bleeding events was higher in the patients with AF with cancers than in those without cancers (4.4 per 100 person-years versus 2.8 per 100 person-years, P = 0.023), and net composite events were also more frequent in patients with AF with cancers than in those without cancers (6.4 per 100 person-years versus 4.0 per 100 person-years, P = 0.004). Patients with AF with cancers showed a significantly higher rate of CRNM bleeding (hazard ratio [HR] 1.54, confidence interval [CI] 1.05-2.25, P = 0.002) than those without cancers.Based on the AF cohort, AF with cancers could face a significantly higher risk for CRNM bleeding events in the long-term OAC than those without cancers.

Evaluation of venous thromboembolism prophylaxis protocol in hematopoietic cell transplant patients

Hematopoietic cell transplant (HCT) recipients are at risk for thromboembolic and bleeding complications. There is limited evidence regarding the optimal approach to managing venous thromboembolism (VTE) prophylaxis in hospitalized patients undergoing HCT. In this retrospective cohort study, we evaluated the incidence of bleeding and VTE events in hospitalized HCT patients who received VTE prophylaxis per our institution’s VTE Prophylaxis Protocol (VPP), with either enoxaparin 40 mg subcutaneously daily or heparin 5 000 units subcutaneously twice daily, compared to historical controls who did not receive VTE prophylaxis. The primary outcome was a composite of major bleeding events, clinically relevant non-major bleeding (CRNMB), and minor bleeding. The secondary outcome was a composite of VTE events. A total of 614 patients were evaluated, including 278 prior to and 336 after implementation of VPP. VTE prophylaxis resulted in no difference in bleeding events (15.1% in the pre-VPP group vs. 14.6% in the post-VPP group, p = 0.86) or composite of major and CRNMB events (0.72% vs. 0.30%, p = 0.59). There was a trend toward lower incidence of VTE events in the post-VPP group which did not reach statistical significance (8.6% vs. 6.0%, p = 0.20). We conclude that VTE prophylaxis does not pose additional bleeding risk in HCT patients.

PO-05-165 COMPARATIVE BLEEDING RISK IN PATIENTS WITH ATRIAL FIBRILLATION WITH CANCER VERSUS WITHOUT CANCER FROM NATIONWIDE PROSPECTIVE COHORT: CODE-AF REGISTRY

Comparison of the bleeding risk for long-term oral anti-coagulation (OAC) in non-valvular atrial fibrillation (AF) patients with cancers and those without cancers has been yet inconsistent The purpose of this study was to clarify the differences in the bleeding risk in AF patients with cancers and those without cancers during the long-term OAC. The CODE-AF prospective registry enrolled 5,902 consecutive patients who were treated for AF at 10 tertiary referral centers in Korea. Of the enrolled patients, 464 (7.8%) patients were diagnosed with cancers and clinically followed for all stroke and bleeding (net composite events). The CODE-AF prospective registry enrolled 5,902 consecutive patients who were treated for AF at 10 tertiary referral centers in Korea. Of the enrolled patients, 464 (7.8%) patients were diagnosed with cancers and clinically followed for all stroke and bleeding (net composite events). The age, CHA2DS2-VASC and HAS-BLED scores were similar between AF patients with cancers and those without cancers. AF patients with cancers had a greater proportion of male, and were equally prescribed non-vitamin K OAC compared to those without cancers. Incidence rate for clinically relevant non-major (CRNM) bleeding events were observed to be higher in the AF patients with cancers than those without cancers (4.4 per 100 person-years vs. 2.8 per 100 person-years, P=0.023), and net composite events were also more frequently observed in the AF patients with cancers than those without cancers (6.4 per 100 person-years vs. 4.0 per 100 person-years, P=0.004). AF patients with cancers showed a significantly higher rate of CRNM bleeding (hazard ratio [HR] 1.54, confidence interval [CI] 1.05 – 2.25, P=0.002) compared with those without cancers. Based on AF prospecitve multicenter cohort, AF with cancers could face a significantly higher risk for CRNM bleeding events in the long-term OAC compared with those without cancers.

278 Eight Pharmacokinetic-related Genetic Variants Were Not Associated with Bleeding from Direct Oral Anticoagulants in Non-valvular Atrial Fibrillation Patients

OBJECTIVES/GOALS: Assess the association of PK-related single nucleotide variants (SNVs) with the risk of bleeding from DOACs in non-valvular AF patients. METHODS/STUDY POPULATION: A retrospective cohort study was carried out with 2,364 Caucasians with non-valvular AF and treated with rivaroxaban or apixaban. Patients were genotyped as part of the genomic biobank at the University of Michigan Health System. The primary endpoint was a composite of major and clinically relevant non-major (CRNM) bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of 8 SNVs in 5 PK genes (ABCB1, ABCG2, CYP3A4, CYP3A5, CYP2J2) with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. Six tests were performed as 3 of the SNVs are in the same haplotype. P-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. RESULTS/ANTICIPATED RESULTS: A total of 412 (17.4%) major and CRNM bleeding events occurred over 2.27 ± 2.03 years of follow-up. None of the PK SNVs were significantly associated with bleeding risk on DOACs in both unadjusted and covariate-adjusted Cox regression models. DISCUSSION/SIGNIFICANCE: The effects of these eight genetic variants on exposure to DOACs may not be strong enough to translate into differences in clinical outcomes. Especially if the genetic inheritance underlying the risk of bleeding from DOACs is polygenic, reinforcing the need for further genomic studies on this subject.

779: FACTOR XA INHIBITORS IN PATIENTS WITH ACUTE KIDNEY INJURY

Introduction: Data is lacking regarding the safety and efficacy of factor Xa inhibitors in patients with acute kidney injury (AKI). The goal of this study is to compare bleeding and thromboembolic events in patients receiving therapeutic doses of apixaban or rivaroxaban versus unfractionated heparin (UFH) in patients with AKI. Methods: This retrospective, observational study evaluated hospitalized adult patients who received therapeutic doses of either apixaban, rivaroxaban, or UFH for at least 24 hours in the setting of AKI as defined by AKIN criteria. Patients were excluded if they met any of the following criteria: non-FDA approved factor-Xa inhibitor indication; COVID admission; major bleeding or clinically relevant non-major bleeding (CRNMB) on admission, embolic event within 30 days of admission; coagulopathy; receipt of a contraindicated medication, or ESRD. Bleeding events were evaluated in accordance with International Society on Thrombosis and Hemostasis criteria. The primary outcome was defined as composite major and clinically relevant non-major bleeding events. Secondary outcomes included comparison of the individual components of the composite bleeding endpoint and thromboembolic events. Results: A total of 500 patients met inclusion criteria, with 250 patients included in the UFH group and factor Xa inhibitor group. AKIN Stage I was most prevalent in the overall study population; patients with AKIN stage III were more likely to be transitioned to UFH (p< 0.01). Surgical patients were more likely to be transitioned to UFH (p< 0.01). Patients transitioned to IV heparin were more likely to undergo a procedure (p< 0.01). After adjusting for confounding factors, patients who received a factor Xa inhibitor experienced a lower risk of composite major bleeding and CRNMB events as compared to UFH (OR: 0.57, 95% CI: 0.34-0.94; p = 0.03). This was driven by a decreased risk of CRNMB in the factor Xa inhibitor group (OR: 0.55, 95% CI: 0.33-0.91, p = 0.02). No significant differences in major bleeding or VTE were noted. Conclusions: Continuation of factor Xa inhibitor therapy in the setting of AKI was associated with a reduced incidence of bleeding events compared to patients transitioned to UFH in accordance with package insert recommendations.

Bleeding Risk in Atrial Fibrillation and Thrombocytopenia: A Propensity Matched Cohort Study

Background: Anticoagulation is the major therapeutic strategy in the management of patients with atrial fibrillation (AF). Thrombocytopenia is a frequent coexisting condition that may predispose to bleeding in these patients. However, the risk of bleeding in patients with AF and thrombocytopenia has not been well studied. Moderate thrombocytopenia (<100,000/μL) was an exclusion criteria in the clinical trials used to approve non-vitamin K oral anticoagulants for stroke prophylaxis. Similarly, studies examining warfarin's safety and efficacy in AF have not included significant numbers of thrombocytopenic patients. This paucity of data describing the safety of oral anticoagulants in patients with AF and thrombocytopenia represents a major challenge in clinical practice. Present treatment guidelines do not include specific guidance for anticoagulation in patients with these coexisting conditions. Thus, the purpose of this study was to compare rates of bleeding among patients with and without thrombocytopenia who begin oral anticoagulation for AF. Methods: A propensity matched cohort study was designed to compare rates of bleeding among patients with thrombocytopenia who began oral anticoagulation for AF between 2015-2020 at a quaternary care hospital in Boston, MA against patients with AF starting anticoagulation in the absence of thrombocytopenia. The thrombocytopenic cohort was defined as having at least two platelet counts on separate days <100,000/μL in the period spanning the 12 weeks preceding the initiation of anticoagulation to 6 weeks following the initiation of anticoagulation. Patients with only one platelet count <100,000/μL were excluded. Individuals from the thrombocytopenic cohort were matched with patients (1:3 ratio) from the non-thrombocytopenic cohort using propensity matching on the basis of age, sex, CHA2DS2-VASc score, and anticoagulant agent used. Bleeding outcomes were determined by blinded manual chart review and verified by a second reviewer; all bleeding events were classified as per the International Society on Thrombosis and Haemostasis. The primary endpoint of the study was the cumulative incidence of clinically relevant bleeding, a composite of major bleeding and clinically relevant non-major bleeding (CRNMB), within one year of the initiation of anticoagulation. Results: The study population included 1,075 patients who started oral anticoagulation for AF (274 with thrombocytopenia, 801 controls). Overall, 38% of the cohort was female, with a median age of 72 years; 14.6% of the total cohort had cancer and 2.8% had liver disease at the time they began anticoagulation. The median CHA2DS2-VASc score was 3 (IQR 2-4). Warfarin (48.2%) and apixaban (39.6%) were the anticoagulants used in the majority of patients. Notably, the thrombocytopenic cohort included more patients with significant comorbidities, such as cancer (23.0% vs 11.7%), liver disease (4.7% vs. 2.1%), and kidney disease (12.8% vs. 7.5%). There were a total 219 bleeding events recorded, including 90 (41.1%) major bleeding events and 122 (55.7%) CRNMB events. (Table 1) The cumulative incidence of clinically relevant bleeding at 1 year was significantly higher (18.3%; 95% CI, 13.6-22.9) in those with thrombocytopenia at the time of starting anticoagulation compared with the control cohort (13.2%; 95% CI, 10.9-15.6) (P < 0.001, Gray test). Similarly, the cumulative incidence of major bleeding at 1 year was 10.1% (95% CI, 6.5-13.7) in those with thrombocytopenia compared with 5.2% (95% CI, 3.7-6.8) among controls (P < 0.001, Gray test). (Figure 1) Conclusions: Oral anticoagulation for AF in patients with thrombocytopenia at the time of starting anticoagulation significantly increased the risk of clinically relevant and major bleeding relative to patients with normal platelet counts. These findings support the need for further characterization of the risk-benefit profile of anticoagulation in this population to guide clinicians faced with this common clinical scenario. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 14063: Eight Pharmacokinetic-Related Genetic Variants Were Not Associated With Bleeding From Direct Oral Anticoagulants in Non-Valvular Atrial Fibrillation Patients

Background. Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing stroke risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy in non-valvular AF since they are as effective and safer than warfarin. Although patients bleed less overall from DOACs, bleeding still is the main safety concern with this therapy. Previous studies have shown that genetic variants modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs, which then affect DOAC plasma concentrations. However, whether those functional PK genetic variants are significantly associated with the risk of bleeding on DOACs is unknown. Aim. Assess the association of PK-related single nucleotide variants (SNVs) with the risk of bleeding from DOACs in non-valvular AF patients. Methods. A retrospective cohort study was carried out with 2,364 Caucasians with non-valvular AF and treated with rivaroxaban or apixaban. Patients were genotyped as part of the genomic biobank at the University of Michigan Health System. The primary endpoint was a composite of major and clinically relevant non-major (CRNM) bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of 8 SNVs in 5 PK genes ( ABCB1 , ABCG2 , CYP3A4 , CYP3A5 , CYP2J2 ) with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. Six tests were performed as 3 of the SNVs are in the same haplotype. P-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results. A total of 412 (17.4%) major and CRNM bleeding events occurred over 2.27 ± 2.03 years of follow-up. None of the PK SNVs were significantly associated with bleeding risk on DOACs (Table 1). Conclusion. SNVs that affect the function of PK genes were not significantly associated with major and CRNM bleeding from rivaroxaban or apixaban in 2,364 AF patients.

Early Versus Late Administration of P2Y 12 Inhibitors in Non-ST Segment Elevation Myocardial Infarction and Delayed Cardiac Catheterization.

Regardless of early invasive or ischemia-guided approaches to non-ST segment elevation myocardial infarction (NSTEMI) management, P2Y 12 inhibitors remain the backbone in therapy. The ideal timing of administration remains unclear. The purpose of this study was to determine the safety and effectiveness of early versus late administration of P2Y 12 inhibitors in patients presenting with an NSTEMI who go to the catheterization laboratory beyond 24 hours from presentation. We performed a single center, retrospective cohort study. Patients were classified into groups depending on whether they received early versus late administration of a P2Y 12 inhibitor. The primary outcome was the rate of major and clinically relevant, nonmajor bleeding (CRNMB). Secondary outcomes included troponin peak and length of stay after cardiac catheterization. Of the 121 patients included, 53 patients were in the early and 68 patients were in the late group. The number of bleeding events were similar between both groups ( P = 1.00). There were 3 (5.7%) major bleeding events in the early group and 5 (7.4%) bleeding events in the late group. There were 5 (9.4%) CRNMB events in the early group and 6 (8.8%) CRNMB events in the late group. There was a significant difference in troponin peak, 4.56 ng/mL in the early group and 1.77 ng/mL in the late group ( P = 0.02). The rate of bleeding did not differ between patients who received early or late administration of P2Y 12 inhibitors for NSTEMI management who undergo delayed cardiac catheterization.

Incidence and clinical impact of bleeding events in older patients with acute venous thromboembolism

AbstractOlder patients anticoagulated for venous thromboembolism (VTE) have an increased risk of bleeding compared with younger patients. Little is known about the clinical impact of anticoagulation-related bleeding in this growing patient group. To prospectively assess the incidence, clinical impact, and predictors of bleeding in older patients anticoagulated for VTE, we analyzed 981 patients aged ≥65 years with acute VTE in a prospective multicenter cohort. Eight-eight percent were anticoagulated with vitamin K antagonists. Outcomes were the occurrence of major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) event during the initial anticoagulation period up to 36 months. We described the incidence and clinical impact of bleeding and examined the association between risk factors and time to a first bleeding using competing risk regression; 100 MB and 125 CRNMB events occurred during follow-up. The incidence of MB and CRNMB was 8.5 (95% confidence interval [CI], 7.0-10.4) and 13.4 events (95% CI, 11.4-15.7) per 100 patient-years, respectively. In patients with MB, 79% required hospitalization, 18% required surgical intervention, and 19% required permanent discontinuation of anticoagulation; 15% of MB were intracranial and 6% were fatal. After adjustment, active cancer (subhazard ratio [SHR], 1.81; 95% CI, 1.12-2.93) and low physical activity (SHR, 1.88; 95% CI, 1.19-2.98) were associated with MB and high risk of falls with CRNMB (SHR, 2.04; 95% CI, 1.39-3.00). Older patients anticoagulated for VTE had a high incidence of MB and CRNMB, and these bleeding episodes caused a great burden of disease. Physicians should carefully weigh the risks/benefits of extended anticoagulation in the older population with VTE.

Single versus multiple and incidental versus symptomatic subsegmental pulmonary embolism: clinical characteristics and outcome.

It remains unexplored if the clinical picture and outcome of subsegmental pulmonary embolism (SSPE) differ between single versus multiple, and incidental versus symptomatic embolism. Consecutive patients anticoagulated for SSPE at the Mayo Thrombophilia Clinic (03/01/2013-12/31/2020) were followed forward to assess venous thromboembolism (VTE) recurrence, mortality, major bleeding, and clinically relevant non-major bleeding (CRNMB); expressed as a rate per 100 person-years. Among 3878 VTE patients, 1541 had pulmonary embolism including 224 (14.6%) with SSPE either single (n = 139) or multiple (n = 85; 46 bilateral and 39 unilateral emboli); 134 had incidental and 90 symptomatic SSPE. Patients with single were less often symptomatic and less often had coexisting DVT than multiple SSPE. Patients with incidental had a two-fold higher frequency of cancer compared to symptomatic SSPE. During the study period, 1 patient with single and 2 with multiple SSPE had VTE recurrence (rate of 1.14 vs 3.63, p = 0.280). Single SSPE patients experienced 2 episodes of major bleeding (rate of 2.36) while the multiple SSPE group had no major bleeding. Seven patients in each group had CRNMB events (rate of 8.20 vs 13.58 for single and multiple SSPE, respectively, p = 0.282). Patients with single SSPE had a higher death rate compared to multiple SSPE (43.07 vs 22.22, p = 0.031) but no difference was noted after adjusting for cancer (p = 0.388). Also, incidental had similar clinical outcomes to symptomatic SSPE.Interpretation Anticoagulated SSPE patients with single and multiple as well as incidental and symptomatic have a different clinical profile but similar clinical outcomes.

Anticoagulation Changes Following Major and Clinically Relevant Nonmajor Bleeding Events in Non-valvular Atrial Fibrillation Patients

Background: Bleeding events are common complications of oral anticoagulant drugs, including both warfarin and the direct oral anticoagulants (DOACs). Some patients have their anticoagulant changed or discontinued after experiencing a bleeding event, while others continue the same treatment. Differences in anticoagulation management between warfarin- and DOAC-treated patients following a bleeding event are unknown. Methods: Patients with non-valvular atrial fibrillation from six anticoagulation clinics taking warfarin or DOAC therapy who experienced an International Society of Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant non-major (CRNM) bleeding event were identified between 2016 and 2020. The primary outcome was management of the anticoagulant following bleeding (discontinuation, change in drug class, and restarting of same drug class). DOAC- and warfarin-treated patients were propensity matched based on the individual elements of the CHA2DS2-VASc and HAS-BLED scores as well as the severity of the bleeding event. Results: Of the 509 patients on warfarin therapy and 246 on DOAC therapy who experienced a major or CRNM bleeding event, the majority of patients continued anticoagulation therapy. The majority of warfarin (231, 62.6%) and DOAC patients (201, 81.7%) restarted their previous anticoagulation. Conclusion: Following a bleeding event, most patients restarted anticoagulation therapy, most often with the same type of anticoagulant that they previously had been taking.

Abstract 9740: Efficacy and Safety of Direct Oral Anticoagulants versus Warfarin in Patients with Venous Thromboembolism or Nonvalvular Atrial Fibrillation and Chronic Kidney Disease a Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Direct oral anticoagulants (DOAC) have proven to be safe and effective alternatives to warfarin for stroke prevention in non-valvular atrial fibrillation (NVAF) as well as treatment of venous thromboembolism (VTE). Chronic kidney disease (CKD) is associated with increased risk of thromboembolism as well as bleeding. The objective of this research is to evaluate the efficacy and safety of DOAC compared to warfarin in patients with either VTE or NVAF across varying renal function. Methods: A systematic literature search using PubMed, Embase (1996 -November 2020), and Cochrane CENTRAL databases was conducted. Randomized controlled trials published in English between 1996 and November, 2020 evaluating the safety and efficacy of DOAC versus warfarin in patients with VTE or NVAF and CKD were included. Outcomes of interest were stroke or thromboembolic events, all-cause mortality, major bleeding (MB), and clinically relevant non-major bleeding (CRNMB). Random effects-model was used for meta-analysis. Risk of bias was assessed by utilizing the Revised Cochrane risk-of-bias tool for randomized trials. Results: After screening and review, a total of 9 randomized controlled trials with 96,103 participants were included. Of those, 81.5% (n=78,361) had a specific classification of renal function throughout the study. Majority of participants had mild to normal (48.5%) renal function, and 35% had mild impairment and moderate and severe renal impairment accounted for 16% and &lt;1%, respectively. DOAC reduced risk of stroke or thromboembolic events compared to warfarin (RR 0.83, CI 95%: 0.77-0.89; p -value&lt;0.01), as well as all-cause mortality (RR 0.91, CI 95%: 0.85-0.97; p -value&lt;0.01). For safety outcomes, MB events were less likely to occur in DOAC group (RR 0.76, CI 95%: 0.69-0.84; p -value&lt;0.01). Whereas, no significant difference was found between DOAC and warfarin in CRNMB events (RR 0.90, CI 95%: 0.73-1.12; p- value 0.36). Conclusion: DOAC demonstrated better efficacy in preventing stroke or thromboembolic events and in decreasing all-cause mortality. DOAC also caused less MB events compared to warfarin. No difference in CRNMB events was detected between these agents.

Pharmacokinetics and Pharmacodynamics of Ionis-FXIRx, an Antisense Inhibitor of Factor XI, in Patients with End-Stage Renal Disease on Hemodialysis

BACKGROUNDPatients with end-stage renal disease (ESRD) on hemodialysis are at high risk of both thrombotic and bleeding events. Experimental and clinical data indicate that reducing factor XI (FXI), a key component of the intrinsic pathway, prevents thrombosis without causing bleeding. FXI activity can be lowered with IONIS-FXIRx, a 2nd generation antisense oligonucleotide that specifically reduces human FXI mRNA expression in the liver. This study sought to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-FXIRx in participants with ESRD. METHODSIn this Phase 2 multicenter study, we enrolled a total of 49 ESRD patients: (A) 6 participants receiving chronic in-center hemodialysis (HD) to receive an open-label single-dose of 300 mg IONIS-FXIRx either 5 minutes before or 10 minutes after HD and assessed the effects of HD on peak (Cmax) and the extent of exposure (AUC0-24hr) parameters of IONIS-FXIRx and (B) another 43 participants in a double-blind design to one of two multiple-dose regimens (200 mg or 300 mg) IONIS-FXIRx or placebo for 12 weeks with 12 weeks of additional follow up. In the double-blind portion, IONIS-FXIRx was administered subcutaneously ~10 minutes after HD. For PK, plasma trough concentration and apparent elimination half-life (t1/2λz) were evaluated. The PD parameters including FXI activity and antigen, aPTT, prothrombin time (PT), and INR were evaluated in the per-protocol population (N= 34) that was defined as all participants who received the complete protocol-specified administration of IONIS-FXIRx or placebo through week 8 and who did not have any major protocol violations. The rate and frequency of clotting on the HD filters and circuit were qualitatively measured with a clotting scale as an exploratory PD analysis. RESULTSThe PK cohort included 6 males (5 white) with a mean age of 61 years. The plasma PK profile of IONIS-FXIRx was not significantly altered whether injected before or after HD. After multiple dosing, plasma Cmax values were dose-dependent and similar between Day 1 (first dose) and Day 78 (last dose), suggesting no accumulation of IONIS-FXIRx in ESRD participants after 12-weeks of dosing. After treatment cessation, IONIS-FXIRx had an apparent elimination half-life of approximately 2 weeks. In the double-blind portion of the study, 22 (51.2%) of the participants were male, 24 (55.8%) were white and the mean age was 59 years. Attenuation of FXI activity was associated with a reduction in the incidence of severe clotting events on both the air filter and dialyzer (Table). The reduction in severe clotting events was observed when FXI activity was < 0.4 U/mL. Consistent with prior observations in healthy subjects, IONIS-FXIRx prolonged aPTT in a time and dose-dependent manner with maximum mean percent changes from baseline of 53.3% (p < 0.05) for the 200 mg dose group and 75.6% (p < 0.05) for the 300 mg dose group at Week 14, but had no effect on PT. Treatment emergent adverse events (TEAEs) were mostly mild; participants reporting serious TEAEs were 1 (16.7%) for the PK cohort, 4 (30.8%) for placebo and 3 (20.0%) each for the 200 mg and 300 mg IONIS-FXIRx dose groups. There were no drug-related SAEs and no drug-related major or clinically-relevant non-major bleeding events. Minor bleeds were primarily observed in the 300 mg multiple-dose group at AV fistula/graft sites but did not correlate with reduction of FXI activity. No clinically significant reductions in platelet counts were reported during the study. CONCLUSIONSThis study demonstrated that (i) HD had no effect on IONIS-FXIRx PK, (ii) IONIS-FXIRx was well tolerated and produced sustained, and dose-dependent reductions in FXI antigen and activity, and (iii) IONIS-FXIRx reduced severe dialysis circuit clotting events beyond standard heparin use. Collectively, these data support further evaluation of IONIS-FXIRx as a potentially safe, effective antithrombotic therapy in ESRD patients on HD. [Display omitted] DisclosuresBethune:Ionis Pharmaceuticals: Employment. Walsh:Population Health Research Institute: Employment; Ionis Pharmaceuticals: Consultancy. Jung:Ionis Pharmaceuticals: Employment. Yu:Ionis Pharmaceuticals: Employment. Geary:Ionis Pharmaceuticals: Employment. Bhanot:Ionis Pharmaceuticals: Employment.

The Impact of Body Weight and Renal Function on the Risk of Bleeding With Direct Oral Anticoagulants in Atrial Fibrillation.

Atrial fibrillation (AF) increases the risk of stroke and direct oral anticoagulants (DOACs) are first-line agents for prevention. Gaps in the literature cause reluctance in prescribing DOACs for patients with renal dysfunction and/or extremes in body weight. To evaluate the impact body weight and renal function have on major and clinically relevant nonmajor (CRNM) bleeding events and ischemic strokes in AF patients receiving a DOAC. This retrospective cohort study included adults with nonvalvular atrial fibrillation (NVAF) or atrial flutter (AFL) receiving a DOAC ≥12 months. The primary outcome was a composite of major and CRNM bleeding events. Secondary outcomes included ischemic stroke and risk factors for bleeding events. Of the 233 patients analyzed, 25 patients experienced a bleeding event. Patients who bled weighed 10 kg less (P = 0.043) than those who did not and had a higher HASBLED score (P = 0.003). Multivariate logistic regression identified weight (P = 0.048), serum creatinine (SCr; P = 0.027), and HASBLED score (P = 0.024) as the significant predictors for experiencing a bleed. Three patients experienced a stroke. This study demonstrates an association between higher baseline SCr, elevated HASBLED score, and lower weight, with an increased risk of bleeding in patients with NVAF or AFL receiving a DOAC. These findings add to prescribing considerations when initiating DOACs. Closer monitoring is advised for patients with significant renal dysfunction and/or low body weight, even with renal dose adjustments.

Treatment of venous thromboembolism in cancer patients: a systematic review and meta-analysis on the efficacy and safety of different direct oral anticoagulants (DOACs).

BackgroundTo evaluate the efficacy and safety of different direct oral anticoagulants (DOACs) compared with low molecular weight heparins (LMWHs) in the treatment of venous thromboembolism (VTE) in cancer patients.MethodsLiterature was searched in databases including Cochrane Library, EMBASE (Ovid), and MEDLINE (PubMed). Eligible studies were included, and data were collected independently by 2 reviewers. We conducted a systematic review of the efficacy and safety of DOACs in the treatment of VTE in cancer patients. The odds ratios (ORs) of different DOACs compared with LMWHs for VTE, deep vein thrombosis (DVT), pulmonary embolism (PE) recurrence, major bleeding, and clinically relevant non-major bleeding (CRNMB), were calculated in meta-analyses and subgroup analyses.ResultsA total of 18 articles were eligible for analyses, including 4 randomized controlled trials (RCTs) and 14 retrospective studies. Both RCTs and retrospective studies confirmed that DOACs decreased the risk of VTE recurrence [RCTs: OR, 0.60; 95% confidence interval (CI), 0.45–0.80; retrospective studies: OR, 0.73; 95% CI, 0.59–0.90] and DVT recurrence (RCTs: OR, 0.54; 95% CI, 0.36–0.80; retrospective studies: OR, 0.20; 95% CI, 0.06–0.63), but not PE recurrence or fatal PE in cancer patients. Subgroup analyses revealed an important role of rivaroxaban in decreasing recurrent VTE. Meanwhile, major bleeding events were not increased in the DOAC group, but the risks of CRNMBs were significantly elevated. Subgroup analyses confirmed the role of rivaroxaban in increasing the risk of major bleeding events and CRNMBs.ConclusionsCompared with LMWHs, DOACs (especially rivaroxaban) significantly reduce the risk of VTE and DVT, but not PE recurrence, in patients with cancer. Although DOACs did not increase the major bleeding events in pooled analysis, rivaroxaban showed an elevated risk of this adverse effect in subgroup analysis. In addition, the risk of CRNMB events was increased after the application of DOACs including rivaroxaban.

Direct Oral Anticoagulants for Prevention of Recurrent Thrombosis in Myeloproliferative Neoplasms

Background: Patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are at increased risk of thrombosis. These myeloproliferative neoplasm (MPN) patients are historically treated with vitamin K antagonists (VKAs) to prevent recurrent thromboembolic events. Direct oral anticoagulants (DOACs) are novel anticoagulants that are being increasingly used in MPNs without robust evidence. We hypothesize that DOAC and VKA therapy have similar efficacy and safety in MPNs with a comparable incidence of recurrent thromboembolic and bleeding events. Methods: Using Looking Glass®, an interactive software that integrates demographic and clinical datasets for the purpose of clinical research, we identified MPN patients who were on systemic anticoagulation (AC) therapy for a documented arterial or venous thrombotic event between 1/1/2014 and 4/1/2019. Medical charts were reviewed to obtain patient demographics, MPN subtype, mutation status, date of MPN diagnosis, date and site of index thrombosis, date of AC initiation, last documented date of therapy, date and site of recurrent thrombosis, changes in therapy; date and type of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) events on AC. Primary outcome was incidence of recurrent thrombotic events while on AC. Secondary outcome was the incidence of MB and CRNMB events. Statistical analyses were performed using two-sided t-tests with α =0.05 for continuous variables, chi-square for categorical variables with samples size &gt;10 and Fisher's exact tests for categorical variables with sample size &lt;10. Results: We identified 53 patients that met the study criteria. Data on demographics, MPN subtype, mutation status, index thrombosis site, and type of AC are reported in Table 1. The majority of the patients in our cohort were females (69.8%), had a diagnosis of ET (71.7%), were JAK2V617F mutated (69.8%), and had a venous index event (75%). Median age for the entire cohort was 66.8 years (IQR 48.1-74.5) while the median age for those who had a recurrent thrombotic event on AC was 56.1 (IQR 46.4-76.1). If patients were switched from one anticoagulant to another, only the first treatment was included in the analysis. 31 (58.5%) of patients were on VKA therapy while 22 (41.5%) were on DOAC therapy. Median time of follow up was 227 and 451 days for DOACs and VKA respectively, (p = 0.01). Rates of thrombosis and bleeding were comparable within anticoagulation class. 5/22 (22.7%) and 6/31 (19.4%) of patients prescribed DOACs and VKA respectively developed recurrent thrombotic events. Median time to recurrent thrombotic event for DOACs as compared to VKA group was 568 vs 734 days (p = 0.29). 5/22 (22.7%) of those prescribed DOACs had bleeding events, 1 MB and 4 CRNMB. 11/31 (35.5%) of those prescribed VKA had bleeding events, 2 MB and 9 CRNMB. Median time to bleeding event for DOACs as compared to VKA was 56 vs 1347 days (p = 0.004). For the 53 patients on any anticoagulation, 11 (20.7%) patients had recurrent events while on AC (DOAC and VKA). In contrast, of the 14 patients who had AC therapy interrupted for any reason, 8 (57.1%) developed recurrent thrombotic events (p = 0.02). Table 2 summarizes these findings. Conclusion: We conducted a retrospective chart review study comparing the incidence of recurrent thromboembolic events on DOAC and VKA therapy. This is the largest study to date of MPN patients treated with DOACs. Based on our data, it appears that patients treated with DOACs have a comparable incidence of recurrent thrombosis and hemorrhagic events when compared to VKA therapy, although our study suggests that bleeding events may occur sooner in patients treated with DOACs. A large percentage of people with interruptions in their AC developed recurrent thrombotic events. Our data further emphasize the profound pro-thrombotic nature of MPN and therefore the need for uninterrupted anticoagulation therapy. Overall, given the comparable incidence of thrombosis and hemorrhage, DOAC therapy appears to be similar to VKA therapy in management of thrombotic complications of MPNs. The limitations of our study were as expected: a small sample size and significantly shorter median time for DOAC follow up as compared to VKA. Future, prospective large-scale studies are needed to confirm the safety and efficacy of DOAC therapy in MPNs. Disclosures Kushnir: Janssen Pharmaceuticals: Research Funding. Billett:Bayer Pharmaceuticals: Research Funding; Janssen Pharmaceuticals: Research Funding; Albert Einstein College of Medicine: Patents &amp; Royalties: Patent application pending for NETs AI software.

Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial

We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI). ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed. From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority). In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events. Daiichi Sankyo.

Renal Function and Outcomes With Dabigatran Dual Antithrombotic Therapy in Atrial Fibrillation Patients After PCI

ObjectivesThe study sought to evaluate the effect of dabigatran dual therapy versus warfarin triple therapy across categories of renal function in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial. BackgroundThe RE-DUAL PCI (NCT02164864) trial of patients with atrial fibrillation undergoing percutaneous coronary intervention reported that dabigatran dual therapy (110 or 150 mg twice daily, plus clopidogrel or ticagrelor) reduced the primary endpoint of major bleeding events (MBE) or clinically relevant nonmajor bleeding events (CRNMBE) compared with warfarin triple therapy, with noninferiority in overall thromboembolic events. MethodsRisk of a first MBE or CRNMBE and the composite of death or thromboembolic event (DTE) or unplanned revascularization were evaluated in 2,725 patients according to baseline creatinine clearance (CrCl) categories: 30 to <50, 50 to <80, and ≥80 ml/min. ResultsCompared with warfarin, dabigatran 110 mg dual therapy reduced risk of MBE or CRNMBE across all categories of CrCl (p for interaction = 0.19). Dabigatran 150 mg dual therapy reduced risk of MBE or CRNMBE regardless of the CrCl category (p for interaction = 0.31). Risk of DTE or unplanned revascularization was similar to warfarin triple therapy for dabigatran 110 mg dual therapy across all CrCl categories. Dabigatran 150 mg dual therapy versus warfarin triple therapy had similar risk for DTE or unplanned revascularization in patients with CrCl 30 to <80 ml/min and lower risk at CrCl ≥80 ml/min (p for interaction = 0.02). ConclusionsIn the RE-DUAL PCI trial, dabigatran dual therapy reduced bleeding events versus warfarin triple therapy irrespective of renal function, with overall similar risks of thromboembolic events but lower risks with dabigatran 150 mg in patients with normal CrCl.

Cancer-Associated Thrombosis and Bleeding Risk in Gastrointestinal Malignancies with Apixaban and Rivaroxaban Compared to Low Molecular Weight Heparin

Background: Randomized control trials (RCT) have examined the safety and efficacy of direct oral anticoagulants (DOACs) compared to dalteparin in patients with cancer-associated thrombosis (CAT). Increased major bleeding (MB) was seen with edoxaban and increased clinically relevant non-major bleeding (CRNMB) was seen with rivaroxaban and there has been specific concern about increased risk of bleeding among patients with gastrointestinal malignancies (GIM). Results from RCTs comparing apixaban to dalteparin in CAT are pending.Objective: Using the Mayo Clinic VTE registry, we examined the rates of MB, CRNMB, and overall bleeding (MB + CRNMB) in patients with GIM treated with anticoagulation for CAT.Methods: Consecutive patients treated for CAT were enrolled into Mayo Clinic VTE Registry between March 1, 2013 and July 27, 2018 and were followed prospectively for safety and efficacy. Clinical, demographic and imaging data were collected from each participant at the time of study recruitment. Cancer type, stage, and treatment with chemotherapy were recorded. Major and CRNMB events were evaluated at 3-month intervals. Clinical status was assessed by written questionnaire in subjects unable to return at 3 months. Unreturned questionnaires were followed up with a scripted phone interview. The study was approved by Mayo Clinic Institutional Review Board.Results: In the 535 subjects in the registry with CAT, the mean age (64.6 vs. 62.8 years), mean BMI (28.4 vs. 28.8), and percent female (46.4% vs 40.6%) were numerically similar between DOAC and LMWH treatment groups (Table 1). Metastatic disease was present in 53.6% and 60.2% and chemotherapy was being administered in 66.5% and 71.2% of DOAC and LMWH treated patients, respectively. Thrombocytopenia (<100x109/L) at initiation of anticoagulation was present in 6.8% of DOAC treated and 7.5% of LMWH treated patients. Among all cancer patients, 110 (21%) patients had a GIM, 58 (53%) were treated with LWMH and 52 (47%) were treated with a DOAC (42% rivaroxaban or 58% apixaban). In all CAT, the rate of MB was similar in DOAC versus LMWH treated patients (7.8 vs. 5.4 per 100 person-years; HR 1.48, 95% CI 0.72-3.05; Table 2). The rate of CRNMB however, was significantly increased in the DOAC patients compared to LMWH treated patients (6.18 vs. 0.44 per 100 person-years; HR 14.7, 95% CI 1.92, 112.26). In the sub-group of patients with GIM, the rate of MB was non-significantly higher in the DOAC versus LMWH treated patients (11.1 vs. 3.9 per 100 person-years; HR 2.90, 95% CI 0.57, 14.73). In contrast to the overall CAT group, the rate of CRNMB was similar in the DOAC compared to LMWH treated patients (2.10 vs. 1.92 per 100 person-years; HR 1.18, 95% CI 0.07, 20.21). In GIM patients, apixaban compared to rivaroxaban had a numerically higher, but non-significant, rate of major bleeding (23.98 vs. 3.50 per 100 person-years; HR 4.0, 95% CI 0.54-29.87). In the overall group of CAT, the risk of major bleeding was similar between apixaban and rivaroxaban (9.51 vs. 6.77 per 100 person-years).Conclusion: In our registry of subjects with CAT, we identified a significantly increased rate of CRNMB and overall bleeding, but not MB with the use of DOACs. In our data, GIM alone does not appear to account for the increased bleeding risk seen in CAT with DOACs, as we demonstrated no significant increase in major, CRNMB, or overall bleeding compared to LMWH. Direct comparison between apixaban and rivaroxaban was limited by sample size and number of events. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.