scholarly journals Safety of Anticoagulant Therapies for Treatment of Venous Thromboembolism in Patients with Cancer

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1178-1178 ◽  
Author(s):  
Michael Streiff ◽  
Dejan Milentijevic ◽  
Keith McCrae ◽  
Daniel Yannicelli ◽  
Jonathan Fortier ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Major Bleeding ◽  
Research Funding ◽  
Hazard Ratio ◽  
Control Cohort ◽  
Bleeding Events ◽  
Employment Equity ◽  
Patients With Cancer ◽  
Equity Ownership ◽  
Major Bleeding Events

Abstract Introduction: Anticoagulation is effective for the treatment of venous thromboembolism (VTE) in cancer patients, but it is also associated with an increased risk of bleeding. Previous clinical trials (e.g., CLOT and CATCH) of LMWH and warfarin for the treatment of VTE in cancer patients reported major bleeding in 3% to 6% of treated patients. The objective of this observational study was to compare the risk of major bleeding in cancer patients treated with anticoagulants for VTE in a real world setting. Methods: Medical and pharmacy claims from the Humana Database from 1/1/2013 to 05/31/2015 were analyzed. Newly diagnosed cancer patients with a first VTE diagnosis occurring after their first cancer diagnosis, and with ≥1 dispensing of an anticoagulant within 7 days after their VTE diagnosis, were selected. Based on the first anticoagulant received, patients were classified into one of the following cohorts: LMWH, warfarin, and rivaroxaban (other agents not included due to low utilization). Inverse probability of treatment weights based on propensity score were used to adjust for differences between treatment cohorts for the following comparisons: LMWH vs. rivaroxaban, LMWH vs. warfarin, and rivaroxaban vs. warfarin. Patients were followed up until the earliest event, either treatment non-persistence (gap > 60 days between the end of the days of supply of a dispensing and the start date of the next dispensing), or end of data availability. Major bleeding events were identified using validated criteria (Cunningham et al., 2011). Kaplan-Meier rates at 3 and 6 months and Cox proportional hazards models were used to compare the risk of bleeding between different treatment cohorts. To better understand the risk of major bleeding in cancer patients unrelated to anticoagulation, a cohort of patients with cancer who did not have VTE and did not receive an anticoagulant was added as a control cohort. Results: A total of 2,428 patients (LMWH: n=660; warfarin: n=1,061; rivaroxaban: n=707) were included. Baseline demographic and clinical characteristics were well balanced among treatment cohorts. Median duration of therapy with LMWH was shorter than rivaroxaban (1.0 vs. 3.0 months, p<.0001) and warfarin (1.0 vs. 3.5 months, p<.0001). Rates of major bleeding for LMWH and rivaroxaban were 8.3% and 8.2%, respectively at 6 months with a hazard ratio (HRs [95% CI]) of 1.03 (0.64-1.65; Figure 1A). In the comparison between LMWH and warfarin cohorts, major bleeding rates were 8.5% and 8.6%, respectively at 6 months with hazard ratio (HRs [95% CI]) of 1.04 (0.69-1.57; Figure 1B). The risk of major bleeding was also similar for rivaroxaban and warfarin cohorts, 9.0% and 8.7%, respectively at 6 months with a hazard ratio (HR [95% CI]) of 1.01 (0.71-1.43; Figure 1C). For the control cohort of cancer patients without VTE and not receiving anticoagulation median follow-up was 5.6 months. Rates of major bleeding events for the control cohort were 2.6% and 4.2 % at 3 and 6 months, respectively. Conclusion: This real world study of cancer patients treated for VTE found that the risk of major bleeding was similar for the 3 most widely prescribed anticoagulants in current clinical practice: LMWH, warfarin, and rivaroxaban. The observed rates of major bleeding were generally higher than what has been reported for LMWH and warfarin in the CLOT and CATCH trials. Patient characteristics such as older age (average age 73 years) could have contributed to the higher major bleeding rate seen in this study compared to the CLOT and CATCH trials, respectively. Figure 1 Rates of Major Bleeding Events LMWH vs. rivaroxaban cohorts Figure 1. Rates of Major Bleeding Events. / LMWH vs. rivaroxaban cohorts Figure 2 LMWH vs. warfarin cohorts Figure 2. LMWH vs. warfarin cohorts Figure 3 rivaroxaban vs. warfarin cohorts Figure 3. rivaroxaban vs. warfarin cohorts Disclosures Streiff: Portola: Research Funding; Janssen: Consultancy, Research Funding; Roche: Research Funding; CSL Behring: Consultancy, Research Funding. Milentijevic:Janssen Scientific Affairs: Employment, Equity Ownership. McCrae:Janssen: Membership on an entity's Board of Directors or advisory committees. Yannicelli:Janssen Scientific Affairs: Employment, Equity Ownership. Fortier:Janssen Pharmaceuticals: Research Funding. Nelson:Janssen Scientific Affairs: Employment, Equity Ownership. Laliberté:Janssen Scientific Affairs: Research Funding. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lefebvre:Janssen Scientific Affairs: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Khorana:Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Leo: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding.

scholarly journals Case Fatality Rate of Recurrent Venous Thromboembolism and Major Bleeding Events Among Patients Treated for Cancer-Associated Venous Thromboembolism: A Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2528-2528 ◽  
Author(s):  
Alym Abdulla ◽  
Wendy Davis ◽  
Namali Ratnaweera ◽  
Brooke Scott ◽  
Agnes Yuet Ying Lee
Keyword(s):  
Major Bleeding ◽  
Research Funding ◽  
Case Fatality Rate ◽  
Case Fatality ◽  
Controlled Trials ◽  
Bleeding Events ◽  
Patients With Cancer ◽  
Recurrent Vte ◽  
Major Bleeding Events

Abstract Background Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients with cancer. Despite therapeutic anticoagulation, the risks of recurrent VTE and major bleeding are approximately 10% and 5%, respectively, during the first 6 months of treatment. Overall mortality ranges from 25% to 40%, depending on the study population. Knowing the case fatality rates of these outcomes is also important for weighing the relative risks and benefits of anticoagulation in patients with cancer-associated VTE but these rates have not been reported previously. Objective To determine the incidence of recurrent VTE and major bleeding events and to calculate the case fatality rates of these outcomes in patients undergoing anticoagulation for cancer-associated VTE. Methods An electronic search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials from January 1980 to May 2018 was performed. English language publications (observational studies and randomized controlled trials [RCTs]) that reported on patients with active cancer and VTE who received anticoagulation with low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or a direct oral anticoagulant (DOAC) for at least 3 months were retrieved for review. In addition, a hand search of references of review articles was done to complement the electronic literature search. Studies that provided information on recurrent VTE, major bleeding events, mortality, and causes of death were included in analyses. Retrospective studies and prospective cohorts with fewer than 50 patients were excluded. Two reviewers independently screened for study eligibility and extracted data onto standardized forms. Study outcomes were recurrent VTE, major bleeding and death. Pooled proportions with 95% confidence intervals (CI) were calculated according to anticoagulant treatment and study design. Results The search identified 7327 studies of which 29 studies (15 prospective cohort studies and 14 randomized controlled trials) were included. Data from 8000 cancer patients followed for a total of 4786 patient-years (range 3 to 36 months) were summarized. The rate of recurrent VTE and fatal recurrent VTE were 15.7% (95% CI, 14.4% to 17.1%) and 2.5% (95% CI, 2.0% to 3.0%) per patient-year of follow-up, respectively, with a case fatality rate of 15.8% (95% CI, 12.7% to 18.8%). A sub-analysis revealed case fatality rates for recurrent VTE to be 16.3% (95% CI, 12.2% to 20.4%) for LMWH, 20.4% (95% CI, 14.0% to 26.8%) for VKA, and 10.8% (95% CI, 3.2% to 18.3%) for DOAC therapies. The rate of major bleeding and fatal major bleeding events were 6.4% (95% CI, 5.5% to 7.3%) and 1.2% (95% CI, 0.8% to 1.6%) per patient-year of follow-up, respectively, with a case fatality rate of 12.3% (95% CI, 8.7% to 15.9%). A sub-analysis revealed case fatality rates for major bleeding events to be 14.9% (95% CI, 9.6% to 20.2%), 27.9% (95% CI, 14.5% to 41.3%), and 1.9% (95% CI, 0% to 5.5%) for LMWH, VKA, and DOAC therapies, respectively. Among RCTs, case fatality for recurrent VTE was 17.3% (95% CI, 13.5% to 21.2%) and for major bleeding was 10.8% (95% CI, 3.2% to 18.3%). Among prospective cohort studies, respective case fatality rates were 12.8% (95% CI, 8.0% to 17.5%) and 15.3% (95% CI, 8.6% to 22.0%). Studies were heterogeneous in the duration of follow up and their reporting of the causes of death and definition of fatal PE. Conclusion The incidences of recurrent VTE and major bleed events are high in patients with cancer-associated VTE on anticoagulant therapy. Case fatality from recurrent thrombosis is higher than the case fatality from major bleeding. Differences among various anticoagulants likely reflect patient selection bias and heterogeneity of studies. Disclosures Lee: BMS: Research Funding; Bayer: Consultancy, Honoraria; LEO Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Honoraria.

Predictors of Major Bleeding in Patients with First Venous Thromboembolism Treated with Vitamin K Antagonists in Clinical Practice in the United Kingdom

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2327-2327
Author(s):  
Alexander T Cohen ◽  
Christopher Wallenhorst ◽  
Anja Katholing ◽  
Melissa Hamilton ◽  
Sreevalsa Unniachan ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Research Funding ◽  
Vitamin K Antagonists ◽  
Medical Illness ◽  
Treatment Episode ◽  
Bleeding Events ◽  
Employment Equity ◽  
History Of ◽  
Equity Ownership ◽  
Active Cancer

Abstract Introduction: The management of venous thromboembolism (VTE) and the prevention of recurrent VTE consists of anticoagulation primarily with Vitamin K Antagonists (VKA). The main adverse effect of anticoagulation is bleeding. This study aimed to investigate the predictors of major bleeding in patients with first VTE treated with VKA. Methods: A cohort study was undertaken using the United Kingdom's Clinical Practice Research Datalink with additional data from hospitalizations and causes of death. Patients with incident first VTE between 2008-2013 treated with VKA, i.e. starting VKA treatment within 60 days after first VTE, were included in the cohort. Major bleeding was defined in accordance with the International Society of Thrombosis and Haemostasis recommendations comprising fatal bleeds, bleeds at a critical site, and bleeding events in association with anemia or blood transfusions. Patients were followed until the end of the first VKA treatment episode. Hazard ratios of potential predictors for major bleeding during the first VKA treatment episode were estimated from Cox regression models which included recognized predictors for major bleeding before the diagnosis of VTE, and a list of potential predictors during VKA treatment. Results: Among 10,118 VKA-treated VTE patients the incidence rate of major bleeding was 2.6 (95% confidence interval (CI), 2.2-3.1) per 100 person-years (145 major bleeds during 5,548 person-years of VKA use). Among baseline characteristics, predictors for major bleeding (Table) included increasing age, and history of a major bleeding and of a non-major clinically relevant bleeding. Furthermore the following events after the first VTE (80 of 145 cases) were also associated with an increased risk of major bleeding: non-major clinically relevant bleeding, HR 2.88 (95% CI, 1.85 - 4.46), active cancer 4.13 (2.48-6.89), trauma 14.05 (7.96-24.82), surgery 3.27 (1.29-8.28), and medical illness 3.03 (1.87-4.90). Additional predictors for major bleeding were new onset or history of moderate/severe liver disease, 7.44 (2.93-18.92), or renal disease, 1.73 (1.19-2.52). Conclusions: Assessment for and awareness of these predictors prior to and during VKA treatment is needed to prevent major bleeding events. Caution is warranted in patients with these independent risk factors. Table 1. Association between factors at first VTE and during VKA treatment and major bleeding Incident major bleeding after first VTE n (%) Crude hazard ratio (95%-CI) Adjusted hazard ratio (95%-CI) Total 145 (100) Age1 <60 26 (17.93) 1 1 60-69 31 (21.38) 2.03 (1.21 - 3.42) 1.83 (1.07 - 3.14) 70-79 39 (26.90) 2.56 (1.56 - 4.21) 2.19 (1.27 - 3.76) 80+ 49 (33.79) 4.52 (2.81 - 7.28) 3.28 (1.90 - 5.68) Gender Female 72 (49.66) 0.98 (0.71 - 1.35) 0.89 (0.63 - 1.25) Type of first VTE DVT 82 (56.55) 1 1 PE 63 (43.45) 0.91 (0.65 - 1.27) 0.78 (0.56 - 1.09) History of bleeding prior to first VTE Non-major clinically relevant 56 (38.62) 2.09 (1.48 - 2.95) 1.75 (1.23 - 2.49) Major bleeding 13 (8.97) 4.47 (2.48 - 8.05) 3.17 (1.73 - 5.80) Prevalence of prior events at the day of the first VTE (duration of exposure) Active cancer (90 days) 14 (9.66) 2.07 (1.20 - 3.60) 0.75 (0.37 - 1.50) Non-active cancer 14 (9.66) 1.40 (0.81 - 2.43) 0.75 (0.42 - 1.37) Trauma (90 days) 11 (7.59) 1.01 (0.54 - 1.86) 1.09 (0.58 - 2.04) Inpatient surgery (90 days) 13 (8.97) 1.00 (0.57 - 1.77) 0.90 (0.48 - 1.68) Medical illness (90 days) 11 (7.59) 1.14 (0.62 - 2.11) 0.71 (0.35 - 1.42) Liver disease Mild 4 (2.76) 1.62 (0.60 - 4.38) 1.15 (0.42 - 3.17) Moderate/severe 5 (3.45) 6.80 (2.78 - 16.64) 7.44 (2.93 - 18.92) Renal disease 50 (34.48) 2.60 (1.84 - 3.66) 1.73 (1.19 - 2.52) Bleeding after first VTE Non-major clinically relevant 27 (18.62) 3.91 (2.55 - 5.99) 2.88 (1.85 - 4.46) Events after first VTE (duration of exposure) Active cancer (90 days) 32 (22.07) 4.76 (3.19 - 7.10) 4.13 (2.48 - 6.89) Trauma (14 days) 14 (9.66) 16.63 (9.49 - 29.12) 14.05 (7.96 - 24.82) Inpatient surgery (14 days) 5 (3.45) 5.79 (2.33 - 14.37) 3.27 (1.29 - 8.28) Medical illness (90 days) 24 (16.55) 3.24 (2.06 - 5.10) 3.03 (1.87 - 4.90) Disclosures Cohen: BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Portola: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jannsen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Honoraria, Research Funding, Speakers Bureau; Boeheringer Ingelheim: Consultancy, Honoraria. Hamilton:BMS: Employment, Equity Ownership. Unniachan:BMS: Employment, Equity Ownership. Martinez:Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Boehringer Ingelheim: Consultancy; Merz Pharma: Research Funding.

Tinzaparin Is Effective and Safe for the Treatment and Extended Secondary Prophylaxis In Cancer Patients with Venous Thromboembolism.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1104-1104 ◽  
Author(s):  
Scott T Tagawa ◽  
Ilene c Weitz ◽  
Casey L. O'Connell ◽  
Leanne Rochanda ◽  
Mckenna Archer ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Major Bleeding ◽  
Initial Treatment ◽  
Research Funding ◽  
Patient Survival ◽  
Pharmaceutical Research ◽  
Secondary Prophylaxis ◽  
Bleeding Events ◽  
Recurrent Vte ◽  
Major Bleeding Events

Abstract Abstract 1104 Background: Venous thromboembolism (VTE) is a major complication in cancer patients. The traditional treatment algorithm for VTE of UF or LMW heparin followed warfarin is associated with a higher risk of recurrent VTE and bleeding in cancer patients. A recent randomized trial has demonstrated that initial treatment and secondary prophylaxis with LMWH is associated with a lower VTE recurrence when compared to secondary prophylaxis with warfarin. We initiated a single arm Phase 2 IRB approved study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis (6 months) of VTE in cancer patients. Included in this study was a prospective analysis of plasma biomarkers to assess whether any biomarkers could predict treatment failure or be predictive of patient survival. Methods: Patients (pts)with objectively confirmed symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) or unexpected PE detected on staging CT scans by the criteria of OConnell et al. (JCO 24:4928, 2006) were eligible for this study, if they had an ECOG score <2 and an estimated 6 month survival. After informed consent, treatment was initiated with tinzaparin 175 U/Kg for 6 months. Planned enrollment was 100 pts. Pts who completed the 6 month study could continue on treatment for an additional 6 months if clinically appropriate. All pts who received at least one injection of tinzaparin were evaluable for efficacy and safety. Study endpoints were objectively confirmed DVT, PE or major bleeding events. Serial blood samples were obtained prior to treatment, at 1 wk, 1 month, 3 months and 6 months. Biomarkers to be studied included D-dimer (D-D), Thrombin-antithrombin complex (TAT), interleukin 6 and 8 (Il-6, Il-8) and plasma tissue factor. Only pts in whom the pretreatment, I week and 1 month blood samples were collected were included in the biomarker analysis. Results: At time of this submission 91 pts were treated on study. Of 91 pts enrolled 39 (42.9%) have completed the 6 months and 5 (5.5%) remain on active treatment. Eight (8.8%) pts withdrew from study for hospice care and one pt was withdrawn due to poor compliance. Forty-two (46%) pts died before 6 months. Ten (11%) pts continued on treatment after 6 months and one pt transitioned to warfarin treatment. Treatment endpoints included 8 (8.8%) pts with recurrent VTE (5 DVT, 3 PE); 2 occurred within the first 4 wks on treatment and the 6 events before month 3. No recurrent VTE occurred after 12wks. Three pts (3%) had major bleeding events. There were no fatal thrombotic or bleeding events. All deaths were considered due to progressive cancer, although the possible fatal VTE in pts who died at home or in hospice could not be excluded. There were 76 (83.5%) pts were evaluable for the biomarker study. Biomarker data failed to show a correlation between the level of D-D, TAT or Il-6 and patient survival from the time of their thrombotic event. However, in pts who developed recurrent VTE after 1 month, the D-D level at month 1 was higher than the pretreatment in 4/6 (66.7%) patients compared to 8/70 (11.4%) pts with no recurrence in whom month 1 samples were obtained. Conclusion: In this prospective study of tinzaparin for initial treatment and secondary prophylaxis of cancer-associated VTE, treatment appeared both safe and efficacious. Our recurrent VTE event rate of 8.8% compares favorably with the 8% recurrent VTE reported in the pts treated with dalteparin. The 3% of patients who had major bleeding events also compares favorably with the CLOT trial. Survival was difficult to predict at the time of enrollment since 46% failed to survive the 6 months. Biomarker data failed to predict survival, but patients who recurred after the first month were more likely to have month 1 D-D levels greater than pretreatment. The reason for the failure of tinzaparin treatment to effectively suppress thrombin generation in these patients remains unexplained. Disclosures: Tagawa: Leo Pharmaceutical: Research Funding; Celgene: Research Funding. Liebman:Leo Pharmaceutical: Research Funding; Celgene: Research Funding.

scholarly journals Risk of Venous Thromboembolism Recurrence Among Rivaroxaban Treated Patients Who Continued Versus Discontinued Therapy: Analyses Among VTE Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 144-144
Author(s):  
Alok A. Khorana ◽  
Jeffrey S Berger ◽  
Philip S Wells ◽  
Roger Seheult ◽  
Veronica Ashton ◽  
...  
Keyword(s):  
New Jersey ◽  
Major Bleeding ◽  
Research Funding ◽  
Index Date ◽  
Bleeding Events ◽  
Employment Equity ◽  
P Values ◽  
Kaplan Meier ◽  
Increased Risk ◽  
Equity Ownership

Abstract Background: The American College of Chest Physicians (ACCP) guidelines for venous thromboembolism (VTE) disease recommend treatment with anticoagulation for at least 3 months in patients with VTE. Moreover, the EINSTEIN-extension study assessed the effect of rivaroxaban on the risk of VTE recurrences in patients who had completed 6 to 12 months of treatment for VTE. Results showed that rivaroxaban significantly reduced the risk of VTE recurrences with a small increased risk of major bleeding. The objective of this study was to assess the risk of VTE recurrences and major bleeding associated with extended rivaroxaban treatment in a real-world setting among all VTE patients (i.e., unprovoked, provoked, and cancer related). Methods: A retrospective study was conducted using Truven Health Analytics MarketScan Databases from 02/2011 to 04/2015. The study included adult patients who initiated rivaroxaban therapy within 7 days after their first VTE and continuously used rivaroxaban for at least 3 months. The end of the initial 3-month rivaroxaban treatment was defined as the index date and patients were categorized into discontinued (treatment ended) and continued cohorts. Patients were followed from index date until end of continuous treatment for the continued cohort or end of data or re-initiation of oral anticoagulant therapy for the discontinued cohort. The outcomes included VTE recurrences identified as a primary diagnosis documented during a hospitalization and major bleeding events identified by a validated algorithm (Cunningham et al., 2011). Kaplan-Meier rates for VTE recurrences and major bleeding events at 3, 6, 9, and 12 months after the index date were compared between cohorts with adjustment for baseline confounding using the inverse probability of treatment weights (IPTW) method based on propensity score. Patients with unprovoked VTEs, defined as not having recent surgery, cancer, pregnancy or estrogen therapy, were also evaluated. Sample sizes of patients with provoked VTEs and cancer were too small to analyze these populations. A sensitivity analysis was also conducted among VTE patients receiving rivaroxaban for at least 6 months. Results: Among the 3-month treatment population, a total of 5,933 (63.4% unprovoked VTE) and 1,536 (68.4% unprovoked VTE) rivaroxaban users formed the continued and discontinued cohorts, respectively. The mean (SD) observation period was 149.3 (124.4) days in the continued cohort and 211.1 (191.6) days in the discontinued cohort. The Kaplan-Meier analysis (Figure 1) showed that patients in the continued cohort had significantly lower rates of VTE recurrences after an additional 3 months (0.70% vs. 1.70%), 6 months (1.41% vs. 2.34%), 9 months (1.82% vs. 3.01%), and 12 months (1.97% vs. 3.01%; all p-values < 0.05) of treatment. No statistically significant differences in the cumulative event rates for major bleeding (Figure 2) were observed between the continued and the discontinued cohort at 3 months (0.58% vs. 0.82%), 6 months (0.91% vs. 0.88%), 9 months (1.33% vs. 1.18%), and 12 months (1.44% vs. 1.44%; all p-values > 0.05). Among the 6-month treatment population, a total of 2,676 (65.9% unprovoked VTE) and 1,127 (70.4% unprovoked VTE) rivaroxaban users formed the continued and discontinued cohorts, respectively. The mean (SD) observation period was 158.5 (130.6) days in the continued cohort and 206.5 (171.5) days in the discontinued cohort. Patients in the continued cohort had lower rates of VTE recurrences after an additional 3 months (0.82% vs. 1.41%), 6 months (1.22% vs. 2.69%), 9 months (1.35% vs. 3.02%), and 12 months (1.72% vs. 3.70%; except at 3 months all p-values < 0.05) of treatment. No differences in the cumulative event rates for major bleeding were observed between the continued and the discontinued cohorts. Similar results were found among patients with unprovoked VTE for the 3- and 6-month analyses. The interaction term between the cohort variable (Continued vs. Discontinued) and the type of VTE (unprovoked vs. other types of VTE) was non-significant in both populations (p-value > 0.05), which suggests that the benefit of extended treatment do not depend on the type of VTE events. Conclusions: Our study results suggest that all patients with VTE who continued rivaroxaban therapy after the first 3-month and 6-month treatment periods had significantly lower risk of VTE recurrences without an increased risk of major bleeding. Disclosures Khorana: Halozyme: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Leo: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding. Berger:AZ: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Wells:BMS/Pfizer: Research Funding; Itreas: Other: Served on a Writing Committee; Janssen Pharmaceuticals: Consultancy; Bayer Healthcare: Other: Speaker Fees and Advisory Board. Seheult:Janssen Scientific Affairs, LLC: Consultancy. Ashton:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment. Laliberté:Janssen Scientific Affairs: Research Funding. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lejeune:Janssen Scientific Affairs: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Wildgoose:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lefebvre:Janssen Scientific Affairs: Research Funding. Kaatz:Bristol Myer Squibb: Honoraria; Pfizer: Honoraria; CSL Behring: Honoraria; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Honoraria; Janssen: Honoraria.

scholarly journals Safety and Efficacy of Apixaban Thromboprophylaxis in Ambulatory Cancer Patients By Renal Function: A Subgroup Analysis of the Avert Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3229-3229
Author(s):  
Tzu-Fei Wang ◽  
Ranjeeta Mallick ◽  
Marc Carrier ◽  
Philip S. Wells
Keyword(s):  
Renal Function ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Research Funding ◽  
Performance Status ◽  
Primary Efficacy ◽  
Efficacy And Safety ◽  
Bleeding Events ◽  
Major Bleeding Events ◽  
Overall Mortality

Abstract Background Patients with cancer have an increased risk of venous thromboembolism (VTE) and associated morbidity and mortality. Renal dysfunction is more common in patients with cancer, leading to heightened risks of bleeding and thrombotic complications. In the AVERT trial, thromboprophylaxis with apixaban resulted in a significantly lower rate of VTE and higher rate of major bleeding compared to placebo among intermediate-to-high-risk ambulatory cancer patients starting chemotherapy. As apixaban depends on some degree of renal clearance, there may be concerns regarding the safety and efficacy of apixaban thromboprophylaxis in patients with renal insufficiency. In this post-hoc analysis of AVERT, we evaluated the efficacy and safety of apixaban thromboprophylaxis according to renal function at randomization. Methods Eligible patients were randomized to apixaban (2.5mg twice daily) or placebo. First dose of study drug was given within 24 hours of the first chemotherapy administration with the intended treatment period of 180 days. For this subgroup analysis, the efficacy and safety of apixaban thromboprophylaxis was evaluated accordingly to renal function (calculated creatinine clearance [CrCl] by Cockcroft-Gault Equation) at randomization. Patients with CrCl &lt; 30 mL/min were excluded from the trial. The primary efficacy outcome was objectively confirmed major VTE (proximal deep vein thrombosis or pulmonary embolism) within 180 days (±3 days) following randomization. The primary efficacy outcome was evaluated by modified intention-to-treat analysis, which included all patients who had undergone randomization and received at least one dose of study medication on or before day 180 (±3 days). The primary safety outcome was major bleeding defined by the International Society on Thrombosis and Haemostasis criteria. The primary safety outcome was evaluated by on-treatment analysis, when events were counted only if they occurred on study drugs or up to two days after discontinuation of the study drugs. Secondary outcomes included clinically relevant non-major bleeding and overall mortality. Results A total of 574 patients underwent randomization, with 563 patients included in the original primary efficacy and safety analysis (288 apixaban and 275 placebo). Upon randomization, 66 (11.5%) patients had CrCl &lt; 60 mL/min and 508 (88.5%) patients had CrCl ≥ 60 mL/min. Patients with CrCl &lt; 60 mL/min were significantly older, more female, had lower weight and fewer with body mass index (BMI) &gt; 35 kg/m 2 and poorer ECOG performance status (Table 1). In patients with CrCl &lt; 60 mL/min, VTE occurred in no patient on apixaban compared to 1 on placebo, and major bleeding episode occurred in 1 on apixaban and 0 on placebo. In patients with CrCl ≥ 60 mL/min, VTE occurred in 13 out of 257 (5.1%) in the apixaban group and 28 out of 242 (11.6%) in the placebo group [HR 0.41 (95% CI 0.26-0.64), p=0.0001] (Table 2). There were no significant differences between apixaban and placebo groups in major bleeding and clinically relevant non-major bleeding events. Overall mortality was significantly lower in the apixaban group (HR 0.25 [95% CI 0.13-0.45], p&lt;0.0001) in patients with CrCl ≥ 60 mL/min. Conclusions In the AVERT trial, patients with CrCl &lt; 60 mL/min were significantly older, more likely to be female, with lower weight or BMI and poorer ECOG performance status. There were very few VTE or major bleeding events in patients with CrCl &lt; 60 mL/min. In patients with CrCl ≥ 60 mL/min, apixaban thromboprophylaxis was associated with a significantly lower rate of VTE and overall mortality compared to placebo, with no significant differences in the rates of major bleeding or clinically relevant non-major bleeding events. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Carrier: Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Servier: Honoraria; Pfizer: Honoraria, Research Funding; Bayer: Honoraria. Wells: Daiichi Sankyo: Honoraria; BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria. OffLabel Disclosure: apixaban for primary thromboporphylaxis in ambulatory cancer patients receiving chemotherapy

scholarly journals Association of Bleeding Severity with Mortality with in-Hospital and Extended Thromboprophylaxis in the Medically Ill in the Magellan Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2441-2441
Author(s):  
Alex C. Spyropoulos ◽  
Gary E. Raskob ◽  
Alexander T Cohen ◽  
Walter Ageno ◽  
Jeffrey I. Weitz ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Increased Risk ◽  
Bayer Healthcare ◽  
Equity Ownership

Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MAGELLAN study (NCT00571649) evaluated whether rivaroxaban (10 mg QD for 35±4 days) compared with enoxaparin (40 mg QD for 10±4 days) followed by placebo could prevent asymptomatic deep vein thrombosis, symptomatic VTE, and VTE-related death. Through Day 35, rivaroxaban was superior to enoxaparin/placebo in the modified intent-to-treat population (4.4% vs 5.7%, RR 0.77, 95%CI, 0.62 to 0.96, p=0.02), but there was an increase in clinically relevant bleeding, the composite of major and non-major clinically relevant (NMCR) bleeding (4.1% vs 1,7%, RR 2.5, 95%CI 1.85-3.25, p<0.001). Although major bleeding has been associated with increased mortality, the relationship between NMCR bleeding and all-cause mortality (ACM) is not established. We hypothesized that subjects in the MAGELLAN trial with major bleeding but not those with NMCR bleeding, would be at an increased risk of ACM irrespective of treatment group. Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 90 visit in 3 mutually exclusive groups: (1) subjects with no major or NMCR bleeding; (2) subjects whose first event was NMCR bleeding; and (3) subjects whose first event was major bleeding. Subjects only developing minimal or trivial bleeding were grouped with those who had no clinically relevant bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates significantly associated with ACM at p<0.05 (age, BMI, history of cancer, history of anemia, inflammatory disease, acute ischemic stroke, and acute respiratory insufficiency), we compared the risk of ACM in subjects with and without bleeding events. Results: The incidence of ACM for subjects who had NMCR bleeding was numerically higher but not significantly increased compared with subjects with no bleeding (20/176, 11.4% vs 468/7763, 6.0%, HR 1.41 95%CI 0.88, 2.25, p=0.151), while subjects with major bleeding were at a significantly increased risk of death (28/59, 47.5% vs 468/7763, 6.0%, HR 7.74 95%CI 5.16, 11.59, p<0.0001). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and may have been underpowered to detect differences in ACM associated with NMCR bleeding. Conclusion: Major bleeding was associated with a significantly increased risk of ACM but NMCR bleeding was not. This suggests that a modest increase in NMCR bleeding associated with extended thromboprophylaxis with rivaroxaban may be acceptable to prevent VTE. Strategies to better select patients at lower risk of bleeding may improve the benefit risk profile of extended thromboprophylaxis with rivaroxaban. Disclosures Spyropoulos: Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Portola: Consultancy; Bayer Healthcare: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Janssen R&D, LLC: Consultancy. Raskob:Janssen R&D, LLC: Consultancy, Honoraria; Novartis: Consultancy; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy; Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Eli Lilly: Consultancy. Cohen:Boston Scientific: Consultancy; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Speakers Bureau; GLG: Consultancy; AbbVie: Consultancy; ACI Clinical: Consultancy; Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Ageno:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Weitz:Janssen R&D, LLC: Consultancy; Bayer Healthcare: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. It is currently under review by FDA for approval as thromboprophylaxis in acutely ill medical patients at risk for venous thromboembolism.

Low Molecular Weight Heparin Thromboprophylaxis in Ambulatory Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 490-490 ◽  
Author(s):  
Nicole M. Kuderer ◽  
Thomas L. Ortel ◽  
Alok A Khorana ◽  
Charles W. Francis ◽  
Gary H. Lyman
Keyword(s):  
Cancer Patients ◽  
Major Bleeding ◽  
Research Funding ◽  
Absolute Risk ◽  
Meta Analysis ◽  
Significant Heterogeneity ◽  
Bleeding Events ◽  
Vte Prophylaxis ◽  
Patients With Cancer ◽  
Increased Risk

Abstract Abstract 490 Background: Patients with cancer experience an increased risk of venous thromboembolism (VTE) throughout the course of their illness. The risk of VTE appears to be greatest among hospitalized cancer patients, in the perioperative period of major surgery and in those receiving systemic cancer therapies. While encouraged in hospitalized and surgical patients, routine VTE prophylaxis for cancer patients is not recommended in the ambulatory setting except in very selective high risk circumstances. A number of randomized clinical trials (RCTs) of low molecular weight heparin (LMWH) in ambulatory cancer patients have been reported with inconsistent results. Presented here are the results from our updated meta-analysis of LMWH prophylaxis, including recently presented RCTs. Methods: A systematic review of RCTs of VTE prophylaxis with LMWH in ambulatory cancer patients was conducted including the results of published and recently presented trials. Electronic databases including Medline, EMBASE, and Cochrane Library were searched along with meeting abstracts from ASCO and ASH. Eligibility criteria included RCTs of ambulatory cancer patients randomized to LMWH or not and reporting rates of VTE as a primary outcome (primary VTE prophylaxis studies) or a secondary outcome. Dual blinded data extraction was performed with conflict resolution by a third party. Following assessment of heterogeneity, meta-analyses using the method of Mantel and Haenszel were conducted providing weighted summary estimates of both relative risk (RR) and absolute risk (AR) ± 95% confidence intervals (95% CI). Primary study outcomes consist of all reported VTE events and all major bleeds. Most trials did not require VTE screening by imaging, precluding a separate analysis of asymptomatic VTE events. Results: A total of 7 RCTs of LMWH in ambulatory patients with cancer were identified with a total of 2,960 patients including 1,685 receiving LMWH and 1,275 controls. These include 3 RCTs with various solid tumors and one RCT each in breast cancer, lung cancer, pancreatic cancer, and glioblastoma. Patients receiving LMWH experienced 47 VTE events compared to 74 control subjects for crude rates of 2.79% and 5.80%, respectively. No significant heterogeneity was observed across trials (Cochran Q=6.19; I2=3.03; P=.40). The RR for VTE across trials was estimated at 0.54 [95% CI: 0.38 – 0.78; P=.001] while the AR decrease was 2.55% [95% CI: 1.06% – 4.05%; P<.001]. The RR for VTE for the 5 primary VTE prophylaxis trials was 0.50 [95% CI: 0.34 – 0.75; P<.001] with an AR decrease estimated at 2.95% [95% CI: 1.26 – 4.63%; P<.001]. Major bleeding events were reported in 30 patients receiving LMWH compared to 15 control subjects for crude rates of 1.78% and 1.18%, respectively. No significant heterogeneity was observed across trials (Cochran Q=5.50; I2=0.0; P=.481). The RR for major bleeding across trials was estimated at 1.74 [95% CI: 0.95 – 3.18; P=.071], while the AR increase was 0.75% [95% CI: 0.17% – 1.33%; P=.011]. The RR for major bleeding in the 5 primary prophylaxis trials was 2.27 [95% CI: 1.12 – 4.59; P=.022] with AR increase estimated at 1.27% [95% CI: 0.27% – 2.27%; P=.013]. Conclusions: LMWH thromboprophylaxis in ambulatory cancer patients is effective and results in a significant 46% relative risk reduction of venous thromboembolism. However, the risk of VTE is low in this setting and the absolute risk reduction with prophylactic anticoagulation is only 2.6%, while concerns remain about the increase in major bleeding events. Additional research is needed to identify ambulatory cancer patients at increased risk for VTE, in whom VTE prophylaxis may have a more favorable risk-benefit ratio. Disclosures: Ortel: Eisai: Research Funding. Khorana:sanofi-aventis: Consultancy; Eisai: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Francis:Eisai: Consultancy, Honoraria.

scholarly journals Prevalence and Burden of Major Bleeding Events in Patients with Von Willebrand Disease Based on Claims Data from the USA

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2222-2222
Author(s):  
Mei Lu ◽  
Abiola Oladapo ◽  
Yanyu Wu ◽  
Sepehr Farahbakhshian ◽  
Bruce Ewenstein
Keyword(s):  
Major Bleeding ◽  
Economic Burden ◽  
Von Willebrand Disease ◽  
Red Blood Cell Transfusion ◽  
Bleeding Events ◽  
Real World Data ◽  
Employment Equity ◽  
Equity Ownership ◽  
Major Bleeding Events ◽  
Von Willebrand

Abstract Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder (clinically symptomatic prevalence rate ~1:10,000). Patients with VWD have impaired hemostasis due to a quantitative or qualitative deficit in von Willebrand Factor (VWF) that alters platelet adhesion and collagen binding and/or decreases FVIII concentrations. Most patients with VWD present with mild-to-moderate mucosal bleeding (epistaxis, menorrhagia), although life-threatening bleeding may also occur, especially in patients with VWD type 3 and some forms of VWD type 2. While bleeds associated with VWD have been well described in the literature, information on the burden associated with major bleeding events (MBE) is limited. Real-world data can be used to help understand the clinical and economic impact of these events. Aims: To estimate the prevalence, healthcare resource utilization (HCRU), and costs associated with MBE among patients with VWD. Methods: Patients with VWD with ≥1 year of continuous enrollment since the eligibility start date were identified from Truven databases (01/2008-12/2016). Patients with MBEs were identified using a medical claim associated with an ICD-9/10 CM diagnosis code for intracranial, GI, or eye bleed; or menorrhagia, epistaxis, and joint bleeds that required red blood cell transfusion in an inpatient (IP) setting or within 7 days of diagnosis in an outpatient (OP) setting. Prevalence was calculated as the proportion of eligible patients with ≥1 MBE during the observation period (from start to the end of continuous eligibility). To evaluate economic burden, patients with ≥1 MBE on or after the first diagnosis of VWD were compared with patients with no MBEs. HCRU and cost in the 12-month continuous enrollment period following the first MBE were compared with those from a similar 12-month period for patients without MBEs. Regression models were used, controlling for demographics, health plan, index year, Charlson Comorbidity Index (CCI), comorbidities, thrombotic events, and HCRU during the 12-month continuously enrolled baseline period. For patients with MBEs, the proportion of patients with comorbidities was compared between the 12-month baseline and study periods using McNemar test. Results: 19,785 VWD patients were identified (mean age 34 years, 75% female) During a median observation of 4 years, 15.1% of patients experienced ≥1 MBE (mean rate: 0.11 ± 0.64 MBE/year). GI bleeding was the most prevalent MBE, occurring in 13.4% of all patients. Although not common, the prevalence of intracranial bleeds (1.1%) was slightly higher in males than females (1.7% vs 0.9%). In the sample to evaluate economic burden, 773 patients with ≥1 MBE (age 44.5 ± 20.1 years) and 4285 patients without MBEs (age 34.2 ± 19.5 years) were selected. Patients with MBEs were significantly (p<0.01) more likely to have an IP admission (OR, 4.1; 95% CI, 3.4-5.0), ER visit (1.8; 1.5-2.1), or OP visit (4.9; 1.8-13.4); they also had significantly longer IP stays (IRR, 3.9; 95% CI, 3.1-4.9) and more frequent IP admissions (3.2; 2.8-3.8), ER visits (2.0; 1.8-2.3), and OP visits (1.3; 1.2-1.3), compared to those without MBEs. Patients with MBEs incurred significantly (p<0.01) higher total healthcare costs (adjusted mean difference, $20,890; 95% CI, $15,524-$29,254) than those without MBEs. Among the 773 patients with MBEs, approximately 1 in 4 patients had a MBE (26.8%) diagnosed in the IP setting. The overall annual mean (± SD) IP length of stay (LOS) was 7.4 ± 19.4 days, with intracranial bleeds associated with the longest mean IP LOS (14.3 ± 19.4 days). The readmission rate was 3.1% for any MBE, and 2.5% for the same type of MBE as the initial bleed. The proportions of patients with anemia (24.2% vs 15.9%; p<0.01) and anxiety (18.6% vs 14.2%; p<0.01) were significantly higher after the MBE than before. Conclusions: In this large retrospective analysis of data from a US commercial healthcare plan, ~15% of patients with VWD experienced MBEs, mostly GI bleeds. While our estimation of some MBEs may be conservative, this is the first study to use a large dataset with sound statistical methods to evaluate the burden associated with MBEs in this population. MBEs were associated with additional comorbidities and high HCRU and costs (driven by inpatient costs), so optimal therapy is essential to prevent MBEs in patients with VWD. Disclosures Lu: Shire: Employment, Equity Ownership. Oladapo:Shire: Employment, Equity Ownership. Wu:Shire: Employment. Farahbakhshian:Shire: Employment, Equity Ownership. Ewenstein:Shire: Employment, Equity Ownership.

Romiplostim in Thrombocytopenic Patients with Low- or Int-1- Risk MDS Results in Reduced Bleeding without Impacting Leukemic Progression: Final Follow-up Results from a Randomized, Double-Blind, Placebo-Controlled Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2000-2000
Author(s):  
Hagop Kantarjian ◽  
Pierre Fenaux ◽  
Mikkael A. Sekeres ◽  
Jeffrey Szer ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Study Drug ◽  
Controlled Study ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Thrombocytopenia occurs in ~50% of patients with low/int-1 risk myelodysplastic syndrome (MDS) and is associated with reduced survival. In a placebo (PBO)-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events [hazard ratio (HR) romiplostim vs PBO 0.83, 95% CI: 0.66−1.05, P = 0.13] and platelet transfusions (relative risk 0.77, 95% CI: 0.66−0.88, P<0.001) and increased IWG hematologic improvement platelets (HI-P) incidence (odds ratio 15.6, 95% CI: 4.7−51.8, P<0.001). Peripheral blast count increases >10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%) and resolved after discontinuation in most cases. In February 2011, the DMC recommended that treatment with study drug be discontinued as the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML, and that transient increases in blast cell counts might put patients at risk for diagnosis of and treatment for AML. Patients were moved into long-term follow-up (LTFU). Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was 6.0% (N = 10) for romiplostim and 4.9% for PBO (N = 4); HR 1.20 (95% CI: 0.38−3.84). This report provides final 5-year LTFU data. Methods: Eligible patients were receiving only supportive care and had IPSS low/int-1 risk MDS and platelets 1) ≤20 × 109/L or 2) ≤50 × 109/L with a history of bleeding. Disease progression to AML was defined as 1) ≥20% blasts in bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim; 2) pathology consistent with leukemia; or 3) antileukemic treatment. Results are presented by treatment group. Results: At baseline, median (Q1, Q3) age was 70 (61, 77) years, the majority (59%) of patients were male; 27.6% were IPSS low risk and 72.4% were int-1 risk. WHO classifications were RCMD: 67.6%, RAEB-1: 13.2%, MDS-U: 11.2%, RA: 4.4%, RCMD-RS: 2.4%, RARS: 0.8%, and RAEB-2: 0.4%. Of 250 patients in the study, 210 entered LTFU and 66 completed the 5 years of LTFU; median (Q1, Q3) follow-up was 27.5 (10.8, 58.7) months. Reasons for discontinuation (death, lost to follow-up, and consent withdrawal) during LTFU were similar in both groups. During the active study period and LTFU, death was reported in 93 (55.7%) patients in the romiplostim group and 45 (54.2%) patients in the PBO group (HR romiplostim vs PBO 1.03, 95% CI: 0.72−1.47) (Figure); mortality rates were greater in those with IPSS int-1 vs low risk for both groups (Table). AML was reported in 20 (11.9%) patients in the romiplostim group and 9 (11.0%) patients in the PBO group (HR 1.06, 95% CI: 0.48−2.33). The proportions of patients who either died or developed AML were 56.9% (N = 95) in the romiplostim group and 55.4% (N = 46) in the PBO group (HR for AML-free survival 1.04, 95% CI: 0.73−1.48) (Figure). Nearly half (N = 14, 48%) of the 29 AML cases occurred in patients who were RAEB-1 at screening (none RAEB-2), and 6 cases were diagnosed because of anti-AML treatment use alone (Table). In LTFU, patient-reported use of MDS therapy (eg, azacitidine or cyclosporine) was 42.8% (N = 59, 95% CI: 34.4%−51.5%) in the romiplostim group and 31.4% (N = 22, 95% CI: 20.9%−43.6%) in the PBO group. AML therapy (eg, chemotherapy) was used in 14 (10.2%) patients in the romiplostim group and 7 (10.0%) patients in the PBO group. Conclusions: Following the decision in 2011 to stop study drug secondary to increased AML rates at that time and transient blasts increases, final 5-year LTFU HRs (romiplostim vs placebo) for death or progression to AML, respectively, are 1.03 (95% CI: 0.72−1.47) and 1.06 (95% CI: 0.48−2.33). In conclusion, romiplostim reduced bleeding events and platelet transfusions, with no increase in AML incidence or impact on survival. Disclosures Kantarjian: Amgen Inc.: Research Funding. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kuendgen:Celgene: Research Funding. Gaidano:Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiktor-Jedrzejczak:Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy, Research Funding; BMS: Research Funding; Sandoz: Consultancy; Amgen Inc.: Research Funding. Carpenter:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

Major Bleeding with Ibrutinib: More Than Expected

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3229-3229 ◽  
Author(s):  
Paul R Kunk ◽  
Joesph Mock ◽  
Michael E. Devitt ◽  
Surabhi Palkimas ◽  
Jeremy Sen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Event ◽  
Lymphocytic Leukemia ◽  
Significant Activity ◽  
University Of Virginia ◽  
Bleeding Events ◽  
Major Bleeding Events

Abstract Introduction: Ibrutinib is a Bruton's tyrosine kinase inhibitor that has significant activity in treating lymphoma. While approved for patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), its activity in other lymphomas and solid tumors is under investigation and its use is increasing dramatically. Overall it is well tolerated compared to chemotherapy, but bleeding has emerged as a common adverse event with rates as high as 50% and major bleeding around 3% (Jones, abstract #1990, 2014 ASH Annual Meeting). As the use of ibrutinib increases outside of a clinical trial setting, the rate of major bleeding is likely to rise. Methods: To better understand the risk of bleeding in ibrutinib treated patients, we reviewed all patients at the University of Virginia and satellite clinics who were treated with ibrutinib between January 2012 and May 2016. Patients were required to be treated for at least 1 month with documented follow up for assessment of adverse events. Medical charts were reviewed for age, gender, ibrutinib indication and dose, length of treatment, concurrent medications, blood tests and bleeding events. All forms of anti-platelets and anticoagulants drugs, as well as medications interacting with cytochrome P450 3A4 (3A4), which metabolizes ibrutinib, were recorded. All bleeding events were recorded and graded according the Common Toxicity Criteria for Adverse Events, v4.0. Major bleeding events were reviewed by all investigators. Results: Eighty-nine patients were identified. Eighteen patients were excluded for insufficient follow up leaving 71 patients for analysis. Median age was 73 years old (44-92) with 74% male. The most common indications for treatment were CLL (65%) and MCL (27%). Most patients were treated with either 420mg (64%) or 560mg (21%). Median length of time on ibrutinib was 412 days, most with ongoing use at time of data collection. Seventy percent of patients were also treated with an anti-platelet medication, mostly aspirin for CAD with several patients on multiple anti-platelet medications. Seventeen percent were treated with an anti-coagulant, mostly apixaban for atrial fibrillation. Thirteen percent of patients (9/71) were treated with combined anti-platelet and anti-coagulant medications. Ten percent of patients were treated with a medication that has a moderate or strong interaction with 3A4. Bleeding of any grade occurred in 56% of patients, mostly bruising and epistaxis. Major bleeding, defined as grade 3 or higher, occurred in 18% of patients. Three patients developed major bleeding after an invasive procedure without ibrutinib being held. One patient died as a result of peri-procedural bleeding. Of the 9 patients treated with combined anti-platelet and anti-coagulant therapy, 78% suffered a major bleeding event. Of the ten patients on ibrutinib alone, without concurrent use of an anti-platelet, anti-coagulant or 3A4 drug interaction, no major bleeding events occurred. Conclusion: In this study examining real world use of ibrutinib, the rates of major bleeding are higher than previously reported. Most patients who suffered major bleeding were also treated with an anti-coagulant and/or anti-platelet medication. As the use of ibrutinib increases outside of clinical trials, a careful review of medications should be performed in addition to adherence to perioperative drug withholding guidelines. Patients requiring anti-coagulant and/or anti-platelet medications while on ibrutinib need careful consideration of the risks and benefits given the higher incidence of bleeding in this population. Table 1 Table 1. Disclosures Portell: AbbVie: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; Acerta: Research Funding. Williams:Janssen and Pharmacyclics: Research Funding; University of Virginia: Employment.

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