scholarly journals Influence of Age and Renal Function on Efficacy and Safety of Dabigatran Versus Warfarin for the Treatment of Acute Venous Thromboembolism: A Pooled Analysis of RE-COVER™ and RE-COVER™ II

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 594-594 ◽  
Author(s):  
Sam Schulman ◽  
Henry Eriksson ◽  
Ajay Kakkar ◽  
Clive Kearon ◽  
Sebastian M Schellong ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Dysfunction ◽  
Older Patients ◽  
Research Funding ◽  
Bleeding Events ◽  
Risk Of Bleeding ◽  
Advisory Boards ◽  
Bayer Healthcare ◽  
Recurrent Vte ◽  
Event Rates

Abstract Background: In the RE-COVER™ and RE-COVER™ II trials, dabigatran etexilate (DE) was as effective as warfarin (W) for prevention of recurrent venous thromboembolism (VTE) in patients with acute VTE, and was associated with a lower risk of bleeding. Objectives: Older patients and patients with renal impairment may be at greater risk of bleeding and/or VTE. In this post-hoc analysis of the pooled dataset from RE-COVER™ and RE-COVER™ II, we assessed rates of VTE recurrence and bleeding with DE and W in patients below and above 75 years according to renal function (normal, or mildly or moderately impaired). Methods: Patients with acute VTE, initially on parenteral anticoagulation, were randomized to either W (started in parallel; international normalized ratio range 2.0‒3.0) or DE 150 mg twice daily for 6 months. Primary efficacy outcome was recurrent, symptomatic VTE/VTE-related death from randomization to the end of the prespecified post-treatment follow-up. Safety outcomes included centrally adjudicated major bleeding events (MBEs), the composite of MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs), and any bleeds from the start of the double-dummy period (treatment with oral DE or W alone) to the end of the 6-month period. Patients with creatinine clearance (CrCL) ≤ 30 mL/min (hence not meeting inclusion criteria) were excluded from this analysis. Results: In all patients aged < 75 years, recurrent VTE/VTE-related death occurred in 65/2241 (2.9%) and 52/2218 (2.3%) patients with DE and W, respectively. In the analysis by renal function, event rates for DE vs W in subgroups with CrCL ≥ 80 (normal), 50–< 80 (mild renal dysfunction), and 30–< 50 mL/min (moderate renal dysfunction), respectively, were 3.1% (57/1828) vs 2.5% (45/1780), 2.1% (8/381) vs 1.5% (6/403), and 0% (0/32) vs 2.9% (1/35). In all patients aged ≥ 75 years, recurrent VTE/VTE-related death occurred in 3/272 (1.1%) and 10/304 (3.3%) patients with DE and W, respectively. Event rates for DE vs W in the normal, mild and moderate renal dysfunction subgroups, respectively, were 3.1% (1/32) vs 5.2% (3/58), 1.3% (2/158) vs 1.9% (3/158), and 0% (0/82) vs 4.5% (4/88). For the safety endpoints, in all patients aged < 75 years, MBEs occurred in (DE vs W, respectively) 16/2169 (0.7%) vs 29/2146 (1.4%) patients, MBEs/CRBEs in 87/2169 (4.0%) vs 153/2146 (7.1%) patients, and any bleeding in 303/2169 (14.0%) vs 430/2146 (20.0%) patients. The table shows event rates by renal function; bleeding rates in this age group were numerically lower for DE than W across all categories of renal function, except for rates of MBEs in patients with moderate dysfunction (6.7% vs 6.5%). Among the older patient group, bleeding event rates for DE vs W were 8/252 (3.2%) vs 11/287 (3.8%) for MBEs, 21/252 (7.9%) vs 35/287 (12.2%) for MBEs/CRBEs, and 48/252 (18.3%) vs 68/287 (23.0%) for any bleeding. The table shows event rates by renal function; the incidences of bleeding were numerically lower for DE vs W across all categories of renal function in older patients, except for MBEs (5.3% vs 3.6%) and MBEs/CRBEs (11.8% vs 9.6%) in the subgroup with moderate renal dysfunction. TablePatientsMBEsPatients, n/N (%)MBEs/CRBEsPatients, n/N (%)Any bleedsPatients, n/N (%)Age(year)CrCL (mL/min)DEWDEWDEW< 7530‒< 502/30 (6.7)2/31 (6.5)3/30 (10.0)4/31 (12.9)6/30 (20.0)8/31 (25.8)50‒< 805/359 (1.4)10/387 (2.6)26/359 (7.2)43/387 (11.1)70/359 (19.5)90/387 (23.3)≥ 809/1780 (0.5)17/1728 (1.0)58/1780 (3.3)106/1728 (6.1)227/1780 (12.8)332/1728 (19.2)≥ 7530‒< 504/76 (5.3)3/83 (3.6)9/76 (11.8)8/83 (9.6)15/76 (19.7)21/83 (25.3)50‒< 804/145 (2.8)6/149 (4.0)10/145 (6.9)23/149 (15.4)27/145 (18.6)35/149 (23.5)≥ 800/31 (0.0)2/55 (3.6)1/31 (3.2)4/55 (7.3)4/31 (12.9 )10/55 (18.2) Conclusions: In DE-treated patients, no increase in VTE recurrence was apparent for older (≥ 75 years) vs younger (< 75 years) patients. Recurrent VTE rates decreased with declining renal function. Bleeding events increased with declining renal function in both age groups irrespective of treatment, but in most subgroups were numerically less frequent with DE than with W. Disclosures Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare: Consultancy; Boehringer Ingelheim (Canada): Consultancy. Schellong:Daiichi Sankyo: advisory boards, advisory boards Other, Honoraria; Bayer Healthcare: advisory boards, advisory boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Boehringer Ingelheim: advisory boards Other, Consultancy, Honoraria. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim: Employment. Kreuzer:Boehringer Ingelheim: Employment. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy.

Influence Of Renal Function On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 212-212 ◽  
Author(s):  
Sam Schulman ◽  
Henry Eriksson ◽  
Samuel Z Goldhaber ◽  
Ajay Kakkar ◽  
Clive Kearon ◽  
...  
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Renal Dysfunction ◽  
Research Funding ◽  
Dabigatran Etexilate ◽  
Parenteral Therapy ◽  
Bleeding Events ◽  
Significant Treatment ◽  
Advisory Boards ◽  
Treatment Interaction

Abstract Background For treatment of acute venous thromboembolism (VTE), dabigatran etexilate was as effective as warfarin with a lower risk of bleeding in two phase III trials, RE-COVER and RE-COVER II. As dabigatran is predominantly renally eliminated, its plasma concentration may be elevated in renally impaired patients, potentially increasing the bleeding risk. Warfarin is primarily metabolized hepatically. Objectives We performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin according to renal function. Methods Patients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double dummy; “oral only” treatment period) for 6 months. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. Results Overall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). Event rates for dabigatran vs warfarin in subgroups with CrCl ≥ 80, 50 to < 80 (mild renal dysfunction), and 30 to < 50 mL/minute (moderate renal dysfunction), respectively, were: 3.1% (58/1860) vs 2.6% (48/1838), 1.9% (10/539) vs 1.6% (9/561), and 0% (0/114) vs 4.1% (5/123). Cox regression analysis showed no statistically significant interaction, indicating similar treatment effects across the CrCL groups. Overall, MBEs were significantly less frequent with dabigatran vs warfarin during the oral treatment only (double-dummy) period (HR 0.60; 95% CI 0.36, 0.99). Results for the respective renal function subgroups are shown in the Table. There was no significant treatment interaction by renal function. MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Renal function subgroup results are shown in the Table. There was no significant treatment interaction by renal function. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no treatment interaction by renal function. Conclusions There was no apparent difference in recurrent VTE or VTE-related mortality across renal function groups. Bleeding events increased with declining renal function but were similar or numerically lower with dabigatran than with warfarin. The results suggest no need for dose adjustment of dabigatran in patients with mild or moderate renal dysfunction. Disclosures: Schulman: Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Portola: Consultancy; Pfizer: Consultancy; Merck: Consultancy; Janssen: Consultancy; BMS: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc: Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria; BMS/Pfizer: Honoraria; Bayer Healthcare: Advisory boards, Advisory boards Other, Consultancy, Honoraria; Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

Influence Of Age On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis Of RE-Cover and RE-Cover II

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2375-2375 ◽  
Author(s):  
Sam Schulman ◽  
Henry Eriksson ◽  
Samuel Z Goldhaber ◽  
Ajay Kakkar ◽  
Clive Kearon ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Research Funding ◽  
Dabigatran Etexilate ◽  
Age Groups ◽  
Age Group ◽  
Parenteral Therapy ◽  
Bleeding Events ◽  
Advisory Boards ◽  
Bayer Healthcare ◽  
Recurrent Vte

Abstract Background In the RE-COVER and RE-COVER II trials, a fixed dose of dabigatran etexilate was as effective as warfarin for prevention of recurrent VTE and was associated with a lower risk of bleeding. It is not known whether this efficacy and difference in bleeding rates is maintained in older patients. Objectives Older patients may be at greater risk of bleeding and/or VTE. Therefore, we performed a subgroup analysis on the pooled RE-COVER and RE-COVER II trial results to investigate the efficacy and safety of dabigatran versus warfarin for the treatment of acute VTE according to age. Methods Patients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double dummy; “oral only” treatment period) for 6 months. Outcomes were centrally adjudicated. The primary efficacy outcome was recurrent, symptomatic, objectively confirmed VTE or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Major bleeding events (MBEs), the composite of MBEs or clinically relevant non-major bleeding events (CRBEs), and any bleeds were counted from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. Results Of 2553 patients randomized to dabigatran, 68 (2.7%) had recurrent VTE or VTE-related death compared with 62 (2.4%) of 2554 patients randomized to warfarin; hazard ratio (HR) 1.09 (95% CI 0.77, 1.54). The incidences of the primary efficacy outcome (dabigatran vs warfarin) by age group were 3.0% (53/1769) versus 2.4% (42/1748) for patients < 65, 2.3% (12/531) versus 2.5% (13/530) for patients 65–75, and 1.2% (3/253) versus 2.5% (7/276) for patients > 75 years; and in a second age-group comparison were 2.8% (67/2418) vs 2.3% (57/2429) for patients < 80 and 0.7% (1/135) versus 4.0% (5/125) for patients ≥ 80 years. Cox regression analysis showed no statistically significant interaction, indicating that there are similar treatment effects across age groups. MBEs were significantly less frequent with dabigatran than with warfarin overall (HR 0.60; 95% CI 0.36, 0.99). Incidences by age group are shown in the Table. MBE/CRBE incidence was also significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). The Table shows event rates for each age group. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall. There was no significant treatment-by-age interaction for MBEs or MBEs/CRBEs or any bleeds in either analysis. Conclusions No differences in recurrent VTE or efficacy were apparent across the age groups. Bleeding events increased with increasing age but numerically were similar or lower with dabigatran than with warfarin regardless of age. The results suggest there is no need for dose adjustment of dabigatran according to age for the treatment of VTE. Disclosures: Schulman: Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai Inc: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc. : Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory Boards, Advisory Boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Kreuzer:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

scholarly journals A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. LBA-6-LBA-6
Author(s):  
Gary E. Raskob ◽  
Nick Van Es ◽  
Peter Verhamme ◽  
Marc Carrier ◽  
Marcello Di Nisio ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Research Funding ◽  
Primary Outcome ◽  
Bleeding Events ◽  
Open Label ◽  
Advisory Committees ◽  
Once Daily ◽  
Vein Thrombosis ◽  
Bayer Healthcare ◽  
Recurrent Vte

Abstract On behalf of the Hokusai VTE Cancer Investigators The treatment of cancer-associated venous thromboembolism (VTE) is challenging because these patients are at increased risk of both recurrent VTE and major bleeding. Low-molecular-weight heparin (LMWH) treatment is standard care for these patients, but requires daily subcutaneous injections. Guidelines recommend LMWH treatment for 6 months, but the risk-benefit beyond this time is uncertain. Direct oral anticoagulants are used for the treatment of VTE in patients without cancer, but their role in patients with cancer- associated VTE is uncertain. In this randomized, open-label non-inferiority trial, cancer patients with acute symptomatic or incidental VTE were assigned to receive LMWH for a minimum of 5 days followed by the oral factor Xa inhibitor edoxaban at a dose of 60 mg once daily (or 30 mg once daily in patients with a creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or subcutaneous dalteparin 200 units per kg once daily for one month followed by 150 units per kg thereafter. Patients received these regimens for up to 12 months. The primary outcome was the composite of the first recurrent VTE or major bleeding event during follow-up for 12 months. Secondary outcomes included recurrent VTE and major bleeding analyzed separately, and survival free of recurrent VTE or major bleeding. The study hypothesis was that edoxaban would be noninferior to dalteparin for the primary outcome with an upper 95% confidence interval [CI] for the hazard ratio below 1.5, and a two-sided alpha of 0.05. All outcomes were independently adjudicated by a committee without knowledge of treatment allocation. This committee also assessed the clinical severity of major bleeding events using categorical criteria defined a priori (categories 1 to 4). From July 2015 through December 2016 a total of 1050 patients were enrolled at 114 centers in 13 countries; 525 were randomized to edoxaban and 525 to dalteparin. At entry, pulmonary embolism with or without deep-vein thrombosis was present in 657 patients (63%) while the remainder had isolated deep-vein thrombosis. Of the 1050 patents, 706 (67%) had symptomatic VTE and the rest were incidental. Active cancer at entry was present in 97% of the patients and 53% had metastatic disease. 1046 patients were included in the modified-intention-to-treat analysis. The primary outcome occurred in 67 of 522 patients (12.8%) in the edoxaban group compared with 71 of 524 patients (13.5%) in the dalteparin group (hazard ratio with edoxaban, 0.97; 95% CI, 0.70 to 1.36; P = 0.0056 for noninferiority) for a risk difference (edoxaban minus dalteparin) of - 0.7% (95% CI, - 4.8 to 3.4). The difference in risk for recurrent VTE was -3.8 % (95% CI, -7.1 to -0.4), whereas the corresponding difference in risk for major bleeding was 3.1% (95% CI, 0.5 to 5.7). The frequencies of severe major bleeding events (categories 3 and 4) were similar during treatment with edoxaban or dalteparin (12 patients in each group respectively). Survival at 12 months free of recurrent VTE and major bleeding in the edoxaban and dalteparin groups was similar (55.0% and 56.5% respectively). Oral edoxaban for up to 12 months is noninferior to subcutaneous dalteparin for the treatment of cancer-associated VTE. Disclosures Raskob: BMS: Consultancy, Honoraria; Eli Lilly: Consultancy; Janssen: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy; Boehringer-Ingelheim: Consultancy; Medscape: Honoraria; Bayer Healthcare: Consultancy; Daiichi Sankyo: Consultancy, Honoraria. Van Es:Daiichi Sankyo: Honoraria; Pfizer: Honoraria. Verhamme:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bayer Healthcare: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy; Medscape: Honoraria; Leo: Honoraria, Research Funding; Sanofi Aventis: Research Funding; Medtronic: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carrier:Daiichi Sankyo: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Leo: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria. Di Nisio:Daiichi: Consultancy, Honoraria. Garcia:Daiichi Sankyo: Honoraria, Research Funding; BMS: Consultancy; Boehringer Ingelheim: Consultancy; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; Medscape: Honoraria; Incyte: Consultancy, Honoraria, Research Funding. Grosso:Daiichi Sankyo: Employment. Kakkar:Daiichi Sankyo: Consultancy, Honoraria; Bayer Healthcare: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi SA: Consultancy, Honoraria; Verseon: Consultancy, Honoraria. Kovacs:Daiichi Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Bristol Myers Squibb: Research Funding. Mercuri:Daiichi Sankyo: Employment, Patents & Royalties: pending properties of edoxaban . Meyer:BMS Pfizer: Research Funding; Leo: Other: travel support; Stago: Other: travel support. Segers:Ionis: Research Funding; Daiichi Sankyo: Research Funding; Janssen: Research Funding. Shi:Daiichi Sankyo: Employment. Wang:Daiichi Sankyo: Honoraria. Yeo:Daiichi Sankyo: Honoraria, Research Funding; Bayer Healthcare: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Leo: Consultancy, Honoraria. Zhang:Daiichi Sankyo: Employment. Zwicker:Daiichi Sankyo: Honoraria; Quercegen Pharma: Research Funding; Parexel: Consultancy. Weitz:Daiichi-Sankyo: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Medscape: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria. Büller:Daiichi Sankyo: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Portola: Consultancy; Medscape: Honoraria; Eli Lilly: Consultancy; Sanofi Aventis: Consultancy; Ionis: Consultancy.

Influence Of Concomitant NSAID Or ASA On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1136-1136 ◽  
Author(s):  
Sam Schulman ◽  
Henry Eriksson ◽  
Samuel Z Goldhaber ◽  
Ajay Kakkar ◽  
Clive Kearon ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Half Life ◽  
Research Funding ◽  
Low Dose ◽  
Dabigatran Etexilate ◽  
Parenteral Therapy ◽  
Bleeding Events ◽  
Advisory Boards ◽  
Bayer Healthcare ◽  
Acute Venous Thromboembolism

Abstract Background In two phase III trials, RE-COVER and RE-COVER II, dabigatran etexilate was as effective as warfarin for treatment of acute venous thromboembolism (VTE), with a lower risk of bleeding. However, some patients may already be taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA), which can have antihemostatic effects. Objectives We performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without concomitant NSAIDs (half-life < 12 hours) or low-dose ASA. Methods Patients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double-dummy; “oral only” treatment period) for 6 months. Concomitant use of ASA ≤ 100 mg/day or NSAIDs with a half-life ≤ 12 hours was permitted. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE, or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy, either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. Results Overall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). The Table shows event rates for dabigatran versus warfarin in subgroups with and without concomitant NSAIDs or low-dose ASA. Cox regression analysis showed no statistically significant interaction, indicating similar treatment effects regardless of presence or absence of these concomitant medications. Overall, MBEs were significantly less frequent with dabigatran than with warfarin during the oral only treatment (double dummy) period (HR 0.60; 95% CI 0.36, 0.99). Likewise, MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Results according to concomitant NSAID or low-dose ASA use at baseline are shown in the Table. There was no significant treatment interaction by concomitant medication status for either MBE or MBE/CRBE. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no treatment interaction by baseline NSAID or low-dose ASA use. Conclusions There was no apparent difference in recurrent VTE or VTE-related mortality across NSAID or low-dose ASA concomitant medication subgroups. The incidence of bleeding events was similar or numerically lower with dabigatran than with warfarin across subgroups. The results suggest that no increased bleeding risk exists when dabigatran is administered with NSAIDs with a half-life < 12 hours or low-dose ASA. Disclosures: Schulman: Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc. : Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory Boards, Advisory Boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

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

2021 ◽  
pp. 106002802199520
Author(s):  
Hannah Whittemore ◽  
Andrew K. Posen ◽  
Erika L. Hellenbart ◽  
Vicki Groo ◽  
Eric Wenzler ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Renal Function ◽  
Body Weight ◽  
Renal Dysfunction ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Events ◽  
Risk Of Bleeding ◽  
Increased Risk ◽  
The Impact

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion and Relevance: 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.

scholarly journals Post-Hoc Analysis of RE-MEDY™ Demonstrates Significant Real-World Net Clinical Benefit for Dabigatran Versus Warfarin in Prevention of Secondary Venous Thromboembolism

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4270-4270 ◽  
Author(s):  
Sam Schulman ◽  
Henry Eriksson ◽  
Ajay Kakkar ◽  
Clive Kearon ◽  
Sebastian M Schellong ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Real World ◽  
Clinical Benefit ◽  
Research Funding ◽  
Systemic Embolism ◽  
Bleeding Events ◽  
Advisory Boards ◽  
Bayer Healthcare ◽  
Cardiovascular Endpoint ◽  
Net Clinical Benefit

Abstract Background: The double-blind, parallel-group, noninferiorityRE-MEDY™ study comparing the direct oral thrombin inhibitor dabigatran etexilate to warfarin in the prevention of secondary venous thromboembolism (VTE) showed non-inferiority of dabigatran to warfarin in both hazard ratio (HR) and risk difference for recurrent symptomatic VTE and related deaths. The benefit-risk balance of dabigatran compared to warfarin in secondary VTE prevention can be further explored by evaluating the net clinical benefit (NCB). Methods: Patients with a diagnosis of VTE received dabigatran 150 mg twice daily (n = 1430), or warfarin adjusted to maintain an international normalized ratio (INR) of 2.0–3.0 (n = 1426), for an additional period of 6–36 months after 3–12 months of anticoagulant therapy. NCB in the RE-MEDY™ study was evaluated narrowly by (1) analyzing nonfatal recurrent VTE, nonfatal myocardial infarction (MI), nonfatal stroke, nonfatal systemic embolism, all-cause death, and major bleeding events (MBEs), and broadly by (2) including clinically relevant bleeding events (CRBEs). The latter is considered more applicable to real-world clinical practice. NCB was also assessed by center time in therapeutic range (cTTR – the mean TTR of all warfarin patients in each center). Results: The narrow NCB (1) was similar between dabigatran and warfarin (HR 1.05, 95% confidence interval [CI]: 0.75–1.46). For the broader NCB (2), a statistically significant difference was evident favoring dabigatran over warfarin (HR 0.73, 95% CI: 0.59–0.91). Stratification of the NCB by cTTR quintiles demonstrated that the positive benefit of dabigatran over warfarin was preserved when comparing to warfarin patients with a good INR control. Conclusion: In the assessment of real-world net clinical benefit in the prevention of secondary VTE, dabigatran was superior to warfarin, irrespective of INR control in the warfarin patients. Table. Net clinical benefit for dabigatran versus warfarin in pooled analyses of RE-MEDY™ Dabigatran (N=1430) n (%) Warfarin (N=1426) n (%) HR (95% CI) p value for superiority Narrow: Composite cardiovascular endpoint* and MBEs (NCB 1) 72 (5.0) 69 (4.8) 1.05 (0.75–1.46) 0.7818 Broad: Composite cardiovascular endpoint*, MBEs and CRBEs (NCB 2) 136 (9.5) 183 (12.8) 0.73 (0.59, 0.91) 0.0058 *Nonfatal recurrent venous thromboembolism (VTE), nonfatal myocardial infarction (MI), nonfatal stroke, nonfatal systemic embolism, all-cause death. Disclosures Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare: Consultancy; Boehringer Ingelheim (Canada): Consultancy. Schellong:Boehringer Ingelheim: advisory boards Other, Consultancy, Honoraria; Bayer Healthcare: advisory boards, advisory boards Other, Consultancy, Honoraria; Daiichi Sankyo: advisory boards, advisory boards Other, Honoraria; BMS/Pfizer: Honoraria. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim: Employment. Kreuzer:Boehringer Ingelheim: Employment. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy.

Influence Of Active Cancer On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 582-582 ◽  
Author(s):  
Sam Schulman ◽  
Henry Eriksson ◽  
Samuel Z Goldhaber ◽  
Ajay Kakkar ◽  
Clive Kearon ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Research Funding ◽  
Dabigatran Etexilate ◽  
Parenteral Therapy ◽  
Bleeding Events ◽  
Significant Treatment ◽  
Advisory Boards ◽  
Bayer Healthcare ◽  
Treatment Interaction ◽  
Active Cancer

Abstract Background In two phase III trials, RE-COVER and RE-COVER II, dabigatran etexilate was as effective as warfarin for treatment of acute venous thromboembolism (VTE), with a lower risk of bleeding. Cancer and its treatments are risk factors for VTE and bleeding. Objectives We performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without active cancer at any time during the study. Active cancer was defined as: a diagnosis of cancer (other than basal-cell or squamous-cell carcinoma of the skin) within 5 years before enrolment; any treatment for cancer within 5 years before enrolment; or recurrent or metastatic cancer. Methods Patients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double dummy; “oral only” treatment period) for 6 months. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. Results Overall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). The Table shows event rates for dabigatran versus warfarin in subgroups with and without active cancer at any time. Cox regression analysis showed that presence of cancer was associated with a statistically significant increase in the likelihood of VTE or VTE-related death. However, there was no significant interaction with treatment, indicating similar treatment effects regardless of the presence or absence of active cancer. Overall, MBEs were significantly less frequent with dabigatran than with warfarin during the oral treatment only (double dummy) period (HR 0.60; 95% CI 0.36, 0.99). Likewise, the MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Results according to cancer status are shown in the Table. Patients with cancer had significantly higher rates of MBEs and MBEs/CRBEs than those without. There was no significant treatment interaction by cancer status for MBEs, whereas the treatment interaction for MBEs/CRBEs was significant (p = 0.0257) with a lower rate of bleeding with dabigatran versus warfarin in patients without compared to with cancer. Any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no significant treatment interaction with cancer status. Conclusions There was a significantly higher frequency of recurrent VTE or VTE-related mortality among patients who had cancer, but the efficacy of dabigatran versus warfarin was similar irrespective of cancer status. The incidence of bleeding events was similar or numerically lower with dabigatran than with warfarin across cancer subgroups. Disclosures: Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer Healthcare: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc.: Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée: Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory boards, Advisory boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.

A Randomized Trial of Long-Term Tinzaparin, a Low Molecular Weight Heparin (LMWH), Versus Warfarin for Treatment of Acute Venous Thromboembolism (VTE) in Cancer Patients - the CATCH Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. LBA-2-LBA-2 ◽  
Author(s):  
Agnes Y.Y. Lee ◽  
Pieter W. Kamphuisen ◽  
Guy Meyer ◽  
Rupert Bauersachs ◽  
Mette S. Janas ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Major Bleeding ◽  
Distant Metastasis ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Bleeding Events ◽  
Open Label ◽  
Once Daily ◽  
Advisory Boards ◽  
Recurrent Vte

Abstract Background Patients with cancer and VTE have a substantial risk of recurrent VTE. LMWH reduces the risk of symptomatic, recurrent VTE compared with warfarin and is recommended as the preferred anticoagulant by consensus guidelines. However, the evidence is based largely on a single, open-label randomized trial (CLOT; Lee et al NEJM 2003). Warfarin is still often used for the treatment of VTE in cancer patients worldwide. Methods The primary objective of this randomized, open-label, multicenter, Phase III trial (CATCH; NCT01130025) was to assess the efficacy of tinzaparin in preventing recurrent VTE in patients with active cancer and acute, symptomatic proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Patients were randomized (stratified by geographic region, tumor characteristic [distant metastasis, no distant metastasis, hematological malignancy] and history of VTE) to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5–10 days overlapped and followed by dose-adjusted warfarin (target INR 2.0–3.0) for 6 months. The primary efficacy outcome was time to recurrent VTE verified by objective, standard imaging and blinded central adjudication; this was a composite primary endpoint that included symptomatic DVT and/or PE, incidental proximal DVT and/or PE and fatal PE. The primary safety endpoint was incidence of major bleeding. All patients were followed up to 6 months or death, whichever came sooner. Blinded central adjudication was also performed for all bleeding events and causes of death. A proportional hazards model for competing risks was applied to all randomized patients, treating all non-VTE-related deaths as competing events. An independent Data Safety Monitoring Board reviewed safety data at regular intervals. Results Nine hundred patients were included from 165 sites in 32 countries across 5 continents. Of these, 449 were randomized to tinzaparin and 451 to warfarin. Mean age was 59 years (range 18–89); 59% female. A total of 77% of patients had a baseline ECOG performance status (PS) of 0–1 and 23% had a PS of 2. The most common primary tumor sites were gynecologic (23%), colorectal (13%), lung (12%), breast (9%); 10% had hematological malignancies. At the time of randomization, metastatic disease was present in 55% of patients and 44% had received prior cancer treatment (chemotherapy, surgery and/or radiation). Time-in-therapeutic range was 47% in the warfarin arm, with 27% above and 26% below the range. Over the 6-month trial period, 31 patients (6.9%) in the tinzaparin arm experienced recurrent VTE compared with 45 (10%) in the warfarin arm (hazard ratio [HR] 0.65 [95% CI 0.41–1.03; P=0.07]) (see figure). There were 2 patients with incidental VTE, both were in the warfarin arm. Symptomatic non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR 0.48 [95% CI 0.24–0.96]; P=0.04). Symptomatic non-fatal PE occurred in 3 patients in the tinzaparin arm and 2 in the warfarin arm; fatal PE occurred in 17 (3.8%) patients in each arm (HR 0.96 [95% CI 0.49–1.88]; P=0.90). There was no difference in the incidence of major bleeding events (n=13 [2.9%] in the tinzaparin arm and 12 [2.7%] in the warfarin arm), but significantly fewer patients experienced clinically relevant non-major bleeding with tinzaparin than warfarin (50 [11%] and 73 [16%] patients, respectively; P=0.03). No difference in mortality was seen with 6-month survival rates of 59% and 60%, respectively. Conclusions In cancer patients with symptomatic VTE, tinzaparin lowered the risk of recurrent VTE compared with warfarin, with a significant reduction in symptomatic DVT and clinically relevant non-major bleeding. No difference in major bleeding or overall mortality was observed. Figure. Cumulative incidence of recurrent VTE in the tinzaparin and warfarin groups. Figure. Cumulative incidence of recurrent VTE in the tinzaparin and warfarin groups. Disclosures Lee: Bayer: Advisory Boards Other, Honoraria; Bristol-Myers Squibb: Advisory Boards, Advisory Boards Other, Research Funding; Boehringer Ingelheim: Honoraria; Daiichi-Sankyo: Advisory Boards, Advisory Boards Other; Eisai: Research Funding; LEO Pharma: Advisory Boards Other; Pfizer: Advisory Boards Other, Honoraria, Research Funding; Sanofi-Aventis: Advisory Boards, Advisory Boards Other; Avivia: Advisory Boards, Advisory Boards Other. Kamphuisen:LEO Pharma: Honoraria, Research Funding. Meyer:Bayer: Research Funding; Boehringer Ingelheim: Research Funding; LEO Pharma: Research Funding; Sanofi-Aventis: Research Funding. Janas:LEO Pharma: Employment. Jarner:LEO Pharma: Employment. Khorana:LEO Pharma: Honoraria, Research Funding.

scholarly journals Comparative Effectiveness and Safety of Extended Anticoagulant Therapy Among Medicare Beneficiaries with Venous Thromboembolism

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 178-178
Author(s):  
Haesuk Park ◽  
Hye-Rim Kang ◽  
Pei-Lin Huang ◽  
Wei-Hsuan Lo-Ciganic ◽  
Eric A Dietrich ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Research Program ◽  
Initial Treatment ◽  
Research Funding ◽  
Oral Anticoagulants ◽  
Medicare Beneficiaries ◽  
Bleeding Events ◽  
Extended Treatment ◽  
Recurrent Vte ◽  
Program Research

Abstract Introduction: Approximately 30% of patients with venous thromboembolism (VTE) experience a recurrence within 10 years of the initial event with their recurrence risk peaking during the first 6-12 months. Two large randomized clinical trials AMPLIFY-EXT and PADIS-PE reported that extended treatment with apixaban and warfarin beyond 6 months of initial treatment reduced recurrent VTE without increasing the rate of major bleeding compared to placebo, respectively. Little is known about real-world effectiveness and safety of extended oral anticoagulation beyond 6 months of initial treatment for Medicare beneficiaries with VTE, despite the fact that VTE disproportionately affects the elderly. We assessed the effectiveness and safety of extended use of apixaban and warfarin beyond 6 months of initial treatment for prevention of recurrent VTE and adverse major bleeding events among Medicare beneficiaries with newly diagnosed VTE. Methods: A retrospective cohort study using 2014-2018 Medicare data (5% samples in 2014-2016 and 15% samples of Medicare beneficiaries in 2017-2018) was conducted for patients aged ≥18 years with a diagnosis of deep vein thrombosis or pulmonary embolism ascertained from inpatient claims. Patients were included if they initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of therapy defined as ≥83% proportion days covered with oral anticoagulants during the initial 6-month period, and received extended treatment with either apixaban or warfarin or no extended therapy. We compared the risks of recurrent VTE and major bleeding between apixaban, warfarin, and no treatment groups. To adjust for differences in baseline characteristics and clinical factors (e.g., HAS-BLED score, active cancer, and provoked VTE) between groups, we used the stabilized inverse probability treatment weighting (IPTW) method. Follow-up continued until the occurrence of the first event, switch to the comparator, disenrollment, death, or end of the study period. Multivariable Cox proportional hazards modeling with IPTW was used to obtain adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI). Results: The study cohort (mean age=74 ±12 years, 40% male, 76% White) consisted of 2,315 users of extended apixaban treatment (83% with 5 mg twice a day and 17% with 2.5 mg twice a day; mean duration=6.2 months), 2,757 users of extended warfarin treatment (mean duration=8.2 months), and 2,328 patients with no extended treatment following completion of an initial 6 months of anticoagulant treatment. The incidence rates of recurrent VTE were 0.42, 1.73, and 1.72 per 100 person-years, and those of major bleeding were 2.28, 3.62, and 1.43 per 100 person-years in the apixaban, warfarin, and no treatment groups, respectively (Table 1). Compared to no extended treatment, the use of apixaban was associated with an 80% decreased risk of recurrent VTE (aHR=0.19, 95%CI=0.06-0.55) without increasing the risk of major bleeding (aHR=1.19, 95%CI=0.65-2.19); the use of warfarin did not lower the risk of recurrent VTE (aHR=0.75, 95%CI=0.42-1.37) but increased the risk of major bleeding (aHR=1.92, 95%CI=1.13-3.25). Compared to the use of warfarin, the use of apixaban was associated with a decreased risk of recurrent VTE (aHR=0.26, 95% CI=0.09-0.76) and no difference in major bleeding risk (aHR=0.61, 95%CI=0.36-1.06). These findings remained consistent in subgroup (e.g., patients with provoked vs. unprovoked VTE, patients with active cancer vs. those without, and patients with chronic kidney diseases vs. those without) and sensitivity analyses (e.g., ≥92% proportion days covered with oral anticoagulants during the initial 6-month period). Conclusions: Compared to no extended therapy, extended anticoagulation with apixaban was associated with a reduced risk of recurrent VTE without increasing the risk of major bleeding, whereas warfarin did not lower risk of recurrent VTE but increased the risk of major bleeding among Medicare beneficiaries with VTE. In the head-to-head comparison, the use of apixaban was more effective than warfarin in preventing recurrent VTE, without increasing the risk of major bleeding events. Our findings suggest that apixaban is an effective and safer option for extended treatment of VTE when compared to warfarin or no treatment among Medicare beneficiaries with VTE. Figure 1 Figure 1. Disclosures Park: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Kang: BMS/Pfizer Alliance American Thrombosis InvestigatorInitiated Research Program: Research Funding. Huang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Lo-Ciganic: MERCK: Research Funding; BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Dietrich: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Murphy: North American Thrombosis Foundation: Honoraria. DeRemer: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding; Portola Pharmaceuticals: Current equity holder in publicly-traded company; BMS advisory board attendee: Honoraria.

scholarly journals Efficacy and Safety of Direct Oral Factor Xa Inhibitors in 795 Morbidly Obese Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 423-423 ◽  
Author(s):  
Margarita Kushnir ◽  
Yun Choi ◽  
Ruth Eisenberg ◽  
Devika Rao ◽  
Seda Tolu ◽  
...  
Keyword(s):  
Major Bleeding ◽  
Research Funding ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Efficacy And Safety ◽  
Bleeding Events ◽  
Prescription Date ◽  
Recurrent Vte

Abstract Background: Studies of acute venous thromboembolism (VTE) and non-valvular atrial fibrillation (AF) have shown comparable therapeutic efficacy and similar or lower bleeding risk for direct oral anticoagulants (DOACs) compared to warfarin. Because the representation of morbidly obese patients (BMI ≥40 kg/m2) in pivotal clinical trials has been minimal, efficacy and safety of DOACs in this population are unclear. Our goal was to investigate whether direct oral factor Xa inhibitors, apixaban and rivaroxaban, are as effective and safe as warfarin in morbidly obese (BMI ≥40) patients. Methods: Using our institutional database, we identified all adult patients at Montefiore Medical Center with BMI ≥40 who were started on anticoagulation with apixaban, rivaroxaban or warfarin, for either AF or VTE, between March 1, 2013 and March 1, 2017. We reviewed charts to obtain detailed information on patient demographics and to document clinical outcomes of recurrent VTE, ischemic stroke (CVA) and bleeding from the first prescription date to the earliest of a thrombotic event, discontinuation of medication, death, or June 30, 2017. VTE and CVA episodes were confirmed by imaging (compression sonography, CT scans, ventilation/perfusion scans, MRIs). Bleeding events were classified according to criteria from the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis. Analyses were stratified by anticoagulation indication. Chi-squared tests or Fisher's exact tests were used to assess statistical significance of the differences in VTE, CVA and bleeding rates between anticoagulant cohorts. Differences in times from first prescription date to VTE, CVA and bleeding were analyzed with Kaplan-Meier curves, Log-rank tests, and Cox proportional hazards models. Data were adjusted for age, CHA2DS2-VASc, and Charlson scores. Subgroup analyses were performed for patients with BMI ≥50 kg/m2. Results: Data on 795 patients were collected. In 366 patients with a history of VTE, the rates of recurrent VTE were low and comparable among the apixaban, rivaroxaban and warfarin cohorts [1/47 (2.1%), 3/152 (2%), and 2/167 (1.2%), respectively, p=0.74]. In the subgroup of individuals with BMI ≥50 kg/m2 (n=92), none of the 40 DOAC patients had recurrent VTE. The rates of clinically relevant bleeding, including major bleeding, among VTE patients, were comparable between the three cohorts. Among the 429 patients with AF, stroke rates were also low and similar among anticoagulant cohorts [1/103 (1%) for apixaban, 4/174 (2.3%) for rivaroxaban, and 2/152 (1.3%) for warfarin, p=0.71]. CVAs were similarly rare in patients with BMI ≥50 (1/19 patients on apixaban, 0/37 on rivaroxaban and 1/44 patients on warfarin). In the AF sample, there was no statistically significant difference in the rate of bleeding, including major bleeding, among the 3 cohorts. In an analysis with combined DOAC cohort (apixaban + rivaroxaban vs. warfarin), the recurrent VTE and stroke rates were still low and comparable. There were more major bleeding events in AF patients on warfarin than the combined DOAC cohort (7.9% vs. 2.9%, p=0.02), a finding that became non-significant when adjusted for age, CHA2DS2-VASc, and Charlson scores (p=0.06). The rates of bleeding, including major bleeding, were comparable among the three anticoagulants in both VTE and AF patients with BMI ≥50. Conclusions: Our study is the largest study examining morbidly obese patients on DOACS and provides further evidence of comparable efficacy and safety of the direct oral anti-Xa inhibitors, compared to warfarin, in morbidly obese patients with AF and VTE. Disclosures Kushnir: Janssen: Research Funding. Billett:Bayer: Consultancy; Janssen: Research Funding.

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