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 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.

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.

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 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.

scholarly journals Dabigatran Etexilate or Warfarin in the Treatment of Acute Venous Thromboembolism in Western European Patients: A Pooled Analysis of RE-COVER® and RE-COVER II™

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4730-4730
Author(s):  
Sebastian Schellong ◽  
Henry Eriksson ◽  
Samuel Z. Goldhaber ◽  
Martin Feuring ◽  
Stefan Hantel ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Research Funding ◽  
Dabigatran Etexilate ◽  
Primary Efficacy ◽  
Bleeding Events ◽  
Primary Efficacy Outcome ◽  
Efficacy Outcome ◽  
Safety Outcomes ◽  
Western European ◽  
Acute Venous Thromboembolism

Abstract Introduction: In the RE-COVER®/RE-COVER II™ global randomized trials investigating the treatment of acute venous thromboembolism (VTE), efficacy and safety outcomes of dabigatran etexilate (dabigatran) versus warfarin were compared. This sub-analysis of pooled RE-COVER®/RE-COVER II™ data compares the safety and efficacy of dabigatran versus warfarin in the Western European sub-population. Methods: In the RE-COVER®/RE-COVER II™ trials, patients with acute VTE, initially receiving parenteral anticoagulation, were randomized to warfarin (INR 2-3) or dabigatran (150 mg twice daily) for 6 months and followed up for 30 days. The primary efficacy outcome was recurrent, symptomatic VTE/VTE-related death. Safety outcomes were major bleeding events (MBEs), a composite of MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeding during the 6-month, oral-only treatment period. All outcomes were centrally adjudicated. Data from the Western European sub-population were analyzed using a Cox regression model with factor treatment stratified by study, assuming different baseline hazards per study. Results: This sub-analysis included 1239 patients for the efficacy analysis (dabigatran n = 613; warfarin n = 626) and 1192 patients for safety (dabigatran n = 588; warfarin n = 604) from all 13 Western European countries participating in the RE-COVER®/RE-COVER II™ trials. For the primary efficacy outcome, the rate of VTE/VTE-related death in patients receiving dabigatran was 2.1% (n = 13) compared with 2.9% (n = 18) in those receiving warfarin. However, this difference did not reach statistical significance (hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.36-1.5). Of the safety outcomes, rates of MBEs were similar between both treatment groups (1.4% for dabigatran [n = 8] and 1.3% for warfarin [n = 8]; HR 1.02; 95% CI, 0.38-2.71). Rates of MBEs/CRBEs were significantly lower in patients receiving dabigatran than in those receiving warfarin at 5.1% (n = 30) and 9.4% (n = 57), respectively (HR 0.52; 95% CI, 0.34-0.82). Any bleeding events were also statistically lower in the dabigatran group (17.5%; n = 103) compared with warfarin (23.8%; n = 144) (HR 0.7; 95% CI, 0.54-0.90). Conclusions: In this Western European sub-analysis of pooled data from the RE-COVER®/ RE-COVER II™ trials, dabigatran was as effective as warfarin in the treatment of acute VTE. There was a significant reduction in MBE/CRBE and in any bleeding events in the dabigatran treatment group. Disclosures Schellong: Boehringer Ingelheim: Consultancy. Eriksson:Boehringer Ingelheim: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy, Research Funding. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim Pharma GmbH and Co. KG: Employment. Kreuzer:Boehringer Ingelheim Pharma GmbH and Co. KG: Employment. Schulman:Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria; Baxter: Honoraria; Octapharma: Research Funding. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding.

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.

scholarly journals Influence of Thrombophilia on the Efficacy of Dabigatran Versus Warfarin for the Extended Treatment of Acute Venous Thromboembolism in RE-MEDY™

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1544-1544 ◽  
Author(s):  
Sam Schulman ◽  
Henry Eriksson ◽  
Samuel Z. Goldhaber ◽  
Ajay Kakkar ◽  
Clive Kearon ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Venous Thromboembolism ◽  
Treatment Efficacy ◽  
Research Funding ◽  
Factor V Leiden ◽  
Factor V ◽  
Total Study Population ◽  
Extended Treatment ◽  
Advisory Boards ◽  
Bayer Healthcare

Abstract Background: Dabigatran etexilate (DE) was noninferior to warfarin for the prevention of recurrent venous thromboembolism (VTE), with a lower risk of bleeding, when administered as extended treatment for VTE in the RE-MEDY™ study (in which we evaluated long-term extension of treatment with dabigatran compared with warfarin). Objectives: Thrombophilia is a major risk factor for VTE recurrence. Therefore, we performed a post-hocsubgroup analysis on data from RE-MEDY™ to investigate the efficacy of DE versus warfarin in patients with and without thrombophilia (congenital or acquired) at baseline. Methods: Patients were aged ≥ 18 years and had objectively-confirmed, symptomatic, proximal deep vein thrombosis or pulmonary embolism (PE) that had been treated with an approved anticoagulant for 3–12 months, or with DE in one of two clinical trials of treatment for acute VTE (RE-COVER™ or RE-COVER™ II). Eligible patients were those at increased risk for recurrent VTE. Patients were randomly allocated to receive DE 150 mg twice daily or warfarin (international normalized ratio range 2.0–3.0) for 6–36 months. The primary efficacy outcome was recurrent, symptomatic, objectively-confirmed VTE or VTE-related death from randomization up to the end of the planned treatment period (6–36 months). No thrombophilia workup was required for enrollment in the trial. Results: Overall, 262/1430 (18.3%) patients randomized to DE and 263/1426 (18.4%) randomized to warfarin had thrombophilia identified at baseline. Factor V Leiden thrombophilia was the most common type (Table). The frequencies of VTE/VTE-related deaths, and of PE, in patients with and without thrombophilia are shown in the Table. Treatment efficacy (DE versus warfarin) was not significantly affected by the presence of thrombophilia. Table DE (n = 1430) Warfarin (n = 1426) Thrombophilia, n (%) No 433 (30.3) 407 (28.5) Yes 262 (18.3) 263 (18.4) Factor V Leiden 131 (9.2) 137 (9.6) Prothrombin mutation 35 (2.4) 28 (2.0) Antithrombin deficiency 11 (0.8) 11 (0.8) Protein C/S deficiencies 25 (1.7) 29 (2.0) Antiphospholipid antibodies and/or lupus anticoagulants 38 (2.7) 54 (3.8) Not tested 735 (51.4) 756 (53.0) VTE/VTE-related deaths, n/N (%) Pulmonary embolism, n/N (%) DE Warfarin DE Warfarin Thrombophilia No 10/433 (2.3) 3/407 (0.7) 3/433 (0.7) 1/407 (0.2) Yes 4/262 (1.5) 6/263 (2.3) 3/262 (1.1) 2/263 (0.8) Not tested 12/735 (1.6) 9/756 (1.2) 4/735 (0.5) 2/756 (0.3) Total study population: Hazard ratio (DE vs warfarin) (95% confidence interval) 1.43 (0.78, 2.61) 1.97 (0.67, 5.76) Treatment (DE vs warfarin) by thrombophilia interaction p = 0.2277 p = 0.9003 p-value from Chi-square test for overall factor effect. Full analysis set. Conclusions: The frequencies of VTE/VTE-related death, and of PE, were similar for DE and warfarin in patients with thrombophilia who were receiving extended treatment for VTE. Treatment efficacy was not affected by the presence of thrombophilia. Disclosures Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding. 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: 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. Friedman:Boehringer Ingelheim: Consultancy. Kreuzer:Boehringer Ingelheim: Employment.

Improvement In Renal Function In Newly Diagnosed Myeloma Improves Survival, but Still Remains Inferior to Those with Normal Renal Function

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2970-2970 ◽  
Author(s):  
Shaji Kumar ◽  
Angela Dispenzieri ◽  
Martha Lacy ◽  
Suzanne R. Hayman ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Renal Function ◽  
Renal Insufficiency ◽  
Serum Creatinine ◽  
Renal Dysfunction ◽  
Research Funding ◽  
Negative Impact ◽  
Newly Diagnosed ◽  
Number Of Patients ◽  
The Impact

Abstract Abstract 2970 Background: Over a quarter of patients (pts) with symptomatic multiple myeloma (MM) have some degree of renal insufficiency at the time of diagnosis. Multiple studies show that presence of renal failure is strong predictor of inferior overall survival in MM. With effective therapy, renal function improves in a considerable number of patients. It is not clear if the return of renal function to normal levels will improve their outcome to that expected for patients without renal dysfunction. Methods: We evaluated 1478 patients with newly diagnosed myeloma seen at Mayo Clinic within 90 days of diagnosis, between January 1999 and January 2009. We examined these patients for improvement in renal function and identified the lowest serum creatinine obtained during the disease course. The outcomes were analyzed with respect to the renal function improvements. Results: The median age at diagnosis was 64 years (range; 22–93) and 50% were male. The median estimated follow up for the entire cohort was 53 months, with 781 patients alive at the time of analysis with a median follow of 3 years. The serum creatinine was over 1.5 mg/dL at diagnosis in 333 (22.5%) pts and over 2.5 mg/dL in 148 (10%) pts. The median overall survival for the 333 patients was 37 mos (95% CI; 28, 40) compared to 56 mos (95% CI; 51, 63) for those < 1.5 mg/dL; P < 0.001. Among the 333 pts with baseline Cr > 1.5 mg/dl, any improvement in Cr was seen in 263 (79%) including an improvement of at least 0.5 mg/dL in 208 (62%) pts. Among the 263 pts with any improvement, the median time to lowest Cr was 4 months (range; 1–13). The median survival of the group of patients with Cr <= 1.5 mg/dl, over 1.5 mg/dL at diagnosis but improved to <= 1.5 mg/dL, or remained >1.5 mg/dL were 56., 40 and 27 mos respectively; P < 0.001, Figure). We then examined the impact of renal function improvement in the group of patients where the baseline Cr was >2.5 mg/dL. The median OS for the 42 (out of 148 pts with Cr > 2.5 at diagnosis) who had improved to <=1.5 mg/dL was 40 mos compared to 56 mos for those with a Cr <= 1.5 mg/dL at diagnosis and 27.4 mos for the 106 pts whose Cr did not decrease to <= 1.5 mg/dL; P < 0.001. Conclusion: The results of this study point toward improved outcome among patients with renal dysfunction in whom renal function improves. However, it shows that this improvement in renal function does not necessarily improve survival to that observed for the patients with a comparable level of serum creatinine at diagnosis. While early treatment of asymptomatic myeloma has been shown to have little impact on overall survival, a strategy of waiting for serious features of target organ damage to appear before initiation of treatment may have a negative impact on survival in some patients, especially patients with high light chain production who have a higher predilection for renal insufficiency. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Lacy:Celgene: Research Funding.

Safety of Weight-Adjusted Dosing of LMWH in Clinically Obese Cancer Patients with Venous Thromboembolism

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 882-882
Author(s):  
Gillian Mount ◽  
Michael J. Kovacs ◽  
Alejandro Lazo-Langner ◽  
Lenicio Siqueira ◽  
Martha L Louzada
Keyword(s):  
Venous Thromboembolism ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Research Funding ◽  
Control Group ◽  
Obese Patients ◽  
Bleeding Events ◽  
Compression Ultrasound ◽  
Bleeding Episodes

Abstract Background: Obesity, defined as a body mass index (BMI) greater than 30 kg/m2, is a well-known risk factor for venous thromboembolism (VTE). Despite this observation, obese patients are under-represented in anticoagulation safety trials. Current guidelines recommend patients with active malignancy and VTE to be treated with long-term low molecular weight heparin (LMWH), but it is unclear whether this practice is safe in obese cancer patients. Objectives: We hypothesized there would be an increased risk of major or clinically significant non-major bleeding in obese cancer patients receiving long-term, actual weight-adjusted LMWH compared to non-obese patients with cancer- associated VTE. Methods: We conducted a single centre retrospective cohort study of obese cancer patients referred to our thrombosis clinic from January 2010 to December 2015. We included all obese cancer patients assessed at the Thrombosis unit who received anticoagulation with LMWH. Obesity was defined as weight above 90 Kg or BMI of 30 kg/m2 or more. The obese patients' data was compared to a non-obese control group of patients with active malignancy treated with LMWH. Major bleeding was defined as a hemoglobin drop of > 20 g/L; clinically overt bleeding; bleeding requiring 2 units or more of packed red blood cells; a hemorrhage requiring permanent cessation of anti-coagulation; or any retroperitoneal or intracranial hemorrhage. Diagnosis of deep venous thrombosis was confirmed when compression ultrasound of the lower extremities showed evidence of thrombus in the calf trifurcation or more proximal veins; or calf thrombosis associated with pulmonary embolism (PE). PE was confirmed when the ventilation-perfusion lung showed at least a large mismatched defect or CT pulmonary angiography demonstrated at least one segmental intra-luminal filling defect. Results: In total, 102 obese cancer patients and 81 non-obese cancer patients met our eligibility criteria. In the obese cohort, 43 (42%) were male, median age 64 (24-89), median weight 96.5 kg (67.3-158), and median BMI 33.7 kg/m2 (27.2-57). 90 (88%) patients had a solid tumour. Median dose of LMWH was 18,000 units (10,000 - 30,000): 78 (76%) were prescribed dalteparin and 22 (22%) tinzaparin. Median follow-up was 191 days (3 - 2622). Baseline characteristics of the control group were similar (Table 1). Total bleeding episodes were significantly different in the 2 groups: total bleeding events were 10 (9.8%) in the obese group (4 were under-dosed based on their weight) and 1 in the control group [RR=7.9; 95% CI (1.04 -60.76) p=0.046)]. Major bleeding events occurred in 6 (5.9%) obese and in none of the non-obese patients [RR=10.4; 95% CI (0.59 -181.05) p=0.11)]. Platelet counts were appropriate in all cases but one, where a non-major bleed occurred in an obese patient with a platelet count of 27. Recurrent VTE occurred in 8 (7.8%) obese and 4 control patients. In the obese cohort, 5 of those patients were receiving under-dosed LMWH based on their weight. There was no statistically significant difference regarding VTE recurrence risk in the obese and control groups [RR=1.59; 95% CI (0.50 -5.09) p=0.44)]. Interestingly, 31 of 96 obese patients (31%) with BMI 30 or above weighed less than 90 kg. Conclusions: Our findings differ from the available literature. In the CLOT trial, total and major bleeding episodes in the LMWH group occurred in 14% and 7%, respectively, with VTE recurrence of 9%. In comparison, our results demonstrate total and major bleeding episodes in our obese cancer patients on LMWH of 9.8% and 5.9%, respectively, with VTE recurrence of 7.8%. Total bleeding was statistically significant compared to a non-obese cancer population, however, limitations in sample size and event rate need to be taken into consideration when interpreting these results. Disclosures Kovacs: Daiichi Sankyo Pharma: Research Funding; Bayer: Honoraria, Research Funding; LEO Pharma: Honoraria; Pfizer: Honoraria, Research Funding. Lazo-Langner:Bayer: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Research Funding. Louzada:Celgene: Consultancy, Honoraria; Pfizer: Honoraria; Bayer: Honoraria; Janssen: Consultancy, Honoraria.

scholarly journals Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children

Blood ◽  
2020 ◽  
Vol 135 (7) ◽  
pp. 491-504 ◽  
Author(s):  
Leonardo R. Brandão ◽  
Manuela Albisetti ◽  
Jacqueline Halton ◽  
Lisa Bomgaars ◽  
Elizabeth Chalmers ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thromboembolism ◽  
Dabigatran Etexilate ◽  
Standard Of Care ◽  
Central Line ◽  
Clinical Risk Factor ◽  
Postthrombotic Syndrome ◽  
Minor Bleeding ◽  
Bleeding Events ◽  
Open Label

Abstract This open-label, single-arm, prospective cohort trial is the first phase 3 safety study to describe outcomes in children treated with dabigatran etexilate for secondary venous thromboembolism (VTE) prevention. Eligible children aged 12 to &lt;18 years (age stratum 1), 2 to &lt;12 years (stratum 2), and &gt;3 months to &lt;2 years (stratum 3) had an objectively confirmed diagnosis of VTE treated with standard of care (SOC) for ≥3 months, or had completed dabigatran or SOC treatment in the DIVERSITY trial (NCT01895777) and had an unresolved clinical thrombosis risk factor requiring further anticoagulation. Children received dabigatran for up to 12 months, or less if the identified VTE clinical risk factor resolved. Primary end points included VTE recurrence, bleeding events, and mortality at 6 and 12 months. Overall, 203 children received dabigatran, with median exposure being 36.3 weeks (range, 0-57 weeks); 171 of 203 (84.2%) and 32 of 203 (15.8%) took capsules and pellets, respectively. Overall, 2 of 203 children (1.0%) experienced on-treatment VTE recurrence, and 3 of 203 (1.5%) experienced major bleeding events, with 2 (1.0%) reporting clinically relevant nonmajor bleeding events, and 37 (18.2%) minor bleeding events. There were no on-treatment deaths. On-treatment postthrombotic syndrome was reported for 2 of 162 children (1.2%) who had deep vein thrombosis or central-line thrombosis as their most recent VTE. Pharmacokinetic/pharmacodynamic relationships of dabigatran were similar to those in adult VTE patients. In summary, dabigatran showed a favorable safety profile for secondary VTE prevention in children aged from &gt;3 months to &lt;18 years with persistent VTE risk factor(s). This trial was registered at www.clinicaltrials.gov as #NCT02197416.

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