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

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.

Download Full-text

Delayed Pulmonary Embolism Following Achilles Tendon Repair

Orthopaedic Journal of Sports Medicine ◽

10.1177/2325967114s00223 ◽

2014 ◽

Vol 2 (11_suppl3) ◽

pp. 2325967114S0022

Author(s):

İlker Çolak ◽

Engin Eceviz ◽

Özgür Baysal ◽

Halil İbrahim Bekler

Keyword(s):

Emergency Department ◽

Pulmonary Embolism ◽

Venous Thromboembolism ◽

Achilles Tendon ◽

Tendon Rupture ◽

Achilles Tendon Rupture ◽

Factor V Leiden ◽

Heterozygous Mutation ◽

Factor V ◽

Dvt Prophylaxis

Objectives: It is well known that venous thromboembolism is a common complication after lower limb injuries which requires long term immobilization, however venous thromboembolism prophylaxis after achilles tendon rupture is stil controversial. In this report our aim is to present a case of pulmonary embolism which developed 47 days after surgical repair of achilles tendon rupture and diagnosed factor V leiden heterozygous mutation. Methods: Case presentation: A 28 – years- old man was admitted to emergency department with left heel pain and he could not bear weight on it. Achilles tendon rupture was confirmed with physical examination and MRI and patient operated under the spinal anesthesia. Tendon was repaired with the modified Kesler technique. Patient was cast-immobilized and ambulating with crutches and rested for 47 days at home, when he was admitted to emergency department again with acute severe dyspnea, pain on right side, hemoptysis. There was no chronic disease history in in the patient´s anamnesis except migraine diagnosis. There were slight inspiratory rales in right lower lobe in auscultation of respiratuary system examination. Cardiovascular system and abdomen examination were normal. Plasma concentration of D-dimer was 1227 μg/mL in the laboratory evaluations. Patient was diagnosed pulmonary embolus (PE) by ventilation/perfusion lung scan. Result of detailed evaluation, genetic analysis showed that patient has factor V leiden heterozygous mutation. Patient hospitalized in Department of Chest Diseases and low-molecular-weight heparin was used to treat and 5 mg orally Warfarin was used for six months. Results: Conclusion: The incidence of deep venus thrombosis (DVT) and PE after Achilles tendon rupture were highly variable in the literature. This could depend on different designs used in studies. The most recent antihrombotic guidelines suggested no DVT prophylaxis for this type injuries. Existing orthopaedic guidelines does not provide optimal DVT/PE prophylaxis for injuries under the knee requires immobilization. Further research is needed to investigate the benefits of DVT prophylaxis on patients following Achilles tendon rupture.

Download Full-text

Risk Factor Profiles in Patients with Different Clinical Manifestations of Venous Thromboembolism: A Focus on the Factor V Leiden Mutation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650613 ◽

1996 ◽

Vol 76 (04) ◽

pp. 510-513 ◽

Cited By ~ 45

Author(s):

Bert Manten ◽

Rudi G J Westendorp ◽

Ted Koster ◽

Pieter H Reitsma ◽

Frits R Rosendaal

Keyword(s):

Pulmonary Embolism ◽

Deep Vein Thrombosis ◽

Venous Thromboembolism ◽

Clinical Manifestations ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Vein Thrombosis ◽

Increased Risk ◽

Deep Vein

Summary Background. Patients with venous thromboembolic disease may present with different clinical manifestations. Factor V Leiden mutation leading to resistance to activated protein C is associated with a sevenfold increased risk for presenting with deep-vein thrombosis. It is not yet established whether carriers of the mutation have a similarly increased risk for manifesting with pulmonary embolism. Methods. From an Anticoagulation Clinic monitoring coumarin therapy, a consecutive series of patients with a first thromboembolic event (objectively proven by current radiological methods) were enrolled. All patients were interviewed and blood was drawn for geno-typing. From the hospital charts and the personal interview, information was obtained on acquired risk factors and the signs and symptoms on hospital admission. Results. 45 patients presented with symptoms of pulmonary embolism only, 211 had only symptoms of deep-vein thrombosis whereas 23 had clinical features of both. In about half of the patients acquired risk factors for venous thromboembolism were present which did not differ between the three groups of patients. Recent surgery had been performed more often in patients presenting with pulmonary embolism than in other patients (33.3% vs. 18.5%, p <0,05). Factor V Leiden was present in 9% of the patients presenting with pulmonary embolism (relative risk: 3.3 95% Cl: 1.0-10.6) and 17% of the patients presenting with deep-vein thrombosis (relative risk: 6.9 95% Cl: 3.6-12.8). The prevalence of factor V Leiden was intermediate in patients with both clinical characteristics. Conclusion. These data suggest that patients with venous thromboembolism have different clinical presentation depending on the risk factor profile. Factor V Leiden may preferentially lead to manifest deep-vein thrombosis. Differences in structure of venous thrombi could underlie differences in embolic tendency.

Download Full-text

Factor V Leiden Thrombophilia in a Female Collegiate Soccer Athlete: A Case Report

Journal of Athletic Training ◽

10.4085/1062-6050-48.2.21 ◽

2013 ◽

Vol 48 (3) ◽

pp. 431-435 ◽

Cited By ~ 3

Author(s):

Kendra Erickson ◽

Michael E. Powers

Keyword(s):

Emergency Department ◽

Pulmonary Embolism ◽

Venous Thromboembolism ◽

Anticoagulant Therapy ◽

Athletic Trainers ◽

Factor V Leiden ◽

Genetic Mutation ◽

Factor V ◽

Care Providers ◽

Factor V Leiden Mutation

Objective: To raise awareness among health care providers caring for an active population to an uncommon genetic mutation that increases the risk for a potentially fatal venous thromboembolism. Background: A 19-year-old previously healthy female collegiate soccer athlete complained of coughing and progressively decreased exercise tolerance, which were attributed to a recent illness and lack of sleep. Later that evening, she complained of dyspnea and pleuritic pain and was referred to the emergency department. Bilateral pulmonary emboli were identified with computed tomography, and a hypercoagulable panel revealed that the patient was heterozygous for the factor V Leiden mutation. Differential Diagnosis: Pneumonia, pneumothorax, pericarditis, pleuritis, gastroesophageal reflux disease, pulmonary embolism. Treatment: Intravenous heparin therapy was initiated immediately in the emergency department. This was followed by inpatient anticoagulant therapy for 5 days and outpatient anticoagulant therapy for an additional 12 months. During this time, the patient was unable to participate in soccer drills or return to competition and was limited to conditioning activities due to the risk of increased bleeding time. Uniqueness: Documented cases of pulmonary embolism in a young athletic population are rare and are usually associated with genetic risk factors. Factor V Leiden is a relatively uncommon genetic mutation that dramatically increases the risk for venous thromboembolism. Although the fatality rate in this population is low, fatality is preventable if the condition is recognized early and managed properly. Conclusions: Athletes should be encouraged to communicate with their athletic trainers regarding any changes in health status or medication usage. When an athlete presents with nonspecific symptoms such as dyspnea and chest pain, athletic trainers should consider the possibility of pulmonary embolism. A high degree of suspicion results in early diagnosis and treatment and may prevent a fatal event.

Download Full-text

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 ◽

10.1182/blood.v122.21.1136.1136 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1136-1136 ◽

Cited By ~ 3

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.

Download Full-text

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 ◽

10.1182/blood.v122.21.2375.2375 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2375-2375 ◽

Cited By ~ 6

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.

Download Full-text

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

Blood ◽

10.1182/blood.v124.21.4270.4270 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4270-4270 ◽

Cited By ~ 2

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.

Download Full-text

Is the Prevalence of the Factor V Leiden Mutation in Patients with Pulmonary Embolism and Deep Vein Thrombosis Really Different?

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614474 ◽

1999 ◽

Vol 81 (03) ◽

pp. 345-348 ◽

Cited By ~ 22

Author(s):

Rosa Karemaker ◽

Philomeen Kuijer ◽

Martin Prins ◽

Harry Büller ◽

Franktien Turkstra

Keyword(s):

Pulmonary Embolism ◽

Deep Vein Thrombosis ◽

Venous Thromboembolism ◽

Odds Ratio ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Vein Thrombosis ◽

Common Odds Ratio ◽

Deep Vein

Summary Introduction. Previous investigations have suggested a lower prevalence of the factor V Leiden mutation in patients with pulmonary embolism, as compared to patients with deep leg vein thrombosis. Methods. We studied unselected patients with pulmonary embolism, in whom we also assessed the presence of deep vein thrombosis by ultra-sonography. We assessed the prevalence of heterozygosity for the factor V Leiden mutation and compared the outcome of patients with a normal ultrasound (primary pulmonary embolism) to those with an abnormal ultrasound (combined form of venous thromboembolism). Furthermore, we performed a literature search to identify all articles regarding the prevalence of heterozygous factor V Leiden mutation in patients with primary deep vein thrombosis, primary pulmonary embolism and a combined form of venous thromboembolism. We calculated a (common) odds ratio for these 3 manifestations of venous thromboembolism, including the current findings. Results. In 92 patients with proven pulmonary embolism, 25 (27%) had also an abnormal ultrasound. In these patients, the prevalence of the factor V Leiden mutation was 24% (95% CI 9%-45%), whereas the mutation was present in 5 of 67 patients with primary pulmonary embolism (7%; 95% CI 2%-16%). The literature analysis indicated the common odds ratio for the presence of heterozygous factor V Leiden mutation in patients with primary deep vein thrombosis, primary pulmonary embolism and the combined form of venous thromboembolism to be 7.9 (95% CI 5-12), 3.5 (95% CI 2-6) and 6.8 (95% CI 3-14), respectively. Conclusion. In patients with primary pulmonary embolism the prevalence of the factor V Leiden mutation appears to be half of that reported in patients with primary deep vein thrombosis. The mechanism remains unclear.

Download Full-text

Venous Thromboembolism Incidence In The Cooperative Study Of Sickle Cell Disease: The Untold Story

Blood ◽

10.1182/blood.v122.21.2214.2214 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2214-2214

Author(s):

Rakhi P. Naik ◽

Carlton Haywood ◽

Michael B. Streiff ◽

Sophie Lanzkron

Keyword(s):

Venous Thromboembolism ◽

Sickle Cell Disease ◽

Incidence Rate ◽

Sickle Cell ◽

Cumulative Incidence ◽

Research Funding ◽

Factor V Leiden ◽

Factor V ◽

Cooperative Study ◽

Cell Disease

Abstract Background An increased risk of venous thromboembolism (VTE) among individuals with sickle cell disease (SCD) has only recently been recognized. Unlike arterial thrombosis such as stroke which primarily occurs in children with SCD, VTE risk in SCD appears to increase in young adulthood. To date, no studies have described the incidence of VTE in adolescents and adults with SCD. We performed a secondary analysis of the largest prospective cohort of SCD patients, the Cooperative Study of Sickle Cell Disease (CSSCD), to estimate the incidence rate and age-specific cumulative incidence of first VTE among SS/Sβ0 patients aged 15 or older. Methods We used available data from Phase 1 of the CSSCD,1 a multi-institution longitudinal prospective study conducted from 1978-1988, to identify cases of first VTE in patients aged 15 or older at enrollment with SS/Sβ0 genotype. Individuals with a history of prior VTE were excluded. VTE was defined as any pulmonary embolism (PE) or deep venous thrombosis (DVT) identified by ICD-9 code except in the case of pregnancy where VTE events were explicitly collected. Because the definition of acute chest syndrome (ACS) in the CSSCD also included PE and because the ICD-9 code for PE was also used for pulmonary infarct in cases of potential ACS, PE cases that were identified during an admission for ACS were included only if a negative chest X-ray was recorded. The date of VTE was recorded as being the date of the annual visit for any interim VTE or as the date of discharge for any VTE that occurred during a hospitalization. 95% Confidence intervals (CI) for incidence rates were calculated using a Poisson distribution assumption. Kaplan-Meier failure curves were generated to estimate age-specific cumulative incidence. Results A total of 1,133 individuals with SS/Sβ0 aged ≥ 15 years with 6,608 years of follow-up were included for analysis. During this study period, 43 incident VTE events were identified. The median age at VTE was 26.3 years (range 17-47 years) and 25 (58%) were female. The overall incidence rate for VTE was 6.5 events/1000 person-years (CI 4.7, 8.8). The Kaplan-Meier failure curve for VTE is shown below. The cumulative incidence of first VTE was estimated as 9.0% (CI 6.4-12.7) by age 30 and 14.1% (CI 10.2-19.2) by age 40. Conclusions The incidence rate of first VTE among SS/Sβ0 patients aged ≥ 15 years appears to be high, with an estimated cumulative incidence by age 40 that far exceeds that for Factor V Leiden carriers (estimated 6.2% by age 65).2 This study underscores the thrombophilic state of SCD and emphasizes the need for further research into the risk factors for VTE in the SCD population. 1. Gaston M, Rosse WF. The cooperative study of sickle cell disease: review of study design and objectives. Am J Pediatr Hematol Oncol 1982; 4: 197-201. 2. Heit JA, Sobell JL, Li H, Sommer S. The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study. J Throm Haemost 2004; 3: 305-11. This Abstract was prepared using CSSCD Research Materials obtained from the NHLBI via BioLINCC (https://biolincc.nhlbi.nih.gov/). Disclosures: Naik: NHLBI: Research Funding. Haywood:NHLBI: Research Funding. Lanzkron:GlycoMimetics, Inc.: Research Funding.

Download Full-text

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 ◽

10.1182/blood.v122.21.582.582 ◽

2013 ◽

Vol 122 (21) ◽

pp. 582-582 ◽

Cited By ~ 11

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.

Download Full-text