Treatment of Acute VTE with Rivaroxaban - Results of the Prospective Dresden Noac Registry (NCT01588119)

Abstract Background: The effectiveness and safety of acute venous thromboembolism (VTE) treatment with rivaroxaban, demonstrated in phase-III trials, needs to be evaluated in unselected patients treated under daily care conditions. Patients and methods: The Dresden NOAC registry is a prospective regional registry in which patients with oral anticoagulation undergo prospective follow- up (FU). So far, more than 3200 patients have been enrolled, including 772 VTE patients with rivaroxaban treatment. For this analysis, only patients with acute VTE who started rivaroxaban within 14 days after diagnosis of VTE and who were enrolled within these 14 days were evaluated with regard to patient characteristics, treatment persistence and clinical outcomes. All reported outcome events were centrally adjudicated based on source documentation and standard definitions. Results: Between December 1st 2011 and March 31st 2016, 407 patients received rivaroxaban for acute VTE treatment (51.6% female, 80.8% DVT; 19.2% PE±DVT, mean age 61.4 years). Mean time between VTE diagnosis and initiation of rivaroxaban was 1.7±3.3 days (median 0d; 25th/75th percentile 0; 1d). At baseline, rivaroxaban doses consisted of 15 mg BID in 93.1%, 20 mg OD in 3.4%, 15 mg OD in 3.2% and 10 mg OD in 0.2% of patients. Reasons for not using 2x15 mg rivaroxaban BID were pre-treatment with therapeutic parenteral anticoagulants for ≥7 d in 14 cases, comorbidities (e.g. bleeding history, renal impairment) in 4 cases and unknown in 10 cases. During FU (mean 762.4±462.7d), the mean rivaroxaban exposure was 357.7±385.9 days. During treatment with rivaroxaban, 4/407 patients (1.0%) experienced a recurrent VTE, which translated into a recurrence rate of 1.0/ 100 pt. years. During treatment, 172/407 (42.3%) patients reported bleeding complications, which in 13 cases (3.2%; 3.3/100 pt. years) were major bleeding according to ISTH definition, including one fatal intracranial bleeding. Patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) had similar rates of recurrent VTE during rivaroxaban treatment (1.01 and 1.01/100 pt. years) but PE patients had numerically higher rates of major bleeding (3.99/100 pt. years compared to 3.09/100 pt.years in the DVT group). Effectiveness and safety profiles were consistent across relevant subgroups (table 1). 18 patients died during FU (2.12/100 pt.years), of which 8 deaths occurred during or within 3 days after last intake of rivaroxaban. Most common causes of death were fatal cardiovascular event (n=7) and terminal malignant disease (n=4), followed by sepsis/infection (n=3), age related death (n=1), fatal bleeding (n=1) and other reasons (n=2). At 6 months (FU completed in 365 pts.), 61.4% of patients were still taking rivaroxaban. The remaining patients had a scheduled end of treatment (28.8%) or were switched to other anticoagulants (7.1%). Therefore, the rate of unplanned complete discontinuation at 6 months was 2.7%. At 12 months (FU completed in 289 pts.), 41.5% of patients were still taking rivaroxaban. The remaining patients had a scheduled end of treatment (45.0%) or were switched to other anticoagulants (8.3%). Therefore, the rate of unplanned complete discontinuation at 12 months was 5.2%. After rivaroxaban interruption for more than 3 days or permanent discontinuation, 21 patients experienced a recurrent VTE (9 PE±DVT, 12 DVT) with a mean time between last intake of rivaroxaban and VTE recurrence of 351.2±282.6 days (range 7-926d). PE was a common manifestation of VTE recurrence and, despite numerically lower bleeding rates after discontinuation, 2 cases of intracranial haemorrhage occurred (table 2). Conclusions: In unselected patients in daily care, rivaroxaban treatment for acute VTE has high effectiveness and acceptable rates major bleeding. Initial dosing was according to label in over 90% of patients and, at 6 and 12 months, persistence to rivaroxaban therapy was excellent with low rates of unplanned complete discontinuation. Fatal VTE and fatal bleeding are rare events during rivaroxaban therapy and all-cause mortality is mostly related to underlying diseases, age or acute co-morbidities. Treatment discontinuation resulted in a relevant increase in VTE recurrence, of which more than 40% manifested as PE. In contrast, major bleeding rates declined after discontinuation but with 1%/year remained at a clinically relevant level, probably due to co-morbidities. Disclosures Marten: Bayer: Honoraria; Daichii Sankyo: Honoraria. Werth:Pfizer: Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Honoraria; Daiichi Sankyo: Honoraria; OmniaMed: Honoraria; LEO-Pharma: Honoraria. Beyer-Westendorf:Pfizer: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; LEO: Consultancy, Honoraria, Research Funding.

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Acute Treatment Of Pulmonary Embolism With Rivaroxaban - Real Life Data From The Prospective Dresden Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v122.21.2380.2380 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2380-2380

Author(s):

Christina Köhler ◽

Sebastian Werth ◽

Luise Tittl ◽

Jan Beyer-Westendorf

Keyword(s):

Pulmonary Embolism ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Complications ◽

Daily Care ◽

Study Results ◽

Bayer Healthcare ◽

Recurrent Vte ◽

Acute Pe

Abstract Background and Objectives In the EINSTEIN PE study rivaroxaban (RX) was found to be as effective as warfarin in the treatment of acute pulmonary embolism (PE) with superior safety. However, study results need to be confirmed in unselected PE patients in daily care. Patients and Methods Using prospectively collected data from a large regional registry of patients treated with novel direct oral anticoagulants (NOAC) in the district of Saxony, Germany, we evaluated the rate of recurrent VTE, other cardiovascular complications and bleeding events in patients receiving rivaroxaban for acute PE. In this ongoing registry, a network of 239 physicians enrols up to 2500 daily care NOAC patients who receive central prospective follow up (FU) by the registry office at day 30 day and quarterly thereafter to collect efficacy and safety data. All outcome events are centrally adjudicated using standard scientific definitions. Results Until July 31th 2013, 2249 patients were enrolled. Of these, 72 patients received RX for acute PE treatment (demographic data in table 1). Registry patients were older than the EINSTEIN PE population (67.3 vs. 55.8 years), 55.6% were female and 23.6% were treated for a recurrent VTE. During follow-up, unplanned rivaroxaban discontinuation rates were low (around 5%; table 1). So far, only one recurrent VTE event occurred (1.7 events per 100 patient years). One patient experienced non-fatal ischaemic stroke within 4 weeks after PE diagnosis (1.7 events per 100 patient years). Bleeding complications were frequent but only 2 major bleeding (non-fatal vaginal bleeds) occurred (3.3 events per 100 patient years). During follow-up three patients died of underlying diseases but none of these deaths were related to VTE or bleeding complications. Conclusion Acute PE treatment with rivaroxaban in daily care is effective, safe and well tolerated with low rates of unplanned treatment discontinuation. Thromboembolic and major bleeding complications are rare and seem to occur predominantly in the early phase of PE treatment. At ASH, updated results from our registry will be presented Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Pfizer: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Bayer Healthcare: Research Funding, Speakers Bureau.

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Real Life Efficacy and Safety of Dabigatran for Stroke Prevention in Atrial Fibrillation – Final Results of the Prospective Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v124.21.1541.1541 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1541-1541

Author(s):

Franziska Ebertz ◽

Sebastian Werth ◽

Christina Köhler ◽

Franziska Michalski ◽

Ulrike Hänsel ◽

...

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Stroke Prevention ◽

Research Funding ◽

Treatment Discontinuation ◽

Bleeding Complications ◽

Systemic Embolism ◽

Daily Care ◽

Kaplan Meier ◽

Central Registry

Abstract Background: Dabigatran is approved for stroke prevention in atrial fibrillation (SPAF) in many countries. However, little is known about the effectiveness and safety of or the persistence with Dabigatran therapy in unselected patients in daily care. Objectives: To evaluate the effectiveness, safety and discontinuation rates of dabigatran anticoagulation in SPAF in daily care. Patients and methods: The prospective NOAC registry was initiated in November 2011. A network of more than 230 physicians in the district of Saxony, Germany, enroll up to 3000 patients in the registry, which are prospectively followed by the central registry office for up to 36 months. Persistence to dabigatran, rates of stroke/TIA/systemic embolism and of NMCR or major bleeding (ISTH definition) during or within 3 days after last intake of dabigatran were assessed using Kaplan-Meier time-to-first-event analysis. Results: Between November 2011 and February 2013, 341 SPAF patients were enrolled with dabigatran (133 with VKA pre-treatment and 208 newly anticoagulated patients). 158 received dabigatran 150 mg BID and 174 received 110 mg BID. Patients on 110 mg BID were significantly older (78 vs. 71 years), more often had diabetes, a history of stroke, a CHADS2 score ≥ 2 and HAS-BLED scores ≥2 (table 1). In the intention-to-treat analysis, stroke/TIA/systemic embolism occurred at a rate of 2.14/100 pt. years. In the valid-for safety analysis (all events during or within 3 days after last intake of dabigatran) stroke/TIA/systemic embolism occurred at a rate of 1.4/100 pt. years, which was numerically lower for patients receiving 150 compared to 110 mg BID (0.7 vs 2.1/100 pt. years; table 2). Major bleeding occurred at a rate of 1.7/100 pt. years and numerically more often in patients receiving 110 instead of 150 mg BID (2.0 vs 1.3/100 pt. years). Similarly, rates of NMCR bleeding (8.9/100 pt. years) were numerically higher in the 110 mg BI cohort (10.3/100 pt. years) compared to the 150 mg BID cohort (7.0/100 pt. years). Treatment discontinuation occurred in a total of 124 patients during follow up, which in a Kaplan-Meier analysis translated into a discontinuation rate of 23.8/100 pt. years. Documented reasons for treatment discontinuation were side effects (40/124; 32.3%), no longer indicated (13/124; 10.5%), worsening of renal function (12/124; 9.7%), bleeding complications (11/124; 8.9%), costs (4/124; 3.2%), inconvenience (13/124; 10.5%); others (31/124; 25%). Conclusion: In unselected patients in daily care, dabigatran is effective and safe with low rates of cardiovascular or major bleeding events. However, within 12 month, about 24.6% (84/341) of patients are switched to other anticoagulants. Disclosures Werth: Bayer: Honoraria. Köhler:Bayer: Honoraria. Beyer-Westendorf:Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding.

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Pattern and Management Of Bleeding Complications With Novel Oral Anticoagulants – Results Of The Prospective Dresden Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v122.21.214.214 ◽

2013 ◽

Vol 122 (21) ◽

pp. 214-214

Author(s):

Kati Förster ◽

Franziska Ebertz ◽

Vera Gelbricht ◽

Denise Röllig ◽

Luise Tittl ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Major Bleeding ◽

Research Funding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Safety Data ◽

Factor Vii ◽

Bleeding Complications ◽

Daily Care

Abstract Background The most common side effect of oral anticoagulants are bleeding complications. In large trials, novel direct oral anticoagulants (NOAC) have been shown to reduce the risk of major bleeding compared to warfarin. However, little is known about the distribution pattern, management and outcome of NOAC-related bleeding complications in daily care. Patients and methods Using data from a large regional registry of patients treated with novel direct oral anticoagulants (NOAC) in the district of Saxony, Germany, we evaluated pattern and management of NOAC-related bleeding complications in daily care. In this ongoing registry, a network of 239 physicians enrols up to 2500 daily care NOAC patients who receive central prospective follow up (FU) by the registry office at day 30 day and quarterly thereafter to collect efficacy and safety data. All outcome events are centrally adjudicated using standard scientific definitions. Results Until July 31th 2013, 2249 patients were enrolled into the registry. Of these, 1738 (77.3%) patients received rivaroxaban, 356 (15.8%) received dabigatran and 155 (6.9%) received apixaban. During follow-up (2674.0 patient years), a total of 825 patients reported 1137 bleeding complications (59.1% minor, 33.9% non-major, clinically relevant (NMCR) and 6.9% major bleeding according to ISTH definition). For non-major bleedings, mucosal and skin bleeding were the most common bleeding sites (67.9% of all bleedings), followed by genitourinary (10.9%) and gastrointestinal bleeding (10.9%). For major bleeding, gastrointestinal bleeding was the most common manifestation (2.8%), followed by genito-urinary (0.6%) bleeding. In 93% of all bleeding events, treatment was not necessary or consisted of conservative treatment with compression, tamponade or red blood transfusion. Surgical or interventional treatment was reqired in 7.0% of all bleedings (0.0% of minor, 13.0% of NMCR and 38.0% of major bleedings). Prothrombin complex concentrate was used in 1.3% (24% of all major bleedings). No patient received recombinant factor VII. Bleeding-associated mortality was 0.5% for all and 7.5% for major bleeding. Of the six fatal bleedings observed, three were intracranial bleedings. Conclusion Bleeding complications are common in daily care NOAC patients and are usually managed conservatively. Only 7% of all observed bleedings fulfil the ISTH criteria of major bleeding (mainly for RBC transfusion criterion) and are managed using interventions, FFP or PCC. Overall, only few NOAC-associated bleeding complications in daily care are fatal, indicating that available management strategies are sufficient. For presentation at ASH, updated results including risk assessments will be reported. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

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Clinical Outcome of Patients with Venous Thromboembolism and Recent Major Bleeding: Findings from a Prospective Registry (RIETE).

Blood ◽

10.1182/blood.v104.11.708.708 ◽

2004 ◽

Vol 104 (11) ◽

pp. 708-708

Author(s):

Manuel Monreal ◽

José Nieto ◽

Ana de Tuesta ◽

Pablo Marchena ◽

Gregorio Tiberio ◽

...

Keyword(s):

Clinical Trials ◽

Venous Thromboembolism ◽

Clinical Outcome ◽

Clinical Outcomes ◽

Major Bleeding ◽

Bleeding Complications ◽

P Value ◽

Minor Bleeding ◽

Fatal Bleeding ◽

Overall Mortality

Abstract Introduction Patients who have experienced a recent major bleeding episode are usually excluded from clinical trials of venous thromboembolism (VTE) treatment. Therefore, recommendations based on evidence from clinical trials of VTE treatment may not be optimal for these patients. The Registro Informatizado de la Enfermedad TromboEmbólica (RIETE), initiated in March 2001, is a multicenter, observational registry gathering data on VTE treatment practices and clinical outcomes in patients with objectively confirmed, symptomatic, acute VTE. The aim of this analysis was to study outcomes in patients with VTE who had experienced major bleeding <30 days prior to VTE diagnosis. Methods Patients with objectively confirmed symptomatic acute VTE are consecutively enrolled into the RIETE registry. Patients are excluded if they are participating in a therapeutic clinical trial or not available for 3-months follow-up. Patient characteristics, details of antithrombotic therapy, and clinical outcomes at 3-months are recorded. Results Of 6361 patients enrolled up to January 2004, 170 (2.7%) had experienced recent major bleeding prior to VTE diagnosis: 69 (40.6%) gastrointestinal tract; 60 (35.3%) intracranial; 41 (24.1%) other. More patients with recent major bleeding had cancer compared with those without recent major bleeding (26.4% vs 20.4%, respectively; p=0.05). More patients who experienced recent major bleeding had undergone surgery <2 months prior to enrollment or had immobility ≥4 days. The incidences of recurrent PE and minor, major, and fatal bleeding complications were also higher in patients who had experienced recent major bleeding (table 1). Patients with recent major bleeding and cancer had an increased incidence of major bleeding compared to those without cancer (20.0% vs. 2.4%, respectively; OR 10.0; 95% CI 2.3–50.0; p<0.001); 11.0% of patients who had recent major bleeding prior to VTE diagnosis and cancer experienced fatal PE compared with none in patients who had recent major bleeding but without cancer (OR 4.1; 95% CI 4.98–17; p<0.05). Conclusion Patients with VTE and recent major bleeding prior to VTE diagnosis (2.7% of total enrolled patients) had poorer clinical outcomes, in terms of bleeding complications, fatal PE and overall mortality compared with those who had not experienced recent major bleeding. In patients who had recent major bleeding prior to VTE diagnosis, those with cancer had a poorer clinical outcome than those without cancer. Table 1. Clinical outcome of enrolled patients 3-month outcome Recent major bleeding No recent major bleeding OR (95% CI) p value n (%) n=170 n=6191 Fatal bleeding 7 (4.1) 41 (0.6) 6.4 (2.6-15) <0.001 Major bleeding 12 (7.1) 146 (2.3) 3.1 (1.6-5.9) 0.001 Minor bleeding 12 (7.1) 172 (2.8) 2.6 (1.4-5.0) <0.005 Fatal (initial) PE 1 (0.6) 14 (0.2) 2.6 (0.2-19) NS Fatal (recurrent) PE 4 (2.4) 33 (0.5) 4.5 (1.3-14) <0.05 Recurrent VTE 8 (4.7) 184 (2.9) 1.6 (0.7-3.4) NS Overall mortality 25 (15.0) 479 (7.7) 2.1 (1.3-3.2) <0.005

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Real Life Efficacy and Safety of Dabigatran for Stroke Prevention in Atrial Fibrillation – First Results of the Prospective Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v120.21.502.502 ◽

2012 ◽

Vol 120 (21) ◽

pp. 502-502

Author(s):

Vera Gelbricht ◽

Sebastian Werth ◽

Christina Koehler ◽

Ulrike Haensel ◽

Luise Tittl ◽

...

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Cardiovascular Events ◽

Safety Data ◽

Real Life ◽

Bleeding Complications ◽

Efficacy And Safety ◽

Daily Care ◽

Short Period

Abstract Abstract 502 Background: In the RE-LY trial, dabigatran (DB) has been found to be at least as effective and safe as warfarin to prevent stroke in atrial fibrillation (AF), which lead to approval in many countries. However, patients in RCT‘s present a selected population treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of new oral anticoagulants (NOAC) need to be confirmed in unselected patients in daily care. Objectives: To evaluate the efficacy, safety and management issues of dabigatran anticoagulation in AF in daily care. Patients and methods: In the district of Saxony, Germany, a network of 200 physicians from private practice and hospitals enrol patients in the prospective NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. In the registry, up to 2000 patients will receive prospective follow up (FU) by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data. Results: Until July31th 2012, 938 patients were registered. Of these, 201 received DB for AF (table 1). The population in our registry is older than in RELY (74.2 vs. 71.5 years) and has a higher CHADS2-Score (2.7 vs. 2.1). Interestingly, 110 mg BID was the preferred dosage in DB patients (55.7%) despite the fact that these patients had higher CHADS2-scores than patients receiving 150 mg BID (2.3 vs. 2.9). Two third of patients were newly anticoagulated and one third was switched from Vitamin-K antagonists, mainly due to poor INR control or bleeding complications. Results of 30-day-, 3-month and 6-month FU are shown in table 2. Currently, FU data cumulate to 86.8 patient years. During FU, Three patients (1.5%) experienced major cardiovascular events (xyz) and another two patients (1.0%) minor cardiovascular events (syncope). Until now, no deaths occurred. Bleeding complications were frequent (14.9%) but major bleeding was rare (n=3; 1.5%) none of which was fatal. At 3 month, 93% of patients were still taking DB but switch to other anticoagulants increased between 3 and 6 month, mainly due to side effects or incompliance. Conclusion: In unselected patients in daily care, DB is effective and safe with low rates of cardiovascular or major bleeding events. However, within 6 month, about 20% of patients are switched to other anticoagulants. Long-term data will be reported. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Bayer provided a grant to support the NOAC registry in part Other, Honoraria; Boehringer Ingelheim: Boehringer provided a grant to support the NOAC registry in part, Boehringer provided a grant to support the NOAC registry in part Other, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

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Changes Of Coagulation Activation Parameters After Discontinuation Of VTE Treatment With Vitamin-K Antagonists, Apixaban, Rivaroxaban Or Dabigatran and Impact On Clinical Outcome After 12 Months

Blood ◽

10.1182/blood.v122.21.3647.3647 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3647-3647

Author(s):

Sebastian Werth ◽

Christina Köhler ◽

Siegmund Gehrisch ◽

Thoralf Stange ◽

Jan Beyer-Westendorf

Keyword(s):

Vitamin K ◽

Research Funding ◽

Vitamin K Antagonists ◽

Activation Parameters ◽

Coagulation Activation ◽

Predictive Values ◽

Blood Samples ◽

End Of Treatment ◽

Recurrent Vte ◽

D Dimer

Abstract Background At the end of VTE treatment, increasing D-Dimer levels after discontinuation of Vitamin-K antagonists (VKA) have been shown to indicate coagulation activation and increased risk of VTE recurrence. However, it is unknown if changes of coagulation activation parameters will be similar after discontinuation of direct oral anticoagulants (DOAC) such as apixaban, rivaroxaban and dabigatran. Furthermore, the clinical impact of these changes is still unclear. Objectives To quantify changes of coagulation activation parameters at the end of VTE treatment with VKA or DOAC and to evaluate their positive predictive value for VTE recurrence at 12 months. Patients and Methods Blood samples for coagulation tests were collected from consenting patients with proximal VTE who discontinued anticoagulation treatment at the end of apixaban, dabigatran or rivaroxaban phase-III VTE treatment trials. Furthermore, similar samples were obtained from VKA patients at the end of treatment. From all patients, samples for D-dimer (DD), prothrombin fragments (F1+2) and thrombin-antithrombin complexes (TAT) measurements were collected at the end of treatment and 4 weeks later. Samples were analysed by blinded lab personnel and statistically evaluated for differences between VKA and DOAC regarding changes between both samples as well as absolute values at 4 weeks. Finally, all patients underwent 12 months follow-up by phone calls to establish rates of recurrent VTE or death from any cause. Results Blood samples were obtained from patients discontinuing apixaban (A; n=37), dabigatran (D; n=17), rivaroxaban (R; n=9) and VKA (n=184), respectively. Absolute values and relative changes of DD, F1+2 and TAT at baseline and 4 weeks were not significantly different between VKA or the DOAC cohorts. Irrespective of the anticoagulant treatment, DD and F1+2 but not TAT demonstrated a significant increase between baseline and week 4 (figure 1). At 12 months, 18 patients (7.3%) had recurrent VTE and 2 patients (0.8%) were dead. Regarding clinical outcomes at 12 months, the negative predictive values (NPV) of DD, F1+2 and TAT were highest for patients after VKA treatment (at least 0.93) and systematically lower for DOAC patients (ranging between 0.86 and 0.91). In contrast, positive predictive values (PPV) of DD, F1+2 and TAT were systematically higher in DOAC patients (0.19 to 0.43) compared to VKA patients (0.03-0.16) with highest values for TAT-complexes > 200% baseline (PPV VKA 0.14; PPV DOAC 0.43), which was also seen in logistic regression analysis with a significant risk increase for VTE/death (Odds ratio for TAT > 200% baseline 5.0; p=0.006). None of the other parameters showed a correlation to the risk of recurrent VTE or death. Conclusion Changes of DD, F1+2 and TAT values post treatment are not different between patients discontinuing VTE treatment with VKA, apixaban, dabigatran or rivaroxaban. NPV of DD, F1+2 and TAT for recurrent VTE/death are higher in VKA than DOAC patients, while PPV are higher in DOAC patients. At 4 weeks, a TAT increase over 200% of baseline value was found to be associated with a 5-fold increase of recurrent VTE or death with a PPV of 0.14 for VKA patients and of 0.43 for DOAC patients. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

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Two Years Versus Six Months of Oral Anticoagulation after a First Episode of Unprovoked Pulmonary Embolism: The Padis PE Multicenter, Double-Blind, Randomized Trial

Blood ◽

10.1182/blood.v124.21.lba-3.lba-3 ◽

2014 ◽

Vol 124 (21) ◽

pp. LBA-3-LBA-3

Author(s):

Francis Couturaud ◽

Olivier Sanchez ◽

Gilles Pernod ◽

Patrick Mismetti ◽

Patrick Jego ◽

...

Keyword(s):

Pulmonary Embolism ◽

Placebo Group ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Composite Outcome ◽

Advisory Committees ◽

Entire Study ◽

Warfarin Group ◽

Recurrent Vte

Abstract Background: Patients with a first episode of unprovoked pulmonary embolism have a high risk of recurrent venous thromboembolism (VTE) after anticoagulation is discontinued. Prolongation of anticoagulant therapy beyond the initial period of 3 to 6 months is associated with a significant reduction of recurrent VTE, but an excess of bleeding events. In addition, most studies assessing prolonged treatment did not follow the patients after treatment had been stopped. Thus, the optimal duration of anticoagulation in patients with a first unprovoked pulmonary embolism remains uncertain. Method: In a multicenter, randomized, double-blind, controlled trial, we compared an additional 18 months of warfarin (target International Normalized Ratio, 2 to 3) with placebo in patients with a first episode of unprovoked pulmonary embolism that had been initially treated with a vitamin K antagonist for 6 uninterrupted months. In both groups, all patients were followed up for an additional median period of 2 years after treatment had been stopped. Primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Secondary outcomes included the composite outcome during the entire study period (i.e. 18 months plus a median follow-up of 2 years), deaths not caused by pulmonary embolism or major bleeding and the components of the composite outcome during the treatment period and during the entire study period. All outcomes were centrally adjudicated. Results: A total of 371 patients were included in the study and analyzed on an intention-to-treat basis. During the treatment period, the composite outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 patients (13.5%) in the placebo group (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.09-0.55; p=0.0004). Recurrent VTE occurred in 3 (1.7%) patients in the warfarin group and in 25 (13.5%) in the placebo group (HR, 0.11; 95%CI, 0.03-0.37); major bleeding occurred in 4 (2.2%) patients in the warfarin group and in 1 (0.5%) in the placebo group (HR, 4.07; 95%CI, 0.45-36.38). Two deaths not related to the study outcome occurred in each group. During the entire median study period of 41 months, the composite outcome occurred in 33 (20.8%) patients in the warfarin group and in 41 (23.5%) in the placebo group (HR, 0.76; 95%CI, 0.48-1.20; p=0.24) (Figure 1). Recurrent VTE occurred in 28 (17.9%) patients in the warfarin group and in 39 (22.1%) in the placebo group (HR, 0.67; 95%CI, 0.41-1.08); major bleeding occurred in 6 (3.5%) patients in the warfarin group and in 4 (2.5%) in the placebo group (HR, 1.57; 95%CI, 0.44-5.55). Thirteen (11.9%) patients died in the warfarin group, four deaths being related to recurrent VTE and one to major bleeding; six (3.6%) patients died in the placebo group from a cause unrelated to recurrent VTE or bleeding (p=0.08). Of the 67 episodes of recurrent VTE, 52 (77.6%) were pulmonary embolism and 58 (86.6%) were unprovoked. Conclusion: After 6 months of anticoagulation for a first episode of unprovoked pulmonary embolism, extending anticoagulation for an additional 18 months was associated with a major reduction in the risk of recurrent VTE or major bleeding during the treatment period. However, this benefit was not maintained after discontinuation of anticoagulation. (ClinicalTrials.gov number NCT00740883). Figure 1. Cumulative risk of the composite outcome (recurrent VTE or major bleeding) over the entire study period Figure 1. Cumulative risk of the composite outcome (recurrent VTE or major bleeding) over the entire study period Disclosures Couturaud: Astra Zeneka: Co-investigator in clinical trial, Co-investigator in clinical trial Other, Membership on an entity's Board of Directors or advisory committees; Bayer: Co-investigator in clinical trial Other, Membership on an entity's Board of Directors or advisory committees. Sanchez:Bayer: Membership on an entity's Board of Directors or advisory committees. Mismetti:Bayer: Membership on an entity's Board of Directors or advisory committees; pfizer: Membership on an entity's Board of Directors or advisory committees; boerhinger ingelheim: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Jego:Bayer: Membership on an entity's Board of Directors or advisory committees; actelion: Research Funding; GlaxoSmithKline: Research Funding. Parent:Bayer: Membership on an entity's Board of Directors or advisory committees. Lorillon:Astra Zeneka: Membership on an entity's Board of Directors or advisory committees, symposium invitation Other; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Girard:Leo Pharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Lacut:Bayer-Healthcare: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Boehringer Ingelheim: Research Funding. Leroyer:Novartis: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Investigator in COPD clinical trials, Investigator in COPD clinical trials Other, Membership on an entity's Board of Directors or advisory committees; Astra Zeneka: Investigator in asthma clinical trials Other, Membership on an entity's Board of Directors or advisory committees. Decousus:Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Meyer:Sanofi-Aventis: Research Funding; LEO Pharma: Research Funding; Bayer: Research Funding; Boehringer Ingelheim: Research Funding. Mottier:Pfizer: Membership on an entity's Board of Directors or advisory committees; bayer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding.

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Do the Safety and Efficacy Outcomes Reported in the Clinical Trials of Direct Oral Anticoagulants (DOAC) Translate to the Real-World?

Blood ◽

10.1182/blood.v126.23.2335.2335 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2335-2335

Author(s):

Shammim Haji ◽

Jignesh P Patel ◽

Vivian Auyeung ◽

Lara N Roberts ◽

Julia Czuprynska ◽

...

Keyword(s):

Clinical Trials ◽

Major Bleeding ◽

Real World ◽

Research Funding ◽

Oral Anticoagulants ◽

Phase Iii ◽

World Population ◽

Safety And Efficacy ◽

The Real ◽

Pooled Data

Abstract Do the safety and efficacy outcomes reported in the clinical trials of direct oral anticoagulants (DOAC) translate to the 'real-world'? Background: A number of DOACs are now available for clinicians to prescribe in clinical practice. Whilst the results from large clinical trials demonstrate that these agents are as effective as vitamin K antagonists, there is some concern that the patients studied in the trials were not representative of patients, clinicians encounter in everyday practice. The aim of our study was to compare the real-world clinic population commenced on a DOAC to that from the clinical trials for these agents, in order to assess potential differences in safety and efficacy. Patients and methods: A retrospective observational cohort study was undertaken. Patients who were initiated on a DOAC (apixaban, dabigatran and rivaroxaban) at a large teaching hospital in South East London between 1st August 2012 and 31st July 2014 were identified through pharmacy issue data with those followed-up for a minimum of 6 months included. Baseline demographic data, rates of stroke/VTE and rates of major/non-major clinically relevant (NMCR) (ISTH definition) bleeding were assessed and compared to pooled data reported from the corresponding Phase III trials. Differences between groups were compared using t-tests or chi-squared tests. Results: During the review period, 748 patients were initiated on a DOAC, 365 for atrial fibrillation (AF) and 383 for venous thromboembolism (VTE). In terms of demographic differences, the real-world AF population comprised more females, were significantly older, had poorer renal function and a lower body weight. In contrast, the real-world VTE population typically had a higher body weight and poorer renal function, compared to the trial population, (table 1). Efficacy of DOACs was found to be similar across both the VTE and AF populations. With respect to safety, the real-world AF population experienced similar rates of major bleeding and a significantly lower rate of NMCR bleeding compared to the trial populations. In contrast, the real-world VTE population experienced a significantly higher rate of major bleeding, particularly gastrointestinal bleeding. Although the rate of NMCR bleeding was similar, there was a significantly higher rate of urogenital bleeding in the real-world VTE population, specifically heavy menstrual bleeding in women. Conclusions: The efficacy outcomes of DOAC use in a real-world AF and VTE population are consistent with the Phase III trials, despite some significant differences in baseline characteristics. However, a significantly increased rate of major bleeding was observed in the real-world VTE population, which requires further investigation. Table 1. Baseline demographic characteristics, efficacy and safety outcomes in the real-world population versus the trial population Atrial Fibrillation Venous Thromboembolism Trial population+N=28,342 Real-world population Trial population++ Real-world population N=365 N=8,716 N=383 Baseline Demographics, mean (SD) unless otherwise specified Age, years 72 (9.6) 76.8 * (12.1) 56.9 (14.2) 55.6 (18.7) Female (%) 10451 (36.9) 215 * (58.9) 3753 (43.1) 184 (48.0) Weight, kg 82.7 (19.5) 77.3 * (22.6) 84.9 (19.6) 88.2 * (23.0) Creatinine clearance, mL/min 69 (26.7) 58.1 * (26.9) 105.8 (40.7) 91.1 * (37.6) Concomitant aspirin therapy 10341 (36.5) 49 * (13.4) - 0 (0) Previous VKA use (%) 15711 (55.4) 193 (52.9) - 85 (22.2) Efficacy (%) All-cause mortality 1695 (6.0) 37 * (9.1) 160 (1.8) 10 (2.5) Stroke 676 (2.4) 8 (2.0) - 1 (0.3) VTE 39 (0.1) 1 (0.2) 192 (2.2) 7 (1.8) Safety (%) Major Bleeding 1419 (5.0) 17 (4.2) 79 (0.9) 15 * (3.8) Intracranial 170 (0.6) 1 (0.2) 6 (0.1) 2 * (0.5) Gastrointestinal 644 (2.3) 8 (2.0) 8 (0.1) 8 * (2.0) Non-major Clinically relevant (NMCR) bleeding 4824 (17.0) 30 * (7.4) 540 (6.2) 26 (6.6) Gastrointestinal - 9 (2.2) 53 (4.2) 10 (2.5) Urogenital 296 (4.2) 16 (3.9) 100 (2.5) 38 * (9.6) +Pooled data from ARISTOTLE, RE-LY and ROCKET-AF trials ++Pooled data from AMPLIFY, RE-COVER and EINSTEIN-PE/DVT trials *p<0.05 Disclosures Patel: Bayer plc: Research Funding. Auyeung:Bayer PLC: Research Funding. Arya:Bayer plc: Research Funding.

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Subgroup Analysis of Patients with Cancer in Xalia - a Non-Interventional Study of Rivaroxaban in Routine Treatment of Deep Vein Thrombosis

Blood ◽

10.1182/blood.v128.22.1438.1438 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1438-1438 ◽

Cited By ~ 1

Author(s):

Alexander G G Turpie ◽

Lorenzo G Mantovani ◽

Sylvia Haas ◽

Reinhold Kreutz ◽

Danja Monje ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Venous Thromboembolism ◽

Major Bleeding ◽

Research Funding ◽

Incidence Rates ◽

Vein Thrombosis ◽

All Cause Mortality ◽

Recurrent Vte ◽

Deep Vein ◽

Active Cancer

Abstract Background: XALIA is a prospective, non-interventional study of rivaroxaban in the treatment of acute deep vein thrombosis. The overall XALIA results showed that rivaroxaban was associated with similarly low rates of major bleeding and symptomatic recurrent venous thromboembolism (VTE) as standard anticoagulation. A subset of patients in XALIA had active cancer at the time of enrolment into the study. Purpose: To describe the demographics, clinical characteristics, treatment strategies and outcomes of patients in XALIA with cancer and VTE. The primary outcomes were major bleeding, recurrent VTE and all-cause mortality. Methods: Patients with deep vein thrombosis with or without concomitant pulmonary embolism aged ≥18 years who had active cancer and were scheduled to receive ≥3 months of anticoagulation with rivaroxaban or standard therapy were eligible. Therapy type, dose and duration were at the physician's discretion. For the purpose of this substudy, we defined the following treatment cohorts: rivaroxaban cohort (patients treated with rivaroxaban alone or who received heparin/fondaparinux for ≤48 hours before switching to rivaroxaban); early switchers cohort (patients treated with rivaroxaban who received heparin/fondaparinux for >48 hours-14 days and/or a vitamin K antagonist [VKA] for 1-14 days before changing to rivaroxaban); standard anticoagulation cohort (patients treated with heparin/fondaparinux and a VKA or a VKA only); and heparin/fondaparinux cohort (patients treated with heparin/fondaparinux alone). Results: Of 5136 patients in XALIA who received study medication, 587 (11.4%) had active cancer at baseline. Of these, 146 (24.9%) received rivaroxaban, 30 (5.1%) were early switchers, 167 (28.4%) received standard anticoagulation (of which 26 [4.4%] received a VKA only) and 244 (41.6%) received heparin/fondaparinux only, of whom 223 (38.0%) received low molecular weight heparin and the remainder other heparins or fondaparinux. Demographics are shown in Table 1. The most common type of active cancer at baseline in all cohorts was genitourinary, with the exception of the heparin/fondaparinux cohort where gastrointestinal cancer was the most common type (Table 2). The incidence rates for the primary outcomes for each cohort are shown in Figure 1. The rates of major bleeding were highest in the standard anticoagulation cohort (n=8 [4.8%]) and lowest in the early switchers (no major bleeding events occurred). The rates of recurrent VTE were similar in the in the rivaroxaban, early switcher and standard anticoagulation cohorts (n=5 [3.4%], n=1 [3.3%] and n=6 [3.6%], respectively) and were highest in the heparin/fondaparinux cohort (n=12 [4.9%]). All-cause mortality was highest in the heparin/fondaparinux cohort (n=61 [25.0%]) and lowest in the early switchers (no deaths occurred). Conclusions: In the real-world XALIA study, 38.0% of patients with cancer received treatment with low molecular weight heparin, which was in line with guidelines. The remaining patients received rivaroxaban, standard anticoagulation or were early switchers. For the three primary outcomes, the lowest incidence rates were observed in the early switcher cohort. The highest rates were in the standard anticoagulation cohort for major bleeding and the heparin/fondaparinux cohort for recurrent VTE and all-cause mortality; rates for all three primary outcomes were low in the rivaroxaban cohort, suggesting that rivaroxaban may be a safe and effective treatment option for patients with VTE and active cancer. Figure 1 Primary outcomes in patients with active cancer at baseline by treatment group. VTE, venous thromboembolism. Figure 1. Primary outcomes in patients with active cancer at baseline by treatment group. / VTE, venous thromboembolism. Disclosures Turpie: Janssen Research & Development, LLC: Consultancy, Honoraria; Bayer Pharma AG: Consultancy, Honoraria. Mantovani:Janssen-Cilag Ltd: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Sankyo: Consultancy; Bayer Pharma AG: Consultancy; Pfizer Inc: Research Funding. Haas:Sanofi SA: Consultancy; Pfizer Inc: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy; Bayer Pharma AG: Consultancy; Aspen Pharmacare: Consultancy. Kreutz:Bayer Pharma AG: Honoraria; Servier Laboratories Ltd: Consultancy; Lundbeck Ltd: Consultancy; Daiichi Sankyo: Consultancy; Berlin-Chemie Menarini: Consultancy; Bayer Pharma AG: Consultancy; Bristol-Myers Squibb: Honoraria; Daiichi Sankyo: Honoraria. Monje:Bayer Pharma AG: Employment. Schneider:Bayer Pharma AG: Employment. van Eickels:Bayer Pharma AG: Employment. Gebel:Bayer Pharma AG: Employment. Ageno:Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Bayer Pharmaceuticals: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Bayer Pharma AG: Consultancy, Honoraria.

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Major Bleeding Complications Among Patients Treated with Ibrutinib and Concomitant Antiplatelet, Anticoagulant, or Supplemental Therapy

Blood ◽

10.1182/blood.v128.22.4387.4387 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4387-4387 ◽

Cited By ~ 4

Author(s):

Aaron Pavlik ◽

Hallie Barr ◽

Emily Dotson ◽

John C. Byrd ◽

Kristie A. Blum ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Event ◽

Antiplatelet Agents ◽

Bleeding Complications ◽

Bleeding Events ◽

Advisory Committees ◽

Major Bleeding Events

Abstract Background: Ibrutinib, an orally bioavailable small molecular inhibitor of Bruton's tyrosine kinase (BTK), is an approved therapy for chronic lymphocytic leukemia (CLL), relapsed mantle cell lymphoma (MCL) and Waldenstrӧm's macroglobulinemia (WM). Beyond B lymphocytes, BTK signaling is important for collagen-mediated platelet activation, and BTK inhibition has been associated with primary hemostatic bleeding events (Levade et al Blood 2014). Although serious bleeding events have been uncommon (1-5%) in clinical trial populations, there is limited data describing the potential for increased serious bleeding incidence when ibrutinib is co-administered with other agents affecting the clotting cascade or platelet function. Methods: We conducted a retrospective cohort study to evaluate the incidence of major bleeding in patients receiving ibrutinib concomitantly with antiplatelet agents (non-steroidal anti-inflammatory agents, ADP inhibitors), anticoagulants (heparins, warfarin, novel oral anticoagulants), or supplements with potential anticoagulant activity (vitamin E and fish oil). Major bleeding events were identified using criteria developed by the International Society on Thrombosis and Haemostasis (Schulman et al J Thromb Haemost 2005). Patients 18-89 years of age and treated with ibrutinib for CLL, MCL, or WM between March 1, 2010 and March 1, 2015 were included. The primary endpoint of this study was the incidence of major bleeding events, but we also sought to identify risk factors associated with the development of major bleeding, focusing on potential drug interactions. Based on the historic prevalence of major bleeding in ibrutinib clinical studies, we calculated that at least 20 major bleeding events would need to be identified in order to perform blinded multinomial regression on the collected data of an estimated 400 patients. Results: 437 eligible patients were included in the analysis. Patients were overwhelmingly male (71.4%) and white (94.8%), with a mean age of 67.1 years (range: 29-89). 53.1% received ibrutinib as participants of a clinical trial, and the remainder received standard-of-care ibrutinib treatment. The table (upper panel) summarizes use of concomitant antihemostatic agents by presence or absence of major bleeding events. Characteristics of the major bleeding events are further detailed in the lower panel. The most commonly observed concomitant antihemostatic medication was aspirin, with 147 patients (33.6%) being exposed to aspirin within the study period. Fourteen instances of major bleeding were observed, corresponding to an overall incidence of 3.2%. These major bleeding events all occurred in CLL patients receiving ibrutinib at the standard dose of 420 mg daily. Two patients had platelet counts less than 50 k/µL at time of the bleeding event. One-half of the major bleeding events were observed in the absence of an antihemostatic medication, and 2 of the observed major bleeding events resulted in death (1 received concomitant warfarin). Fourteen patients (3.3%) in the group without major bleeding were on anticoagulation, 4 being warfarin. The most common sites of major bleeding were gastrointestinal (50%), intracranial (14.3%) and thoracic (14.3%). While most patients developing major bleeding permanently discontinued ibrutinib (57.1%), approximately one third of the patients who developed major bleeding subsequently resumed ibrutinib following resolution of the bleeding event. Subsequently, these patients did not experience a recurrent major bleeding event. The rate of major bleeding did not meet power to detect statistical differences in bleeding events when comparing concomitant therapy, Conclusions: Our observed incidence of major bleeding is consistent with previous controlled clinical trials, suggesting similar safety profile when ibrutinib is used outside of a controlled setting. Major bleeding events were uncommon despite the frequent co-administration of antiplatelet agents. However, because we modified practice early to avoid therapeutic anticoagulation during ibrutinib therapy whenever possible, the number of patients receiving such drugs in combination was small and precludes inferences regarding safety. Table Table. Disclosures Blum: Pharmacyclics: Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Woyach:Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding. Christian:Pharmacyclics: Research Funding; Janssen: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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