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Mark Crowther - One of the best experts on this subject based on the ideXlab platform.
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rivaroxaban for treatment of suspected or confirmed heparin induced thrombocytopenia study
Journal of Thrombosis and Haemostasis, 2016Co-Authors: Loriann Linkins, Theodore E Warkentin, Sudeep Shivakumar, Menaka Pai, Rizwan A Manji, Philip S Wells, Ishac Nazi, Mark CrowtherAbstract:Essentials Heparin-induced thrombocytopenia (HIT) is a thrombogenic condition that is difficult to treat. We evaluated rivaroxaban as a treatment option in patients with suspected or confirmed HIT. One patient had recurrent thrombosis and 9/10 patients with thrombocytopenia had platelet recovery. Rivaroxaban may be an effective and safe treatment option for HIT. SummaryBackground Rivaroxaban is a direct oral anti-Xa inhibitor that has the potential to greatly simplify treatment of heparin-induced thrombocytopenia (HIT). Objectives To evaluate the efficacy and safety of rivaroxaban in this patient population, we conducted a multicenter, single-arm, prospective cohort study of patients with suspected or confirmed HIT. Patients/Methods Twenty-two consecutive adults with suspected or confirmed HIT received rivaroxaban 15 mg bid until a local HIT assay result was available. Participants with a positive local assay result continued rivaroxaban 15 mg bid until platelet recovery (or until day 21 if they had acute thrombosis at study entry), then stepped down to rivaroxaban 20 mg daily until day 30. Results and Conclusions The primary outcome measure, incidence of new symptomatic, objectively-confirmed venous and Arterial Thromboembolism at 30 days, occurred in one HIT-positive participant (4.5%; 95% confidence interval [CI], 0–23.5%) and one HIT-positive participant required limb amputation despite platelet recovery. Platelet recovery was achieved in nine out of 10 HIT-positive patients with thrombocytopenia. Rivaroxaban appears to be effective for treating patients with confirmed HIT, although the small number of patients enrolled limits precision.
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rivaroxaban for treatment of suspected or confirmed heparin induced thrombocytopenia study
Blood, 2015Co-Authors: Loriann Linkins, Theodore E Warkentin, Sudeep Shivakumar, Menaka Pai, Rizwan A Manji, Philip S Wells, Ishac Nazi, Mark CrowtherAbstract:Rivaroxaban is an ideal potential alternative for treatment of heparin-induced thrombocytopenia because it is administered orally by fixed dosing, requires no routine coagulation monitoring and has been proven effective in the treatment of venous and Arterial Thromboembolism in other settings. The Rivaroxaban for HIT Study prospectively evaluated the efficacy and safety of patients with suspected or confirmed HIT who were treated with rivaroxaban [NCT01598168 - investigator sponsored study funded by Bayer] Methods: Canadian multicenter, single-arm, prospective cohort study of patients with confirmed or suspected HIT (4Ts score ≥4) treated with rivaroxaban 15 mg bid until the diagnosis was supported or refuted using the local HIT assay. Participants with HIT (positive local assay result) received rivaroxaban 15 mg bid until platelet recovery (or until Day 21 if the patient had acute thrombosis; HITT) then stepped down to rivaroxaban 20 mg daily until Day 30. Central testing with the serotonin-release assay (SRA) was performed (not in real-time at all centres). HIT positive was defined as a 4Ts score ≥4 plus serotonin release ≥50%. The primary outcome measure was the incidence of new symptomatic, objectively-confirmed venous and Arterial Thromboembolism in the combined cohort of patients with suspected and confirmed HIT at 30 days. Secondary objectives included incidence of symptomatic Thromboembolism while on treatment with rivaroxaban (combined cohort) and the following outcomes among SRA-positive participants while on treatment with rivaroxaban: incidence of venous and Arterial Thromboembolism, incidence of major bleeding, and time to platelet recovery. Sample size of 200 participants (10 to 30 with SRA-confirmed HIT) was based on feasibility and an anticipated thrombotic event rate in the study population (combined cohort) of 6.5% at 30 days (5% in HIT negative; 11% in HIT positive while on rivaroxaban). Results: 22 participants (12 HIT positive) were enrolled between January 2013 and July 2015. The study was terminated early due to poor recruitment, but after enrolling the minimum expected number of HIT positive participants. Of the 12 HIT positive participants (SRA, mean release 95%), 3(25%) had HITT at time of study entry and 6 had received at least one dose of fondaparinux prior to study enrolment. Half of the HIT positive participants were enrolled in study after the SRA result had already been reported as positive. After 371 days of exposure to rivaroxaban (combined cohort), 1 HIT positive participant had possible symptomatic recurrent VTE (4.5%, 95% CI: 0 to 23.5%), 1 HIT positive participant had major bleeding (9 days after rivaroxaban was held) and there were 4 deaths (cancer 2, sepsis 1, end-stage COPD 1). The single episode of possible recurrent VTE was extension of previously documented apheresis catheter-related arm DVT in a HIT positive participant who presented on Day 7 with worsening arm pain. A repeat ultrasound showed extension of DVT; however a baseline scan had not been performed at time of study entry. Interestingly, the same participant failed treatment with fondaparinux prior to study enrolment (development of erythematous plaques at injection sites and failure of platelets to rise). His apheresis catheter was removed on Day 8, rivaroxaban was continued and complete resolution of his symptoms as well as platelet recovery was achieved. One HIT positive participant presented with evidence of bilateral lower limb Arterial ischemia (HIT-related acute Arterial thrombosis on documented chronic peripheral vascular disease) at the time of study enrolment. Despite achieving platelet recovery, he underwent bilateral below knee amputation on Day 16. Out of the 12 HIT positive participants, 11 achieved platelet recovery with mean time to recovery 9 days. The single participant who did not achieve platelet recovery received only 2 doses of rivaroxaban before it was held due to a transient rise in liver enzymes. Rivaroxaban was never restarted because he bled while receiving fondaparinux as an alternative. Conclusions: Rivaroxaban appears to be effective for treating patients with confirmed HIT, although lack of a comparator and a small sample size are limitations of our findings. The advantages of rivaroxaban over other agents currently used to treat HIT such as ease of administration, lack of routine coagulation monitoring and low cost make it an attractive option. Disclosures Linkins:Pfizer: Honoraria; Bayer: Honoraria, Research Funding. Off Label Use: rivaroxaban has not been approved for treatment of heparin-induced thrombocytopenia. Warkentin:W.L. Gore: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Honoraria; Pfizer: Consultancy. Pai:Bayer: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS-Pfizer: Membership on an entity9s Board of Directors or advisory committees; Sanofi: Membership on an entity9s Board of Directors or advisory committees. Shivakumar:Bayer: Honoraria. Wells:Bayer: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS-Pfizer: Research Funding. Wu:Pfizer Canada: Membership on an entity9s Board of Directors or advisory committees; Leopharma: Membership on an entity9s Board of Directors or advisory committees.
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acute management of bleeding in patients on novel oral anticoagulants
European Heart Journal, 2013Co-Authors: Deborah M Siegal, Mark CrowtherAbstract:Novel oral anticoagulants that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are currently available for prevention of venous Thromboembolism (VTE) after orthopaedic surgery, treatment of acute VTE, and prevention of Arterial Thromboembolism in non-valvular atrial fibrillation. These agents offer advantages over VKAs, including rapid onset, shorter half-lives, fewer drug interactions, and lack of need for routine monitoring. However, there are no established agents to reverse their anticoagulant effect. We review the risk of bleeding with the novel oral anticoagulants and the limitations of conventional coagulation assays for measuring anticoagulant effect. We provide an approach to the management of patients with bleeding complications with evidence for various interventions for reversal, where available.
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combined aspirin oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease a meta analysis of randomized trials
JAMA Internal Medicine, 2007Co-Authors: Francesco Dentali, James D Douketis, Wendy Lim, Mark CrowtherAbstract:Background For patients receiving oral anticoagulant (OAC) therapy, deciding whether to add aspirin to their treatment is a common clinical scenario with no clear guidelines to aid practice. We performed a systematic review and meta-analysis of randomized controlled trials comparing these 2 treatment strategies (combined aspirin-OAC therapy vs OAC therapy alone) to assess the therapeutic benefits and risks. Data Sources Randomized controlled trials published up to June 2005 in MEDLINE, EMBASE, and Cochrane Library databases. Study Selection Randomized controlled trials with at least 3 months of follow-up that compared aspirin-OAC therapy with OAC therapy alone, in which OAC was administered to achieve the same target international normalized ratio or was given at the same fixed dose in both treatment arms. Data Extraction Two reviewers independently extracted data on study characteristics and outcomes. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated for study outcomes in patients receiving aspirin-OAC therapy and OAC therapy alone. Data Synthesis Ten studies were included, totaling 4180 patients. The risk for Arterial Thromboembolism was lower in patients receiving combined aspirin-OAC therapy compared with OAC therapy alone (OR, 0.66; 95% CI, 0.52-0.84). However, these benefits were limited to patients with a mechanical heart valve (OR, 0.27; 95% CI, 0.15-0.49). There was no difference in the risk for Arterial Thromboembolism with these treatments in patients with atrial fibrillation (OR, 0.99; 95% CI, 0.47-2.07) or coronary artery disease (OR, 0.69; 95% CI, 0.35-1.36). There was no difference in all-cause mortality with either treatment (OR, 0.98; 95% CI, 0.77-1.25). The risk for major bleeding was higher in patients receiving aspirin-OAC therapy compared with OAC therapy alone (OR, 1.43; 95% CI, 1.00-2.02). Conclusion Our findings question the current practice of using combined aspirin-OAC therapy except in patients with a mechanical heart valve, given the questionable benefits in reducing thromboembolic events and the increased risk of major bleeding.
James D Douketis - One of the best experts on this subject based on the ideXlab platform.
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effect of direct oral anticoagulant patient and surgery characteristics on clinical outcomes in the perioperative anticoagulation use for surgery evaluation study
TH open : companion journal to thrombosis and haemostasis, 2020Co-Authors: Kira Macdougall, James D Douketis, Joanne Duncan, Alfonso Tafur, Nathan P Clark, Julien Dastous, Sam Schulman, Alex C SpyropoulosAbstract:Introduction The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) Study assessed a standardized perioperative management strategy in patients with atrial fibrillation who were taking a direct oral anticoagulant (DOAC) and required an elective surgery or procedure. The aim of this substudy is to analyze the safety of this management strategy across different patient subgroups, according to four presurgical variables: (1) DOAC type and dose, (2) surgery/procedure bleed risk, (3) patient renal function, and (4) age. Methods Clinical outcomes analyzed included major bleeding (MB), Arterial Thromboembolism, any bleeding, and any Thromboembolism. We used descriptive statistics to summarize clinical outcomes, where the frequency, proportion, and 95% confidence interval were reported. Fisher's exact tests were used for testing the null hypothesis of independence between the clinical outcome and patient characteristic, where the test p-values were reported. Results There were 3,007 patients with atrial fibrillation requiring perioperative DOAC management. There was no significant difference in bleeding or thromboembolic outcomes according to DOAC type/dose regimen, renal function, or patient age. The rate of MB was significantly higher with high bleed risk procedures than low bleed risk procedures in apixaban-treated patients (2.9 vs. 0.59%; p Conclusion Our results suggest that in DOAC-treated patients who received standardized perioperative management, surgical bleed risk is an important determinant of bleeding but not thromboembolic outcomes, although this finding was not consistent across all DOACs. There were no differences in bleeding and Thromboembolism according to DOAC type and dose, renal function, or age.
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perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant
JAMA Internal Medicine, 2019Co-Authors: James D Douketis, Alex C Spyropoulos, Joanne Duncan, Marc Carrier, Gregoire Le Gal, Alfonso Tafur, Thomas Vanassche, Peter Verhamme, Sudeep Shivakumar, Peter L GrossAbstract:Importance Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. Objective To investigate the safety of a standardized perioperative DOAC management strategy. Design, Setting, and Participants The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. Interventions A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low–bleeding-risk procedure and 2 days before a high–bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low–bleeding-risk procedure and 2 to 3 days after a high–bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. Main Outcomes and Measures Major bleeding and Arterial Thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level ( Results The 3007 patients with AF (mean [SD] age of 72.5 [9.39] years; 1988 men [66.1%]) comprised 1257 (41.8%) in the apixaban cohort, 668 (22.2%) in the dabigatran cohort, and 1082 (36.0%) in the rivaroxaban cohort; 1007 patients (33.5%) had a high–bleeding-risk procedure. The 30-day postoperative rate of major bleeding was 1.35% (95% CI, 0%-2.00%) in the apixaban cohort, 0.90% (95% CI, 0%-1.73%) in the dabigatran cohort, and 1.85% (95% CI, 0%-2.65%) in the rivaroxaban cohort. The rate of Arterial Thromboembolism was 0.16% (95% CI, 0%-0.48%) in the apixaban cohort, 0.60% (95% CI, 0%-1.33%) in the dabigatran cohort, and 0.37% (95% CI, 0%-0.82%) in the rivaroxaban cohort. In patients with a high–bleeding-risk procedure, the rates of major bleeding were 2.96% (95% CI, 0%-4.68%) in the apixaban cohort and 2.95% (95% CI, 0%-4.76%) in the rivaroxaban cohort. Conclusions and Relevance In this study, patients with AF who had DOAC therapy interruption for elective surgery or procedure, a perioperative management strategy without heparin bridging or coagulation function testing was associated with low rates of major bleeding and Arterial Thromboembolism.
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perioperative bridging anticoagulation in patients with atrial fibrillation
The New England Journal of Medicine, 2015Co-Authors: James D Douketis, Alex C Spyropoulos, Scott Kaatz, Richard C Becker, Joseph A Caprini, Andrew Dunn, David A Garcia, Alan M Jacobson, Amir K Jaffer, David F KongAbstract:BACKGROUND It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecularweight heparin for the prevention of perioperative Arterial Thromboembolism and would be superior to bridging with respect to major bleeding. METHODS We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were Arterial Thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding. RESULTS In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of Arterial Thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], −0.6 to 0.8; P = 0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P = 0.005 for superiority). CONCLUSIONS In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of Arterial Thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.)
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combined aspirin oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease a meta analysis of randomized trials
JAMA Internal Medicine, 2007Co-Authors: Francesco Dentali, James D Douketis, Wendy Lim, Mark CrowtherAbstract:Background For patients receiving oral anticoagulant (OAC) therapy, deciding whether to add aspirin to their treatment is a common clinical scenario with no clear guidelines to aid practice. We performed a systematic review and meta-analysis of randomized controlled trials comparing these 2 treatment strategies (combined aspirin-OAC therapy vs OAC therapy alone) to assess the therapeutic benefits and risks. Data Sources Randomized controlled trials published up to June 2005 in MEDLINE, EMBASE, and Cochrane Library databases. Study Selection Randomized controlled trials with at least 3 months of follow-up that compared aspirin-OAC therapy with OAC therapy alone, in which OAC was administered to achieve the same target international normalized ratio or was given at the same fixed dose in both treatment arms. Data Extraction Two reviewers independently extracted data on study characteristics and outcomes. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated for study outcomes in patients receiving aspirin-OAC therapy and OAC therapy alone. Data Synthesis Ten studies were included, totaling 4180 patients. The risk for Arterial Thromboembolism was lower in patients receiving combined aspirin-OAC therapy compared with OAC therapy alone (OR, 0.66; 95% CI, 0.52-0.84). However, these benefits were limited to patients with a mechanical heart valve (OR, 0.27; 95% CI, 0.15-0.49). There was no difference in the risk for Arterial Thromboembolism with these treatments in patients with atrial fibrillation (OR, 0.99; 95% CI, 0.47-2.07) or coronary artery disease (OR, 0.69; 95% CI, 0.35-1.36). There was no difference in all-cause mortality with either treatment (OR, 0.98; 95% CI, 0.77-1.25). The risk for major bleeding was higher in patients receiving aspirin-OAC therapy compared with OAC therapy alone (OR, 1.43; 95% CI, 1.00-2.02). Conclusion Our findings question the current practice of using combined aspirin-OAC therapy except in patients with a mechanical heart valve, given the questionable benefits in reducing thromboembolic events and the increased risk of major bleeding.
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Low-Molecular-Weight Heparin as Bridging Anticoagulation During Interruption of Warfarin Assessment of a Standardized Periprocedural Anticoagulation Regimen
JAMA Internal Medicine, 2004Co-Authors: James D Douketis, Judith Johnson, Alexander G G TurpieAbstract:Background:Thetreatmentofpatientsatincreasedrisk forArterialThromboembolismwhorequiretemporaryinterruptionofwarfarinsodiumtherapyisacommonclinical problem. We investigated the efficacy and safety of a standardizedperiproceduralanticoagulationregimenwith low-molecular-weight heparin. Methods: We studied 650 consecutive patients with a mechanical heart valve, chronic atrial fibrillation, or embolicstrokewhorequiredinterruptionofwarfarintherapy because of an invasive procedure. Warfarin was stopped 5 or 6 days before the procedure, and patients received subcutaneous dalteparin sodium, 100 IU/kg twice daily, starting 3 days before the procedure. The risk of postprocedural bleeding determined postprocedural anticoagulant management. In patients undergoing a non– high-bleeding-risk procedure who had adequate postproceduralhemostasis,warfarinwasresumedonthe evening of the procedure, and dalteparin sodium, 100 IU/kg twice daily, was resumed on the next day and continued until the international normalized ratio was 2.0 or more. If postprocedural hemostasis was not secured, theresumptionofdalteparinwasdelayed.Inpatientsundergoing a high-bleeding-risk procedure, warfarin was resumed on the evening of the procedure, but dalteparin was not given after the procedure. Results: Patients were followed up during the preproceduralandpostproceduralperiodforameanof13.8days (range, 10-18 days). In 542 patients who underwent a non–high-bleeding-risk procedure, there were 2 thromboembolic events (0.4%), 4 major bleeding episodes (0.7%),and32episodesofincreasedwound-relatedblood loss that precluded postprocedural dalteparin administration (5.9%). In 108 patients who underwent a highbleeding-riskprocedure,therewere2deaths(1.8%)possibly due to Thromboembolism and 2 major bleeding episodes (1.8%). Conclusions: In patients at increased risk for Arterial Thromboembolism who require temporary interruption of warfarin therapy, a standardized periprocedural anticoagulant regimen with low-molecular-weight heparin is associated with a low risk of thromboembolic and major bleeding complications.
Klaas Heinemann - One of the best experts on this subject based on the ideXlab platform.
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cardiovascular and general safety of a 24 day regimen of drospirenone containing combined oral contraceptives final results from the international active surveillance study of women taking oral contraceptives
Contraception, 2014Co-Authors: Jurgen Dinger, Kristina Bardenheuer, Klaas HeinemannAbstract:Abstract Objectives The “International Active Surveillance Study of Women Taking Oral Contraceptives” investigated the risks of short- and long-term use of an extended 24-day regimen of drospirenone and ethinylestradiol (DRSP 24d ) compared to established oral contraceptives (OCs) in a routine clinical setting. Study Design Prospective, controlled, noninterventional cohort study conducted in the United States and six European countries with three main cohorts: new users of DRSP 24d , DRSP 21d (21-day regimens of DRSP-containing OCs), and non-DRSP (OCs without DRSP). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular venous Thromboembolism (VTE). Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Primary statistical variable was the VTE hazard ratio (HR) for DRSP 24d vs. non-DRSP. Results A total of 2285 study centers enrolled 85,109 women. Study participants were followed for 2 to 6 years, which generated 206,296 woman-years (WY) of observation. A low loss to follow-up of 3.3% was achieved. DRSP 24d , DRSP 21d , non-DRSP and levonorgestrel-containing OCs (LNG) showed similar incidence rates of venous and Arterial Thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events. VTE incidence rates for DRSP 24d , DRSP 21d , non-DRSP and LNG were 7.2, 9.4, 9.6 and 9.8 VTE/10,000 WY, respectively. Adjusted HRs for DRSP 24d vs. non-DRSP and DRSP 24d vs. LNG were 0.8 [95% confidence interval (CI), 0.5–1.3] and 0.8 (95% CI, 0.4–1.5). Conclusion DRSP 24d , DRSP 21d , non-DRSP and LNG use was associated with similar risks of serious adverse events, and particularly VTE, during routine clinical use. Implication Statement The 24-day regimen of drospirenone-containing combined OCs is associated with similar risks of venous and Arterial Thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events compared to 21-day regimens of drospirenone-containing combined OCs, OCs without drospirenone and LNGs.
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cardiovascular risk associated with the use of an etonogestrel containing vaginal ring
Obstetrics & Gynecology, 2013Co-Authors: Jurgen Dinger, Sabine Mohner, Klaas HeinemannAbstract:OBJECTIVE: To compare the risks of short-term and long-term use of an etonogestrel-containing and ethinylestradiol-containing vaginal ring and combined oral contraceptive pills (OCPs) in a routine clinical study population. METHODS: This was a prospective, controlled, noninterventional cohort study performed in the United States and five European countries with the following two cohorts: new users of the vaginal ring and new users of combined OCPs (starters, switchers, or restarters). The study population included 33,295 users of the vaginal ring or combined OCPs recruited by 1,661 study centers. Follow-up of study participants occurred for 2 to 4 years. Main clinical outcomes of interest were cardiovascular outcomes, particularly venous and Arterial Thromboembolism. These outcomes were validated by attending physicians and further adjudicated by an independent board. Comprehensive follow-up ensured low loss to follow-up. Statistical analyses were based on Cox regression models. Primary statistical variable was the venous thromboembolic hazard ratio (HR) for the vaginal ring compared with combined OCPs. RESULTS: Study participants were followed-up for 66,489 woman-years. Loss to follow-up was 2.9%. The venous Thromboembolism incidence rates for the vaginal ring users and combined OCPs users were 8.3 and 9.2 per 10,000 woman-years, respectively. Cox regression analysis yielded crude and adjusted HRs for the vaginal ring users compared with combined OCPs users of 0.9 and 0.8 for venous Thromboembolism (95% confidence intervals [CIs] 0.5–1.6 and 0.5–1.5) and 0.8 and 0.7 (95% CIs 0.2–2.5 and 0.2–2.3) for Arterial Thromboembolism, respectively. CONCLUSION: Vaginal ring use and combined OCP use were associated with a similar venous and Arterial thromboembolic risk during routine clinical use.
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cardiovascular risk associated with the use of an etonogestrel containing vaginal ring
Obstetrics & Gynecology, 2013Co-Authors: Jurgen Dinger, Sabine Mohner, Klaas HeinemannAbstract:OBJECTIVE: To compare the risks of short-term and long-term use of an etonogestrel-containing and ethinylestradiol-containing vaginal ring and combined oral contraceptive pills (OCPs) in a routine clinical study population. METHODS: This was a prospective, controlled, noninterventional cohort study performed in the United States and five European countries with the following two cohorts: new users of the vaginal ring and new users of combined OCPs (starters, switchers, or restarters). The study population included 33,295 users of the vaginal ring or combined OCPs recruited by 1,661 study centers. Follow-up of study participants occurred for 2 to 4 years. Main clinical outcomes of interest were cardiovascular outcomes, particularly venous and Arterial Thromboembolism. These outcomes were validated by attending physicians and further adjudicated by an independent board. Comprehensive follow-up ensured low loss to follow-up. Statistical analyses were based on Cox regression models. Primary statistical variable was the venous thromboembolic hazard ratio (HR) for the vaginal ring compared with combined OCPs. RESULTS: Study participants were followed-up for 66,489 woman-years. Loss to follow-up was 2.9%. The venous Thromboembolism incidence rates for the vaginal ring users and combined OCPs users were 8.3 and 9.2 per 10,000 woman-years, respectively. Cox regression analysis yielded crude and adjusted HRs for the vaginal ring users compared with combined OCPs users of 0.9 and 0.8 for venous Thromboembolism (95% confidence intervals [CIs] 0.5–1.6 and 0.5–1.5) and 0.8 and 0.7 (95% CIs 0.2–2.5 and 0.2–2.3) for Arterial Thromboembolism, respectively. CONCLUSION: Vaginal ring use and combined OCP use were associated with a similar venous and Arterial thromboembolic risk during routine clinical use.
Jurgen Dinger - One of the best experts on this subject based on the ideXlab platform.
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cardiovascular and general safety of a 24 day regimen of drospirenone containing combined oral contraceptives final results from the international active surveillance study of women taking oral contraceptives
Contraception, 2014Co-Authors: Jurgen Dinger, Kristina Bardenheuer, Klaas HeinemannAbstract:Abstract Objectives The “International Active Surveillance Study of Women Taking Oral Contraceptives” investigated the risks of short- and long-term use of an extended 24-day regimen of drospirenone and ethinylestradiol (DRSP 24d ) compared to established oral contraceptives (OCs) in a routine clinical setting. Study Design Prospective, controlled, noninterventional cohort study conducted in the United States and six European countries with three main cohorts: new users of DRSP 24d , DRSP 21d (21-day regimens of DRSP-containing OCs), and non-DRSP (OCs without DRSP). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular venous Thromboembolism (VTE). Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Primary statistical variable was the VTE hazard ratio (HR) for DRSP 24d vs. non-DRSP. Results A total of 2285 study centers enrolled 85,109 women. Study participants were followed for 2 to 6 years, which generated 206,296 woman-years (WY) of observation. A low loss to follow-up of 3.3% was achieved. DRSP 24d , DRSP 21d , non-DRSP and levonorgestrel-containing OCs (LNG) showed similar incidence rates of venous and Arterial Thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events. VTE incidence rates for DRSP 24d , DRSP 21d , non-DRSP and LNG were 7.2, 9.4, 9.6 and 9.8 VTE/10,000 WY, respectively. Adjusted HRs for DRSP 24d vs. non-DRSP and DRSP 24d vs. LNG were 0.8 [95% confidence interval (CI), 0.5–1.3] and 0.8 (95% CI, 0.4–1.5). Conclusion DRSP 24d , DRSP 21d , non-DRSP and LNG use was associated with similar risks of serious adverse events, and particularly VTE, during routine clinical use. Implication Statement The 24-day regimen of drospirenone-containing combined OCs is associated with similar risks of venous and Arterial Thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events compared to 21-day regimens of drospirenone-containing combined OCs, OCs without drospirenone and LNGs.
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cardiovascular risk associated with the use of an etonogestrel containing vaginal ring
Obstetrics & Gynecology, 2013Co-Authors: Jurgen Dinger, Sabine Mohner, Klaas HeinemannAbstract:OBJECTIVE: To compare the risks of short-term and long-term use of an etonogestrel-containing and ethinylestradiol-containing vaginal ring and combined oral contraceptive pills (OCPs) in a routine clinical study population. METHODS: This was a prospective, controlled, noninterventional cohort study performed in the United States and five European countries with the following two cohorts: new users of the vaginal ring and new users of combined OCPs (starters, switchers, or restarters). The study population included 33,295 users of the vaginal ring or combined OCPs recruited by 1,661 study centers. Follow-up of study participants occurred for 2 to 4 years. Main clinical outcomes of interest were cardiovascular outcomes, particularly venous and Arterial Thromboembolism. These outcomes were validated by attending physicians and further adjudicated by an independent board. Comprehensive follow-up ensured low loss to follow-up. Statistical analyses were based on Cox regression models. Primary statistical variable was the venous thromboembolic hazard ratio (HR) for the vaginal ring compared with combined OCPs. RESULTS: Study participants were followed-up for 66,489 woman-years. Loss to follow-up was 2.9%. The venous Thromboembolism incidence rates for the vaginal ring users and combined OCPs users were 8.3 and 9.2 per 10,000 woman-years, respectively. Cox regression analysis yielded crude and adjusted HRs for the vaginal ring users compared with combined OCPs users of 0.9 and 0.8 for venous Thromboembolism (95% confidence intervals [CIs] 0.5–1.6 and 0.5–1.5) and 0.8 and 0.7 (95% CIs 0.2–2.5 and 0.2–2.3) for Arterial Thromboembolism, respectively. CONCLUSION: Vaginal ring use and combined OCP use were associated with a similar venous and Arterial thromboembolic risk during routine clinical use.
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cardiovascular risk associated with the use of an etonogestrel containing vaginal ring
Obstetrics & Gynecology, 2013Co-Authors: Jurgen Dinger, Sabine Mohner, Klaas HeinemannAbstract:OBJECTIVE: To compare the risks of short-term and long-term use of an etonogestrel-containing and ethinylestradiol-containing vaginal ring and combined oral contraceptive pills (OCPs) in a routine clinical study population. METHODS: This was a prospective, controlled, noninterventional cohort study performed in the United States and five European countries with the following two cohorts: new users of the vaginal ring and new users of combined OCPs (starters, switchers, or restarters). The study population included 33,295 users of the vaginal ring or combined OCPs recruited by 1,661 study centers. Follow-up of study participants occurred for 2 to 4 years. Main clinical outcomes of interest were cardiovascular outcomes, particularly venous and Arterial Thromboembolism. These outcomes were validated by attending physicians and further adjudicated by an independent board. Comprehensive follow-up ensured low loss to follow-up. Statistical analyses were based on Cox regression models. Primary statistical variable was the venous thromboembolic hazard ratio (HR) for the vaginal ring compared with combined OCPs. RESULTS: Study participants were followed-up for 66,489 woman-years. Loss to follow-up was 2.9%. The venous Thromboembolism incidence rates for the vaginal ring users and combined OCPs users were 8.3 and 9.2 per 10,000 woman-years, respectively. Cox regression analysis yielded crude and adjusted HRs for the vaginal ring users compared with combined OCPs users of 0.9 and 0.8 for venous Thromboembolism (95% confidence intervals [CIs] 0.5–1.6 and 0.5–1.5) and 0.8 and 0.7 (95% CIs 0.2–2.5 and 0.2–2.3) for Arterial Thromboembolism, respectively. CONCLUSION: Vaginal ring use and combined OCP use were associated with a similar venous and Arterial thromboembolic risk during routine clinical use.
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the safety of a drospirenone containing oral contraceptive final results from the european active surveillance study on oral contraceptives based on 142 475 women years of observation
Contraception, 2007Co-Authors: Jurgen Dinger, Lothar A J Heinemann, Dorthe KuhlhabichAbstract:Abstract Objectives The study was conducted to compare risks of adverse cardiovascular and other events associated with the use of drospirenone (DRSP)-containing oral contraceptives (OCs) and other OCs. Methods and Materials The European Active Surveillance study (EURAS) was a multinational, prospective, noninterventional cohort study of new users of DRSP, levonorgestrel (LNG) and other progestin-containing OCs. Semiannual follow-up was based on mailed questionnaires, with additional follow-up procedures when needed. Results Overall, 58,674 women were followed for 142,475 women-years of observation. Loss to follow-up was 2.4%. Serious adverse and fatal events were rare, and rate ratios were close to unity (1.0). Cox regression analysis of cardiovascular outcomes yielded hazard ratios for DRSP-containing vs. LNG-containing and other OCs of 1.0 and 0.8 (upper 95% confidence limits, 1.8 and 1.3) for venous, and 0.3 and 0.3 (upper 95% confidence limits, 1.2 and 1.5) for Arterial Thromboembolism, respectively. Conclusions Risks of adverse cardiovascular and other serious events in users of a DRSP-containing OC are similar to those associated with the use of other OCs.
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reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized placebo controlled crossover study in healthy subjects
Circulation, 2011Co-Authors: Elise S Eerenberg, Pieter Willem Kamphuisen, Meertien K Sijpkens, Joost C M Meijers, Harry R Buller, Marcel LeviAbstract:Background— Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and Arterial Thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results— In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2 ½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus 12.3±0.7 seconds at baseline; P P P =0.002) and normalized with PCC (114±26%; P Conclusion— Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study. Clinical Trial Registration— URL: www.trialregister.nl. Unique identifier: NTR2272.
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reversal of rivaroxaban and dabigatran by prothrombin complex concentrate
Circulation, 2011Co-Authors: Elise S Eerenberg, Pieter Willem Kamphuisen, Meertien K Sijpkens, Joost C M Meijers, Harry R Buller, Marcel LeviAbstract:Background—Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and Arterial Thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results—In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus...
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reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized placebo controlled crossover study in healthy subjects
Circulation, 2011Co-Authors: Elise S Eerenberg, Pieter Willem Kamphuisen, Meertien K Sijpkens, Joost C M Meijers, Harry R Buller, Marcel LeviAbstract:Background—Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin, respectively. Clinical studies on the prevention and treatment of venous and Arterial Thromboembolism show promising results. A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation. This study evaluated the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of these drugs. Methods and Results—In a randomized, double-blind, placebo-controlled study, 12 healthy male volunteers received rivaroxaban 20 mg twice daily (n=6) or dabigatran 150 mg twice daily (n=6) for 2½ days, followed by either a single bolus of 50 IU/kg PCC (Cofact) or a similar volume of saline. After a washout period, this procedure was repeated with the other anticoagulant treatment. Rivaroxaban induced a significant prolongation of the prothrombin time (15.8±1.3 versus...