Thromboembolic Events After Vitamin K Antagonist Reversal With 4-Factor Prothrombin Complex Concentrate: Exploratory Analyses of Two Randomized, Plasma-Controlled Studies - 19/12/15
, Majed A. Refaai, MD b, Joshua N. Goldstein, MD, PhD c, Astrid Schneider, PhD d, Laurel Omert, MD e, Amy Harman, MS e, Martin L. Lee, PhD f, Ravi Sarode, MD gAbstract |
Study objective |
We evaluated thromboembolic events after vitamin K antagonist reversal in post hoc analyses of pooled data from 2 randomized trials comparing 4-factor prothrombin complex concentrate (4F-PCC) (Beriplex/Kcentra) with plasma.
Methods |
Unblinded investigators identified thromboembolic events, using standardized terms (such as “myocardial infarction,” “deep vein thrombosis,” “pulmonary embolism,” and “ischemic stroke”). A blinded safety adjudication board reviewed serious thromboembolic events, as well as those referred by an independent unblinded data and safety monitoring board. We descriptively compared thromboembolic event and patient characteristics between treatment groups and included detailed patient-level outcome descriptions. We did not power the trials to assess safety.
Results |
We enrolled 388 patients (4F-PCC: n=191; plasma: n=197) in the trials. Thromboembolic events occurred in 14 of 191 patients (7.3%) in the 4F-PCC group and 14 of 197 (7.1%) in the plasma group (risk difference 0.2%; 95% confidence interval −5.5% to 6.0%). Investigators reported serious thromboembolic events in 16 patients (4F-PCC: n=8; plasma: n=8); the data and safety monitoring board referred 2 additional myocardial ischemia events (plasma group) to the safety adjudication board for review. The safety adjudication board judged serious thromboembolic events in 10 patients (4F-PCC: n=4; plasma: n=6) as possibly treatment related. There were 8 vascular thromboembolic events in the 4F-PCC group versus 4 in the plasma group, and 1 versus 6 cardiac events, respectively. Among patients with thromboembolic events, 3 deaths occurred in each treatment group. All-cause mortality for the pooled population was 13 per group. We observed no relationship between thromboembolic event occurrence and factor levels transiently above the upper limit of normal; there were no notable differences in median factor or proteins C and S levels up to 24 hours postinfusion start in patients with and without thromboembolic events.
Conclusion |
The incidence of thromboembolic events after vitamin K antagonist reversal with 4F-PCC or plasma was similar and independent of coagulation factor levels; small differences in the number of thromboembolic event subtypes were observed between treatment groups.
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| Please see page 97 for the Editor’s Capsule Summary of this article. |
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| Supervising editor: Donald M. Yealy, MD |
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| Author contributions: JNG, AS, and RS participated in the study concept and design. MAR obtained research funding. TJM, MAR, and AS undertook recruitment of participating centers and patients and managed the data, including quality control. TJM, MAR, JNG, AS, and RS supervised the conduct of the trial. TJM and JNG supervised data collection. TJM, JNG, AS, LO, MLL, and RS analyzed and interpreted the data. TJM had full access to all the data and takes responsibility for the integrity and accuracy of the data analysis. MLL provided statistical advice. LO and AH provided administrative, technical, and material support. TJM, AS, LO, and AH drafted the article, and all authors contributed substantially to its revision and approved it for submission. TJM takes responsibility for the paper as a whole. |
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| Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article as per ICMJE conflict of interest guidelines (see www.icmje.org/). The studies were sponsored by CSL Behring. Preparation and review of the article, as well as the decision to submit the article for publication, were performed by a publication steering committee that included academic medical experts and representatives of the sponsor. Medical writing assistance was funded by the sponsor. Drs. Milling and Refaai have received consulting fees and serve on the speakers’ bureau for CSL Behring. Dr. Goldstein has received consulting fees and research funding from CSL Behring. Drs. Schneider and Omert and Ms. Harman are employees of CSL Behring. Dr. Lee has received consulting fees from CSL Behring. Dr. Sarode has received consulting fees and honoraria from CSL Behring. |
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Vol 67 - N° 1
P. 96 - janvier 2016 Retour au numéro
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