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Four-factor prothrombin complex concentrate shows promise for urgent vitamin K antagonist reversal
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Treatment with four-factor prothrombin complex concentrate was superior to plasma for the urgent reversal of vitamin K antagonist-induced anticoagulation prior to surgery, according to phase 3b study results.
Four-factor prothrombin complex concentrate (4F-PCC; Beriplex/Kcentra/Confidex, CSL Behring) was associated with rapid international normalized ratio (INR) reversal and effective hemostasis, results showed.
Joshua N. Goldstein, MD, PhD, of the department of emergency medicine at Massachusetts General Hospital and the department of surgery at Harvard Medical School, and colleagues evaluated data from 168 patients aged 18 years or older in need of rapid vitamin K antagonist reversal before an urgent surgery or invasive procedure.
Researchers randomly assigned patients to receive a single dosage of 4F-PCC (n = 87) or plasma (n = 81).
Effective hemostasis and INR reduction to 1.3 or lower 30 minutes after infusion served as the study’s co-primary endpoints.
Results showed 90% of patients (n = 78) who received 4F-PCC achieved effective hemostasis, compared with 75% (n = 61) of patients who received plasma. This 14.3% difference demonstrates non-inferiority and superiority of 4F-PCC compared with plasma (95% CI, 2.8-25.8), researchers wrote.
More patients in the 4F-PCC cohort achieved rapid INR reduction (55% vs. 10%). These data also suggest the non-inferiority and superiority of 4F-PCC compared with plasma (difference, 45.3%; 95% CI, 31.9-56.4).
Adverse events occurred in a similar number of patients in each arm (4F-PCC, n = 49; plasma, n = 53). More patients who received plasma experienced thromboembolic adverse events (8% vs. 7%), fluid overload or similar cardiac events (13% vs. 3%) and late bleeding events (5% vs. 3%).
These results may impact treatment procedures for effective hemostasis and rapid INR reversal, according to the researchers.
“To our knowledge, this trial is the first adequately powered comparison of 4F-PCC and plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions,” Goldstein and colleagues wrote. “Not only was 4F-PCC non-inferior to plasma for hemostatic efficacy (the comparison we were primarily powered to test), but it was additionally superior for this endpoint (an effect we had less than 70% power to detect). 4F-PCC was also both non-inferior and superior to plasma for the co-primary event of rapid INR reduction.” – by Cameron Kelsall
Disclosure: The study was funded by CSL Behring. The researchers report consulting fees, honoraria and research grants from; employment with; and speakers bureau and consultant/advisory roles with Alexion, CSL Behring, Instrument Laboratories, Kedrion and Octapharma.
Perspective
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Harry S. Jacob, MD, FRCPath(Hon)
This good news regarding an effective antidote for warfarin toxicity with 4F-PCC is further amplified by two presentations at the ASH Annual Meeting and Exposition in December. More and more, it appears that new oral anti-thrombin and anti-Factor X agents are equal or superior in efficacy to warfarin as chronic anticoagulants and possibly safer, producing less severe bleeding. However, enthusiasm for their use has been tempered by a lack of reversal strategies in case of bleeding (analogous to vitamin K reversal for warfarin-induced bleeding).Therefore, the recent ASH presentations by Grottke and colleagues (Grottke O, et al. Abstract 346. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco) and by Perlstein and colleagues (Perlstein I, et al. Abstract 345. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco) do much to alleviate safety concerns about the newer agents.
The Grottke study showed a PCC formulation was remarkably effective in completely rescuing severely traumatized animals exposed to dabigatran (Pradaxa, Boehringer Ingelheim) that bled to death without PCC infusion, and the Perlstein study showed a PCC formulation rapidly reversed the anticoagulant effects in humans exposed to apixaban (Eliquis; Bristol-Myers Squibb, Pfizer).
My guess is that warfarin and INR testing soon will be extinct. It also should be noted that these concentrates are effective without inducing vascular overload — a disincentive for the use of large volumes of plasma that can be considered for unwanted bleeding in cardiac-compromised patients with atrial fibrillation.
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