ARTICLE IN BRIEF
Investigators reported that Octaplex, a four-factor prothrombin complex concentrate, was faster and safer than fresh frozen plasma for urgent warfarin reversal; the four-factor PCC was associated with fewer adverse events, faster INR (international normalized ratio) reversal, and less need for red blood cell transfusion.
For nearly 50 years, warfarin has been the most widely used anticoagulant in the world. But since the drug's inception, clinicians and researchers have been working hard to find the safest and most efficacious way to reverse one of warfarin's serious side effects: the risk (in 3 to 7 percent of patients) for major, life-threatening bleeding. There is no universal consensus to date on how to stop bleeding in these patients, but the most common methods are either prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP), both of which may be administered with intravenous vitamin K.
But investigators reported in the July 23 online edition of Circulation that Octaplex, a four-factor PCC (containing coagulation Factors II, VII, IX, and X and Proteins C and S), was faster and safer than fresh frozen plasma; the four-factor PCC was associated with fewer adverse events, faster INR (international normalized ratio) reversal, and less need for red blood cell transfusion. [The US Food & Drug Administration recently accepted Octapharma USA's Biological License Application for Octaplex.]
In their paper, Jeffrey Joseph Perry, MD, senior scientist in clinical epidemiology at Ottawa Hospital Research Institute in Canada, and colleagues compared the two anticoagulants and assessed adverse events within seven days, including death and thromboembolic events.
“These findings suggest that [the four-factor PCC] should be a preferred choice over plasma for rapid reversal of warfarin induced coagulopathies,” Dr. Perry told Neurology Today. “We believe that this study will result in a change in practice for centers using frozen plasma as first line treatment for rapid reversal of warfarin induced coagulopathies.”
STUDY PROTOCOL, FINDINGS
In a non-blinded, retrospective cohort study from the emergency departments of two hospitals in Canada, investigators reviewed medical records of patients in the emergency department who received either FFP (149) or PCC (165) to reverse bleeding after warfarin use. “We included adult patients on warfarin with an INR ≥1.5 who received frozen plasma or Octaplex. Our primary outcome was serious adverse events (death, ischemic stroke, myocardial infarction, heart failure, venous thromboembolism or peripheral arterial thromboembolism) within 7 days. Secondary outcomes included time to INR reversal, hospital length of stay and red blood cells transfused within 48 hours,” Dr. Perry and colleagues wrote.
Patients were excluded if they were younger than 18, if there was no documentation of the patient taking warfarin, if frozen plasma or PCC was administered without an initial INR check, or if they received both frozen plasma and PCC within 7 days. For the PCC group, 40 mL (≈1000 IU prothrombin complex concentrate) were administered, and INR was checked again about fifteen minutes post-administration.
The rate of serious adverse events in the FFP group was 19.5 percent, compared with 9.7 percent in the PCC group (p=0.014, Relative Risk [RR] 2.0, 95% CI 1.1 to 3.5). Even after adjusting for baseline history and reason for treatment, this difference in event rates was significant (p=0.038, adjusted RR 1.85, 95% CI 1.03 to 3.3). Using FFP, median INR reversal was 11.8 hours, compared with 5.7 hours using PCC (p<0. 0001). The mean red cell transfusion was 3.2 using FFP and 1.4 using PCC (p<.0001).
“While we suspected that the time to reversal would be faster using [the four-factor PCC] and the red blood cell transfusion need would be less, we were somewhat surprised by the significant difference in serious adverse events in favor of [PCC] treatment. However, this finding on univariate analysis remained consistent following multivariable regression analysis,” Dr. Perry wrote to Neurology Today in an e-mail.
Despite the fact that statistical adjustments were conducted for important baseline imbalances between groups in this study, Dr. Perry acknowledged that it would be more powerful to conduct a blinded randomized, controlled study of these treatments in order to replicate these findings, and that a subsequent analysis comparing costs of these treatments would also be helpful.
“The study provides provocative evidence supporting what many have suspected — that PCC is faster and safe,” said Kevin Sheth, MD, an assistant professor of neurology and chief of the Neurocritical Care and Emergency Neurology Division at Yale University School of Medicine. Dr. Sheth, who is also a member of the editorial advisory board at Neurology Today, noted that this is one of the few head-to-head studies done in the emergency setting for warfarin reversal.
Michael N. Diringer, MD, professor of neurology and neurosurgery, section chief of neurological critical care at Washington University School of Medicine, said: “There has been some discrepancy between the published guidelines that all recommend some combination of Vitamin K and prothrombin complex and the practice, at least, in the US where people have relied primarily on fresh, frozen plasma. I think a lot of this has to do with availability or lack of availability of prothrombin complex.”
Overall, Dr. Diringer said this was a well done and well described study. But he told Neurology Today that he was a little surprised that TRALI (transfusion-related acute lung injury) was not listed as one of the adverse events “because that's a major issue with any transfusion, and it's most common with FFP transfusions,” he said.
[In addition, adverse events associated with PCC include immediate allergic reactions, heparin-induced thrombocytopenia, and thromboembolic complications.]
Responding to Dr. Diringer's comments, Dr. Perry said in an e-mail to Neurology Today: “TRALI is a very rare event, and we are aware of only one definite case within our cohorts. Due to poor case definitions, if there were patients with TRALI in our cohort, we suspect that they would have been classified within the death or heart failure group (the one TRALI case was classified within this group).”
Other limitations, Dr. Sheth said, were the retrospective collection of data and lack of standardized timing of administration between the two comparison groups. “Most importantly, the timing of INR checks was not systematic,” he added.
This study is just one more important piece, according to Dr. Diringer, and “if you combine this paper with the study that CSL Behring just completed [that led to the FDA approval of K-Centra, another four-factor PCC], I think there's going to be a huge change in practice coming.” For example, he said that his institution has used Vitamin K and FFP almost exclusively until very recently. “Now, people have really switched over more and more to using prothrombin complex as the primary agent,” he said.
“One would especially like to use PCC in patients who may not tolerate the volume load that accompanies FFP,” said Dr. Sheth.
FURTHER STUDY, QUESTIONS
“The study needs to be confirmed prospectively with standardized time measurements of INR and administration protocols. Ultimately, we should see a difference in some objective measure of bleeding (for example, hematoma expansion) and ideally outcomes in order to justify a practice change,” said Dr. Sheth. A cost-benefit analysis would also be helpful, he said, but must ultimately incorporate differences in long-term outcomes.
If you add up all the related costs of the treatments, Dr. Diringer believes FFP and PCC administration are likely similar. “In fact, I found one paper doing a cost-analysis projection in England comparing the two [PCC and frozen plasma], which says that prothrombin complex was cost-effective because of reduced complications and other related costs.” The study, published in Clinical Therapeutics in 2010, found that PCC was more cost-effective than fresh frozen plasma.
Dr. Diringer noted that a new class of anticoagulants are coming out — factor Xa inhibitors, which act directly upon Factor X in the coagulation cascade, without using antithrombin as a mediator. “For patients who have atrial fibrillation or who currently take warfarin, these new agents are much easier to use — they don't need blood work all the time or require dietary limitations — but neither FFP or PCC can reverse them if there's a bleeding problem. In fact, nobody really knows how to reverse them if there's a bleeding problem,” he told Neurology Today.