For patients who experience intracranial hemorrhage related to vitamin K antagonists (VKA-ICH), hematoma expansion can be a major cause of mortality. The optimal method for normalizing the international normalized ratio (INR) to a safe range, however, is unclear.
In a multicenter, prospective, open-label, randomized trial, researchers, led by Thorsten Steiner, MD, from the Department of Neurology at Klinikum Frankfurt HÃ¶chst in Germany, compared the safety and efficacy of two methods of hemostatic management, fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Results of the study were published in Lancet Neurology.
"Our trial is the first randomized controlled trial to compare anticoagulation reversal with FFP or PCC in patients with ICH specifically," Dr. Steiner and colleagues explained. "In the absence of evidence from randomized controlled trials of VKA-ICH, treatment guidelines recommend using PCC or FFP on the basis of plausibility, or [they] refrain [entirely] from making any recommendations."
Results from this study, however, suggest that four-factor PCC might be superior to FFP for faster INR normalization and for controlling hematoma expansion.
The trial included 50 adult patients with VKA-ICH (intracerebral or subdural) that was diagnosed by cerebral computed tomography (CT) scans within 12 hours of symptom onset who also had an INR of at least 2.0. Patients were excluded if they had:
- traumatic or secondary ICH
- concurrent acute ischemic events
- congestive heart failure
- thrombotic events within the past 30 days
Patients were randomized 1:1 to receive either of the following treatments within one hour of initial cerebral CT scan:
- 20 mL/kg of intravenous (IV) FFP (after blood group typing or by using AB group plasma supplied by local transfusion units; n=23)
- 30 IU/kg of IV four-factor PCC (n=27)
In addition, patients received 10 mg of IV vitamin K. Patients with an INR >1.2 at three hours after the start of treatment received PCC as a rescue treatment.
Patients were recruited from six certified stroke centers in Germany that had experience treating VKA-ICH, between August 7, 2009, and January 9, 2015. The mean patient age was 75.6 years, and 38 percent (n=19) were women. At baseline, patients in the PCC group appeared to have higher median hematoma volumes (13.2 mL [range = 0.2-43.9] vs. 13.0 mL [range = 0.6-78.1]; no p values reported), and more hematomas seemed to be located in the brainstem and within the ventricles compared with patients in the FFP group (11% vs. 4% in the brainstem; 7% vs. 0% in the ventricles; no p values reported).
Dr. Steiner and colleagues measured blood volume and INR in each patient at baseline as well as at three hours, 24 hours, and 72 hours after treatment initiation.
Nine percent of patients in the FFP group (n=2) and 67 percent of patients in the PCC group (n=18) had an INR â‰¤1.2 or lower within three hours of treatment initiation (the study's primary endpoint), meaning patients treated with PCC were significantly more likely to reach a normalized INR than those treated with FFP (odds ratio [OR] = 30.6; 95% CI 4.7-197.9; p=0.003). (See TABLE for additional FFS and PCC outcomes.)
Most patients in the FFP group, compared with the PCC group (83% vs. 26%; no p values reported), received subsequent PCC because the INR was not normalized at three hours.
The researchers also found that hematoma expansion at three hours was higher in the FFP cohort compared with the PCC cohort (adjusted difference = 16.9 mL; 95% CI 2.5-31.3; p=0.023).
The trial was halted early on February 6, 2015, due to safety concerns and because of the significant differences in hematoma expansion between the treatment groups. "Since this termination was unplanned, effect of treatment on hematoma expansion might have been biased away from the null," the authors wrote.
A total of 43 serious adverse events (AEs) were reported in 26 patients (20 FFP vs. 23 PCC). Six serious AEs were associated with FFP (hematoma expansion, n=4; anaphylactic reaction, n=1; ischemic stroke, n=1), and two were related to PCC (ischemic stroke, n=1; pulmonary embolism, n=1).
Death or hematoma expansion of >15 percent above baseline at three hours occurred in 73 percent of the FFP group (n=16) compared with 58 percent in the PCC group (n=15; OR=2.0; 95% CI 0.6-7.3; p=0.29).
At 24 hours, the adjusted difference in hematoma expansion was 16.4 mL (95% CI 2.9-29.9; p=0.018), and hematoma expansion of >15 percent occurred in 70 percent of patients with cerebral CT data available (n=14).
"Despite the introduction of novel oral anticoagulants, which carry a substantially lower risk of ICH, VKA-ICH is likely to remain a great challenge for the foreseeable future, because VKAs are still frequently prescribed for stroke prevention," Dr. Steiner and colleagues concluded. "Although an effect of the modification of early intracranial hematoma on clinical endpoints remains to be shown in a phase III trial, our findings support the notion of rapid anticoagulation reversal in VKA-ICH with PCC treatment."
The study is limited by its small patient population and number of recruiting centers. One recruiting center, they noted, enrolled a large percentage of patients, which could limit the generalizability of these findings. Small sample size prevented drawing meaningful conclusions about differences in survival or meaningful recovery.
Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): A randomised trial. Lancet Neurol. 2016;15:566-73.
|TABLE. Treatment Outcomes|
|Fresh Frozen Plasma
|Prothrombin Complex Concentrate
|INR <1.2 within 3 hours||2
|Deaths at 90 days||8
|No proportional hazard assumed||0.14|
|Time until INR <1.2 (minutes)||1,482
|No proportional hazard assumed||0.50|
|Hematoma expansion at 3 hours (mL)||23.7
|Hematoma expansion at 24 hours (mL)||22.1
|INR = international normalized ratio; OR = odds ratio
*Change in mean volume between baseline and follow-up cerebral CT