The study design of this non-inferiority trial is very effectively laid out by the investigators, and patients with an acute major bleed with an INR greater than or equal to 2 across nearly 40 sites in the United States and Europe were assigned to treatment with either 4-factor PCC (Kcentra, although the authors do refer to it throughout the study by Beriplex, the brand name of the product outside the United States) or fresh frozen plasma (FFP). The investigators used a fairly sophisticated randomization method to ensure that treatment arms were balanced in terms of the number of patients and the type and location of the bleed. The authors aimed to determine the effects of these treatments with two primary endpoints: (1) hemostatic efficacy from the start of the infusion for a period of 24 hours following the infusion and (2) rapid reduction in INR to less than or equal to 1.3 one-half hour following completion of the infusion. The investigators also analyzed a number of secondary endpoints, including plasma levels of vitamin K dependent clotting factors, time to INR correction, proportion of patients requiring PRBC transfusion, all-cause mortality at 45 days, and safety and tolerability of the treatments.
The dose of 4-factor PCC used in this study was based on initial INR and body weight, and is comparable to the dosing recommendations of the product, as provided here. Interestingly, the dose of FFP utilized was also based on these parameters as well, and patients only received what is typically deemed to be the standard dose of FFP in the setting of life-threatening bleed if the INR was greater than 6; otherwise a dose of 10 or 12 mL/kg was administered in patients had an INR between 2 to less than 4 and an INR between 4 to less than 6, respectively. In addition, all patients received intravenous phytonadione (vitamin K) at a dose of 5 to 10 mg as a slow infusion.
An efficacy scale for hemostasis was developed that ranged from “excellent” to “poor/none”, with predefined laboratory and other clinical criteria related to the type of bleed being evaluated to determine if this outcome measure was met. Patients were deemed to have failed therapy and have a rating of “poor/none” if supplementary treatment was necessary to control the bleed and/or if PRBC transfusion was necessary within 24 hours of treatment.
216 patients were randomized to treatment, with 103 patients in the 4-factor PCC arm and 109 patients in the FFP arm. Nearly half of all patients were female, with an average age of nearly 70 years. 70% of all patients resided in the United States. Median baseline INR in the 4-factor PCC arm was 3.90 versus 3.60 in the FFP arm. Nearly 65% of all bleeds were gastrointestinal and/or other non-visible bleeds while approximately 12% of all patients had intracranial hemorrhage (ICH). The majority patients were on therapy with a vitamin K antagonist for arrhythmia (57.1 and 51% respectively) with an average duration of treatment of nearly two years. The five most commonly reported comorbidities experienced by patients in the study included hypertension, atrial fibrillation, anemia, coronary artery disease, and congestive heart failure. The investigators do report that hematologic values at baseline were comparable at baseline, although this data is not presented. Nearly half of all patients did require at least one transfusion of PRBCs in both treatment arms, with an average of 1.4 and 1.2 units required for those receiving 4-factor PCC and FFP, respectively.
In terms of hemostasis, 72.4% of patients achieved “excellent” or “good” hemostasis with 4-factor PCC compared to 65.4% of patients who received FFP, which deemed 4-factor PCC to be non-inferior to FFP (95% CI -5.8 to 19.9 [lower limit: greater than -10%]). In a subanalysis based on bleeding type, there were no statistically significant differences in hemostatic efficacy between treatments. The effect of hemostasis was more pronounced with 4-factor PCC versus FFP in those patients with visible and musculoskeletal bleeding (82.6% versus 50% at four hours) compared to gastrointestinal, intracranial, and non-visible bleeding (69.3% versus 71.1% at 24 hours). Interestingly enough, in those patients with ICH, 41.7% of patients in the 4-factor PCC arm achieved “excellent” or “good” hemostasis, while 58.3% of patients in the FFP arm reached these same endpoints.
62.2% of patients who received 4-factor PCC demonstrated rapid INR correction to less than or equal to 1.3 one-half hour after completion of the infusion versus 9.6% of patients who received FFP. The investigators do go on to further point out that one hour after the initiation of the infusion, 69% of patients reached the an INR of ≤ 1.3 with 4-factor PCC compared to none in the FFP arm, and at 24 hours after completion of the infusion, 88% of patients in the 4-factor PCC arm achieved this goal compared to 58% of patients in the FFP arm. After conducting a post-hoc analysis, the investigators determined that 4-factor PCC demonstrated an INR reduction that was superior to FFP.
The investigators also measured the plasma levels of vitamin K dependent clotting factors and proteins C and S and found higher levels of these factors in patients receiving 4-factor PCC compared to FFP at 30 minutes post-infusion. However, between 3 and 24 hours following infusion, levels of these factors in those receiving FFP resembled those levels observed in patients who received 4-factor PCC.
In terms of safety, treatment-related adverse events occurred in 10 patients in the 4-factor PCC arm versus 23 patients in the FFP arm. 8 patients in the 4-factor PCC arm and 4 patients in the FFP arm experienced thromboembolic adverse events, and four of these events were deemed to be related to treatment in the 4-factor PCC arm compared to 3 in the FFP arm. 32 patients who received 4-factor PCC had serious adverse events, with two patients experiencing treatment-related events (deep vein thrombosis  and ischemic stroke ). In the FFP arm, 26 patients experienced a serious adverse event, with myocardial ischemia , fluid overload , and respiratory failure  deemed as being related to treatment.
At 45 days post infusion, 10 patients who received 4-factor PCC (9.7%) died compared to 5 patients in the FFP arm (4.6%). Six deaths in the 4-factor PCC arm occurred within 30 days of treatment, and all 5 in the FFP arm occurred within 30 days. The causes of death in those patients treated with 4-factor PCC were increase in ICH, worsening of cardiogenic heart failure, sudden death (deemed by the blinded safety adjudication board to be possibly related to treatment and occurring seven days after treatment), sepsis, acute renal failure, pancreatic cancer, cardiopulmonary arrest, respiratory failure, stage IV lung cancer, and myocardial infarction. 8 of the patients in the 4-factor PCC group were placed on comfort care prior to death. In those who died following treatment of FFP, none were determined to be related to treatment and four of these patients were placed on comfort care.
The authors do conclude that 4-factor PCC is a reasonable alternative to FFP in the management of acute major bleeding secondary to vitamin K antagonists.
For some, these results may seem to be a bit of a letdown after waiting for quite some time for this study to be published. Am I surprised and/or impressed by the results? Not really, for a number of reasons.
We already know PCC does work relatively quickly (within half an hour) in reducing INR. We also know that (1) FFP will really only effectively decrease INR to 1.6; and (2) the onset of activity of FFP can range anywhere from 4 to 6 hours. So is a goal INR of less than or equal to 1.3 for this study really and truly achievable with FFP in the real world?
In addition, although the rate of INR reduction may be important, what is more worthy is the ability for the treatment to reflect the values in the patient (i.e. achievement of hemostasis). Yes, more patients in the 4-factor PCC arm did achieve a rapid INR reduction compared to those who received FFP, but the investigators of the trial were not able to demonstrate superiority with hemostatic efficacy. The mantra of “treat the patient, not the number” can be modified in this case to “treat the patient, not only the number.”
What this study does add that not many studies have previously done is an evaluation of hemostatic efficacy with stratification of patients based on the type of bleed. One interesting observation that can be made from this study is that for life-threatening non-visible bleeding (gastrointestinal and ICH), nearly the same rate of hemostasis was collectively achieved with 4-factor PCC and FFP at 24 hours; and 30% of patients still did not effectively achieve hemostasis. We are talking 3 out of every 10 patients here- not an insignificant proportion, especially since most of the patients in this study happened to present with life-threatening gastrointestinal bleed. These results may demonstrate that a risk-benefit analysis would need to be taken into account if considering the use of Kcentra for off-label purposes in the management of such bleeds secondary to the novel oral anticoagulants (dabigatran, rivaroxaban, and apixaban). Hopefully, we will provided with more guidance on this as more studies are conducted to evaluate the efficacy of 4-factor PCC to manage life-threatening bleeding secondary to these agents.
Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a four-factor prothrombin complex concentrate (4F-PCC) in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013 Aug 9. [Epub ahead of print]