The role of hemostatic therapy in anticoagulation-associated intracerebral hemorrhage: intuition versus evidence.

Previous studies have shown that patients with anticoagulation (warfarin)-associated intracerebral hemorrhage (WAICH) have poor outcome and greater mortality. The mechanisms by which warfarin worsens intracerebral hemorrhage (ICH) outcome are not clearly defined and include larger hematoma volumes at presentation, ongoing bleeding leading to greater hematoma expansion, and greater age and burden of medical comorbidities among warfarin users.1 The intuition that hematoma expansion is a consistent predictor of poor outcome after ICH and is potentially modifiable led to the general recommendation that correcting the international normalized ratio (INR) as rapidly as possible to stop ongoing bleeding in these patients should be the goal of therapy. Warfarin reduces the availability of vitamin K and the maturation of its dependent coagulation factors (VKDCF) II, VII, IX, and X and is thought to exert its anticoagulant effects mostly through reductions in factors II (prothrombin) and X levels. Therefore, vitamin K should be given to reverse the effects of warfarin. However, the full effect of vitamin K may take up to 24 hours to develop. Faster reversal requires restoration of VKDCF, in particular factors II and X. Drs Diringer and Zazulia eloquently detail the advantages and disadvantages of fresh-frozen plasma (FFP), protrhrombin complex concentrate (PCC), and factor VIIa. Although FFP contains all of the VKDCF, different PCC preparations differ in the relative amounts of VKDCF; most contain low levels of factor VII. Therefore, the adjunctive use of FFP with PCC may be considered as a source of factor VII to achieve complete reversal of the anticoagulant effect of warfarin. The potential safety concerns regarding PCC and factor VIIa argue against their combined use in routine circumstances. Our experts agree on most aspects of the management of our patient. They advocate rapid reversal of elevated INR using vitamin K and FFP and discourage the use of factor VIIa. They only disagree on whether PCC should be used in addition to FFP. We should point out that the choice of any of these approaches is largely based on clinical judgment and intuition that rapidly reversing INR will minimize hematoma expansion sufficiently enough to improve clinical outcomes and that the premise of targeting hematoma expansion to improve outcome, although appealing, has not translated into clinical benefit in recent ICH trials. Let us step back and analyze the available supporting evidence, or lack of it. Indeed, accumulating data show that the rate of INR correction is greater and the time to correction is shorter when FFP is supplemented with PCC or even factor VIIa, compared with FFP alone, in WAICH. However, there are no adequate randomized controlled trials to determine if this rapid correction of INR is associated with a reduction in hematoma expansion or results in improved outcome and decreased mortality. In fact, available evidence points to the contrary. In a small randomized study of only 13 patients, no difference in neurological outcomes was noted between patients receiving FFP alone and those receiving FFP and PCC despite a significant difference in INR correction favoring the latter group. More convincing are recent data from the Canadian prospective registry of PCC use in WAICH.2 Although approximately 80% of the patients had complete INR correction to 1.5 within 1 hour of PCC therapy, significant hematoma expansion still occurred in 47% of patients and the in-hospital mortality rate was 44% in patients with WAICH. In addition, several thrombotic events occurred within 30 days of treatment, including ischemic strokes, myocardial infarction, and venous thrombosis. These data clearly indicate that although rapid INR correction is sensible and achievable, it may not be sufficient to alter the poor prognosis in WAICH. We generally agree with Dr Stapf’s position that the use of PCC requires more study before routinely supporting its use. The ongoing INR Normalization in Coumadin Associated ICH (INCH) trial examining the use of PCC and FFP in patients with anticoagulation-associated ICH, in reducing INR to 1.2 (as the primary end point) and