Hemostatic Therapy Should Not Be Used for Acute Treatment of Anticoagulation-Related Intracerebral Hemorrhage
“Just say no” was the slogan used in a US advertising campaign in the mid-1980s discouraging young people from engaging in recreational and potentially harmful drug use. In the context of this controversy, the same motto comes to mind when considering the routine use of conceptually exciting but medically unproven therapies outside the setting of controlled clinical studies.
Trial-and-error treatment strategies and off-label therapies are even more worrisome in a situation in which the patient's clinical status is insufficiently defined. In the abstracted case description, the side of the hemorrhage is unknown, and other than being qualified as “lobar,” no details are provided on hematoma location and potential ventricular extension. More importantly, the patient's neurological deficit and crucial vital parameters (such as blood pressure, body temperature) are unknown.
Assuming that no potentially negative outcome predictor has been cited simply because there is none, the patient's “intracerebral hemorrhage (ICH) score” is 0 leading to an estimated 30-day mortality risk trending toward zero.1 An immediate indication for any surgical rescue procedure (such as ventricular drainage or hematoma evacuation) appears unlikely in this context. With respect to the clinical management plan as defined by the questions given subsequently, the patient may therefore be best treated as follows.
Should the Patient Receive Vitamin K and Fresh-Frozen Plasma to Reverse the International Normalized Ratio?
Yes, just go with the 2010 American Heart Association/American Stroke Association guidelines: “Patients with ICH whose INR [international normalized ratio] is elevated due to oral anticoagulants should have their warfarin withheld, receive therapy to replace vitamin K-dependent factors and correct the INR, and receive intravenous vitamin K” (Class I; Level of Evidence: C).2
If So, What Is the Appropriate Targeted International Normalized Ratio Level?
The goal of warfarin reversal is to achieve international normalized ratio normalization (0.8–1.2) during the acute bleeding phase. The therapeutic dilemma in a patient with a prosthetic heart valve arises from the risk of subsequent thromboembolic (8.6 per 100 patient-years) or local valve complications (1.8 per 100 patient-years) after anticoagulation has been stopped.3 Sad to say, but the currently available data from case series are unclear as to whether or not anticoagulation should be reintroduced early or late after warfarin reversal.4 Therefore, no common standard or recommendation can be offered at this point. The author's personal rule of thumb is to introduce intravenous heparin (targeting a 1.5- to 2-fold activated partial thromboplastin time elevation) after a therapeutic window of 24 to 72 hours and a CT scan documenting bleeding cessation.
Should Other Hemostatic Agents Such as Prothrombin Complex Concentrates or Recombinant Factor VIIa Be Used Instead of (or in Combination With) Fresh-Frozen Plasma?
The preferred option is to “just say no” to such a management plan for several reasons. According to current American Heart Association/American Stroke Association guidelines, recombinant factor VIIa is not recommended for spontaneous ICH in general (Class III; Level of Evidence: A) nor for the reversal of oral anticoagulants (Class III; Level of Evidence: C).2 Those considering off-label use of the drug should also keep in mind that no clinical data are available on the risk–benefit ratio of such therapy in patients with mechanical heart valves. The results of the Fast Assessment of Stroke and Transient Ischemic Attack (FAST) study already showed patients with ICH without known valvular disease who were treated using the most effective (80 μg/kg) dose of recombinant factor VIIa developed arterial thromboembolic in 8%, a figure unlikely to decrease in the presence of a mechanical heart valve.5 From a broader economic perspective, the average cost of a single treatment of recombinant factor VIIa (approximately $4000) does not appear justified as long as the clinical benefit remains unproven.
As to the use of prothrombin complex concentrates (PCCs), the guidelines are more ambiguous: Similar to recombinant factor VIIa, PCCs may also increase the risk of thrombotic complications, although this effect was minor in a recent literature review.6 When compared with standard fresh-frozen plasma treatment in warfarin-related ICH, PCCs seem to normalize the international normalized ratio more rapidly but have not yet been shown to improve outcome.2 Despite the fact that PCCs have not received US Food and Drug Administration approval for the reversal of warfarin, the current guidelines offer a somewhat lukewarm recommendation “to consider PCCs as an alternative to FFP [fresh-frozen plasma]” (Class IIa; Level of Evidence: B).2
Most importantly, the best medical management plan should include the patient's admission to a dedicated stroke and/or intensive care unit allowing monitoring and normalization of vital parameters (blood glucose, blood pressure, body temperature, etc), prospective assessment of the patient's clinical status as well as prevention and appropriate treatment of secondary complications (such as infection, seizures, deep vein thrombosis, etc).7 A dynamic stroke team seeking optimal therapy may also screen the patient and eventually offer participation in one of the ongoing medical ICH trials for blood pressure management such as Intensive Blood Pressure Reduction In Acute Cerebral Hemorrhage Trial (INTERACT2; NCT00716079), ICH Acutely Decreasing Arterial Pressure Trial (ADAPT; NCT00963976), Antihypertensive Treatment of Cerebral Hemorrhage (ATACH-II; NCT01176565), or the International Normalized Ratio (INR) Normalization in Coumadin Associated Intracerebral Haemorrhage (INCH) trial (NCT00928915), which systematically compares PCCs with fresh-frozen plasma treatment in warfarin-related patients with ICH. The hope is that these ongoing trials and the recently proposed European Research Network on Intracerebral Haemorrhage (EURONICH) research priorities foster plans to improve current treatment standards by testing alternative molecules for intravenous hemostatic therapy in patients with acute ICH.8
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 2 of a 3-part article. Parts 1 and 3 appear on pages 2535 and 2539, respectively.
- Received December 16, 2011.
- Revision received January 19, 2012.
- Accepted January 20, 2012.
- © 2012 American Heart Association, Inc.
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