Correspondence

Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage

N Engl J Med 2005; 352:2133-2134May 19, 2005

Article

To the Editor:

The trial conducted by Mayer et al. (Feb. 24 issue),1 showing that recombinant activated factor VII (rFVIIa) is beneficial for treating acute intracerebral hemorrhage, for which treatment options are extremely limited, is very exciting. The trial showed a reduction in hematoma growth (the primary end point); however, it is the associated reduction in mortality that most likely will influence practitioners to use this therapy. Although patients in a deep coma (defined as a score of less than 6 on the Glasgow Coma Scale [GCS]), whose mortality rate is extremely high,2 were excluded from the trial, the ranges of the baseline GCS scores shown in Table 1 of the article indicate that some of the patients in the placebo group met this exclusion criterion. We wonder how many patients in the placebo group had GCS scores of less than 6 before administration of the study drug, because excluding as few as two deaths in this group would result in a P value for mortality that would no longer be less than 0.05. Since rFVIIa was associated with an increased risk of arterial thromboembolic adverse events (P=0.01), some of which were fatal, balancing the benefits and risks associated with this therapy is extremely important. Moreover, thromboembolic events should continue to be analyzed as prospectively defined outcomes in all future trials.

Jan O. Friedrich, M.D., D.Phil.
University of Toronto, Toronto, ON M5B 1W8, Canada
j.friedrich@utoronto.ca

2 References

1. 1

   Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-785
   Full Text | Web of Science | Medline

2. 2

   Hemphill JC III, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891-897
   CrossRef | Web of Science | Medline

To the Editor:

Mayer and colleagues provided placebo or rFVIIa to more than 84 percent of the patients in each test group who had lesions in the putamen, globus pallidus, or thalamus. The likely primary or contributing cause of bleeding in many of these patients was elevated blood pressure; however, the reduction in blood pressure at three hours was minimal. It is important to know what trends in blood pressure were observed in the respective subgroups between imaging studies.

It is unclear what fraction of the 7 percent incidence of thromboembolic serious adverse events among the patients treated with rFVIIa occurred among those enrolled after the midpoint of the trial, when a change was made to “exclude patients with any history of thrombotic vaso-occlusive disease.” This change raises the possibility that the incidence of adverse thrombosis might be higher in a broader patient population.

Kevin N. Sheth, M.D.
Massachusetts General Hospital, Boston, MA 02114
ksheth@partners.org

Author/Editor Response

As Dr. Friedrich notes, patients with GCS scores of 5 or less, indicative of deep coma, were excluded according to our study protocol. However, a single patient in the placebo group was assigned a baseline GCS score of 3. This patient actually had an intermediate level of consciousness but was intubated and sedated for transportation at the time of the screening evaluation. Hence, the local investigator enrolled the patient in the trial, and the patient was included in the intention-to-treat analysis. We do not believe that the inclusion of this patient invalidates the main findings of our study.

As Dr. Sheth notes, the mean systolic blood pressure was elevated at baseline in our patients; elevated blood pressure has been shown to be an important factor contributing to the occurrence of intracerebral hemorrhage. Blood pressure fell progressively between the imaging studies from 178/97 mm Hg at baseline, to 154/85 mm Hg at 24 hours and 150/80 mm Hg at 72 hours, with minimal differences among the treatment groups. Thus, it seems unlikely that differences in blood-pressure control account for the observed treatment effect of rFVIIa. We are currently conducting a more detailed analysis of the effect of blood pressure and other physiological variables on hematoma growth.

We amended the trial protocol to exclude patients with any history of symptomatic thromboembolic or vaso-occlusive disease after enrolling 197 of the 399 subjects. Exactly 13 thromboembolic serious adverse events occurred before this amendment, and 13 occurred after it. In a preliminary analysis of all 485 patients with intracerebral hemorrhage enrolled in our three phase 2 trials conducted to date,1,2 including the current trial, a history of thromboembolic disease was not found to predict acute thromboembolic complications related to rFVIIa administration. In fact, in our planned phase 3 confirmatory trial, we intend once again to include patients with a history of thromboembolic events.

Stephan A. Mayer, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10025
sam14@columbia.edu

Nikolai C. Brun, M.D., Ph.D.
Novo Nordisk, DK-2880 Bagsvaerd, Denmark

2 References

1. 1

   Mayer SA, Brun NC, Broderick J, et al. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke 2005;36:74-79
   CrossRef | Web of Science | Medline

2. 2

   Mayer SA, Brun N, Broderick J, et al. Safety and preliminary efficacy of recombinant coagulation factor VIIa in acute intracerebral hemorrhage: U.S. Phase 2A Study. Stroke 2004;35:332-332 abstract.
   Web of Science

Citing Articles (3)

Citing Articles

1. 1

   Jean-françois Hardy, Sylvain Bélisle, Philippe Van der Linden. 2010. Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients. , 278-292.
   CrossRef

2. 2

   Brian A. Bruckner, Daniel J. DiBardino, Qian Ning, Alfred Adeboygeun, Karim Mahmoud, Jamie Valdes, John Eze, Paul M. Allison, Denton A. Cooley, Igor D. Gregoric, Oscar H. Frazier. (2009) High Incidence of Thromboembolic Events in Left Ventricular Assist Device Patients Treated With Recombinant Activated Factor VII. The Journal of Heart and Lung Transplantation 28:8, 785-790
   CrossRef

3. 3

   Jean-François Hardy, Sylvain Bélisle, Philippe Van der Linden. (2008) Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients: A Review of 17 Randomized Controlled Trials. The Annals of Thoracic Surgery 86:3, 1038-1048
   CrossRef