From Trials to “Real Life”
Necessity of Efficacy
See related article, pages 2660–2664
Primary intracerebral hemorrhage (ICH) is a devastating disease with a very poor outcome: 40% of patients will die within the first month, and two thirds of survivors will never regain independency.1 To date, there is no specific treatment beyond supportive medical care. Recently, recombinant factor VIIa (rFVIIa) was tested in phase 2 trials in ICH patients:2,3 the results of the largest phase II trial are encouraging in terms of safety issues and open a new area for the management of ICH because this trial provides some efficacy data.2
In this issue of Stroke, Flaherty et al4 discuss the potential applicability of rFVIIa in a population-based registry of ICH and suggest that 13.1% to 17.5% of patients with primary ICH may be eligible for this treatment. Taking into account epidemiological data5 and Flaherty’s results,4 5 to 6 patients might be eligible each year in a Western population of 100 000 inhabitants. This study is of major importance because the successful translation of new treatments from trials into “real life” is of crucial importance.
However, we should bear in mind that the trial suggesting efficacy of rFVIIa only enrolled 399 patients and was designed to evaluate safety and not efficacy of the drug.
By projecting the results on a population-based registry, the authors underline the burden of the disease and how far we are in the management of primary ICH. If rFVIIa is proven effective in a large randomized trial, we will have to rethink the entire management of ICH, which was rather chaotic until now. Flaherty’s study is important because it provides data that will help to earn time in research. Attempts to educate the public about the importance of early medical evaluation for the signs of stroke have been marginally successful so far. In addition to public education, we will also have to motivate and educate physicians, including neurologists and stroke physicians, who, in many institutions, do not consider primary ICH an emergency at the same level as acute cerebral ischemia. There are several reasons underlying this behavior, the lack of a specific therapy being probably a major one. Another may be that some primary ICHs still arrive in neurosurgical departments despite the results of the International Surgical Trial in Intracerebral Haemorrhage (STICH).6 Triage by emergency departments will have to improve, and ICH will have to become an emergency that all hospitals should be able to treat. Unlike ischemic stroke, which may have many differential diagnoses needing the expertise of a specialized stroke physician, and in which early findings of an established infarct on computed tomography (CT) might be missed by a nonexperienced radiologist, the diagnosis of an ICH on CT scan is easy, and thereby the decision to administer rFVIIa should be pretty straightforward. Community hospitals will need to be able to administer rFVIIa to appropriate patients, even before referral to a stroke unit.
Flaherty et al4 considered that only 13.1% to 17.5% of patients with ICH could receive the treatment according to exclusion criteria used in the phase 2 study.2 These figures may be underestimated because many questions remain unsettled and may lead to an increased proportion of eligible patients. What would be the optimal therapeutic window: 4 hours or more? Is the treatment effective in anticoagulation-induced ICH, in thrombolytic induced hemorrhages, in malformative hemorrhages, or in hemorrhagic changes within an infarct? On the other hand, what will be the rate of thromboembolic complications in practice? The authors suggest that mortality reduction could save >1200 lives annually in the United States and prevent death or severe disability in >1800 patients. Future studies will also have to focus on high-risk populations such as Asians.
Therefore, if efficacy of rFVIIa remains to be proven, efficacy of our organization in the management of ICH also has to improve.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
Broderick J, Adams HP Jr, Barsan W, Feinberg W, Feldmann E, Grotta J, Kase C, Krieger D, Mayberg M, Tilley B, Zabramski JM, Zuccarello M. Guidelines for the management of spontaneous intracerebral hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1999; 30: 905–915.
Mayer S, Brun NC, Broderick J, Davis S, Diringer MN, Skolnick BE; Europe/AustralAsia NovoSeven ICH Trial Investigators. Safety and feasibility of recombinant factor VIIa for acute intracerebral hemorrhage. Stroke. 2005; 36: 74–79.
Flaherty ML, Woo D, Haverbusch M, Moomaw CJ, Sekar P, Sauerbeck L, Kissela B, Kleindorfer D, Broderick JP. Potential applicability of recombinant factor VIIa for intracerebral hemorrhage. Stroke. 2005; 36: 2660–2664.
Mendelow A, Gregson BA, Fernandes HM, Murray GD, Teasdale GM, Hope DT, Karimi A, Shaw DM, Barer DH; STICH Investigators. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the international surgical trial in intracerebral haemorrhage (STICH): a randomised trial. Lancet. 2005; 365: 387–397.