|Year : 2007 | Volume
| Issue : 1 | Page : 31-33
It is premature to use recombinant activated coagulation factor VIIa in intracerebral hemorrhage
Professor of Neurology, All India Institute of Medical Sciences, New Delhi, India
Room No. 704, 7th Floor, Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Prasad K. It is premature to use recombinant activated coagulation factor VIIa in intracerebral hemorrhage. Ann Indian Acad Neurol 2007;10:31-3
Recombinant activated coagulation factor VIIa (rFVIIa) is a vitamin K-dependent glycoprotein, similar in structure and function to plasma-derived human factor VIIa (FVIIa) which is one of the plasma proteins involved in the coagulation cascade following blood vessel injury. rFVIIa is an activator of coagulation factor X and can induce a thrombin burst even in the absence of coagulation factor VIII (FVIII) or IX (fIX). rFVIIa initiates coagulation only at the site of injury as it binds only to the locally activated platelets.
On the basis of clinical and experimental data it has been proposed that rfVIIa may prevent expansion of hematoma, as rfVIIa provides its hemostatic effect via interactions with other elements of the coagulation system locally at the site of bleeding. This results in enhanced generation of thrombin, increased formation of fibrin and stabilization of fibrin clot. Thus, rFVIIa stops bleeding from a ruptured vessel.
Hematomas expand during the first hours after onset of symptoms of intracerebral hemorrhage (ICH). It has been demonstrated that about 26% of hematomas continue to grow within the first hours after the initial CT scan and about 12% grow further after this (growth is defined as an increase of >33%). rFVIIa may prevent the expansion through mechanisms mentioned above. Based on the encouraging results of initial animal studies, dose escalation trials were concluded. After the conclusion of the dose escalation trials, efficacy and safety of rfVIIa has been evaluated by multi-centre, randomized, double blind parallel group, placebo controlled trial in 2002-2004, which is the main paper often cited to justify the use of rfVIIa in ICH. A critical appraisal of the paper reveals the following reasons to support the contention that it is premature to use rFVIIa in ICH:
Lack of phase III study
The study by Mayer et al was a phase II study with three different doses of rFVIIa compared to placebo to determine which of the three doses are likely to be safe and effective. Before a new drug is approved for clinical use, a phase III study is required. A phase III study (FAST) is ongoing and physicians must await the results of the study before starting its use in clinical practice.
Negative results of survival analysis
There were four groups in the study. The first analysis of the results did not reveal any statistically significant difference among the groups ( P =0.10 by the log-rank test comparing all four groups). Investigators had anticipated that this might happen and therefore, had pre-specified that an analysis with all three rfVIIa groups together would be compared to the placebo group. When this was done, a statistically significant difference emerged in favour of rfVIIa ( P =0.02 by the Chi-square test for the comparison of the three rFVIIa groups combined with placebo). What does it tells us? It tells that rfVIIa might be superior to placebo but it does not tell us at what dose it would be so?
Effective dose is not known
The study fails to inform a clinician about the dose at which it might be effective. One needs to conduct another study with the most likely effective dose to confirm or refute the finding obtained in the second analysis.
Unclear risk-benefit profile
The risks associated with rFVIIa are unsettling. We know that ICH is associated with high mortality but the main cause of death is the 'mass effect' of the hematoma. Very few patients die of myocardial infarction. Non-fatal myocardial infarction and cerebral infarctions are rare during the acute phase of ICH. In the study by Mayer et al , the incidence of cerebral infarction and non-fatal myocardial infarctions were rather too high. Most likely these were due to prothrombotic effects of rFVIIa. The investigators were themselves concerned about this effect and that is why "midway through the trial, the last criterion was amended to exclude patients with any history of thrombotic or vaso-occlusive disease". The last criterion referred to in the preceding sentence consisted of symptomatic thrombotic or vaso-occlusive disease (i.e., angina, claudication, deep-vein thrombosis or cerebral or myocardial infarction) within 30 days before the onset of symptoms of intracerebral hemorrhage. This reminds me of the study of antifibrinolytic therapy for aneurysmal subarachnoid hemorrhage. Roos et al in their Cochrane review concluded that antifibrinolytic treatment decreased the risk of re-bleeding (OR 0.55, 95% confidence interval (CI) 0.42 to 0.71), but, on the other hand it increased the risk of cerebral ischaemia (OR 1.39, 95% CI 1.07 to 1.82). Overall, the conclusion is that the antifibrinolytic treatment does not improve clinical outcome because the benefit is offset by an increase in poor outcome caused by cerebral ischaemia. Therefore, it may be prudent to wait for the results of FAST to appreciate the full extent of risk versus benefit of rFVIIa.
They study by Mayer et al , shows a mean lesion volume reduction of 5.4 ml (10.8 ml in control group and 5.4 ml in rFVIIa group). However, the mortality difference in absolute term is 11% (29% in controls vs. 18% in combined rfVIIa groups). The mean volume reduction of 5.4 ml in absolute terms cannot adequately explain the mortality reduction. This calls for consideration of some alternative explanation. Was the placebo group sicker than the rFVIIa groups? Possibly yes, the percentage of brainstem hemorrhages was 6.25% in the placebo group and 3.30% in the rFVIIa group. This alone may also not explain the mortality differences, but raises doubts that some factors other than treatment effect might be responsible for this difference.
ICH is a serious condition. It is associated with high mortality, mainly due to 'mass effect' of the hematoma. Surgery can reduce the mass effect and thus decrease mortality by 5% and increase disability-free survival by 6%. But we know that in STICH trial there was statistically non-significant reduction in mortality to the extent of 1%. Even the meta-analysis by Prasad et al projected a reduction in mortality of 5%. In view of this, taking the findings of Mayer et al at point estimate, it shows that rFVIIa can reduce mortality by 11%. We calculated the 95% CI around the estimate, which turns out to be -1% to -21%. The CI indicates that data is sparse and more studies to conform the findings may be desirable. It may be relevant to keep in mind the fraxiparine in ischaemic stroke study (FISS) where fraxiparine showed a decrease of 20% in unfavourable outcome, but in FISS-bis trial, that was launched to confirm the results of FISS trial, there was no difference in mortality. We must, therefore, wait for the results of FAST trial, before concluding anything definitively.
Not approved for clinical use
To the best of my knowledge, rFVIIa has not been approved for clinical use in ICH anywhere in the world. It has not been approved for clinical use in India by the Drug Controller General of India. Any use without the approval is illegal and subject to regulatory and penal action.
Kinds of patients who will benefit not clearly established
We don't have clear knowledge who are the patients likely to benefit from rFVIIa. We know this well for carotid endarterectomy. We know to some extent for t-PA, but we don't know for rFVIIa. To know this, more and bigger trials than the one by Mayer et al and a meta-analysis of the trials are needed. FAST trial may provide some data for this.
In conclusion, rFVIIa should be considered an investigational drug at the current state of knowledge and should not be used outside the context of RCTs. In this connection, it may be important to mention that in the World Congress of Stroke 2006, Cape Town, a scientist from the company made a plenary presentation on the topic. In the discussion, I asked him to clarify whether he advocates use of rFVIIa in clinical practice at present. He clearly answered- 'no' and clarified that company is not asking anyone to use the drug as of now, rather would like that the use or otherwise may be done only after the results of the phase III trial is available.
It may also be pertinent to carry out a trial in India, where the number of patients admitted to hospitals with ICH is relatively high. The likely frequency of use of an effective medical therapy like rFVIIa is high in India. As patients often reach hospital late in India, the trial may also help to examine the usefulness of the drug with wider time window. Another intervention worth examining in such a trial is comparison of less expensive fresh frozen plasma with rFVIIa. Efforts from all concerned to launch such a trial in India are required.
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