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Correspondence: When an article is eligible for submission of Correspondence, a link to the response form is available within the full-text article. You must be a current subscriber who has activated the online portion of your subscription in order to send a Correspondence. Any reader can read published Correspondence.
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Correspondence:Correspondence published:
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Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa
- Salvador Cruz-Flores (26 December 2006)
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Reply from the Authors
- Rebecca M Sugg, James C Grotta (26 December 2006)
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Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa
- Stephan A Mayer, On behalf of the FAST Trial Steering Committee (26 December 2006)
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Salvador Cruz-Flores, Saint Louis University 3635 Vista Ave. St. Louis , MO 63110
Send Correspondence to journal:
cruzfls{at}slu.edu Salvador Cruz-Flores
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Sugg et al provide data to support the concern about thromboembolic events in patients receiving Factor rVIIa for intracerebral hemorrhage. [1] The reader has to value the information for the sake of patient safety but the analysis provided by the authors has limitations that warrant discussion. By the authors’ own admission, the study is partially retrospective. Additionally, it was not randomized so there was neither concealment of allocation nor blinded outcome assessment. Moreover, the evaluation of endpoints such as myocardial infarction (MI) and increased troponin was systematically different. Importantly, even when the average number of troponin measurements per patient was similar in both groups, in the methods section the authors state:"...most nontreatment patients received serial ECG and cardiac enzyme evaluations every 8 hours..." implying that not all patients had such measurements. They also mentioned that after the third patient treated, the exclusion criteria were expanded to add the history of thromboembolic events, thus raising the question about what prompted such decision. Another issue is clarification of the number of patients in both groups who were treated with fresh frozen plasma or cryoprecipitate for warfarin-related hemorrhage. It could be argued that patients receiving warfarin have a higher risk for thromboembolic events at baseline due to the condition requiring anticoagulation. These problems introduce bias that clouds the conclusions. [2,3,4] The authors mentioned the detrimental effect of the small sample size. However, results are provided as p values, giving a sense of certainty because they were “significant.” The strength and precision of association in light of such small sample size are better understood when presented with a point estimate and a confidence interval. [5] We entered the numbers in a 2x2 table and obtained an OR= 8.9 [CI: 1.49, 56.7] p= 0.01 for the risk of increased troponin and OR= 12.1 [CI: 0.8, 367.6] p= 0.06 for the risk of myocardial infarction. These numbers indicate the presence of an increased risk for events but highlight the lack of precision of such estimates. Finally, these numbers although stronger that the p value, are also subject to the limitations introduced by bias. Considering these issues in study design, the conclusions, although important, have to be considered with some reservation due to the presence of bias. Nevertheless, given the concerns for safety it is extremely important to continue to monitor these events to establish the safety profile of the drug and its risk-benefit ratio. References 1.Sugg RM, Gonzales NR, Matherne DE, et al. Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa. Neurology 2006 67: 1053- 1055. 2.Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet 2002; 359: 248–252. 3.Schulz KF, Grimes DA. Allocation concealment in randomised trials:defending against deciphering. Lancet 2002;359:614-618. 4.Schulz KF, Grimes DA. Blinding in randomised trials:hiding who got what. Lancet 2002;359:696-700. 5.Guyatt G, Jaeschke R, Heddle N, Cook D et al. Basic statistics for Clinicians: 2. Interpreting study results: Confidence intervals. CMAJ 1995;152:169-173. Disclosure: Dr. Cruz-Flores received a grant from NovoNordisk to participate in a phase III trial of Factor VIIa in intracerebral hemorrhage. |
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Rebecca M Sugg, University of Alabama at Birmingham WP 155 619 19th Street South Birmingham, Alabama 35249, James C Grotta
Send Correspondence to journal:
rsugg{at}uabmc.edu Rebecca M Sugg, et al.
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We read the correspondence from Dr. Cruz-Flores regarding our article and would like to provide additional information regarding our study. As we stated, not all patients in the non-treatment group received three sets of cardiac enzymes/ECGs. These were patients not receiving factor VIIa who were without cardiac symptoms and with two sets of normal cardiac enzymes/ECGs. However, the average number of measurements per patient was similar in each group. Our decision to expand the exclusion criteria to add history of thromboembolic events was prompted by one of our treatment patients experiencing myocardial infarction resulting in death directly following infusion of factor VIIa. We agree that the use of warfarin and the administration of fresh frozen plasma or cryoprecipitate is interesting. However, of the five patients in our non-treated group and the two patients in our treated group with coagulopathic origin of ICH and who received either FFP or cryoprecipitate, none experienced elevated troponin or myocardial infarction. Finally, although we realize there are many issues with the design of our study, we agree that our results support the need for further investigation of the risk-benefit ratio and safety profile of factor VIIa in the treatment of patients with ICH. Disclosure: The authors report no conflicts of interest. |
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Stephan A Mayer, Columbia University 710 West 168th Street, Box 39, New York, NY 10032, On behalf of the FAST Trial Steering Committee
Send Correspondence to journal:
sam14{at}columbia.edu Stephan A Mayer, et al.
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In our phase IIB of the seven myocardial ischemic adverse events that occurred among 399 treated patients, only one led to an echocardiographic wall motion abnormality and none were directly fatal. The report by Sugg et al reminds us that while many of the troponin elevations associated with rFVIIa therapy are minor and well-tolerated, sometimes these complications can be extremely serious.
In addition to data from clinical trials, we agree with the accompanying editorial [4] that the best way to add to our understanding of these risks and benefits moving forward will be to collect information in a comprehensive disease-based registry.
The report by Subramanian et al described ten ICH patients treated with 40 µg/kg of rFVIIa.[2] Seven had intraventricular hemorrhage (IVH) on their baseline scans; of these, five developed progressive ventricular enlargement and in two cases emergent ventriculostomy was required. The authors speculate that rFVIIa may in some way increase the risk of hydrocephalus after ICH by impairing the resolution of ventricular blood.
Although this is an interesting hypothesis, it has been considered that rFVIIa promotes clot formation only within the vasculature when given intravenously after ICH. In our phase IIB clinical trial, we found that rFVIIa reduced IVH volume growth, [5] and there was no increase in the proportion of patients treated with external ventricular drainage with rFVIIa compared to placebo (2% versus 3% respectively).
In the ongoing Phase III FAST trial, 816 patients will be randomized to receive placebo, 20, or 80 µg/kg of rFVIIa. Troponin values are being monitored in all subjects and cardivascular thromboembolic adverse events are being assessed. A blinded digital analysis of CT scans will also allow us to determine whether rFVIIa increases the risk of developing hydrocephalus.
We are encouraging the FAST investigators to continue their high current rate of enrollment so that we can get more answers to the important safety questions raised in these articles as soon as possible. In the meantime, the FAST Trial Steering Committee cannot advocate “compassionate” use of rFVIIa for ICH. If the results of our phase IIB trial are confirmed, however, this stance may urgently need to be reconsidered.
References
1. Sugg RM, Gonzales NR, Matherne DE, et al. Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa. Neurology 2006 67: 1053-1055.
2. Subramaniam S, Demchuk AM, Watson T, Barber PA, Hill MD. Unexpected posthemorrhagic hydrocephalus in patients treated with rFVIIa. Neurology 2006; 67: 1096
3. Mayer SA, Brun N, Begtrup K, et al for the NovoSeven ICH Trial Investigators: Recombinant activated factor VII for acute intracerebral hemorrhage. New Engl J Med 2005;352:777-785.
4. Steven M. Greenberg. Is "compassionate use" compassionate?: rFVIIa for intracerebral hemorrhage. Neurology 2006 67: 934-935.
5. Steiner T, Diringer MN, Schneider D, et al for the Recombinant Activated Factor VII ICH Trial Investigators. Dynamics of intraventricular hemorrhage in patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of hemostatic therapy with recombinant activated factor VII. Neurosurgery 2006 (in press).
Disclosure: Dr. Mayer reports receiving research support, unrestricted educational grants, consulting fees, and speaking honoraria from Novo Nordisk.
The authors of the articles cited in references 1 and 2 had the opportunity to respond to this Correspondence but declined. |
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