Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage

Mayer, Stephan A.; Brun, Nikolai C.; Begtrup, Kamilla; Broderick, Joseph P.; Davis, Stephen M.; Diringer, Michael N.; Skolnick, Brett E.; Steiner, Thorsten

doi:10.1056/nejmoa0707534

Cited by 1,150 publications

(835 citation statements)

References 23 publications

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“…These results are in accordance with the potent antihemorrhagic activity we had previously demonstrated in murine models of mild and severe bleeding 20. Moreover, reduction in hematoma expansion achieved with CM352 was accompanied by a substantial improvement in functional and neurological recovery, in marked contrast with clinical trials of rFVIIa, which reduced hematoma growth but did not improve survival or functional outcome after ICH 9. The use of the antifibrinolytic agents ε‐aminocaproic acid and TXA has been proposed after ICH (STOP‐AUST trial)11; however, the only experimental evidence available shows that TXA exacerbates edema in a mouse model of warfarin‐associated ICH 29.…”

Section: Discussionsupporting

confidence: 90%

“…Strategies addressing hematoma expansion by lowering blood pressure,7 surgical hematoma removal,8 reversal of anticoagulants,3 or hemostatic therapy with rFVIIa9 have provided evidence of reduced hematoma growth, but results regarding long‐term therapeutic benefit have been mainly disappointing 4. Moreover, to our knowledge, only a few preclinical studies have been conducted to assess the effects of the pharmacological modulation of hematoma growth 6.…”

Section: Discussionmentioning

confidence: 99%

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CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Rodríguez

Sobrino

López-Arias

et al. 2017

JAHA

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BackgroundIntracerebral hemorrhage (ICH) is an acute neurological disorder with high mortality and no effective treatment. In addition to the initial bleeding event, rebleeding and hematoma expansion are associated with poor outcome in these patients. We studied the effectiveness of the new antifibrinolytic agent CM352, a short‐half‐life matrix metalloproteinase inhibitor, for achieving early hemostasis and improving functional recovery in a rat model of collagenase‐induced ICH.Methods and Results ICH was induced by striatal injection of collagenase, and 1 hour later, rats received an intravenous injection of saline (n=6) or CM352 (1 mg/kg, n=6). Hematoma (basal and after 3 and 24 hours) and lesion (14 days) volumes were quantified on T2‐weighted (T2) magnetic resonance images. Neurological and functional recovery was evaluated by using Bederson score and a cylinder test (basal, 24 hours, and 14 days). Early treatment (1 hour) with CM352 was efficient reducing hematoma expansion at 3 hours (P<0.01) and, more markedly, at 24 hours (P<0.01). Decreased bleeding after antifibrinolytic treatment was accompanied by reduced interleukin‐6 levels at 3 hours (P<0.05) and smaller lesion volume at 14 days (P<0.01). CM352 drastically reduced sensorimotor impairment (cylinder test) after ICH in rats at 24 hours (P<0.01) and 14 days (P<0.01). Similarly, it also attenuated neurological deficit (Bederson scale) at 24 hours (P<0.01) and 14 days (P<0.01). Interestingly, late (3 hours) CM352 administration also resulted in reduced lesion size and better functional outcome.Conclusions CM352, a new antifibrinolytic agent and matrix metalloproteinase inhibitor, effectively prevented hematoma growth and reduced lesion size in ICH in association with improved functional and neurological recovery.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Rodríguez

Sobrino

López-Arias

et al. 2017

JAHA

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“…However, recently published results of a phase three randomized trial including 841 patients of ICH by the same group concluded that haemostatic therapy with rFVIIa reduced growth of the haematoma but did not improve survival or functional outcome after ICH [20]. Study also showed increased risk of thromboembolism, particularly arterial, in rFVIIa treated group.…”

Section: Spontaneous Intracerebral Hemorrhage (Ich)mentioning

confidence: 99%

Rational Use of Recombinant Factor VIIa in Clinical Practice

Dutta

Verma

2013

Indian J Hematol Blood Transfus

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In the United States, the FDA-approved indications for recombinant factor VIIa is for bypassing inhibitors to factors VIII and IX in patients with hemophilia A and B respectively and for treatment of congenital factor VII deficiency. In European countries, rFVIIa is licensed for the above indications as well as for Glanzmann's thrombasthenia. In absence of high-quality data favoring off-label use of this agent and laboratory test to predict response to this agent, and in view of high cost of rFVIIa, off-label use of recombinant factor VIIa should be restricted to only when hemorrhage has not responded to transfusion or other conventional therapy. It appears, two such conditions where recombinant factor VIIa may be beneficial are traumatic and postpartum hemorrhages.

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“…A high response rate in the placebo arm can affect the potential of detecting treatment effects in clinical trials 20, 21, 22. In the CHIMES study, almost half in the placebo group achieved functional independence (mRS 0 to 1) at the end of 3 months.…”

Section: Discussionmentioning

confidence: 99%

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

Venketasubramanian

Lee

Wong

et al. 2015

Journal of Evidence-Based Medicine

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ObjectiveThe CHIMES Study compared MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. We aimed to verify if patient selection based on two prognostic factors (ie, stroke severity and time to treatment) improves detection of a treatment effect with MLC601.MethodsAnalyses were performed using data from the CHIMES Study, an international, randomized, placebo‐controlled, double‐blind trial comparing MLC601 to placebo in patients with ischemic stroke of intermediate severity in the preceding 72 hours. Three subgroups, that is, onset to treatment time (OTT) ≥48 hours; baseline National Institute of Health Stroke Scale (NIHSS) ≥10; both OTT ≥48 hours and baseline NIHSS ≥10, were analyzed using modified Rankin Scale (mRS) ≤1 and a composite endpoint of mRS ≤1, Barthel Index ≥95, and NIHSS ≤1 at month 3.ResultsPlacebo response rates were lower (ie, worse natural outcome) among subgroups with prognostic factors. Conversely, MLC601 treatment effects were significantly higher in the subgroups with prognostic factors than for the entire cohort, being highest among patients with both OTT ≥48 hours and baseline NIHSS of 10 to 14: odds ratios of 2.18 (95% CI 1.02 to 4.65) for month 3 mRS ≤1 and 3.88 (95% CI 1.03 to 14.71) for the composite endpoint.Conclusions: Patients who have moderately severe strokes and longer OTT demonstrate better treatment effects with MLC601. These factors can guide patient selection in future trials.

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Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage

Abstract: Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. (ClinicalTrials.gov number, NCT00127283 [ClinicalTrials.gov].).

Cited by 1,150 publications

References 23 publications

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Rational Use of Recombinant Factor VIIa in Clinical Practice

The value of patient selection in demonstrating treatment effect in stroke recovery trials: lessons from the CHIMES study of MLC601 (NeuroAiD)

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