Medical Treatment Early Hemostatic Therapy

The use of hemostatic agents designed to arrest ongoing hemorrhage in the hyperacute setting constitutes one of the most promising interventions to improve the outcome of patients with ICH (17). In that, hematoma expansion is most common in the first few hours after bleeding onset, the effectiveness of this treatment depends on its very early administration. Hemostatic agents may theoretically increase the risk of thrombotic complications. Therefore, the results of a recently conducted Phase 2 trial, which proved the feasibility and safety of this therapeutic strategy, are of great importance (18,19). The information yielded from the trial has already become available for the use of activated recombinant factor VII (rFVIIa), which is a genetically altered agent resembling a natural clotting factor.

This randomized, double-blinded, placebo-controlled, dose-escalation trial tested the use of 6 different doses of rFVIIa versus placebo in 47 patients with ICH within 3 hr of ictus onset (18). Mean age of participants was 61 ± 15 years, median GCS was 14, and mean ICH volume was 21 ± 24 mL (range, 1-151 mL). ICH was ganglionic in 72% of cases, and intraventricular extension was present in 45%. Treatment was initiated after a median interval of 181 min (range, 120-265 min) from hematoma onset. ICH growth was documented in 17% at 1 hr and 19% at 24 hr. No differences were observed in hematoma growth or functional outcome among the treatment groups, but the study was not powered to assess efficacy. Twelve serious adverse events occurred, including 5 deaths; all fatalities were primarily caused by the ICH itself. No relationship was detected between the frequency, type, or severity of side effects and rFVIIa dose. Six adverse events were considered possibly related to treatment, but only two were potentially severe (popliteal deep venous thrombosis in the acute phase in one case and T-wave inversion at 24 hr without elevation of creatinine kinase isoenzyme MB (CK-MB) level in the other). No cases of consumption coagulopathy, systemic embolism, or excessive cerebral edema causing neurologic deterioration were reported. The authors reasonably concluded that this small Phase 2 trial did not raise major safety concerns and that a larger trial was justified to confirm the safety and evaluate the effectiveness of rFVIIa in the treatment of acute ICH.

Another Phase 2B (19), dose-ranging, proof-of-concept trial randomized 399 patients with primary ICH (confirmed by CT scan) within 3 hr after onset of symptoms to receive rFVIIa 40 |g/kg body weight (BW; 108 patients), 80 |g/kg BW (92 patients), 160 |g/kg BW (103 patients), or placebo (96 patients) (18). Patients were excluded if they had a GCS > 6, history of coagulopathy or recent use of oral anticoagulants, or any history of thrombotic or vaso-occlusive disease. Treatment was started within 1 hr of obtaining the CT scan and administered in a double-blinded fashion. The primary outcome measure was the percentage change in the hematoma volume at 24 hr. Clinical outcomes were assessed at 90 days using various validated scales. Analysis followed the intention-to-treat principle. Baseline characteristics were similar in all groups, although the degree of acute blood pressure elevation was not reported. Location of the hematoma was deep in more than 80% of cases, and median GCS was 14. Mean hematoma volume at baseline was 27 mL (range, 0.4-153 mL). Mean time from symptom onset to initiation of treatment was 167 ± 32 min.

Increase in hematoma volume was lower in the rFVIIa arms than in the placebo group (p = 0.01 for the difference between placebo and the combined rFVIIa groups), and the difference was more pronounced with the higher doses of rFVIIa. Mean percentage increase from baseline was 29% with placebo, versus 16%, 14%, and 11% with the 3 escalating doses, respectively. This reflected absolute volume differences of 3.3, 4.5, and 5.8 mL in the 3 treatment doses. Benefit was greater when therapy was initiated within 3 hr of symptom onset. Total lesion volume [ICH + intraventricular hemorrhage (IVH) + edema] was also significantly reduced in the treatment groups; the estimated mean total volume reduction at 72 hr was 11 mL for the combined treatment groups. Mortality at 3 months was 29% in the placebo group versus 18% in the treatment groups combined (p = 0.02; relative risk reduction 5 38%; Fig. 1) . Functional outcome was also significantly better in patients who received rFVIIa; a 16% absolute reduction in the number of patients with modified Rankin score of 4 to 6 at 90 days was associated with the use of rFVIIa. In terms of functional outcome, the best dose was 80 |g/kg BW. Severe arterial thromboembolic events were significantly more frequent among patients treated with rFVIIa (5% vs. 0% with placebo; p = 0.01), including 2 cases of ischemic stroke that were fatal and 5 more that were disabling. Rates of venous thromboembolic events did not differ between

Figure 1 Survival at 90 days according to study group. Mortality was reduced by approximately 35% in each rFVIIa group, as compared to placebo group (p=0.10 by the log-rank test, comparing all 4 groups; p=0.02 by the chi-square test for the comparison of the three rFVIIa groups combined with placebo). Source: From Ref. 19.

groups. Only 2% of the serious thromboembolic events were considered possibly or probably related to the drug.

In summary, this trial showed that early infusion of rFVIIa can ameliorate ICH growth, with a resulting favorable impact on functional outcome. However, it did not dispel concerns that the treatment might increase the risk of serious arterial vascular events. The investigators concluded that further research is still needed to identify the best candidates for the safe use of this hemostatic treatment, as well as the ideal dose and optimal time window for its administration. The cost of the drug is high—up to $12 per patient—but may be offset by reduced hospital stay and rehabilitation time.

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