European Cooperative Acute Stroke Study II

In the wake of the NINDS rtPA Stroke Study, ECASS II was undertaken to determine if rtPA could be effective even when administered more than 3 hr after the onset of stroke symptoms. ECASS II is the largest randomized trial of thrombolytic therapy that has been conducted in acute stroke to date, enrolling 800 patients in 108 centers throughout Europe, Australia, and New Zealand, randomly assigning them to rtPA, using the NINDS Stroke Study dosing regimen versus placebo (43). To prevent the large number of protocol violations observed in ECASS I, the steering committee for ECASS II undertook more rigorous training of investigators to improve interpretation of CT scans and treat hypertension appropriately. The primary endpoint was a favorable outcome on the mRS, using the dichotomized method of analysis employed in the NINDS study. Only 158 (19.8%) of the 800 patients were enrolled, randomized, and treated within 3 hr of stroke symptom onset. A favorable outcome of no more than 1 point on the mRS was seen in 40.3% of patients in the rtPA group and 36.6% in the placebo group, but this was not statistically significant. Post hoc analysis based on a dichotomized mRS that represented physical independence (0-2) uncovered a statistically significant benefit to treatment with rtPA, with 54.3% of treated patients returning to independence, compared to 46% of placebo patients (p=0.024). Symptomatic ICH occurred more frequently in the rtPA-treated group (8.8%), compared to 3.4% in the placebo group, but no difference in mortality at 30 or 90 days was observed. The ECASS investigators concluded that their data failed to support the use of rtPA beyond 3 hr.

As in ECASS I and the NINDS rtPA Stroke Study, risk factors for hemorrhagic transformation of infarct were identified in post hoc analysis of the ECASS II data set. In ECASS I, screening for risk factors associated with postthrombolytic hemorrhage was focused on radiographic criteria for ICH. In the NINDS study, hemorrhagic transformation was classified into symptomatic or asymptomatic hemorrhage, regardless of appearance on CT. In ECASS II, as in ECASS I, analysis of risk factors for ICH relied on categorization of HI and PH, but investigators surveyed clinical criteria to address symptomatic expression of ICH (SICH). Similar to ECASS I, the study protocol in ECASS II required a baseline CT scan to determine eligibility, a second CT at 22 to 36 hr, and a third scan on day 7 postrandomization. Review of post-thrombolytic brain hemorrhage in ECASS II showed that HIs occurred in 283 (35.7%), PHs in 60 (7.6%), and SICHs in 49 (6.2%) of the aggregated sample (44). HIs were no more frequent in the rtPA group than in the placebo group, as in ECASS I, whereas PHs and SICHs were associated with active thrombolysis. Logistic regression analyses showed significant interactions for poor outcome—defined as mRS 5 (severely disabled and dependent on nursing care) or 6 (death)—between rtPA exposure and PH (OR: 4.8; 95% CI: 1.2-24.7) and between rtPA use and SICH (OR: 6.9; 95% CI: 1.8-30.3), suggesting that both categories of hemorrhagic transformation were not only more common but were also more severe in rtPA-treated patients. Significant risk factors for PH were exposure to rtPA, extent of parenchymal hypoattenuation on baseline CT scan, history of congestive heart failure, increased age, and baseline systolic blood pressure. However, logistic regression analysis showed that interactions between rtPA exposure and any of the remaining factors were significant only for increased age and prior aspirin exposure, suggesting that PHs that resulted from rtPA use in ECASS II were more frequent in older patients and in those who used aspirin before stroke. Significant risk factors for SICH included exposure to rtPA, history of congestive heart failure, extent of parenchymal hypoattenuation on baseline CT, and increased age, with no interaction detected on subsequent regression analysis. This secondary analysis of hemorrhagic risk in ECASS II confirmed the importance of the volume of hypoattenuated brain seen on baseline CT as a risk factor for serious ICH and suggested, but could not confirm, that older patients and those with prior use of aspirin are at higher risk. As with the hemorrhagic risk factors identified in the ECASS I and NINDS rtPA Stroke Studies, these variables would have to be confirmed in independent trials before they could be applied to risk stratification for rtPA use in daily practice.

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