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Death

I 26%

25%

27%

21% I

39%

I 21% I 23%

I 17% I

Glasgow Outcome Scale

1 2 3-4 Death

32%

22%

25%

21% I

44%

17% 22%

I 17% I

FIGURE 3.2 Differences between IV rt-PA and placebo-treated patients on four assessment scales using data taken from part II of the 1995 NINDS trial.24 Values do not total 100% because of rounding. The odds ratio for a global favorable outcome with intravenous rt-PA was 1.7 (95% CI 1.2-2.6, p = 0.008). The global favorable outcome was defined as NIHSS, 0-1; Barthel Index, 95-100; modified Rankin Scale, 0-1; and Glasgow Outcome Scale, 5.

FIGURE 3.2 Differences between IV rt-PA and placebo-treated patients on four assessment scales using data taken from part II of the 1995 NINDS trial.24 Values do not total 100% because of rounding. The odds ratio for a global favorable outcome with intravenous rt-PA was 1.7 (95% CI 1.2-2.6, p = 0.008). The global favorable outcome was defined as NIHSS, 0-1; Barthel Index, 95-100; modified Rankin Scale, 0-1; and Glasgow Outcome Scale, 5.

Intravenous rt-PA: More Than 3 Hours Beyond Stroke Onset

Three large randomized trials, the European Cooperative Acute Stroke Study (ECASS) parts I and II, and the Alteplase Thrombolysis for Acute Noninterven-tional Therapy in Ischemic Stroke (ATLANTIS), have investigated the efficacy of IV rt-PA in acute stroke beyond the 3-hour window. All three studies showed high rates of sICH complicating rt-PA treatment, and no overall efficacy of rt-PA.

ECASS-I, reported in 1995, was the first large randomized controlled trial of IV thromblysis.28 Patients with acute ischemic hemispheric stroke and moderate-to-severe clinical deficits, presenting within 6 hours of stroke onset, were randomized to rt-PA (n = 313) or placebo (n = 307). The rt-PA dose was 1.1 mg/kg, with 10% given as a bolus and the remaining 90% infused over 60 minutes. Patients with very severe stroke signs (hemiplegia, impaired consciousness, or forced head or eye deviation), or signs of infarction involving more than one-third of the middle cerebral artery (MCA) territory on the initial computed tomography (CT) scan were excluded because of preliminary studies showing little evidence for a beneficial effect of thrombolysis in those groups.29 A post hoc analysis, including a centralized blinded re-review of the initial CT scans, showed a high proportion of protocol violations (18%). Most violations were because the initial CT showed more extensive infarction than allowed by the trial protocol.

The primary hypotheses of ECASS-I were that rt-PA-treated patients, compared to placebo, would have a >15-point difference in BI score and >1 grade difference in mRS score at 90 days. Intent-to-treat analyses showed no difference in either the BI scores (p = 0.99) or the mRS scores (p = 0.41). Parenchymal hematoma on post-treatment CT was seen in 20% of rt-PA-treated patients and 7% of placebo controls (p < 0.001). There was a higher 90-day mortality in the rt-PA-treated group compared to the placebo group (22% vs. 16%, p = 0.04), partly because there were more deaths attributed to intracranial hemorrhage (6% vs. 2%, p = 0.02). When the data were reanalyzed, excluding patients with protocol violations, there was no difference in the BI-scores (p = 0.14) but there was a difference in the mRS scores (median 90-day mRS was 2 in the rt-PA group and 3 in the placebo group, p = 0.04).

ECASS-II was designed to test a lower dose of rt-PA (0.9 mg/kg) during the same 0-6-hours time period after stroke onset, using similar inclusion criteria as in ECASS-I.30 The primary endpoint was the proportion with a favorable outcome on the mRS scale (defined as a score of 0 or 1). There was no difference in this outcome between rt-PA-treated and placebo controls (40% vs. 37%, p = 0.28). A separate analysis of the 158 subjects enrolled within 3 hours of stroke onset also showed no difference in the proportion with a favorable outcome (42% vs. 38%, p = 0.63); this result, however, must be treated with caution because in ECASS-II there was a substantially lower number of patients treated within 3 hours of stroke onset, compared to the 1995 NINDS rt-PA study. Parenchymal hematoma on post-treatment CT was seen in 12% of rt-PA-treated and 3% of placebo patients (p < 0.001). The 90-day mortality rate was 11% for the rt-PA group and 11% for the placebo group (p = 0.54). Protocol violations were much less frequent in ECASS-II compared to ECASS-I (9% vs. 18%), probably because of standardized training in CT interpretation at the study sites.

The ATLANTIS trial was designed to test the hypothesis that rt-PA, at a dose of 0.9 mg/kg, would result in better outcomes when given to patients within 6 hours of stroke onset.31 The trial was stopped early, after 142 patients were enrolled, because of a high rate of sICH in patients enrolled 5-6 hours after stroke symptom onset (4/ 22 rt-PA compared to 0/24 placebo, p = 0.03).31 It was decided to start a new trial, enrolling patients 0-5 hours after stroke (ATLANTIS Part B).32 However, the time window for ATLANTIS Part B was changed to 3-5 hours after the first 31 patients were enrolled because of FDA approval for IV rt-PA use within 3 hours of stroke onset. Acute ischemic stroke patients were randomized to 0.9 mg/kg rt-PA (n = 307) or placebo (n = 306).32 The primary outcome was the proportion with an excellent recovery, defined as an NIHSS score of 0 or 1 at 90 days. There was no difference in the primary outcome (35% of rt-PA-treated patients and 34% of placebo patients had an excellent recovery, p = 0.89). In the rt-PA-treated group, there was a higher rate of sICH (7% vs. 1%, p < 0.001) and a trend toward higher mortality (11% vs. 7%, p = 0.08).

The combined experience with IV rt-PA treatment beyond 3 hours, therefore, suggests reduced effectiveness compared to treatment within 3 hours. A pooled analysis of the ATLANTIS, ECASS, and NINDS rt-PA studies confirmed that the odds of a favorable 3-month outcome, defined as minimal or no poststroke disability on the BI, mRS, and NIHSS, decreased with increasing stroke onset to start of treatment time (OTT) (p = 0.005).33 The odds ratios for favorable outcome with rt-PA treatment were 2.8 (95% CI 1.8-4.5) for OTT 0-90 minutes, 1.6 (95% CI 1.1-2.2) for 91-180 minutes, 1.4 (95% CI 1.1-1.9) for 181-270 minutes, and 1.2 (95% CI 0.9-1.5) for 271-360 minutes. This finding, that earlier treatment is associated with more therapeutic efficacy, supports the adage that in the delivery of acute stroke therapy "time is brain.''34 The rate of sICH was not associated with OTT.33

rt-PA-RELATED HEMORRHAGE

Posttreatment sICH is the most feared complication of IV rt-PA treatment. The independent risk factors for sICH in the NINDS rt-PA study were rt-PA treatment, severity of the neurological deficit, and evidence of brain edema or mass effect on the pretreatment CT.35 Increased age was a risk factor in the univariate analysis (p = 0.05), but was no longer significant after controlling for the other factors. The regression model showed relatively low sensitivity and specificity for age as a predictor of sICH, suggesting that it is not clinically useful for patient selection. Moreover, there was no convincing evidence that rt-PA was ineffective in the patients at highest risk of sICH. Those with mass effect or edema on pretreatment CT had a nonsignificantly increased odds of favorable outcome with rt-PA (OR 3.4, 95% CI 0.6-20.7); the wide confidence intervals reflect the small number of rt-PA-treated patients with mass effect or edema (n = 16). Patients with NIHSS > 20 had an increased odds of favorable outcome with rt-PA treatment (OR 4.3, 95% CI 1.6-11.9). Therefore, there is little justification for withholding rt-PA treatment because of high stroke severity.

Risk factors for rt-PA-related hemorrhage have also been determined from the ECASS-I and ECASS-II data. In those studies, the hemorrhages were divided into hemorrhagic infarction, consisting of small petechiae without mass effect, and parenchymal hematoma, consisting of a blood clot sometimes accompanied by mass effect.35 Most sICH was caused by parenchymal hematoma rather than hemorrhagic infarction.36 For analysis, the extent of hypoattenuation on the pre-treatment CT scan was categorized into 0%, <33%, and >33% of the MCA territory. In ECASS-I, risk factors for parenchymal hematoma were rt-PA and age; risk factors for sICH were not reported.35 In ECASS-II, the independent risk factors for parenchymal hematoma were rt-PA, extent of hypoattenuation on the pretreatment CT scan, history of congestive heart failure, increasing age, and baseline systolic blood pressure.37 In the rt-PA-treated group, treatment with aspirin was an additional risk factor.37 The risk factors for sICH were the same, with the exception that baseline systolic blood pressure was no longer significant.37 Similar to the NINDS data, there was no combination of factors that predicted the future occurrence of sICH with high sensitivity and specificity.

These data therefore suggest that rt-PA should not be withheld for fear of sICH, even when risk factors for sICH are present. The possible exception, based on the ECASS-II data, is when extensive hypoattenuation, greater than one third of the MCA territory, is present.37 An American Academy of Chest Physicians guideline statement recommends against treatment with rt-PA when there are CT signs of infarction in greater than one third of the MCA territory, although it is acknowledged that there is insufficient evidence to make definite conclusions about the degree of risk.38 There has been a concern that the elderly, particularly those >80 years old, may be at special risk of rt-PA-related sICH. Among the rt-PA trials, >80 year-olds were only enrolled in the 1995 NINDS rt-PA study and separate outcomes were not reported among this fairly small subgroup. Nonrandomized studies, however, suggest that rt-PA may be safe and effective in >80-year- olds.39,40 Control of elevated blood pressure to <185/11041 and avoidance of concurrent administration of antiplatelet agents for 24 hours are reasonable steps to minimize the risk of sICH in all rt-PA-treated patients.

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