Systemic Thrombolysis in Patients With Acute Ischemic Stroke and Internal Carotid ARtery Occlusion

Patient Population and Study Design

ICARO was a case-control study of prospectively collected data performed in 27 centers in 7 countries. Cases were consecutive patients with acute ischemic stroke and ICA occlusion on admission (as shown by carotid ultrasound or CTA or MRA) treated with intravenous rtPA within 4.5 hours from symptom onset. Controls were patients with acute ischemic stroke and ICA occlusion not treated with rtPA because the onset of stroke symptoms was either between 4.5 and 12 hours before admission or uncertain, as is the case for stroke at waking. Cases and controls were matched for age, gender, and severity of stroke. The matching procedure was performed in absence of any information about the patient final outcome. Inclusion and exclusion criteria were those of the SITS-MOST study,⁸ except for the 80-year age limit. Patients of both genders were eligible for inclusion in the study if they were older than 18 years of age and had a clinical diagnosis of acute ischemic stroke associated with ICA occlusion. Acute stroke was defined as sudden onset of an acute focal neurological deficit, such as impairment of language, motor function, cognition, gaze, vision, or neglect (or a combination of these). Stroke symptoms were to be present for at least 30 minutes without significant improvement before treatment. Symptoms must have been distinguished from an episode of generalized ischemia (ie, syncope), seizure, or migraine disorder. On admission, a cerebral CT scan was required to exclude patients with intracranial bleeding. In some cases, MRI was performed instead of CT. Cases received 0.9 mg of rtPA (Actilyse; Boehringer Ingelheim or Activase; Genetech) per kilogram, administered intravenously (with an upper limit of 90 mg). Of the total dose, 10% was administered as a bolus and the remainder was administered by continuous intravenous infusion over a period of 60 minutes. Neurological deficit was assessed using the National Institute of Health Stroke Scale. Follow-up neuroimaging was performed between 24 and 36 hours after admission. Further brain CT scans were performed at discretion of the investigators.

Patients gave informed consent to thrombolytic treatment and to retrieval of data and follow-up procedures, according to the regulations in participating countries. Patients were excluded from the study if they had symptoms >4.5 hours for cases and >12 hours for controls.

Outcome Measures

The primary efficacy study outcome was disability at day 90 (3-month visit), as assessed by means of the modified Rankin scale, dichotomized as favorable outcome (score of 0–2) or unfavorable outcome (score of 3–6). Safety outcomes were overall mortality at day 90, any intracranial bleeding,² fatal intracranial bleeding, and other serious adverse events.

Statistical Analysis

Comparisons of patient features in the thrombolysis group and the non thrombolysis group were performed using the Mann-Whitney U test. Data were given as mean and standard deviation (±SD) or median with interquartile range when appropriate. For the outcome measures (efficacy and safety end points), between-group differences were calculated with the Mann-Whitney U test. Ninety-five percent CI were calculated for odds ratio (OR). Because of the nonrandomized design, an adjusted analysis (logistic regression) of the outcome end points was performed. This analysis was performed by including all baseline variables in the model and retaining those that were significant at P<0.10.

The calculation of the sample size was based on an anticipated increase in the rate of patients with favorable outcome at 3 months (mRS score, 0–2) from 25% in the control group³ to 38% in the treated group, for α=0.05 and power of 80%. On the basis of these data, we anticipated that at least 200 patients per group were required.

Efficacy

Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%), corresponding to an absolute risk reduction of 8.3% (OR, 1.56; 95% CI, 1.04–2.35; P=0.039). Regression analysis for favorable outcome was performed adjusting for the following confounding baseline variables: study group assignment, age, gender, baseline National Institute of Health Stroke Scale score, smoking status, history of stroke or transient ischemic attack, baseline glycemia, presence of atrial fibrillation, dissection of the ICA, previous use of statins, and the methods used for the diagnosis of ICA occlusion. In the adjusted analysis, treatment with rtPA remained significantly associated with a favorable outcome (OR, 1.80; 95% CI, 1.03–3.15; P=0.037). The results of the analysis related to further functional outcomes are summarized in Table 2. The overall distribution of scores by the modified Rankin scale is shown in the Figure.

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Figure.

Distribution of scores on the modified Rankin Scale.

A further analysis of mRS score 0 to 1 at 3 months was also performed; 51 cases (20.2%) had mRS score 0 to 1, as compared with 25 controls (9.9%), representing an absolute improvement of 10.3% (OR, 2.04; 95% CI, 1.22–3.41; P=0.008). In the adjusted analysis, treatment with rtPA remained significantly associated with a mRS score 0 to 1 at 3 months (OR, 2.59; 95% CI, 1.38–4.85; P=0.003).

Safety

A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%), corresponding to an absolute risk increase of 10.3% (OR, 1.89; 95% CI, 1.21–2.95; P=0.005). Regression analysis for unfavorable outcome was performed adjusting for the following confounding baseline variables: study group assignment, age, gender, baseline National Institute of Health Stroke Scale score, smoking status, history of stroke or transient ischemic attack, baseline systolic and diastolic blood pressure, presence of atrial fibrillation, dissection of the ICA, atherosclerotic etiology, and the methods used for the diagnosis of ICA occlusion. In the adjusted analysis, treatment with rtPA remained significantly associated with mortality (OR, 2.28; 95% CI, 1.36–3.22; P=0.001). The causes of death are shown in Table 3. There were significantly more cases of fatal malignant edema in the rtPA group compared to controls (21 patients [8.3%] and 8 patients [3.2%], respectively; P=0.013).

There were more cases of intracranial bleeding (17.8% versus 11.1%; OR, 1.67; 95% CI, 1.01–2.76; P=0.050) and fatal intracranial bleeding (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87–58.71; P=0.068) among cases than controls. Five patients had other serious adverse events related to treatment with rtPA (3 gastrointestinal bleeding cases and 2 tongue edema cases).

In the 33 patients treated with rtPA not included in the analysis because of absence of matched controls, the mortality rate was 15%, whereas 33% of these patients had a mRS score 0 to 2 after 90 days. After inclusion of these patients in the regression logistic model, treatment with rtPA remained significantly associated with a favorable outcome (OR, 1.92; 95% CI, 1.13–3.25; P=0.015) and with increased mortality (OR, 2.25; 95% CI, 1.35–3.75; P=0.002).