Systemic Thrombolysis in Patients With Acute Ischemic Stroke and Internal Carotid ARtery Occlusion
The ICARO Study
Background and Purpose—The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients.
Methods—ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0–2) or unfavorable (score of 3–6). Safety outcomes were death and any intracranial bleeding.
Results—Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03–3.15; P=0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36–3.22; P=0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87–58.71; P=0.068) in the cases than in the controls.
Conclusions—In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.
In patients with acute ischemic stroke, intravenous thrombolysis can restore neurological functions if administered early and is recommended to be administered as soon as intracranial bleeding is ruled out by CT.1,2 Identifying site and nature of the vascular occlusion is not considered as a prerequisite for thrombolysis.1,2 Under these circumstances, patients with extracranial internal carotid artery (ICA) occlusion who present with acute ischemic stroke within 4.5 hours of symptom onset are currently treated with recombinant tissue-type plasminogen activator (rtPA). However, whether thrombolytic therapy is beneficial in these patients remains controversial.3 Angiography-controlled studies of intra-arterial or intravenous thrombolysis in acute cerebral ischemia showed a low recanalization rate in patients with extracranial ICA occlusion,4 suggesting that in these patients rtPA treatment may be less beneficial.4,5 Furthermore, in the only randomized trial of intravenous thrombolysis that used baseline vascular imaging (EPITHET), patients with ICA occlusion treated with rtPA in the 3- to 6-hour window had much worse outcomes compared to placebo-treated patients (modified Rankin Scale [mRS] score, 5–6 at 3 months: rtPA 88% versus placebo 38%; OR, 11.2; 95% confidence interval [CI], 1.1–120.4; P=0.04).6 Conversely, ultrasound-based studies have shown that recanalization of proximal middle cerebral artery clot is achievable even in the presence of ICA occlusion and is strongly associated with a favorable outcome.7
The aim of this case-control multicenter study in patients with acute stroke and ICA occlusion was to evaluate the efficacy and safety of intravenous rtPA administered within 4.5 hours from symptom onset in comparison to a control group of patients with acute stroke and ICA occlusion not treated with rtPA.
Patients and Methods
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.
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.
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.
We analyzed 286 consecutive patients treated with rtPA; 33 patients were excluded from the primary analysis because of absence of matched controls. Thus, 253 cases and 253 controls were included in the final analysis. Baseline demographic and clinical characteristics of the 2 groups were similar (Table 1). The patients excluded from the study had a mean age of 52.3 years and a mean National Institute of Health Stroke Scale score on admission of 15.9; 22 were males, 16 were current smokers, 2 had diabetes mellitus, 7 had hyperlipidemia, 14 had hypertension, 2 had atrial fibrillation, 7 were using antiplatelets, 1 was using statins, 7 had ICA occlusion attributable to atherosclerosis and 14 had ICA occlusion attributable to dissection. In comparison to the 253 cases included in the analysis, the excluded cases were younger (P<0.0001), had a higher rate of ICA occlusion attributable to dissection (P=0.001) and a lower rate attributable to atherosclerosis (P<0.0001), and less often had diabetes (P=0.042).
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.
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).
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).
In this nonrandomized, case-control, multicenter study, patients with acute ischemic stroke associated with ICA occlusion had a clinical benefit from treatment with intravenous thrombolysis regarding their functional outcome; however, an increase in mortality and cerebral bleeding was the trade-off for this benefit. The results of this study confirm that patients with acute ischemic stroke associated with ICA occlusion have a severe 3-month outcome, as shown by the low rate of patients with a mRS score <3. Intravenous thrombolysis provides an increased chance of returning to a nondisabled state. It is of particular clinical relevance that the functional independence as expressed by a mRS score between 0 and 1 was >2-fold increased in cases as compared to controls.
Our results emphasize the difficult balance between reduced dependency and increased mortality. Whether achieving a reduced level of dependency can be justified by the increased risk of death is a difficult judgment and may vary from patient to patient.
The interpretation of the increase in death associated with thrombolytic treatment is not univocally explained. Patients with occlusion of the ICA generally have a large infarcted area surrounded by a large edema, which may be exacerbated by thrombolytic treatment. Forced reperfusion of the irreversibly damaged tissue may increase edema formation and enlarge developing infarcts with a deleterious increase of intracranial pressure. In this study, intravenous thrombolysis was associated with an almost 3-fold increase in the rate of fatal malignant edema in comparison with standard treatment. However, as a contrasting finding from ECASS-III,2 among patients with large infarct, those not receiving thrombolysis died more often from malignant edema.2 Reperfusion-associated damage may not be the only explanation for several reasons. In patients with ICA occlusion, we would expect a large thrombus with reduced propensity to lyse and subsequent reperfusion. Previous studies have shown that recanalization is strongly associated with improved functional outcomes and reduced mortality.9 Controlled trials of thrombolysis in patients with acute ischemic stroke showed greater benefit of intravenous rtPA over placebo in patients with occlusion of middle cerebral artery as compared to those with occlusion of ICA.3,4
Patients with ICA occlusion may be potential candidates for trials using other reperfusion strategies, such as the combined intravenous and intra-arterial thrombolysis or intra-arterial thrombolysis. Alternatively, patients with ICA occlusion may be more suitable for rescue interventional therapies, such as intra-arterial thrombolysis and mechanical thrombectomy, if intravenous thrombolysis fails to achieve recanalization and reperfusion.
Our study has several limitations. The control group included mostly patients not treated with rtPA as they arrived to hospital after 4.5 hours from stroke onset. Early arrival to the stroke unit positively influenced patient disability at discharge and after 3 months.10 However, we found an increase in mortality in patients who arrived to hospital early and were treated with rtPA. This result does not seem attributable to the arrival time, but probably to the treatment itself.
Our study was designed to include patients with proximal ICA occlusion. However, we also included patients with distal ICA occlusion because >50% of the patients had ICA occlusion diagnosed on ultrasonography. Thus, we cannot be certain that an absence of flow at the origin of the ICA on Doppler ultrasound is always caused by a proximal occlusion. Missing information about the exact location of the ICA occlusion may be a limitation of the study because the site of ICA occlusion has prognostic implications.11,12 Other limitations of this study include lack of central adjudication of the outcome events as well as vascular imaging for accurate diagnosis of ICA occlusion and its reperfusion.
Concerning the diagnosis of ICA occlusion, 3 different imaging methods were used with some degree of imbalance between cases and controls. More cases had ICA occlusion diagnosed with MRA or CTA than controls, whereas ultrasound examinations were more frequently used in controls than in cases. The accuracy of these methods in the diagnosis of ICA occlusion in comparison to the gold standard (digital angiography) is similar without significant heterogeneity. MRA has a sensitivity of 98% and a specificity of 100% versus digital angiography, CT angiography has a sensitivity of 97% and a specificity of 99%, and ultrasound examination has a sensitivity of 96% and a specificity of 100%.13–15 For this reason, we believe that the differences between cases and controls regarding the methods used for the diagnosis of ICA occlusion did not influence the results of the study.
However, our study also has some strengths. We included an adequate sample size of patients, cases and controls were matched for risk factors, and the matching procedure was performed in blind manner for the clinical outcome.
In patients with stroke attributable to internal carotid artery occlusion, thrombolytic therapy appears to result in a significant reduction in the proportion of patients dependent for activities of daily living. Increases in deaths and in intracranial hemorrhages are the trade-offs for this clinical benefit, emphasizing the difficult balance between benefit and harm of thrombolytic therapy. In view of the nonrandomized nature of this study, these results should be interpreted with caution.
The study was conducted under the nonfinancial auspices of the Italian Stroke Association. M.P. received honoraria as a member of the speaker bureau of Sanofi-Aventis. G.A. received honoraria as a member of the speaker bureau of Astra Zeneca and Bayer. D.L. has had consultancy roles for and has contributed to advisory boards, steering committees, and adjudication committees for Sanofi-Aventis, Servier, Boehringer Ingelheim, AstraZeneca, Novo-Nordisk, Allergan, Bayer, Ebewe, CoLucid Pharma, Brainsgate, Photothera, Lundbeck, and GSK, fees for which were paid toward research at ADRINORD (Association pour le Développement de la Recherche et de l'Innovation dans le Nord-Pas de Calais) or the research account of the hospital (délégation à la recherche du CHU de Lille). He was reimbursed for travel or accommodation expenses needed for the participation on these boards and committees. He was associate editor of the Journal of Neurology, Neurosurgery and Psychiatry from 2004 to 2010. D.T. was paid for expert testimony by Boehringer Ingelheim, Pfizer, and Sanofi-Aventis. The other authors have nothing to disclose.
Bo Norrving, MD, PhD, was the Guest Editor for this paper.
- Received June 23, 2011.
- Accepted August 12, 2011.
- © 2012 American Heart Association, Inc.
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