Combined IV and intra-arterial thrombolysis for acute ischemic stroke

IV recombinant tissue plasminogen activator (rt-PA) administered to appropriately selected patients is the only Food and Drug Administration–approved treatment for acute ischemic stroke.¹ Recently, there has been increased interest in the combination of IV and intra-arterial (IA) therapy. This approach has the advantage of early initiation of treatment with subsequent angiographic documentation of cerebrovascular anatomy and, further, more localized IA thrombolysis, if required.

Our group previously participated in the Emergency Management of Stroke (EMS) and Interventional Management of Stroke (IMS) Studies, which tested the IV/IA approach in 115 patients.^2,3 We now present outcomes for 62 patients from a local registry treated with an IV/IA strategy after the EMS Trial but before the IMS Study.

Methods.

This report describes 62 nonrandomized patients with acute ischemic stroke treated with the intention of using a combined IV/IA approach between October 1998 and March 2001 by investigators at the University of Cincinnati. In the Cincinnati model of stroke treatment, stroke team members take calls regarding potential thrombolytic candidates from all hospitals in the Greater Cincinnati/Northern Kentucky region and drive to the call site to initiate evaluation and treatment. If patients receive IV thrombolysis alone, they are typically admitted to the local hospital. If IV/IA therapy is contemplated, patients are transferred to one of three tertiary hospitals for angiography after initiation of IV rt-PA at the outside hospital.

For the current series, patients were considered eligible for IV/IA treatment if they met criteria used in the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial and had a NIH Stroke Scale (NIHSS) score of ≥10.¹ Patients with scores of <10 were excluded because previous studies have shown they have considerably lower rates of large-vessel occlusion.⁴ Excluded patients were treated with IV rt-PA as appropriate. There were no upper age restrictions. Informed consent was obtained from the patient or legal proxy.

Treatment consisted of IV rt-PA (0.6 mg/kg, 60 mg maximum, 15% bolus over 1 minute with the remainder over 30 minutes) followed by immediate cerebral angiography and up to 22 mg of additional IA rt-PA delivered locally or regionally over 2 hours. The IV dose of 0.6 mg/kg was chosen based on prior clinical dose escalation trials suggesting efficacy in this range.⁵ The 15% bolus was chosen to provide a dose equivalent to a 10% bolus of 0.9 mg/kg rt-PA.³ Protocols for the angiographic procedure were comparable with those in the IMS Trial, except that heparin infusions were not standardized.³

Time to thrombolytic administration, occurrence of symptomatic intracerebral hemorrhage (ICH), and 3-month modified Rankin Scale (mRS) scores (obtained by telephone interview) were recorded. Angiographic recanalization for IV/IA patients was documented using the Thrombolysis in Myocardial Infarction (TIMI) Scale, where TIMI 0 = no recanalization, TIMI 1 = minimal flow, TIMI 2 = partial recanalization, and TIMI 3 = complete recanalization. Asymptomatic hemorrhagic conversion of cerebral infarctions and asymptomatic ICH were not documented for this cohort. Statistical comparisons were made using the Fisher exact test. Treatment results for 20 of the patients included in this series have been previously published.²

Results.

There were 37 women and 25 men with a mean age of 69 years (range 20 to 89 years); 8 patients were older than 80 years. Median baseline NIHSS score was 18 (range 11 to 34). Median time to initiation of IV rt-PA therapy was 129 minutes. Forty-seven of 62 patients (76%) had IV therapy initiated at a community hospital followed by immediate transfer to a tertiary center for angiography. IA thrombolysis was not performed in 18 patients (29%) because of distal emboli (7), difficulties in catheterization (5), recanalizing occlusion (2), no occlusive lesion seen (2), large infarct on CT (1), and nonneurologic symptoms (1). In the remaining 44 patients, median time to initiation of IA rt-PA was 226 minutes (235 minutes among 35 patients transferred from an outlying hospital vs 195 minutes for 9 patients treated at the site of presentation).

For patients with clot seen at angiography (excluding very distal emboli), the sites of arterial occlusion and degrees of arterial recanalization after therapy are presented in table 1. Neurologic outcomes at 3 months are presented in table 2. There was one puncture site hematoma/pseudoaneurysm as a complication of angiography. Mortality was higher among persons older than 80 (5/8, 63%) than among those age 80 or younger (6/54, 11%; p =0.003); however, patients over age 80 had higher baseline NIHSS scores (see table 2). Functional outcomes, as measured by 3-month mRS, were also worse for patients over age 80 (p = 0.005). There were five (8%) symptomatic ICHs, four of which, in combination with the presenting infarction, were fatal; two hemorrhages occurred in patients over age 80 vs three in persons 80 or younger (p = 0.12). Among patients with an initial NIHSS score of >20, a greater number (12/25, 48%) achieved a 3-month mRS score of 0 to 2 than patients in the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial with an NIHSS score of >20 who were treated with rt-PA (9/48, 19%; p = 0.014) or placebo (8/60, 13%; p = 0.001; National Institute of Neurological Disorders and Stroke Stroke Trial data provided by personal communication, Y. Palesch, PhD). A comparison of outcomes in the EMS Trial, IMS Study, National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial, and the current series is presented in table 3.

Discussion.

Our center and several other academic institutions now have considerable experience with IV/IA therapy.^3,4,6,7 The results of our series are consistent with the EMS and IMS Trials of combined IV/IA therapy, with 35% of patients achieving a 3-month mRS score of 0 to 1 and 50% achieving a score of 0 to 2 (see table 3).

A potential advantage of IV/IA therapy vs IV therapy is the ability to infuse rt-PA at the site of clot. It is hoped the combined approach will be more effective than IV rt-PA for treating severe ischemic strokes with large clot burden, as occurs with proximal middle cerebral artery, carotid terminus, and basilar artery occlusions. Other studies have shown that only a minority of such occlusions are opened by IV rt-PA.^3,8,9 In the current series, rates of good outcome (mRS score 0 to 2) for patients presenting with an NIHSS score of >20 were greater than for historical rt-PA- or placebo-treated patients in the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial.

A potential advantage of the IV/IA approach vs IA therapy is early initiation of (IV) treatment while the resources for angiography are being mobilized. Approximately three-fourths of patients in this series had IV rt-PA begun at community hospitals before transfer to a tertiary hospital, thus reducing time to treatment, an important goal as earlier initiation of thrombolysis led to better outcomes in IV rt-PA trials.¹⁰

The totality of our experience suggests that IV/IA therapy is relatively safe, especially given the stroke severity of patients presenting with an NIHSS score of ≥10. A caveat regards patients older than 80. Mortality and hemorrhage rates in this group were high, prompting exclusion of patients over age 80 from the IMS Trial.

Our study has several limitations. Although our experience suggests caution when treating persons older than 80 with IV/IA therapy, the poor natural history of elderly patients with large infarcts makes it possible that such patients will still benefit from combined treatment. This report is a retrospective analysis of a nonrandomized case series. As such, it was not intended to establish the efficacy of IV/IA therapy in comparison with IV therapy. A large, randomized Phase III trial comparing IV and IV/IA thrombolysis is now being planned.

Acknowledgment

The authors thank Mary Gaskill-Shipley, MD, and Robert Ernst, MD, for their clinical support.