This Article Abstract Full Text (PDF) All Versions of this Article: 35/4/904    most recent 01.STR.0000121641.77121.98v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Search for Related Content PubMed PubMed Citation Related Collections Thrombolysis Emergency treatment of Stroke Angiography Related Article

(Stroke. 2004;35:904.)
© 2004 American Heart Association, Inc.

Original Contributions

Combined Intravenous and Intra-Arterial Recanalization for Acute Ischemic Stroke: The Interventional Management of Stroke Study

The IMS Study Investigators

From University of Cincinnati, Cincinnati, Ohio.

Correspondence to Dr Joseph Broderick, Professor and Chair, Department of Neurology, University of Cincinnati, 231 Bethesda Avenue, PO Box 670525, Cincinnati, OH 45267-0525. E-mail joseph.broderick{at}uc.edu

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Appendix References

 
Background and Purpose— To investigate the feasibility and safety of a combined intravenous (IV) and intra-arterial (IA) approach to recanalization in patients with ischemic stroke.

Materials and Methods— Subjects ages 18 to 80 with an NIH Stroke Scale (NIHSS) 10 at baseline had IV recombinant tissue plasminogen activator (rt-PA) started (0.6 mg/kg, 60 mg maximum over 30 minutes) within 3 hours of onset. Additional rt-PA was then administered via microcatheter at the site of the thrombus up to a total dose of 22 mg over 2 hours of infusion or until thrombolysis. Primary comparisons were with similar subsets of placebo and rt-PA–treated subjects from the NINDS rt-PA Stroke Trial.

Results— The 80 subjects had a median baseline NIHSS score of 18. The median time to initiation of IV rt-PA was 140 minutes as compared with 108 minutes for placebo and 90 minutes for rt-PA–treated subjects in the NINDS rt-PA Stroke Trial. The 3-month mortality in Interventional Management Study (IMS) subjects (16%) was numerically lower but not statistically different than the mortality of placebo (24%) and rt-PA–treated subjects (21%) in the NINDS rt-PA Stroke Trial. The rate of symptomatic intracerebral hemorrhage (6.3%) in IMS subjects was similar to that of rt-PA–treated subjects (6.6%) but higher than the rate in placebo-treated subjects (1.0%, P=0.018) in the NINDS rt-PA Stroke Trial. IMS subjects had a significantly better outcome at 3 months than NINDS placebo-treated subjects for all outcome measures (odds ratios 2).

Conclusions— A randomized trial of standard IV rt-PA as compared with a combined IV and IA approach is needed.

Key Words: tissue plasminogen activator • thrombolytic therapy • controlled clinical trials

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Appendix References

 
Intravenous (IV) recombinant tissue plasminogen activator (rt-PA) within 3 hours of stroke onset is the first and currently only FDA-approved therapy for acute ischemic stroke. Treatment of ischemic stroke with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) may be life changing if recanalization is achieved. In angiographic controlled pilot trials of IV rt-PA, the rate of recanalization of major arterial occlusions with IV rt-PA is low, with partial or complete recanalization of only 10% of occluded internal carotid arteries and 25% of occluded proximal middle cerebral arteries.^1–3 A pilot trial of IV t-PA using transcranial Doppler to monitor vascular patency has reported higher rates of early recanalization and early reocclusion in some patients.⁴ In addition, in the National Institute of Neurologic Disease and Stroke (NINDS) rt-PA Stroke Trial, only 10% of patients with a severe deficit (NIH Stroke Scale [NIHSS] >20) who received IV rt-PA had minor or no functional disability at 3 months as compared with 2% of placebo-treated patients.

Intra-arterial (IA) interventions for acute ischemic stroke have been touted as superior to IV rt-PA in their ability to recanalize major intracranial arterial occlusions.⁵ In the PROACT II Trial, 40% of the 121 subjects treated with IA recombinant pro-urokinase (r-proUK) and IV heparin within 6 hours of onset achieved a Rankin of 0 to 2 at 3 months as compared with 25% of the 59 subjects treated with IV heparin alone.⁵ Of the subjects treated with IA r-proUK, 20% had total recanalization of a middle cerebral artery occlusion, and an additional 46% had partial recanalization. However, the median time to start of IA therapy was 5.3 hours, and recanalization, when it occurred, often happened >7 hours after stroke onset.

See Editorial Comment, page 911

Such a long delay to initiation of recanalization limits the effectiveness of IA therapy. Randomized trials of IV rt-PA have demonstrated that the effectiveness of rt-PA is strongly dependent on the time to start of therapy, with the greatest benefit occurring in subjects who have treatment started within 90 minutes.⁶ The concept of combining the advantages of IV rt-PA (speed of initiation and widespread availability) and IA recanalization (titrated dosing, mechanical aids to recanalization, and possible superior and earlier recanalization) was first explored in a small pilot study of 35 subjects, The Emergency Management of Stroke (EMS) Study.⁷ Several subsequent case series have reported encouraging results using a combined IV and IA approach.^8–10 Based on these results, the Interventional Management of Stroke (IMS) Study, funded by the NINDS, began in 2001. The goal of this study was to further investigate the feasibility and safety of a combined IV and IA approach to recanalization.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion Appendix References

 
The IMS Study is a 17-center, open-labeled, single-arm pilot study. The IMS Study was designed to investigate the feasibility and safety of a combined IV and IA approach to recanalization using rt-PA in 80 subjects with ischemic stroke. Primary pre-specified comparisons of IMS subjects to historical subjects in the NINDS rt-PA Stroke Trial with similar age and baseline NIHSS scores were performed.

Inclusion and exclusion criteria are listed in online Table I. To maximize early treatment of subjects, each treatment center was mandated to begin IV rt-PA within 2 hours of onset in at least 2 subjects of each 7-patient block (rule of two). The protocol was approved by the Institutional Review Board at each participating center.

View this table: [in this window] [in a new window]   TABLE I. Inclusion Criteria and Exclusion Criteria

Study Protocol
After all inclusion and exclusion criteria had been met and informed consent was obtained, subjects received IV rt-PA (Activase 0.6 mg/kg, 60 mg maximum, 15% of the dose as a bolus over 1 minute with the remainder administered over 30 minutes) followed by immediate cerebral angiography (Figure 1). The IV dose and protocol were the same as that used for the earlier EMS study ⁷ except for the bolus dose, which was increased from 10% to 15%. The reason for slightly increasing the percentage administered as a bolus in the IMS Study was to make the bolus equivalent to the total IV bolus of rt-PA used for the NINDS rt-PA Stroke Trial.

View larger version (18K): [in this window] [in a new window]   Figure 1. Interventional Management of Stroke (IMS) Study flowchart.

If a thrombus was identified in an appropriate intracranial artery such as the middle cerebral artery, anterior cerebral, posterior cerebral artery, or basilar artery, then no further injections were administered and IA thrombolytic therapy was initiated immediately, as per the following protocol. If the patient did not have an occlusion in the vascular territory appropriate for the patient’s symptoms, then no IA rt-PA was administered and the angiographic procedure was terminated. See online journal article for complete angiographic protocol.

After initiation of IV rt-PA therapy, the subject was transported immediately to the neuro-angiography suite. The femoral artery was punctured using a Seldinger single wall and/or micropuncture technique by an experienced interventionist. An appropriate size sheath (5 French to 7 French) was placed into the accessed femoral artery, and the sheath side arm was connected to a continuous heparinized saline flush (1000 U/1000 mL 0.9% normal saline) at 30 mL/h. The sheath was sutured in place to prevent inadvertent dislodgment.

A diagnostic 4-French to 7-French catheter was then placed through the sheath and advanced under fluoroscopic guidance into the symptomatic artery. If the suspected distribution of ischemia was in the carotid artery, then injection into the common carotid artery was performed to examine the carotid bifurcation. If it was technically difficult to gain safe access of the high cervical internal carotid artery, then the catheter could be left in the common carotid artery. If a carotid occlusion was identified, with failure to opacify the carotid terminus, then the opposite carotid artery and/or vertebral artery was injected to identify collateral flow. If the suspected arterial distribution was the vertebral basilar system, then selective injection of one or both vertebral arteries was performed.

A 2000-unit bolus of IV heparin was administered once the thrombus was identified and the decision was made to administer IA rt-PA. A heparin infusion was maintained at 450 U per hour during the IA study drug infusion and was discontinued at the end of the procedure. A heparin flush solution (approximately 40 U of heparin per hour) was administered via access sheath and the guide catheter and was continued until the catheter was removed.

A 2.3-French tapered, variable stiffness, end-hold rapid transit or prowler microcatheter was then passed over the micro-guidewire to the level of occlusion. IA rt-PA had to begin within 5 hours of symptom onset. Two mg of rt-PA was injected through the catheter over 2 minutes beyond the thrombus. The catheter was then retracted into the thrombus, and 2 mg of rt-PA was injected over 2 minutes directly into the thrombus. Infusion of rt-PA was then started at the rate of 9 mg/h for up to 2 hours of infusion time using an infusion pump. Two centers used a pulse-spray technique approximating the infusion rate. Repeat arteriogram was performed every 15 minutes after the start of infusion, using isomolar contrast. If at the time of the repeat arteriogram the vessel was not patent or had recanalized partly, then the catheter could be introduced further into the vessel for additional thrombus access. The guidewire and microcatheter could also be passed through the thrombus every 15 minutes. The infusion was continued for a maximum of 2 hours or until thrombolysis was achieved. The patient’s neurologic function was evaluated every 15 minutes during the intra-arterial (IA) procedure. If the arterial catheter could not be maneuvered to the site of the thrombus, then rt-PA at the same dose was selectively infused into the artery proximal to the site of the thrombus (regional infusion). The total maximum dose of rt-PA (both IV and IA) in the study was 82 mg as compared with a maximum dose of 90 mg in the NINDS rt-PA Stroke Trial.

If the patient had a significant stenosis or occlusion of the internal carotid, vertebral, or basilar arteries proximal to occlusive thrombus, then the stenosis/occlusion could be traversed with the microcatheter to approach a distal occlusive thrombus.

Termination of the IA treatment procedure occurred if there was: (1) arteriographic mass effect that could not be explained by early edema; (2) suspicion of extravasation of contrast suggesting vessel rupture; (3) CT demonstration of hemorrhage (ie, for a patient whose condition deteriorates and the procedure is interrupted for a CT, the procedure could be re-started if the CT shows no hemorrhage); (4) worsening of clinical deficit that was not explained by arteriographic findings; (5) seizure; (6) achievement of thrombolysis in myocardial infarction (TIMI) 3; or (7) 120 minutes of IA infusion of rt-PA that had occurred. IA infusion of rt-PA was to be discontinued beyond 7 hours from symptom onset. No angioplasty or stenting procedure was allowed as part of the protocol. In addition to these criteria for stopping IA t-PA, investigators were also allowed to apply clinical judgment in determining when to stop IA therapy based on the perceived risks and benefits.

Medical Management and Evaluation (See Online Journal Version)
Medical management of subjects enrolled into the study followed the National Institute of Neurologic Disease and Stroke (NINDS) rt-PA Stroke Trial protocol. ¹¹ An NIH Stroke Scale (NIHSS) ^12,13 was performed in every patient at baseline, immediately before initiation of IV rt-PA, after completion of IA rt-PA therapy, at 24±6 hours, at 5 days, or at discharge from hospital, and 90±7 days after the stroke. In addition, a modified Rankin scale (MRS) ¹⁴ to indicate the patient’s functional status before the qualifying stroke (pre-event) was obtained at baseline. Functional outcome at 3 months was assessed by the Barthel index, ¹⁵ the MRS, ¹⁴ and the Glasgow Outcome Scale. ¹⁶

Primary Measures of Safety and Outcome
The primary safety measure of the study was life-threatening bleeding complications during the first 36 hours after completion of rt-PA infusion, as it was for the NINDS rt-PA Stroke Trial. ^11,17 A significant life-threatening bleeding complication is defined as: (1) development of intracerebral hematoma or hemorrhagic infarction with clinical deterioration likely to result in permanent disability or death; or (2) other severe systemic bleeding complications such as groin hematoma, retroperitoneal hematoma, or gastrointestinal bleeding requiring transfusion of 3 units of blood replacement or major surgical intervention. Intracerebral hemorrhages were classified radiographically according to the method used by Von Kummer et al in the ECASS Trials: parenchymal hematoma (PH)-1, PH-2, hemorrhagic infarction (HI)-1, and HI-2 (see Table 3 for definitions). ¹⁸

The primary measure of outcome for this pilot study was a modified Rankin scale (MRS) of 0 or 1 at 3 months. Secondary efficacy endpoints included: (1) patient outcome as measured by the MRS (with favorable outcome defined as 0 to 2 at 3 months); (2) NIHSS (with favorable outcome defined as NIHSS score 2) at 24 hours; (3) the rate of recanalization (thrombolysis in myocardial infarction [lrsqb]TIMI] grades 2 or 3) at completion of angiography; (4) other favorable patient outcomes as measured by Barthel index score of 95 to 100, Glasgow Outcome Scale score of 0 to 1, and NIHSS score of 0 or 1; (5) quality of life at 3 months as defined by the EuroQol scale;¹⁹ and (6) global outcome endpoint that included the MRS, NIHSS, Barthel index, and Glasgow Outcome Scale at 3 months. The NINDS Data Safety Monitoring Committee reviewed all safety and outcome results of the IMS Study.

Statistical Methodology
The purpose of this pilot study was to assess the safety and outcome of combined IV and IA therapy to determine if it is futile to proceed to a larger randomized trial. For the sample size estimation, we used the proportions of successful outcomes obtained from subsets of placebo and rt-PA–treated subjects from parts I and II of the NINDS rt-PA Stroke Trial whose ages were 18 to 80 with a baseline NIHSS 10.

Logistic regression analyses were performed for the primary analysis of mortality and favorable outcome adjusting for predefined baseline co-variates that have been associated with outcome in previous randomized thrombolytic studies.^20–23 These included the baseline NIHSS score, time to treatment, and age. We also performed a secondary logistic regression analysis that included any other variables that were significantly different between IMS subjects and the comparison groups from the NINDS rt-PA Stroke Trial. A global test²⁴ (using the 4 primary outcome measures in the NINDS rt-PA Stroke Trial) was also performed, again adjusting for baseline co-variates.

With the exception of the primary analysis of the proportion of successful outcome (MRS=0 or 1), interpretation of P values should be made with caution because multiple analyses, considered exploratory, were performed.

	Results

Top Abstract Introduction Materials and Methods Results Discussion Appendix References

 
The IMS Study began enrollment at the first IMS center on January 31, 2001. The last of the 17 centers became eligible for enrollment on May 7, 2001; 1477 subjects were screened to enroll the pre-specified 80 subjects. Study recruitment was completed on October 23, 2001, approximately 14 months earlier than expected. Seventy-nine of the subjects continued participation as planned. One patient was lost to follow-up after the 7-day follow-up had been completed.

Of the 80 subjects (40 men), there were 64 whites, 7 blacks, 4 Hispanics, 4 Asians, and 1 Middle Easterner. Flow of subjects in the study is presented in Figure 2.

View larger version (26K): [in this window] [in a new window]   Figure 2. IMS patient flow.

Twenty-nine of the 80 subjects had IV rt-PA started within 2 hours of stroke symptom onset, and the median time to initiation of IV rt-PA was 140 minutes, as shown in Table 1. Of the 80 patients, 13 had IV t-PA started at a community hospital and were then transferred to the tertiary center. The mean time to start of IV t-PA in these 13 patients was 134 minutes (SD=26 minutes) and the mean time to start of IA t-PA was 231 minutes (SD=30). Twelve of the 80 patients were evaluated at a community hospital and then transferred to the referral hospital for start of IV t-PA therapy. The mean time to start of t-PA was in these patients was 169 minutes (SD=14), with a mean delay of 35 minutes compared with those in whom IV t-PA was started before transfer. Fifty-five patients presented to the tertiary hospital. The mean time to treatment with IV t-PA was 130 minutes (SD=30). Table 1 also summarizes the time to angiography, and time to initiation of IA rt-PA. The mean total dose of rt-PA for IMS subjects (59 mg; SD=14.4) was significantly less than the dose of IV rt-PA in subjects treated as part of the NINDS rt-PA Stroke Trial (69 mg; SD=13.5; P<0.0001).

View this table: [in this window] [in a new window]   TABLE 1. Time to Treatment in the IMS Study

Online Table II compares the baseline characteristics of the IMS subjects and the placebo and rt-PA-treated cohorts from the NINDS rt-PA Stroke Trial. IMS subjects were more likely to have early CT changes on the baseline CT, atrial fibrillation, a higher baseline systolic blood pressure, and lower baseline serum glucose; they were less likely to be black and to have a previous myocardial infarction. IMS subjects had IV rt-PA begun significantly later (median 140 minutes) as compared with placebo (108 minutes) and rt-PA–treated subjects (90 minutes) in the NINDS rt-PA Stroke Trial.

View this table: [in this window] [in a new window]   TABLE II. Baseline Comparisons Between IMS and NINDS rt-PA Trial Cohorts (Ages 18 - 80 and Baseline NIHSS 10)

The 3-month mortality in IMS subjects was numerically lower but not statistically different than the mortality of placebo and rt-PA–treated subjects in the NINDS rt-PA Stroke Trial (Table 2). Seven of the 13 deaths in IMS subjects occurred within 7 days. One was judged to be definitely related (1) and one remotely related to study drug or procedure. Both were subjects with symptomatic intracerebral hemorrhage (ICH). Five deaths were related to the severity of the initial stroke.

View this table: [in this window] [in a new window]   TABLE 2. Safety Results: IMS and NINDS rt-PA Trial Cohorts (Ages 18–80 and Baseline NIHSS10)

View this table: [in this window] [in a new window]   TABLE 3. Categorization of Intracerebral Hemorrhages IMS Study by ECASS Criteria

Four deaths occurred between 7 and 30 days. Of these, one was judged as probably related and another possibly related to the study drug or procedure. Both were subjects with symptomatic ICH. The third death was related to a new ischemic stroke that occurred 9 days after therapy, and the fourth patient’s death occurred at 19 days and was related to the severity of the initial stroke. The 2 deaths between 30 and 90 days were related to cardiac causes (severe aortic stenosis).

The rates of symptomatic intracerebral hemorrhage, PH2 intracerebral hemorrhages, and severe systemic hemorrhage in IMS subjects were similar to those of rt-PA–treated subjects in the NINDS rt-PA Stroke Trial (Tables 2 and 3, Figure 3). The rate of symptomatic intracerebral hemorrhage was higher than the rate in placebo-treated subjects in the NINDS rt-PA Stroke Trial. The rate of asymptomatic intracerebral hemorrhage in IMS subjects was higher than the rate of asymptomatic intracerebral hemorrhage in the rt-PA–treated subjects in the NINDS rt-PA Stroke Trial.

View larger version (94K): [in this window] [in a new window]   Figure 3. Five subjects with symptomatic ICH in the IMS Study.

Procedure-related complications included 2 pseudo-aneurysms at the puncture site. One of these events was considered severe because it resulted in a retroperitoneal hematoma that required transfusion of 3 units of packed red cells. Three other complications at the groin site included "severe" oozing or hematomas. One patient had a retroperitoneal hematoma that required transfusion of 3 units of packed red cells; the second patient had a groin hematoma and other sites of oozing that required 2 units of packed red cells; and the third patient had severe oozing at the groin site that did not require transfusion.

Two additional severe bleeding events required transfusion. One occurred in a patient with a gastrointestinal hemorrhage of an undetermined source that resulted in transfusion 21 days after rt-PA administration. Another similar event, anemia of undetermined origin, also required transfusion of 3 units of packed red cells. This patient experienced a severe transfusion reaction.

Three suspected vessel perforations of occluded middle cerebral arteries occurred during the angiographic procedure (contrast extravasation) without subsequent documentation of intracranial bleeding. Two perforations occurred in the M1 segment of the middle cerebral artery and were thought to be related to blind navigation secondary to the pathologic thrombus. No IA rt-PA was administered in these 2 subjects. A third perforation involved the posterior division of the middle cerebral artery and was related to patient movement. This patient had received 8.5 mg of rt-PA intra-arterially before ending the procedure after extravasation of contrast was noted. All 3 cases are reported as asymptomatic ICHs.

There were 4 recurrent strokes (see online article for details). Two of these recurrent strokes were intracerebral hemorrhages. The first occurred on day 20 after carotid endarterectomy for severe carotid stenosis in the distribution of the original stroke. The second intracerebral hemorrhage occurred on day 64 when the patient had an international normalized ratio (INR) of 6 while administered Coumadin. The 2 new ischemic strokes occurred on day 1 and day 8. Four subjects underwent hemi-craniectomy because of severe brain edema and mass effect. Mild angioedema occurred in 1 patient.

During the first 24 hours after enrollment, muscle relaxants were administered to 16 (20%) of the 80 subjects, and 57 (71%) received sedative medications. Study investigators at the 24-hour NIHSS assessment, a secondary efficacy endpoint, noted that 7 (9%) of the subjects in the population had an assessment that was affected by sedation and/or muscle relaxant medications.

IMS subjects had a better outcome than NINDS placebo-treated subjects for the primary outcome measure (MRS of 0 or 1 at 3 months, Table 4). IMS subjects also had a better outcome by all secondary measures after adjustment for baseline NIHSS, age, and time to treatment (Table 4). IMS subjects had a similar 3-month outcome as compared with subjects treated with rt-PA in the NINDS rt-PA Stroke Trial, although odds ratio trended in favor of IMS subjects (Table 4). There was no statistically significant difference in any outcome measure for those patients treated at the top 3 enrolling sites versus all other sites.

View this table: [in this window] [in a new window]   TABLE 4. Three-Month Outcome: IMS and NINDS rt-PA Trial Cohorts (Ages 18–80 and Baseline NIHSS 10)

Of the 77 subjects who underwent an angiographic procedure, 28 had major occlusions or high-grade stenoses of the internal carotid artery in addition to distal disease in the middle cerebral artery and its branches. For the 62 subjects who received IA rt-PA in addition to IV t-PA, the rate of complete recanalization (TIMI 3 flow) was 11% (7/62) and the rate of partial or complete recanalization (TIMI 2 or 3 flow) was 56% (35/62) after a maximum of 2 hours of infusion (see online Table III for data concerning sites of occlusion and recanalization). Of the 35 patients who achieved TIMI 2 or 3 flow, 34% had a favorable outcome (MRS of 0 to 1 at 3 months) as compared with 12% of those patients who achieved only TIMI 0 or 1 flow (P=0.013). Of those subjects who received IA rt-PA within 3 hours of onset, 43% (7/16) had MRS of 0 to 1 at 3 months as compared with 13% (3/24) of subjects who received IA rt-PA within 3 to 4 hours and 27% (6/22) of those who received IA rt-PA after 4 hours (IA 3 hours versus IA >3 hours; 0=0.095 by Fisher exact test).

View this table: [in this window] [in a new window]   TABLE III. Locations of Arterial Occlusion Lesions (AOL) at Baseline Angiogram

Protocol violations included no angiogram in 1 patient (magnetic resonance angiography showed no occlusion in this patient who had returned to near normal). IV heparin use after the angiographic procedure but before the 24-hour CT occurred in 3 subjects. One patient had IV rt-PA started at 3 hours and 1 minute. Another patient had IA rt-PA started after 5 hours from onset and received IA infusion of rt-PA beyond 7 hours. One patient had placement of a carotid stent outside of the protocol. Finally, no administration of IA rt-PA was administered in 1 patient who had a 99% stenosis of the intima carotid artery with thrombus plus emboli in the fourth divisions of the middle cerebral artery. Medication errors occurred in 4 subjects who had the proper dose of commercially available rt-PA delivered intravenously, rather than study drug, after informed consent had been obtained.

Sixteen subjects received <18 mg of IA rt-PA via infusion for reasons other than the defined protocol criteria. In 10 subjects, the treating investigator indicated achievement of maximum lysis that was determined to be <TIMI 3 flow on subsequent review by the central angiographic reader. In 6 instances, the treating investigator indicated major clinical improvement as the reason for stopping IA t-PA despite incomplete recanalization. Of these 6 subjects, 5 did not achieve a TIMI 3 flow but averaged an NIHSS improvement of 7.6, as measured by the immediate pre-IA and post-IA NIHSS. One subject showed no documented change on NIHSS on the post-IA NIHSS but was heavily sedated. This patient improved by 4 points on the NIHSS at 24 hours.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Appendix References

 
The IMS Study demonstrates that a combined IV and IA approach to recanalization, using rt-PA begun within 3 hours of onset, is feasible and may have comparable safety to full-dose IV rt-PA as administered during the NINDS rt-PA Stroke Trial. In addition, as compared with placebo subjects of similar baseline severity and age in the NINDS rt-PA Stroke Trial, IMS subjects were significantly more likely to have an excellent outcome at 3 months, both before and after adjustment for baseline NIHSS, age, and time to treatment (odds ratio of 2). Based on these pre-specified comparisons with historical controls from the NINDS rt-PA Stroke Trial, a randomized concurrently controlled trial of standard IV rt-PA as compared with a combined IV and IA approach started within 3 hours of stroke onset is warranted.

The IMS subjects represent the most severely affected group of subjects treated as part of a controlled trial of recanalization therapy. To our knowledge, a median baseline NIHSS score of 18 is the highest of any controlled trial of recanalization published to date. In addition, the amount of vascular disease and burden of thrombus exceeds that in any other previous recanalization trial. Of the 80 IMS subjects, 28 (35%) had major occlusions of the carotid artery, usually in addition to distal occlusions in the middle cerebral artery. By comparison, the PROACT II Study included only those subjects with an M1 or M2 occlusion.⁵ Such severely affected subjects with a large thrombus burden are most appropriate for a combined IV/IA approach. IV rt-PA alone results in partial or total recanalization in 10% of subjects with an internal carotid artery occlusion, and only one third of subjects with occlusions of the middle cerebral artery.^1–3

The mortality rate and rate of symptomatic intracerebral hemorrhage in the IMS Study are similar to those in other reported series of combined IV/IA rt-PA^7–10 In addition, the proportion of favorable outcome at 3 months in the IMS Study is similar to what has been reported in these case series of combined IV/IA rt-PA. The great advantage of the combined approach, as compared with IA therapy alone, is that effective treatment can begin much more quickly before referral to the comprehensive stroke center. In addition, it is likely that some of the IMS subjects who had no visible thrombus or with distal occlusions on the first baseline angiographic images may have had larger proximal occlusions before initiation of IV rt-PA.

Although the mortality rate and rate of symptomatic intracerebral hemorrhage was similar between IMS subjects and rt-PA–treated subjects in the NINDS rt-PA Stroke Trial, the rate of asymptomatic intracerebral hemorrhage during the first 36 hours was higher in the IMS Study. However, only 6 (7.5%) subjects had PH2-type hematomas that have been associated with neurologic deterioration and poor outcome.¹⁸ In addition, the total overall rate of intracerebral hemorrhage in the IMS Study is similar to the overall rate of intracerebral hemorrhage in the PROACT II Study of 54%.⁵ IMS subjects with occlusions of the internal carotid artery, with or without distal occlusions, were particularly likely to have hemorrhagic change (20 of 28 [71%]). By comparison, only 15 of the 36 (42%) subjects with occlusions in the middle cerebral artery or vertebral artery system had any hemorrhagic change.

We have subsequently begun an IMS II pilot study in a predetermined sample of 72 subjects. This study is identical to IMS I, except that the catheter infusing the rt-PA into the thrombus also delivers low-intensity ultrasound within the thrombus to accelerate thrombolysis (EKOS MicroLysUS System). After completion of the IMS II study, we plan to proceed to a randomized trial of combined IV/IA recanalization as compared with standard IV rt-PA, each begun within 3 hours of onset. Improved methods of recanalization and better outcome in patients with acute ischemic stroke are clearly needed.

	Appendix

Top Abstract Introduction Materials and Methods Results Discussion Appendix References

 
Please see online appendix for complete list of participating hospitals, centers, and investigators (available online at http://www.ahajournals.org).

View this table: [in this window] [in a new window]   Appendix: List of Centers/Hospitals, Investigators, and Recruitment by Center

	Acknowledgments

 
This study was funded by the National Institute of Neurological Diseases and Stroke (NINDS #NS39160). rt-PA was supplied by Genentech, Inc. and the microcatheters were supplied by Cordis Neurovascular, Inc.

Received July 8, 2003; revision received September 11, 2003; accepted October 3, 2003.

	References

Top Abstract Introduction Materials and Methods Results Discussion Appendix References

 

1. Wolpert S, Bruckmann H, Greenlee R, Wechsler L, Pessin M, del Zoppo G, rt-PA Acute Stroke Study Group. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. Am J Neuro Radiol. 1993; 14: 3–13.[Abstract]
2. Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, Kitano K, Tsutsumi A, Yamadori A. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology. 1992; 42: 976–982.[Abstract/Free Full Text]
3. Yamaguchi T, Hayakawa T, Kiuchi H, for the Japanese Thrombolysis Study Group. Intravenous tissue plasminogen activator ameliorates the outcome of hyperacute embolic stroke. Cerebrovascular Dis. 1993; 3: 269–272.[CrossRef]
4. Alexandrov AV. Ultrasound-enhanced thrombolysis for stroke: clinical significance. Eur J Ultrasound. 2002; 16: 131–140.[CrossRef][Medline] [Order article via Infotrieve]
5. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999; 282: 2003–2011.[Abstract/Free Full Text]
6. The ATLANTIS, ECASS, NINDS rt-PA Study Group Investigators. Better outcome with early stroke treatment: a pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA Stroke Trials. Lancet. 2004; in press.
7. Lewandowski CA, Frankel M, Tomsick TA, Broderick J, Frey J, Clark W, Starkman S, Grotta J, Spilker J, Khoury J, Brott T. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999; 30: 2598–2605.[Abstract/Free Full Text]
8. Ernst R, Pancioli A, Tomsick T, Kissela B, Woo D, Kanter D, Jauch E, Carrozzella J, Spilker J, Broderick J. Combined intravenous and intra-arterial recombinant tissue plasminogen activator in acute ischemic stroke. Stroke. 2000; 31: 2552–2557.[Abstract/Free Full Text]
9. Hill MD, Barber PA, Demchuk AM, Newcommon NJ, Cole-Haskayne A, Ryckborst K, Sopher L, Button A, Hu W, Hudon ME, Morrish W, Frayne R, Sevick RJ, Buchan AM. Acute intravenous–intra-arterial revascularization therapy for severe ischemic stroke. Stroke. 2002; 33: 279–282.[Abstract/Free Full Text]
10. Suarez JI, Zaidat OO, Sunshine JL, Tarr R, Selman WR, Landis DM. Endovascular administration after intravenous infusion of thrombolytic agents for the treatment of patients with acute ischemic strokes. Neurosurgery. 2002; 50: 251–260.[CrossRef][Medline] [Order article via Infotrieve]
11. NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581–1587.[Abstract/Free Full Text]
12. Brott T, Adams HJ, Olinger C, Marler J, Barsan W, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, Rorick M, Moomaw C, Walker M. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989; 20: 864–870.[Abstract/Free Full Text]
13. Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, Haley EC, Grotta J, Marler J. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke. 1994; 25: 2220–2226.[Abstract]
14. Van Swieten J, Koudstaal P, Visser M, Schouten H, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988; 19: 604–607.[Abstract/Free Full Text]
15. Mahoney F, Barthel D. Functional evaluation: the Barthel index. Md State Med J. 1965; 14: 61–65.[Medline] [Order article via Infotrieve]
16. Jennett B, Bond M. Assessment of outcome after severe brain injury: a practical scale. Lancet. 1975; 1: 480–484.[Medline] [Order article via Infotrieve]
17. NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997; 28: 2109–2118.[Abstract/Free Full Text]
18. Berger C, Fiorelli M, Steiner T, Schabitz WR, Bozzao L, Bluhmki E, Hacke W, von Kummer R. Hemorrhagic transformation of ischemic brain tissue: asymptomatic or symptomatic? Stroke. 2001; 32: 1330–1335.[Abstract/Free Full Text]
19. Dorman PJ, Dennis M, Sandercock P. How do scores on the EuroQol relate to scores on the SF-36 after stroke? Stroke. 1999; 30: 2146–2151.[Abstract/Free Full Text]
20. NINDS t-PA Stroke Study Group. Generalized efficacy of t-PA for acute stroke: subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. 1997; 28: 2119–2125.[Abstract/Free Full Text]
21. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez Tejedor E, Trouillas P. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998; 352: 1245–1251.[CrossRef][Medline] [Order article via Infotrieve]
22. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999; 282: 2019–2026.[Abstract/Free Full Text]
23. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne M. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA. 1995; 274: 1017–1025.[Abstract]
24. Tilley BC, Marler J, Geller NL, Lu M, Legler J, Brott T, Lyden P, Grotta J. Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and Stroke t-PA Stroke Trial. Stroke. 1996; 27: 2136–2142.[Abstract/Free Full Text]

Related Article:

Editorial Comment—More Than One Way to Lyse a Clot

Scott E. Kasner
Stroke 2004 35: 911-912. [Full Text] [PDF]

This article has been cited by other articles:

				V. Mahajan, P.T. Minshew, J. Khoury, P.P. Shu, M. Muzaffar, T. Abruzzo, J.L. Leach, and T.A. Tomsick Eye Position Information on CT Increases the Identification of Acute Ischemic Hypoattenuation AJNR Am. J. Neuroradiol., June 1, 2008; 29(6): 1144 - 1146. [Abstract] [Full Text] [PDF]

				S. Sugiura, K. Iwaisako, S. Toyota, and H. Takimoto Simultaneous Treatment with Intravenous Recombinant Tissue Plasminogen Activator and Endovascular Therapy for Acute Ischemic Stroke Within 3 Hours of Onset AJNR Am. J. Neuroradiol., June 1, 2008; 29(6): 1061 - 1066. [Abstract] [Full Text] [PDF]

				T.N. Nguyen, S. Lanthier, and D. Roy Iatrogenic Arterial Perforation during Acute Stroke Interventions AJNR Am. J. Neuroradiol., May 1, 2008; 29(5): 974 - 975. [Abstract] [Full Text] [PDF]

				C. Nichols, P. Khatri, T. Tomsick, and J. Broderick Advantages of a Combined Approach to Recanalization Therapy Stroke, April 1, 2008; 39(4): e71 - e71. [Full Text] [PDF]

				L. Valvassori, A. Ciccone, and R. Sterzi Response to Letter by Nichols et al Stroke, April 1, 2008; 39(4): e72 - e72. [Full Text] [PDF]

				W. S. Smith, G. Sung, J. Saver, R. Budzik, G. Duckwiler, D. S. Liebeskind, H. L. Lutsep, M. M. Rymer, R. T. Higashida, S. Starkman, et al. Mechanical Thrombectomy for Acute Ischemic Stroke: Final Results of the Multi MERCI Trial Stroke, April 1, 2008; 39(4): 1205 - 1212. [Abstract] [Full Text] [PDF]

				P. Khatri, R. A. Taylor, V. Palumbo, V. Rajajee, J. M. Katz, J. A. Chalela, A. Geers, J. Haymore, D. M. Kolansky, S. E. Kasner, et al. The safety and efficacy of thrombolysis for strokes after cardiac catheterization. J. Am. Coll. Cardiol., March 4, 2008; 51(9): 906 - 911. [Abstract] [Full Text] [PDF]

				T. Tomsick, J. Broderick, J. Carrozella, P. Khatri, M. Hill, Y. Palesch, J. Khoury, and for the Interventional Management of Stroke II Inv Revascularization Results in the Interventional Management of Stroke II Trial AJNR Am. J. Neuroradiol., March 1, 2008; 29(3): 582 - 587. [Abstract] [Full Text] [PDF]

				S. King, P. Khatri, J. Carrozella, J. Spilker, J. Broderick, M. Hill, T. Tomsick, and for the IMS & IIMS II Investigators Anterior Cerebral Artery Emboli in Combined Intravenous and Intra-arterial rtPA Treatment of Acute Ischemic Stroke in the IMS I and II Trials AJNR Am. J. Neuroradiol., November 1, 2007; 28(10): 1890 - 1894. [Abstract] [Full Text] [PDF]

				J. Broderick, S. Connolly, E. Feldmann, D. Hanley, C. Kase, D. Krieger, M. Mayberg, L. Morgenstern, C. S. Ogilvy, P. Vespa, et al. REPRINT: Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, October 16, 2007; 116(16): e391 - e413. [Abstract] [Full Text] [PDF]

				J.-H. Rha and J. L. Saver Response to Letter by Kent and Mandava Stroke, October 1, 2007; 38(10): e104 - e104. [Full Text] [PDF]

				L. B. Goldstein Acute Ischemic Stroke Treatment in 2007 Circulation, September 25, 2007; 116(13): 1504 - 1514. [Full Text] [PDF]

				H. B. van der Worp and J. van Gijn Acute Ischemic Stroke N. Engl. J. Med., August 9, 2007; 357(6): 572 - 579. [Full Text] [PDF]

				N.A. Vora, R. Gupta, A.J. Thomas, M.B. Horowitz, A.H. Tayal, M.D. Hammer, K. Uchino, L.R. Wechsler, and T.G. Jovin Factors Predicting Hemorrhagic Complications after Multimodal Reperfusion Therapy for Acute Ischemic Stroke AJNR Am. J. Neuroradiol., August 1, 2007; 28(7): 1391 - 1394. [Abstract] [Full Text] [PDF]

				The IMS II Trial Investigators The Interventional Management of Stroke (IMS) II Study Stroke, July 1, 2007; 38(7): 2127 - 2135. [Abstract] [Full Text] [PDF]

				H. P. Mattle Intravenous or Intra-Arterial Thrombolysis?: It's Time to Find the Right Approach for the Right Patient Stroke, July 1, 2007; 38(7): 2038 - 2040. [Full Text] [PDF]

				P. Mandava and T. A. Kent Intra-arterial therapies for acute ischemic stroke Neurology, June 12, 2007; 68(24): 2132 - 2139. [Abstract] [Full Text] [PDF]

				P. J. Lindsberg and H. P. Mattle Response to Letter by Vatankhah et al Stroke, June 1, 2007; 38(6): e30 - e30. [Full Text] [PDF]

				J. Broderick, S. Connolly, E. Feldmann, D. Hanley, C. Kase, D. Krieger, M. Mayberg, L. Morgenstern, C. S. Ogilvy, P. Vespa, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults: 2007 Update: A Guideline From the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke, June 1, 2007; 38(6): 2001 - 2023. [Abstract] [Full Text] [PDF]

H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text]