Low Rates of Acute Recanalization With IntravenousRecombinant Tissue Plasminogen Activator in

Ischemic StrokeReal-World Experience and a Call for Action

Rohit Bhatia, MD, DM, DNB; Michael D. Hill, MD, FRCPC; Nandavar Shobha, DNB, DM;Bijoy Menon, MD, DM; Simerpreet Bal, MD, DM; Puneet Kochar, MD; Tim Watson, MD, FRCPC;

Mayank Goyal, MD, FRCPC; Andrew M. Demchuk, MD, FRCPC

Background and Purpose—Acute rates of recanalization after intravenous (IV) recombinant tissue plasminogen activator(rt-PA) in proximal vessel occlusion have been estimated sparingly, typically using transcranial Doppler (TCD). Weaimed to study acute recanalization rates of IV rt-PA in CT angiogram-proven proximal (internal carotid artery [ICA],M1 middle cerebral artery [MCA], M2-MCA, and basilar artery) occlusions and their effects on outcome.

Materials and Methods—The CT angiogram database of the Calgary stroke program was reviewed for the period 2002 to2009. All patients with proximal vessel occlusions receiving IV rt-PA who were assessed for recanalization by TCD orangiogram (for acute endovascular treatment) were included for analysis. Rates of acute recanalization as observed onTCD/first run of angiogram and postendovascular therapy recanalization rates were noted. Modified Rankin Scale score�2 at 3 months was used as a good outcome.

Results—Among 1341 patients in the CT angiogram database, 388 patients with proximal occlusion were identified. Ofthese, 216 patients had received IV rt-PA; 127 patients underwent further imaging to assess recanalization. Among thepatients undergoing TCD (n�46) and cerebral angiogram (n�103), only 27 (21.25%) patients had acute recanalization.By occlusion subtype, the rates of recanalization were: distal ICA (with or without ICA neck occlusion or stenoticdisease) 1 of 24 (4.4%); M1-MCA (with or without ICA neck occlusion or stenotic disease) 21 of 65 (32.3%); M2-MCA4 of 13 (30.8%); and basilar artery 1 of 25 (4%). Onset to rt-PA time was comparable in patients with and withoutrecanalization. Recanalization (P�0.0001; risk ratio, 2.7; 95% confidence interval, 1.5–4.6) was the strongest predictorof outcome (adjusted for age and National Institutes of Health Stroke Scale score).

Conclusions—A low rate of acute recanalization was observed with IV rt-PA in proximal vessel occlusions identified bybaseline CT angiogram. Recanalization was the strongest predictor of good outcome. (Stroke. 2010;41:2254-2258.)

Key Words: intracranial occlusion � ischemic stroke � recanalization � thrombolysis

Intravenous (IV) recombinant tissue plasminogen activator(rt-PA) treatment for acute ischemic stroke1,2 works by

achieving recanalization of intracranial occlusion resulting inrestoration of flow and prevention of infarct expansion.3 Dataon recanalization after IV thrombolysis are limited to smallangiographic and transcranial Doppler (TCD) monitoringstudies.4 None of the major IV thrombolysis trials hasassessed the baseline occlusion status or recanalization ratesafter treatment. In an era when there is increasing use ofendovascular therapies for recanalization, in the absence ofrobust evidence from randomized controlled trials, there is adesperate need for clear data on the rates of recanalizationwith IV rt-PA.5 The present study reports the rates of acute

recanalization of proximal intracranial vessel occlusionsidentified by baseline CT angiography (CTA) among acuteischemic stroke patients treated with IV rt-PA.

Patients and MethodsWe identified patients presenting with acute ischemic stroke secondaryto major vessel occlusion from the CT Angiography database of theCalgary Stroke Program at the Foothills Medical Centre, University ofCalgary, Canada. The Calgary CTA database is a Human Research andEthics Board-approved retrospective study of patients with an acutestroke syndrome presentation who have been imaged with CTA of theextracranial and intracranial circulations. All patients had acuteischemic stroke diagnosed based on history and examination by aneurologist. The decision to perform CTA was made at the discretion

Received June 3, 2010; accepted June 18, 2010.From Departments of Clinical Neurosciences (M.D.H., N.S., B.M., S.B., P.K., T.W., M.G., A.M.D.), Radiology (M.D.H., P.K., M.G., A.M.D.),

Medicine (M.D.H.), and Community Health Sciences (M.D.H.), Foothills Hospital, University of Calgary, Calgary, Alberta, Canada; Department ofNeurology (R.B.), All India Institute of Medical Sciences, New Delhi, India.

Correspondence to Dr Rohit Bhatia, MD, DM, DNB, Associate Professor, Department of Neurology, Room No. 3, VI Floor, Neurosciences Centre,All India Institute of Medical Sciences, New Delhi 110029, India. E-mail rohitbhatia71@yahoo.com

© 2010 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.592535

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of the treating stroke neurologist or stroke fellow; in practice, nearlyall acute stroke cases undergo acute CTA at the time of the brain CTat our institution. We performed standard noncontrast CT on amultislice scanner (GE Medical Systems or Siemens, SiemensMedical Solutions) using 170 mV and 120 mAS with 5-mm slicethickness. Coverage was from skull base to vertex with continuousaxial slices parallel to the orbitomeatal line. CTA was performedwith a helical scan technique. We obtained acquisitions after a singlebolus IV contrast injection of 90 to 120 mL of the iodinated,nonionic, hypo-osmolar XCM ioversol (Optiray-320; MallinckrodtMedical Inc) into an antecubital vein at 3 to 5 mL/sec. Imageacquisition was auto-triggered by the appearance of contrast media inthe ascending aorta. Minimum coverage was from foramen magnumto centrum semiovale with 0.6-mm to 1.0-mm slice thickness.

A thorough search was made for any vascular stenosis or occlu-sion on the CTA. The occlusions were categorized into M1 middlecerebral artery (MCA; including tandem proximal extracranial ca-rotid occlusions or stenosis plus M1-MCA), M2-MCA (includingtandem proximal extracranial carotid occlusions or stenosis plusM2-MCA), distal internal carotid artery (ICA) terminus (T or L)type, carotid occlusion (including tandem proximal extracranialcarotid occlusions or stenosis plus ICA terminus), and vertebro-basilar occlusion. In eligible patients, treatment with IV rt-PA at adose of 0.9 mg/kg was started as soon as possible. Clinical,demographics, and risk factor profile, as well as treatment processinterval times, were noted in all patients. The stroke mechanism wasclassified using the TOAST criteria. Patients enrolled in the Inter-national Management of Stroke III study were excluded. The datawere prospectively recorded in the charts by stroke staff or clinicalstroke fellows during the hospital stay and in the clinic files onfollow-up and were retrospectively extracted.

TCD was performed by experienced staff to assess the recanali-zation status of the occluded vessel during the rt-PA infusion. TCDwas started concurrently with rt-PA administration and was per-formed for a maximum of 120 minutes. Standard thrombolysis inbrain ischemia (TIBI) grading (TIBI 0 to 5) was used to score thevessel flow.6,7 Recanalization was defined as partial (TIBI 3, 4) orcomplete (TIBI 5). Among the patients undergoing cerebral angiog-raphy for endovascular revascularization (using chemical or mechan-ical thrombolysis either alone or in combination), the recanalizationstatus was assessed at the initial performance of the angiogram andwas graded using thrombolysis in myocardial ischemia (TIMI)grading (0 to 3). TIMI grades were classified into absent (TIMI 0–1)and partial (TIMI 2) or complete recanalization (TIMI 3). TIBIscores on TCD have been shown to have good correlation withangiographic TIMI scoring system. After endovascular treatment, thesame angiographic grading was applied to assess the final degree ofrecanalization.

Patients were categorized by recanalization status into early afterrt-PA (group 1), postendovascular treatment (group 2), and nonre-canalization (group 3). The primary outcome was recanalizationdefined as TIMI 2 to 3 or TIBI 3 to 5. Secondary outcomes weremodified Rankin Scale score 0 to 2 and death at 90 days. Data arereported using standard descriptive statistics. We used conventionallevels of significance at alpha of 0.05, and all tests were 2-tailed. Amultivariable model to assess clinical outcome was developed usinga generalized linear model with log link and binomial distribution togenerate risk ratios directly. Only main effects were assessed in themultivariable model. The modeling approach was to provide ad-justed measures of association including known predictors of theoutcome in question. We therefore aimed, a priori, to adjust for age,gender, baseline National Institutes of Health Stroke Scale score,baseline Alberta Stroke Program Early CT Score (ASPECTS),onset-to-treatment time, and occlusion location. Occlusion locationwas considered a forced variable in the model. Parsimonious modelsare reported, including only variables that achieved a conventionallevel of significance. Backwards elimination was used to eliminatevariable one by one until a parsimonious model was developed.

ResultsFrom the CTA database, 1341 patients were reviewed and388 patients were identified with an ischemic stroke second-ary to an acute vessel occlusion. Among these, 216 patientshad received IV rt-PA. A total of 127 patients underwentfurther evaluation for recanalization status either by TCD orby angiogram or both (Table 1). The groups were comparableexcept for a low prevalence of diabetes mellitus in the IVrt-PA alone group. Occlusion locations and recanalizationrates are shown in Table 2.

TCD was attempted in 54 patients but 8 had no temporalinsonation window. Ten (21.7%) of 46 patients achievedTIBI 5 grade of recanalization, 5 (10.9%) patients had TIBI 3,and 31 (67.4%) patients did not achieve recanalization; 103patients underwent emergent angiography for endovasculartreatment. The median time from stroke onset to groinpuncture was 227 minutes (range, 85–1320 minutes; n�103).The median time from onset to recanalization was 272minutes (range, 105–660 minutes; n�86). Among these 103patients, 12 (11.7%) patients had recanalization at the firstangiogram, of which TIMI 3 grade was seen in 11 (10.7%)patients and TIMI 2 was seen in 1 (1.0%) patient. The overallrate of partial and complete TCD and angiographic evidenceof acute recanalization are shown in Table 2.

There was a strong relationship of recanalization with goodoutcome; 52 of 86 (60.5%) patients who had recanalizationhad a good outcome compared with 10 of 41 (24.3%) of thosewithout recanalization (relative risk, 2.5; 95% CI, 1.4–4.3).Patients with recanalization early had a significantly betteroutcome than those with recanalization later (Figure). Themortality rates were significantly different between thegroups and were lowest among those with early recanaliza-tion (Table 1). Among the occlusion sites, best outcomeswere achieved for M2-MCA (77%), followed by M1-MCA�/� proximal ICA (60%), basilar artery (32%), and ICAterminus T, L�/� proximal ICA (17%; P�0.0001, Fisherexact test). A multivariable model showed that recanalizationwas the strongest predictor of good outcome (Table 3). Thesymptomatic ICH rate was 6.8%.

DiscussionOur study shows a low rate of acute recanalization with IVrt-PA in a CTA-proven occlusion cohort with severe stroke.The data also confirm an independent and strong associationof recanalization (especially early) with good outcome andreduced mortality. The outcomes improved with a proximalto a distal gradient, suggesting that the burden of thrombus isimportant.8

In the only angiographic study of systemic thrombolysis(which is now nearly 2 decades old), del Zoppo et al4

observed that overall frequency of extracranial ICA recana-lization was 8%, and that of MCA stem and distal occlusionwere 26.1% and 38.1%, respectively. In the Combined Lysisof Thrombus in Brain Ischemia Using Transcranial Ultra-sound and Systemic t-PA (CLOTBUST) trial9 comparing IVrt-PA and continuous TCD (target group) to IV rt-PA alone,27% vs 13% achieved complete recanalization at 1 hour. Riboet al10 studied 179 patients with cerebral occlusion treatedwith IV rt-PA. At 1 hour, the continuous TCD recanalization

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status was partial in 28% and complete in 17%. The proba-bility of recanalization decreased significantly after the first60 minutes. Another study11 of 31 patients with documentedocclusion on initial CTA found early recanalization(thrombolysis in cerebral infarction �2) at angiogram in 7(22.6%) patients (mean time between rt-PA and DSA was120 minutes). Using MRA for recanalization assessment overtime after rt-PA therapy, among 42 MCA occlusions (30 M1and 12 M2), complete recanalization and partial recanaliza-tion were observed in 52.3% at 1 hour (19% complete and

33% partial), which increased to 80.9% (47.6% and 3.3%) at24 hours, with a rate much lower in ICA occlusions.12

Observations from previous studies also suggest that recana-lization with rt-PA is better with more distal occlusions thanproximal and worse for ICA and tandem occlusions, as wasobserved in our study.13–14

Because early recanalization is an important determinant ofgood outcome, assessment for the same is critical afterthrombolytic therapy. Timely endovascular recanalizationmay be a strong consideration when the target vessel oc-

Table 1. Baseline Characteristics and Clinical Outcomes

All (n�127)

After IV rt-PARecanalization

(n�27)

After EndovascularRecanalization

(n�59)

NoRecanalization

(n�41)

P (for theComparison

Across 3 Groups)

Demographics

Age, median (25th–75th percentiles) 67 (34–88) 73 (61–82) 66 (54–73) 67 (58–79) 0.059

Female (n) 45% (57) 37% (10) 42% (25) 54% (22) 0.355

Clinical variables

Hypertension (n) 72% (92) 67% (18) 76% (45) 71% (29) 0.616

Diabetes (n) 19% (24) 4% (1) 25% (15) 20% (8) 0.044

Smoking (n) 33% (42) 22% (6) 39% (23) 32% (13) 0.285

Atrial fibrillation (n) 32% (40) 26% (7) 31% (18) 37% (15) 0.660

Coronary artery disease (n) 20% (26) 26% (7) 19% (11) 20% (8) 0.716

Dyslipidemia (n) 24% (30) 15% (4) 31% (18) 20% (8) 0.242

Statin use (n) 19% (24) 15% (4) 24% (14) 15% (6) 0.446

Antiplatelet use (n) 30% (38) 22% (6) 36% (21) 27% (11) 0.437

TOAST (n)

Large artery 30% (38) 37% (10) 29% (17) 27% (11)

Cardioembolic 48% (61) 44% (12) 48% (28) 51% (21) 0.866

Indeterminate 13% (17) 15% (4) 15% (9) 10% (4)

Other 9% (11) 4% (1) 8% (5) 12% (5)

NIHSS, median (25th–75th

percentiles)17 (12–21) 18 (14–21) 17 (11–21) 17 (11–21) 0.877

ASPECTS, median (25th–75th

percentiles)8 (6–9) 8 (7–9) 8 (6–10) 8 (6–10) 0.979

Treatment process and outcomes

Onset to rt-PA time, median(25th–75th percentiles), min

136 (92–190) 128 (97–214) 130 (85–185) 152 (97–195) 0.441

Onset to recanalization time, median(25th–75th percentiles), min

272 (210–347) 215 (175–274) 303 (237–358) . . . 0.0007

Mortality (n) 19.7% (25) 7.4% (2) 13.6% (8) 36.6% (15) 0.005

mRS score �2 at 3 months (n) 48.8% (62) 77.8% (21) 52.5% (31) 24.4% (10) �0.0001

IV indicate intravenous; mRS, modified Rankin Scale; rt-PA, recombinant tissue plasminogen activator.

Table 2. Baseline Occlusions and Proportional Recanalization

Occlusion LocationRecanalization

(All)RecanalizationAfter IV rt-PA

Recanalization AfterEndovascular Treatment

NoRecanalization

M1-MCA 75.4% (49) 32.3% (21) 43.1% (28) 24.6% (16)

ICA terminus (T, L) occlusion 43.5% (10) 4.4% (1) 39.1% (9) 56.5% (13)

M2-MCA 92.3% (12) 30.8% (4) 61.5% (8) 7.7% (1)

BA 56.0% (14) 4.0% (1) 52.0% (13) 44.0% (11)

All 67.7% (86) 21.3% (27) 46.5% (59) 32.3% (41)

BA indicates basilar artery; ICA, internal carotid artery; IV, intravenous; MCA, middle cerebral artery; rt-PA, recombinanttissue plasminogen activator.

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cluded is a proximal T-occlusion or basilar artery occlusion,both of which have a low rate of recanalization after systemicthrombolysis in a given patient. Other issues like spontaneousand delayed recanalization, relationship of early and laterecanalization to clinical outcomes, and whether a combinedIV intra-arterial approach leads to a better outcome areimportant. Recanalization has been observed to be associatedwith good clinical outcome,15 and recent reanalysis of Inter-national Management of Stroke trials16 and a publishedRECANALISE study17 have suggested better outcomes witha shorter time from onset and recanalization. Our findings areconsistent with previous data because patients treated with IVrt-PA and those with recanalization were more likely to havea good outcome compared to those with later intra-arterialrecanalization. The difference in time to recanalization wasalmost 90 minutes (215 minutes from onset vs 303 minutesfrom onset) on average between the 2 groups, which couldexplain this difference in outcomes. These data provide anovel assessment of thrombolytic effect using baseline CTangiography and early follow-up vascular imaging for com-parison. We believe that any study of thrombolysis, whetherIV or intra-arterial or both, must include an assessment of theprimary treatment target—the vessel. The International Man-agement of Stroke III trial18 includes a posttreatment assess-ment of the vessel with 24-hour CTA; however, it remains

uncertain what the best time to evaluate vessel status is as amarker of therapeutic efficacy.

There are limitations to this study. It is a retrospectivelycollected data, and not all patients treated with IV rt-PAunderwent angiogram, leading to a potential bias. We didinclude both the TCD and angiogram data to remove selec-tion bias as much as possible. Within the angiogram group,most patients underwent angiography directly to ascertainrecanalization status emergently. Although clinical improve-ment is an important marker, many patients do not showrapidity of improvement after IV rt-PA. We do feel thatwaiting for clinical recovery and losing vital time is notjustified in general and may produce unnecessary delays toangiography. The true benefit of a combined approach vsstandard IV rt-PA can only be ascertained in a randomizedtrial such as International Management of Stroke III.18 Wehave not included patients treated with IV rt-PA in absence ofCTA, in whom occlusion localization is likely based onclinical presentation and CT findings. However, we wanted ahomogenous cohort of patients, and the same bias could betrue of studies using the hyperdense MCA sign as the endpoint for outcomes.19

ConclusionIn summary, the rate of acute recanalization demonstrated byTCD/angiogram is low in acute ischemic stroke patientstreated with IV rt-PA alone and is worse for those with distalICA and basilar artery occlusions. This is significantlyimproved with an endovascular approach. Recanalizationachieved either with rt-PA or with a combined approach is astrong predictor of a good outcome.

AcknowledgmentsThe authors acknowledge the contribution of the entire Calgarystroke program.

Sources of FundingThis work was supported by the Heart and Stroke Foundation ofAlberta, NWT, and Nunavut.

DisclosuresNone.

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Figure. Relationship of recanalization with good outcome at 3months in different groups.

Table 3. Multivariable Model and Modified Rankin Scale Score0 to 2 Outcome

Variable RR 95% CI P

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2.0 1.1–3.5 0.009

No recanalization (referencecategory)

1 . . . . . .

bNIHSS 0.96 0.94–0.99 0.001

Hypertension 0.7 0.5–0.9 0.015

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Tim Watson, Mayank Goyal and Andrew M. DemchukRohit Bhatia, Michael D. Hill, Nandavar Shobha, Bijoy Menon, Simerpreet Bal, Puneet Kochar,

Activator in Ischemic Stroke: Real-World Experience and a Call for ActionLow Rates of Acute Recanalization With Intravenous Recombinant Tissue Plasminogen

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2010 American Heart Association, Inc. All rights reserved.

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Stroke 日本語版 Vol. 5, No. 426

虚血性脳卒中における急性期の組換え型組織プラスミノゲン活性化因子静注による再開通率の低さ

— 実地臨床における経験と対策の必要性Low Rates of Acute Recanalization With Intravenous Recombinant Tissue Plasminogen

Activator in Ischemic Stroke ― Real-World Experience and a Call for Action

Rohit Bhatia, MD, DM, DNB5; Michael D. Hill, MD, FRCPC1,2,3,4; Nandavar Shobha, DNB, DM1; Bijoy Menon, MD, DM1; Simerpreet Bal, MD, DM1; Puneet Kochar, MD1,2; Tim Watson, MD, FRCPC1; Mayank Goyal, MD, FRCPC1,2; Andrew M. Demchuk, MD, FRCPC1,2

1 Departments of Clinical Neurosciences, 2 Radiology, 3 Medicine, and 4 Community Health Sciences, Foothills Hospital, University of Calgary, Calgary, Alberta, Canada; 5 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.

Abstract

背景および目的：近位血管閉塞に対し，急性期に組換え型組織プラスミノゲン活性化因子（rt-PA）を静注した場合の再開通率を推定した研究は少なく，また評価手段には経頭蓋超音波ドプラ検査（TCD）が用いられることが多い。本研究の目的は，CT血管造影によって確認された近位［内頸動脈（ICA），中大脳動脈M1（M1-MCA），M2-MCA，脳底動脈］閉塞に対し，rt-PA静注を実施した場合の急性期再開通率とその転帰への影響を検討することであった。材料および方法：カルガリー脳卒中プログラムの 2002 ～2009 年の CT血管造影データベースのレビューから，近位血管閉塞に対して rt-PA静注を行い，TCDまたは血管造影（急性期血管内治療のため）により再開通の評価を行ったすべての患者を分析に含めた。TCD／初回血管造影で観察された急性期再開通率および血管内治療後の再開通率を算出した。3カ月時の改変Rankin 尺度（mRS）のスコアが 2以下の場合を，転帰良好とみなした。結果：CT血管造影データベースに収載された 1,341 例のうち，近位閉塞が認められたのは 388 例であった。この

うち 216 例に rt-PA静注が行われ，127 例に画像検査による再開通の評価が行われた。TCD（46 例）および脳血管造影（103 例）を実施した患者のうち，急性期に再開通が得られたのは 27 例（21.25％）にすぎなかった。閉塞の型別にみた再開通率は，ICA遠位部（ICA頸部閉塞または狭窄症あり・なし）が 24 例中 1例（4.4％），M1-MCA（ICA頸部閉塞または狭窄症あり・なし）が 65 例中 21 例（32.3％），M2-MCAが 13 例中 4例（30.8％），脳底動脈が25 例中 1例（4％）であった。再開通例と非再開通例における閉塞出現からrt-PA投与までの時間に差はみられなかった。再開通は最も有力な転帰予測因子であった（年齢およびNIHSSスコアについて補正）（p ＜ 0.0001，リスク比＝2.7，95％信頼区間：1.5 ～ 4.6）。結論：治療前のCT血管造影によって確認された近位血管閉塞に対し，rt-PA静注を行った場合の急性期再開通率は低かった。再開通は，良好な転帰を示す最も有力な予測因子であった。

Stroke 2010; 41: 2254-2258

90 日後の転帰

パーセントmRS：0～ 2 mRS：3～ 5 死亡

0 20 40 60 80 100

52.5

24.4

77.8

33.9

36.6

7.4

13.6

39.0

14.8急性期のrt-PA 静注による再開通

再開通なし

急性期以降のrt-PA 動注による再開通

図 各群における再開通と3カ月時の良好な転帰との関係

表3 多変数モデルと改変Rankin 尺度（mRS）のスコアが0～2の転帰

変数 RR 95％ CI p 値

IV rt-PA 後の再開通 2.7 1.5 ～ 4.5 <0.0001

血管内治療後の再開通 2.0 1.1 ～ 3.5 0.009

再開通なし（対照分類） 1 … …

bNIHSS 0.96 0.94 ～ 0.99 0.001

高血圧 0.7 0.5 ～ 0.9 0.015

bNIHSS は，ベースラインの NIHSS（National Institutes of Health Stroke Scale）スコアを示す。CI：信頼区間，IV：静脈内，RR：リスク比，rt-PA：組織プラスミノゲン活性化因子。本モデルにおいては治療回数と血栓部位の双方が検討されたが，どちらも臨床転帰の予測因子に関連しないため，本モデルには含まれない

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