IMS III
Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke
Year of Publication: 2013
Authors: Broderick JP, Palesch YY, Demchuk AM, et al; Interventional Management of Stroke (IMS) III Investigators
Journal: New England Journal of Medicine
Citation: N Engl J Med 2013;368(10):893–903. DOI: 10.1056/NEJMoa1214300
PDF: Clinical Question
In patients with moderate-to-severe acute ischemic stroke who received IV t-PA within 3 hours of onset, does adding endovascular therapy improve 90-day functional independence compared with IV t-PA alone?
Bottom Line
Adding endovascular therapy after IV t-PA did not improve 90-day functional independence over IV t-PA alone (40.8% vs 38.7%; adjusted difference 1.5 pp, 95% CI −6.1 to 9.1) and was stopped early for futility. Safety was comparable, though asymptomatic ICH and SAH were more frequent with endovascular therapy. Because the trial used mostly first-generation devices (Merci/Penumbra) with prolonged time-to-groin puncture and did not routinely require CTA-confirmed LVO, it did not settle endovascular efficacy — later stent-retriever era trials (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT) did.
Major Points
- Phase 3, international, open-label, blinded-endpoint RCT at 58 centers in USA, Canada, Australia, and Europe (2006–2012); 2:1 randomization of IV t-PA + endovascular therapy vs IV t-PA alone.
- Stopped early for futility after 656 of planned 900 patients randomized (crossed pre-specified futility boundary on conditional power <20%).
- Primary outcome (mRS 0–2 at 90 d): 40.8% endovascular vs 38.7% IV t-PA alone; adjusted absolute difference 1.5 pp (95% CI −6.1 to 9.1); van Elteren P=0.25 for full mRS distribution.
- No benefit in either NIHSS stratum (≥20 or 8–19) and no significant interaction with age, sex, atrial fibrillation, time-to-tPA, or CTA-documented occlusion.
- 90-day mortality similar (19.1% vs 21.6%, P=0.52); symptomatic ICH within 30 h similar (6.2% vs 5.9%, P=0.83); parenchymal hematoma type 2 similar (6.0% vs 6.3%).
- Asymptomatic ICH (27.4% vs 18.9%, P=0.01) and subarachnoid hemorrhage (11.5% vs 5.8%, P=0.02) higher with endovascular therapy; device/procedural complications 16.1% in endovascular arm.
- Endovascular reperfusion (TICI 2–3) high: 65% ICA, 81% M1, 70% single M2, 77% multiple M2; TICI 2b–3 lower: 38% ICA, 44% M1, 44% single M2, 23% multiple M2. Better mRS with higher TICI (12.7% at TICI 0 → 71.4% at TICI 3, P<0.001).
- Devices reflected era: mostly intra-arterial t-PA, Merci, and Penumbra; only 4 patients received Solitaire (stent retriever); mean time from t-PA to groin puncture ~32 min longer than in IMS I.
- Routine CTA to require LVO was not mandatory throughout enrollment; roughly one-third of endovascular patients had no treatable occlusion at angiography, diluting a potential benefit.
Design
Study Type: International, phase 3, randomized, open-label, blinded-endpoint (PROBE) trial
Randomization: 1
Blinding: Open-label treatment; 90-day mRS assessed by investigators unaware of treatment assignment (blinded endpoint).
Enrollment Period: August 25, 2006 – April 17, 2012
Follow-up Duration: 90 days (primary outcome)
Centers: 58
Countries: USA, Canada, Australia, Netherlands, France, Switzerland, Germany, Spain
Sample Size: 656
Power Calculation: Planned 900 patients to detect a 10-percentage-point absolute increase in mRS 0–2 at 90 days (assumed 40% in IV t-PA arm), two-sided α=0.05, power 0.80, inflation factor 1.03 for ~2% non-compliance, O'Brien–Fleming alpha-spending for 3 interim analyses.
Analysis: Intention-to-treat; Cochran–Mantel–Haenszel test adjusted for dichotomized baseline NIHSS (8–19 vs ≥20); van Elteren test for ordinal mRS. Unfavorable outcome imputed for missing/out-of-window primary outcomes. Pre-specified futility rule: conditional power <20% under alternative.
Inclusion Criteria
- Age 18–82 years
- Acute ischemic stroke treated with IV t-PA within 3 h of symptom onset
- Baseline NIHSS ≥10 (moderate-to-severe deficit)
- After amendment 3: NIHSS 8–9 with CT angiographic evidence of occlusion of the M1 segment of MCA, internal carotid artery, or basilar artery (at sites where CTA was standard of care)
- Randomization within 40 minutes after start of IV t-PA infusion
- Angiographic procedure able to begin within 5 h and be completed within 7 h of symptom onset
- Written informed consent from patient or legal representative
Exclusion Criteria
- Age <18 or >82 years
- NIHSS <8 (or <10 without CTA-confirmed proximal occlusion)
- IV t-PA not started within 3 h of symptom onset
- Inability to randomize within 40 minutes after initiation of t-PA
- Angiographic procedure not startable within 5 h or completable within 7 h of onset
- Standard contraindications to IV t-PA and to endovascular intervention (detailed in Supplementary Table 1)
Baseline Characteristics
| Characteristic | Endovascular + IV t-PA (n=434) | IV t-PA alone (n=222) |
|---|---|---|
| Median age (yr) | 69 (range 23–89) | 68 (range 23–84) |
| Male n (%) | 218 (50.2%) | 122 (55.0%) |
| Black n (%) | 51 (11.8%) | 19 (8.6%) |
| Hispanic n (%) | 11 (2.5%) | 12 (5.4%) |
| Median NIHSS | 17 (range 7–40) | 16 (range 8–30) |
| ASPECTS 8–10 n (%) | 247 (56.9%) | 131 (59.0%) |
| Left hemisphere stroke n (%) | 224 (51.6%) | 106 (47.7%) |
| Right hemisphere stroke n (%) | 197 (45.4%) | 109 (49.1%) |
| Brainstem/cerebellum n (%) | 10 (2.3%) | 4 (1.8%) |
| Atrial fibrillation n (%) | 153 (35.3%) | 70 (31.5%) |
| Hypertension n (%) | 319 (73.5%) | 171 (77.0%) |
| Diabetes n (%) | 94 (21.7%) | 54 (24.3%) |
| CHF n (%) | 50 (11.5%) | 31 (14.0%) |
| Coronary artery disease n (%) | 102 (23.5%) | 72 (32.4%) — P=0.01 vs endovascular |
| Hyperlipidemia n (%) | 215 (49.5%) | 112 (50.5%) |
| Serum glucose (mmol/L, mean±SD) | 7.4 ± 2.9 | 7.6 ± 3.1 |
| Time onset to IV t-PA (min, mean±SD) | 122.4 ± 33.7 | 121.2 ± 33.8 |
| Baseline mRS 0 n (%) | 379 (87.3%) | 197 (88.7%) |
| SBP (mm Hg, mean±SD) | 148 ± 21.3 | 147.3 ± 24 |
| Current antiplatelet n (%) | 186 (42.9%) | 108 (48.6%) |
| Current statin n (%) | 155 (35.7%) | 83 (37.4%) |
| Median INR | 1.0 (range 0.9–1.7) | 1.0 (range 0.9–1.7) |
Arms
| Field | Endovascular therapy after IV t-PA | Control |
|---|---|---|
| Intervention | Standard-dose IV t-PA (0.9 mg/kg, 10% bolus + 1-h infusion, max 90 mg; two-thirds dose used before amendment 5 in June 2011), followed by angiography and, when a treatable occlusion was present, endovascular therapy — intra-arterial t-PA via microcatheter or EKOS MicroSonic system, or thrombectomy with Merci retriever, Penumbra System, or Solitaire FR revascularization device; intraprocedural heparin 2000-U bolus then 450 U/h. | Standard-dose IV t-PA 0.9 mg/kg (10% bolus, remainder over 1 h; max 90 mg); no endovascular therapy. |
| N | 434 | 222 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Modified Rankin Scale score ≤2 (functional independence) at 90 days, adjusted for baseline NIHSS stratum (8–19 vs ≥20); intention-to-treat with unfavorable imputation for missing/out-of-window assessments. | Primary | 38.7% (IV t-PA alone, n=222) | 40.8% (endovascular + IV t-PA, n=434) | Not significant (van Elteren P=0.25 for full mRS distribution) | |
| mRS 0–2 at 90 d, NIHSS ≥20 subgroup | Secondary | IV t-PA alone | endovascular arm | 0.06 (van Elteren) | |
| mRS 0–2 at 90 d, NIHSS 8–19 subgroup | Secondary | IV t-PA alone | endovascular arm | 0.83 (van Elteren) | |
| Full mRS distribution at 90 d (ordinal) | Secondary | — | — | 0.25 (van Elteren) | |
| Procedural reperfusion TICI 2–3, ICA occlusion | Secondary | — | 65% (endovascular, n=65) | ||
| Procedural reperfusion TICI 2–3, M1 occlusion | Secondary | — | 81% (endovascular, n=135) | ||
| Procedural reperfusion TICI 2b–3, M1 occlusion | Secondary | — | 44% (endovascular) | ||
| 24-h recanalization on CTA (M1 occlusion) | Secondary | 68% (IV t-PA alone) | 86% (endovascular) | ||
| 24-h recanalization on CTA (ICA occlusion) | Secondary | 35% (IV t-PA alone) | 81% (endovascular) | ||
| mRS 0–2 at 90 d vs procedural TICI (endovascular arm) | Secondary | — | 12.7% at TICI 0 → 27.6% TICI 1 → 34.3% TICI 2a → 47.9% TICI 2b → 71.4% TICI 3 | <0.001 | |
| Death within 7 days | Safety | 24/222 (10.8%) | 52/434 (12.0%) | 0.57 | |
| Death within 90 days | Safety | 48/222 (21.6%) | 83/434 (19.1%) | 0.52 | |
| Symptomatic ICH within 30 h | Safety | 13/222 (5.9%) | 27/434 (6.2%) | 0.83 | |
| Asymptomatic ICH within 30 h | Safety | 42/222 (18.9%) | 119/434 (27.4%) | 0.01 | |
| Parenchymal hematoma type 2 within 30 h | Safety | 13/207 (6.3%) | 25/417 (6.0%) | 0.90 | |
| Parenchymal hematoma type 1 within 30 h | Safety | 3/207 (1.4%) | 15/417 (3.6%) | 0.12 | |
| Subarachnoid hemorrhage | Safety | 12/207 (5.8%) | 48/417 (11.5%) | 0.02 | |
| Intraventricular hemorrhage | Safety | 10/207 (4.8%) | 27/417 (6.5%) | 0.40 | |
| Major non-intracerebral bleeding within 5 days | Safety | 5/222 (2.3%) | 13/434 (3.0%) | 0.55 | |
| Recurrent stroke within 90 days | Safety | 14/222 (6.3%) | 22/434 (5.1%) | 0.54 | |
| Device or procedural complication | Safety | — | 70/434 (16.1%) |
Subgroup Analysis
Pre-specified subgroups (NIHSS stratum, time from onset to IV t-PA, presence/absence of CTA-documented arterial occlusion, age, sex, atrial fibrillation) showed no significant interaction with treatment effect. Numerical direction favored endovascular therapy for patients treated with IV t-PA within 2 h of onset and for those with time from t-PA to groin puncture ≤90 min, but neither reached significance. Among patients with NIHSS ≥20 treated within 2 h of onset, difference was 14.0 pp (99% CI −6.2 to 34.1).
Criticisms
- First-generation devices dominated: only 4 patients received Solitaire (stent retriever) before trial stopped; results predate the stent-retriever era demonstrated by MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, and REVASCAT (2015).
- CTA-confirmed large-vessel occlusion was not required for the majority of enrollment — ~one-third of endovascular patients had no treatable occlusion at angiography, diluting a potential treatment effect.
- Time to endovascular treatment was ~32 minutes longer than in IMS I, undermining the reperfusion-efficacy relationship known to be time-dependent.
- Two-thirds-dose IV t-PA was used in the endovascular arm before amendment 5 (mid-2011); dose asymmetry across the trial complicates interpretation.
- Stopped early for futility after 656 of 900 patients — conditional-power stopping may under-detect a modest benefit, particularly in LVO subgroups.
- Open-label design with blinded endpoint (PROBE); acute imaging and management differences could bias assessment.
- Predominantly white population (only 11.8% Black, 2.5% Hispanic in endovascular arm) and upper age cap of 82 years limit generalizability.
- Endovascular arm used heterogeneous techniques (IA t-PA, EKOS, Merci, Penumbra, few stent retrievers), preventing device-specific inference.
- Higher rate of asymptomatic ICH and SAH in the endovascular arm was not clinically consequential here but signals procedural bleeding risk.
Funding
National Institutes of Health / National Institute of Neurological Disorders and Stroke grants UC U01NS052220, MUSC U01NS054630, and U01NS077304. Genentech supplied t-PA for endovascular use; EKOS, Concentric Medical, and Cordis Neurovascular supplied catheters; Genentech, EKOS, and Boehringer Ingelheim supported investigator meetings. Industry sponsors were not involved in study design, conduct, or manuscript preparation beyond ensuring FDA-approved device use.
Based on: IMS III (New England Journal of Medicine, 2013)
Authors: Broderick JP, Palesch YY, Demchuk AM, et al; Interventional Management of Stroke (IMS) III Investigators
Citation: N Engl J Med 2013;368(10):893–903. DOI: 10.1056/NEJMoa1214300
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