CHOICE2
(2026)Objective
In adults with anterior-circulation large vessel occlusion stroke and successful thrombectomy (expanded TICI 2b50-3), does adjunctive intra-arterial alteplase (0.225 mg/kg, max 20 mg over 15 min) improve 90-day functional outcome and cerebral reperfusion vs thrombectomy alone.
Study Summary
• Secondary: residual hypoperfusion on 36-h CT perfusion 28.6% vs 50.5%; adjusted risk difference −22.0% (95% CI, −31.5 to −12.4); P<.001.
• Safety: mortality at 90 d 12.1% vs 6.4%; adjusted risk difference 5.9% (95% CI, 0.5-11.3); P=.03; symptomatic ICH 1.4% vs 0.5%, P=.33.
Intervention
Adjunctive intra-arterial alteplase 0.225 mg/kg (max 20 mg) infused over 15 min via microcatheter positioned in terminal ipsilateral ICA immediately after successful thrombectomy vs thrombectomy alone
Inclusion Criteria
Adults ≥18 y with acute ischemic stroke from isolated ICA, MCA (M1 or proximal M2), or anterior cerebral artery occlusion; prestroke mRS ≤1; endovascular thrombectomy achieving expanded TICI 2b50-3; treatment within 4.5 h of last known well (ASPECTS ≥6 on NCCT) or up to 24 h with advanced imaging showing salvageable tissue; NIHSS ≤25 at admission
Study Design
Arms: Thrombectomy + intra-arterial alteplase (n=221 randomized; 214 in mFAS/primary analysis) vs Thrombectomy alone (n=219)
Patients per Arm: 221 vs 219 (N=440 randomized; 433 in modified full analysis set — 214 vs 219)
Outcome
• Secondary: residual hypoperfusion at 36 h 28.6% (55/192) vs 50.5% (96/190), adjusted RD −22.0% (95% CI, −31.5 to −12.4), P<.001; volume of hypoperfusion 5.0 (3.7-6.6) vs 6.1 (4.5-8.2) mL, ratio 0.82 (95% CI, 0.55-1.23), P=.34; infarct expansion ratio 56.6 (42.9-74.6) vs 65.4 (49.6-86.2), ratio 0.87 (95% CI, 0.59-1.28), P=.47; Barthel 95-100 63.6% vs 58.4%, RD 5.1 (95% CI, −4.1 to 14.3), P=.28; EQ-5D-5L median 0.9 vs 0.8, adjusted median difference 0.07 (95% CI, 0.01-0.12), P=.02; ordinal mRS shift P=.08 (proportional-odds violated).
• mRS distribution at 90 d (IA-alteplase vs control): 0: 29.4 vs 21.9; 1: 28.0 vs 20.5; 2: 8.9 vs 21.9; 3: 15.0 vs 17.4; 4: 4.2 vs 7.3; 5: 2.3 vs 4.6; 6: 12.1 vs 6.4.
• Safety: sICH at 36 h 1.4% (3/214) vs 0.5% (1/219), adjusted OR 3.10 (95% CI, 0.32-30.0), P=.33; mortality 90 d 12.1% (26/214) vs 6.4% (14/219), adjusted RD 5.9% (95% CI, 0.5-11.3), P=.03; parenchymal hematoma type II 1.9% vs 1.8%; any serious AE 28.5% vs 25.1%; vessel reocclusion 5 vs 2.
• Procedural: median time symptom onset → study treatment 280 min (IQR 200-582); thrombectomy duration 32 min (IQR 23-46); expanded TICI 3 at randomization in 54.7% vs 60.3%.
Bottom Line
In this multicenter Spanish RCT (n=440) of anterior-circulation LVO stroke with successful thrombectomy (eTICI 2b50-3), adjunctive intra-arterial alteplase (0.225 mg/kg, max 20 mg) increased 90-day mRS 0-1 from 42.5% to 57.5% (adjusted RD 15.0%, 95% CI 5.7-24.3; P=.002; NNT ≈ 7). Residual hypoperfusion at 36 h was halved (28.6% vs 50.5%). Symptomatic ICH was not increased (1.4% vs 0.5%; P=.33), but 90-day mortality was higher (12.1% vs 6.4%; adjusted RD 5.9%, 95% CI 0.5-11.3; P=.03), warranting further study.
Major Points
- Investigator-initiated, multicenter, open-label, blinded-endpoint, phase 3 RCT at 14 Spanish stroke centers (Dec 11, 2023 – Nov 26, 2025); 440 randomized (221 vs 219); 433 in modified full analysis set (214 vs 219).
- Population: anterior-circulation LVO (ICA, MCA M1/proximal M2, or ACA) treated with thrombectomy within 24 h and achieving expanded TICI 2b50-3; median NIHSS 15, median ASPECTS 10, prior IV thrombolysis in 274/433 (63%; 192 alteplase, 82 tenecteplase).
- Primary outcome — mRS 0-1 at 90 d: 57.5% (123/214) IA-alteplase vs 42.5% (93/219) control; adjusted risk difference 15.0% (95% CI, 5.7-24.3); P=.002; consistent across prespecified subgroups (age, sex, prior IV lytic, eTICI, time-to-reperfusion, glucose).
- Ordinal (shift) analysis of 90-d mRS: no significant between-group difference (P=.08); proportional-odds assumption was violated, so the common OR is not interpretable.
- Secondary imaging — residual hypoperfusion on 36-h CT perfusion: 28.6% (55/192) vs 50.5% (96/190); adjusted RD −22.0% (95% CI, −31.5 to −12.4); P<.001. Even in patients with complete angiographic reperfusion (eTICI 3), residual hypoperfusion was 14.6% vs 25.8% (post hoc).
- Volume of hypoperfusion (5.0 vs 6.1 mL) and infarct expansion ratio (56.6 vs 65.4) did not differ significantly.
- Patient-reported EQ-5D-5L median 0.9 vs 0.8; adjusted median difference 0.07 (95% CI, 0.01-0.12); P=.02. Barthel Index 95-100: 63.6% vs 58.4% (RD 5.1, 95% CI −4.1 to 14.3; P=.28).
- Safety — symptomatic ICH at 36 h: 1.4% (3/214) vs 0.5% (1/219); adjusted OR 3.10 (95% CI, 0.32-30.0); P=.33. Parenchymal hematoma type II 1.9% vs 1.8%; any asymptomatic ICH 24.3% vs 20.1%.
- Mortality at 90 d: 12.1% (26/214) vs 6.4% (14/219); adjusted RD 5.9% (95% CI, 0.5-11.3); P=.03. Only 1 death was adjudicated as related to the study medication; most deaths occurred beyond the first week.
- A recent meta-analysis of 6 RCTs (n=1971) showed no difference in 90-d mortality (18.3% vs 18.3%; RR 1.00) or sICH (RR 1.14) with adjunctive IA thrombolysis, suggesting the CHOICE-2 mortality signal may reflect random variation.
Study Design
- Study Type
- Investigator-initiated, multicenter, open-label, blinded-outcome-assessment, phase 3 randomized clinical trial
- Randomization
- Yes
- Blinding
- Open-label to treating clinicians and patients regarding group assignment; outcome assessors, imaging core-laboratory readers, and statisticians remained blinded to allocation throughout; mRS assessed by certified central assessors via telephone/video.
- Sample Size
- 440
- Follow-up
- 90 days (primary endpoint)
- Centers
- 14
- Countries
- Spain
Primary Outcome
Definition: Excellent functional outcome — modified Rankin Scale score of 0 or 1 at 90 days, adjudicated by central blinded assessors
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 93/219 (42.5%) | 123/214 (57.5%) | - (5.7 to 24.3) | .002 |
Limitations & Criticisms
- Open-label design (placebo not feasible due to continent-wide alteplase shortage prioritizing active-drug production); mitigated by central blinded outcome assessment.
- Higher 90-day mortality in the intervention arm (12.1% vs 6.4%; RD 5.9%, 95% CI 0.5-11.3; P=.03) — although only 1 death was adjudicated related to study medication and most deaths were late, requires further investigation.
- Ordinal (shift) analysis of mRS was not significant (P=.08) and proportional-odds assumption was violated, so the binary excellent-outcome effect may not translate into whole-scale improvement across the disability spectrum.
- Noncontrast CT limits sensitivity for volumetric infarct measurements and detection of subtle infarct progression — possibly explaining the dissociation between improved perfusion and unchanged infarct expansion ratio.
- Incomplete documentation of screening exclusions (443 patients: 'reason not available') may have introduced selection bias.
- Trial conducted almost exclusively in Spain (~92%; 35/433 patients [8%] were from 19 different countries outside Spain) within a single national health system with relatively uniform care — limits generalizability, particularly to racially/ethnically diverse populations underrepresented here.
- Residual baseline imbalances possible (median age 2 y higher in intervention arm), though post hoc adjustments did not materially alter results.
- Some secondary outcomes had missing CT-perfusion data (22 IA-alteplase and 29 control patients missing follow-up perfusion, 10-13%).
Citation
JAMA. 2026;335(21):1859-1869. DOI: 10.1001/jama.2026.5164