Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial

JAMA Neurol. 2016 Feb;73(2):190-6. doi: 10.1001/jamaneurol.2015.3886.


Importance: Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known.

Objective: To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT.

Design, setting, and participants: The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015.

Main outcomes and measures: Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion.

Results: Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours.

Conclusion and relevance: For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion.

Trial registration: trialregister.nl Identifier: NTR1804.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Brain Ischemia / diagnosis
  • Brain Ischemia / drug therapy
  • Brain Ischemia / surgery*
  • Endovascular Procedures / methods
  • Female
  • Fibrinolytic Agents / administration & dosage
  • Fibrinolytic Agents / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Reperfusion*
  • Stroke / diagnosis
  • Stroke / drug therapy
  • Stroke / surgery*
  • Time Factors
  • Tissue Plasminogen Activator / administration & dosage
  • Tissue Plasminogen Activator / therapeutic use*
  • Treatment Outcome


  • Fibrinolytic Agents
  • Tissue Plasminogen Activator

Associated data

  • NTR/NTR1804