The earlier tpa is given, the better GWTG evidence

Saver JL, Fonarow GC, Smith EE. et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke.  JAMA 2013; 309; 2480-2488. 

Authors used real world data based on GWTG registry, covering 54,353 patients treated between 2003-2012 at 1395 institutions, and analysed in fifteen minute increments for treatment effects.  Across the ninety minute increments (0-90, 91-180, 181-270 minutes) there was no difference in hospital characteristics such as treatment time or volume, treatment rates, or designation as a stroke center.  Patients treated in first ninety minutes had higher NIHSS scores (mean 12) than those treated in the 181-270 time frame  (mean 9.0).  Nonetheless, faster treatment . 

Findings based on fifteen minute increments showed less mortality  for each 15 minute increment (0.96 OR), and increased odds of independent ambulation at discharge (or 1.03 per 15 minute increment). 

IST 3 -- benefits of tpa in elderly at greater than three hours

Sandercock P, Wardlaw JM, Lindley RI, et al.  The benefits and harms of  intravenous thrombolysis with recombinant tissue plasminogen activator within six hours of acute ischaemic stroke(the third international stroke trial IST 3); a randomized control trial.  Lancet 2012; 379: 2352-2363.

 

Study looked at tpa among patients without clear indication or contraindication to tpa, in a European study.  Due to approval initially in Europe for age < 79  and use within 3 hours of onset, this study was in effect for those >79, and those outside 3 hours, in Europe.  Study looked at tpa + usual care v. usual care. 156 sites enrolled 2025 patients.   53 % were > 79, 72 % were treated after 3 hours after stroke onset but thin six hours.  There was no significant difference in the dichotomized outcome, the initial primary measure, but by shift analsysi of the Oxford Handicap scores, TPA improved the odds of a one level improvement in the outcome.  sICH occurred in 7 % v. 1 % of the control group. 

 

In the subset treated within 3 hours, the primary dichotomized outcome occurred more with tpa than with the control group (OR 1.64) 

Wardlaw JM, Murray V, Berge E. et al.  Recombinant tissue plasminogen activator  for acute ischaemic stroke: an updfated systematic review and metanalysis.  Lancet 2012; 309: 2480-2488.

An updated metaanalysis of tpa trials that included IST 3 showed that ivv tpa given within 3 hours of stroke improved the odds of a good functional outcome (OR 1.53)

Large percent of posterior circulation strokes missed by acute MRI; however tpa does not usually resolve diffusion deficits on MRI

Hotter B, Kufner A, Malzahn U. et al.  Validity of negative high resolution diffusion weighted imaging in transient cerebrovascular events.  Stroke 2013; 44:2598-2600

 

151 patients with suspected stroke and negative DWI in first twenty four hours , 63 underwent followup MRI showing stroke in seven (11%).  5/7 had at least one point on NIHSS. 

 

Oppenheim C, Stanescu R, Dormont D, et al.  False negative diffusion weighted MR findings in acute ischemic stroke.  AJNR 2000; 21: 1434-1440

 

older study showing miss rate of about 20 %

 

Schellinger PD, Bryan RN, Caplan LR et al.  Evidence -based guideline: the role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology; 2010; 75:177-185.

 

guideline from AAN cautioning that sensitivity of MRI to diagnose stroke is imperfect.

 

Albach FN, Brunecker P, Usnich T, et al.  Complete early reversal of diffusion weighted imaging hyperintensities after ischemic stroke is mainly limited to small embolic lesions.  Stroke 2013; 44:1043-1048

Authors studied 153 patients with an average NIHSS of 4 who received tpa; and underwent MRI on admission and in subsequent week.  97/611 (16%) of MRI diffusion hyperintensities resolved, but only 2 % of patients had ALL of their diffusion abnormalities resolve after receiving tpa.