Each year, 22 million people worldwide will experience a stroke. 50% of these are ischemic strokes. For years, there were no effective treatments for these patients. As a result, the burden of ischemic stroke was enormous. Patients often experience debilitating strokes requiring round-the-clock care. Acute ischemic strokes represent the leading cause of disability in our society and the third most common cause of death. In the mid-1990’s, thrombolytic agents began to emerge as a potential therapy for this disease.

Thrombolytic agents were first used in the treatment of myocardial infarction (MI) in the early 1980’s. At this time, the treatment of MI was similarly limited. Stents were not used and so patients either got CABG or simply had completion of their infarcts while physicians crossed their fingers. Lytic agents were shown across multiple studies and over 60,000 patients to offer a 1-2% improvement in mortality. Based again on multiple studies, it was additionally found that the benefit of lytic agents in MI was only present in those with STEMI and was indirectly related to the time from onset of symptoms. Therefore, the earlier in the disease process that lytics were given, the better the outcome. This led to the idea that “time is heart.”

The evidence in MI formed the basis for the application of lytic agents, specifically alteplase, to ischemic strokes. The theory again was that there was a clot sitting in a vessel and administration of a lytic agent would dissolve the clot and improve patient outcomes. “Time is brain” was pushed hard as well but not based on data pertaining to stroke but based on the data pertaining to MI.

Prior to the publication of the NINDS article, there were two major RCTs investigating the use of thrombolytics in ischemic stroke: MAST-I and ECASS I. Both of these studies looked at patients presenting within 6 hours of symptom onset and found no benefit to the administration of streptokinase.

The NINDS article which we’ll discuss in a bit was not the first trial looking at the utility of lytic agents in stroke. Prior to NINDS, there were two major RCTs – MAST-I and ECASS I. Both of these studies looked at a 6-hour time window (i.e. symptoms starting within 6 hours of drug administration) and found no benefit when streptokinase was given.

Clinical Question

Does the addition of alteplase (tPA) to standard care improve functional outcomes in patients with ischemic stroke who present less than 3 hours after onset of symptoms?


All patients that had an ischemic stroke with a clearly defined time of onset, a deficit measurable on the NIHSS and a baseline CT scan showing no ICH.


Administration of IV t-PA (0.9mg/kg)




NINDS Part 1: Improvement of > 4 points from baseline NIHSS within 24 hours
NINDS Part 2: Improvement in Barthel index, Modified Rankin Scale (mRS), Glasgow outcome scale and NIHSS at 90 days.


Randomized, double blind trial that was split into two parts


Patients with a prior stroke or serious head trauma within 3 months, major surgery within 14 days, history of ICH, systolic BP > 185 mmHg, DBP > 110 mmHg, rapidly improving symptoms, symptoms suggestive of an SAH, GI or urinary tract hemorrhage within last 21 days, arterial puncture at non-compressible site within 7 days or seizure at onset of stroke. Patients taking anticoagulants or received heparin within 48 hours (and an elevated aptt), PT > 15 seconds, platelets < 100,000/mm3, glucose < 50 mg/dl or > 400 mg/dl and patients requiring aggressive treatment of BP to get under 185/110.

Primary Results

Critical Findings

Part 1

Primary Endpoint: > 4 point improvement in NIHSS at 24 hours

  • N = 291
  • tPA – 47% (67/144) (47%)
  • Placebo 39% (57/147)
  • No statistically significant difference at 24 hours

Part 2

Primary endpoint: Improvement in stroke scale (Barthel Index, mRS, Glasgow Outcome Score and NIHSS) at 90 days

  • N = 333
  • <2 mRS at 90d: 26% placebo vs. 39% tPA (13% absolute benefit)
  • NNT=8

Regardless of which stroke scale you looked at, tPA patients did better.

Secondary endpoint: > 4 point improvement in NIHSS at 24 hours

  • tPA 48% vs. placebo 39%
  • No statistically significant difference


Symptomatic ICH

  • tPA: 6.4% (20/312) – 45%(9/20) mortality rate
  • Placebo: 0.64% (2/312) – 50% (1/2) mortality rate

Asymptomatic ICH

  • tPA 4.4% (14/312)
  • Placebo 2.9 % (9/312)
  • NNH = 16 patients


  • Double-blind with adequate randomization
  • Excellent follow up 99% (619/624)


  • Patients were not consecutively recruited
  • Baseline imbalance in patient severity
    • More patients in placebo group had large-vessel occlusions
    • Statistically significant imbalance in initial stroke scale (favoring tPA group)
  • Extensive exclusion criteria many of which are subjective
  • Fragility Index = 3 (number of outcomes needed to be changed to lose statistical significance)

Other Issues

  • Contrary to tradition, this article published results from two different studies. Although the methods and intervention are the same in parts 1 and 2, the primary outcome is different. It is unclear from the publication whether this was a planned design or if this study was stopped after 291 patients at which time the authors analyzed that group, found no difference in the primary outcome and the switched the primary outcome. This is a major issue in the methodology.

Author's Conclusions

“Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.”

Our Conclusions

We agree with the authors that it is clear that tPA increases the risk of development of a symptomatic intracerberal hemorrhage in comparison to placebo. However, we question the validity of the purported benefits. Baseline imbalance in the treatment arms and potential methodological manipulation make these results questionable. Of note, the results of this study have NEVER been replicated.

Potential Impact To Current Practice

This study is at the heart of all stroke care in the last 20 years.

Bottom Line

While there is likely a group of ischemic stroke patients that benefits from the administration of systemic thrombolytics, this study does not help us define that group.

Read More

SMART Thrombolytics for Acute Stroke

SGEM #70: The Secret of NINDS (Thrombolysis for Acute Ischemic Stroke)

EMCrit Podcast #116 – the tPA for Ischemic Stroke Debate

PulmCrit: What is the Fragility Index of the NINDS trial