tPA and CVA

The treatment of acute ischemic CVA with TPA from 3 to 4.5 hours after symptom onset

1)  Tissue plasminogen activator for acute ischemic stroke.  The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.  NEJM. 1995;333:1581-7.

NINDS is a RCT trial in two parts evaluating the use of TPA in ischemic CVA when given within 3 hours of symptom onset.  Part 1 (291 patients) evaluated clinical activity, or whether there was  significant neurologic improvement at 24 hours.  Results of Part 1 were negative (no difference at 24 hours between TPA and placebo).  Part 2 evaluated clinical outcome at 3 months, using patients from Part 1 and an additional 333 patients.   Part 2 demonstrated significant results:  as compared with placebo, patients treated with TPA were at least 30% more likely to have minimal or no disability at 90 days on clinical assessment scales (absolute increase in favorable outcome 11%, NNT 9).  This is balanced against a 10X increased risk of symptomatic intracranial hemorrhage (6.4% in TPA group, 0.6% in placebo group).   A couple of common criticisms of NINDS:  first, the trial selectively enrolled an equal number of patients treated within 0-90 and 91-180 minutes of stroke onset, with greater benefit shown for those in the former group.  In general practice, you wouldn’t see as many patients qualify for early treatment, making the results less generalizable.  Second, stroke severity in the group treated from 90-180 minutes was greater in the placebo than in the tPA group, again potentially biasing the results in favor of treatment. 

The AHA gave TPA a Class I  recommendation for use in ischemic CVA in 2000.  Few studies have provoked the degree of rancorous debate and number of re-analyses as NINDS.  At JC we mentioned the graphical analysis of the NINDS data from one of TPA/CVA’s biggest opponents, Jerry Hoffman (with Dave Schriger, Annals of EM, Sept. 2009).  Their article is attached, and they promoted it as an attempt to bring transparency to the data, and to offer individual patient analysis rather than conclusions about groups of patients.   In the spirit of being fair and balanced, I have also attached a pooled analysis of ATLANTIS, ECASS, and NINDS by Hacke et al published in Lancet in 2004 (thanks Ejaaz).  Although ATLANTIS, ECASS I and ECASS II enrolled most patients after 3 hours, in studies evaluating patients  in these trials enrolled in under 3 hours, there were trends towards benefit in those treated with TPA (references available on request).


Although ACEP and CAEM both recommend the use of TPA in acute ischemic stroke up to 3 hours after symptom onset, they strongly reiterate the need to follow the strict inclusion/exclusion criteria from NINDS and to establish institutional safety guidelines (ACEP and CAEM), and to advocate for neuroradiologist and close neurology involvement (CAEM).  AAEM states that efficacy, safety and applicability evidence is insufficient to warrant the classification of TPA in CVA as standard of care.

Things became even more heated this year, when the AHA gave a Class I (Level B evidence) recommendation for the use of TPA in the setting of CVA from 3-4.5 hours after symptom onset.  This expansion of the time window was based on one study: ECASS III

2) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.  NEJM. 2008;359:1317-29. 

ECASS III was a RCT of 821 patients, alteplase vs placebo, time to treatment 3-4.5 hours after symptom onset with a median time for administration of 4 hours.  Primary outcome:  disability at 3 months (dichotomized modified Rankin scale-favorable or unfavorable), with a secondary efficacy end point of a 90 day global outcome measure.   Mean NIHSS stroke scale 11.  With regards to the primary endpoint, there was a statistically significant increase in the number of patients with favorable outcome when comparing alteplase to placebo (52.4% vs. 45.2%, absolute increase in favorable outcome 7.4%, odds ratio 1.34, NNT 13.5).  The secondary outcome was also significantly improved with alteplase as compared with placebo.   There was no significant difference in mortality (7.7% alteplase, 8.4% placebo).  The incidence of symptomatic ICH was significantly increased (over 2X) in the alteplase group (7.9% vs. 3.5% by NINDS definition). 

Although the AHA based their recommendation uniquely on ECASS III, there are a number of other earlier published thrombolytic/CVA trials which attempted to push the time window and had negative results.  As one example, we reviewed ATLANTIS

3) Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset.   The ATLANTIS Study:  a randomized controlled trial.  JAMA. 1999;282:2019-26.

ATLANTIS was designed to run concurrently with NINDS, assessing efficacy and safety of TPA when administered from 0-6 hours after symptom onset in patients with ischemic CVA.   However, safety concerns resulted in stopping enrollment after 5 hours.  Then, when the results of NINDS were published, the trial protocol was again changed, with the treatment window changed to 3-5 hours after symptom onset.  ITT population 613 patients.  Primary outcome excellent neuro recovery at 90 days (NIHSS score less than/equal 1). No significant difference in patients treated with TPA vs. placebo on either primary outcome or on secondary functional outcome measures Symptomatic ICH 7.0% with TPA, 1.1% placebo (significant), but no significant difference in mortality.

Our clinical vignette patient would have met the inclusion/exclusion criteria for both ECASS III and ATLANTIS.   There will be continued controversy surrounding the use of TPA in acute ischemic stroke, whether the patient is ready for the drug 2 or 4 hours after symptom onset.  Many scientists have called for more studies, but given the cost involved with mounting these large multi-center trials, it’s unlikely to happen (definitely no interest on the part of Genentech!).   Within the group of physicians present at JC, there were also a variety of opinions on TPA’s merit.  Certainly one’s own personal opinions are likely to influence how you present the pros/cons of TPA to a patient and family. 

For all 3 of these studies, there are concerns about internal validity (how many patients were screened and not enrolled in these studies involving 100 + centers) and external validity (what happens when you move the treatment setting from a highly regulated stroke center to the general community-in Cleveland, 16% symptomatic ICH rate, and 3X the mortality in patients treated with TPA vs. placebo).

Other important points: the exclusion criteria for ECASS III are extensive!!  It’s imperative to be familiar with the ECASS III exclusion criteria, in order not to tip the narrow balance between benefit and risk.  A couple of examples:  all three trials used a BP of 185/100 as an exclusion criteria.  ATLANTIS and ECASS III specified that IV BP meds were not allowed.  Also, both ATLANTIS and ECASS III excluded patients >80 years old.  This excludes a large number of patients.  Patients with severe strokes were excluded in both ECASS III and ATLANTIS.  Although patients with more severe strokes have a greater risk of ICH, they also have great potential to be helped by TPA and avoid severe disability (see:  the NINDS t-PA Stroke Study Group. Stroke. 1997 Nov;28(11):2109-18  and the attached pooled analysis-thanks again Ejaaz).  This ties in to the broader philosophical question of personal risk.  We discussed that one approach with patients/families is to assess the degree to which a patient is a risk taker (“I’d rather  take a chance of bleeding into my brain than be a vegetable”) or risk averse (“the weakness isn’t too bad, and with aggressive rehab, is likely to improve”).   Considering the value system of your patient is the third pillar of Evidence Based Medicine (besides examining the evidence and using clinical experience).  Joan Coughlin also brought up the excellent point that although it’s not exciting, early aggressive rehab is extremely important in stroke care, and can help many patients achieve significant improvement (in ATLANTIS, with baseline NIHSS score of 11, 32% of placebo patients with excellent neuro recovery, and in ECASS III, 45%).


In the TPA/CVA packet in the ED, there are simple statistics about the risk/benefit of TPA when given within 3 hours.   This information may be helpful when speaking with patients/families, but you will now also need similar talking points for the extended time window.  It was recommended by several seasoned faculty to be familiar with both NINDS and ECASS III (and ideally, the other thrombolytic trials).  This will give you the best chance to share as accurate and balanced information as possible when advising patients and families about this complicated, high stakes therapeutic decision.