Key
Clinical Questions Case
Outcome
Current
Concepts in the Use of tPA in Ischemic Stroke Patients:
Information from the NINDS Clinical Trials
Reanalysis and Recent Phase IV Studies
Case
Presentation
A 46 year old emergency physician with 20 years of Emergency Medicine
experience ponders the use of tPA in the treatment of ED patients with
acute ischemic stroke. He is aware of the medical literature, and has
read the 1995 NEJM NINDS clinical trial study that established the efficacy
of the tPA in improving outcome in acute stroke patients. He understands
the risks and benefits of tPA use, and knows that a recent reanalysis
of the data has been conducted. He has heard lectures presented by emergency
physicians, some who state that the drug is the industry standard, and
others that are concerned that there is insufficient data to support
its broad use. He has read the many statements from Emergency Medicine
societies, most of which suggest that the drug is effective when used
properly.
This EM physician has used tPA in stroke patients with success. He has
heard from colleagues that there are lawsuits out there, most related
to a failure to use tPA, not because of complications following tPA
use.
What approach should this EM physician take in learning more about tPA
use in the Emergency Department?
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Key
Clinical Questions and Learning Points
What
were the results of the original NINDS trial, in which tPA was used
as treatment for acute ischemic stroke?
The NINDS tPA acute stroke trial published in the New England Journal
of Medicine in 1995 reported a study of 624 patients, half of whom were
randomly treated with tPA within 3 hours of stroke onset. The tPA group
demonstrated an absolute benefit in favorable outcome of 12% (global
odds ratio 1.7) with a symptomatic intracerebral hemorrhage rate of
6.4% (10 times the placebo group).
Why was a reanalysis of the NINDS tPA data performed? What did
it show?
A reanalysis of the NINDS clinical trials data was conducted because
of questions about the original analysis of the NINDS study. The committee
was charged with addressing specific concerns about the study, specifically
whether imbalances in the baseline stroke severity in the tPA treated
and the placebo groups invalidated the entire trial.
The NINDS Re-analysis was published in October 2004 in the journal Stroke
stating that a clinically important and statistically significant benefit
of tPA therapy was identified (adjusted tPA to placebo odds ratio of
a favorable outcome of 2.1). This improved outcome was noted despite
baseline stroke severity imbalances and an increased incidence of symptomatic
ICH. Because the NINDS trial was not powered to detect any subgroup
differences, the committee could not specifically state that any one
subgroup did better or worse.
What did the reanalysis of the NINDS data tell us regarding:
stroke severity imbalances, blood pressure management, risk factors
for symptomatic ICH, and predicting subgroups more likely to have a
favorable outcome as a result of tPA therapy?
The committee adjusted for baseline stroke severity in the two treatment
groups when calculating the global odds ratio of a favorable outcome.
The committee stated: “Despite an increased incidence of symptomatic
intracerebral hemorrhage in t-PA treated patients and subgroup imbalances
in baseline stroke severity subgroup imbalances, the adjusted analysis
demonstrated a statistically significant, and clinically important,
benefit for treating acute ischemic stroke patients with IV t-PA within
three hours of symptom onset.”
Regarding blood pressure management, the committee stated: “We
concluded that a number of problems preclude the use of the study’s
blood pressure information in either statistical analyses or clinical
management.”
When analyzing the ability to predict complications, including ICH,
the committee observed that age, baseline NIHSS, and the interaction
between the two, were related to a decreased likelihood of having a
favorable outcome. A risk factor score using combinations of age, baseline
NIHSS, admission glucose, and CT scan findings predicted ICH occurrence
and a decreased likelihood of a favorable outcome. However, this information
must be utilized very cautiously in the management of individual patients,
since the study was not powered to study outcome in particular subgroups.
What did the NINDS reanalysis tell us about OTT (stroke onset
time to treatment time) and patient outcome?
Regarding time to treatment, the committee stated: “Based on our
analyses, and the observation that the distribution of the OTT values
was substantially nonlinear, the Review Committee concluded there was
no evidence that the effectiveness of tPA treatment decreased as the
time from stroke onset increased.”
How does the meta-analysis of the safety data in post approval
use of tPA for acute stroke reports compare with the NINDS trial data?
A meta-analysis of safety data from 15 reports of post-approval tPA
use in 2639 acute stroke patients was published in the journal Stroke
in 2003. The very favorable outcome rate was 37%, the symptomatic intracerebral
hemorrhage rate was 5.2% with a mean total death rate of 13.4%, both
slightly lower than in the NINDS trial. The author suggests that when
the protocol utilized in the NINDS trial is followed, it is possible
to replicate the beneficial outcome and adverse event profiles seen
in the original study and reanalysis.
What can be learned from the report of the pooled analysis of the randomized,
placebo controlled tPA trials for acute stroke?
A pooled analysis of tPA therapy in the six randomized acute stroke
trials was published in Lancet in 2004. This analysis included data
from the NINDS Parts I and II, Atlantis A and B, and ECASS I and II
studies. The report concludes that the sooner tPA therapy was given,
the greater the benefit, especially if tPA is started within 90 minutes
of stroke symptom onset. This may be due, in part both to improved favorable
outcome odds ratios and lower ICH rates in patients treated prior to
90 minutes from the stroke onset time.
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Patient
ED Treatment and Hospital Outcome
The emergency physician learned more about the use of tPA in the ED.
After reading the most recent analyses and reviewing lectures on the
FERNE website, www.ferne.org, he understood that tPA probably can be
used efficaciously when it is provided per the NINDS protocol.
He met with the neurologists, radiologists, primary care providers,
and administrators at his hospital. They agreed that a protocol for
the rapid assessment and treatment of stroke patients, including the
use of tPA and necessary adjuncts, should be developed. They developed
a protocol off-line, one that incorporated the specific NINDS treatment
protocol. They then planned to utilize the protocol in treating acute
ischemic stroke patients once the hospital staff was in-serviced on
the agreed upon treatment plan. Patients are now being treated using
the new protocol and patient outcomes are expected to match those found
in the NINDS trial.
This new stroke collaborative group is also looking into becoming a
designated primary stroke center. They look forward to new data that
will allow them to continue to improve the care of the stroke patients
that they treat in the Emergency Department.
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