Yep they are. tPA is a failure,
only a 12% full recovery rate using it. It may save your life, it did mine, but the proper endpoint to measure is full recovery and that is a massive failure.
https://www.medscape.com/viewarticle/895370
The Argument for Thrombolytic Therapy in Stroke
This commentary is in part a response to a recent
Medscape article
by cardiologist Dr John Mandrola, in which he argues against the use of
intravenous tissue plasminogen activator (IV tPA) to treat acute
ischemic stroke. I want to start by pointing out that Dr Mandrola does
not distinguish between IV tPA treatment trials with different
time-to-treatment windows and includes two streptokinase trials to cast
doubt on the efficacy of IV tPA. In my interpretation of the literature,
tPA treatment is efficacious when used within 4.5 hours of stroke
onset, as shown by individual trials and meta-analyses.
[1,2,3,4]
Helmi L. Lutsep, MD
Studies have shown the enormous effect of time to
treatment with IV tPA and outcomes, with the greatest benefit up to 3
hours after stroke onset.
[3,4,5]
It is not surprising that the IST-3 trial, referred to by Dr Mandrola
as "the strongest argument against tPA in stroke," was a negative trial.
[6]
The trial sought to show benefit of IV tPA up to 6 hours after stroke.
While the primary endpoint, the proportion of patients that were alive
and independent at 6 months, was not met, secondary analyses did show
that patients treated with IV tPA up to 6 hours after strokes survived
with less disability.
Data demonstrate that the use of IV tPA in real life is at
least as safe as it was in the NINDS trial. While Dr Mandrola cites the
Cleveland Clinic experience published in the year 2000,
[7] he neglects to point out an updated report from the Cleveland Clinic after initiation of a stroke quality-improvement program.
[8] The symptomatic intracranial hemorrhage rates were similar to those in the NINDS trial.
The
Standard Treatment with Alteplase to Reverse Stroke (STARS) study was a
large phase 4 study mandated by the FDA to assess the safety and
clinical outcomes following IV tPA therapy in clinical practice.
[9]
The study showed favorable clinical outcomes and low rates of
symptomatic hemorrhage. Giving tPA to a patient who turns out to have a
stroke mimic also does not engender the great concern that Dr Mandrola
fears it does. Studies show that the risk for intracranial hemorrhage is
significantly lower in stroke mimics than in stroke patients treated
with IV tPA.
[10]
Many
of the challenges raised about the results of the NINDS and ECASS III
trials are based on concerns regarding putative imbalances in the
severity of the strokes in the treatment and placebo arms of the trials.
An independent analysis of the NINDS trial commissioned by the NINDS
determined that the "findings support the use of t-PA to treat patients
with acute ischemic stroke within 3 hours of onset under the NINDS t-PA
trial protocol."
[11]
The ECASS III publication included a post hoc intention-to-treat
analysis adjusted for confounding baseline variables, including the
baseline National Institutes of Health Stroke Scale score.
[2] In this adjusted analysis, treatment was still significantly associated with a favorable outcome.
The
discussion about the endpoints chosen for acute stroke treatment trials
is an important one. Stroke is a leading cause of adult disability. My
patients tell me that they fear disability from stroke more than they do
death. Disability is considered the most important measure to employ in
an acute stroke randomized controlled trial.
[12]
While the NINDS and ECASS III trials did not show lower death rates
with tPA, they revealed a significant reduction in disability.
[1,2]
Dr
Mandrola talks about the "subjective primary endpoint" in ECASS III.
Each modified Rankin Scale score is, in fact, precisely defined, and in
ECASS III, investigators were instructed in the use of the modified
Rankin scale by watching video clips from a training DVD.
[2]
Clinically relevant treatment effects extend beyond the dichotomized
results of the trial. In ECASS III, a post hoc stratified analysis of
the modified Rankin score distribution at day 90 also showed a favorable
outcome with tPA as compared with placebo.
[2]
The
NINDS and ECASS III trials, as well as a meta-analyses of all of the IV
tPA trials, show benefit for treatment with IV tPA up to 4.5 hours from
symptom onset, with the greatest benefits within the 3-hour window.
[1,2,4,5]
In a pooled, individual patient-level analysis of the tPA trials that
enrolled patients within the 3-hour time window (1549 participants), tPA
increased the disability-free outcome at 3 months compared with
controls by 32.9% versus 23.1%,
P < .0001.
[4]
All
potential acute ischemic stroke patients meeting criteria for the use
of IV tPA should be offered treatment. The facts are clear, and all that
remains is further provider and patient education.
