Emergency physicians rely on professional organizations such as ACEP to provide data driven information to help inform clinical practice.

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ACEP Now: Vol 40 – No 04 – April 2021

Excerpt

There are 13 RCTs of thrombolytics for AIS (see Table 1). Four were stopped early for harm (bleeding) or futility, and all 13 failed to show a statistical benefit after the reanalysis of NINDS-2 and ECASS-III.

Concern 3: Table 1 summarizes RCTs evaluating various thrombolytics for treatment of acute ischemic stroke. Because this table includes results from streptokinase and desmoteplase trials and from trials allowing time of alteplase treatment up to 6 hours from onset, inappropriate conclusions may be made about the safety and efficacy of alteplase for treatment of acute ischemic stroke.

Activase was FDA-approved for the treatment of acute ischemic stroke within 3 hours of symptom onset, based on the data from the two-part NINDS trial.¹⁶ While symptomatic intracranial hemorrhage (sICH) was significantly higher in the Activase group (6.4 percent) versus placebo (0.6 percent), mortality was lower in the Activase arm (17.3 percent) compared to the placebo arm (20.5 percent).

FDA Clearance:

• Activase is not FDA-approved for use in treatment of acute ischemic stroke 3–4.5 hours from onset.
• Activase is FDA-approved for the treatment of acute ischemic stroke within 3 hours from onset of symptoms.
• Please refer to the product prescribing information for the full FDA-approved indications and safety information, available at www.gene.com/download/pdf/activase_prescribing.pdf.

Emergency physicians rely on professional organizations such as ACEP to provide data-driven information to help inform clinical practice. Physicians are then responsible for evaluating the data and using their best judgment for incorporation into practice. This analysis requires presentation of unbiased material with each side impartially represented.

Respectfully yours,

Rachel Garvin, MD, Senior Medical Director, Lytics, Genentech, Emergency Physician and Neuro Critical Care Specialist

Michael Liberman, MD, Senior Group Medical Director, Lytics US Medical Affairs, Genentech

References

1. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS trial. Ann Emerg Med. 2009;54(3):329-336.
2. Saver JL, Gornbein J, Starkman S. Response to: “A graphic reanalysis of the NINDS Trial.” Ann Emerg Med. 2010;55(2):226-227; author reply 229.
3. Dewey HM, Churilov L, Blacker D, et al. Response to “A graphic reanalysis of the NINDS Trial.” Ann Emerg Med. 2010;55(2):227-229; author reply 229.
4. Saver JL, Gornbein J, Starkman S. Graphic reanalysis of the two NINDS-tPA trials confirms substantial treatment benefit. Stroke. 2010;41(10):2381-2390.
5. Alper BS, Foster G, Thabane L, et al. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evid Based Med. 2020;25(5):168-171.
6. Activase [package insert]. South San Francisco, CA: Genentech, Inc.; 2018.

The Authors Respond

We are grateful for the letter by Garvin and Liberman, employees of Genentech. Our ACEP Now article was focused on the 2020 reanalysis of ECASS III by Alper et al, which added to the uncertainty about stroke thrombolysis. The 1995 NINDS trials were background information on the uncertainty.^1,2

For a treatment to be scientifically sound, there must be replication of studies, minimization of bias, and healthy debate. These requirements have not been met for stroke thrombolysis. Discussions on controversies contribute to our understanding of deficiencies in existing data. The most glaring issue on this subject is the absence of replication studies suggesting benefit. The medical literature is replete with initially “positive” studies followed by larger, more reliable “negative” studies. This has contributed to the phenomenon of medical reversal whereby newer, superior results contradict current practice.³ There are many examples where society guidelines promoting harmful treatments (eg, steroids for spinal cord injury) were later overturned.⁴

The concerns about the National Institutes of Health Stroke Scale (NIHSS) being a nonlinear scale are recognized. These concerns, although theoretically valid, do not appear to be relevant to NINDS, as the delta NIHSS was the same for all the treatment arms at every area of the scale—it changed equally with (early or later) tPA as with placebo for small strokes, for moderate ones, and for severe strokes. Changes in NIHSS measure discrete elements of neurological function rather than the more important overall functional status. Still, we might ask, “just how did tPA lead to better overall outcomes … if it had no effect on any element of neurological function?”⁵

Alper et al also raised concerns around the dangers of selective analysis of trials. They refer to this as “selective analysis reporting bias” and state this could be involved in the stroke literature, specifically the reporting of ECASS III.⁶ In reality, reanalyses are not often done. There is evidence that, when they are conducted, they frequently change the direction and magnitude of effect size and statistical significance.⁷

No claim was made in the ACEP Now article as to which analysis was correct. The bottom line stated that the reanalysis by Alper et al does not support a patient-oriented benefit of tPA given 3–4.5 hours after onset of stroke symptoms and confirms the known potential harm. This agrees with the conclusions of Alper et al’s reanalysis, and we echo their call for the readers to reconsider the use of tPA in this time window.

Excerpt

Conclusions: Reanalysis of the ECASS III trial data with multiple approaches adjusting for baseline imbalances does not support any significant benefits and continues to support harms for the use of alteplase 3–4.5 hours after stroke onset. Clinicians, patients, and policymakers should reconsider interpretations and decisions regarding management of acute ischaemic stroke that were based on ECASS III results.

tPA is not FDA-approved in the 3–4.5-hour time frame. However, the 2015 ACEP policy does discuss the use of tPA in this time window. The recommendations were stated in the ACEP Now article background section and included a link to the full ACEP policy statement.⁸ This highlighted the importance of shared decision making about the potential benefits and potential harms of tPA in this time frame.

The table in our article provides some details on 13 foundational randomized control trials (RCTs) evaluating thrombolysis for acute ischemic stroke. Each thrombolytic agent is clearly identified. There is no definitive data to suggest one thrombolytic agent is better than another.⁹ To selectively highlight two “positive” tPA trials (both with questionable efficacy on reanalysis) and omit the other 11 RCTs (six tPA and five non-tPA) that did not report benefit for their primary outcome is a form of the  “Texas sharpshooter fallacy” (ie, “counting” the positive trials but ignoring the negative ones).¹0 Or putting it differently, all the evidence is positive, as long as we reject any evidence that fails to be positive.