COMMENTARY

tPA in Stroke: 'The Facts Are Clear'

Helmi L. Lutsep, MD

Disclosures

April 20, 2018

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.

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