There are dueling laments between what could be called “the stroke industrial complex” and the physicians on the front line. Tissue plasminogen activator (tPA) for acute ischemic stroke, in so many words, is repeatedly touted by a handful of guideline-writing experts as simply having “proven benefit.” Their primary lament is the paucity of acute stroke patients receiving tPA. Clinicians on the front line, however, see the perverse incentives wrought by such guidelines and mandates, including the detrimental impact on systems of patient care and costs of prioritizing “quality” targets. Our pragmatic concerns are for the safety of patients and of cautious concern regarding the appropriateness of therapy.

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In order to protect our patients, many physicians, and the ACEP Clinical Policy statement, hew closely to the exclusion criteria.¹ These exclusion criteria are intended to maximize the safety margin for tPA by minimizing life-threatening intra- and extracranial bleeding. These absolute and relative exclusion criteria are quite conservative and have been under siege for quite some time by the proponents of tPA.

Most recently, the American Heart Association has issued a new update regarding the scientific rationale for inclusion and exclusion criteria for tPA in acute ischemic stroke.² This document reviews most of the historical exclusions for tPA and makes new recommendations for the use of tPA based on the accumulated evidence. Unsurprisingly, given the conflicts of interest pervasive in the stroke guideline genre, the recommendations are almost universally in favor of giving more tPA. Unfortunately, the authors compound the issue by grossly overstating the strength of the evidence supporting their recommendations.

For example, these authors address the use of tPA in the elderly population. Most trials excluded patients over age 80, and of the 1,711 elderly patients evaluated in clinical trials, 1,617 are from the open-label IST-3 trial. Despite the biases inherent to IST-3, tPA use did not provide a statistically significant favorable outcome at three months. No robust randomized trial data regarding death rates are available, but multiple observational series demonstrate increased risk of intracranial hemorrhage and death in the elderly compared with younger patients receiving tPA. Nonsensically, the authors state “intravenous alteplase administration within three hours is equally recommended for patients less than 80 and more than 80 years of age.” This recommendation, in which limited and conflicting data are presented, is given their strongest Class I recommendation, based on the highest level of evidence.

Likewise, the authors comment on stroke severity in this guideline, noting the relative exclusion of both very mild and very severe strokes. Again, these authors recommend use of tPA for very severe strokes with Level A evidence while noting the National Institute of Neurological Disorders and Stroke (NINDS) enrolled “relatively few patients” and IST-3’s adjusted odds ratio for good outcome with increasing the National Institutes of Health Stroke Scale (NIHSS) did not reach statistical significance.

More concerning is the authors’ approach to mild stroke syndromes. The authors recommend tPA as “proven clinical benefit” for “mild but disabling” stroke symptoms with Level A evidence. They do so in the same breath as acknowledging, “Because nearly 3,000 such cases of ischemic stroke were excluded from the two NINDS trials for mild symptoms, any analysis of mild symptoms within the two NINDS trials is difficult to interpret.” Furthermore, in a reversal from other recommendations touting favorable findings from IST-3, the authors of this section ignore the neutral outcomes of 612 patients treated with NIHSS 0-5 in that trial. These authors assured endorsement of use of tPA in mild stroke syndromes would seem to suggest its use is a settled question, even though Genentech is funding the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis, or PRISMS, trial designed to investigate essentially this exact cohort.³

Rapidly improving symptoms are frequently cited as treatment exclusions. Transient cerebral ischemia, after all, is not an indication for tPA. In the section addressing this clinical scenario, these authors cite the work of The Re-Examining Acute Eligibility for Thrombolysis (TREAT) Task Force.⁴ As if the acronym of this expert panel was not an apparent enough bias, support for this panel was received from Genentech. Participants in the meeting had all travel expenses paid by Genentech, and most of the panel representatives had some conflict of interest due to a relationship with Genentech. The foregone conclusion of this panel, reiterated in these guidelines, is that improving symptoms should not exclude patients from tPA.

Frankly, the general theme of this document is that tPA should be given or considered for most of the previous exclusion criteria. This includes such apparently concerning clinical scenarios such as recent major surgery, recent major trauma, a known left-sided heart thrombus, recent gastrointestinal or genitourinary bleeding, and known extra-axial neoplasms. These authors also recommend considering tPA for patients with dementia and end-stage malignancy and those already moderately disabled without substantially framing the question of appropriateness. Finally, these authors also implicitly endorse the slash-and-burn processes taking root in our emergency departments by stating the 2 percent incidence of intracranial hemorrhage in stroke mimics is safety margin enough to not delay tPA administration to make an accurate diagnosis.

One could assume an altruistic interest in patients as the motivating factor behind the expanded use of tPA. However, the underlying funding for much of the work cited by these authors comes from Genentech, whose stroke symposia are fixtures at annual meetings. The pervasive use of tPA, embedded in guidelines, quality measures, and reinforced by statements about the “standard of care,” directly benefits its bottom line. Few statistics are available on the annual revenue derived from tPA since Genentech was purchased by Roche, but thrombolytics accounted for approximately $250 million in sales in 2008. Since then, Genentech has more than doubled the cost of alteplase from approximately $30/mg to more than $60/mg and, as these articles demonstrate, redoubled its efforts to expand indications.⁵

The original NINDS trials enrolled a few hundred patients each. Other rigorous trials, each with their own flaws and conflicts of interest, enrolled similar numbers. Now, 20 years later, rather than prove the safety and effectiveness of tPA for these expanded indications, these recommendations selectively overstate the quality of supporting evidence or simply use the absence of evidence to the contrary as justification.

It is frankly impossible to estimate any of the magnitudes of benefit or harms from the practices endorsed by this new guideline, but it is safe to assume the purported current benefit of tPA is certainly the ceiling. Likewise, as the original contraindications were intended to improve the safety margin of tPA, the anticipated harms must be greater. This is not the sort of work that improves the lives of our patients. We do not need to expand the use of tPA; rather, we ought to be pursuing research that helps us narrow the treatment cohort to those with the stroke syndromes and comorbidities with the ideal risk/benefit profile.

References

1. Brown MD, Burton JH, Nazarian DJ, et al. Clinical policy: use of intravenous tissue plasminogen activator for the management of acute ischemic stroke in the emergency department. Ann Emerg Med. 2015;66(3):322-333.e31.
2. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016;47(2):581-641.
3. A study of the efficacy and safety of Activase (alteplase) in patients with mild stroke (PRISMS). Accessed Feb. 28, 2016.
4. Levine SR, Khatri P, Broderick JP, et al. Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion criteria: part 1: rapidly improving stroke symptoms. Stroke. 2013;44(9):2500-2505.
5. Kleindorfer D, Broderick JP, Demaershalk BM, et al. The cost of alteplase has more than doubled over the past decade. Stroke. 2016;47:AWP78.