The American Heart Association/American Stroke Association has issued a new scientific statement on the rationale for the inclusion and exclusion criteria for intravenous alteplase (tissue plasminogen activator [tPA]) in acute ischemic stroke.
The statement evaluates the evidence for the various inclusion and exclusion criteria and makes recommendations on how clinicians might use tPA in clinical practice.
"Who to treat and who not to treat with tPA is a daily issue for physicians managing patients with acute stroke," coauthor Dawn Kleindorfer, MD, University of Cincinnati, Ohio, told Medscape Medical News. "The problems occur because the inclusion and exclusion criteria on the alteplase label do not match up well with clinical experience. This document, which is intended to be a companion to the acute stroke management guidelines, was drawn up to help clinicians make decisions on who to treat and to identify key areas that should be prioritized for further research."
She noted that the statement recommends several scenarios where the eligibility criteria for alteplase in acute ischemic stroke could be relaxed somewhat, which could vastly increase the number of patients who could benefit.
The statement was published online December 22 in Stroke.
As part of the introduction in the paper, the authors report that although the benefit of alteplase is well established, only around 5% of patients with acute ischemic stroke in the United States receive this treatment. They note that the most common exclusion for alteplase is failure to arrive at the hospital in time, with only around 22% to 31% of patients presenting to an emergency department within 3 hours from symptom onset.
The statement notes, however, that numerous other clinical, radiologic, and laboratory-related exclusion criteria for alteplase — mostly related to hemorrhagic risk — are considered standard of care. One study estimated that even if all patients with ischemic stroke arrived within the treatment time window, only 29% would have been eligible for alteplase.
Some Exclusions Controversial
It states that some of these exclusions for alteplase are controversial, and many stroke experts across the country consider some of these exclusion criteria to be "relative" and others to be "absolute." Opinion on which patients should be treated varies widely.
"The intent of this advisory statement is to critically review and evaluate the science behind each of the alteplase eligibility criteria (indications and contraindications alike) and to explore some popular myths about treatment," the authors write. "If successful, we will help with alteplase eligibility decision making today and identify research priorities for the future that potentially could broaden the eligibility for and treatment with alteplase."
"We anticipate that this scientific statement will assist the clinician to better engage with patients experiencing an acute stroke and their families in a shared decision-making model with an up-to-date understanding of the current literature," they add.
It concludes: "Some exclusions and myths already have extensive scientific study such as the clear benefit of alteplase treatment in elderly stroke patients, in those with severe stroke, in those with diabetes mellitus and hyperglycemia, and in those with minor EICs [early ischemic changes] evident on CT [computed tomography]. Some exclusions such as recent intracranial surgery are likely based on common sense and very likely will never have a randomized clinical trial to evaluate safety. Most contraindications or warnings range somewhere in between."
One of the strongest recommendations made is that elderly patients should be eligible for tPA.
The authors note that the alteplase label states that in patients older than 75 years of age, the risks of alteplase therapy may be increased, and in patients older than age 80 years the effectiveness of intravenous treatment with alteplase is not well established and requires further study.
But the statement makes the recommendation (class I; level of evidence A) that older patients should be treated. It says: "For otherwise medically eligible patients ≥18 years of age, intravenous alteplase administration within 3 hours is equally recommended for patients <80 and >80 years of age."
The statement acknowledges that older age is an adverse prognostic factor in stroke but that this does not modify the treatment effect of thrombolysis. "Although older patients have poorer outcomes, higher mortality, and higher rates of sICH [symptomatic intracerebral hemorrhage] than those <80 years of age, compared with control subjects, intravenous alteplase provides a better chance of being independent at 3 months across all age groups."
Noting that the alteplase label has recently been updated to remove restrictions on use in mild or very severe strokes, the statement makes strong recommendations in favor of treating both very severe strokes and mild disabling strokes with tPA, saying there is proven clinical benefit in both scenarios.
The grey area is use in milder ischemic strokes that are judged as nondisabling. The statement says alteplase "may be considered' in such patients and more study is needed to further define the risk-to-benefit ratio.
"One of the problems in this area is that everyone has different opinions on what encompasses a mild stroke," Dr Kleindorfer commented. "The stroke scales used are not good at predicting who is going to be left the most disabled. At the moment there isn't a cut off on the NIHSS [National Institutes of Health Stroke Scale] as to what defines a mild stroke."
On patients who are rapidly improving (another exclusion that has recently been removed from the label) the document says tPA is "reasonable" for patients who present with moderate to severe ischemic stroke and demonstrate early improvement but remain moderately impaired and potentially disabled.
An issue that has long been the subject of debate is how long after stroke onset should tPA be given.
The US Food and Drug Administration label states that treatment should be initiated only within 3 hours after the onset of stroke symptoms (based on the original National Institute of Neurologic Diseases and Stroke trial). However, the new statement recommends that "Intravenous alteplase treatment in the 3- to 4.5-hour time window is also recommended for those patients younger than 80 years of age without a history of both diabetes mellitus and prior stroke, NIHSS score < 25, not taking any OACs [oral anticoagulants], and without imaging evidence of ischemic injury involving more than one third of the MCA [middle cerebral artery] territory."
The statement reviews and gives recommendations on many other specific patient groups as well.
Key Areas for Research
Finally, the authors highlight several areas as high priority for future study. These include the following:
Patients with mild stroke;
Use of multimodal cerebral imaging as a "tissue clock" to identify patients who may benefit from tPA based on tissue viability rather than an arbitrary time window, which may be especially relevant to patients who wake up with their deficits and it is unclear when the stroke actually occurred;
Patients taking anticoagulants, those with periprocedural or perioperative ischemic stroke, and those who have had a recent pervious stroke — all of whom are thought to be at some degree of increased bleeding risk;
Those with preexisting disabilities or dementia, with new risk prediction models needed that include both the risk for hemorrhagic transformation and the chances of an improved outcome.
The authors also call for international harmonization on alteplase labeling and treatment guidelines. Dr Kleindorfer explained that the many variations in recommendations between different countries make the picture even more confusing.
Stroke. Published online December 22, 2015. Full text
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Cite this: New AHA/ASA Statement on Expanding Use of tPA in Stroke - Medscape - Jan 15, 2016.