Age and stroke-scale cutoffs limiting which ischemic stroke patients should receive intravenous alteplase (tPA) are not supported by the existing evidence, according to a new scientific statement from the American Heart Association (AHA) and the American Stroke Association (ASA). (Stroke 2016;47:581; http://bit.ly/1qJFjKr.) Emergency physicians have often clashed with neurologists — who made up the bulk of the membership on the writing panel — but in this case, leaders in emergency medicine have found little to dispute.
“As clinical practice has evolved over the course of the past 20-plus years of tPA administration, some stroke clinicians have pushed the boundaries on a number of the inclusion and exclusion criteria,” said Opeolu Adeoye, MD, an associate professor of emergency medicine and neurosurgery at the University of Cincinnati and the only emergency physician on the writing panel for the scientific statement. “Our interest was in seeing what the evidence was for some of those changes in clinical practice that we have all observed.”
The statement does not have the force of a guideline; it evaluates the current science behind alteplase eligibility criteria, but specifically stated that it is an adjunct to, not a replacement for, existing guidelines: “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. 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.”
The statement covers a number of areas, including the use of alteplase in patients with a history of taking blood thinners, those with recent trauma or major surgery, and individuals with milder ischemic symptoms that are judged to be non-disabling, but the two most significant, said Dr. Adeoye, are the age and stroke-scale recommendations.
“Clinically, those ‘relative’ contraindications are the things that people have pushed the boundaries on, and have essentially found that the medication may be safely administered in those instances,” he said.
The current U.S. Food and Drug Administration (FDA) label identifies advanced age as a warning factor in the use of alteplase, stating that the risks of the drug may be increased and should be weighed against expected benefits for patients over 75.
Only three randomized controlled trials have assessed the use of alteplase in patients 80 and older, the panel found. The NINDS alteplase trials included only 69 patients in this age group, and the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) included just 25. By far, the largest population of 80-plus stroke patients studied was in the third International Stroke Trial (IST-3), which had 1,515 in the alteplase group and 1,520 in the control group. The AHA-ASA panel analyzed survival and functional benefits, along with safety (primarily symptomatic intracerebral hemorrhage) in these trials and meta-analyses and observational studies.
They found Class I, Level A evidence to support the statement that alteplase administration is equally recommended for patients over 80 and those 80 and under for otherwise medically eligible patients 18 and over. Older age is an adverse prognostic factor in stroke, they found, but does not modify the effects of tPA or add to its risks. Alteplase also gives older patients a better chance of being independent at three months post-stroke, they wrote.
The original FDA alteplase label included a warning that patients with NIHSS stroke severity greater than 22 be treated “with caution” primarily because these patients are more likely to hemorrhage (with or without alteplase treatment). Alteplase does increase the frequency of early hemorrhage, but the scientific statement panel noted that it “substantially improves the final functional outcome for more severe strokes, including the higher risk of hemorrhage.” Accordingly, they state that IV tPA is “indicated” within the three-hour window for more severe stroke patients, again categorizing the evidence as Class I, Level A.
Treatment is also indicated for patients with mild stroke symptoms that are still judged by the clinician to be disabling, despite low NIHSS scores, the statement said. “A significant proportion of mild stroke patients remain at significant risk for poor outcome despite relatively mild presenting stroke severity,” the panel wrote. This recommendation, too, is a Class I, Level A. The evidence for or against treatment of patients with mild stroke symptoms that are judged as nondisabling, however, is lacking; the panel ranked it as Class IIb, Level C, and said while tPA in these patients “may be considered,” they cautioned that more study was needed and treatment risks should be weighed against possible benefits.
Dr. Adeoye cautioned that stroke clinicians and researchers must be careful in their expectations of what resources are available to the more remotely practicing emergency physician. “Certainly the availability of telemedicine allows the more isolated physician to have access to some of the resources of the major academic centers, but it's not ubiquitous yet. We still have a lot of people in practice trying the best they can to make the best decision for the patient in front of them,” he said.
Controversial or Not?
Some emergency medicine commentators have taken issue with AHA-ASA alteplase recommendations, but the chair of the American College of Emergency Physicians' Clinical Policies Subcommittee that wrote ACEP's guidelines for tPA use in the ED, Michael Brown, MD, MSc, said he found little to debate. (“ACEP — Minus the Neurologists — Tempers its tPA Policy,” EMN 2015;37:1; http://emn.online/1VSqQck.)
“For example, the recommendation that we weigh treatment risks against possible benefits in patients with milder ischemic symptoms that are judged to be non-disabling, I think it makes sense,” he said. “And I couldn't agree more with the panel's call for more research in this area. There is one current study that I'm aware of looking at patients with NIHSS scores from 0-5, and randomizing them to tPA or placebo.”
That study, known as PRISMS, is enrolling more than 900 patients with mild, not clearly disabling strokes, and is expected to report results in 2018. It is being sponsored by Genentech, the maker of Activase, however, Dr. Brown said, because “they tried to get government funding but were unable to do so.”
He pointed out that while the risk of bleeding is very low in this patient population, the expected magnitude of potential benefit from alteplase would also be lower. “We can't extrapolate the benefits from more severe patients. We are at the point of equipoise with this patient population presenting with mild stroke, and we really don't know the answers. Hopefully PRISMS will give us those answers.”
Dr. Brown also concurred with the panel's statement that patients with moderate to severe strokes should still be considered candidates for tPA if they have demonstrated some improvement but remain moderately impaired.
Other statements, such as those on patients who are pregnant or in early postpartum stages (tPA may be considered when the anticipated benefits of treating moderate to severe stroke outweigh the risks of uterine bleeding) and patients with low platelet counts (tPA not recommended, but don't wait for lab values if there's no reason to suspect thrombocytopenia because of its rarity) are classed as Level C.
“A lot of this is made on very soft evidence, and their recommendations do seem to be very cautious, with which we would agree,” Dr. Brown said. “We didn't include recommendations regarding pregnancy in our ACEP statement because there is so little evidence out there. But their statements in these categories and others, like patients who have had trauma or major surgery recently, are carefully considered and reasonable.”
Dr. Brown also said he would not challenge the panel's statement that the use of intravenous tPA in patients with a past history of intracranial hemorrhage is “potentially harmful,” with an evidence Level C.
The original label for alteplase and the 2013 AHA/ASA guidelines listed a history of ICH as a contraindication to IV tPA, but the new FDA label only lists recent ICH as a warning, and has removed it from the contraindication section. The panel stated, “Similar to earlier reviews of intravenous alteplase exclusion criteria, the literature offers only a handful of cases in the context of larger retrospective reviews. The lack of any data on this issue is possibly the reason the revised FDA label removed any history of ICH as a contraindication and added a warning against recent ICH only.”
Dr. Brown said emergency physicians do not have much evidence to back up an absolute contraindication. “In this category and throughout the document, this statement gives more power to the individual physician to make the decision about tPA, based on the characteristics of the patient. I wouldn't argue with that,” he said.
One of the only areas in which Dr. Brown called the panel's recommendations into question was on stroke mimics like psychogenic pseudostroke, conversion disorder, and malingering. The panel noted that the risk of symptomatic ICH in the stroke mimic population is quite low, and that “starting intravenous alteplase is probably recommended in preference over delaying treatment to pursue additional diagnostic studies,” classifying the recommendation as Class IIa, Level B.
“I'm not so sure about that,” Dr. Brown said. “Most of the time, in the ED setting, if we think it's malingering or a conversion disorder, we don't give those people IV tPA. If you see a patient who looks like a stroke but you're questioning whether or not it's a mimic, I think that's a judgment call. And they don't specify the threshold of pre-test probability.”
Dr. Brown said he found the statement uncontroversial, and he praised the inclusion of an emergency physician in the AHA/ASA panel, even though it was dominated by neurologists. “When we developed our clinical policy on tPA, we asked for input from the neurology community but did not include any neurologists on the panel. (Ann Emerg Med 2015;66:322.) Ideally, in the future, we will have better harmonization of our guidelines.”
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