A draft of a new clinical policy from the American College of Emergency Physicians (ACEP) takes a much more conservative approach on using intravenous tPA for managing acute ischemic stroke in the emergency department than the current guidelines, which were approved in 2012.
Those guidelines provoked a fair amount of controversy, with some emergency physicians saying the treatment was too risky and had little potential for benefit. (“The ‘Biggest, Baddest’ Controversy in EM,” EMN 2013;35:1; http://bit.ly/EMN12.)
A year later, an article in the British Medical Journal questioned the reliability of the guidelines, calling them more industry marketing than tools of evidence-based medicine. (2013;346:f3830.) That report also questioned some of the committee members' conflicts of interest, some undeclared, and the “committee stacking” of the joint American Academy of Neurology-ACEP panel with experts with known viewpoints on a particular side of an issue. Seven of eight members of the AAN-ACEP committee, the BMJ article said, had previously spoken or written on the benefits of tPA for stroke, and “[n]ot one skeptic was included on the panel.” (“Conflicts of Interest on Guidelines Ramp Up tPA Controversy,” EMN 2013;35:1; http://bit.ly/1hAdtVi.)
ACEP announced last year that it would begin working on an independent policy on tPA for stroke, and that result, now in draft form, diverges from the policy it formulated with the AAN. In answer to critical question 1, “Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset?” the 2015 draft, obtained by Emergency Medicine News, offers the following recommendations:
“Level A recommendations. The increased risk of symptomatic intracerebral hemorrhage (approximately 7% compared to a baseline of 1%) must be considered when deciding whether to administer IV tPA to acute ischemic stroke patients.
“Level B recommendations. With a goal to improve functional outcomes, IV tPA may be given to carefully selected acute ischemic stroke patients within 3 hours after symptom onset at institutions where systems are in place to safely administer the medication.
“Level C recommendations. Shared decision-making between the patient (and/or their surrogate) and a member of the healthcare team must include a discussion of potential benefits and harms prior to the decision whether to administer IV tPA for acute ischemic stroke. (Consensus recommendation.)” (Download the draft at http://bit.ly/1yrT10e.)
The front-loading of hemorrhage risk as a level A recommendation and the cautious “may be given to carefully selected acute ischemic stroke patients” language in the level B recommendation stand in stark contrast to the 2012 document, which does not mention the increased risk of ICH in response to critical question 1 at all. Instead, it says: “In order to improve functional outcomes, IV tPA should be offered to acute ischemic stroke patients who meet National Institute of Neurological Disorders and Stroke (NINDS) inclusion/exclusion criteria and can be treated within 3 hours after symptom onset.” (Italics added.)
Members of the ACEP tPA policy subcommittee, chaired by Michael D. Brown, MD, MSc, declined to comment on the draft because it is still being reviewed, and they noted that revisions are likely before it is submitted to the ACEP Board of Directors for consideration, something they speculated should happen by June.
Non-committee members, however, weren't reluctant to share their opinions. David Newman, MD, the director of clinical research in emergency medicine at Mt. Sinai School of Medicine in New York City, praised the draft as a “tremendous improvement” in process and content.
“The process of developing this policy has been and is transparent. Anybody can take a good look at how the document was developed step-by-step, and that wasn't the case before,” he said. “This is an immense leap forward, and I think everybody's happy about that, whether they agree or disagree with the actual product. People are happy that the process adheres to the IOM's standards for the development of clinical practice guidelines.” (Read the Institute of Medicine document at http://bit.ly/18pWIyE.)
Dr. Newman praised the use of methodologists to review the literature and to make recommendations to the committee about what that literature supported. “That seems to have been an important device for moving the guidelines in a different direction,” he said. “They've dialed back a little bit on the recommendation for the use of tPA in the setting of stroke. Personally, I still think we're a little more aggressive with tPA in this setting than what the science calls for, but the draft guideline isn't far off, and clearly there is appreciation for the fact that tPA is a potentially fatal drug.”
The new policy document spotlights the fact that only one trial — the original NINDS trial that led to tPA's approval for use in acute ischemic stroke within three hours of onset — showed benefit for this indication. “We have a total of under 10,000 patients in trials at this point, and we clearly haven't figured out exactly who is going to be in the group that benefits,” said Dr. Newman, the driving force behind www.thennt.com, a website that independently evaluates therapies and accepts no outside funding or advertisements. It concluded that no consistent or reliable benefit could be found in using thrombolytics for stroke after reviewing all of the 12 high-quality trials. They pointed out that six of those studies found no benefit of tPA for stroke, four found it harmful and stopped the trials early, and two found benefit. (Read The NNT's analysis of thrombolytics for stroke at http://bit.ly/NNTthrombo.)
“You need thousands more randomized trials to get to the level of subgroup analysis to figure out the group you help and the group you may be harming. With tPA for acute MI, it took 60,000 patients before we realized that it was those with ST-elevation on an EKG who benefit, and others either are harmed or don't benefit,” he said.
The more cautious tone of the proposed new policy is “not totally unexpected, given all the pushback on the earlier version,” said Robert Wears, MD, PhD, a professor of emergency medicine at the University of Florida and a leading patient safety expert who served on the committee that developed the 2012 policy. “This is one of the general problems with guidelines that goes far beyond this situation. It's not clear whether they should precede practice or follow it. You could make the argument that the earlier policy was an attempt to be in advance of practice, and this is following practice.”
Dr. Wears said the new draft seems to be more in line with what most emergency physicians feel comfortable doing, but called into question the general utility of guidelines. “That approach tends to overemphasize a certain sort of very narrow category of evidence, and underemphasize a lot of practical wisdom,” he said. “It stresses a kind of a hyper-rationality that I'm not sure always applies in the much more variegated world of practice.”
In fact, he said, the current emphasis on eliminating variability in practice through evidence-based standards may be swinging the pendulum too far. “If you're at a center where they're really set up to do tPA and people have a lot of experience with it, then things may be different than if you're an emergency physician in a community hospital where your neurologists are lukewarm about it. In that case, maybe you should be more conservative if you don't have that infrastructure around you to be sure it can be done safely. This may be controversial, but I think this is one place where variation of practice is important. Human beings are variable, and I think mindlessly trying to drive it out is not an intelligent strategy.”
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