Guidelines for tPA – An alternate view

Just as there is division in our specialty regarding tPA for ischemic stroke, diversity of opinion exists within the ACEP leadership ranks. Following the Board’s approval of this new clinical policy, in the spirit of transparency, ACEP leadership asked me to draft the minority opinion on this topic.

With respect to clinical guidelines, one size must fit all. When considerable controversy exists and reasonable minds can disagree on the interpretation of the available evidence, then perhaps drafting a guideline is not only impossible but also inappropriate. Development of guidelines should be a search for scientific truth, a truth that can be applied by all. The ultimate goal of any guideline is to provide guidance once the dust has settled from debate and a clear right answer has emerged. If not accepted by all, or even most, consensus has not been reached. Caution must be taken by those drafting guidelines for the many, to avoid amplification of the perspectives of the few.

ACEP’s recent clinical policy regarding the administration of tPA for ischemic stroke is an excellent example of a topic, fraught with controversy and a lack of consensus, which results in maneuvering a square peg into a round hole. Forcing premature closure and drawing early conclusions, while the clinical evidence and science are still being debated and are in evolution, is ill advised. The fact that the panel could reach consensus is less than comforting, when it is possible that at least as many experts in our field share a perspective in direct opposition to the panel’s conclusions.

I have to compliment the Clinical Policies Committee for attempting to accomplish the impossible, given a task that was unattainable. It seems that this question was asked when no reasonable consensus could possibly be reached. Spending 8 years to craft a policy on a topic of such complexity heightens the likelihood of creating bias. Establishing a false standard of care and disenfranchising those not in support of its conclusions are inevitable consequences. Another Herculean request made of the commit- tee was to draft this policy to meet the needs, not only of all emergency physicians, but also neurologists. From a purely political perspective, this makes wonderful sense, and building bridges with other specialties is generally a good thing. Remarkably, emergency physicians and neurologists have usually not shared the same perspective on this issue. So, the fact that this committee was tasked with collaborating with the American Academy of Neurology may have foreshadowed its shortcomings before pen was put to paper. Perhaps, the salient question is: Why was the committee charged with such a task in the first place?

The committee members probably reached consensus with the usual tools of negotiation and compromise, but if your position must be compromised to accommodate the views of another, the result is a compromised position. In many circumstances, this creates a good result for all. However, when drafting a clinical policy, too much compromise may result in a dilutional effect not meeting the needs of those most affected by the policy. Compromises may be appropriate when discussing nuances such as dosing. However, when giving guidance on efficacy and/or safety, clear consensus must be diligently sought, and careful consideration of all opinions must occur to ensure a fair and balanced conclusion. An example of fair compromise is the recommendation to administer aspirin for STEMI. No compromise is needed to recommend aspirin. The data are irrefutable, and consensus exists in the house of medicine. However, dosing between 162 mg and 325 mg is less clear. Thus, some compromise in dosing is reasonable.

Some, including the committee, may believe that tPA has attained consensus, and the evidence is irrefutable. Therefore, ACEP’s, and the average emergency physician’s, position was not compromised to draft this policy. Such a thought raises serious concerns. If the committee feels that consensus has been reached and no reasonable emergency physician could interpret the data differently, we have a problem. Again, a specialty society guideline should reflect consensus opinion of members who are well read in the scientific literature. Beyond myself, many others have a persistent healthy skepticism regarding this treatment. Consider just a short list of well-known and highly regarded emergency medicine educators who reach a conclusion different from that of the committee: Drs. Jerry Hoffman, David Newman, Dave Schriger, Ryan Radecki, Stuart Swadron, Billy Mallon, Al Sacchetti , and Greg Henry. On this topic, there is no clear consensus among the thought leaders within our specialty.

Undoubtedly, the most prominent zealot advocating for tPA skepticism is Dr. Hoffman. If consensus is the goal, I am puzzled that he was not included in the panel. Although I cannot speak to the individual perspectives of the panel members, it is clear that several members have an established history of being pro-tPA. It seems reasonable to include in the panel those with a different perspective. Focusing on process, if a panel is balanced with a heterogeneity of opinion, adequate consideration of all perspectives is much more likely to result. Criticisms could be made that opposition of opinion may result in a stalemate. However, if consensus is elusive, then this should indicate the topic may just be too controversial for guideline development, and furthermore, avoiding such controversy or conflict may result in a policy not reflecting diversity of opinion.

My goal is not to debate the literature in detail, but to illustrate, using the policy’s stated logic, why the evidence is insufficient for a level A recommendation. I ask you to accept one statement: Controversy in interpretation of the data exists, precluding consensus in our specialty. Let’s focus on the Level A recommendation for tPA for stroke within 3 hours of symptom onset. For your reference, here is the definition of an ACEP Level A recommendation:

“Level A recommendations. Generally accepted principles for patient management that reflect a high degree of clinical certainty (i.e., based on strength of evidence Class I or overwhelming evidence from strength of evidence Class II studies that directly address all of the issues).

I applaud the panel for noting that NINDS was the only positive trial, along with a Class II meta-analysis, including NINDS, supporting this recommendation. However, I do have concerns that this amount of evidence was deemed sufficient for a Level A recommendation. The policy also points out that other large, randomized trials have been conducted (e.g. Australian Streptokinase trial, Multicenter Acute Stroke Trial–Italy, Multicenter Acute Stroke Trial–Europe and ECASS I). No benefit was shown, and “Some were halted early because of excessive mortality in the treatment arm.” Unfortunately, these studies were discounted, as their design differed from NINDS in timing of administration, dose, or thrombolytic agent. ECASS II, a Class I study with the same dose, but a longer time frame (6 hours), was also discussed. The document states there was no difference in outcomes, even for the 20% of patients treated within 3 hours. However, the parenchymal intracranial hemorrhage (ICH) rate was 12% in the tPA group compared to 3% of controls. Atlantis (also 6 hours) was also reviewed.

They noted it was discontinued after enrolling 142 patients due to an increased ICH rate in those treated within 5-6 hours. The protocol was modified to 0-5 hours, and after enrolling 31 patients was modified again to 3-5 hours. Again, the panel concluded that no difference in efficacy was shown, but a difference in ICH rate of 7% v. 1% was experienced. In 59 patients treated within 3 hours, 61% of the tPA vs. 26% of the controls met the primary endpoint (NIHSS score of 0-1 at 90 days).

Despite the limitations noted by the panel in many of these studies, they cited the Class II meta-analysis as evidence for support of their Level A recommendation. That meta-analysis included the data from some of these studies (NINDS, ECASS, ATLANTIS, and EPITHET). How can one discount a study’s results to later accept a reanalysis via compiled data from a meta-analysis using those same studies? If this approach is acceptable, why was Dr. Hoffman and Dr. Schriger’s graphic reanalysis of NINDS discounted? The policy reports that the authors concluded that tPA had a minimal change on NIHSS scores at 90 days. The policy appropriately points out that change in NIHSS was not a primary outcome of NINDS. However, the graphic reanalysis provides a value added perspective. The small beneficial difference demonstrated in NINDS disappears when change in NIHSS score is measured. The clinical policy’s analysis of the data may just as reasonably be interpreted to show that the data are inconclusive or too limited to prove benefit or safety.

Is this purely an academic discussion? No. As a risk manager, I will attest to the fact that “Lytic Gation” (litigation from tPA in stroke) is a real issue, and a lack of administration is a common allegation. It has been reported that physicians are more likely to be sued for not giving tPA than for the complications associated with giving it.

But according to Dr. David Newman’s analysis, the raw numbers for lawsuits don’t equate to likelihood. When the number of patients receiving the drug who experience complications and the large number of those eligible who do not get the drug are considered, the likelihood is probably the same.

With this policy in place, a physician whose best judgment suggests that giving tPA is not the right approach will be in direct conflict with the policy, which will then be used as evidence of negligence. It is therefore likely that more patients will receive tPA. Considering the possibility that the benefit of the drug is actually marginal or just due to chance, additional patients will thus be subject to unnecessary harm. This Level A recommendation places the TPA skeptic in the untenable position of being in conflict with the policy for not giving the drug to an eligible patient or giving it in spite of reservations about modest benefit and significant risk of harm. A well-crafted policy should reflect the science in such a way as to support, or at least not undermine, the clinician who favors either approach.

The work of the College is important, with far-reaching implications. With the authority to guide clinicians and shape the practice of our specialty comes an immense responsibility to advocate for our patients and members when the evidence is clear, seek diversity of opinion and recommend further investigation when it’s not, and have the wisdom to recognize the difference between the two.

Dr. Klauer is ACEP Council Vice Speaker and Director, Center for Emergency Medicine Education and Assistant Clinical Professor, Mich-igan State University College of Osteopathic Medicine, East Lansing.

Joint clinical policy based on current evidence

ACEP and the American Academy of Neurology (AAN) developed a joint clinical policy about the use of Intravenous tPA for managing emergency patients with acute ischemic stroke. The policy, approved by the ACEP Board of Directors and endorsed by the AAN Board of Directors, and published in the February issue of Annals of Emergency Medicine:

• Is evidence-based and designed to help clinicians answer questions when considering the use of tPA.
• Was developed using the ACEP clinical policy development process with the methodology being jointly agreed upon by ACEP and AAN.
• Is based on a thorough review of the medical literature. Evidence was graded using a weighted grading scheme defined in the clinical policy.
• Involved extensive reviews by emergency physicians, including those known to be in opposition to tPA and external reviewers from the Society for Academic Emergency Medicine, Emergency Nurses Association, American College of Physicians, Neurocritical Care Society, American Academy of Fam- ily Physicians, National Stroke Association, and the American Stroke Association.

This clinical policy is supported by the Emergency Nurses’ Association and endorsed by the Neurocritical Care Society. It was funded solely by ACEP and AAN. Companies were not allowed to participate in the development of or in funding the development or initial publication of the clinical policy. This clinical policy was not developed by “consensus” but by using a well-defined and well-established methodology. The recommendations are evidence-based. The clinical policy clearly states that the recommendations “are not intended to represent the only diagnostic and management options,” nor does it state that every acute ischemic stroke patient should receive intravenous tPA. It does say IV tPA should be offered to acute ischemic stroke patients who meet NINDS inclusion/exclusion criteria and can be treated within 3 hours after symptom onset; however, the effectiveness of tPA is less well established in institutions without the systems in place to safely administer the medication (Level A recommendation). Clearly, clinicians opting not to provide an acute ischemic stroke patient IV tPA should document their clinical decision making.

It does say IV tPA should be considered in acute ischemic stroke patients who meet ECASS III inclusion/exclusion criteria and can be treated between 3 to 4.5 hours after symptom onset; however, the effectiveness of tPA is less well established in institutions without the systems in place to safely administer the medication (Level B recommendation).

ACEP worked with AAN on this joint policy at the urging of members of both organizations. It reflects more than 8 years of work by a task force that was sensitive to the controversies but committed to an unbiased analysis of the literature.

Dr. Jagoda is professor and chair, the department of emergency medicine, Mount Sinai School of Medicine, and medical director of the emergency department at Mount Sinai Hospital, New York, N.Y. He was part of the development panel for the IV tPA clinical policy and is a member of the ACEP News Editorial Advisory Board.