ACEP has published a draft version of their new Clinical Policy statement regarding the use of IV tPA in acute ischemic stroke. As before, the policy statement aims to answer the questions:
(1) Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset?
(2) Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset?
Most readers of this blog are familiar with the mild uproar the previous version caused, and this revision opens by stating “changes to the ACEP clinical policies development process have been implemented, the grading forms used to rate published research have continued to evolve, and newer research articles have been published.” Left unsaid, in presumably a bit of diplomacy, were the conflicts of interest befouling the prior work. Notably absent from this work is any involvement from the American Academy of Neurology.
What’s new, with a new methodology-focused rather than conflicted-expert-opinion approach? Most obviously, there’s a new Level A recommendation – focused on the only consistent finding across all tPA trials: clinicians must consider a 7% incidence of symptomatic intracranial hemorrhage, compared with 1% in the placebo cohorts. The previously Level A recommendation to treat within 3 hours has been downgraded to Level B. Treatment up to 4.5 hours remains Level B. Finally, a new Level C recommendation includes a consensus statement recommending shared decision-making between the patient and a member of the healthcare team regarding the potential benefits and harms.
Most of the reaction on Twitter has been, essentially, a declaration of victory. And, in a sense, it is certainly a powerful statement regarding the ability for like-minded patient advocates and evidence purists to coalesce through alternative media and initiate a major change in policy. To critique this new effort is a bit of punishing the good for lack of manifesting perfect, but there are a number of oddities worth providing feedback to the writing committee:
- The authors provide a curious statement: “The 2012 IV tPA clinical policy recommendation to ‘offer’ tPA to patients presenting with acute ischemic stroke within 3 hours of symptom onset was consistent with other national guidelines. Unfortunately, the essence of the term ‘offer’ may have been lost to readers and has therefore been avoided in this revision.” I rather find “offer” a lovely term, in the sense it expresses a cooperative process for proceeding forward with a mutually agreed upon treatment strategy. Rather than discard the term, clarification might have been reasonable.
- They mention ATLANTIS as Class III evidence with regard to the 3-4.5 hour question. I can see how its classification may be downgraded given the multiple protocol revisions. That said, its inability to find a treatment benefit in spite of extensive sponsor involvement ought be a more powerful negative weighting than currently acknowledged. Given the biases favoring the treatment group in ECASS III (given a Class II evidence label), the cumulative evidence probably does not support a Level B recommendation for the 3-4.5 hour window.
- One of my Australian colleagues in private communication brings up a small letter from Bradley Shy, previously covered on this blog, mentioning a statistical change to ECASS III. This statement could acknowledge this post-publication correction and its implications regarding the aforementioned imbalance between groups.
- The authors fail to acknowledge the heterogeneity of acute ischemic stroke syndromes and patient substrates, and the utter paucity of individualized risk or benefit assessment tools – in no small consequence of the small sample sizes of the few trials rated as Class I or Class II evidence. This is a powerful platform with which to state clinical equipoise exists for continued placebo-controlled randomization. As we see from the endovascular trials, the acute recanalization rate of IV tPA is as low as 40% – with many patients re-occluding following completion of the infusion. Patients need to be selected less broadly with respect to likelihood of benefit compared with supportive care. I believe tPA helps some patients, but it should be a goal to dramatically reduce the costs and collateral damage associated with rushing to treat mimics and patients without a favorable balance of risks and benefits. For these authors to recommend treatment in “carefully selected patients” and “shared decision-making”, more guidance should be provided – and absent the evidence to support such guidance, they should be calling for more trials!
The comment period is open until March 13, 2015.
“Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department DRAFT”
The SAEM EBM interest group is compiling comments on the evidence for feedback to the SAEM board of directors. These are my additional comments after having had additional time to digest:
- I agree with sICH as a Level A recommendation. Both RCTs and observational registries tend to support such a recommendation. Whether the pooled risk estimates are usable in knowledge translation to individual patients is less clear. The risk of sICH is highly variable depending on individual patient substrate. There are several risk stratification instruments described in the literature, but none are specifically recommended/endorsed/prospectively validated in large populations.
- It is uncertain regarding the NINDS data whether their intention is to present pooled Part 1 and Part 2. The prior clinical policy used only Part 2 for their NNT calculation, giving rise to an NNT of 8 instead of 6. It appears they are pooling the data from both parts here. Either is fine as long as it’s explicitly stated – the primary outcome differed, but the enrollment and eligibility should have been the same.
- ECASS seems to be missing from their evidentiary table. The ECASS 3-hour cohort data is available as a secondary analysis. However, such would probably be Class III data of no real consequence for the recommendation.
- Level B is probably an acceptable level of recommendation for tPA within the 0-3 hour window. “Moderate clinical certainty” is reasonable, mostly on the strength of the Class III data. However, the “systems in place to safely administer the medication” is not clearly addressed in the text. Most of the published clinical trial and observational evidence involves acute evaluation by stroke neurology. Does the primary stroke center certification practically replicate the conditions in which patients were enrolled in these trials/registries? Perhaps this should be split out into a separate recommendation regarding the required setting for safe/timely/accurate administration.
- Level B is difficult to justify for the 3 to 4.5 hour time window. There is Class II evidence from ECASS III (downgraded due to potential for bias) demonstrating a small benefit. The authors then cite Class III trial evidence from IST-3 and ATLANTIS in which no benefit was demonstrated. Then, they cite the individual patient meta-analysis having similar effect size to ECASS III – because many of the patients in that subgroup come from ECASS III. Basically, there’s only a single piece of Class II evidence and then inconsistent Class III evidence, which doesn’t meet criteria state for a Level B recommendation (1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).
- With both Level B recommendations, the authors also reference “carefully selected” patients, but do not cite evidentiary basis regarding how to select said patients other than listing the enrollment criteria of trials. If the “careful selection” is strict NINDS or ECASS III criteria, this should be explicitly stated in the recommendation.
- The Level C recommendations to have shared decision-making with patients and surrogates ought to be obvious standard medical practice, but I suppose it bears repeating given the publications regarding implied consent for tPA. They mention two publications regarding review and development of such tools, but there is no evidence supporting their efficacy or effectiveness in use. Frankly, calling them a starting point in such a heterogenous population is along the lines of the broken clock that’s right twice a day. I would rather say their dependence on group-level data minimizes their practical utility, and clinician expertise will be the best tool for individual patient risk assessment.