Just a few months ago, alteplase for acute ischemic stroke was assaulted in the pages of the BMJ. Academic debate on this subject is hardly novel, as the controversy within the ivory tower has dragged on almost since thrombolytics for stroke received therapeutic approval.
However, as the use of alteplase grows, the number of patients harmed by its use has correspondingly increased. Regardless of the perceived benefits of the treatment, the resulting harms have accumulated into a full public outcry, with family members of those harmed petitioning the government for increased oversight. There are now two ongoing reviews in the United Kingdom – the Medicines and Healthcare products Regulatory Agency review has been joined by the Academy of Medical Sciences. A full 38 minute segment on BBC Radio 4 details several personal stories, and contains snippets of interviews with the renowned David Newman, among others.
In the same vein, the American College of Emergency Physicians has finally released their revision to the highly-conflicted 2012 policy statement regarding treatment of acute ischemic stroke. Substantially altered from the 2012 version, ACEP has dramatically weakened the prior recommendations to reflect the paucity of randomized trial evidence. While two pivotal trials demonstrated significant absolute benefit, such trials enroll simply a few hundred patients in the setting of vastly heterogenous presentations and prognoses for acute stroke.
The new policy statement issues two recommendations for offering alteplase to qualifying patients, both under the “Level B” classification – representing “recommendations” for patient care subject to “moderate clinical certainty”. This is a change from the previous guideline, which provided concise recommendations favoring treatment within three hours as Class A. The new recommendations:
- With a goal to improve functional outcomes, IV tPA should be offered and may be given to selected patients with acute ischemic stroke within 3 hours after symptom onset at institutions where systems are in place to safely administer the medication. The increased risk of sICH should be considered when deciding whether to administer IV tPA to patients with acute ischemic stroke.
Despite the known risk of sICH and the variability in the degree of benefit functional outcomes, IV tPA may be offered and may be given to carefully selected patients with acute ischemic stroke within 3 to 4.5 hours after symptom onset at institutions where systems are in place to safely administer the medication.
It remains to be seen whether these recommendations substantially alter clinical practice or encourage additional investigation. Beyond 3 hours – the timeframe most critiqued by Alpers et al – alteplase remains unapproved for use by the FDA, and by these guidelines need not be offered to patients.
As always, the hope is these developments will spur further, prospective, independent evaluation. We need thousands, not hundreds, of patients in well-designed trials devoid of conflict-of-interest. Otherwise, we continue to place patients at risk, both from the harms of alteplase or the harms of potentially not receiving a truly beneficial therapy.