Wednesday, October 11, 2017

Two Steps Forward, One Step Back: The Questionable Practice of Reversal of Anticoagulation to Facilitate rt-PA Administration for Stroke

In the process of caring for patients suffering from acute ischemic stroke (AIS), a cognitive bias shifts the focus of our typical approach to drug therapy selection. Rather than approach a problem and determine whether a drug is going to help, in the case of alteplase for AIS, we often look for reasons not to give this drug (contraindications) and fail to ask whether the given patient will benefit. Fewer still will ask, what is the patient oriented benefit? This shift in clinical reasoning is highlighted in this case report describing the reversal of heparin in order to facilitate alteplase administration.(1) This cognitive bias is further reflected in framing of the issue of whether or not we are treating enough patients with alteplase, as described by the authors quoting epidemiologic data. This bias can be remedied by reflecting on the evidence to support the use of alteplase for AIS.

The only supporting evidence for alteplase in AIS comes to us from the NINDS-2 (NINDS 1 & 2, two studies published in one manuscript) and ECASS-3.(2,3) In these studies, the benefits observed were improvement in functional neurologic outcomes at 90 days.  These improvements are not to be confused with a return to baseline function or a curative intervention. Furthermore, NINDS-1 failed to demonstrate superiority of alteplase in improving NIHSS by at least 4 points or neurologic recovery at 24 hours. If you continued to line up the studies where alteplase failed to show improvement in primary outcomes or was stopped early due to futility you have a list including: ECASS-1, ECASS-2, ATLANTIS-A, ATLANTIS-B.(4-7) Not to mention the curious results of the uncontrolled, analysis of registry data ITS-3 study.(8)  However, pause to consider the risk versus benefit: reduction in disability versus intracranial hemorrhage (fatal or not).  Furthermore, these potential harms are the best case scenario given the strict inclusion and exclusion criteria from these studies. In practice, each time we venture outside, we increase the risk of harm without proven increase in potential benefit.(9,10,11,12,13)

When faced with almost certain peril, Dr Ian Malcolm asked “[you] scientists were so preoccupied with whether or not they could, they didn’t stop to think if they should.”(14)  While this quote refers to the genetic engineering and creation of dinosaurs in a fictional story, it cuts through to the core of the issue described in this case. Stroke care has been rapidly advanced in recent years and the patient population exposed to alteplase continues to increase. While we continue to see the strict inclusion and exclusion criteria for this drug slip away, we must remember to stop and think although we can treat this patient with alteplase, should we?

I read with great interest the case report presented by Drs. Fontaine and Smith where a patient was treated with protamine sulfate to reverse unfractionated heparin in order to administer alteplase for AIS following a percutaneous coronary intervention (PCI). It is worth noting that the prasugrel, aspirin and tirofiban that were administered during PCI were not attempted to be reversed. An analysis of 965 patients treated with alteplase found that dual antiplatelet therapy was associated with a significantly increased risk of symptomatic intracranial hemorrhage.(15) In this case, the patient experienced what the authors’ described as a favorable outcome with a modified rankin score of 3 at three months follow up. This outcome would not be included in the primary endpoints of favorable neurologic outcome in either the NINDS-2 or ECASS-3, as scores of 2 or greater were considered “unfavorable” in these trials. While a modified rankin score improvement from 5 to 3 at three months is a positive finding, one should not attribute this outcome to alteplase without acknowledging the improvements made in the totality of stroke rehabilitation care.

This trend in reversing anticoagulant therapy in order to administer alteplase for acute ischemic stroke is troubling given the lack of evidence to support safety and efficacy. Given the minute clinical patient oriented outcome benefits with alteplase for AIS, using reversal strategies to facilitate thrombolytic therapy should not be conducted outside of research settings.

Craig Cocchio, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
CHRISTUS Trinity Mother Frances Health System

Kyle DeWitt, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
The University of Vermont Medical Center

Scott Deitrich, Pharm.D., BCPS
Emergency Medicine Clinical Pharmacist
Poudre Valley Hospital

  1. Fontaine, G. V. and Smith, S. M. Alteplase for acute ischemic stroke after heparin reversal with protamine – a case report and review. Pharmacotherapy. Accepted Author Manuscript
  2. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995 Dec 14;333(24):1581-7
  3. Hacke W, Kaste M, Bluhmki E, et al.Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29
  4. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995 Oct 4;274(13):1017-25.
  5. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators.Lancet. 1998 Oct 17;352(9136):1245-51
  6. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. Stroke 2000 Apr;31(4):811-6
  7. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke.JAMA. 1999 Dec 1;282(21):2019-26.
  8. IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.Lancet. 2012 Jun 23;379(9834):2352-63.
  9. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke. 2003 Dec; 34(12):2847-50.
  10. Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-type plasminogen activator for treatment of acute stroke: the Standard Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA. March 1 2000;283(9):1145–1150.
  11. Lopez-Yunez AM, Bruno A, Williams LS, et al. Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke. January 2001;32(1):12–16.
  12. Tsivgoulis G, Frey JL, Flaster M, et al. Pre-tissue plasminogen activator blood pressure levels and risk of symptomatic intracerebral hemorrhage. Stroke. November 2009;40(11):3631–3634.
  13. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med. 2002;162:1994–2001.
  14. Cucchiara B, Kasner SE, Tanne D, et al. Factors associated with intracerebral hemorrhage after thrombolytic therapy for ischemic stroke: pooled analysis of placebo data from the Stroke-Acute Ischemic NXY Treatment (SAINT) I and SAINT II Trials. Stroke. 2009 Sep;40(9):3067-72.

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