For a treatment to be scientifically sound, there must be replication of studies, minimization of bias, and healthy debate. These requirements have not been met for stroke thrombolysis.

You Might Also Like

• After Re-Analysis, No Trials Show Efficacy of tPA in Acute Ischemic Stroke
• Endovascular Therapy With or Without tPA—What Do the Studies Say?
• Clinical Policy on tPA for Ischemic Stroke Important for Emergency Medicine

Explore This Issue

ACEP Now: Vol 40 – No 04 – April 2021

It is important to note that there have been no “positive” replication studies. In addition, two tPA trials were stopped early due to harm or futility.^11,12 Importantly, it is recognized that harms are underreported in RCTs, systematic reviews, and meta-analysis (SRMA).^13,14

Garvin and Liberman are correct that symptomatic intracranial hemorrhage (sICH) was higher in the tPA group and mortality was lower compared to placebo. However, they failed to mention the statistical result. The harm (5.8 percent absolute increase in sICH) was statistically significant (P <0.001) while the benefit (absolute decrease in mortality 3.2 percent) was not (P=0.3). Shinton raised concerns regarding the NINDS methodology, stating “the evidence of benefit is precarious.”¹⁵ Overall, there is more confidence in the increase in harm (bleeding) than the potential decrease in mortality. In fact, two recent SRMA have reported a statistical increase in early mortality with tPA and a nonstatistical increase in late mortality.^16,17

We note that Garvin and Liberman introduce the idea of being unbiased and impartial. The potential financial conflicts of interest (COI) around tPA have been documented and are a powerful form of bias.¹⁸ It is also known that COI can introduce bias into RCTs and SRMAs and need to be managed during guideline drafting.^19–21 It is ironic that two Genentech employees suggest we are biased when there has been so much pro-tPA promotion in major journals. Indeed, in “Everyone’s a Little Biased (Even Physicians),” Cain and Detsky point out that “everyone is likely capable of rationalizing beliefs and denying influences that bias them. The most important action physicians can take as a profession is to recognize this.”²²

We agree that physicians are responsible for evaluating the data and using their best judgment for incorporation into practice. We encourage physicians to read and critically appraise the primary literature, reflect upon their clinical experience, and engage with patients about their values and preferences. This is the foundation of evidence-based medicine.

Respectfully,

Ken Milne, MSc, MD, CCFP(EM), FCFP, FRRMS, Schulich School of Medicine and Dentistry, Western University

Daniel M. Fatovich, MBBS, FACEM, PhD, professor of emergency medicine, University of Western Australia; head of the Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research 

References

1. Alper BS, Foster G, Thabane L, et al. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evid Based Med. 2020;25(5):168-171.
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;333(24):1581-1587
3. Prasad V, Cifu A. Medical reversal: why we must raise the bar before adopting new technologies. Yale J Biol Med. 2011;84(4):471-478.
4. Lenzer J. Why we can’t trust clinical guidelines. BMJ. 2013;346:f3830.
5. Fatovich DM. Believing is seeing: stroke thrombolysis remains unproven after the third International Stroke Trial (IST-3). Emerg Med Australas. 2012;24(5):477-479.
6. Alper BS. The dangers of selective analysis: has stroke treatment been misguided for a decade? BMJ website. Accessed March 26, 2021.
7. Ebrahim S, Sohani ZN, Montoya L, et al. Reanalyses of randomized clinical trial data. JAMA. 2014;312(10):1024-1032.
8. Brown MD, Burton JH, Nazarian DJ, et al. Clinical policy: use of intravenous tissue plasminogen activator for the management of acute ischemic stroke in the emergency department. Ann Emerg Med. 2015;66(3):322-333.
9. Wardlaw JM, Koumellis P, Liu M. Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke. Cochrane Database Syst Rev. 2013(5):CD000514.
10. The Texas Sharpshooter. Your Logical Fallacy Is website. Accessed March 26, 2021.
11. Clark WM, Wissman S, Albers GW, et al. 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;282(21):2019-2026.
12. Clark WM, Albers GW, Madden KP, et al. 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;31(4):811-816.
13. Hodkinson A, Kirkham JJ, Tudur-Smith C, et al. Reporting of harms data in RCTs: a systematic review of empirical assessments against the CONSORT harms extension. BMJ Open. 2013;3(9):e003436. 
14. Zorzela L, Golder S, Liu Y, et al. Quality of reporting in systematic reviews of adverse events: systematic review. BMJ. 2014;348:f7668.
15. Shinton R. Questions about authorisation of alteplase for ischaemic stroke. Lancet. 2014;384(9944):659-660.
16. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384(9958):1929-1935.
17. Donaldson L, Fitzgerald E, Flower O, et al. Review article: Why is there still a debate regarding the safety and efficacy of intravenous thrombolysis in the management of presumed acute ischaemic stroke? A systematic review and meta-analysis. Emerg Med Australas. 2016;28(5):496-510.
18. Lenzer J. Alteplase for stroke: money and optimistic claims buttress the “brain attack” campaign. BMJ. 2002;324(7339):723-729.
19. Lundh A, Lexchin J, Mintzes B, et al. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2017;2:MR000033.
20. Hansen C, Lundh A, Rasmussen K, et al. Financial conflicts of interest in systematic reviews: associations with results, conclusions, and methodological quality. Cochrane Database Syst Rev. 2019;8(8):MR000047.
21. Institute of Medicine (US) Committee on Standards for Developing Trustworthy Clinical Practice Guidelines. Graham R, Mancher M, Miller Wolman D, et al, eds. Clinical Practice Guidelines We Can Trust. Washington, D.C.: National Academies Press (US); 2011.
22. Cain DM, Detsky AS. Everyone‘s a little bit biased (even physicians). JAMA. 2008;299(24):2893-2895.