EM-CCM Conference: January 2014
Presented by Dr. LoCascio
Summary by Dr. Grock
The Case:
67 yo F pmhx ESRD on HD, HTN with slurred speech and Left sided weakness starting at 19:30. H&P and work-up significant for BP 208/95, R gaze preference, L facial droop, decreased strength to LUE/LLE. CT Head had a Dense MCA Sign. Stroke code was called. Pt’s NIHSS was 14. Neuro recommended giving tpa after BP control. After labetolol 10 mg IVP x 2, tpa was given at 21:45. Pt was admitted to the MICU. Her neuro status is unchanged.
TPA discussion
ACEP Guidelines based on NINDS trial and ECASS III (These are currently being reconsider Ed.):
– 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. (Level A recommendation)
– In order to improve functional outcomes, 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 (Level B recommendation)
NINDS review:
Part 1 – 291 patients, did not show statistically significant improvement on NIHSS within 24 hours. Six percent of TPA patients had “symptomatic ICH”, 3% of which died due to ICH.
Part 2 – 333 patients, no difference in mortality, but an OR of 1.7 (1.1-2.6) improvement in Modified Rankin. Seven percent of TPA patients had symptomatic ICH with 2.9% fatal ICH.
Criticism of NINDS include: Changed methodology half way through from NIHSS improvement in 24 hours to Improved Modified Rankin at 90 days. Patients in the placebo group were more impaired initially, possibly indicating that the difference at 90 days was due to confounding. Also, NINDS required entry of a patient receiving tpa vs placebo in < 90 minutes per patient entered >90 minutes. Yet the recommendation is to give TPA for those meeting NINDS inclusion/exclusion criteria as long as symptom onset is less than 3 hours.
Conclusion: Increased ICH, statistically significant though possibly confounded improvement, same mortality in tpa vs placebo. NNT 8 NNH 17
ECASS 3 Review
ECASS 1 – 620 patients received 1.1 mg/kg tpa within 6 hours from CVA onset, and showed no benefit in Modified Rankin Scale at 90 days.
ECASS 2 – 800 patients given 0.9mg/kg tpa within 6 hours and showed no benefit in Modified Rakin Scale at 90 days.
ECASS 3: Alteplase given in 3-4.5 hours after stroke in a narrower group of patients. They found no mortality change, an increased risk of ICH (8%ICH vs 3.5% in alteplace vs placebo with 0.7% vs 0% fatal ICH), and a benefit from TPA with P=0.04. NNT 14 NNH 23
Other studies
Australia streptokinase study: no benefit
Mast-I: stopped due to harm. ASA and streptokinase patients had a significantly higher < 10 day mortality/ICH MAST-E: streptokinase in CVA < 6 hours. Stopped early because of increased mortality.
Atlantis – TPA in 3-5 hours. No benefit found. Stopped due to increased ICH and death in tpa group.
Cochrane Reviews: No difference in time to tpa and agent does not matter. “The available data is insufficient”
Conclusion: We are left with a very limited idea of who, if any, this drug offers true benefit.
The Panel
Paraphrasing of Dr. Brander
TPA won’t save lives, and for most people, it will neither help nor hurt. The goal is to decrease disability. People treated earlier do better. In fact, TPA in less than 90min has an NNT of 14, at 3 hours the NNT is 26 to 28. For the trials up to 6 hours, the brain is already dead. Giving TPA won’t help and longer times to treatment, especially beyond 4.5 hours, increases risk of ICH. Most Important factors: time, exclusion and inclusion criteria, does history match CT findings, and local experience. In our experience, rates of ICH from TPA is 2-3%. Discuss TPA with your patient and be careful who you give it to.
Paraphrasing of Dr. Zehtabchi
There have been 12 RCTs with only 2 showing benefit. Five were stopped due to harm, and five showed no harm but no benefit. The data is far from convincing. NINDS showed a benefit in less than three hours. ECASS 3 had a narrow spectrum of patients due to more exclusion criteria. The OR 1.3 (Cl 1.02 to 1.7) in ECASS 3 is barely significant as an OR of 1.0 signifies no benefit. IST -3 was very biased towards tpA. It still showed improvement in 35% of placebo versus 37% in TPA.
One problem with the meta-analysis of TPA is that the trials stopped for harm are under-represented because they ended up with less patients. From 0 to 3 hours, I believe there is a modest benefit. Beyond three hours, it is uncertain. Keep in mind, the FDA has not approved TPA here. I recommend discussing TPA risks/benefits with patients.
Paraphrasing of Dr. Wiener
In the NINDS trial, the placebo group had larger vessel strokes and were sicker. This introduces a potential bias into the results. Keep in mind that NIHSS of 5-22 do better with TPA.
Paraphrasing of Dr. Levine
Stroke is the highest combined death disabled disease in the world. In large vessel strokes, 2 milllion neurons die every minute. The longer time before the artery is opened, the less benefit. Furthermore, strokes have very hetergenous etiologies. The clots can be newly formed, calcified, atherosclerotic, or everything in between. We do not know the consistency of the clot at presentation, or which responds best to tpa.
I believe there is a benefit to TPA. The NINDS trial was conservative because the FDA wanted to find rankin 0 or 1. They wanted a cure. They also defined “harm” as any ICH. Only half of the ICH in NINDS caused any harm in terms of outcome. My interpretation of the data: NNT 3 to get any measurable improvement in rankin. If you define harm as ICH affecting care, the rate is only 3%, or a NNH 33. For the NINDS group, TPA is 10 times more likely to help than hurt here. For those with severe CVA defined as NIHSS >25, TPA helps much less with only a 6% improvement.
I believe that TPA vs Placebo has no difference in mortality despite increased death from ICH in the tpa group because the people who improve from tpa are half as likely to die from other causes. Receiving TPA in the first hour is four times more likely to help than at 3 hours. Make sure you have properly defined benefit vs harm. Follow the guidelines including the exclusion and inclusion criteria carefully, and talk to your patients.
Lastly, what to say to your patients?
Read the trials. We all know the way the doctor presents the information can sway the patient either way. Is it an NNT of 3, 8 or 14? Is the NNH 17 or 33?
Furthermore, the negative studies talked about above are disregarded due to time of TPA administration and that other thrombolysis agents were used. Per Cochrane, these differences should not matter. What do you (the reader) think?
My Investigations Into How to Talk to Patients
A lit review of informed consent for tpa showed that 15% of patients who receive TPA have no documented consent or discussion and only 80% of consents were adequately understood by the patient or family.
AAEM has a great picture representation of NINDS data here: http://www.aaem.org/UserFiles/file/tpaedtool-AAEM.pdf
Here is an informed consent from Boston Medical Center: http://www.bmc.org/Documents/tPA-patient-info-consent-form.pdf
Still haven’t had enough of the debate?
In case you missed it, check out the debate from the last AllNYC EM Conference that was posted on EmCrit: http://emcrit.org/podcasts/tpa-for-ischemic-stroke-debate/
References
- National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333:1581-1587.
- Ingall TJ, O’Fallon WM, Asplund K, et al. Findgins from the reanalysis of NINDS tissue plasminogen activator for acute ischemic stroke treatment tria. Stroke. 2004; 35: 2418-2424.
- Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. 1996; 276: 961-966.
- Multicentre Acute Stroke Trial-Italy (MAST-I) Group. Randomized controlled trial of streptokinase, aspirin and combination of both in treatment of acute ischemic stroke. Lancet. 1995; 346: 1509-1514.
- The Multicentre Acute Stroke Trial-Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med. 1996; 335: 145-150. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995; 274: 1017-1025.
- Hacke W, Kaste M, Fieschi C, et al. Ransomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Second European Australasian Acute Stroke Study Investigators. Lancet. 1998; 352: 1245-1251.
- Hacke W, Kaste M, Bluhmki E. et al. ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359: 1317-1329.
- Clark WM, Wissmand S, Albers GW, et al. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke Study Investigators. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. JAMA. 1999; 282: 2019-2026.
- Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010; 375: 1695-1703. Hoffman JR, Schriger DL. A graphic reanlysis of the NINDS trial. Ann Emerg Med. 2009; 54: 329-336.
- Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000213. DOI: 10.1002/14651858.CD000213.pub2.
- Wardlaw JM, Koumellis P, Liu M. Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD000514. DOI: 10.1002/14651858.CD000514.pub3
- Thomas et al. Variability in the Perception of Informed Consent for IV TPA during Telestroke Consultation. Front Neurol. 2012;3:128
Jay Khadpe MD
- Editor in Chief of "The Original Kings of County"
- Assistant Professor of Emergency Medicine
- Assistant Residency Director
- SUNY Downstate / Kings County Hospital
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1 Comment
Ian deSouza · March 4, 2014 at 12:06 pm
This was a great conference and I am grateful for the participation of the panel members (putting aside obvious conflicts of interest for those who were “pro”).
Organizations and panels making high-level recommendations based on half of a study where the methods were adjusted halfway through the study is what is problematic here. In contrast, the benefit of thrombolysis for MI was established after study of 60K patients. So, why did we jump to “accept” TPA for stroke so soon? If we are saying that it is part of “throwing the kitchen sink” at a debilitating, costly disease without any other available treatments, then proponents should admit to that and stop continuously trying to sell me an unreliable used car.
Neurologists have also begun to use this therapy with less and less stringent inclusion/exclusion criteria – the NINDS criteria is often “modified” to reflect what proponents will call “common sense” thinking. Is this acceptable? This is a dangerous slippery slope what will get more slippery without further, good-quality study.
Pro-TPA panel members claim that TPA is very safe for most CVAs and the associated intracranial hemorrhages are usually insignificant. If this is true, then why don’t the neurologists take responsibility of these patients on their service in the stroke units? Why then is it policy that post-TPA patients take up MICU beds? This exacerbates issues with ED overcrowding and affects intensive care of other critically ill patients – care that typically clearer benefits than TPA for CVA.