In 1995 (boy, I was 8 years old then), 3 multi-center randomized clinical trials (2 published studies) demonstrated that intravenous tissue plasminogen activator (IV tPA), when given within the first 3 hours of stroke symptom onset, could significantly reduce long-term disability in select patient populations. In a third iteration of one of those trials, the treatment window was extended to 4.5 hours with similar efficacy. And some centers have used it 48 hours or more after strokes affecting the posterior circulation. Since that time, we have also seen a number of outcome measures improve with the use of this “clot busting” medication—things like residual neurologic deficits, cognitive performance, and even mortality. In 2014, after many years of failed clinical trials, a new intervention was found to improve functional outcomes in selected acute stroke patients. Stent-retriever devices, when utilized in the first 6 to 8 hours of acute stroke onset, could successfully extract large clots from proximal anterior intracranial vessels. And this dramatically impacts clinical outcome, more-so than IV tPA alone.
So this begs the question, if mechanical thrombectomy is so much more powerful than IV tPA, doesn’t that render tPA antiquated? And should we even continue to use IV tPA if we have such a powerful therapy? The answer may be obvious to you, but it wasn’t to me. I had to speak with Dr. Sheryl Martin-Schild about it, who joins me in this week’s episode of BrainWaves.
In choosing between IV tPA and mechanical thrombectomy, one major factor is time. IV tPA has been approved for select patients up to 4.5 hours after symptom onset, and this time window has been extended to 6 hours according to 2015 American Heart Association Guidelines. This allows an additional 10-15% of patients to be treated, says Martin-Schild.
A second reason why patients may undergo thrombectomy and NOT intravenous thrombolysis would be if they are therapeutic anticoagulation. This is an absolute contraindication to IV tPA, but not for mechanical thrombectomy. So that decision is simple.
The podcast could have ended there, with the two only real reasons to defer IV tPA for acute ischemic stroke and go straight to thrombectomy being (1) the patient presented outside the treatment time window or (2) they are on anticoagulation. But we had to do whatever we could to really convince those naysayers out there that IV tPA is still a standard of care in acute ischemic stroke! According to the 2015 scientific rationale paper, prior exclusion criteria like recent seizure and NIHSS score <4 are no longer acceptable exclusion criteria. These people also deserve treatment, and outdated guidelines should be recognized by emergency treatment providers for what they really are: OUTDATED.
But that also is not enough. Some people have come across recent papers such as the pooled analysis of the SWIFT and STAR trials from JAMA 2017 that indicated thrombectomy + tPA was not superior to for any of the outcome measures (successful reperfusion, functional independence at 90d, 90d mortality, or symptomatic ICH). And while these prospective findings are substantiated by additional retrospective data, they must be interpreted with the most extreme caution–or extreme vetting, even for JAMA standards. Because the analysis from JAMA 2017 was a post-hoc subgroup analysis of cherry picked studies. So always be aware of methods when you come across papers like these.
Ultimately, IV tPA is not dead. Yes, stent-retriever-assisted mechanical thrombectomy is extremely beneficial for selected patients with acute ischemic stroke. But it is important for us to recognize that this intervention should be performed in conjunction with IV tPA wherever possible. As more and more patients are diverted to endovascular-capable stroke centers, one can only hope that this does not reduce IV tPA use among patients who would most certainly have benefited from this tried-and-true treatment. With IV tPA treatment rates as low as they are already, I don’t think we should be looking for more reasons to withhold therapy. Juice ’em!
The content in this episode was vetted and approved by Sheryl Martin-Schild. The BrainWaves podcast and online content are intended for medical education only and should not be used for clinical decision making.
- Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The european cooperative acute stroke study (ecass). JAMA : the journal of the American Medical Association. 1995;274:1017-1025
- Tissue plasminogen activator for acute ischemic stroke. The national institute of neurological disorders and stroke rt-pa stroke study group. The New England journal of medicine. 1995;333:1581-1587
- Saver JL, Gornbein J, Grotta J, Liebeskind D, Lutsep H, Schwamm L, et al. Number needed to treat to benefit and to harm for intravenous tissue plasminogen activator therapy in the 3- to 4.5-hour window: Joint outcome table analysis of the ecass 3 trial. Stroke; a journal of cerebral circulation. 2009;40:2433-2437
- Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723-1731
- Demaerschalk BM, Kleindorfer DO, Adeoye OM, Demchuk AM, Fugate JE, Grotta JC, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the american heart association/american stroke association. Stroke; a journal of cerebral circulation. 2016;47:581-641
- Coutinho JM, Liebeskind DS, Slater LA, Nogueira RG, Clark W, Davalos A, et al. Combined intravenous thrombolysis and thrombectomy vs thrombectomy alone for acute ischemic stroke: A pooled analysis of the swift and star studies. JAMA Neurol. 2017;74:268-274
- Rai AT, Boo S, Buseman C, Adcock AK, Tarabishy AR, Miller MM, et al. Intravenous thrombolysis before endovascular therapy for large vessel strokes can lead to significantly higher hospital costs without improving outcomes. J Neurointerv Surg. 2017