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Emergency medicine professor and neurology professor Dr. Rhonda Cadena explores the controversy behind the administration of tPA for acute ischemic strokes.

The question of the safety and efficacy of alteplase (tPA) for the treatment of acute ischemic stroke (AIS) has been debated by emergency physicians (EPs) for many years. Differences of opinion have been expressed since the National Institute of Neurological Disorders and Stroke (NINDS) trial was published in 1995 showing that patients treated with alteplase were more likely to have little or no disability at 3 months compared to placebo1. Even though the data have been reanalyzed and other studies have been done with similar results2-4, all of these studies seem to have led to more questions than answers by many EPs. Alteplase has been approved by the FDA for the treatment of AIS since 1996 and is currently a class IA recommendation by the AHA/ASA for treatment of AIS within 3 hours and a IB recommendation for qualifying patients in the 3-4.5 hour window5, but its use still remains limited. It has been reported that 8-11.5% of patients presenting to the emergency department with an AIS are eligible for tPA6,7 but only about 2% of those patients receive treatment8,9.

When it comes to tPA for the treatment of AIS, unfortunately it seems to come down to the question of “are you for it or against it?”. Those who are against the use of tPA interpret the data in a way that supports their decision and those who support its use trust in the data that is available. You will hear a lot of arguments on both sides and it is important to interpret those arguments in a way that fits your practice and population of patients so that you can make an informed decision.

In a recent EPM survey questioning the use of tPA by EPs, 7% of respondents said that they never use tPA and only 39% of those who used the drug did so because they felt it led to an improvement in outcome. Of the remaining EPs who used tPA, 12% of those who responded said they used it due to fear of being sued if they didn’t, 8% said they didn’t feel it would do any good but used it because they felt it was expected, and 33% deferred to the judgment of a neurologist. Interestingly, even though only 14% of respondents always use tPA on their patients, 68% would want the drug themselves if they were experiencing symptoms of a stroke, either because they felt the data supported an improved outcome (48%) or they would rather die of a hemorrhage than to run the risk of not improving (45%) (Plaster, EPM August 2013). Although the survey was unscientific, it does give some insight into the trepidation regarding the use of tPA by some physicians.

Hemorrhage Risk
Of course the biggest concern of EPs is the risk of hemorrhage that can be fatal. If we are going to use a drug with that kind of risk, we want to be sure of the benefits. The NINDS trial showed that tPA carries a 6.4% risk of symptomatic intracerebral hemorrhage ( ) versus placebo (0.6%). This result has also been shown in other studies2,10-12. It is important to point out that although nearly half of the symptomatic hemorrhages were fatal, the 90-day mortality between the control and study groups was no different, suggesting that those patients who did not receive tPA still died as a complication of the stroke. Higher percentages of sICH and mortality with tPA administration have been reported in some studies13-15 but this was likely as a result of a large number of protocol deviations including treatment beyond the 3-hour time window, administration of antiplatelets or anticoagulants in the first 24 hours, or uncontrolled blood pressures, all of which have been shown to increase the risk of ICH.

15 minutes make a difference
The use of tPA for the treatment of AIS is time sensitive in order to improve outcome and decrease the risk of hemorrhage. In the NINDS trial, all patients were treated within 3 hours. The first ATLANTIS trial was stopped early due to an increased risk of sICH seen with treatment in the 5-6 hour range16. Therefore, treatment times were changed to 3-5 hours in the second ATLANTIS trial (part B)17. In ATLANTIS B, there was no overall difference in outcome in tPA versus placebo patients, however, the mean treatment time was still high at 4.5 hours. When the patients that were treated within 3 hours were analyzed, there was a more likely chance of excellent functional recovery versus placebo. In ECASS I and II18, treatment was up to 6 hours but re-analysis showed that ICH risk was increased beyond 4.5 hours, so a 270-minute window was used for the patients in ECASS III10.  In addition, a subgroup analysis in ECASS III further classified the patient with increased hemorrhage risk after 3 hours to be those patients who were diabetics with a previous stroke, and those on anticoagulation, regardless of the INR. Therefore, the studies that present the rates of sICH should be interpreted with caution if they treated beyond 3 hours without proper patient selection. The rate of sICH decreases as the time to treatment is shortened. In a recent review of the national Get with the Guidelines (GWTG)-Stroke registry in which 58,353 tPA-treated patients were analyzed, every 15-minute faster interval to treatment was associated with fewer symptomatic intracerebral hemorrhages, reduced in-hospital mortality, more patients with independent ambulation at discharge, and more patients discharged to home.12

Stroke Mimics
EPs know that the treatment with tPA is time sensitive, but some feel uncomfortable with the risk of hemorrhage if tPA is given to a stroke mimic such as hemiplegic migraine, seizure, or conversion disorder if they do not have time to rule out these conditions. Recent studies have reported stroke mimic conditions in up to 30% of the patients treated with tPA for symptoms suggestive of acute ischemic stroke.19-22 These four studies showed data on 198 stroke mimics, and only reported two intracerebral hemorrhages, both of which had a good outcome.

‘Mild’ stroke to you but not to the patient
In addition to concerns for stroke mimics, some EPs question the appropriate NIHSS that benefits from treatment with tPA while minimizing risks. Very large strokes were excluded in ECASS I and II (large complete hemispheric) and ECASS III (NIHSS > 25). The NINDS studies included all patients with a measurable NIHSS without an upper limit, ranging from NIHSS 1-37. Although NINDS found a greater risk of sICH in larger strokes, the 90 day mortality in the treated group was the same in the placebo group and there was still an improved functional outcome in the treated group.23

Small strokes were excluded in ECASS I and II (Scandanavian Stroke Scale > 50, estimated NIHSS 3-4), ATLANTIS (NIHSS < 4), and although NINDS included patients with NIHSS ≥ 1, it did not include patients with rapidly improving symptoms or many minor deficits.1 A subgroup analysis was done on these patients and tPA was found to be beneficial in the lower ranges of NIHSS reported in the study26, however, the numbers were small and difficult to interpret. This is unfortunate because small strokes can still lead to considerable disability or can worsen after presentation. A recent review of the GWTG-stroke registry reported on 29,200 patients that presented to the ED within 2 hours of symptom onset who did not get tPA due to rapidly improving symptoms or a report of a mild stroke (most NIHSS ≤ 5). Of those patients, 28% were not discharged home (includes 2% who died or who were discharged to hospice) and another 28% could not ambulate without assistance at hospital discharge.24  Therefore, instead of excluding a patient for tPA due to mild symptoms, it makes sense to weigh the risks of tPA with the neurological deficit and consult with the patient and family regarding options. For example, a patient with an NIHSS of 4 due to mild arm weakness, flattening of the nasolabial fold, mild sensory deficit and a little dysarthria is different than a patient with an NIHSS 4 who cannot communicate effectively, or yet another patient with an NIHSS 4 with a flaccid leg that makes it difficult to ambulate without assistance. If none of these patients improve and are left with these deficits, are the patients themselves willing to accept the outcome? Are we as treating physicians comfortable enough with the outcome in such cases to withhold tPA? It is difficult to combine the outcomes that are important to us with those that are important to the patient.

Morbidity of stroke survivors
When it comes to the assessment of benefit, what outcomes matter to us? Mortality is an easy dichotomized outcome but how do we measure morbidity? What is the most important outcome to the patient suffering a stroke; is it mortality, functional independence or psychosocial debility?

Although our biggest fear when we treat patients is the risk of hemorrhage and death, the EPM survey suggests that if many of us were patients, the worst outcome would be living with the stroke deficit. Along with that idea, the most commonly used outcome in the literature as a measure of excellent outcome is the modified Rankin score (mRS) of 0-1, in which the patient is left with minimal or no residual deficits and is able to do all activities that were done prior to the stroke. Patients treated with tPA are 30% more likely to have this outcome over patients treated with placebo.

And what time period is the best for outcome assessment? As EPs we are taught to think of the short term outcomes such as death within 30 days or return to ED within 7 days but post-stroke care, with or without tPA, involves comprehensive rehabilitation that may take many months.  For example, the IST-3 randomized-controlled trial showed increased deaths in the first 7 days in patients treated with tPA. However, even in their population that included >50% of patients older than 80 years old and >70% of patients treated beyond 3-hours, the 6-month mortality was no different between the groups.25 Treatment of stroke is multifaceted and involves prevention, early recognition and treatment, secondary prevention to prevent recurrence, and multidisciplinary rehabilitation. Resources available to each patient are different and rehabilitation may be very limited for many patients, so this further complicates comparisons of the stroke trials and outcomes. For the small or moderate sized strokes, a 3 month outcome is probably adequate but in the more severe strokes rehabilitation continues beyond 3 months.

Clinical Decision Making
In conclusion, alteplase is the only treatment available for acute ischemic stroke that is effective in some patients. In order to improve tPA effectiveness and minimize risks, patients with symptoms suggestive of an AIS should get rapid assessment and treatment with tPA after careful review of the contraindications. Given that smaller strokes can still be associated with considerable long term neurological morbidity, treatment should still be considered in those patients after weighing the risks and benefits and in consultation with the patient and family. Advanced age should also not be a limiting factor. Although the NINDS trial showed an increased risk of sICH in patients over 75 years old, there was no difference in mortality at 90 days and those patients still had an improved functional outcome and, therefore, stand to benefit from tPA if given within 3 hours of symptom onset. Patients over 80 years old were excluded from the ECASS III study, so at this time we do not know the specific risks of treating older patients beyond the 3 hour window so that decision should also be made in consultation with the family regarding risks. After tPA treatment, it is important to control the blood pressure and avoid the use of antiplatelets or anticoagulants in order to minimize complications.  

Regardless of the controversy surrounding the use of tPA for AIS, as emergency physicians, we owe it to the patient to present all treatment options with review of the risks and benefits of each option. Alteplase is not the best treatment for all patients with stroke, but should be considered in the ED within 3 hours of occurrence if there are no contraindications, as long as established protocols can be followed to minimize complications.


Rhonda Cadena, MD, is an assistant professor of emergency medicine and neurology at the University of North Carolina. Dr. Cadena has never received pharmaceutical support for her clinical or research activities.

References

  1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group Tissue Plasminogen Activator for Acute Ischemic Stroke. N Engl J Med. 1995;333:1581-1588
  2. Wahlgren N, Ahmed N, Davalos A, et al, for the SITS-MOST investigators. Thrombolysis with aletplase for acute ischaemic stroke in the safe implementation of thrombolysis in stroke-monitoring study (SITS-MOST): an observational study. Lancet. 2007;369:275-82.
  3. Ingall TJ, O’Fallon WM, Asplund K, et al. Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial. Stroke. 2004;35:2418-24.
  4. Lees KR, Bluhmki E, von Kummer R, et al, for the ECASS, ATLANTIS, NINDS, and EPITHET rt-PA Study Group Investigators. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375:1695-703.
  5. Jauch, EC, Saver JL, Adams HP, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2013;44:870-947
  6. Hills NK, Johnston SC. Why are eligible thrombolysis candidates left untreated? Am J Prev Med. 2006;31(suppl 6):S210-6.
  7. Kleindorfer DLC, Kissela B, Schneider A, et al. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: A population-based study. Stroke. 2004;35:e27-29.
  8. Katzan IL, Hammer MD, Hixson ED, et al. Utilization of intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol. 2004;61(3):346-50.
  9. Kleindorfoer DLC, Xu Y, Moomaw CJ, et al. US geographic distribution of rt-PA utilization by hospital for scute ischemic stroke. Stroke. 2099;40(11):3580-4.
  10. Hacke W, Kaste M, Bluhmki E, et al, for the ECASS investigators. Alteplase compared with placebo within 3 to 4.5 hours for acute ischemic stroke. N Engl J Med. 2008;359:1317-29.
  11. Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA. 2013;309(23):2480-2488
  12. Scott PA, Frederiksen SM, Kalbfleisch JD, et al. Safety of intravenous thrombolytic use in four emergency departments without acute stroke teams. Acad Emerg Med. 2010;17(10):1062-1071.
  13. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke, The Cleveland area experience. JAMA. 2000;283(9):1151-58.
  14. Bravata DM, Kim N, Concato J, Krumholz HM, and Brass LM. Thrombolysis for Acute Stroke in Routine Clinical Practice. Arch Intern Med. 2002;162:1994-2001.
  15. Lopez-Yunez AM, Bruno A, Williams LS, et al. Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage. Stroke. 2001;32:12-16.
  16. Clark WM, Albers GW, Madden KP, et al. Thrombolytic therapy in acute ischemic stroke study investigators. The rtPA (altelplase) 0- to 6-hour acute stroke trial, part A: results of a double-blind, placebo-controlled, multicenter study. Stroke. 2000;21:811-816.
  17. Clark WM, Wissman S, Albers GW, et al. Alteplase Thrombolysis for Acute Nonintervential Therapy is 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;282:2019-26.
  18. Hacke W, Kaste M, Fieschi C et al, for the ECASS study investigators. Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II). Lancet. 1998;352:1245-51.
  19. Chernyshev OY, Martin-Schild S, Albright KC, et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology. 2010;74:1340-45.
  20. Mehta S, Vora N, Edgell RC, et l. Stroke mimics under the drip-and-ship paradigm. J Stroke and Cerebrovasc Dis. Aug 2013;ahead of print.
  21. Zinkstok SM, Engelter ST, Gensicke H, et al. Safety of thrombolysis in stroke mimics: results from a multicenter cohort study Stroke. 2013;44:1080-1084
  22. Winkler DT, Fluri F, Fuhr P, et al. Thrombolysis in Stroke Mimics: Frequency, Clinical Characteristics, and Outcome. Stroke. 2009;40:1522-1525
  23. The NINDS t-PA Stroke Study Group. Generalized efficacy of tPA for acute stroke. Subgroup analysis of the NINDS t-PA stroke trial. Stroke. 1997;28;2119-2125.
  24. Smith EE, Fonarow GC, Reeves MJ, et al. Outcomes in Mild or Rapidly Improving Stroke Not Treated With Intravenous Recombinant Tissue-Type Plasminogen Activator Findings From Get With The Guidelines–Stroke. Stroke. 2011;42:3110-3115
  25. IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 hours of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomized controlled trial. Lancet. 2012;379:2352-63.
 

Comments   

# A "Balanced" Approach to tPA?George Hansen 2013-11-13 09:28
If tPA indisputably produced good improvement in 30% of CVA patients to whom it was administered, there would not be any controversy. However, this benefit is disputable. The results of the NINDS trial haven't been definitively shown not to be a statistical aberration. The data snooping and torturing done by investigators trying to sell tPA hasn't removed doubt. A truly balanced approach would be to say that tPA might produce 30% improvement, and way that against risk and cost.
Whatever happened to "Reversible Ischemic Neurological Deficits?" In the days before tPA, many patients improved spontaneously. Now ER doctors and neurologists blindly attribute any improvement to tPA.
Reply
# Physiotherapist Camberwell 2013-11-27 18:54
The therapist has been trained to take care of their patient. They surely know all the approach.
Reply
# Emergency PhysicianDavid Ghilarducci MD FACEP 2013-12-03 09:31
I applaud Dr. Cadena and EP Monthly for finally offering another side to the story about tPA. She said it best that when it comes to tPA it’s a question of if your are for it or against it and data is not likely to sway you from one camp to another.

The editors of EP Monthly have certainly been in one camp this past year. Klauer (May 2013) criticizes efforts to identify the subset of patients in the Wake-Up-Stroke category that may benefit from tPA. Newman (July) looked at 12 major trials and concluded no benefit and only harm. His NNT analysis (see website http://www.thennt.com/nnt/thrombolytics-for-stroke/) includes studies using streptokinase and high dose tPA up to 6 hours from time of onset, all of which is off label in the United States. It is also unfortunate that his NNT analysis did not include two peer reviewed articles that focused on NNT for tPA (Saver 2004, Saver 2009).

At least he mentioned - though discounted as flawed - the Cochrane review which gave a favorable recommendation for tPA.

And perhaps most ironically, Plaster (August 2013) concludes that conflict of interest must be the reason that 3 professional organizations (including our own) for their Level A recommendation for tPA for acute ischemic stroke. The only data he provides is EP Monthly’s own survey of EPs in which he concludes that 67% of us erroneously favor tPA for ourselves or a loved one for the wrong reasons.

It is now 17 years since the FDA approval of tPA for AIS. Depending on who we listened to back then we made up our minds early which camp we were in. This confirmation bias leads us to continue to select data that supports our staked positions, even if it is no longer relevant. The editors of EP Monthly are no different.

In the meantime, when it comes to stroke, the medical community has gone to great lengths to bypass our specialty. The whole concept of stroke centers is to include the emergency department if they are willing, and go around them if they're not. Let us continue to review the data for ourselves and not let dogmatic positions dictate how we will care for our patients.
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