Stroke is the fifth leading cause of death in the United States, killing approximately 1 in 140,000 Americans each year. The vast majority—about 85%–are ischemic strokes, caused but a clot in a cerebral artery. Over half of patients aged 65 and older will become permanently disabled following a stroke. While the medical community has made progress in targeting and mitigating the known risk factors, emergency room physicians and neurologists remain at the front lines as they care for patients at the moment of crisis and work efficiently to save patients’ lives and brains. With the adage, “time is brain” weighing heavy on healthcare providers’ actions, we must take a rigorous look at the research that guides emergent stroke care to ensure health care providers are delivering the best care to their patients.
Landmark tPA studies in ischemic stroke
Until 1995, there was no effective treatment to reduce neurological injury following acute ischemic stroke. Patients were managed supportively, their neurological outcomes and even mortality essentially left to chance. However in 1995, NINDS investigators reported that patients given tissue plasminogen activator (tPA) within 3 hours of stroke symptoms were thirty percent more likely to have minimal or no disability three months after the stroke compared to placebo.1 Unfortunately, enthusiasm was tempered by the well-known risks of the medication. Patients given tPA had a significantly increased (6.4% versus 0.6 percent) risk of symptomatic intracerebral hemorrhage and ultimately there was no significant difference in overall mortality between groups at three months. The Europeans Cooperative Acute Stroke Study (ECAS) III followed, another landmark trial supporting tPA use.2 In this study, investigators determined that tPA use could be extended to 4.5 hours after stroke onset, and confirmed that disability was reduced 90 days after stroke. Subsequent studies showed a benefit of giving tPA up to 6 hours after the onset of symptoms.2,3,4 Again, all of the studies confirmed that tPA increased risk of symptomatic intracranial hemorrhage. Despite this risk, the lack of alternative treatment options for the disabling disease has made tPA the mainstay of emergent ischemic stroke treatment.
Flawed design of landmark tPA studies
Despite the initial enthusiasm, all was not as it seemed. After in depth analysis of these two landmark studies, some inconsistencies began to take shape. Years later, further information came to light from the NINDS study indicating that the patients in the two groups were not appropriately matched.3 The baseline stroke severity in the tPA group was significantly different from that of the placebo group. More patients with mild National Institutes of Health Stroke Scale (NIHSS) scores (19% vs. 4.2%) and less with severe strokes (18% vs 27.5%) were found in the tPA group treated after 90 minutes. These significant differences were masked by the mean between group NIHSS scores provided in the initial study. As such, the medical community justifiably raised concern about important confounding factor. Likewise, the ECAS III study results have been called into question. The placebo arm contained more subjects with severe stroke, and almost twice as many patients with a prior personal history of stroke. This difference in baseline demographics becomes more significant because ECAS III only showed positive results after its first two iterations, and failed to show a benefit of thrombolytic treatment.2 Furthermore, the primary endpoints used were inherently flawed. The study used the modified Rankin Score (mRS) as the primary endpoint but dichotomized patients into groups of scores of 0-1 and 2-6, artificially grouping patients with mild impairment (a score of 2) with patients who died (a score of 6). A reanalysis that dichotomized the subjects into groups of 0-2 and 3-6 showed that there was no significant benefit of tPA at 90 days, the primary endpoint assessed in the study.
Further analysis does not consistently show a benefit of tPA
In addition to the problems with the landmark studies supporting tPA use, other clinical trials did not identify a benefit for the medication. The largest clinical trial of tPA, the Third International Stroke Trial (IST-3) did not show a mortality benefit.5 While the study evaluated patients up to 6 hours following stroke, the median time from onset was 4.2 hours. The study revealed no significant difference between groups in terms of mortality and independence at 6 months although there was a statistically significant difference in favor of tPA in terms of disability as measured by the Oxford Handicap Scale. There was also a higher risk of early death and symptomatic intracranial hemorrhage in the group treated with tPA.
Following the publication of the NINDS trial, multiple independent investigators reevaluated the data to determine if the outcomes were justified. The conclusions were not uniform. While some post hoc analyses upheld the outcomes of the NINDS trial, a group convened by the NIH noted that there were “imbalances” in the baseline stroke severity between groups and acknowledged that their analysis was “not powered to identify treatment differences between subgroups.”6 Hoffman and Schringer7 reevaluated the primary data and determined that disability outcomes were more dependent on stroke severity than tPA use, and that benefits of tPA diminished or disappeared at the 90-day mark.
Despite the concerns that have been raised over the data and mixed results, the AHA/ASA Stroke Early Management Guidelines strongly support tPA for patients within 3-4.5 hours after symptom onset, as do many medical professional societies. In hospitals and emergency rooms, however, there remains controversy regarding the best use of tPA in stroke patients. In fact, recent media has covered the difference of opinion in the medical field. The fact remains that there is a significant diversity in care and only about 5% of Americans with acute ischemic stroke receive tPA (Hughes, 2016) both due to controversy regarding its benefit and the difficulty in providing the medication to patients in a timely manner.
tPA in real life
Overall, clinical studies show a decrease in the severity of stroke and mortality rates in subjects in clinical trials.2 However this does not necessarily reflect real world practices, especially those seen outside of stroke centers. Not every emergency department is a stroke center and not every patient has access to such a level of care despite guideline goals. Stroke is not always easily diagnosed and there are conditions that mimic stroke, placing patients at real risk for being exposed to the risks of tPA without any benefit. For example, a study looking at community hospitals revealed that half of patients treated with tPA received it inappropriately, and that the rate of symptomatic intracerebral hemorrhage was almost 16%8, much higher than the 2-4% risk found more recently in clinical trials.2,5
The stroke research upholds the fact that specialized stroke centers with efficient and accurate diagnostic tools and management protocols provide the best outcomes for patients. The decision to use tPA should be made in a setting of highly trained and knowledgeable practitioners who are able to weigh the risks and benefits for the individual patient. With the increased risk of intracranial hemorrhage and early death, tPA use should never be a knee jerk reaction, but rather a well-considered decision. It is difficult to see the medical community abandon tPA for ischemic stroke; however, it is likely that we will see a refinement in the way we assess pre-tPA risk and select patients for tPA treatment.
1. Tissue Plasminogen Activator for Acute Ischemic Stroke. N Engl J Med. 1995;333(24):1581-1587. doi:10.1056/nejm199512143332401
2. 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;359(13):1317-1329. doi:10.1056/NEJMoa0804656
3. Marler JR, Tilley BC, Lu M, et al. Early Stroke Treatment Associated with Better Outcome: The Ninds Rt-Pa Stroke Study. Neurology. 2000;55(11):1649-1655.
4. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for Acute Ischaemic Stroke. Cochrane Database Syst Rev. 2014(7):Cd000213. doi:10.1002/14651858.CD000213.pub3
5. Sandercock P, Wardlaw JM, Lindley RI, et al. 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;379(9834):2352-2363. doi:10.1016/s0140-6736(12)60768-5
6. 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(10):2418-2424. doi:10.1161/01.Str.0000140891.70547.56
7. Hoffman JR, Schriger DL. A Graphic Reanalysis of the Ninds Trial. Ann Emerg Med. 2009;54(3):329-336, 336 e321-335. doi:10.1016/j.annemergmed.2009.03.019
8. 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):1151-1158.