Will EPsʼ Reluctance to Embrace Thrombolysis for Stroke Lead to Lawsuits?

FigureA 66-year-old man presents with weakness and dizziness. The triage note says that he is a poor historian. There is no bed available immediately, and 35 minutes later his daughter arrives and says that he has speech difficulty he did not have three hours before. He is placed in a room, where some left-sided weakness is noted, which probably can be dated in onset to two hours prior to arrival in the emergency department. You obtain a head CT, which shows no acute bleed or effacement of sulci. The ED has access to teleradiography, and the radiologist sees no gross abnormality. It now has been three hours and 40 minutes since stroke onset, and the patient is admitted to a staff neurologist, the third one you called. The patient ultimately regains the ability to walk normally, but he still has some difficulty with speech and swallowing, and does not regain full use of his left side. He is retired, but claims that he cannot play the piano or sing in the men's choir. The family asks about a miracle stroke drug that can be given in the ED to reverse all neurologic deficits, but by the time you receive an official CT report, the three-hour time window has elapsed. You are somewhat relieved because you do not work at a stroke center, you have doubts about the quality of the neuroradiologic skills of your radiologists, and you know that your staff neurologists are, to say the least, not aggressive. A lawsuit is filed by the family. Ischemic Stroke Ischemic stroke is a major medical problem in the United States, where approximately 600,000 new cases occur each year. In the United States and Canada, stroke is the third leading cause of death, with an age and sex adjusted incidence of approximately 1000 per 100,000 in the 65- to 74-year-old group and approximately 2000 per 100,000 in the 75- to 84-year-old group. (Stroke 1999; 30:2523.) If blood flow to a specific region is restored within a critical time frame, there is functional recovery of the ischemic penumbra. The hypothesis that intravenous thrombolytic therapy may restore blood flow and improve outcome in acute ischemic stroke was not tested in large randomized trials until the 1990s. The first successful large prospective trial of therapy for acute ischemic stroke was announced in December 1995. (New Engl JMed 1995;333:1581.) This trial changed the attitude for many that there was little benefit to active therapy except for supportive care and rehabilitation. The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA study group reported that patients given recombinant tissue plasminogen activator (rt-PA) intravenously within three hours of onset of ischemic stroke were at least 30 percent more likely to have minimal or no disability three months later compared with patients who received placebo. A total of 624 patients with symptoms of acute ischemic stroke were randomly assigned to treatment with rt-PA (alteplase) or placebo within three hours of symptom onset. The dose of rt-PA given was 0.9 mg/kg up to 90 mg, 10 percent as a bolus, the rest infused over 60 minutes. This is still the FDA-approved dose. This study was at once perhaps the most influential of the decade and, within the emergency medicine community, one of the most controversial. The incidence of symptomatic brain hemorrhage within the first 36 hours was 6.4 percent in the rt-PA group versus 0.6 percent in the placebo group (p < .001). There was, however, no significant difference in overall mortality between the two groups. Treatment with alteplase led to a complete recovery at three months as measured by the NIH stroke scale in 38 percent of patients compared with 21 percent who received placebo. (New Engl J Med 1995;333:1581.) The Food and Drug Administration subsequently approved IV rt-PA for acute ischemic stroke in June 1996. The first guidelines for the use of thrombolytic treatment published by the American Heart Association appeared in 1997. (Advanced Cardiac Life Support. New York, NY: American Heart Association; 1997: Ch. 10: 1.) The NINDS alteplase stroke study to this day is the only large randomized trial that documented benefit from the treatment of acute ischemic stroke with intravenous thrombolytic therapy. The success of the trial is felt to be related to its strict exclusion criteria and its treatment of patients within three hours of symptom onset. The impact of this study has been felt in many ways. The NINDS trial specified that treatment be started within 180 minutes of onset of symptoms. Some regions of the country have made tremendous efforts to educate patients, families, and medical emergency personnel to call for help earlier for possible neurologic events. Hospitals have organized to offer emergency treatment for stroke, including urgent imaging, and to obtain specialty stroke center certification. Why the Controversy? A number of trials have examined the use of thrombolytic agents with time windows beyond three hours in treating acute ischemic stroke, with unfortunate results. Some of these involved streptokinase, not rt-PA. The Multicenter Acute Stroke Trial-Italy (MAST-I) and the Australian Streptokinase Trial (AST) both suggested that most excess hemorrhages and early deaths occurred in patients treated after three hours of symptom onset. The MAST-I study, published in 1995, randomized 622 patients with acute ischemic stroke to one of four treatment arms: 1.5 million units of intravenous streptokinase (SK) over one hour; 300 mg aspirin a day for 10 days; streptokinase and aspirin in the above doses; and placebo. Enrollment was terminated after an interim analysis showed a statistically significant increase in the six-month mortality among the patients treated with SK and aspirin. (Lancet 1995;346:1506.) The Multicenter Acute Stroke Trial-Europe (MAST-E), published in 1996, randomized 310 patients from France and the United Kingdom with acute ischemic stroke to treatment within six hours of symptom onset with either placebo or SK 1.5 million units over one hour. The study was terminated after an interim analysis showed a significantly higher mortality rate among SK-treated patients at 10 days and approached significance at three months (45% versus 34%, p = 0.06). There was no significant difference between groups in the primary composite of death and disability at six months. (N Engl J Med 1996;335:145.) The Australian Streptokinase (AST) Trial, published in 1996, randomized 340 patients from France and the United Kingdom with acute ischemic stroke to treatment within six hours of symptom onset with either placebo or SK 1.5 million units over one hour. The study was terminated early when an interim analysis revealed a significantly higher 90-day mortality among SK-treated patients (43% versus 22%). (Lancet 1995;346:56.) A post-hoc analysis suggested that treatment of patients more than three hours after the onset of symptoms increased the risk of adverse outcomes. (JAMA 1996;276:961.) There is some question about why rt-PA should be any safer or more efficacious than streptokinase, which has been demonstrated to be unsafe and without efficacy. This is true especially because thrombolytic trials for MI had tens of thousands of patients enrolled, while the stroke trials numbered patients only in the hundreds. In fact, rt-PA didn't always look good either. The European Cooperative Acute Stroke Study group (ECASS-I) treated 615 study patients, and evaluated rt-PA 1.1 mg/kg body weight given intravenously within six hours of onset of symptoms. It reported no benefit in the treated group. The upper dose limit was 100 mg per patient, with a bolus of 10 percent of the dose given over one to two minutes, followed by a 60-minute infusion. The occurrence of large parenchymal hemorrhages was significantly more frequent in the rt-PA-treated patients than in the placebo group. Mortality rates were higher in the rt-PA-treated group (17.9%) than in the placebo group (12.7%). There was a significant improvement in clinical outcomes at three months in a population derived by excluding 109 “protocol violators,” those patients with extensive pretreatment CT abnormalities. The authors concluded in their report, published in 1995, that “intravenous thrombolysis cannot be currently recommended for use in an unselected population of patients with acute ischemic stroke.” (JAMA 1995;274:1017.) Next month: Problems with thrombolysis and determining if the therapy is standard of care.

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