Although thrombolysis with recombinant tissue plasminogen activator (rt-PA) remains the only proven FDA-approved therapy for acute ischemic stroke, few patients receive this treatment. Current data suggest that only about 0.9-1.5% of all stroke patients receive thrombolysis, 1,2 even though approximately 20-50% of these patients seek medical attention within three hours of symptom onset. , 3-5 While there are many reasons for this, one aspect that has received only limited attention is the inclusion and exclusion criteria used for deciding upon treatment. Many acute stroke rt-PA treatment protocols strictly adhere to the criteria used in the original rt-PA NINDS treatment trial , 6 as well as additional poorly established criteria such as exclusion of older patients, and cutoffs based upon the severity of the patients’ neurological deficit. In fact, several studies have reported that such criteria may be too strict, unnecessarily excluding patients from treatment., 7-9 For example, it is not uncommon to exclude patients on the basis of age (often a cutoff of ≥ 80), or stroke severity, even though such cut offs were not used in the original National Institute of Neurological Disorders and Stroke (NINDS) study., 6 In addition, many hospitals do not adhere to current guidelines of acute stroke management, which recommend rapid evaluation and treatment of the patient within 60 minutes (i.e., the “golden hour”) of presentation in the emergency department. Additionally, many patients are excluded on the basis of neurological deficits that are felt to be “too mild” to treat, even though studies suggest that as many as 20-30% of such patients are subsequently left disabled. , 7-9

At California Pacific Medical Center, stroke treatment criteria have been revised to incorporate the latest and most progressive stroke research findings. Moreover, researchers are pioneering innovative approaches to acute stroke management incorporating the latest technology. Great strides have been made in reducing the time needed to evaluate and treat a patient by streamlining the process of providing definitive treatment. This is reflected in the substantial increase in the use of thrombolysis for acute ischemic stroke at California Pacific over the past few years. Currently, approximately 25% [range 6-42%] of ischemic stroke patients we see receive thrombolytic therapy, 5-10 times the national average. In addition, these stroke treatment criteria permit treatment in many patients that are excluded by other protocols. For example, patients ≥ 80 years old are eligible for treatment. In fact, approximately 50% of California Pacific rt-PA treated patients are over 80 years old and about 20% are over 90 years old. Despite this, outcomes are comparable or better than those reported in major rt-PA stroke trials even though the patients treated were substantially younger in those studies. More than half (57%) of rt-PA treated patients at California Pacific experience no significant residual functional impairment at discharge.

Recent IV rt-PA treatment at CPMC results in substantial increases in thrombolysis utilization and discharge home.

A recent analysis of IV rt-PA 2007-2008 data reveals a nearly 50% increase in the use of IV rt-PA. This was associated with a 125% increase in the number of patients discharged home and a death rate of only 2%. “These are among the best IV rt-PA outcome statistics that I am aware of,” noted David Tong, M.D. and Medical Director of the California Pacific Comprehensive Stroke Care Center. “And I believe it is reflective of the new time window for treatment, coupled with state-of-the-art evaluation and management of these patients. We are pleased with our data, and wish to share our knowledge with others so that many more might benefit.”

2008 CPMC Stroke Data.

Using neuroimaging to aid management

Advanced neuroimaging of stroke patients may be a key factor in determining appropriate treatment. We are studying the use of computed tomography perfusion (CTP) scanning and CT angiography (CTA) to help clinical decision making, and have found it to be extremely useful in the management of many patients with acute cerebrovascular disease. These protocols may permit us to use tissue-based rather than time-based criteria for treatment. In the near future, all patients may be managed in this way, greatly improving our ability to treat the patient appropriately and with better results.

These techniques may be particularly useful in patients outside conventional time windows for treatment, where there is uncertainty as to whether there is benefit in the individual patients. This is especially pertinent to patients who transfer to California Pacific, owing to the intrinsic delay in treatment inherent when transferring from one institution to another. In this way the time window for treatment may be safely increased to be many hours longer than the current three-hour standard.

Stroke treatment continues to evolve rapidly. The clinical advancements achieved can only lead to better patient outcomes.

IV rt-PA treatment window expands to 4.5 hours

The recent publication of the European Cooperative Acute Stroke Study 3 has found that IV rt-PA treatment in acute ischemic stroke is effective up to 4.5 hours after symptom onset.10 In this landmark trial, 821 acute stroke patients were randomized between 3-4.5 hours after symptom onset. Treatment criteria were virtually identical to the original NINDS 0-3h rt-PA trial. The mean time to treatment was 4 hours. Patients receiving IV rt-PA were about 30% more likely to have a good outcome (defined as no symptoms, or no disability despite symptoms) than untreated patients (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P = 0.04). Symptomatic hemorrhage was higher in treated patients, but only modestly (2.8% versus 0.2% P = 0.008), and mortality was lower in treated patients.

“This study is a milestone in the treatment of acute ischemic stroke,” noted Dr. Tong. “We now have strong evidence that there is an opportunity to treat more of our acute stroke patients with a safe and effective therapy. We are already changing our treatment protocols to reflect this important finding and are helping other centers modify their treatment criteria as well.”

References

1. Schumacher HC, Bateman BT, Boden-Albala B, Berman MF, Mohr JP, Sacco RL, Pile-Spellman J. Use of thrombolysis in acute ischemic stroke: Analysis of the nationwide inpatient sample 1999 to 2004. Ann Emerg Med. 2007;50:99-107
2. Reed SD, Cramer SC, Blough DK, Meyer K, Jarvik JG. Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals. Stroke. 2001;32:1832-1840
3. Qureshi AI, Kirmani JF, Sayed MA, Safdar A, Ahmed S, Ferguson R, Hershey LA, Qazi KJ. Time to hospital arrival, use of thrombolytics, and in-hospital outcomes in ischemic stroke. Neurology. 2005;64:2115-2120
4. Romano JG, Muller N, Merino JG, Forteza AM, Koch S, Rabinstein AA. In-hospital delays to stroke thrombolysis: Paradoxical effect of early arrival. Neurological Research. 2007;29:664-666
5. Zweifler RM, Mendizabal JE, Cunningham S, Shah AK, Rothrock JF. Hospital presentation after stroke in a community sample: The mobile stroke project. Southern Medical Journal. 2002;95:1263-1268
6. 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
7. Nedeltchev K, Schwegler B, Haefeli T, Brekenfeld C, Gralla J, Fischer U, Arnold M, Remonda L, Schroth G, Mattle HP. Outcome of stroke with mild or rapidly improving symptoms. Stroke; a Journal of Cerebral Circulation. 2007;38:2531-2535
8. Smith EE, Abdullah AR, Petkovska I, Rosenthal E, Koroshetz WJ, Schwamm LH. Poor outcomes in patients who do not receive intravenous tissue plasminogen activator because of mild or improving ischemic stroke. Stroke; a Journal of Cerebral Circulation. 2005;36:2497-2499
9. De Keyser J, Gdovinova Z, Uyttenboogaart M, Vroomen PC, Luijckx GJ. Intravenous alteplase for stroke: Beyond the guidelines and in particular clinical situations. Stroke; a Journal of Cerebral Circulation. 2007;38:2612-2618
10. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England Journal of Medicine. 2008;359:1317-1329