Aspirin and Clopidogrel in the Acute Treatment of Ischemic Stroke

According to data published by the American Heart Association (AHA) in their 2006 update of heart disease and stroke statistics, "on average, someone in the United States suffers a stroke every 45 seconds."¹ Furthermore, the AHA reports, approximately 700,000 persons annually experience a new or recurrent stroke, 88% of which are ischemic: however, only "8% to 12% of ischemic strokes result in death within 30 days." Because the majority of persons survive ischemic stroke, there is a need for a broader armamentarium of thrombolytic therapies than that which currently exists.

While current therapies such as tissue plasminogen activator (tPA) and revascularization are effective in the acute management of ischemic stroke and transient ischemic attack (TIA), the majority of patients are ineligible to receive them. Tissue plasminogen factor, for example, the only FDA-approved antiplatelet intervention for ischemic stroke, must be administered within 3 hours of symptom onset. This small treatment window effectively eliminates the majority of patients, such as those who do not know that they are having a stroke, those who cannot articulate that they are having a stroke, those who live in remote areas, and those who live alone.

One option that could increase the acute treatment window for ischemic stroke is the loading of aspirin and clopidogrel (Plavix) within 36 hours of symp- tom onset of stroke or TIA. Results of a pilot study presented at last year's annual meeting of the American Academy of Neurology in San Diego in May are promising.²

THE LOAD STUDY

In the Examining the Safety of Loading of Aspirin and Clopidogrel in Acute Ischemic Stroke and TIA (LOAD) study, 40 consecutive ischemic stroke patients were treated with 325 mg of aspirin and 375 mg of clopidogrel within 36 hours of symptom onset. The pilot trial enrolled patients who were ineligible for thrombolytic or revascularization therapies and who presented within 24 hours of ischemic stroke symptom onset to the University of Texas Houston Stroke Team at Memorial Hermann Hospital. The mean age of participants was 64 years; the majority of the study population was male (52.5%) and many were African American (40%). None of the participants had a previous history of ischemic cerebral hemorrhage, which was an exclusion criterion. Two patients had experienced TIA before, and 9 had a previous history of myocardial infarct.

"Only 9% of patients had a history of ischemic stroke, and 2% had received tPA before this study," said Dawn Matherne-Meyer, MSN, a family nurse practitioner in the Neurology Department at the University of Texas, Houston Medical School, and lead investigator in the study. With respect to prior medications, small percentages of patients were taking aspirin or clopidogrel or aspirin/extended-release dipyridamole (Aggrenox). "Most of those patients were persons who were experiencing their second stroke, but 82.5% of the study group were not taking any medications," Matherne-Meyer said.

Within 36 hours of symptom onset, patients were administered a loading dose of 325 mg of aspirin and 375 mg of clopidogrel. Antiplatelet use following the loading dose was provided at the discretion of the treating physician. At 30 (± 6) hours following the administration of antiplatelet therapy, patients underwent brain imaging. The primary study outcome was bleeding complications up to day 7 of hospitalization or discharge, whichever occurred first.

The investigators used the 15-item National Institute of Health Stroke Scale (NIHSS) to determine the neurologic impact of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. The NIHSS was administered at 24 hours after antiplatelet loading and on day 7 of hospitalization or discharge. The mean patient NIHSS score on admission to the LOAD study was 6. An increase in the NIHSS score of 2 points or more was defined as "neurologic worsening."

SAFETY AND EFFICACY

The mean time to presentation at the Memorial Hermann Hospital was 8 hours and 43 minutes for men experiencing stroke and 9 hours and 46 minutes for women experiencing stroke. The mean elapsed time from presentation to treatment was 12 hours and 32 minutes, with a median time of 8 hours and 25 minutes.

Overall, 37.5% (n = 15) of the patients had an improvement of 2 or more points on the NIHSS 24 hours after antiplatelet administration. At discharge, 57.5% (n = 23) had an NIHSS improvement of 2 or more points.

There was no neurologic deterioration reported at 24 hours posttreatment in any patient, and at discharge, neurologic deterioration was deemed to have occurred in only 1 patient. No incidences of intracerebral hemorrhage were detected on brain imaging, nor were any cases of systemic hemorrhage or mortality reported. One case (2.5%) of symptomatic hypoxic ischemia was reported at 43 hours after loading aspirin/clopidogrel.

Surprising efficacy data also were uncovered in the study although the study was not powered for efficacy. "We have a very large database of stroke patients in Houston--approximately 3000 patients. So we matched controls for age, NIHSS [score], race, time admitted to the emergency room after onset of stroke symptoms, or last-seen-normal time," Matherne- Meyer explained. "The patients who didn't receive aspirin and clopidogrel antiplatelet loading therapy were 17.2% more likely to experience a neurologic worsening than those who did," she said. "We were surprised when we saw how large the difference was between the 2 patient populations," she said. Consequently, further studies are planned to see whether these results are replicable.

With respect to current antithrombotic therapy in the 40 participants, 33 (82.5%) are taking no medications, 3 (7.5%) are taking aspirin, 1 (2.5%) is tak- ing clopidogrel, 2 (5%) are taking aspirin/extended-release dipyridamole, and 1 (2.5%) is taking warfarin.

IMPLICATIONS

Although tPA has been available for approximately a decade, its use has not increased during that time. "The national reported rate of ischemic stroke patients treated with tPA is approximately 2% to 3%. Data presented at last year's International Stroke Conference [February 2006 in Kissimmee, Florida] showed that the number is closer to 1% to 2%," said Matherne-Meyer. "Even though there have been public information and education campaigns and there's more information available about treating stroke emergently, we don't see the number of patients being treated earlier increasing," she said. "If only 1% to 2% of patients [in the US] are receiving tPA, there are many patients for whom there is no standard, acute therapy," she said. "We wanted to evaluate what would be applicable in any setting, be it academic, rural, or a community hospital," said Matherne-Meyer.

The idea for combination clopidogrel and aspirin therapy originated from a review of the cardiology literature on loading of antiplatelet therapy, Matherne-Meyer explained. "We determined that people are familiar with aspirin and [clopidogrel] and that they could be used readily. The cardiology data are promising," she said.

The implications of the LOAD data, albeit from a pilot study, are broad, and if the results are confirmed in a second, larger study, they could significantly alter the current acute management of ischemic stroke and TIA that would affect family members and caregivers as well as patients.

"Given the data from the pilot study, we feel that it absolutely is feasible to move along and are now subsequently planning an appropriately powered safety trial to evaluate bleeding rates in both patient populations--loaded and nonloaded," Matherne-Meyer said. "If the patient has had clopidogrel within the past 7 days, he or she is ineligible. We really want to evaluate how platelets respond to the loading of clopidogrel and aspirin in patients who are clopidogrel-naive," she remarked.

Even when the studies are done and the treatments are approved and made available, an emphasis on public education must continue. "Today, in many cultures, stroke is still seen as a disease of the elderly, and there's not a lot to be done about it. We need not only to have a variety of acute therapies available for when these patients come into the emergency room, but also to keep trying to educate these patients about coming in so that their strokes are treated early," Matherne-Meyer said.

REFERENCES

1. Heart Disease and Stroke Statistics: 2006 Update. The American Heart Association. Available at: www.americanheart.org/downloadable/heart/1140534985281Statsupdate06book.pdf Accessed November 30, 2006.
2. Matherne CA, Albright KC, Allison TA, Grotta JC. LOAD: examining the safety of loading of aspirin and clopidogrel in acute ischemic stroke and TIA. Neurology. 2006;66(suppl 2):A315.