ARTICLE IN BRIEF
In a trial in China, investigators reported that a short course of combination therapy — clopidogrel and aspiring — reduced the risk of subsequent stroke by 32 percent.
Standard treatment for acute transient ischemic attack (TIA) or a minor ischemic stroke calls for aspirin to reduce the risk of a more serious stroke in the days, weeks, and months ahead. But results from a new study conducted in China showed that adding another antiplatelet, clopidogrel, to the aspirin regimen led to a 32 percent reduction in the risk for subsequent stroke compared with taking aspirin alone.
S. Claiborne Johnston, MD, PhD, a professor of neurology and associate vice chancellor of research at the University of California, San Francisco (UCSF), a senior author of the China study, and the principal investigator of a similar ongoing study in the US, said that he was hoping for a small effect. But when the numbers came in, he was surprised, and excited. “Nothing has ever come close to this,” said Dr. Johnston, who is also director of the UCSF Clinical and Translational Science Institute. Yongjun Wang, MD, professor and chair of neurology at Tiantan Hospital, was also a principal investigator of the trial.
Dr. Johnston believes that the study, published in the July 4 New England Journal of Medicine, will lead to immediate changes in the way neurologists prevent subsequent strokes in China. Clopidogrel has only been tested as an individual therapy in the first few days following TIA or acute minor stroke and the combination of aspirin and clopidogrel is not effective after this initial period.
The study was conducted in 114 centers throughout China. The investigators recruited 5,170 patients — ages 40 and older — who had been diagnosed with a minor stroke or TIA within 24 hours of the event and randomly assigned them to combination therapy — clopidogrel and aspirin — or to placebo plus aspirin. Those on combination therapy received a clopidogrel dose of 300 mg on the first day followed by clopidogrel at 75 mg daily for days two to 90; the participants were also given 75 mg aspirin for the first 21 days of the intervention. Patients in the placebo group took the 75 mg dose of aspirin daily for the entire 90 days of the study.
As to why patients were given aspirin for only the first 21 days in the combination therapy group, Dr. Johnston explained that they wanted to reduce the risk of hemorrhage outside the acute period. “Trials in the later period have shown that the benefit in reducing ischemic events should be balanced with an increased risk in hemorrhage outside the acute period,” he wrote in an e-mail to Neurology Today.
At the 90-day follow-up, the investigators found that 8.2 percent of the patients who received combination therapy suffered a subsequent stroke compared with 11.7 percent of those taking only aspirin (p<0.001). The clinicians were worried about the possible increased risk of moderate or severe hemorrhage with the added antiplatelet, but it was the same in both groups, 0.3 percent.
The study was funded by the Ministry of Science and Technology of the People's Republic of China.
Other studies have failed to show a benefit of combination therapy and observed an increased risk of hemorrhage. Dr. Johnston suspects that there were several reasons for the different outcomes, including finding patients with TIA or minor stroke in the first few hours of the event.
He said that the dramatic benefit of the combination therapy was surprising because the genetics of the Chinese make it more difficult to metabolize clopidogrel. Therefore, he said, “the benefit of the therapy in the US could be even stronger but bleeding risk might also be greater.”
In addition to the CHANCE trial, the Platelet-Oriented Inhibition in New TIA (POINT) study is ongoing in the US, Dr. Johnston noted. The POINT study, for which he is a lead investigator, is using a higher loading dose of clopidogrel (600 mg) and the investigators are beginning treatment within the first 12 hours of TIA or minor stroke onset. (For more on the trial, which is being sponsored by the National Institute of Neurological Disorders and Stroke, see http://1.usa.gov/138cT8T.)
“It is wonderful to have a positive trial in stroke treatment,” said Dr. Johnston. “If the numbers are right, a combination treatment could prevent tens of thousands of strokes a year. We haven't had a solidly positive stroke trial in a long time.” He cautions, however, that the study findings must be replicated in the on-going trials.
EXPERTS WEIGH IN
In a commentary accompanying the study, Graeme J. Hankey, MD, a stroke expert at the University of Western Australia and Royal Perth Hospital, noted that the CHANCE investigators “completed a large, scientifically rigorous trial that proves the concept that dual antiplatelet therapy can be more effective than single antiplatelet therapy in preventing early recurrent stroke in patients with acute symptomatic atherothrombosis (predominantly intracranial) of the brain.”
But he noted that the CHANCE investigators had to screen 41,561 patients with stroke or TIA to find 5,170 appropriate patients (12.4 percent), suggesting that the results cannot be generalized to most patients. “The study excluded patients with major ischemic stroke, who are at risk for hemorrhagic transformation, and patients with TIA due to isolated sensory, visual, or vertiginous syndromes, who are at low risk for recurrence,” he said.
Ralph L. Sacco MD, professor and Olemberg chair of neurology and executive director of the McKnight Brain Institute and chief of neurology at Jackson Memorial and Miller School of Medicine at the University of Miami, agreed that the study findings are “convincing. However, clopidogrel and aspirin have not been found to be efficacious in the long-term treatment for prevention of stroke recurrence in a variety of trials and can increase the risk of bleeding.”
“This trial offers hope that the short-term combination antiplatelets may be worth the increased bleeding risk to improve outcomes,” he said. “Other studies continue to assess this more aggressive antiplatelet option among US patients since Chinese patients could have different stroke subtypes and higher risks of recurrence.”
Robert G. Hart, MD, a professor of medicine (neurology) at McMaster University's Population Health Research Institute in Hamilton, Ontario, agreed. “An important study, to be sure. The controversy is whether the results can be generalized to North American patients (since there is the suspicion that strokes in China are due to a different spectrum of cerebrovascular disorders).”
He pointed out that results from the POINT study in North America are two to four years away (unless stopped early for efficacy).
McMaster University's Michael Sharma, MD, associate professor of medicine (neurology), added that other antiplatelet therapies have been tried unsuccessfully in stroke. He said the incidence of subsequent stroke in the Chinese study population was higher than it is in the US. In areas surrounding major stroke centers, the 90-day stroke rate is 3 to 5 percent, down from 10 percent. “Maybe we are seeing different types of patients,” he said. “People in China, Korea, and Japan have higher rates of intracranial atherosclerosis, and that is more amenable to dual antiplatelet therapy.”
Also, he said, the clinicians selected TIA patients for the study who were at high risk, which could have strengthened the study effects. They recruited patients with ABCD2 scores of four or higher and NIH Stroke Scale scores under four.
He said that “if the treatments are used in tandem, neurologists must be careful to select the high-risk patient and then begin treatment within the first 24 hours.”
Dr. Sharma pointed out that diagnosing TIA is challenging. About 40 percent of the patients referred to stroke centers with the diagnosis did not have a TIA, he pointed out, adding that ABCD2 is good at screening out individuals who do not have TIA.
The US study — POINT — “will be very important in confirming what we see in our patients and how big the benefit is,” he added.