Short course of aspirin, clopidogrel cuts stroke risk

Pauline Anderson

February 12, 2013

Honolulu, HI - A relatively short course of aspirin plus clopidogrel immediately after a transient ischemic attack (TIA) or minor stroke outperforms aspirin alone in cutting the risk of a subsequent stroke, and it does this without a significant increased risk of major bleeding complications, results of a large trial show.

Results of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial were presented here at the International Stroke Conference 2013.

The CHANCE trial, carried out exclusively in China, is a few steps ahead of a similar trial, the Platelet-Oriented Inhibition in New TIA and Stroke (POINT) trial, now enrolling mostly in the US.

Although CHANCE was a "well-done" trial and its results showed "a larger treatment effect," it's important to note that healthcare in China is different from that in the US, said CHANCE co-principal investigator Dr S Claiborne Johnston (University of California, San Francisco).

"Secondary-prevention practices are not as robust there as they are in Europe and in North America, and that could have impacted the trial," he said in an interview. "Also, usually genetic differences don't matter, but in this case they might, because there are differences in polymorphisms that affect clopidogrel metabolism in Asian populations."

For these reasons, although American physicians might see the CHANCE trial as a signal to go ahead and use combined therapy, "I think it's wise for us to wait for a confirmatory trial outside of China," said Johnston, who is also co-principal investigator of the POINT trial.

CHANCE co-principal investigator Dr Yongjun Wang (Beijing TianTan Hospital, Capital Medical University, China) presented the full results here.

High risk for hemorrhage

The study enrolled 5170 patients at least 40 years of age who had suffered a TIA or minor stroke. Within 24 hours of their symptom onset, they were randomized to one of two groups: aspirin (75-300 mg one-day loading dose followed by 75 mg/day) plus placebo, or the same aspirin regimen plus clopidogrel (loading dose of 300 mg followed by 75 mg/day).

Patients in the combination group were taken off aspirin at 21 days because of the concern that Chinese patients, as with other Asian populations, are at relatively high risk of hemorrhage. "Frankly, that belief comes from epidemiological studies, but the epidemiology may just reflect underlying risk factors and not a true propensity for it," said Johnston. He pointed out that the studies testing this have not been in the acute period.

The study showed that stroke occurred less frequently in those receiving both aspirin and clopidogrel. At 90 days, the hazard ratio (HR) for survival free of stroke—either ischemic or hemorrhagic—in the combination group was 0.68 (95% CI 0.57-0.81; p<0.001)

For the secondary outcome of combined events (stroke, MI, vascular death), the HR was 0.69 (95% CI 0.58-0.82; p<0.001). The risk of hemorrhagic stroke was the same in the two groups (0.3%).

Notably, severe bleeding events occurred at a similar rate in the two groups (0.2% in each). Although mild bleeding occurred more often in the combination group (1.2% vs 0.7%), Johnston noted that these events included events such as nose bleeds. "We did not see a signal that the combination was unsafe."

Both aspirin and clopidogrel affect the platelet, but through different pathways. "Together, the two are much more powerful than either one alone," said Johnston.

CHANCE was the first trial to focus on the acute period in TIA and minor stroke, which Johnston emphasized is not being seen nearly enough in the emergency department. "People with TIA and minor stroke are not coming in acutely or they're calling the office and being seen in clinic," he said. "We need to remind people that this really is an emergency and it should be treated right away."

Asked whether the combination therapy would be an acceptable approach for more severe strokes, Johnston said it's impossible to know "where to draw the line." The researchers will do more subgroup analyses looking at stroke severity, but Johnston pointed out that "there was no difference between the TIA and stroke in terms of rates of hemorrhagic stroke or in the efficacy of the combination."

Compared with elsewhere in the world, the risk of stroke is very high in China. "There are a whole lot more strokes in China than there are in the US, and even if you add Europe, you still have more strokes in China," said Johnston.

Healthcare differences

Because the trial was so large and because standards for clinical research have improved dramatically in China, the CHANCE results are "incredibly important" and should have a major effect on public health around the world, said Johnston. However, he noted that about two-thirds of the Chinese patients in the study had hypertension, and less than half were on any drug for hypertension during follow-up. Undertreatment, he said, could "certainly" affect the absolute effect size that's seen in the trial.

It's probably wise to await results of the POINT trial before changing treatment approaches in North America, said Johnston. Interim POINT results will be available in May, he said. "That will provide an opportunity to say it's very important to continue POINT or it's not important to continue POINT."

The POINT trial, which is about a third of the way through recruitment, differs slightly from CHANCE, said Johnston. For example, it includes a higher loading dose of clopidogrel and requires enrollment within 12 hours instead of 24 hours. As well, patients in the combination group continue with aspirin for 90 days instead of stopping at 21 days as in the CHANCE study.

Johnston pointed out a graph showing times for survival free of stroke for the treatment groups. "Most of the separation in the two curves occurs just in the first couple of days, so certainly by 21 days, the curves are almost parallel."

POINT includes mainly centers in the US, although some sites have been added internationally.

The idea of comparing aspirin plus clopidogrel in a North American trial dates back more than a decade, but the researchers ran into funding difficulties when the drug manufacturer pulled its backing. This, said Johnston, substantially delayed the start of the trial.

When asked about next steps for CHANCE, Johnston said the Chinese researchers will look at ancillary studies of biomarkers and subtyping based on vascular imaging. As well, they plan to provide outcomes at one year that will include results related to cognition.

Helpful information

Invited to comment on the CHANCE trial results, Dr Larry B Goldstein (Duke University, Durham, NC), a POINT investigator, said the information is "quite helpful" and could eventually alter the current treatment practice, which is aspirin alone. "This would suggest that aspirin with clopidogrel over a relatively short course may have some benefit."

He added that the "key" is the short course of the combination aspirin plus clopidogrel treatment. He pointed out that other trials, including SPS3 and MATCH, found that long-term combinations are associated with an increased risk of major bleeding complications.

"Over the longer term, the addition of a more potent antiplatelet drug or combinations in general seem to carry a much higher risk of bleeding that attenuates any benefit they have in reducing ischemic stroke risk," said Goldstein. "In our current guidelines, there is actually a contraindication for the combination for long-term secondary stroke prevention."

The lack of increased risk of bleeding, at least in the short term, "is quite encouraging," said Goldstein. He added that bleeding complications are more of a concern in Asia than in the US, which has a much more ethnically diverse population and where the proportion of Asians is relatively low.

Neither Johnston nor Goldstein reports any relevant conflicts of interest .


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