Short DAPT Bests Aspirin at Preventing Recurrent Events After Stroke, TIA

Patients given dual antiplatelet therapy (DAPT) immediately following a mild-to-moderate stroke or high-risk transient ischemic attack have a lower risk of recurrent events compared with those prescribed aspirin alone, according to a new meta-analysis.

“Antiplatelet monotherapy should no longer be the standard of care for these patients,” senior author Arman Qamar, MD, MPH (NorthShore University Health System, Evanston, IL), told TCTMD. “All of these patients, if the risk of bleeding is not high, should receive aspirin and a P2Y12 inhibitor, preferably clopidogrel, for a period of 21 days and then transition to antiplatelet monotherapy.”

Published online this week ahead of print in Stroke, the study, led by Kirtipal Bhatia, MD (Icahn School of Medicine at Mount Sinai, New York, NY), includes data from 21,459 patients in four randomized trials comparing short-term DAPT (21-90 days) to aspirin alone in this population: FASTER, CHANCE, POINT, and THALES.

“The choice really is clear that dual antiplatelet therapy is the right drug for these patients,” said S. Claiborne “Clay” Johnston, MD, PhD (Dell Medical School, University of Texas at Austin), principal investigator for THALES.

As for which P2Y12 inhibitor to use, there are not yet enough data to support a top contender, he told TCTMD. “Either clopidogrel or ticagrelor is a very reasonable choice along with aspirin. The not reasonable choice is to treat with only one drug. We've just got way too much data to say that that's an acceptable option. And concerns about hemorrhage should not outweigh the benefit. The benefit is so much stronger than the risk, it really drives the need to treat these patients.”

Personalized Medicine Potential

Compared with aspirin alone, up to 3 months of DAPT was associated with a lower risk of recurrent stroke (RR 0.76; 95% CI 0.68-0.83), albeit with a higher risk of major bleeding (RR 2.22; 95% CI 1.14-4.34) over follow-up ranging from 30-90 days.

Overall, patients on DAPT had lower risks of MACE (RR 0.76; 95% CI 0.69-0.84) and recurrent ischemic events (RR 0.74; 95% CI 0.67-0.82), and there was no difference seen for hemorrhagic stroke.

The mean age of patients across all four trials was 62-68 years, while the proportion of female patients in the studies ranged from 3% to 47%.

These findings have implications for the future of personalized medicine, Qamar said, specifying that not all strokes and TIAs should be treated alike. “This meta-analysis validates the fact that in these patients, aspirin monotherapy should not be the routine treatment and that most patients should be receiving dual antiplatelet therapy—a short course,” he said. “Generally, in these trials it has been somewhere from 21 to 90 days, but a 21-day regimen has appeared reasonable.”

Johnston agreed. “I worry that people haven't taken those trials to heart and haven’t really been treating patients appropriately with dual antiplatelet therapy,” he said. “So even though we have had three consistent trials and two different drugs that have been tested along with aspirin, I know that a bunch of patients who would be appropriate candidates for dual antiplatelet therapy are not being treated. This is an important reminder to people that they should be.”

I know that a bunch of patients who would be appropriate candidates for dual antiplatelet therapy are not being treated. This is an important reminder to people that they should be. S. Claiborne “Clay” Johnston

The higher risk of bleeding observed with DAPT shouldn’t be ignored, but appears to be driven by ticagrelor use, Qamar noted. While the ongoing CHANCE-2 trial might give more clarity on that endpoint, he said in the meantime he “would encourage physicians who take care of these patients to perhaps funnel the CHANCE approach, which gives us the right balance with aspirin and clopidogrel for 21 days and then antiplatelet monotherapy. They may be able to get a significant reduction in ischemic events without much increase in the risk of major bleeding.”

Johnston criticized the meta-analysis for only including relative risks and not absolute risks, stressing that “the reduction in ischemic events is quite a bit larger than the increased risk of hemorrhage.” Additionally, while the study authors talk about DAPT being tailored to patients based on their risk of ischemia or hemorrhage, “the reality is we don't know how to individualize it,” he said. “There is no evidence that age or sex or weight or history of diabetes or hypertension or any of those things would allow you to pick off a patient who was more likely to benefit from dual antiplatelet therapy or less likely to be harmed by it.”

Future Directions

Using platelet function or genetic testing to guide P2Y12 inhibitor choice might be an option for further personalization in this population, but research is limited, Qamar said. “For all my patients in practice who I have on clopidogrel, I always do either a genetic testing or platelet function testing,” he said. “Pharmacogenomic testing is so inexpensive that when they come in with stroke, for example, there's no out of pocket payment, it costs less than $100. So I would say, why not use it to guide our therapies?”

Johnston agreed on the potential for this kind of testing—and said that its use in CHANCE-2 should give further information—but for now the results often come back too slowly to be used practically. “Then the question becomes: why not just treat with a drug where the genetics don't matter? So that's the conundrum we get into,” he explained.

If CHANCE-2, which is being conducted in China, is positive, “then it may be that we should repeat that in a country with less Asian ancestry,” Johnston continued, since the clopidogrel nonresponsiveness tends to be higher in that population. “But the other thing to recognize is that in these trials, even with clopidogrel and aspirin or ticagrelor and aspirin, the event rates are still high and many patients are still having thrombotic events much more commonly than hemorrhagic events. We have room to do better, so I think that's an area that needs to be evaluated.”

Qamar added that he would also like to see future studies include a greater proportion of female patients as well as those with cardioembolic stroke and those needing anticoagulation who have received thrombolytic therapy, populations often excluded from past trials.