Meeting News

Clopidogrel, aspirin combination lowers stroke odds, raises brain bleeding risk

S. Claiborne Johnston

The combination of clopidogrel and aspirin may lower the risk for major ischemic events among patients with minor ischemic stroke or high-risk transient ischemic attack compared with aspirin alone, according to results of the POINT study.

Although this combination may lower ischemic event risk, it may raise the risk for major hemorrhagic bleeding, researchers reported at the European Stroke Organization Conference. The results were simultaneously published in The New England Journal of Medicine.

“The stroke risk is just too high in the short period after TIA and minor stroke. We needed to start developing treatments to reduce this risk,” S. Claiborne Johnston, MD, PhD, vice president for medical affairs and dean of the Dell Medical School at the University of Texas at Austin, told Cardiology Today. “We have another treatment to prevent secondary stroke in high-risk patients. It works pretty well, but does carry a small risk of major hemorrhage, which is predominantly systemic hemorrhage. This should all look familiar to cardiologists. They have been using clopidogrel and aspirin together in ACS for years.”

After a trial in a Chinese cohort showed a combination antiplatelet therapy was successful in reducing risk for recurrent stroke, Johnston and colleagues conducted a 4,881-patient randomized trial to see whether the results could be duplicated in an international population.

Patients with minor ischemic stroke or high-risk TIA were randomly assigned clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day plus aspirin 50 mg to 325 mg per day, or aspirin alone.

The primary efficacy outcome in a time-to-event analysis was the risk for a composite of major ischemic events, defined as ischemic stroke, MI or death from an ischemic vascular event at 90 days.

Eighty-four percent of the anticipated patients were enrolled before the study was halted due to data and safety monitoring board determination that the combination therapy was linked to lower risk for major ischemic events and higher risk for major hemorrhage at 90 days compared with aspirin.

Major ischemic events occurred in 5% of patients assigned clopidogrel plus aspirin and in 6.5% of patients assigned aspirin plus placebo (HR = 0.75; 95% CI, 0.59-0.95).

In the cohort receiving clopidogrel plus aspirin, 0.9% of patients experienced major hemorrhage vs. 0.4% in the cohort that received aspirin plus placebo (HR = 2.32; 95% CI, 1.1-4.87).

“The most important thing to remember is that these are patients being treated within 12 hours of onset of TIA or stroke symptoms, and they were only treated for 90 days,” Johnston said. “Even during the 90 days, the benefits were greater earlier while the risk of hemorrhage was fairly constant throughout the treatment period.”

In a related editorial, James C. Grotta, MD, from the Stroke Research Program and Mobile Stroke Unit, Memorial Hermann Hospital, Houston, wrote the results suggest that the combination of aspirin plus clopidogrel reduces the chance of recurrent ischemic stroke during the high-risk period in the first few weeks after a TIA or noncardioembolic ischemic stroke, but if dual therapy is used, it should be confined to the first 3 weeks after a TIA or minor stroke, after which the patient should be transitioned to monotherapy.

“If patient follow-up and adherence to therapy are not reliable, then dual therapy perhaps should not be considered. Dual therapy may also not be advisable in patients with an uncertain diagnosis of TIA, who either would have been excluded from the trial or did not benefit,” Grotta wrote. “Finally, patients who are at increased risk for bleeding, such as those with cerebral microbleeding or a history of brain or systemic bleeding, were excluded from this trial and may not be appropriate candidates for such dual therapy. The POINT trial has provided useful data to help us further personalize our efforts in preventing recurrent stroke.” – by Dave Quaile

References:

Johnston SC, et al. Official Welcome and Large Clinical Trials. Presented at: European Stroke Organization Conference; May 16-18, 2018; Gothenburg, Sweden.

Grotta JC, et al. N Engl J Med. 2018;doi:10.1056/NEJMe1806043.

Johnston SC, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1800410.

Disclosures: Grotta reports he receives personal fees and nonfinancial support from Boehringer Ingelheim, Frazer Corp., Genentech, Haemonetics Corp. and Stryker. Johnston reports he has received grant support from AstraZeneca.

S. Claiborne Johnston

The combination of clopidogrel and aspirin may lower the risk for major ischemic events among patients with minor ischemic stroke or high-risk transient ischemic attack compared with aspirin alone, according to results of the POINT study.

Although this combination may lower ischemic event risk, it may raise the risk for major hemorrhagic bleeding, researchers reported at the European Stroke Organization Conference. The results were simultaneously published in The New England Journal of Medicine.

“The stroke risk is just too high in the short period after TIA and minor stroke. We needed to start developing treatments to reduce this risk,” S. Claiborne Johnston, MD, PhD, vice president for medical affairs and dean of the Dell Medical School at the University of Texas at Austin, told Cardiology Today. “We have another treatment to prevent secondary stroke in high-risk patients. It works pretty well, but does carry a small risk of major hemorrhage, which is predominantly systemic hemorrhage. This should all look familiar to cardiologists. They have been using clopidogrel and aspirin together in ACS for years.”

After a trial in a Chinese cohort showed a combination antiplatelet therapy was successful in reducing risk for recurrent stroke, Johnston and colleagues conducted a 4,881-patient randomized trial to see whether the results could be duplicated in an international population.

Patients with minor ischemic stroke or high-risk TIA were randomly assigned clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day plus aspirin 50 mg to 325 mg per day, or aspirin alone.

The primary efficacy outcome in a time-to-event analysis was the risk for a composite of major ischemic events, defined as ischemic stroke, MI or death from an ischemic vascular event at 90 days.

Eighty-four percent of the anticipated patients were enrolled before the study was halted due to data and safety monitoring board determination that the combination therapy was linked to lower risk for major ischemic events and higher risk for major hemorrhage at 90 days compared with aspirin.

Major ischemic events occurred in 5% of patients assigned clopidogrel plus aspirin and in 6.5% of patients assigned aspirin plus placebo (HR = 0.75; 95% CI, 0.59-0.95).

In the cohort receiving clopidogrel plus aspirin, 0.9% of patients experienced major hemorrhage vs. 0.4% in the cohort that received aspirin plus placebo (HR = 2.32; 95% CI, 1.1-4.87).

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“The most important thing to remember is that these are patients being treated within 12 hours of onset of TIA or stroke symptoms, and they were only treated for 90 days,” Johnston said. “Even during the 90 days, the benefits were greater earlier while the risk of hemorrhage was fairly constant throughout the treatment period.”

In a related editorial, James C. Grotta, MD, from the Stroke Research Program and Mobile Stroke Unit, Memorial Hermann Hospital, Houston, wrote the results suggest that the combination of aspirin plus clopidogrel reduces the chance of recurrent ischemic stroke during the high-risk period in the first few weeks after a TIA or noncardioembolic ischemic stroke, but if dual therapy is used, it should be confined to the first 3 weeks after a TIA or minor stroke, after which the patient should be transitioned to monotherapy.

“If patient follow-up and adherence to therapy are not reliable, then dual therapy perhaps should not be considered. Dual therapy may also not be advisable in patients with an uncertain diagnosis of TIA, who either would have been excluded from the trial or did not benefit,” Grotta wrote. “Finally, patients who are at increased risk for bleeding, such as those with cerebral microbleeding or a history of brain or systemic bleeding, were excluded from this trial and may not be appropriate candidates for such dual therapy. The POINT trial has provided useful data to help us further personalize our efforts in preventing recurrent stroke.” – by Dave Quaile

References:

Johnston SC, et al. Official Welcome and Large Clinical Trials. Presented at: European Stroke Organization Conference; May 16-18, 2018; Gothenburg, Sweden.

Grotta JC, et al. N Engl J Med. 2018;doi:10.1056/NEJMe1806043.

Johnston SC, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1800410.

Disclosures: Grotta reports he receives personal fees and nonfinancial support from Boehringer Ingelheim, Frazer Corp., Genentech, Haemonetics Corp. and Stryker. Johnston reports he has received grant support from AstraZeneca.