Ticagrelor-Aspirin Combo: Fewer Repeat Strokes, but More Bleeds

The combination of ticagrelor and aspirin is superior to aspirin alone in reducing the risk for secondary stroke, transient ischemic attack (TIA), and death, new data show.

However, severe bleeding was more common in the ticagrelor-aspirin group than in the aspirin-only group.

"We found that ticagrelor plus aspirin reduced the risk of stroke or death, compared to aspirin alone in patients presenting acutely with stroke or TIA," reported lead author S. Claiborne Johnston, MD, PhD, dean and vice president for medical affairs, Dell Medical School, the University of Texas, Austin.

Although the combination also increased the risk for major hemorrhage, that increase was small and would not overwhelm the benefit, he told Medscape Medical News.

The study was published online July 16 in The New England Journal of Medicine.

Attractive Properties

"Lots of patients have stroke in the days to weeks after first presenting with a stroke or TIA," said Johnston, who is also the Frank and Charmaine Denius Distinguished Dean's Chair at Dell Medical School.

"Aspirin has been the standard of care but is only partially effective. Clopidogrel plus aspirin is another option that has recently been proven, [but] ticagrelor has attractive properties as an antiplatelet agent and works synergistically with aspirin," he added.

Ticagrelor is a direct-acting antiplatelet agent that does not depend on metabolic activation and that "reversibly binds" and inhibits the P2Y12 receptor on platelets.

Previous research has evaluated clopidogrel and aspirin for the secondary prevention of ischemic stroke or TIA. In an earlier trial, ticagrelor was no better than aspirin in preventing these subsequent events. However, the investigators note that the combination of the two drugs has not been well studied.

The randomized, placebo-controlled, double-blind trial involved 11,016 patients at 414 sites in 28 countries. Patients who had had mild to moderate acute noncardioembolic ischemic stroke (mean age, 65 years; 39% women; roughly 54% White) were randomly assigned to receive either ticagrelor plus aspirin (n = 5523) or aspirin alone (n = 5493) for 30 days. Of these patients, 91% had sustained a stroke, and 9% had sustained a TIA.

Thirty days was chosen as the treatment period because the risk for subsequent stroke tends to occur mainly in the first month after an acute ischemic stroke or TIA.

The primary outcome was "a composite of stroke or death in a time-to-first-event analysis from randomization to 30 days of follow-up."

For the study, "stroke" encompassed ischemic, hemorrhagic, or stroke of undetermined type, and "death" included deaths of all causes.

Secondary outcomes included first subsequent ischemic stroke and disability (defined as a score of >1 on the Rankin Scale).

Almost all patients (99.5%) were taking aspirin during the treatment period, and most were also taking an antihypertensive and a statin (74% and 83%, respectively).

Patients in the ticagrelor-aspirin group had fewer primary-outcome events in comparison with those in the aspirin-only group (303 patients [5.5%] vs 362 patients [6.6%]; hazard ratio [HR], 0.83; 95% CI, 0.71 – 0.96; P = .02).

Incidents of subsequent ischemic stroke were similarly lower in the ticagrelor-aspirin group in comparison with the aspirin-only group (276 patients [5.0%] vs 345 patients [6.3%]; HR, 0.79; 95% CI, 0.68 – 0.93; P = .004).

On the other hand, there was no significant difference between the groups in the incidence of overall disability (23.8% of the patients in the ticagrelor-aspirin group and in 24.1% of the patients in the aspirin group; odds ratio, 0.98; 95% CI, 0.89 – 1.07; P = .61).

There were differences between the groups in severe bleeding, which occurred in 28 patients (0.5%) in the ticagrelor-aspirin group and in seven patients (0.15) in the ticagrelor group (HR, 3.99; 95% CI, 1.74 – 9.14; P = .001).

Moreover, more patients in the ticagrelor-aspirin group experienced a composite of intracranial hemorrhage or fatal bleeding compared to the aspirin-only group (0.4% vs 0.1%). Fatal bleeding occurred in 0.2% of patients in the ticagrelor-aspirin group, vs 0.1% of patients in the aspirin group.

More patients in the ticagrelor-aspirin group permanently discontinued the treatment because of bleeding than in the aspirin-only group (2.8% vs 0.6%).

"The benefit from treatment with ticagrelor-aspirin, as compared with aspirin alone, would be expected to result in a number needed to treat of 92 to prevent one primary outcome event, and a number needed to harm of 263 for severe bleeding," the authors note.

Risks vs Benefits

Commenting on the study for Medscape Medical News, Konark Malhotra, MD, a vascular neurologist at Allegheny Health Network, Pittsburgh, Pennsylvania, noted that ticagrelor is an antiplatelet medication "that adds to the armamentarium of stroke neurologists for the treatment of mild acute ischemic or high-risk TIA patients."

Malhotra, who was not involved with the study, added that the "combined use of ticagrelor and aspirin is effective in the reduction of ischemic events, however, at the expense of increased risk of bleeding events."

In an accompanying editorial, Peter Rothwell, FMedSci, of the Wolfson Center for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom, who was not involved with the study, suggests that the "bleeding risk associated with ticagrelor and aspirin might exceed the benefit among lower-risk patients who make up the majority in practice, and so the results should not be overgeneralized."

Moreover, "regardless of which combination of antiplatelet therapy is favored for the high-risk minority, all patients should receive aspirin immediately after TIA, unless aspirin is contraindicated."

He noted that "too many patients are sent home from emergency departments without this simple treatment that substantially reduces the risk and severity of early recurrent stroke."

The study was supported by AstraZeneca. Johnston has received a grant from AstraZeneca and nonfinancial support from SANOFI. Rothwell has received personal fees from Bayer and BMS. Malhotra has disclosed no relevant financial relationships.

N Engl J Med. Published online July 16, 2020. Abstract

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