ROME – Adding ticagrelor at 60 mg twice daily in patients on low-dose aspirin due to a prior MI reduced their risk of a first stroke by 25% in a secondary analysis of the landmark PEGASUS-TIMI 54 trial, Marc P. Bonaca, MD, reported at the annual congress of the European Society of Cardiology.
PEGASUS-TIMI 54 was a randomized, double-blind, placebo-controlled clinical trial conducted in more than 21,000 stable patients on low-dose aspirin with a history of an acute MI 1-3 years earlier. The significant reduction in secondary cardiovascular events seen in this study during a median 33 months of follow-up (N Engl J Med. 2015 May 7;372:1791-800) led to approval of ticagrelor (Brilinta) at 60 mg twice daily for long-term secondary prevention.
But while PEGASUS-TIMI 54 was a secondary prevention study in terms of cardiovascular events, it was actually a primary prevention study in terms of stroke, since patients with a history of stroke weren’t eligible for enrollment. And in this trial, recipients of ticagrelor at 50 mg twice daily experienced a 25% reduction in the risk of stroke relative to placebo, from 1.94% at 3 years to 1.47%. This benefit was driven by fewer ischemic strokes, with no increase in hemorrhagic strokes seen with ticagrelor. And therein lies a clinical take home point: “When evaluating the overall benefits and risks of long-term ticagrelor in patients with prior MI, stroke reduction should also be considered,” according to Dr. Bonaca of Brigham and Women’s Hospital, Boston.
All strokes were adjudicated and subclassified by a blinded central committee. A total of 213 stroke events occurred during follow-up: 81% ischemic, 7% hemorrhagic, 4% ischemic with hemorrhagic conversion, and 8% unknown; 18% of the strokes were fatal. Another 15% resulted in moderate or severe disability at 30 days. All PEGASUS-TIMI 54 participants were on aspirin and more than 90% were on statin therapy.
The strokes that occurred in patients on ticagrelor were generally less severe than in controls. The risk of having a modified Rankin score of 3-6, which encompasses outcomes ranging from moderate disability to death, was reduced by 43% in stroke patients on ticagrelor relative to those on placebo, the cardiologist continued.
To ensure that the stroke benefit with ticagrelor seen in PEGASUS-TIMI 54 wasn’t a fluke, Dr. Bonaca and his coinvestigators performed a meta-analysis of four placebo-controlled randomized trials of more intensive versus less intensive antiplatelet therapy in nearly 45,000 participants with coronary disease in the CHARISMA, DAPT, PEGASUS-TIMI 54, and TRA 2*P-TIMI 50 trials. A total of 532 strokes occurred in this enlarged analysis. More intensive antiplatelet therapy – typically adding a second drug to low-dose aspirin – resulted in a 34% reduction in ischemic stroke, compared with low-dose aspirin and placebo.
Excluding from the meta-analysis the large subgroup of patients in TRA 2*P-TIMI 50 who were on triple-drug antiplatelet therapy, investigators were left with 32,348 participants in the four trials who were randomized to dual-antiplatelet therapy or monotherapy with aspirin. In this population, there was no increase in the risk of hemorrhagic stroke associated with more intensive antiplatelet therapy, according to Dr. Bonaca.
Session co-chair Keith A.A. Fox, MD, of the University of Edinburgh, noted that various studies have shown monotherapy with aspirin or another antiplatelet agent reduces stroke risk by about 15%, and now PEGASUS-TIMI 54 shows that ticagrelor plus aspirin decreases stroke risk by 25%. He posed a direct question: “How much is too much?”
“More and more antiplatelet therapy begets more bleeding, so I think that more than two agents may be approaching too much, although it really depends on what agents you’re using and in what dosages,” Dr. Bonaca replied.
He reported serving as a consultant to AstraZeneca, Merck, and Bayer.
Simultaneous with Dr. Bonaca’s presentation at ESC 2016 in Rome, the new report from PEGASUS-TIMI 54 including the four-trial meta-analysis was published online (Circulation. 2016 Aug 30. doi: circulationaha.116.024637).