In the original PLATO (PLATelet inhibition and patient Outcomes) trial, 18,624 ACS patients were randomized to aspirin plus ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). Ticagrelor, a potent direct P2Y12 ADP receptor antagonist, reduced the rate of the primary composite endpoint of cardiovascular death, MI, or stroke without increasing overall major bleeding.

For the substudy, investigators led by Christopher P. Cannon, MD, of Brigham and Women's Hospital (Boston, MA), compared total ischemic and bleeding events between the treatment groups, including first and subsequent occurrences.

Ongoing Reduction in Ischemic Events

Over follow-up of 6 to 12 months, 1,888 patients suffered a primary endpoint event, and 318 patients experienced multiple occurrences of such events. Compared with clopidogrel, ticagrelor reduced the risk not only of the first occurrence of the primary endpoint but also of the second occurrence and the total number of occurrences, resulting in a number needed to treat (NNT) of 54. A similar pattern was seen for 2 other prespecified composite ischemic outcomes: the primary endpoint plus severe recurrent ischemia, recurrent ischemia, TIA, and arterial thrombotic events (NNT = 35), and the primary endpoint plus urgent revascularization (NNT = 47; table 1).

Table 1. Ischemic Outcomes with Ticagrelor vs. Clopidogrel^a

^a All P values < 0.001

In terms of safety, on-treatment analysis showed that rates of PLATO major bleeding were similar between therapies for first (HR 1.04; P = 0.43), recurrent (RR 1.02; P = 0.89), and total events (RR 1.03; P = 0.53), with subsequent bleeds relatively uncommon compared with initial bleeds in both arms. However, ticagrelor increased the total number of PLATO major or minor bleeds (RR 1.09; P = 0.02), with the difference driven by the first occurrence of the composite bleeding endpoint.

After a bleeding event, there were no differences between treatment groups in the percentage of patients who discontinued randomized therapy (eg, 10.8% for both after PLATO major or minor bleeding).

Overall Benefit Strengthened

The authors write that “when taking all events into account, the benefit of using ticagrelor in patients with ACS is even larger than previously reported with the protocol-based analyses focusing only on the first event.”

Moreover, they add, the data suggest that the bleeding risk with ticagrelor is highest initially and wanes after a first bleed, so patients who continue on ticagrelor after an initial event are relatively unlikely to develop recurrent bleeding.

Dr. Cannon and colleagues note that the results are consistent with the effects of more potent platelet inhibition with prasugrel vs. clopidogrel and intensive vs. standard statin therapy, with the more intensive strategy reducing both first and recurrent events.

“Clinically, these results have important implications for guiding physicians to continue ticagrelor therapy, rather than changing therapy to alternative agents, even for patients who may experience an event while on treatment,” the authors conclude. 

Study Details

A graded increase in the number of comorbidities and cardiac risk factors was observed among patients who experienced none, 1, or multiple events. Specifically, those with multiple events were more likely to be older, female, have diabetes, a history of MI or CABG, impaired renal function, and hypertension. With regard to the index ACS event, unlike STEMI patients, NSTEMI patients were more likely to experience multiple events (P < 0.001). 

Related Stories:

• Ticagrelor More Effective Than Clopidogrel in ACS—With No Extra Bleeding
• PLATO Substudy Shows Greater Platelet Inhibition with Ticagrelor vs. Clopidogrel
• PLATO Subanalysis: Ticagrelor Cost-Effective in ACS Patients