Acute Coronary Syndrome
Ticagrelor is used in combination with aspirin to reduce the risk of thrombotic cardiovascular events (e.g., cardiovascular death, myocardial infarction [MI]) in patients with an acute coronary syndrome (unstable angina, non-ST-segment-elevation MI [ NSTEMI], or ST-segment-elevation MI [ STEMI]) who are to be managed medically or with an invasive strategy (percutaneous coronary intervention [PCI] with or without coronary artery stent placement, coronary artery bypass grafting [CABG]). In a large, randomized study (The Study of Platelet Inhibition and Patient Outcomes [PLATO]) in patients with an acute coronary syndrome (ACS), ticagrelor was more effective than clopidogrel in reducing the rate of the composite end point of cardiovascular death, MI, or stroke without increasing the risk of major bleeding over that observed with clopidogrel. The benefits of ticagrelor over clopidogrel consisted principally of reductions in cardiovascular death and MI; there was no difference in the rate of stroke. Ticagrelor also was associated with a reduction in the rate of stent thrombosis in those undergoing PCI and a reduction in death from any cause. In this and other clinical studies, ticagrelor was given in conjunction with aspirin therapy.
Dual-drug antiplatelet therapy with a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin is part of the current standard of care in patients with ACS. The American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), the Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Chest Physicians (ACCP), and other experts recommend antiplatelet therapy with a P2Y12-receptor antagonist and aspirin for treatment and secondary prevention of ACS. These experts generally recommend ticagrelor or clopidogrel as the P2Y12-receptor antagonist in patients with ACS who are treated medically without stenting; because prasugrel has been studied principally in patients undergoing planned PCI, recommendations for the use of this drug are restricted to that population. In patients with ACS who are being managed medically, therapy with a P2Y12 receptor antagonist should be continued for up to 12 months, while aspirin should be continued indefinitely. In patients undergoing PCI with stent placement (bare-metal or drug-eluting), a loading dose of ticagrelor, clopidogrel, or prasugrel is recommended, followed by maintenance therapy with one of these agents for at least 12 months (unless the risk of bleeding outweighs the anticipated net benefit of therapy); aspirin also should be continued indefinitely in such patients.
The relative role of ticagrelor versus other P2Y12-receptor antagonists in the management of ACS remains to be fully established. While current ACCF/AHA guidelines make no recommendations regarding the P2Y12-receptor antagonist of choice, ACCP suggests the use of ticagrelor over clopidogrel in patients with ACS (who are or are not undergoing PCI). The European Society of Cardiology (ESC) generally recommends ticagrelor or prasugrel over clopidogrel in patients with non-ST-segment elevation ACS; according to ESC, clopidogrel should be considered an alternative in such patients unable to receive ticagrelor or prasugrel therapy. Other clinicians state that because of its reversibility and faster offset of action, ticagrelor may be preferred over the irreversible P2Y12-receptor antagonists (clopidogrel, prasugrel) in patients with ACS who are being managed with an early invasive strategy (e.g., those in whom coronary anatomy has not been determined and who are likely to undergo CABG); switching from clopidogrel or prasugrel to ticagrelor therapy 5-7 days prior to CABG is considered reasonable in such patients. Ticagrelor also may be a reasonable alternative in patients who are nonresponsive to clopidogrel based on studies demonstrating that ticagrelor not only inhibits platelet aggregation in clopidogrel nonresponders, but also produces greater inhibition of platelet aggregation than clopidogrel in patients who remain responsive to clopidogrel. When selecting an appropriate antiplatelet regimen for the management of patients with ACS, clinicians should consider individual risks of ischemia and bleeding as well as the specific characteristics (e.g., adverse effects, drug interaction potential) of the drugs.
The current indication for ticagrelor is based principally on an international, randomized, double-blind study (PLATO) in more than 18,000 patients hospitalized for ACS. The study compared efficacy and safety of ticagrelor versus clopidogrel in reducing the rate of death from vascular causes, nonfatal MI (excluding silent MI), or nonfatal stroke in these patients. Because the study was designed to evaluate patients at hospital presentation or diagnosis (''upstream''), patients with various types of ACS were enrolled, including those with NSTEMI in whom conservative or invasive management was planned and those with STEMI undergoing primary PCI. Approximately 50% of patients were pretreated with clopidogrel prior to randomization; PCI was performed in about 64% of the patients and approximately 10% underwent CABG. Within 24 hours of symptom onset and before PCI, patients received either ticagrelor (180-mg loading dose followed by 90 mg twice daily) or clopidogrel (300-mg loading dose followed by 75 mg daily) in addition to aspirin and other standard therapy; treatment was continued for at least 6 months up to a maximum of 12 months. Those undergoing PCI received an additional loading dose of study drug at the time of PCI (90 mg of ticagrelor if more than 24 hours had passed since the initial loading dose or 300 mg of clopidogrel at the investigator's discretion). Aspirin was administered to all patients in the study at a recommended loading dose of 160-500 mg and daily maintenance dosage of 75-100 mg; higher maintenance dosages (e.g., 325 mg daily for 6 months following stent placement) were permitted based on clinician judgment.
In the PLATO study, ticagrelor substantially reduced the rate of the primary composite end point of cardiovascular death, nonfatal MI, or nonfatal stroke compared with clopidogrel. The primary outcome occurred in 9.8% of patients receiving ticagrelor compared with 11.7% of those receiving clopidogrel, a relative risk reduction of 16%. The difference in treatment effect was apparent by 30 days and maintained throughout the 12-month study period. The benefit associated with ticagrelor was based on a reduction in the incidence of cardiovascular death and MI, but not stroke. Although the overall rate of stroke was similar between the treatment groups, hemorrhagic strokes were more frequent in patients receiving ticagrelor. Among patients who received a coronary artery stent during the study, the rate of stent thrombosis was substantially lower with ticagrelor than with clopidogrel regardless of the type of stent (bare-metal or drug-eluting) implanted. In addition, death from any cause was reduced with ticagrelor (1.4% absolute reduction, 22% relative reduction). Some experts state, however, that additional study is needed to confirm this mortality benefit since all-cause mortality was not evaluated as a primary outcome in the PLATO study. The overall rate of major bleeding was similar for patients who received ticagrelor or clopidogrel; however, ticagrelor was associated with a higher incidence of non-CABG related major bleeding, including fatal intracranial bleeding.
In the PLATO study, clinical outcomes with ticagrelor generally were consistent across subgroups of patients with ACS regardless of whether a conservative or invasive management strategy was employed and regardless of the type of antiplatelet therapy received prior to the index ACS event. However, the benefits of ticagrelor appeared to be reduced in patients enrolled in North America compared with those enrolled in other regions. Results of additional statistical analyses of a variety of baseline and procedural differences between the US and non-US regions identified aspirin maintenance dosage as a possible factor accounting for this regional discrepancy. These analyses showed that ticagrelor was associated with a more favorable response than clopidogrel in patients receiving low (100 mg or less daily) maintenance dosages of aspirin. This was seen in both US and non-US patients; however, substantially more (about 54%) US patients were treated with aspirin dosages exceeding 300 mg daily, whereas patients in other countries rarely (only about 2% of patients) received such high aspirin dosages. Because of inherent limitations of subgroup analyses and the possibility that the effect of aspirin dosage on ticagrelor outcome could be due to chance, these findings should be interpreted with caution. Nevertheless, the manufacturer states that aspirin dosage should be limited to 75-100 mg daily in patients receiving ticagrelor; higher dosages do not have an established benefit in the management of ACS and may be associated with reduced efficacy of ticagrelor.