A New Antiplatelet Agent for Patients with ACS
Abstract & Commentary
By Andrew J. Boyle, MD, PhD
Source: Wallentin L, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:e-pub ahead of print.
Dual antiplatelet therapy with aspirin and clopidogrel has become the standard of care for patients suffering an acute coronary syndrome (ACS). However, there remains a significant incidence of recurrent ACS and mortality even in patients treated with dual antiplatelet therapy. Furthermore, clopidogrel is an irreversible platelet inhibitor, and patients requiring urgent surgery are at higher risk of bleeding if operated on within 5-7 days of clopidogrel use. There remains a need for more effective platelet inhibition with a reversible antiplatelet agent. Ticagrelor is an orally active antiplatelet drug that acts on the P2Y12 ADP receptor on the platelet surface (the same receptor targeted by clopidogrel) to produce a more efficient platelet inhibition than clopidogrel, which is also reversible. Wallentin et al performed a large, multi-center, randomized, controlled, double-blind trial, the PLATO study, to compare ticagrelor and clopidogrel in patients presenting with ACS.
Enrollment criteria were ST elevation myocardial infarction (STEMI) and non-ST elevation ACS (NSTEACS) with high-risk features. High-risk NSTEACS were ones with at least two of the following: ST segment deviation, elevated biomarkers, or at least one risk factor (age > 60, prior myocardial infarction [MI], CABG or stroke, known coronary artery disease [CAD] or cerebrovascular disease with > 50% stenosis, diabetes, peripheral arterial disease, or chronic renal impairment). Exclusion criteria were contraindication to antiplatelet therapy, need for anti-coagulation, increased risk of bradycardia, and concomitant therapy with strong cytochrome P450 3A inhibitors or inducers. Patients were randomly assigned to receive ticagrelor (180 mg loading dose, followed by 90 mg bid; n = 9,333) or clopidogrel (300 mg loading dose if naïve, followed by 75 mg daily; n = 9291). Medications were administered a median of five hours after admission and 11 hours after onset of symptoms. All patients also received aspirin (preferred loading dose 325 mg, followed by 75-100 mg daily). Those undergoing percutaneous coronary intervention (PCI) received an extra dose of drugs at the time of the procedure (ticagrelor 90 mg or clopidogrel 300 mg).
The primary endpoint, a composite of vascular death, MI, and stroke, occurred in 9.8% of the ticagrelor group and 11.7% of the clopidogrel group at 12 months (hazard ratio 0.84; p < 0.001). There were multiple pre-defined secondary endpoints in this study. For patients undergoing invasive management strategy, ticagrelor resulted in lower primary endpoint (8.9% vs. 10.6%; p = 0.003), and lower rate of stent thrombosis (1.3% vs. 1.9%; p = 0.009). Compared to clopidogrel, ticagrelor resulted in lower rates of MI (5.8% vs. 6.9%; p = 0.005), vascular death (4.0% vs. 5.1%; p = 0.001), and total mortality (4.5% vs. 5.9%; p < 0.001). There was no difference in stroke rate between groups, but a trend toward higher hemorrhagic stroke in the ticagrelor group (0.2% vs 0.1%; p = 0.10). There was no difference between groups in major bleeding, fatal or life-threatening bleeding. However, the ticagrelor group had higher non-CABG-related major bleeding (4.5% vs 3.8%; p = 0.03) and fatal intracranial bleeding (0.1% vs. 0.01%; p = 0.02). On the other hand, the ticagrelor group had fewer episodes of other types of fatal bleeding (0.1% vs. 0.3%; p = 0.03).
Ticagrelor was not without side effects. Dyspnea was more common with ticagrelor (13.8% vs. 7.8%; p < 0.001), as was a rise in serum creatinine (11% vs. 9%; p < 0.001) and serum uric acid (15% vs. 7%; p < 0.001). There was also an increase in ventricular pauses > 3 seconds in the first week (5.8% vs. 3.6%; p = 0.01), but this was no longer apparent at 30 days, and there was no difference in the rates of bradycardia, syncope, heart block or requirement for pacemaker. Discontinuation of the drug for adverse effects was more common with ticagrelor (7.4% vs. 6.0%; p < 0.001). Wallentin et al conclude that in patients presenting with ACS, with or without ST elevation, treatment with ticagrelor compared to clopidogrel significantly reduced the rate of death from vascular causes, MI, or stroke without an increase in the overall incidence of bleeding, but with an increase in the rate of non-procedure-related bleeding.
The results of the PLATO study presented at the recent European Society of Cardiology meeting, and simultaneously published in the New England Journal of Medicine, demonstrate a significant reduction in the incidence of vascular death, MI, and stroke, with no appreciable increase in bleeding risk using ticagrelor compared to clopidogrel in patients with ACS. This is a very large study (> 18,000 patients) with robust endpoints that were consistent across multiple subgroups tested. Multiple secondary and exploratory endpoints were also consistent. With recent concerns regarding clopidogrel resistance, we welcome newer therapies that can reduce ischemic complications in patients presenting with ACS. Importantly, those undergoing invasive or non-invasive strategies seemed to benefit to similar degrees with the use of ticagrelor over clopidogrel. These results challenge the doctrine that more effective antiplatelet action must be accompanied by increased bleeding risk.
Although the reduction in ischemic endpoints is promising, several issues should be noted. Firstly, in subgroup analysis, the benefits of ticagrelor over clopidogrel appeared to be attenuated in the North American cohort for unknown reasons. Secondly, ticagrelor can produce bradycardia, so patients at risk for bradycardia were excluded from the study, as were patients taking strong cytochrome P450 inhibitors or inducers. However, the use of ticagrelor did not translate into a higher rate of bradycardia, and similar numbers of patients were able to be treated with beta-blockers in each group. Thirdly, Ticagrelor was associated with a higher discontinuation rate for adverse events and patient preference. In addition, it is a twice-daily drug, which may also lower patient compliance. Caution must be exercised in patients in whom poor compliance may be catastrophic, such as those at high risk for stent thrombosis with multiple drug-eluting stents. Fourthly, the mean exposure to the study drug was only 277 days in each group; thus, the long-term differences between ticagrelor and clopidogrel remain unknown. Finally, ticagrelor does not have FDA approval for use in the United States at this time.