By: Ronik Saha, Pharm.D. Candidate c/o 2013
–
Clopidogrel (Plavix®) is a thienopyridine antiplatelet agent, which exerts its antiplatelet effects via in vivo conversion to an active thiol metabolite that irreversibly blocks the P2Y-12 component of platelet ADP receptors. This prevents activation of the GP2B/3A complex, thereby preventing platelet aggregation. Along with aspirin, clopidogrel reduces the rate of atherothrombotic events (e.g. myocardial infarction and stroke) in patients with acute coronary syndrome (ACS) with or without ST-segment elevation. Ticagrelor (Brilinta®) is a reversible antagonist of the P2Y-12 component of platelet ADP receptors that prevents activation of the GP2B/3A complex. Ticagrelor also reduces the rate of atherothrombotic events in patients with ACS with or without ST-segment elevation in conjunction with aspirin.1
The Platelet Inhibition and Patient Outcomes (PLATO) study sought to determine whether ticagrelor was superior to clopidogrel for the prevention of thromboembolic events and death in patients with ACS. The primary outcome measured in this study was death of study participants from cardiovascular or cerebrovascular causes. The primary endpoint occurred significantly less often in the ticagrelor group than in the clopidogrel group (in 9.8% of patients vs. 11.7% at 12 months; hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Furthermore, the hierarchical testing of secondary end points showed significant reductions in the ticagrelor group as compared to the clopidogrel group, with respect to the rates of the composite end point of death from any cause, myocardial infarction, or stroke (10.2% vs. 12.3%, P<0.001).1
The PLATO trial also examined the incidences of adverse reactions. First, the ticagrelor and clopidogrel groups did not differ significantly with regard to the rates of major bleeding, as defined in the trial (11.6% and 11.2%, respectively; P=0.43). The study showed that greater platelet inhibition with ticagrelor was not associated with an increase in the rate of any major bleeding. However, dyspnea was more common in the ticagrelor group than in the clopidogrel group (in 13.8% of patients vs. 7.8%). It is also important to note that discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, P<0.001).1
PLATO did indeed demonstrate that in patients with ACS, treatment with ticagrelor (compared to clopidogrel) significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke. It achieved this without a significant increase in the rate of major bleeding. However, several key factors will limit ticagrelor’s use in clinical practice. First, dyspnea is a serious adverse effect that can be very troublesome for patients, and PLATO showed that it occurred more frequently in patients on ticagrelor. Second, the package insert for Brilinta® states, “maintenance doses of aspirin above 100mg reduce the effectiveness of Brilinta® and should be avoided.”2 Other antiplatelet drugs, such as Plavix®, do not have this warning. This black box warning contraindicates the use of ticagrelor in patients who might require higher doses of aspirin to show a therapeutic effect in anticoagulation therapy. Third, the high cost of Brilinta® will most likely limit its use in patients; Plavix® will be available from generic manufacturers in May.3 Most insurance companies will probably be reluctant to place Brilinta® on their formularies, as well. As alluded above, Plavix® is a frequently prescribed medication and will soon be available as a generic.
Although ticagrelor does show an advantage over clopidogrel in terms of therapeutic efficacy, clopidogrel will most likely remain the drug of choice in preventing thromboembolic events in patients with ACS for years to come because of the cost and limitations to the use of ticagrelor.
SOURCES:
- Wallentin, Lars et al. “Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes”. N Engl J Med 2009; 361:1045-1057. Epub 2009 Sept 10.
- Brilinta (Package Insert). AstraZeneca, Wilmington, DE; July 2011
- Moisse, Katie. “10 Top-Selling Drugs Coming Off Patent”. ABC News Website Online. July 25, 2011. < http://abcnews.go.com/Health/Drugs/prescription-drug-prices-plummet/story?id=14152014#.Tx-GFPmwW1w> Accessed January 24, 2012.
