By Jeffrey Zimmet, MD, PhD
SOURCES: Cowper PA, et al. Economic analysis of ticagrelor therapy from a U.S. perspective: Results from the PLATO study. J Am Coll Cardiol 2015;65:465-476; Kazi DS, Hlatky MA. A delicate balance: The cost effectiveness of new antiplatelet agents [editorial]. J Am Coll Cardiol 2015;65:477-479.
The PLATO trial randomized more than 18,000 acute coronary syndrome (ACS) patients to dual anti-platelet therapy with aspirin plus either clopidogrel or the newer P2Y12 inhibitor ticagrelor. Compared with clopidogrel-treated patients, those on ticagrelor had lower rates of death and myocardial infarction at 1 year. Despite superior ischemic outcomes, both ticagrelor and the thienopyridine prasugrel have been relatively slow to be adopted in the United States. This is at least in part due to the cost differential, as the older clopidogrel is available as a generic, while the newer agents enjoy continued brand exclusivity. The National Average Drug Acquisition Cost data collected by CMS currently reports a 70-fold difference in price between clopidogrel and ticagrelor.
In this prospectively designed cost-effectiveness analysis, the authors used U.S. estimates of resource use and associated costs, but employed effectiveness data from the trial as a whole. Recall that the 1400 or so U.S. patients did not show the same degree of benefit from ticagrelor compared with patients in the rest of the world. In post-hoc analyses, higher average maintenance doses of aspirin in North American patients were identified as a potential modifier, leading to the FDA black box warning against use of aspirin doses > 100 mg in combination with ticagrelor. The authors made the assumption that the use of low-dose aspirin would produce similar reductions in clinical events among U.S. patients, as in the overall PLATO trial.
During the index hospitalization, costs were similar between groups, with comparable degrees of revascularization and no significant difference in mean number of readmissions. No significant difference in non pharmaceutical medical expenditures was noted between groups. A lifetime extrapolation model projected that life expectancy of ticagrelor patients would exceed that of clopidogrel patients by 0.14 quality-adjusted life years (QALYs), or 2.6 months. Based on an incremental drug cost of $2172 for ticagrelor vs generic clopidogrel for 12 months, they calculated the incremental cost-effectiveness ratio (ICER) for ticagrelor compared with clopidogrel of $29,665/QALY. In this analysis, ticagrelor appeared to be more cost effective in patients who underwent invasive revascularization ($27,331/QALY) than among patients who were managed conservatively ($47,068/QALY).
Using commonly accepted willingness-to-pay thresholds of $50,000 and $100,000/quality-adjusted life-year, the authors concluded that the additional costs of improved life expectancy with ticagrelor compare favorably with accepted standards for medical interventions in the United States.
This is an interesting study that addresses a central point regarding value in health care. When newer, more costly therapies become available, cost effectiveness is all too easy to overlook in the metrics of treatment decisions.
It is important to note several things about this study. The first involves the PLATO study itself, and the apparent paradox wherein U.S. patients did not show the same relative benefit of ticagrelor (indeed, when analyzed separately they did not show benefit at all) compared with the rest of the world. The FDA has adopted the judgement of the post-hoc analysis that concluded that higher aspirin doses among North American patients were responsible for this effect, and, therefore, the approval for ticagrelor carries a warning against use in combination with doses of aspirin > 100 mg. Although this study assumes the level of benefit from PLATO as a whole, there is no guarantee that this will occur in U.S. patients taking the lower aspirin dose.
In an accompanying editorial, Drs. Kazi and Hlatky note that we should use caution extrapolating the results of a randomized trial to real-world practice. The twice-daily dosing of ticagrelor, along with the higher noted rate of subjective dyspnea, may well have effects on medication adherence that will be more marked outside the context of a clinical trial, for example. They also discuss the fact that alternative agents such as prasugrel, and varying strategies such as individualized assessment with genotyping or platelet function testing of clopidogrel’s likely efficacy need to be considered. As they point out, “Incremental cost effectiveness is always defined relative to an alternative, and the PLATO study examined only one of the many strategies for post-ACS antiplatelet use.”
Although these estimates should ultimately be revised with post-marketing real world data, for now, this study provides reassurance that ticagrelor hits generally accepted metrics for U.S. cost effectiveness, and treatment decisions may be made based on the best available clinical data.