Author + information
- aInova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, Virginia
- bSystematic Investigation and Research on Interventions and Outcomes (SIRIO) MEDICINE Research Network, Falls Church, Virginia
- cAcademic Medical Center-University of Amsterdam, Naarden, the Netherlands
- ↵∗Address for correspondence:
Dr. Eliano P. Navarese, Inova Heart and Vascular Institute, 3300 Gallows Road, Falls Church, Virginia 22042.
Dual antiplatelet therapy (DAPT) with acetylsalicylic acid and a P2Y12 receptor inhibitor is the mainstay of secondary prevention in patients with acute myocardial infarction (MI) (1). Ticagrelor is a potent, reversibly binding, direct-acting P2Y12 receptor antagonist with established efficacy for the first year after MI. Despite treatments for secondary prevention, patients with previous MI remain at high risk for recurrent thrombotic events (2). Post hoc analyses have suggested that the addition of clopidogrel to aspirin has resulted in benefit for certain patient subgroups, including those with a history of MI (3,4). These findings have delineated a potential benefit of long-term DAPT in specific subgroups of patients at high risk of ischemic events. The recent PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial (5) determined whether the benefit of ticagrelor extended to patients with a previous MI. In this study, 21,162 patients with a history of spontaneous MI that occurred 1 to 3 years before enrollment were randomized to 3 arms, all on a background of low-dose aspirin, ticagrelor 90 or 60 mg twice a day, or placebo. Median follow-up was 33 months. Both doses of ticagrelor, each compared with placebo, significantly reduced the primary endpoint of cardiovascular death, MI, or stroke. Major and minor bleeding rates significantly increased. The U.S. Food and Drug Administration (FDA) ultimately approved ticagrelor at the 60 mg dose to be used in patients with a history of MI beyond the first year.
In this issue of the Journal, Magnuson et al. (6) present a timely economic analysis from the U.S. health care perspective of the cost effectiveness of ticagrelor therapy beyond 1 year in patients with previous MI based on patient-level cost and outcome data prospectively collected alongside the PEGASUS-TIMI 54 trial. Several analytical methods were applied to project long-term survival, cost, and cost effectiveness of using a FDA-approved lower dose ticagrelor regimen (60 mg twice daily) beyond 1 year after MI, rather than aspirin alone. Medical resource use data were collected over a median 33-month follow-up.
Their findings indicated that ticagrelor at a dose of 60 mg twice daily for up to 3 years in conjunction with low-dose aspirin was associated with an increase in quality-adjusted life expectancy of 0.078 years and incremental costs of $7,435, which yielded an incremental cost-effectiveness ratio (ICER) of $94,917 per quality-adjusted life expectancy years (QALYs) gained, compared with aspirin alone. In this analysis, high-risk groups had more favorable ICERs, including patients with diabetes, renal dysfunction (all with ICERs $50 to $70K/QALY gained), patients age <75 years (ICER: $44,779/QALY gained), and patients with peripheral artery disease (ICER: $13,427/QALY gained). Hospitalization costs were similar for ticagrelor and placebo.
Cost-effectiveness studies influence the coverage, reimbursement, and use of many cardiovascular health technologies; therefore, these studies merit careful evaluation. DAPT with aspirin and a P2Y12 inhibitor reduces ischemic recurrences in patients with coronary artery disease treated with coronary stents. However, this benefit is counterbalanced by higher bleeding risk, which is linearly related to the treatment duration (1). Thus, both ischemic and bleeding risks have the potential to negatively affect prognosis. Intensification of antiplatelet therapy, with the addition of a P2Y12 inhibitor to aspirin monotherapy, and prolongation of DAPT, warrants a tradeoff between decreasing ischemic risk and increasing bleeding risk.
Bleeding liability should be therefore considered when planning a contemporary economic evaluation of an antiplatelet treatment. At variance with previous economic analyses that have overlooked the impact of bleeding on survival and related costs, Magnuson et al. elaborated on an economic model that was calibrated with the incorporation of bleeding. As a result, in the base case model, the ICER for ticagrelor versus placebo was $94,917/QALY gained, which is >$50,000/QALY gained, which is regarded as the best benchmark for assessing the cost effectiveness of an intervention. In the analysis from the entire study cohort, ticagrelor therefore had only an intermediate value in light of the increased long-term bleeding rates. To generate some uncertainty, the analysis of outpatient care costs that might have biased findings in favor of ticagrelor due to the higher bleeding rates in the outpatient population on ticagrelor treatment was excluded. Despite the strengths of this study, an intrinsic limitation was that incremental cost effectiveness is always defined relative to an alternative; in the current study, ticagrelor was compared with placebo and not with an active treatment. The results of post hoc analyses in the clopidogrel era (3,4) suggest a class effect of long-term P2Y12 inhibition among patients with previous MI. Clopidogrel has been available as a generic medication since 2012 and is less expensive than ticagrelor. As a consequence, it is possible to predict that the estimated cost per ischemic event avoided differs by nearly 45-fold between the 2 alternatives.
Because the ICER involves a tradeoff between dollars spent and health benefits gained, the ranges of benefit reflect the current willingness of society to pay for a specific benefit, and therefore, they are a matter of public policy rather than a scientifically based assessment of true cost effectiveness. For example, costs associated with bleeding admissions tended to be lower than costs associated with cardiovascular admissions because the costs applied to the hospitalizations were diagnosis-related, group-specific Medicare reimbursement rates for the type of event observed.
Aside from economic considerations, a prominent question is how the results of this analysis could be applied to real-world practice. The study was modeled based on the inclusion criteria of the original PEGASUS trial. In the study, patients with a previous gastrointestinal bleed were excluded. Subjects enrolled had to have ≥1 additional atherothrombotic risk factor. Therefore, the population evaluated in the PEGASUS trial could not represent the entire population of patients in clinical practice. In a recent study that applied the PEGASUS trial eligibility criteria to the national ACTION Registry–GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry–Get with the Guidelines), only less than one-half of all patients with MI met the PEGASUS eligibility criteria (7).
However, the analysis by Magnuson et al. has the merit to implement the concept of a net clinical benefit approach in an economic evaluation model by weighing the ischemic benefit associated with ticagrelor with the bleeding risk and associated costs. Based on the results of the current study, from a cost-effective perspective, it appears reasonable to continue ticagrelor beyond 1 year in the patients with only the highest ischemic risk. These findings highlight the importance of careful scrutiny of eligibility as applied to individual patients in routine practice.
The contribution by Magnuson et al. provides a more granular understanding of the cost-effectiveness ratio of ticagrelor beyond 1 year after MI; yet, this is not the end of the saga. Like most medical treatments, antiplatelet therapy is associated with heterogeneity in benefit; a nonpatient-centered strategy is intrinsically inefficient in terms of cost, safety, and outcomes. As we enter the era of personalized medicine, treatment decisions can be tailored to the level of risk of individual patients, and the anticipated benefits costs and adverse effects from added therapy. For example, to optimize antiplatelet strategies, Markov models were recently developed that compared the cost effectiveness of different strategies (CYP2C19*2 genotype-guided antiplatelet strategy vs. the empiric use of antiplatelet therapies); in 1 study (8), genotype-guided therapy was less costly and more effective than clopidogrel and prasugrel.
It is our opinion that future studies should be directed to the generation of personalized medicine models that ultimately integrate the demographic characteristics, biological data, and genomic information of patients. These models should target antiplatelet therapy with the potential to usher in a new era of individualized treatment strategies that maximize the clinical efficacy while minimizing bleeding complications and associated costs.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Navarese has received speaker fees from Sanofi-Regeneron and Amgen; and grants from Amgen. Dr. Tijssen has reported that he has no relationships relevant to the contents of this paper to disclose.
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