Author + information
- Somjot S. Brar, MD, MPH∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Somjot S. Brar, Kaiser Permanente Los Angeles Medical Center, 4867 Sunset Boulevard, 3rd Floor, Room 3755, Los Angeles, California 90027.
- coronary artery disease
- percutaneous coronary intervention
- platelet aggregation inhibitors
- risk factors
The optimal duration of dual antiplatelet therapy remains uncertain. Recent data have suggested that, in some patients, dual antiplatelet therapy for a total of 30 months from the time of percutaneous coronary intervention (PCI) may be of benefit (1). However, the benefit of dual antiplatelet therapy in other high-risk patient populations, such as those with a history of myocardial infarction, remains less clear. It is plausible that patients with previous myocardial infarction would be at high risk for future cardiovascular events, including reinfarction, such that they would benefit from longer-term dual antiplatelet therapy.
This hypothesis was explored in the 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, in which 21,162 high-risk patients who had a myocardial infarction 1 to 3 years earlier were randomized in a 1:1:1 ratio to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo (2). Both doses of ticagrelor decreased the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke while increasing the risk for TIMI (Thrombolysis In Myocardial Infarction) major bleeding. For the 90-mg dose, the absolute risk difference for the composite ischemic primary endpoint was −1.19%, favoring ticagrelor over placebo, and the incidence of TIMI major bleeding was 1.54%, favoring placebo over ticagrelor. For the 60-mg dose, the absolute risk difference for the ischemic primary endpoint was −1.27%, favoring ticagrelor, and the incidence of TIMI major bleeding was 1.24%, favoring placebo. Thus, if the ischemic and bleeding primary endpoints are given equal weight, 90 mg of ticagrelor twice daily in this patient population results in a small net harm. In contrast, the 60-mg dose of ticagrelor yields a net absolute benefit of −0.03% compared with placebo. This equates to a number needed to treat for a net clinical benefit of 3,333 patients. It is important to note that patients at heightened risk for bleeding, such as those with prior stroke, recent bleeding, or need for oral anticoagulants, were excluded from the trial. On the basis of these observations and assumptions, it is plausible that ticagrelor would not have benefit in high-risk patients with a history of myocardial infarction and higher than average bleeding risk. Moreover, one may reasonably conclude that ticagrelor 90 mg would be challenging to use in this same population, given that the rate of major bleeding slightly exceeds the reduction in ischemic events. The decision to treat will, of course, depend upon patient preferences, underlying risks, and weights given to ischemic and major bleeding events.
In this issue of the Journal, Storey et al. (3) report the pharmacokinetic and pharmacodynamic effects of ticagrelor 90 mg versus 60 mg twice daily in 180 patients treated for more than 4 weeks from the PEGASUS trial. This substudy provides novel and important insights into the findings of the main trial. Blood samples were obtained in the morning prior to the maintenance dose and again 2 h later. All patients were treated with aspirin 75 to 150 mg daily. Plasma levels of ticagrelor and its active metabolite were measured, as was platelet function using multiple methods.
Storey et al. (3) report that ticagrelor 60 and 90 mg both had similar mean pre-maintenance dose platelet reaction units: 59 ± 63 and 47 ± 43, respectively. This was despite the ticagrelor levels in the 60-mg group being approximately two-thirds of those in the 90-mg group. Moreover, platelet reactivity pre- and post-maintenance dose, measured according to the various assays, was not significantly different between doses. For example, high platelet reactivity, defined as platelet reaction units >208, was very infrequent with 60 mg for the pre-maintenance dose (3.5% or 2 patients) and was absent post-dose. There was only slight variability in platelet reactivity in the 60-mg group compared with the 90-mg group, which the authors hypothesized may have been due, in part, to noncompliance by a small number of patients. In summary, these results provide important mechanistic insight into why the ischemic events in the trial were similar between the 60- and 90-mg doses.
These data also raise questions as to whether the 60-mg dose is the optimal dose and should be the focus of further investigation. The clinically relevant pharmacokinetics and pharmacodynamics of the 60-mg dose, as characterized in this platelet substudy, are not significantly different than the 90-mg dose of ticagrelor. There were no significant differences between doses in platelet reactivity across multiple assays. Moreover, the 60-mg dose was better tolerated, yielding greater compliance; discontinuation for dyspnea was lower for the 60-mg dose (4.55% vs. 6.5%; p < 0.001). Given a marginally lower risk of bleeding, no significant difference in platelet reactivity, better tolerability, and similar reduction in ischemic events, ticagrelor 60 mg twice daily is the preferable dose in this population. This observation alone warrants a reassessment of the preferred ticagrelor dose in other populations.
In the PEGASUS trial, patients had to have a history of myocardial infarction and 1 additional risk factor for inclusion: age 65 years or older; diabetes mellitus; multivessel coronary artery disease; or chronic renal dysfunction. Despite the heightened ischemic risk, the net clinical benefit was slight in this cohort, suggesting that general predictors of increased ischemic risk may not be sufficient to identify patients likely to realize a more robust net clinical benefit from long-term dual antiplatelet therapy.
The Chinese concept of yin-yang describes seemingly opposite forces, extrapolated here to refer to the prevention of ischemic events and avoidance of bleeding complications, which are actually interdependent. As such, the present data show that we are reaching a threshold benefit with P2Y12 inhibitors; that is, further platelet inhibition yields increased major bleeding, which negates any reduction in ischemic events. The data by Storey et al. (3), along with the findings of the main study, highlight the importance of identifying better methods for risk stratification at the patient and population level for both ischemic and bleeding events. Populations with very high ischemic risk have been described. Some of these may be suitable candidates for long-term dual antiplatelet therapy. For example, patients undergoing percutaneous coronary intervention of a saphenous vein graft have an approximately 10% to 30% rate of death or myocardial infarction within 2 years and 35% to 50% at 5 years from the index procedure (4). Moreover, the event rates appear to be correlated to the duration of dual antiplatelet therapy. The bleeding risk in this setting is unlikely to exceed the rate of ischemic events at 2 and 5 years. Thus, the challenge now is how to identify these very high-risk populations so that patients likely to benefit from prolonged dual antiplatelet therapy are targeted for treatment. Building the evidence base for each high-risk cohort may be a challenge. Clinical trials may not be feasible in each high-risk population, but a clinical trial utilizing a suitable risk prediction algorithm could be accomplished.
Newer, more robust methods of risk prediction, such as machine learning, that consider more candidate variables and can be incorporated into electronic health records may provide the needed balance between complexity of the prediction algorithm and ease of use from the health care provider’s perspective (5,6). Moreover, this information would have the greatest effect if provided at the point of care (7). These challenges can be overcome, and in doing so, we have the potential to further personalize care and improve outcomes by identifying and treating those most likely to benefit from long-term dual antiplatelet therapy.
↵∗ 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. Brar has reported that he has no relationships relevant to the contents of this paper to disclose.
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