Author + information
- Robert J. Applegate, MD∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Robert J. Applegate, Section of Cardiovascular Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1045.
In today’s practice a growing emphasis has been placed on the risk of bleeding arising from therapies aimed at suppressing thrombotic and ischemic events after percutaneous coronary intervention (PCI), particularly in patients requiring concomitant oral anticoagulant therapy (OAC). In an ideal world reduction of both thrombosis and ischemic risks would be achieved with minimal bleeding and with a single medication. Currently, however, dual-antiplatelet therapy (DAPT) is needed for patients undergoing stenting, and is superior to anticoagulation for this indication, and OAC is needed to reduce the thrombotic risk from conditions such as atrial fibrillation and mechanical heart valves, whereas DAPT or a P2Y12 inhibitor is not as effective. Because the need for OAC in patients undergoing stent placement is not infrequent, the need for triple anticoagulant therapy (TAT) (i.e., DAPT and OAC) is common. Unfortunately, these patients are exposed to a higher bleeding risk as a result of the combination therapy that often makes optimal management challenging. At the end of the day, the clinician is forced to walk a tightrope between the need to reduce thrombosis and ischemia while minimizing bleeding risk in patients requiring TAT. However, there are only limited randomized clinical data to guide decision making in these patients.
The ISAR-TRIPLE (Triple Therapy in Patients on Oral Anticoagulation after Drug Eluting Stent Implantation) trial randomized 604 patients to 6 weeks versus 6 months of TAT after PCI with drug-eluting stents (DES), achieved by discontinuing clopidogrel at these time points (1). The primary study endpoint was a composite of death, myocardial infarction (MI), definite stent thrombosis, stroke or Thrombolysis In Myocardial Infarction (TIMI) major bleeding. At 9 months, the primary composite endpoint occurred in 9.8% of patients treated with 6 weeks of TAT, and in 8.8% of those receiving 6 months of TAT (hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 0.68 to 1.91; p = 0.63). Secondary endpoints of thrombotic and ischemic events, and bleeding, were also similar for the 2 groups. The authors concluded that the shorter duration of TAT was not superior to 6 months of TAT. However, many have interpreted this study to indicate that short term TAT is preferable to longer term TAT, particularly in patients at high risk for bleeding. Taking a somewhat different approach, the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) trial evaluated the impact of omitting aspirin in patients requiring antithrombotic therapy after stent placement and compared OAC plus clopidogrel therapy to TAT (2). The primary study endpoint was any bleeding to 1 year after PCI, which occurred in 19.4% of OAC plus clopidogrel patients (n = 279), and 44.6% of TAT patients (HR: 0.36; 95% CI: 0.26 to 0.50; p < 0.001). A composite ischemic endpoint of death, MI, stroke, target revascularization, and stent thrombosis occurred in 11.1% of double therapy and 17.6% of TAT (HR: 0.56; 95% CI: 0.35 to 0.91; p = 0.025). The reduction in both bleeding and ischemic events in the WOEST trial was somewhat unanticipated, given the belief that DAPT is necessary in the first month after stenting and in light of the results of the ISAR-TRIPLE trial (i.e., no difference in bleeding). Nonetheless, these results are intriguing. However, they also point out how much there is to learn about identifying the most important factors influencing thrombotic, ischemic as well as bleeding events in patients requiring TAT. Current guidelines recommend minimizing the duration of TAT in patients requiring DAPT for stents and concomitant OAC but the optimal duration and combination of TAT remains unclear.
In this issue of JACC: Cardiovascular Interventions, Koskinas et al. (3) provide observations from the Bern PCI registry of prospectively collected clinical outcomes data on 8,772 consecutive patients undergoing PCI. A total of 568 of these patients had an indication for OAC, and these investigators stratified clinical outcomes by duration of TAT: 43% were discharged on a regimen of 1 month of TAT and 57% on a regimen of more than 1 month of TAT (median 3 months). The primary endpoint was a composite of cardiac death, MI, stroke, definite stent thrombosis or TIMI major bleeding within 1 year of follow-up. As the authors describe, this “natural dichotomization” was a result of following clinical guidelines and practice in which higher bleeding risk patients were treated with shorter duration of TAT. This contention is supported by the clinical baseline characteristics of the patients receiving 1 month of TAT: they were more commonly female, had higher HAS-BLED scores (hypertension, abnormal liver or renal function, stroke or thromboembolism, bleeding history, elderly >age 65, drug consumption, or alcohol abuse), and less often received a DES. In multivariable analyses the composite primary endpoint occurred in 9.5% of 1 month TAT patients, and in 12.9% of longer TAT patients (HR: 1.007; 95% CI: 0.56 to 2.06; p = 0.84). The secondary composite ischemic endpoint (cardiac death, MI, stroke or definite stent thrombosis) between the 2 groups was similar with a HR of 1.12 (95% CI: 0.55 to 2.29; p = 0.76), as was the composite secondary bleeding endpoint (Bleeding Academic Research Consortium bleeding ≥3, or TIMI major bleeding; HR: 0.62; 95% CI: 0.21 to 1.80; p = 0.37). These results were consistent in stratified analysis in patients with acute coronary syndrome (ACS) (vs. non-ACS) as well as those undergoing PCI with DES (vs. BMS). The authors concluded that 1 month of TAT, used preferentially in patients with higher estimated bleeding risk, was associated with similar net clinical outcomes compared with longer TAT durations, up to 1 year of clinical follow-up.
Although adequately powered randomized clinical trials provide the strongest data to help shape practice, the clinician is often faced with substantial gaps in knowledge when trying to decide on optimal therapy in any single patient. The findings from the Bern PCI registry support the strategy of limiting TAT to 1 month in patients with high bleeding risk who require OAC after coronary stenting: bleeding comparable to a more prolonged period of TAT (although in patients at lower risk of bleeding) without an increase in ischemic events. However, given the observational nature of these findings these results should be viewed as hypothesis generating, as acknowledged by the authors. In addition to the nonrandomized nature of the study there are a couple of aspects of the study that merit discussion and may have an impact on the ability to generalize these observations. First, cessation of TAT was most often achieved by discontinuing the P2Y12 inhibitor in both groups (85% in the short TAT group, 92% in the longer TAT group) (L. Raber, personal communication, May 2016), similar to the ISAR-TRIPLE trial. This is an important point as there are insufficient data to date indicating whether or not cessation of aspirin or a P2Y12 inhibitor is the optimal strategy in patients receiving DES requiring concomitant OAC therapy. Moreover, it is not clear that outcomes in patients receiving the newer P2Y12 inhibitors ticagrelor or prasugrel would be similar to those in patients receiving clopidogrel requiring OAC therapy. Only limited data are available indicating that use of prasugrel as part of TAT is associated with a higher bleeding risk. Second, there were disparities of use of DES versus BMS between the 2 groups with BMS and standalone percutaneous coronary angioplasty used in 50% of 1 month TAT patients, but in only 9.3% of longer TAT patients. Additionally, there was a substantial difference in the type of DES used between the 2 groups. Whether or not these disparities had an impact on the study observations is unclear but it certainly gives one pause in attempting to translate the findings beyond the study population.
Clinical investigation of the optimal approach to the patient requiring both DAPT and OAC is complicated by many factors, including the nonuniform distribution of ischemic risk after stenting, as well as an uncertain effect of the type and intensity of anticoagulation on the bleeding risk. The risk of stent thrombosis and ischemic events post-PCI is highest in the first month after PCI, and is strongly influenced by clinical presentation. Patients with ST-segment elevation MI have substantially higher early stent thrombosis rates than patients with stable ischemic heart disease. Moreover, the complexity of coronary disease, stent type, and comorbid illnesses also influence the risk of stent thrombosis and these affects may not be simply additive. In contrast, the risk of thrombotic events such as stroke in patients with atrial fibrillation, as well as the bleeding risk in patients requiring OAC is more consistent across time. Use of OAC carries with it a cumulative risk determined by the duration of the need for, and intensity, of anticoagulant therapy. The use of novel oral anticoagulant agents introduces yet another variable in this complex milieu. With such a complex interaction of the risk of thrombotic and ischemic events, as well as that of bleeding, it is not surprising that identifying the definitive duration of optimal TAT in patients requiring both OAC and DAPT has been uncertain.
Two large randomized clinical trials are now enrolling patients to help shed light on the optimal duration, and combination of antiplatelet and OAC to be used in patients requiring TAT. In the PIONEER AF-PCI (A Study Exploring Two Strategies of Rivaroxaban [JNJ39039039; BAY-59-7939] and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) trial (NCT01830543) the safety and efficacy of 2 rivaroxaban (RIV) treatment strategies and 1 vitamin K antagonist (VKA) strategy will be assessed in 2,100 patients with nonvalvular atrial fibrillation who undergo coronary stenting: 15 mg of RIV and clopidogrel (or other P2Y12 inhibitor) for 12 months without aspirin; 2.5 mg twice daily (bid) RIV, 81 mg aspirin, and 1, 6, or 12 months of a P2Y12 inhibitor; and dose-adjusted International Normalized Ratio (2 to 3 target) with VKA, and DAPT for 1, 6, or 12 months (4). In the REDUAL-PCI (Evaluation of Dual Therapy with Dabigatran vs Triple Therapy with Warfarin in Patients with AF that undergo a PCI with Stenting) study (NCT02164864) 2,500 patients with nonvalvular atrial fibrillation who under coronary stenting will be randomized to 1 of 2 “dual therapy” arms: 110 mg of dabigatran etexilate bid and clopidogrel or ticagrelor, or 150 mg dabigatran etexilate bid and clopidogrel or ticagrelor, and compared to “triple therapy” with a VKA, 100 mg aspirin, and clopidogrel or ticagrelor (5). Although the trial results are greatly anticipated, it is unlikely that either 1 or both of these trials will address all of the issues outlined previously that affect ischemic and bleeding rates in patients requiring both DAPT and OAC.
At the end of the day, the type, and duration, of OAC and antiplatelet therapy needs to be individualized, recognizing the differential impact of clinical presentation leading to coronary intervention, the bleeding risk of the patient, and the intensity and need of OAC. The results of the Bern PCI registry should provide some comfort to practitioners that in patients identified at the time of a coronary intervention to have a higher than normal bleeding risk, a shorter duration of triple therapy can be safely considered, although the exact duration of which remains to be determined. As more data similar to that provided by the Bern PCI registry are available, the tightrope that the clinician walks between reducing bleeding while minimizing ischemic events in patients who require both DAPT and OAC should get wider (more confidence) and lower to the ground (softer fall).
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Applegate has reported that he has no relationships relevant to the contents of this paper to disclose.
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- ↵Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting (REDUAL-PCI). Available at: https://clinicaltrials.gov/ct2/show/NCT02164864. Accessed May 17, 2016.