Prof. Francesco Franchi
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the treatment of choice for the prevention of thrombotic events after percutaneous coronary intervention (PCI) [1,2]. Current guidelines recommend DAPT for at least 4 weeks in patients undergoing elective bare metal stenting (BMS) and for 12 months in patients receiving DES or undergoing stenting for an acute coro-nary syndrome [1,2]. Indeed, since premature cessation of DAPT is thought to be a major determinant of stent thrombosis, cardiologists frequently recommend even more prolonged DAPT in patients without bleeding issues. Although the thrombotic risk is highest during the first month after DES implantation and still high within the first 6 months [3,4], a safe time period for antiplatelet therapy discontinuation has not been defined yet. Moreover, within 24 months of stent implantations, ~22% of patients need to undergo non-cardiac surgery and therefore need to discontinue at least one antiplatelet drug . The PARIS (patterns of non-adherence to antiplatelet regimens in stented patients) study was a prospective, multicenter, observational registry enrolling all-comer patients (n=5,018) undergoing stent implantation to assess the association between different modes of DAPT cessation and the incidence of ischemic and bleeding events .The novelty of the study was that for the first time DAPT cessation was not simply evaluated as a yes/no event but was classified according to different prespecified modalities:
The first finding of the study is that physician-recommended DAPT “discontinuation” (only thienopyridine in 87% of cases) was associated with better outcomes, leading to a 37% relative risk re-duction compared to patients who continued antiplatelet therapy. Since the study embraces the limita-tions associated with a registry design (i.e. significant differences in the baseline characteristics), a causal inference between recommended discontinuation and thrombotic risk is not allowed, but these data clearly show that discontinuation of DAPT in low-risk patients should be considered safe, especially af-ter 6 months from stent implantation.These findings contrast with some earlier reports suggesting a po-tential protective effect with longer DAPT durations after PCI [7,8]. However, the results of the present study are perfectly in line with those of more recent studies conducted in the setting of the better per-forming second-generation DES, and showing no benefit with longer DAPT duration [9,10].Moreover, the majority of patients enrolled in PARIS underwent PCI for stable coronary artery disease, a clinical setting in which even a 3-months DAPT has recently shown to be non-inferior to a 12-months strategy .In PARIS, 10.5% of patients had “interruption” of DAPT (both antiplatelet agents in 70% of cases) during the 24-months follow-up and this was associated with a numerical increase in ischemic events (HR: 1.41; 95% CI: 0.94-2.12). However, this trend was mainly driven by a significant increase in target lesion revascularization, while there was no increased risk of thrombotic events. Indeed, these findings are difficult to interpret since DAPT is not known to directly prevent in-stent restenosis and may therefore represent just a play of chance of a sub-group analysis or a consequence of differences in baseline characteristics. In line with this, also the protective effect of DAPT discontinuation on the inci-dence of target lesion revascularization is surprising and hard to interpret from a pathophysiological point of view. The absence of increased thrombotic risk with temporary DAPT interruption for surgery is not totally unexpected.In fact, the mean duration of interruption was short (6.2 days) and, more im-portantly, shorter than the complete offset of thienopyridines used in this study, indicating that patients were not completely uncovered from antiplatelet effects during that time frame . Moreover, the majority of the interruptions occurred in the second year after PCI, when DAPT is usually no longer recommended and the risk of thrombotic complications is very low. Therefore, the study confirms that the risk of DAPT interruption attenuates over time and stopping one or two antiplatelet agents may be con-sidered a safe procedure, especially after 6 months from stent implantation and in stable patients, as re-cently shown by Hawn et al . Hence, the advocated use of bridging strategies seems not to be re-quired in this setting, being considered only in patients with a recent acute coronary syndrome.In the PARIS study, the only cessation modality associated with an increased risk was “disrup-tion” due to bleeding or non-compliance. This occurred in about 10% of patients at year 1 and 14% of patients over 2 years, and led to a 50% relative risk increase in the occurrence of ischemic events, in-cluding myocardial infarction, stent thrombosis and cardiac death. However, it is important to note that the risk was the highest in the first 7 days after disruption and then attenuated over time, with no in-creased risk after 30 days. Further, the risk was significantly increased only when both antiplatelet drugs were withdrawn, which occurred in 50% of cases.Once again, we should interpret these results consi-dering the different risk profile of these patients, with a higher number of acute coronary syndromes among disrupting patients. Another important limitation is that we cannot discriminate if this higher number of events occurred in patients who stopped DAPT because of non-compliance or because of bleeding issues.Since this latter is a well-known risk factor for thrombotic events , the net clinical effect of DAPT cessation is still not fully elucidated from these findings.
In conclusion, despite the limitations deriving from its observational design, the PARIS registry taught us that, in the setting of new generation stents, the risk following DAPT cessation is very hetero-geneous and is based on patients risk profile as well as mode and timing of cessation. Further, it confirms that no benefit is achieved with a prolonged antiplatelet therapy and that, when recommended by physicians, both discontinuation and brief interruption are safe. The overall contribution of interruption of disruption on cardiac risk is very small, accounting for only 5.4% of events, and it attenuates over time after stenting and after DAPT cessation. Indeed, future studies are needed to better elucidate the impact of DAPT cessation in different clinical settings as well as how outcomes may be affected by car-diac and non-cardiac surgeries .
1. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Per-cutaneous Cardiovascular Interventions (EAPCI), Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J. 2010;31:2501-55.2. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutane-ous Coronary Intervention. A report of the American College of Cardiology Founda-tion/American Heart Association Task Force on Practice Guidelines and the Society for Cardi-ovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58:e44-122.3. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:2126-30.4. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation. 2007;116:745-54.5. Hawn MT, Graham LA, Richman JS, et al. Risk of major adverse cardiac events following non-cardiac surgery in patients with coronary stents. JAMA. 2013;310:1462-72.6. Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet. 2013;382:1714-22.7. Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol. 2006;98:352-6.8. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes af-ter drug-eluting stent implantation. JAMA. 2007;297:159-68.9. Cassese S, Byrne RA, Tada T, King LA, Kastrati A. Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: a meta-analysis of randomized trials. Eur Heart J. 2012;33:3078-87.10. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation. 2014;129:304-12.11. Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zo-tarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA. 2013;310:2510-22.12. Price MJ, Walder JS, Baker BA, et al. Recovery of platelet function after discontinuation of pra-sugrel or clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease: the recovery trial. J Am Coll Cardiol. 2012;59:2338-43.13. Hawn MT, Graham LA, Richman JS, et al. Risk of major adverse cardiac events following non-cardiac surgery in patients with coronary stents. JAMA. 2013;310:1462-72.14. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774-82.15. Capodanno D, Angiolillo DJ. Management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac surgery. Circulation. 2013;128:2785-98.
Our mission: To reduce the burden of cardiovascular disease
© 2018 European Society of Cardiology. All rights reserved