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Optimal Duration of Dual Antiplatelet Therapy After Coronary Stent Implantation
Optimal Duration of Dual Antiplatelet Therapy After Coronary Stent Implantation Guy Witberg, MD*, Eli Lev, MD, and Ran Kornowski, MD Dual antiplatelet pharmacotherapy reduces ischemic events at the cost of excess bleeding in patients who underwent coronary stenting. The currently recommended treatment period is based on trials held some 20 years ago and not relevant to current clinical practice. In recent years, numerous clinical trials have tried to answer the question of what is the optimal duration of therapy to maximize clinical benefit. These trials showed 2 seemingly conflicting answers—on one hand, shorter treatment duration seems to be safer in reducing bleeding while not increasing ischemic events, and on the other hand, longer duration is superior in terms of preventing ischemic events albeit at the cost of increased bleeding rates. In this review, we summarize the evidence favoring each approach, highlight the limitations of the various pivotal clinical trials in this field, review future directions of research and changes in practice that may influence the duration of antiplatelet therapy, and attempt to propose a personalized approach to achieve maximal benefit for the individual patient. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;-:-e-) Coronary artery disease (CAD) remains a major cause of mortality and morbidity in the western world.1 The clinical manifestations of CAD range from stable angina through acute coronary syndromes (ACS) and myocardial infarction (MI). Platelets play a key role in the pathophysiology of ACS because thrombosis of coronary plaques is the primary cause for these events.2 Platelet aggregation inhibition using aspirin has been the foundation of treatment for ACS for decades, regardless of additional treatment strategy.3 Since the early 2000s, dual antiplatelet pharmacotherapy (DAPT) with thienopyridine medications added to aspirin has become the standard of care for ACS.4,5 This drug combination also emerged as the treatment of choice after coronary stent implantation.6e8 One of the major unsettled issues regarding DAPT is the optimal duration of treatment in stable patients and patients with ACS who underwent coronary stenting. Recent years have seen new data in support of seemingly 2 conflicting practices: for example, prolonging versus shortening the duration of DAPT intake after coronary stenting. The purpose of this review was to present the most contemporary knowledge on this issue and to propose an algorithm for guiding clinicians as to the optimal time point for cessation of DAPT. Establishing the Benefits of DAPT After Coronary Stenting The benefits of DAPT were first shown in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial by reducing the composite end point of cardiovascular events by 20% compared to aspirin treatment alone.4 The CURE trial included patients with ACS sustaining noneST-segment
Department of cardiology, Rabin Medical Center, Petah Tikva, Israel. Manuscript received May 30, 2015; revised manuscript received and accepted August 18, 2015. See page 5 for disclosure information. *Corresponding author: Tel: (þ972) 39377107; fax: (þ972) 39377103. E-mail address: [email protected] (G. Witberg). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.08.029
elevation myocardial infarction events and <25% underwent percutaneous coronary intervention (PCI). A separate analysis of the trial, the PCI-CURE substudy showed even greater benefit with 30% risk reduction (RR) for cardiovascular events at mean treatment duration of 8 months.5 A post hoc analysis of the CURE trial also showed that the benefits of DAPT continued to accrue up to 9 months after noneSTsegment elevation myocardial infarction and/or PCI, laying the foundation for recommending prolonged DAPT period.9 The findings of the PCI-CURE were duplicated a year later by the Clopidogrel for the Reduction of Events During Observation (CREDO) trial that included the same patient population but was restricted to patients planned for invasive treatment.10 This trial showed a 27% reduction in mortality/ MI/stroke with 12 months of DAPT compared to aspirin treatment alone. In both the PCI-CURE and CREDO trials, major bleeding was not increased in a statistically significant level with DAPT compared to aspirin alone. The importance of DAPT became more evident with the increasing use of drug-eluting stents (DES) in the mid-tolate 2000s.11 Such a shift in practice raised the issue of stent thrombosis (ST), in particular, late (30 days to 1 year) and/or very late (>1 year) ST to the forefront of interventional cardiology. Premature interruption of DAPT was established by large observational trials to be the most powerful predictor of late ST.12 These findings led to a statement by the American College of Cardiology/American Heart Association which was adopted worldwide, stressing the importance of completing 12 months of DAPT after coronary stent implantation.13 By this time, the duration of DAPT was dictated by the perceived risk of late ST and also by that the first-generation DESs were used in clinical practice (e.g., Cypher and Taxus DES). Changes in Practice Challenging the Standard Duration of DAPT In recent years, 3 factors have challenged the recommended duration of DAPT. www.ajconline.org
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Table 1 Major Randomized Controlled Trial examining optimal DAPT duration A <12 months vs. 12 months+ DAPT Duration Trial
Sample size
Protocol
Primary endpoint
Results of primary endpoint
EXCELLENT23
1,443
6 vs. 12 months DAPT
4.8% vs 4.3%
OPTIMIZE24
3,119
3 vs. 12 months DAPT
PRODIGY25
2,013
6 vs. 24 months DAPT
RESET26
2,117
3 vs. 12 months DAPT
ITALIC27
1,894
6 vs. 24 months DAPT
ISAR-SAFE28
4,000
6 vs. 12 months DAPT
CVD/MI/TVR at 12 months Death/MI/CVA/Major Bleeding at 12 months Death/MI/CVA at 24 months CVD/MI/ST/TVR/Bleeding at 12 months Death/MI/CVA/TVR/Major Bleeding at 12 months Death/MI/CVA/ST/Major Bleeding at 9 months
6% vs 5.8% 10% vs. 10.1% 4.7% vs. 4.7% 1.6% vs. 1.5% 1.5% vs. 1.6%
B 12 months vs. 12 months+ DAPT Duration Trial
Sample size
Protocol
ARCTIC INTERUPTION29
1,259
12 vs.18-30 months DAPT
DES-LATE30
5,045
12 vs. 36 months DAPT
DAPT31
9,961
12 vs. 30 months DAPT
PEGASUS TIMI-5435
21,162
12 vs. additional 33 months (mean) of Ticagrelor(90/60 mg BID)
Primary endpoint Death/MI/CVA/ST/TVR at median 17 months follow up CVD/MI/CVA from 12 to 36 months Coprimary endpoints: 1)ST 2) Death/MI/CVA from 12 to 30 months Efficacy: CVD/MI/CVA Safety: TIMI major bleeding
Results of primary endpoint 4% vs. 4%
2.4% vs. 2.6% 1)1.4% vs. 0.4% 2)5.9% vs. 4.3%
Efficacy: 9.04% vs. 7.85% vs. 7.77% Safety: 1.06% vs. 2.60% vs. 2.30%
Summary of the design and results of the major clinical trials examining the optimal DAPT duration. A - trials aimed at proving non inferiority of shorter duration DAPT to 12 months or more DAPT. B - trials aimed at proving superiority of longer duration DAPT to 12 months of DAPT. In each row the rate of the primary endpoint of the shorter duration DAPT arm is listed first. DAPT ¼ Dual Antiplatelet Platelet Therapy; CVD ¼ CardioVascular Death; MI ¼ Myocardial Infarction; CAV ¼ CerebroVascular Accident; ST ¼ Stent Thrombosis; TVR ¼ Target Vessel Revascularization.
i. The replacement of the first-generation DESs with second-generation platforms, designed with a better safety and biocompatibility profile especially with regards to endothelial healing and the continued risk of ST.14e17 Such an evolution raised the possibility of shortening DAPT duration to reduce bleeding risk without putting patients at increased risk for ST. ii. Findings from large prospective observational trials which have shown that the risk of ST is not significantly reduced after 1 year and remains roughly the same through 2 years18 and even up to 4 to 5 years of follow-up.19,20 The cumulative data raised the question whether DAPT should be continued beyond 1 year to reduce late cardiovascular ischemic events including late ST beyond 1 year. iii. The availability of second-generation P2Y12 inhibitors such as prasugrel and ticagrelor,21,22 that proved to be superior to clopidogrel in prevention of ischemic cardiovascular events but at a cost of increased bleeding risk. The question was raised
again whether prolongation of DAPT is indicated using these novel antithrombotic medications to improve overall cardiovascular outcomes. Evidence Supporting Shorter DAPT Duration The safety of shortened DAPT duration has been studied in several randomized controlled trials published in recent years (Table 1).23e28 These trials mostly included patients with stable CAD who were treated using second-generation DESs; thus, the issue of DAPT intake specifically after ACS has not been fully addressed. Nonetheless, these trials clearly showed that shorter duration of DAPT (3 to 6 months) might be equivalent to 1 year of treatment in terms of ST and overall ischemic events and significantly reduced bleeding episodes, including life-threatening bleeding events. The latest meta-analysis of these trials29 found no increased mortality and showed a significant reduction in major bleeding events with earlier interruption of DAPT. A common finding in all the trials was a very low rate of ischemic
Review/Optimal Duration of Antiplatelet Therapy
coronary events in total, and late ST in particular, compared to previous observational trials. This is believed to be related to the improved PCI techniques and/or medical treatment aimed at secondary prevention. The clinical data mentioned previously were the basis for the European Society of Cardiology 2014 revascularization guidelines recommendation to shorten DAPT duration to 6 months for patients with stable CAD treated with second-generation DES.6 The DAPT recommendations after ACS with or without PCI remain the same, for example, 1 year after stenting. It is important however to remember several limitations of the trials supporting shorter DAPT duration: Most of these trials included patients with stable CAD with a low percentage of ACS (apart from the PRODIGY [Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study] trial.25) A relatively small sample size that did not allow for evaluation of ST as a primary end point. The exclusion of patients with complex coronary anatomy,23 or in stent restenosis,24 limiting the external validity of the results. A heterogenous definition of the bleeding component in the composite primary end point. The early termination of several of the trials27,28 due to slow recruitment and lower than expected rate of clinical outcomes. The treatment arm allocation was not blinded from the attending physicians. All but one of the trials25 did not report patient adherence to the prescribed DAPT regimen. Evidence in Favor of Prolonged DAPT Duration Three randomised clinical trials (RCTs) tested the benefits of prolonged DAPT (Table 1): The Duration of Clopidogrel Therapy After Drug-Eluting Stent (DES-LATE) trial30 randomized 5,045 patients who underwent DES implantation, completed 12 months of DAPT with clopidogrel with no experience of any ischemic/bleeding event, continued DAPT versus aspirin treatment alone for additional 24 months. At the end of follow-up, there was no difference in terms of the primary composite end point (cardiovascular death/MI/stroke) or any of the secondary end points including ST. Major bleeding was numerically but not statistically increased with prolonged DAPT. When considering net clinical benefit (ischemic events plus major bleeding), there was again no statistically significant difference between the 2 groups. Because the main driver for prolonging DAPT duration was reducing the occurrence of very late ST, the major limitation of the DES-LATE trial was the sample size which was not large enough to show reductions in ST. The most significant attempt to show benefits from DAPT prolongation was conducted in the DAPT trial.31 The DAPT trial was initiated in response to a call by the Food and Drug Administration to design a large-scale randomized control trial to test the benefits of prolonged DAPT period with a primary end point of ST. The DAPT trial randomized 9,961 patients, free of clinical events after 12 months of DAPT intake after DES implantation to prolonged DAPT intake
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(additional 18 months, overall 30 months) or continued aspirin alone. Patients were followed for an additional 3 months after discontinuation of DAPT versus placebo (i.e., 30 to 33 months after stenting). Importantly, 42% of patients underwent PCI because of ACS and 33% of the patients received the more potent P2Y12 inhibitor prasugrel. The DAPT trial showed significant reduction in both coprimary efficacy end points in favor of prolonged DAPT: (1) ST was 0.4% versus 1.4% (hazard ratio [HR] 0.29, p <0.001) and (2) major adverse cardiovascular and cerebrovascular events were 4.3% versus 5.9% (HR, p <0.001). Analysis of secondary end points showed a significant reduction in MI (2.1% vs 4.1%; HR 0.47, p <0.001). However, the main safety end point of major bleeding was increased with prolonged DAPT (2.5% vs 1.6%, p ¼ 0.001). The results were not related to the type of theinopyridine used during the trial. We think that the important findings of the DAPT trial should be viewed in context of several important considerations: The overall effect on mortality: there was a strong trend toward increased overall mortality rates in the prolonged DAPT arm compared to placebo (RR 1.32, p ¼ 0.052). The increment was solely due to a more than double rate of noncardiovascular mortality (RR 2.23, p ¼ 0.002), mainly cancer related. The investigators later conducted a meta-analysis of all the RCTs that compared longer versus shorter duration of DAPT and found no association between overall mortality and longer DAPT duration with or without the DAPT trial results.32 The external validity of the trial: of 22,866 patients screened, only 43% were eventually randomized, 58% of screened but not randomized patients were eligible to participate but were not included mainly because of withdrawal of consent. This raised a theoretical possibility for a selection bias and thus weakened the generalizability of the trial results to an all-comers PCI population. The magnitude of the overall benefit from prolonged DAPT: because there is no beneficial effect of prolonged DAPT on overall mortality, the decision whether to recommend longer DAPT duration depends on the balance between the improved ischemic outcomes and the increased risk of bleeding. The DES-LATE trial investigators approached this issue by presenting a primary end point of net clinical benefit that included both ischemic and bleeding events. However, this approach is somewhat problematic because of the heterogenous nature and different prognostic effect of both MI versus bleeding.33 The DAPT trial investigators considered this issue differently and separated the primary end points into efficacy (prevention of ischemic events) and safety (bleeding). This decision was based on the Markov model that predicts the RR in ST and major adverse cardiovascular events required to justify the added risk of bleeding. The model is applied to support prolonging the duration of DAPT in terms of quality-adjusted life years (QALY).34 This approach is probably more appropriate, and the referenced Markov model represents the most advanced attempt to find a solution to the
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Table 2 Risk factors for stent thrombosis after PCI Factors related to patient High on treatment platelet reactivity Low compliance to antiplatelet drugs Reduced ejection fraction Stenting during ACS Chronic inflammatory disease/ malignancy Diabetes mellitus
Factors related to PCI Stent type (BMS/1ST/2nd generation DES) Total length of stents Overlapping stents Small vessel stenting Bifurcation side branch stenting Incomplete stent apposition/ expansion Undersized stent
ACS ¼ acute coronary syndrome; BMS ¼ bare metal stent; DES ¼ drugeluting stent; PCI ¼ percutaneous coronary interventions.
Table 3 Risk factors for bleeding following PCI Factors related to patient Use of oral anticoagulation drugs Prolonged DAPT duration Chronic kidney/liver disease Malignancy Prior CVA Low body weight Prior bleeding Thrombocytopenia Bleeding diathesis
Factors related to PCI Short term bleeding: Access site Sheath size Not using vascular closure device
CVA ¼ cerebrovascular accident; DAPT ¼ dual antiplatelet pharmacotherapy; PCI ¼ percutaneous coronary interventions.
issue of balancing the benefits and hazards of prolonged DAPT. However, when exploring the eventual benefits in terms of QALY predicted by the referred model, the gains for prolonged DAPT are relatively small (approximately 0.5 QALY at most). Hence, when considering cost-effectiveness factors, using the previously cited benefits in QALY and at the current price of clopidogrel and prasugrel in the United States, the cost of prolonging DAPT will range from $58,000 to $97,000 per QALY which is higher than the accepted $50,000 per QALY benchmark. Extended DAPT duration with second-generation P2Y12 inhibitors: The recently published PEGASUS TIMI-54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagre- lor Compared to Placebo on a Background of AspirineThrombolysis in Myocardial Infarction 54) trial35 randomized 22,162 patients who were 1 to 3 (median 1.7) years after MI (53% had STEMI) to receive either placebo or 1 of 2 doses of ticagrelor for a median duration of 33 months. The trial showed that extended DAPT with both doses of ticagrelor significantly reduced the primary end point of cardiovascular mortality/MI/stroke compared to placebo (RR 0.15, p ¼ 0.008 and RR 0.16, p ¼ 0.004 for the 90 and 60 mg twice daily doses, respectively). This was driven by a reduction in MI (RR 0.19, p ¼ 0.01 and RR 0.16, p ¼ 0.03) and stroke (RR 0.18, p ¼ 0.14 and RR
Table 4 Proposed duration of dual antiplatelet therapy after coronary stenting according to the individual risks category for ischemic and bleeding events (as detailed in Tables 2 and 3) adapted from Binder R, Luscher F. Duration of dual antiplatelet therapy after coronary artery stenting: where is the sweet spot between ischemia and bleeding? Eur Heart J 2015; 36:1207-1211 Risk for ischemic events
Risk of bleeding
4
Low
Moderate
High
6 months
12 months
30 months
Moderate
3-6 months
6-12 months
12 months
High
3 months
3-6 months
6-12 months
Low
0.25, p ¼ 0.03). There was no significant reduction in overall and/or cardiovascular mortality. Major bleeding rates were again higher with extended DAPT and did not seem to differ between the 2 ticagrelor doses (HR 2.69, p <0.001 and HR 2.32, p <0.001 for the 90 and 60 mg twice daily doses, respectively). These results are in accordance with the DAPT trial and strengthen the evidence of improved efficacy associated with extended duration of DAPT. How to Settle the Conflicting Data? One important fact needs to be emphasized when reviewing the seemingly conflicting evidence from the RCTs mentioned previously. The trials that sought to prove the benefit of prolonged DAPT duration included only patients who completed 1 year of DAPT after stent implantation and were free of clinical events, whereas the trials that sought to show equivalence from shortened DAPT randomized patients immediately after stenting. Therefore, the 2 sets of trials (i.e., prolonged vs shortened DAPT) are not meant for comparison. Moreover, the aim of prolonging DAPT beyond 1 year relates also to the overall matter of secondary prevention of cardiovascular events, not necessarily related to the stent per se. These events may have been captured in the DAPT study, whereas in the shorter duration trials, the benefit in terms of secondary prevention may have gone unnoticed because of the shorter follow-up duration. Summary and Conclusions Considering the synthesis of data mentioned previously, there is still no consensus as to the optimal duration of DAPT after coronary stenting. The main hindrance for making precise patient-centered decisions regarding DAPT duration is the clinicians’ lack of a validated tool to predict the clinical impact of cessation versus prolongation of DAPT for the individual patient, at each time point after coronary stenting and/or cardiovascular event. We foresee the impact of the integration into clinical practice of new and more potent antithrombotic and cholesterol-lowering medications and the development of new stents and scaffolds, with biocompatible or fully resorbable materials assisted by precise coronary imaging modalities. On the basis of the currently available information, we conclude that there should be no “one size fits all” approach
Review/Optimal Duration of Antiplatelet Therapy
toward the decision of DAPT duration after stenting. The main factors that need to be considered are as follows: The clinical scenario: A presentation of stable CAD without coronary complexity supports an earlier cessation of DAPT as endorsed by the European Society of Cardiology revascularization guidelines6 (but as yet not endorsed in the United States). The relative risks for bleeding versus ischemic events (Tables 2 and 3). The type of stent used: Both the DAPT trial and a recent meta-analysis of trials comparing efficacy of longer versus shorter duration of DAPT36 reported more benefits for prolonged DAPT in patients treated by first- versus second-generation DES. This seems to be a temporary dilemma as no first-generation DESs are expected to remain in use in the future. We agree with the most contemporary approaches37; the question of whether to stop or continue the DAPT should be addressed individually for each patient at 6 and 12 months after stenting. Furthermore, at each time point, all individual factors related to ischemic and bleeding risks should be reviewed and used to make the optimal decision (Table 4). Finally, better tools for risk prediction are needed to optimize clinical benefit from DAPT in patients who underwent coronary stent implantation.
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11. 12.
13.
Disclosures The authors have no conflicts of interest to disclose. 1. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J 2014;35: 2950e2959. 2. Kasotakis G, Pipinos II, Lynch TG. Current evidence and clinical implications of aspirin resistance. J Vasc Surg 2009;50:1500e1510. 3. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009;373:1849e1860. 4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494e502. 5. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358: 527e533. 6. Authors/Task Force members, Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Jüni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541e2619. 7. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ,
14.
15.
16.
17.
18.
19.
20.
5
Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent anticoagulation restenosis study investigators. N Engl J Med 1998;339:1665e1671. Albiero R, Hall P, Itoh A, Blengino S, Nakamura S, Martini G, Ferraro M, Colombo A. Results of a consecutive series of patients receiving only antiplatelet therapy after optimized stent implantation. Comparison of aspirin alone versus combined ticlopidine and aspirin therapy. Circulation 1996;93:412e422. Yusuf S, Mehta SR, Zhao F, Gersh BJ, Commerford PJ, Blumenthal M, Budaj A, Wittlinger T, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events Trial (CURE) Investigators. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 2003;107:966e972. Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators; Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411e2420. Epstein AJ, Polsky D, Yang F, Yang L, Groeneveld PW. Coronary revascularization trends in the United States, 2001-2008. JAMA 2011;305:1769e1776. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drugeluting stents. JAMA 2005;293:2126e2130. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, O’Gara P, Whitlow P; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol 2007;49:734e739. Bangalore S, Kumar S, Fusaro M, Amoroso N, Attubato MJ, Feit F, Bhatt DL, Slater J. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-year of follow-up from randomized trials. Circulation 2012;125:2873e2891. Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Sabaté M, Valgimigli M, Frati G, Kedhi E, Smits PC, Kaiser C, Genereux P, Galatius S, Kirtane AJ, Stone GW. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network metaanalysis. Lancet 2012;379:1393e1402. Camenzind E, Boersma E, Wijns W, Mauri L, Rademaker-Havinga T, Ordoubadi FF, Suttorp MJ, Al Kurdi M, Steg PG; PROTECT Steering Committee and Investigators. Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drugeluting stent type. Eur Heart J 2014;35:1932e1948. Silber S, Kirtane AJ, Belardi JA, Liu M, Brar S, Rothman M, Windecker S. Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation. Eur Heart J 2014;35: 1949e1956. Kimura T, Morimoto T, Nakagawa Y, Tamura T, Kadota K, Yasumoto H, Nishikawa H, Hiasa Y, Muramatsu T, Meguro T, Inoue N, Honda H, Hayashi Y, Miyazaki S, Oshima S, Honda T, Shiode N, Namura M, Sone T, Nobuyoshi M, Kita T, Mitsudo K; j-Cypher Registry Investigators. Antiplatelet therapy and stent thrombosis after sirolimuseluting stent implantation. Circulation 2009;119:987e995. Kimura T, Morimoto T, Nakagawa Y, Kawai K, Miyazaki S, Muramatsu T, Shiode N, Namura M, Sone T, Oshima S, Nishikawa H, Hiasa Y, Hayashi Y, Nobuyoshi M, Mitudo K; j-Cypher Registry Investigators. Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: five-year outcome of the j-Cypher Registry. Circulation 2012;125:584e591. Wenaweser P, Daemen J, Zwahlen M, van Domburg R, Jüni P, Vaina S, Hellige G, Tsuchida K, Morger C, Boersma E, Kukreja N, Meier B, Serruys PW, Windecker S. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice.4-year results from a large 2institutional cohort study. J Am Coll Cardiol 2008;52:1134e1140.
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21. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITONTIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001e2015. 22. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045e1057. 23. Gwon HC, Hahn JY, Park KW, Song YB, Chae IH, Lim DS, Han KR, Choi JH, Choi SH, Kang HJ, Koo BK, Ahn T, Yoon JH, Jeong MH, Hong TJ, Chung WY, Choi YJ, Hur SH, Kwon HM, Jeon DW, Kim BO, Park SH, Lee NH, Jeon HK, Jang Y, Kim HS. Six-month versus 12-month dual antiplatelet therapy after implantation of drugeluting stents: the Efficacy of Xience/Promus versus Cypher to reduce late loss after stenting (EXCELLENT) randomized, multicenter study. Circulation 2012;125:505e513. 24. Feres F, Costa RA, Abizaid A, Leon MB, Marin-Neto JA, Botelho RV, King SB 3rd, Negoita M, Liu M, de Paula JE, Mangione JA, Meireles GX, Castello HJ Jr, Nicolela EL Jr, Perin MA, Devito FS, Labrunie A, Salvadori D Jr, Gusmão M, Staico R, Costa JR Jr, de Castro JP, Abizaid AS, Bhatt DL; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510e2522. 25. Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G, Tumscitz C, Castriota F, Colombo F, Tebaldi M, Fucà G, Kubbajeh M, Cangiano E, Minarelli M, Scalone A, Cavazza C, Frangione A, Borghesi M, Marchesini J, Parrinello G, Ferrari R; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dualantiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015e2026. 26. Kim BK, Hong MK, Shin DH, Nam CM, Kim JS, Ko YG, Choi D, Kang TS, Park BE, Kang WC, Lee SH, Yoon JH, Hong BK, Kwon HM, Jang Y; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET trial (Real Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimuseluting stent implantation). J Am Coll Cardiol 2012;60:1340e1348. 27. Gilard M, Barragan P, Noryani AA, Noor HA, Majwal T, Hovasse T, Castellant P, Schneeberger M, Maillard L, Bressolette E, Wojcik J, Delarche N, Blanchard D, Jouve B, Ormezzano O, Paganelli F, Levy G, Sainsous J, Carrie D, Furber A, Berland J, Darremont O, Le Breton H, Lyuycx-Bore A, Gommeaux A, Cassat C, Kermarrec A, Cazaux P, Druelles P, Dauphin R, Armengaud J, Dupouy P, Champagnac D, Ohlmann P, Endresen K, Benamer H, Kiss RG, Ungi I, Boschat J, Morice MC. Six-month versus 24-month dual antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial. J Am Coll Cardiol 2015;65:777e786. 28. Schulz-Schüpke S, Byrne RA, Ten Berg JM, Neumann FJ, Han Y, Adriaenssens T, Tölg R, Seyfarth M, Maeng M, Zrenner B, Jacobshagen C, Mudra H, von Hodenberg E, Wöhrle J, Angiolillo DJ, von Merzljak B, Rifatov N, Kufner S, Morath T, Feuchtenberger A, Ibrahim T, Janssen PW, Valina C, Li Y, Desmet W, Abdel-Wahab M,
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31.
32.
33. 34.
35.
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Tiroch K, Hengstenberg C, Bernlochner I, Fischer M, Schunkert H, Laugwitz KL, Schömig A, Mehilli J, Kastrati A; Intracoronary Stenting and Antithrombotic Regimen: Safety And Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) Trial Investigators. ISAR-SAFE: a randomized, double-blind, placebocontrolled trial of 6 versus 12 months of clopidogrel therapy after drugeluting stenting. Eur Heart J 2015;36:1252e1263. Collet JP, Silvain J, Barthélémy O, Rangé G, Cayla G, Van Belle E, Cuisset T, Elhadad S, Schiele F, Lhoest N, Ohlmann P, Carrié D, Rousseau H, Aubry P, Monségu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Beygui F, Vicaut E, Montalescot G; ARCTIC investigators. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014;384:1577e1585. Lee CW, Ahn JM, Park DW, Kang SJ, Lee SW, Kim YH, Park SW, Han S, Lee SG, Seong IW, Rha SW, Jeong MH, Lim DS, Yoon JH, Hur SH, Choi YS, Yang JY, Lee NH, Kim HS, Lee BK, Kim KS, Lee SU, Chae JK, Cheong SS, Suh IW, Park HS, Nah DY, Jeon DS, Seung KB, Lee K, Jang JS, Park SJ. Optimal duration of dual antiplatelet therapy after drugeluting stent implantation: a randomized, controlled trial. Circulation 2014;129:304e312. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371: 2155e2166. Elmariah S, Mauri L, Doros G, Galper BZ, O’Neill KE, Steg PG, Kereiakes DJ, Yeh RW. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet 2015;385: 792e798. Yeh RW, Cohen DJ, Mauri L. Close encounters with errors of the second kind: evaluating risks and benefits of long-term dual antiplatelet therapy. Eur Heart J 2015;36:1216e1218. Garg P, Galper BZ, Cohen DJ, Yeh RW, Mauri L. Balancing the risks of bleeding and stent thrombosis: a decision analytic model to compare durations of dual antiplatelet therapy after drug-eluting stents. Am Heart J 2015;169:222e233. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791e1800. Giustino G, Baber U, Sartori S, Mehran R, Mastoris I, Kini AS, Sharma SK, Pocock SJ, Dangas GD. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol 2015;65: 1298e1310. Binder R, Luscher F. Duration of dual antiplatelet therapy after coronary artery stenting: where is the sweet spot between ischaemia and bleeding? Eur Heart J 2015;36:1207e1211.
Department of cardiology, Rabin Medical Center, Petah Tikva, Israel. Manuscript received May 30, 2015; revised manuscript received and accepted August 18, 2015. See page 5 for disclosure information. *Corresponding author: Tel: (þ972) 39377107; fax: (þ972) 39377103. E-mail address: [email protected] (G. Witberg). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.08.029
elevation myocardial infarction events and <25% underwent percutaneous coronary intervention (PCI). A separate analysis of the trial, the PCI-CURE substudy showed even greater benefit with 30% risk reduction (RR) for cardiovascular events at mean treatment duration of 8 months.5 A post hoc analysis of the CURE trial also showed that the benefits of DAPT continued to accrue up to 9 months after noneSTsegment elevation myocardial infarction and/or PCI, laying the foundation for recommending prolonged DAPT period.9 The findings of the PCI-CURE were duplicated a year later by the Clopidogrel for the Reduction of Events During Observation (CREDO) trial that included the same patient population but was restricted to patients planned for invasive treatment.10 This trial showed a 27% reduction in mortality/ MI/stroke with 12 months of DAPT compared to aspirin treatment alone. In both the PCI-CURE and CREDO trials, major bleeding was not increased in a statistically significant level with DAPT compared to aspirin alone. The importance of DAPT became more evident with the increasing use of drug-eluting stents (DES) in the mid-tolate 2000s.11 Such a shift in practice raised the issue of stent thrombosis (ST), in particular, late (30 days to 1 year) and/or very late (>1 year) ST to the forefront of interventional cardiology. Premature interruption of DAPT was established by large observational trials to be the most powerful predictor of late ST.12 These findings led to a statement by the American College of Cardiology/American Heart Association which was adopted worldwide, stressing the importance of completing 12 months of DAPT after coronary stent implantation.13 By this time, the duration of DAPT was dictated by the perceived risk of late ST and also by that the first-generation DESs were used in clinical practice (e.g., Cypher and Taxus DES). Changes in Practice Challenging the Standard Duration of DAPT In recent years, 3 factors have challenged the recommended duration of DAPT. www.ajconline.org
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Table 1 Major Randomized Controlled Trial examining optimal DAPT duration A <12 months vs. 12 months+ DAPT Duration Trial
Sample size
Protocol
Primary endpoint
Results of primary endpoint
EXCELLENT23
1,443
6 vs. 12 months DAPT
4.8% vs 4.3%
OPTIMIZE24
3,119
3 vs. 12 months DAPT
PRODIGY25
2,013
6 vs. 24 months DAPT
RESET26
2,117
3 vs. 12 months DAPT
ITALIC27
1,894
6 vs. 24 months DAPT
ISAR-SAFE28
4,000
6 vs. 12 months DAPT
CVD/MI/TVR at 12 months Death/MI/CVA/Major Bleeding at 12 months Death/MI/CVA at 24 months CVD/MI/ST/TVR/Bleeding at 12 months Death/MI/CVA/TVR/Major Bleeding at 12 months Death/MI/CVA/ST/Major Bleeding at 9 months
6% vs 5.8% 10% vs. 10.1% 4.7% vs. 4.7% 1.6% vs. 1.5% 1.5% vs. 1.6%
B 12 months vs. 12 months+ DAPT Duration Trial
Sample size
Protocol
ARCTIC INTERUPTION29
1,259
12 vs.18-30 months DAPT
DES-LATE30
5,045
12 vs. 36 months DAPT
DAPT31
9,961
12 vs. 30 months DAPT
PEGASUS TIMI-5435
21,162
12 vs. additional 33 months (mean) of Ticagrelor(90/60 mg BID)
Primary endpoint Death/MI/CVA/ST/TVR at median 17 months follow up CVD/MI/CVA from 12 to 36 months Coprimary endpoints: 1)ST 2) Death/MI/CVA from 12 to 30 months Efficacy: CVD/MI/CVA Safety: TIMI major bleeding
Results of primary endpoint 4% vs. 4%
2.4% vs. 2.6% 1)1.4% vs. 0.4% 2)5.9% vs. 4.3%
Efficacy: 9.04% vs. 7.85% vs. 7.77% Safety: 1.06% vs. 2.60% vs. 2.30%
Summary of the design and results of the major clinical trials examining the optimal DAPT duration. A - trials aimed at proving non inferiority of shorter duration DAPT to 12 months or more DAPT. B - trials aimed at proving superiority of longer duration DAPT to 12 months of DAPT. In each row the rate of the primary endpoint of the shorter duration DAPT arm is listed first. DAPT ¼ Dual Antiplatelet Platelet Therapy; CVD ¼ CardioVascular Death; MI ¼ Myocardial Infarction; CAV ¼ CerebroVascular Accident; ST ¼ Stent Thrombosis; TVR ¼ Target Vessel Revascularization.
i. The replacement of the first-generation DESs with second-generation platforms, designed with a better safety and biocompatibility profile especially with regards to endothelial healing and the continued risk of ST.14e17 Such an evolution raised the possibility of shortening DAPT duration to reduce bleeding risk without putting patients at increased risk for ST. ii. Findings from large prospective observational trials which have shown that the risk of ST is not significantly reduced after 1 year and remains roughly the same through 2 years18 and even up to 4 to 5 years of follow-up.19,20 The cumulative data raised the question whether DAPT should be continued beyond 1 year to reduce late cardiovascular ischemic events including late ST beyond 1 year. iii. The availability of second-generation P2Y12 inhibitors such as prasugrel and ticagrelor,21,22 that proved to be superior to clopidogrel in prevention of ischemic cardiovascular events but at a cost of increased bleeding risk. The question was raised
again whether prolongation of DAPT is indicated using these novel antithrombotic medications to improve overall cardiovascular outcomes. Evidence Supporting Shorter DAPT Duration The safety of shortened DAPT duration has been studied in several randomized controlled trials published in recent years (Table 1).23e28 These trials mostly included patients with stable CAD who were treated using second-generation DESs; thus, the issue of DAPT intake specifically after ACS has not been fully addressed. Nonetheless, these trials clearly showed that shorter duration of DAPT (3 to 6 months) might be equivalent to 1 year of treatment in terms of ST and overall ischemic events and significantly reduced bleeding episodes, including life-threatening bleeding events. The latest meta-analysis of these trials29 found no increased mortality and showed a significant reduction in major bleeding events with earlier interruption of DAPT. A common finding in all the trials was a very low rate of ischemic
Review/Optimal Duration of Antiplatelet Therapy
coronary events in total, and late ST in particular, compared to previous observational trials. This is believed to be related to the improved PCI techniques and/or medical treatment aimed at secondary prevention. The clinical data mentioned previously were the basis for the European Society of Cardiology 2014 revascularization guidelines recommendation to shorten DAPT duration to 6 months for patients with stable CAD treated with second-generation DES.6 The DAPT recommendations after ACS with or without PCI remain the same, for example, 1 year after stenting. It is important however to remember several limitations of the trials supporting shorter DAPT duration: Most of these trials included patients with stable CAD with a low percentage of ACS (apart from the PRODIGY [Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study] trial.25) A relatively small sample size that did not allow for evaluation of ST as a primary end point. The exclusion of patients with complex coronary anatomy,23 or in stent restenosis,24 limiting the external validity of the results. A heterogenous definition of the bleeding component in the composite primary end point. The early termination of several of the trials27,28 due to slow recruitment and lower than expected rate of clinical outcomes. The treatment arm allocation was not blinded from the attending physicians. All but one of the trials25 did not report patient adherence to the prescribed DAPT regimen. Evidence in Favor of Prolonged DAPT Duration Three randomised clinical trials (RCTs) tested the benefits of prolonged DAPT (Table 1): The Duration of Clopidogrel Therapy After Drug-Eluting Stent (DES-LATE) trial30 randomized 5,045 patients who underwent DES implantation, completed 12 months of DAPT with clopidogrel with no experience of any ischemic/bleeding event, continued DAPT versus aspirin treatment alone for additional 24 months. At the end of follow-up, there was no difference in terms of the primary composite end point (cardiovascular death/MI/stroke) or any of the secondary end points including ST. Major bleeding was numerically but not statistically increased with prolonged DAPT. When considering net clinical benefit (ischemic events plus major bleeding), there was again no statistically significant difference between the 2 groups. Because the main driver for prolonging DAPT duration was reducing the occurrence of very late ST, the major limitation of the DES-LATE trial was the sample size which was not large enough to show reductions in ST. The most significant attempt to show benefits from DAPT prolongation was conducted in the DAPT trial.31 The DAPT trial was initiated in response to a call by the Food and Drug Administration to design a large-scale randomized control trial to test the benefits of prolonged DAPT period with a primary end point of ST. The DAPT trial randomized 9,961 patients, free of clinical events after 12 months of DAPT intake after DES implantation to prolonged DAPT intake
3
(additional 18 months, overall 30 months) or continued aspirin alone. Patients were followed for an additional 3 months after discontinuation of DAPT versus placebo (i.e., 30 to 33 months after stenting). Importantly, 42% of patients underwent PCI because of ACS and 33% of the patients received the more potent P2Y12 inhibitor prasugrel. The DAPT trial showed significant reduction in both coprimary efficacy end points in favor of prolonged DAPT: (1) ST was 0.4% versus 1.4% (hazard ratio [HR] 0.29, p <0.001) and (2) major adverse cardiovascular and cerebrovascular events were 4.3% versus 5.9% (HR, p <0.001). Analysis of secondary end points showed a significant reduction in MI (2.1% vs 4.1%; HR 0.47, p <0.001). However, the main safety end point of major bleeding was increased with prolonged DAPT (2.5% vs 1.6%, p ¼ 0.001). The results were not related to the type of theinopyridine used during the trial. We think that the important findings of the DAPT trial should be viewed in context of several important considerations: The overall effect on mortality: there was a strong trend toward increased overall mortality rates in the prolonged DAPT arm compared to placebo (RR 1.32, p ¼ 0.052). The increment was solely due to a more than double rate of noncardiovascular mortality (RR 2.23, p ¼ 0.002), mainly cancer related. The investigators later conducted a meta-analysis of all the RCTs that compared longer versus shorter duration of DAPT and found no association between overall mortality and longer DAPT duration with or without the DAPT trial results.32 The external validity of the trial: of 22,866 patients screened, only 43% were eventually randomized, 58% of screened but not randomized patients were eligible to participate but were not included mainly because of withdrawal of consent. This raised a theoretical possibility for a selection bias and thus weakened the generalizability of the trial results to an all-comers PCI population. The magnitude of the overall benefit from prolonged DAPT: because there is no beneficial effect of prolonged DAPT on overall mortality, the decision whether to recommend longer DAPT duration depends on the balance between the improved ischemic outcomes and the increased risk of bleeding. The DES-LATE trial investigators approached this issue by presenting a primary end point of net clinical benefit that included both ischemic and bleeding events. However, this approach is somewhat problematic because of the heterogenous nature and different prognostic effect of both MI versus bleeding.33 The DAPT trial investigators considered this issue differently and separated the primary end points into efficacy (prevention of ischemic events) and safety (bleeding). This decision was based on the Markov model that predicts the RR in ST and major adverse cardiovascular events required to justify the added risk of bleeding. The model is applied to support prolonging the duration of DAPT in terms of quality-adjusted life years (QALY).34 This approach is probably more appropriate, and the referenced Markov model represents the most advanced attempt to find a solution to the
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Table 2 Risk factors for stent thrombosis after PCI Factors related to patient High on treatment platelet reactivity Low compliance to antiplatelet drugs Reduced ejection fraction Stenting during ACS Chronic inflammatory disease/ malignancy Diabetes mellitus
Factors related to PCI Stent type (BMS/1ST/2nd generation DES) Total length of stents Overlapping stents Small vessel stenting Bifurcation side branch stenting Incomplete stent apposition/ expansion Undersized stent
ACS ¼ acute coronary syndrome; BMS ¼ bare metal stent; DES ¼ drugeluting stent; PCI ¼ percutaneous coronary interventions.
Table 3 Risk factors for bleeding following PCI Factors related to patient Use of oral anticoagulation drugs Prolonged DAPT duration Chronic kidney/liver disease Malignancy Prior CVA Low body weight Prior bleeding Thrombocytopenia Bleeding diathesis
Factors related to PCI Short term bleeding: Access site Sheath size Not using vascular closure device
CVA ¼ cerebrovascular accident; DAPT ¼ dual antiplatelet pharmacotherapy; PCI ¼ percutaneous coronary interventions.
issue of balancing the benefits and hazards of prolonged DAPT. However, when exploring the eventual benefits in terms of QALY predicted by the referred model, the gains for prolonged DAPT are relatively small (approximately 0.5 QALY at most). Hence, when considering cost-effectiveness factors, using the previously cited benefits in QALY and at the current price of clopidogrel and prasugrel in the United States, the cost of prolonging DAPT will range from $58,000 to $97,000 per QALY which is higher than the accepted $50,000 per QALY benchmark. Extended DAPT duration with second-generation P2Y12 inhibitors: The recently published PEGASUS TIMI-54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagre- lor Compared to Placebo on a Background of AspirineThrombolysis in Myocardial Infarction 54) trial35 randomized 22,162 patients who were 1 to 3 (median 1.7) years after MI (53% had STEMI) to receive either placebo or 1 of 2 doses of ticagrelor for a median duration of 33 months. The trial showed that extended DAPT with both doses of ticagrelor significantly reduced the primary end point of cardiovascular mortality/MI/stroke compared to placebo (RR 0.15, p ¼ 0.008 and RR 0.16, p ¼ 0.004 for the 90 and 60 mg twice daily doses, respectively). This was driven by a reduction in MI (RR 0.19, p ¼ 0.01 and RR 0.16, p ¼ 0.03) and stroke (RR 0.18, p ¼ 0.14 and RR
Table 4 Proposed duration of dual antiplatelet therapy after coronary stenting according to the individual risks category for ischemic and bleeding events (as detailed in Tables 2 and 3) adapted from Binder R, Luscher F. Duration of dual antiplatelet therapy after coronary artery stenting: where is the sweet spot between ischemia and bleeding? Eur Heart J 2015; 36:1207-1211 Risk for ischemic events
Risk of bleeding
4
Low
Moderate
High
6 months
12 months
30 months
Moderate
3-6 months
6-12 months
12 months
High
3 months
3-6 months
6-12 months
Low
0.25, p ¼ 0.03). There was no significant reduction in overall and/or cardiovascular mortality. Major bleeding rates were again higher with extended DAPT and did not seem to differ between the 2 ticagrelor doses (HR 2.69, p <0.001 and HR 2.32, p <0.001 for the 90 and 60 mg twice daily doses, respectively). These results are in accordance with the DAPT trial and strengthen the evidence of improved efficacy associated with extended duration of DAPT. How to Settle the Conflicting Data? One important fact needs to be emphasized when reviewing the seemingly conflicting evidence from the RCTs mentioned previously. The trials that sought to prove the benefit of prolonged DAPT duration included only patients who completed 1 year of DAPT after stent implantation and were free of clinical events, whereas the trials that sought to show equivalence from shortened DAPT randomized patients immediately after stenting. Therefore, the 2 sets of trials (i.e., prolonged vs shortened DAPT) are not meant for comparison. Moreover, the aim of prolonging DAPT beyond 1 year relates also to the overall matter of secondary prevention of cardiovascular events, not necessarily related to the stent per se. These events may have been captured in the DAPT study, whereas in the shorter duration trials, the benefit in terms of secondary prevention may have gone unnoticed because of the shorter follow-up duration. Summary and Conclusions Considering the synthesis of data mentioned previously, there is still no consensus as to the optimal duration of DAPT after coronary stenting. The main hindrance for making precise patient-centered decisions regarding DAPT duration is the clinicians’ lack of a validated tool to predict the clinical impact of cessation versus prolongation of DAPT for the individual patient, at each time point after coronary stenting and/or cardiovascular event. We foresee the impact of the integration into clinical practice of new and more potent antithrombotic and cholesterol-lowering medications and the development of new stents and scaffolds, with biocompatible or fully resorbable materials assisted by precise coronary imaging modalities. On the basis of the currently available information, we conclude that there should be no “one size fits all” approach
Review/Optimal Duration of Antiplatelet Therapy
toward the decision of DAPT duration after stenting. The main factors that need to be considered are as follows: The clinical scenario: A presentation of stable CAD without coronary complexity supports an earlier cessation of DAPT as endorsed by the European Society of Cardiology revascularization guidelines6 (but as yet not endorsed in the United States). The relative risks for bleeding versus ischemic events (Tables 2 and 3). The type of stent used: Both the DAPT trial and a recent meta-analysis of trials comparing efficacy of longer versus shorter duration of DAPT36 reported more benefits for prolonged DAPT in patients treated by first- versus second-generation DES. This seems to be a temporary dilemma as no first-generation DESs are expected to remain in use in the future. We agree with the most contemporary approaches37; the question of whether to stop or continue the DAPT should be addressed individually for each patient at 6 and 12 months after stenting. Furthermore, at each time point, all individual factors related to ischemic and bleeding risks should be reviewed and used to make the optimal decision (Table 4). Finally, better tools for risk prediction are needed to optimize clinical benefit from DAPT in patients who underwent coronary stent implantation.
8.
9.
10.
11. 12.
13.
Disclosures The authors have no conflicts of interest to disclose. 1. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J 2014;35: 2950e2959. 2. Kasotakis G, Pipinos II, Lynch TG. Current evidence and clinical implications of aspirin resistance. J Vasc Surg 2009;50:1500e1510. 3. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009;373:1849e1860. 4. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494e502. 5. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358: 527e533. 6. Authors/Task Force members, Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Jüni P, Kappetein AP, Kastrati A, Knuuti J, Landmesser U, Laufer G, Neumann FJ, Richter DJ, Schauerte P, Sousa Uva M, Stefanini GG, Taggart DP, Torracca L, Valgimigli M, Wijns W, Witkowski A. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541e2619. 7. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ,
14.
15.
16.
17.
18.
19.
20.
5
Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent anticoagulation restenosis study investigators. N Engl J Med 1998;339:1665e1671. Albiero R, Hall P, Itoh A, Blengino S, Nakamura S, Martini G, Ferraro M, Colombo A. Results of a consecutive series of patients receiving only antiplatelet therapy after optimized stent implantation. Comparison of aspirin alone versus combined ticlopidine and aspirin therapy. Circulation 1996;93:412e422. Yusuf S, Mehta SR, Zhao F, Gersh BJ, Commerford PJ, Blumenthal M, Budaj A, Wittlinger T, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events Trial (CURE) Investigators. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 2003;107:966e972. Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators; Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411e2420. Epstein AJ, Polsky D, Yang F, Yang L, Groeneveld PW. Coronary revascularization trends in the United States, 2001-2008. JAMA 2011;305:1769e1776. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drugeluting stents. JAMA 2005;293:2126e2130. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, O’Gara P, Whitlow P; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol 2007;49:734e739. Bangalore S, Kumar S, Fusaro M, Amoroso N, Attubato MJ, Feit F, Bhatt DL, Slater J. Short- and long-term outcomes with drug-eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of 117 762 patient-year of follow-up from randomized trials. Circulation 2012;125:2873e2891. Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Sabaté M, Valgimigli M, Frati G, Kedhi E, Smits PC, Kaiser C, Genereux P, Galatius S, Kirtane AJ, Stone GW. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network metaanalysis. Lancet 2012;379:1393e1402. Camenzind E, Boersma E, Wijns W, Mauri L, Rademaker-Havinga T, Ordoubadi FF, Suttorp MJ, Al Kurdi M, Steg PG; PROTECT Steering Committee and Investigators. Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drugeluting stent type. Eur Heart J 2014;35:1932e1948. Silber S, Kirtane AJ, Belardi JA, Liu M, Brar S, Rothman M, Windecker S. Lack of association between dual antiplatelet therapy use and stent thrombosis between 1 and 12 months following resolute zotarolimus-eluting stent implantation. Eur Heart J 2014;35: 1949e1956. Kimura T, Morimoto T, Nakagawa Y, Tamura T, Kadota K, Yasumoto H, Nishikawa H, Hiasa Y, Muramatsu T, Meguro T, Inoue N, Honda H, Hayashi Y, Miyazaki S, Oshima S, Honda T, Shiode N, Namura M, Sone T, Nobuyoshi M, Kita T, Mitsudo K; j-Cypher Registry Investigators. Antiplatelet therapy and stent thrombosis after sirolimuseluting stent implantation. Circulation 2009;119:987e995. Kimura T, Morimoto T, Nakagawa Y, Kawai K, Miyazaki S, Muramatsu T, Shiode N, Namura M, Sone T, Oshima S, Nishikawa H, Hiasa Y, Hayashi Y, Nobuyoshi M, Mitudo K; j-Cypher Registry Investigators. Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: five-year outcome of the j-Cypher Registry. Circulation 2012;125:584e591. Wenaweser P, Daemen J, Zwahlen M, van Domburg R, Jüni P, Vaina S, Hellige G, Tsuchida K, Morger C, Boersma E, Kukreja N, Meier B, Serruys PW, Windecker S. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice.4-year results from a large 2institutional cohort study. J Am Coll Cardiol 2008;52:1134e1140.
6
The American Journal of Cardiology (www.ajconline.org)
21. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITONTIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001e2015. 22. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, PLATO Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045e1057. 23. Gwon HC, Hahn JY, Park KW, Song YB, Chae IH, Lim DS, Han KR, Choi JH, Choi SH, Kang HJ, Koo BK, Ahn T, Yoon JH, Jeong MH, Hong TJ, Chung WY, Choi YJ, Hur SH, Kwon HM, Jeon DW, Kim BO, Park SH, Lee NH, Jeon HK, Jang Y, Kim HS. Six-month versus 12-month dual antiplatelet therapy after implantation of drugeluting stents: the Efficacy of Xience/Promus versus Cypher to reduce late loss after stenting (EXCELLENT) randomized, multicenter study. Circulation 2012;125:505e513. 24. Feres F, Costa RA, Abizaid A, Leon MB, Marin-Neto JA, Botelho RV, King SB 3rd, Negoita M, Liu M, de Paula JE, Mangione JA, Meireles GX, Castello HJ Jr, Nicolela EL Jr, Perin MA, Devito FS, Labrunie A, Salvadori D Jr, Gusmão M, Staico R, Costa JR Jr, de Castro JP, Abizaid AS, Bhatt DL; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510e2522. 25. Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G, Tumscitz C, Castriota F, Colombo F, Tebaldi M, Fucà G, Kubbajeh M, Cangiano E, Minarelli M, Scalone A, Cavazza C, Frangione A, Borghesi M, Marchesini J, Parrinello G, Ferrari R; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dualantiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125:2015e2026. 26. Kim BK, Hong MK, Shin DH, Nam CM, Kim JS, Ko YG, Choi D, Kang TS, Park BE, Kang WC, Lee SH, Yoon JH, Hong BK, Kwon HM, Jang Y; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET trial (Real Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimuseluting stent implantation). J Am Coll Cardiol 2012;60:1340e1348. 27. Gilard M, Barragan P, Noryani AA, Noor HA, Majwal T, Hovasse T, Castellant P, Schneeberger M, Maillard L, Bressolette E, Wojcik J, Delarche N, Blanchard D, Jouve B, Ormezzano O, Paganelli F, Levy G, Sainsous J, Carrie D, Furber A, Berland J, Darremont O, Le Breton H, Lyuycx-Bore A, Gommeaux A, Cassat C, Kermarrec A, Cazaux P, Druelles P, Dauphin R, Armengaud J, Dupouy P, Champagnac D, Ohlmann P, Endresen K, Benamer H, Kiss RG, Ungi I, Boschat J, Morice MC. Six-month versus 24-month dual antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial. J Am Coll Cardiol 2015;65:777e786. 28. Schulz-Schüpke S, Byrne RA, Ten Berg JM, Neumann FJ, Han Y, Adriaenssens T, Tölg R, Seyfarth M, Maeng M, Zrenner B, Jacobshagen C, Mudra H, von Hodenberg E, Wöhrle J, Angiolillo DJ, von Merzljak B, Rifatov N, Kufner S, Morath T, Feuchtenberger A, Ibrahim T, Janssen PW, Valina C, Li Y, Desmet W, Abdel-Wahab M,
29.
30.
31.
32.
33. 34.
35.
36.
37.
Tiroch K, Hengstenberg C, Bernlochner I, Fischer M, Schunkert H, Laugwitz KL, Schömig A, Mehilli J, Kastrati A; Intracoronary Stenting and Antithrombotic Regimen: Safety And Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting (ISAR-SAFE) Trial Investigators. ISAR-SAFE: a randomized, double-blind, placebocontrolled trial of 6 versus 12 months of clopidogrel therapy after drugeluting stenting. Eur Heart J 2015;36:1252e1263. Collet JP, Silvain J, Barthélémy O, Rangé G, Cayla G, Van Belle E, Cuisset T, Elhadad S, Schiele F, Lhoest N, Ohlmann P, Carrié D, Rousseau H, Aubry P, Monségu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Beygui F, Vicaut E, Montalescot G; ARCTIC investigators. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014;384:1577e1585. Lee CW, Ahn JM, Park DW, Kang SJ, Lee SW, Kim YH, Park SW, Han S, Lee SG, Seong IW, Rha SW, Jeong MH, Lim DS, Yoon JH, Hur SH, Choi YS, Yang JY, Lee NH, Kim HS, Lee BK, Kim KS, Lee SU, Chae JK, Cheong SS, Suh IW, Park HS, Nah DY, Jeon DS, Seung KB, Lee K, Jang JS, Park SJ. Optimal duration of dual antiplatelet therapy after drugeluting stent implantation: a randomized, controlled trial. Circulation 2014;129:304e312. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371: 2155e2166. Elmariah S, Mauri L, Doros G, Galper BZ, O’Neill KE, Steg PG, Kereiakes DJ, Yeh RW. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet 2015;385: 792e798. Yeh RW, Cohen DJ, Mauri L. Close encounters with errors of the second kind: evaluating risks and benefits of long-term dual antiplatelet therapy. Eur Heart J 2015;36:1216e1218. Garg P, Galper BZ, Cohen DJ, Yeh RW, Mauri L. Balancing the risks of bleeding and stent thrombosis: a decision analytic model to compare durations of dual antiplatelet therapy after drug-eluting stents. Am Heart J 2015;169:222e233. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791e1800. Giustino G, Baber U, Sartori S, Mehran R, Mastoris I, Kini AS, Sharma SK, Pocock SJ, Dangas GD. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol 2015;65: 1298e1310. Binder R, Luscher F. Duration of dual antiplatelet therapy after coronary artery stenting: where is the sweet spot between ischaemia and bleeding? Eur Heart J 2015;36:1207e1211.