Dual Antiplatelet Therapy Duration: A Review of Current Available Evidence

Clinical Therapeutics/Volume ], Number ], 2016

Dual Antiplatelet Therapy Duration: A Review of Current Available Evidence Ioannis Mastoris, MD1,2; Priyanka Maria Mathias, MD2; and George D. Dangas, MD, PhD1 1

Icahn School of Medicine, Mount Sinai Hospital, New York, New York; and 2Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York

ABSTRACT Purpose: Multiple regimens of antiplatelet and anticoagulation therapy have been used in the past in patients undergoing percutaneous coronary intervention (PCI). Later trials of PCI stenting demonstrated the efficacy of dual-antiplatelet therapy (DAPT) in reducing stent- and non–stent-related thrombotic events in this specific population. Nonetheless, the required duration of DAPT has not yet been elucidated. In this article we sought to identify various randomized clinical trials (RCTs), pooled analyses, meta-analyses, and data pertaining to the optimal duration of DAPT and attempt some recommendations based on patients’ clinical and procedural profiles. Methods: We performed an extensive search using MEDLINE, Scopus, Cochrane Library, and Internet sources for abstracts, manuscripts, and conference reports without any language or date restrictions. In our review we included all available evidence from RCTs, meta-analyses, observational studies, and abstracts pertaining to our topic. Search results that were deemed irrelevant or that would not serve the goal or topic of our review were excluded. Results: Our search yielded 10 RCTs directly comparing different durations of DAPT, 3 metaanalyses amassing the evidence resulting from randomized data, and numerous observational studies that served the aim of our review. The observational studies included in the manuscript are directly related to instances in which RCTs could not be performed or introduce important concepts related to the duration of DAPT. Implications: There is no conclusive evidence that determines the mandatory DAPT duration after PCI. In addition, there are distinct patient populations that need specific treatment regimens, such as diabetic patients or those on long-term oral anticoagulation.

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Therefore, clinical judgement and meticulous examination of all pertaining risk factors are required for each individual. These factors include those related to a patient’s characteristics, treatment procedures, lesion complexity, and stent type. Currently ongoing studies are anticipated to further elucidate and integrate our understanding with regard to DAPT. (Clin Ther. 2016;]:]]]–]]]) & 2016 Elsevier HS Journals, Inc. All rights reserved. Key words: dual antiplatelet therapy, DAPT duration, percutaneous coronary intervention.

INTRODUCTION Since its inception, percutaneous coronary intervention (PCI) accompanied by stent implantation has always been followed by various types of platelet inhibition. The importance of platelet inhibition was shown early in studies in which patients treated with a combination of aspirin and dipyridamole before PCI had lower rates of evidenced thrombi after successful percutaneous transluminal coronary angioplasty.1 Different regimens have been used to reduce increased platelet and endothelial thrombogenicity after PCI, including aspirin, warfarin, dipyridamole, and ticlopidine.2–5 In 2001, the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study6 found that the addition of clopidogrel to a regimen of aspirin resulted in a 2% reduction in the risks for cardiovascular events, including myocardial infarction (MI) and stroke, in patients with acute coronary syndromes (ACSs), although with an associated increase (1%) in major bleeding events. The CREDO Accepted for publication February 12, 2016. http://dx.doi.org/10.1016/j.clinthera.2016.02.016 0149-2918/$ - see front matter & 2016 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics (Clopidogrel for the Reduction of Events during Observation) trial7 found that prolonged therapy with clopidogrel after PCI also significantly reduced the risk for death, MI, and stroke at 1 year after randomization. Later on, the Percutaneous Coronary Interventions Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) substudy6,8 demonstrated that the initiation of clopidogrel before PCI and its continuation for a mean of 8 months after PCI with stent implantation, along with aspirin, would confer a considerable mortality benefit in patients receiving a stent compared with those treated solely with aspirin. This finding was confirmed by later studies.9 Therefore, the combined use of 2 antiplatelet medications has been established as the standard of care in patients undergoing PCI.10 While DAPT has been shown to protect against ischemic events, this benefit is accompanied by an increased risk for bleeding complications. Thus, the need for an ideal duration of DAPT in those patients is an important consideration for treating physicians. Multiple studies have been conducted in an effort to elucidate this complex question.11–22 The development of new stent platforms, new PCI techniques, and new pharmacologic agents has perplexed the situation even more.23 To date, there has been no clear answer as to what should be the recommended duration of DAPT. Safety concerns regarding prolonged-duration DAPT were originally expressed in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) study.9 In this study, although DAPT had no effect in ischemic outcomes in patients with stable coronary artery disease (CAD), it was associated with a significant increase in moderate bleeding and a numeric but nonsignificant increase in severe/fatal bleeding events. Rather, an individualized approach is needed when considering the total duration of DAPT therapy. In this article, we aimed to review the current literature available in a systematic way and to provide helpful direction regarding this important but still controversial topic.

MATERIALS AND METHODS We searched MEDLINE, Scopus, Cochrane Library, and Internet sources for abstracts, manuscripts, and conference reports without any language or date restrictions. To meet the goals of our review, we

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included randomized clinical trials (RCTs), pooled analyses, meta-analyses, and observational studies pertinent to the topic of our review. The following terms have been used alone or in combination: dual antiplatelet therapy, drug-eluting stent, clopidogrel, aspirin, randomized clinical trial, and percutaneous coronary intervention. Prespecified inclusion criteria were: (1) comparison between DAPT (aspirin plus a thienopyridine) versus aspirin alone, and (2) PCI with drug-eluting stent (DES) implantation. Prespecified exclusion criteria were: (1) duplicated data, and (2) ongoing trials without final results.

RESULTS Current Randomized Data on DAPT Duration A total of 10 RCTs have been conducted to date pertaining to the duration of antiplatelet therapy after PCI stenting during the acute (ST-elevation MI) or nonacute (non–ST-elevation acute coronary syndromes [NSTEACS]-stable angina) setting.11–21 Of note, all of these trials used clopidogrel as the additional antiplatelet factor, and no data on the newer agents (ie, prasugrel and ticagrelor) were available. In broad terms, 2 categories of trials exist: (1) those that have tested the continuation of DAPT for 412 months, and (2) those that have tested a shorter course of therapy of o12 months.

Trials Comparing a 3- to 6-Month versus a 12-Month Regimen The majority of trials have focused their interest in reducing the duration of DAPT therapy to o12 months (12 months is the duration recommended in current guidelines)24,25, given the latest advances in stents; second-generation DESs; and, more recently, bioabsorbable scaffolds and drug platforms. The EXCELLENT (Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting) trial11 was the first trial that aimed to provide answers on this topic. Overall, it enrolled 1443 patients and compared a 12-month versus a 6-month course of DAPT in both stable (49%) and ACS (51%) patients receiving either an everolimus or sirolimus DES. The general characteristics of this study population, as well as for the rest of the studies included in the present review, are available in Table I. The primary outcome was defined as target vessel failure, including a composite of cardiac death, MI, or target vessel revascularization

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] 2016 Table I. Characteristics of the randomized clinical trials included in this review of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention. Duration, mo Trial

Year

N

% of Patients

SL- Follow- PlaceboDAPT DAPT Up* Controlled

3- or 6-mo discontinued DAPT trials ISAR-SAFE22 2014 4000 6

12

6

Yes

ITALIC17

2014 1894

6

12

6

No

SECURITY16

2014 1399

6

12

12‡

No

OPTIMIZE15

2014 3119

3

12

12

No

PRODIGY21

2012 1970

6

24

23

No

EXCELLENT11

2011 1443

6

12

12

No

RESET12

2012 2117

3

12

12

No

12-mo discontinued DAPT trials 2014 9961 DAPT20

12

30

21

Yes

12

48

42

No

DES-LATE13,14

2014 5045

Primary End Point Composite of death, MI, stroke, and ST or TIMI major bleeding at 15 mo after PCI Composite of death, MI, repeated TVR, stroke, and TIMI major bleeding at 12 mo after PCI Composite of cardiac death, MI, stroke, and ST or BARC 3 or 5 bleeding at 12 mo after PCI Composite of death, MI, stroke, and major bleeding at 12 mo after PCI Composite of death, MI, and cerebrovascular accident at 24 mo after PCI Composite of cardiac death, MI, and TVR at 12 mo after PCI Composite of cardiac death, MI, ST, ischemiadriven TVR, and bleeding at 12 mo after PCI ST; composite of death, MI, or stroke; and moderate or severe GUSTO bleeding Composite of cardiac death, MI, and stroke at 24 mo after PCI

1G- 2GMean Age, y DM ACS DES DES 67

25

40

10

89

62

37

24

–

100†

65

31 38§

–

100

61

35 32§

–

100

68

24

75

25

50

63

38

51

25

75

62

29

55

21

85‖

62

31

43

38

60

62

28

61

64

30

3

I. Mastoris et al.

(continued)

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ACS = acute coronary syndrome; BARC = Bleeding Academic Research Consortium; DAPT = dual antiplatelet therapy; DES = drug-eluting stent; DM = diabetes mellitus; G = generation; GUSTO = Global Use of Strategies to Open Occluded Coronary Arteries classification; L-DAPT = longer-term dual antiplatelet therapy; MI = myocardial infarction; PCI = percutaneous coronary intervention; S-DAPT = shorter-term dual antiplatelet therapy; ST = stent thrombosis; TIA = transient ischemic attack; TIMI = Thrombolysis in Myocardial Infarction; TVR = target vessel revascularization. * Duration of follow-up from randomization. † Xience V Everolimus-Eluting Stent only (Abbott Vascular, Santa Clara, California). ‡ Maximum duration of follow-up was 24 months; however, maximum duration of DAPT was 12 months. In the analyses, outcomes at 12 months were included. § High-risk acute coronary syndromes excluded. ‖ 100% Endeavor Zotarolimus-Eluting Stent (Medtronic Inc, Minneapolis, Minnesota) in the 3-month group.

60 40 – 34 64 Composite of death, MI, stroke, TIA, urgent revascularization, and ST No 17 6–18 12 2014 1259 ARCTICInterruption18,19

Trial

Table I. (continued).

Year

N

SL- Follow- PlaceboDAPT DAPT Up* Controlled

Duration, mo

Primary End Point

Mean 1G- 2GAge, y DM ACS DES DES

% of Patients

Clinical Therapeutics at 1 year after index procedure. The study had outstanding rates of DAPT adherence in both the 12-month (99.3%) and 6-month (99.9%) groups. The results showed that at 1 year after PCI, a shorter duration of 6 months would not confer a higher risk for thrombotic events except for stent thrombosis (ST), the prevalence of which, although not statistically different, was numerically higher in the shorter-duration group (4.8% vs 4.3%; P ¼ 0.6). Furthermore, there was increased bleeding in patients with a longer mean DAPT duration, although this finding was not statistically significant (0.6% vs 1.4%; P ¼ 0.12). This finding was homogeneous among the different subgroups, and only diabetic patients appeared to gain further antithrombotic protection from full-course DAPT (Pinteraction o 0.001). In the same direction as the previous trial, the RESET (Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy After Endeavor ZotarolimusEluting Stent Implantation) trial12 was a prospective, open-label trial comparing a 3-month versus a 12-month course of DAPT in 2117 patients who received a zotarolimus DES or any other commercially available DES. The randomization was further stratified by clinical characteristics, such as diabetes mellitus (DM) and ACS, or by lesion characteristics, such as lesion duration. The study was conducted at 26 sites in Korea, enrolling patients with a diagnosis of angina or acute MI with 450% diameter stenosis and who presented for elective PCI. In this noninferiority trial, the primary end point was defined as the composite of cardiovascular death, MI, ST, target lesion revascularization/target vessel revascularization or any bleeding at 12 months of follow-up (net adverse cardiovascular events). No difference was demonstrated between the 2 groups with regard to the primary end point (4.7% vs 4.7%; difference, 0%; 95% CI, –2.5 to 2.5; Pnoninferiority ¼ 0.84). Importantly, individual clinical outcomes were also similar between the 2 groups. No superiority analysis was provided in the results of the study. Similar conclusions were drawn in the OPTIMIZE (Optimized Duration of Clopidogrel Therapy After Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice) study.15 OPTIMIZE was a multicenter, randomized, open-label, activecontrolled trial that enrolled 3119 patients who presented with stable CAD and low-risk ACS. Patients received PCI with the zotarolimus DES and either

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I. Mastoris et al. 3-month or 12-month DAPT. The primary end point was defined as the net adverse clinical and cerebral events, including all-cause death, MI, stroke, or major bleeding at 12 months of follow-up after randomization. Key secondary end points were major adverse cardiovascular events, as well as individual outcomes of the composite outcome. As demonstrated by the results, both net adverse clinical and cerebral events (6.0% vs 5.8%; P ¼ 0.84) and major adverse cardiovascular events (8.3% vs 7.4%; P ¼ 0.36) were similar between the 2 groups. Different timeframe analyses (0–90 days and 90 days to 1 year) did not reveal any time-dependent variations in events rates. In the past 2 years, the ISAR-SAFE22 and SECURITY16 trials have examined the outcomes after PCI of a 6-month course of DAPT compared with the standard 12-month therapy. ISAR-SAFE (Randomized, Double-Blind, Placebo-Controlled Trial of 6 vs 12 Month Clopidogrel Therapy After Implantation of a Drug-Eluting Stent)22 was designed as a double-blind, placebo-controlled, noninferiority trial comparing a composite outcome of death, MI, ST, stroke, and Thrombolysis in Myocardial Infarction– defined major bleeding between the 2 regimens (N ¼ 4000). The study has been hampered by slow enrollment and unexpectedly low event rates in the control group, and as a consequence, conclusions should be guarded. The primary end point occurred in 29 (1.5%) of the people assigned to 6-month treatment compared with 32 (1.6%) in the longerduration group (20.1%, 95% confidence upper limit, 0.5%; one-sided 97.5% confidence upper limit, 0.6%; Pnoninferiority o 0.001; HR ¼ 0.91; 95% CI, 0.55– 1.50, Psuperiority ¼ 0.70). SECURITY (Second-Generation Drug Eluting Stent Implantation Followed by 6- Versus12-Month Dual Antiplatelet Therapy)16 was a multinational, prospective, randomized, noninferiority trial that compared a 6-month course to a 12-month course of DAPT, with up to 24 months of follow-up after randomization of the patients. End points of the study were the same as those in the previous studies, including a primary composite outcome of ischemic events, such as cardiac death, MI, stroke, ST, and Bleeding Academic Research Consortium criteria type 3 or 5 bleeding at 12 months. Because of enrollment difficulties, only 1399 patients were randomized, rendering the study unable to detect significant differences in terms of superiority. However, the upper limit of the 95% CI was lower than the preset margin

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of 2% (P o 0.05), supporting the noninferiority hypothesis of the trial. No statistical differences were observed in the secondary outcomes. Two trials have tested a 24- versus a 6-month course of DAPT after DES implantation. In PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia),21 6- and 24-month strategies were compared using a balanced mixture of stents (bare metal stents [BMSs], first and second generation). At 2 years, the rates of a composite of all-cause death, MI, or cerebrovascular accident were similar between the 2 groups (HR ¼ 0.98; 95% CI, 0.74–1.29; P ¼ 0.91), and the non–coronary artery bypass grafting–associated bleeding event rate (Bleeding Academic Research Consortium classification 2, 3, or 5) was almost 2-fold higher in the longterm treatment group (HR ¼ 2.17; 95% CI, 1.44– 3.22; P ¼ 0.00018). Landmark analysis at 6 months of follow-up showed a numerically higher cumulative incidence of the composite end point without reaching statistical significance. ITALIC (Is There a Life for DES After Discontinuation of Clopidogrel)17 was a randomized study that assigned patients with confirmed nonresistance to aspirin to the 6 vs 24 months DAPT. A total of 2031 patients were enrolled in 70 European and Middle Eastern centers. The trial was prematurely terminated due to recruitment problems, randomizing 941 patients to long-duration DAPT versus 953 to 6-month of DAPT. The difference in the primary end point of ischemic and bleeding events was not significant (24 months, 1.5%; 6 months, 1.6%; P ¼ 0.85). Noninferiority was demonstrated for 6- versus 24month DAPT, with an absolute risk difference of 0.11% (95% CI, 1.04%–1.26%; Pnoninferiority ¼ 0.0002). Importantly, no differences in ST complications were observed. The rationale of these studies evaluating a shorter DAPT duration has been based on evidence from later stent studies comparing older to newer stent platforms and different medication eluted.23 The effects of DAPT duration on stent outcomes were reported in a substudy of the PRODIGY trial, in which the zotarolimus DES performed significantly better than did the everolimus and paclitaxel DESs.26 While the effects of DAPT duration on stent outcomes have not widely reported, it is thought that second-generation stents may be associated with a lower risk for ischemic events.

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Clinical Therapeutics

Trials Comparing a 12-Month Regimen versus a Longer Treatment Regimen The first study evaluating DAPT duration was a merged analysis of the ZEST-LATE (Evaluation of the Long-Term Safety After Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or Paclitaxel-Eluting Stent Implantation for Coronary Lesions—Late Coronary Arterial Thrombotic Events) and REAL-LATE (Correlation of Clopidogrel Therapy Discontinuation in Real-World Patients Treated With Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events) studies, known as DES-LATE (Optimal Duration of Clopidogrel Therapy With DES To Reduce Late Coronary Arterial Thrombotic Events).13,14 The combined analysis found that in patients free of adverse events for 12 months after DES implantation, prolongation of DAPT for 2 years did not offer any additional benefit. Rather, an unexpectedly higher rate of ischemic events was observed in the DAPT group (HR = 1.65; 95% CI, 0.8–3.36; P = 0.17). In an extended analysis of the previous analysis totaling 5045 patients, the extended DAPT regimen did not offer any additional benefit.27 The recently published DAPT (Dual Antiplatelet Therapy) trial20,28 was a large-scale, international, multicenter, placebo-controlled trial that randomized 9961 event-free patients after the first year after DESPCI to either continue with DAPT for another 18 months or to discontinuation of the thienopyridine. The co-primary efficacy end points were ST and the composite of death, MI, and stroke during the period from 12 to 30 months after DES implantation. The primary tolerability end point was moderate to severe bleeding. The results of this massive trial changed the perspective on longer-duration DAPT by demonstrating a significant late benefit in stent-related (0.4 vs 1.4; P o 0.001) and non–stent-related ischemic events (4.3 vs 5.9; P o 0.001) with prolonged DAPT.7 Nonetheless, the ischemic benefit of prolonged DAPT was counterbalanced by an increased risk for major bleeding (5.6 vs 2.9; P o 0.001) and a controversial finding toward higher all-cause mortality (2.0 vs 1.5; P ¼ 0.05). Of note, increased risks for ST and MI were seen in the 3 months after thienopyridine discontinuation, as presented in the supplementary appendix of the trial. Finally, ARCTIC-Interruption (Assessment by Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for

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DES Implantation and of Treatment Interruption Versus Continuation 1 Year After Stenting)18,19 was a prospective, multicenter, open-label study planned as an extension of the ARCTIC trial and randomly assigned 2440 patients to platelet function testing with subsequent adjustment or to conventional treatment with DAPT after PCI-DES. A total of 1259 eligible patients were randomized in the study. At a median follow-up of 17 months, the rates of the primary end point (a composite of death, MI, ST, stroke, and urgent revascularization) were similar between the shorter- and longer-duration courses. Major bleeding events were numerically higher although non-significantly different with longer DAPT duration (1% vs o0.5%; P = 0.073), suggesting that prolongation of DAPT may only confer an increased bleeding risk without realized ischemic risk reduction.

What the Pooled Data Suggest Multiple trials evaluating ideal DAPT duration have not provided the medical community with a clear message regarding what would be the answer to this controversial topic. As such, some pooled analyses have tried clarifying this issue. A meta-analysis by Giustino et al29 pooled and analyzed data from all available trials. A total of 10 RCTs including a massive 32,135 patients were analyzed. The groups of patients were classified as short (S)-DAPT (defined as the per-protocol minimum-duration of DAPT after DES implantation in each RCT) and long (L)-DAPT (defined as the perprotocol period of DAPT prolongation after S-DAPT in each RCT). The investigators of this meta-analysis concluded that compared with L-DAPT, S-DAPT was associated with a higher rate of ST (odds ratio [OR] ¼ 1.71; 95% CI, 1.26–2.32; P ¼ 0.001). An important interaction between DAPT duration and stents was demonstrated, suggesting that the effect of S-DAPT on ST was attenuated with the use of the secondgeneration DES (OR ¼ 1.67; 95% CI, 0.99–2.80) but was significant with use of first-generation DESs (OR ¼ 4.55; 95% CI, 2.32–8.92; Pinteraction ¼ 0.01). S-DAPT was associated with a significantly lower risk for clinically significant bleeding (OR ¼ 0.61; 95% CI, 0.51–0.73; P o 0.001). Finally, a nonsignificant trend toward lower all-cause mortality was observed in the S-DAPT group (OR ¼ 0.87; 95% CI, 0.74– 1.01; P ¼ 0.07). Volume ] Number ]

I. Mastoris et al. In addition, a pairwise and Bayesian meta-analysis by Palmerini et al30 identified 31,666 patients enrolled in clinical trials and aimed to evaluate mortality and other clinically important outcomes using several analytical approaches. Similar to the previous metaanalysis, DAPT duration was defined as short- and long-term using the same definitions. By frequent pairwise meta-analysis, shorter DAPT duration was associated with significantly lower all-cause mortality when compared with longer DAPT duration (HR ¼ 0.82; 95% CI, 0.69–0.98; P ¼ 0.02), without an obvious heterogeneity among groups analyzed. This important finding was mostly attributed to the reduction of noncardiac death, underlining the great importance of lower rates of bleeding in the shortduration group. Nonetheless, shorter duration was conspicuously associated with an increased incidence of thrombotic events such as MI (HR ¼ 1.51; 95% CI, 1.28–1.77; P o 0.001) and ST (HR ¼ 2.04; 95% CI, 1.48–2.8, P o 0.0001). A different perspective regarding mortality is provided by another meta-analysis that included the largest number of participants in clinical trials (N ¼ 69,644). In this study by Elmariah et al,31 prolonged treatment with DAPT beyond 12 months was not associated with increased all-cause mortality (HR ¼ 1.04; 95% CI, 0.96–1.18; P ¼ 0.17) with both cardiovascular-related (HR ¼ 1.01; 95% CI, 0.93– 1.13; P ¼ NS) and non–cardiovascular-related (HR ¼ 1.04; 95% CI, 0.9–1.26; P ¼ NS) mortality being similar. Serial sensitivity analyses performed with sequential exclusion of studies as well as restriction of analysis to only 10 trials did not reveal any different result.

Antiplatelet Therapy in Patients with an Indication for Oral Anticoagulation Lately, antithrombotic therapy after PCI in patients with an indication of anticoagulation (due to atrial fibrillation, deep vein thrombosis, and mechanical valves) has been a matter of debate. While existing revascularization guidelines advocate for a tripletherapy strategy, atrial fibrillation guidelines suggest single antiplatelet and anticoagulation therapy in patients with a high bleeding risk, although supporting evidence is rather lacking.32–35 A recent RCT in patients with an indication for anticoagulation undergoing PCI ( 28% elective PCI) compared triple

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therapy (DAPT þ warfarin) versus dual (clopidogrel þ warfarin).36 Not surprisingly, at 1-year of followup, patients on the dual regimen had lower rates of bleeding events (HR ¼ 0.36; 95% CI, 0.26–0.50; P o 0.0001) and death from any cause (HR ¼ 0.39; 95% CI, 0.16–0.93; P ¼ 0.027), suggesting that triple antithrombotic therapy may be harmful in populations with multiple comorbidities. Data from RE-LY (Concomitant Use of Antiplatelet Therapy With Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy)37 showed a significant increase in major bleeding in those treated with oral anticoagulant therapy when also treated with single (60% increase) or dual (230% increase) antiplatelet therapy. Furthermore, In the APPRAISE-2 (Apixaban With Antiplatelet Therapy After Acute Coronary Syndrome) trial27 comparing apixaban with placebo after ACS, treatment with apixaban led to significantly greater prevalence of bleeding, as assessed by Thrombolysis in Myocardial Infarction– defined major bleeding and other bleeding scales. The vast majority of patients in the study were treated with DAPT. The study was prematurely stopped by the Data and Safety Monitoring Board. Analysis of data from enrolled patients did not show any benefit in reduction in ischemic outcomes. As a result, an astute approach is required in the care of these patients. The implementation of ischemic (CHADS-2 [congestive heart failure, hypertension, age Z75 years, DM (1 point for presence of each), and stroke/transient ischemic attack (2 points)], CHA2DS2-VAsc [congestive heart failure, hypertension, age Z75 years (1 point each), DM (2 points), and stroke/ transient ischemic attack (2 points), vascular disease]) and bleeding risk (HAS-BLED [hypertension (uncontrolled systolic blood pressure 4160 mm Hg), abnormal renal and/or liver function, previous stroke, bleeding history or predisposition, labile international normalized ratios, elderly, and concomitant drugs and/or alcohol excess]) scores in patient risk stratification is of the essence in guiding patients’ care, although it seems that their use is not homogeneous among physicians.38–41

Patients with Diabetes In an observational study including approximately 29,000 patients undergoing PCI but not treated with current-generation DESs, patients were stratified as nondiabetic (non-DM), those with DM treated with oral medications or diet, and those with DM treated

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Clinical Therapeutics

Table II. Guideline recommendations for dual antiplatelet therapy in patients undergoing percutaneous coronary intervention.

Patient Population

US Guidelines32

Stent (BMS or DES) At least 12 mo. Longer in ACS durations may be considered in patients with DES. BMS in stable At least 1 mo (2 wk if patient high bleeding risk, ideally 12 mo) DES in stable At least 12 mo patient Secondary Could be considered prevention

UK National European Society of Institute for Health Cardiology and Care Excellence Guidelines33,43 Guidelines

Australian Guidelines

Up to 12 mo

Up to 12 mo

12 mo

At least 1 mo

According to device US guidelines instructions agreement

6 mo

At least 12 mo

US guidelines agreement Restricted to No May be considered patients with high recommendation in patients with ischemic risk recurrent events

ACS = acute coronary syndrome; BMS = bare metal stent; DES = drug-eluting stent; PCI = percutaneous coronary intervention.

with insulin.42 Treatment with DAPT using aspirin and clopidogrel extending further than 12 months lowered the risk for death and MI compared with those treated for r12 months. The finding appeared to be restricted to patients with DM and also was confined to DESs rather than BMSs. Severe bleeding events were infrequent and not higher with prolonged DAPT.

Current Guideline Recommendations Current guideline recommendations are found in Table II. Starting in 2011, the US guidelines32 have assigned a Class I recommendation to the following strategies:

 Lifelong continuation of aspirin  Thienopyridines should be used for at least 12 months after PCI for ACS.

 In non-ACS patients and in patients with a lower risk for bleeding, clopidogrel should be administered for at least 12 months after DES implantation.

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 In patients receiving a BMS for a non-ACS indication, clopidogrel should be given for at least 1 month (ideally for 12 months).

The previous recommendations are open to different interpretations and suggest that stopping DAPT at earlier than 12 months is reasonable as long as the patient is at a higher risk for bleeding that greatly exceeds the ischemic risk. Nonetheless, prolonged DAPT can be considered in patients with high ischemic risk characteristics and associated low bleeding risk as stated by the recent 2014 AHA/ACC guideline for the management of patients with NSTEACS.24 The 2014 European guidelines on myocardial revascularization adopt a more liberal approach in DAPT management, taking into consideration data from newer studies.33,43 Ergo, the European guidelines recommend DAPT for a maximum of 12 months after ACS, for only 1 month after BMS implantation for non-ACS indications, and for only 6 months after DES implantation for non-ACS indications.

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I. Mastoris et al.

Clinical Decision Making, from Scylla to Charybdis The uncertainty and inconsistencies regarding optimal DAPT duration are reflected in the current recommendations from the 2 major cardiologic societies. While the European Society of Cardiology suggests a minimum duration of 6 months after DES implantation, the ACC/AHA joint guidelines adopt a conservative approach of 12 months. The background under which DAPT cessation occurs has been shown to affect subsequent events. In the PARIS (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients) registry, physician-guided discontinuation of DAPT (patient deemed no longer needed DAPT) was associated with lower prevalences of ischemic and bleeding events, whereas DAPT interruption (due to bleeding or noncompliance) led to a higher incidence of thrombotic events.44 Clinical decisions are hard to make, especially when the gist of evidence available is controversial and not pointing in a specific direction. Medicine is an art in the current background of evidence and science. These are provided by current RCTs and observational studies producing data-guided results, sometimes under a protected and unrealistic environment compared with clinical practice. It is especially in this kind of unreal setting that treatment effect is evaluated. Very often though, data can be inconclusive. In this setting, clinical decisions rely on the physician to critically evaluate and combine data, patient-related information, and clinical experience to devise an acceptable patient-oriented management. The decision to either continue or stop DAPT after a mandatory period is reflected by this concept. An initial period of DAPT is required after DES implantation to prevent stent- and non–stent-related thrombotic complications. During this mandatory period, any cessation of DAPT can result in thrombotic events.44–48 This initial period can vary from 3 to 12 months and is highly affected by patient comorbidities, presentation, lesion complexity, extent of the disease, and type of stent implanted. Continuation of DAPT beyond that required period needs an astute and shrewd physician’s approach.49 Prolongation of DAPT can be of benefit in select patient groups, such as diabetic patients. But as shown can also confer an unacceptably higher risk for bleeding, eventually affecting morbidity and mortality.20 Ergo, a careful and realistic approach of patient management is of paramount importance for tailored therapy.

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A tool providing assistance to physicians has been recently presented, originating from the DAPT trial.50 The scale can be found at http://www.daptstudy.org/ forclinicians/score_calculator.htm and is the result of analysis in 11,648 trial participants who completed 12 months of DAPT without incident and were randomly assigned to continue taking aspirin with or without a thienopyridine. The investigators used multivariate models to predict the composite of MI and ST (ischemia model) and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) classification of moderate/severe bleeding (bleeding model) over time, then combined this information into a positive or negative integer, dubbed the DAPT score. The DAPT score ranges from –2 to 10 and is made up of the following factors: age, DM status, smoking status, PCI or MI history, presence of chronic heart failure or left ventricular ejection fraction o30%, and index procedural characteristics (MI at presentation, vein-graft PCI, and stent diameter). In the models deriving the score, older age exclusively predicted increased bleeding risk, while exclusive predictors of increased ischemic events included history of PCI and/or MI, stent diameter 43 mm, chronic heart failure or left ventricular ejection fraction o30%, and MI at presentation. Characteristics that predicted both bleeding and combined ischemic events had a minimal impact on net treatment effect and were left out of the final DAPT Score assessment. Among patients who did not have a major ischemic or bleeding event within the first year after PCI, the DAPT score can identify patients in whom ischemic benefits outweighed bleeding risk and in patients in whom bleeding risk outweighed ischemic benefits. This risk score could represent a useful tool in the armamentarium of the treating physician when making a decision regarding the continuation of DAPT. However, given the fact that this tool is still new, its utility in daily clinical practice has to be further validated in different patient cohorts. As shown in the PROTECT trial,51 coronary thrombotic events after PCI can be classified as either stent- or non–stent-related. DAPT results in reduction of both types of events by attenuating platelet reactivity and agreeability.52 Thrombotic pathophysiology has distinct aspects and is characterized by patient-, stent-, and procedurerelated factors.46–49,53–55 Initial presentation (ACS versus stable angina), DM, chronic kidney disease,

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Clinical Therapeutics

Percutaneous coronary intervention with DES

DAPT

Duration?

Individual clinical characteristics

Elderly patients Female gender Peptic ulcer disease AV malformations Chronic liver disease Coagulopathy

Medication: NSAIDs, anticoagulation Uncontrolled HTN End stage renal disease Poor adherence Active malignancy

Stop DAPT after pre-specified

period

Male gender Diabetes Renal feilure Acute coronary syndromes Peripheral vascular disease segment

Lesion complexity Prior ischemic event Stent overlap Left ventricular dysfunction Smoking

Continue DAPT after prespecified period

Figure. Guidance for tailoring dual antiplatelet therapy (DAPT), according to risk factors for ischemia and bleeding, in patients undergoing percutaneous coronary intervention.

CAD equivalents, and left ventricular dysfunction constitute patient-related factors. Procedure-related factors include lesion complexity, vessel calcification, number of diseased vessels, procedural success (stent apposition and complications), and number of stents implanted. Finally, stent-related factors would include polymer sensitivity resulting in defective endothelium apposition, stent thickness, and strut thrombogenicity. All of these factors should be considered when evaluating thrombotic risk in patients undergoing PCI. In those who present with a constellation of risk factors, prolongation of DAPT beyond the required period would be both plausible and attractive. On the contrary, some objective bleeding scores exist in literature that could be used to gauge bleeding risk, although they are not tuned to a PCI population. The HASBLED score has been used to evaluate bleeding risk in patients who present with atrial fibrillation and would not perfectly fit for the purposes of PCI populations.41 Otherwise, more intuitive and straightforward factors such as malignancy, thrombocytopenia, anemia, white blood cell count, low platelet reactivity, frailty and other genetic factors have been described in literature.39,56,57 The Figure summarizes factors attributable to the risks for ischemia and bleeding and provides objective guidance in tailoring DAPT.

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Ongoing Research The percolation of powerful antiplatelet drugs in daily practice, along with the implantation of safer stent platforms, have shifted clinical research interests to alternative treatment strategies that primarily aim at the withdrawal of agents and will greater add to our understanding. In an effort to reduce bleeding events, the currently ongoing GLOBAL LEADERS study (Comparative Effectiveness of 1 Month of Ticagrelor Plus Aspirin Followed by Ticagrelor Monotherapy Versus a Current-Day Intensive Dual Antiplatelet Therapy in All-Comers Patients Undergoing Percutaneous Coronary Intervention With Bivalirudin and BioMatrix Family Drug-Eluting Stent Use; ClinicalTrials.gov identifier: NCT01813435) plans to randomize 16,000 patients to receive either a 1-month standard DAPT regimen followed by ticagrelor monotherapy for 24 months versus standard 1-year therapy followed by lifelong aspirin treatment. Quite similarly, TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention; ClinicalTrials.gov; NCT02270242) will determine the impact of antiplatelet monotherapy with ticagrelor alone versus DAPT with ticagrelor plus low-dose aspirin for 12 months in reducing bleeding among high-risk patients undergoing PCI who have completed a 3-month course of aspirin plus ticagrelor.

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CONCLUSIONS As is evident in this review, the optimal choice of DAPT duration and even DAPT components are not yet well-defined. In that context of controversy, clinical judgement and acumen of the treating physician taking into consideration all different aspects pertaining to DAPT are needed to make appropriate clinical decisions. The critical evaluation of the risk for ischemia versus bleeding in each patient should be the primary consideration when determining the duration of DAPT for patients undergoing PCI.

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ACKNOWLEDGMENTS Authors deny receiving any grants, honoraria, consultancies, speakers’ bureau or advisory-board positions, and significant stock holdings. No study sponsors were involved in the design, collection, presentation and explanation of data.

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CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article. 13.

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Address correspondence to: Ioannis Mastoris, MD, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, NY 10029. E-mail: [email protected]

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