# Duration of dual antiplatelet therapy following drug-eluting stent implantation: A systemic review and meta-analysis of randomized controlled trials with longer follow up

Abhishek Sharma, Sahil Agrawal, Aakash Garg, Ajay Vallakati, Carl Lavie, Gerald Helft

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Abhishek Sharma, Sahil Agrawal, Aakash Garg, Ajay Vallakati, Carl Lavie, et al.. Duration of dual antiplatelet therapy following drug-eluting stent implantation: A systemic review and meta-analysis of randomized controlled trials with longer follow up. Catheterization and Cardiovascular Interventions, 2017, 90 (1), pp.31-37. 10.1002/ccd.27123. inserm-03970284

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# Duration of dual antiplatelet therapy following drug-eluting stent implantation: A systemic review and meta-analysis of randomized controlled trials with longer follow up

Abhishek Sharma, MD<fnref n="1" />,<fnref n="2" /> ID | Sahil Agrawal, MD<fnref n="3" /> ID | Aakash Garg, MD<fnref n="4" /> |

Ajay Vallakati, MD<fnref n="5" /> | Carl J. Lavie, MD<fnref n="6" /> | Gerald Helft, MD<fnref n="7" />,<fnref n="8" />

## Correspondence

Abhishek Sharma, MD, Division of Cardiovascular Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203.

Email: abhisheksharma4@mamc@gmail.com

The editor's choice video can be viewed online at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1522-726X/homepage/cci_editor_s.choice_papers_and_videos.htm.

**Objective:** To evaluate the long term efficacy and safety of long duration DAPT (L-DAPT) compared to short duration DAPT (S-DAPT) after drug-eluting stent (DES) implantation.

**Methods:** We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomized controlled trials (RCTs) assessing the clinical impact of L-DAPT versus S-DAPT after DES and have mean follow up period of at least 2 years or longer. Primary end point was stent thrombosis (ST). Secondary endpoints were all-cause mortality, cardiac mortality, myocardial infarction (MI), target vessel revascularization (TVR), thrombolysis in myocardial infarction (TIMI) major bleeding and stroke. Event rates were compared using a random effects model.

**Results:** We identified five RCTs in which 19,760 patients were randomized to S-DAPT (N = 9,810) and L-DAPT (n = 9,950), respectively. Compared with L-DAPT, S-DAPT was associated with higher rate of MI (odds ratio [OR] 1.48, 95% confidence interval [CI] [1.04, 2.10]). There were no significant differences between S-DAPT and L-DAPT in terms of all cause mortality, cardiac mortality, ST, TVR or stroke (OR 0.90, 95% CI [0.73, 1.12]; OR 1.02, 95% CI [0.80, 1.30]; OR 1.59, 95% CI [0.77, 3.27]; OR 0.87 95% CI [0.67, 1.14]; and OR 1.08 95% CI [0.81, 1.46], respectively). However, rate of TIMI major bleeding was significantly lower with S-DAPT compared to L-DAPT (OR 0.64, 95% CI [0.41, 0.99]).

**Conclusions:** In the present analysis of RCTs with longer follow up (2 years or longer), S-DAPT compared with L-DAPT, was associated with higher rate of MI and lower rate of major bleeding without any significant difference in the rates of all cause mortality, cardiac mortality, ST, TVR, and stroke.

## KEYWORDS

drug eluting stents, dual anti-platelet therapy, myocardial infarction, stent thrombosis

**Abbreviations:** ACSacute coronary syndrome; CI, confidence interval; CV, cardiovascular; DAPT, dual antiplatelet therapy; DES, drug eluting stent(s); L-DAPT, long duration dual antiplatelet therapy; MI, myocardial infarction; OR, odds ratio; RCT, randomized controlled trial; S-DAPT, short duration dual antiplatelet therapy; ST, stent thrombosis.

## 1 | INTRODUCTION

Dual anti-platelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is recommended for 6–12 months after DES to reduce stent thrombosis (ST) and non-stent related ischemic events [1,2], however, optimal DAPT

<footnote n="1">¹Division of Cardiovascular Medicine, State University of New York Downstate Medical Center, New York, New York</footnote>

<footnote n="2">²Institute of Cardiovascular Science and Technology, Brooklyn, New York</footnote>

<footnote n="3">³Division of Cardiology, St. Luke's University Health Network, Bethlehem, Pennsylvania</footnote>

<footnote n="4">⁴Department of Medicine, St. Peter's University Hospital, Rutgers-Robert Wood Johnson Hospital, New Brunswick, New Jersey</footnote>

<footnote n="5">⁵Division of Cardiology, Metrohealth Medical Center, Case Western Reserve University, Cleveland, Ohio</footnote>

<footnote n="6">⁶Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School-the University of Queensland School of Medicine, New Orleans, Louisiana</footnote>

<footnote n="7">⁷Institut de Cardiologie, Hôpital Pitié-Salpétrière, Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, boulevard de l'Hôpital, Paris, France</footnote>

<footnote n="8">⁸Institute of Cardiometabolism and Nutrition, Hôpital Pitié-Salpétrière, Paris, France</footnote>
<figure><img src="image_2.png" /><figcaption>FIGURE 1 The preferred reporting items for systematic reviews and meta-analyses. (PRISMA) flow chart for the trial selection process</figcaption></figure>

duration remains debatable. Several randomized control trials (RCTs) and meta-analysis including these trials have attempted to compare differences in outcomes between strategies of short (S) (3–6 months) and longer (L) (12–30 months) durations of DAPT and have reported conflicting results [3–10]. In general, the events rates in these trials were small thereby affecting statistical power. Furthermore, the optimal duration of dual antiplatelet therapy after drug-eluting stent implantation (OPTID-UAL) trial [10] which showed no reduction in ischemic events with L-DAPT (48 months) over standard (12 months) DAPT, after an extended median follow up of 33 months was prematurely terminated due to slow enrolment. In this background of the generally low rates of ischemic events at shorter follow ups, we conducted this updated meta-analysis to compare the efficacy and safety of strategies of S-DAPT versus L-DAPT strategy after DES implantation by restricting inclusion to randomized studies with follow-up durations of 24 months or longer.

## 2 | METHODS

### 2.1 | Study design

We followed the PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement for reporting systematic reviews and meta-analyses of RCTs for reporting results of our meta-analysis [11].

### 2.2 | Data sources and search strategy

We systematically searched PubMed, CINAHL, Cochrane CENTRAL, Embase, Scopus and Web of Science databases for randomized clinical trials comparing different durations of DAPT after coronary DES implantation. Pertinent trials were also searched in clinicaltrials.gov and in the

proceedings of major international cardiology meetings (American College of Cardiology [ACC], American Heart Association [AHA], European Society of Cardiology [ESC], The Society for Cardiac Angiography and Interventions [SCAI]). DAPT was defined as aspirin plus a P2Y12 receptor inhibitor, after coronary DES implantation. S-DAPT and L-DAPT were defined as duration of DAPT after DES implantation of 12 months or less and longer than 12 months, respectively. All relevant combinations of following keywords "aspirin," "P2Y12 receptor inhibitor," "clopidogrel," "Plavix," "prasugrel," "Effient," "ticagrelor," "Brilinta," "thienopyridine," "dual antiplatelet therapy," "DAPT," "drug eluting stent/s," "DES," "death," "mortality," "survival," "cardiac mortality," "stent thrombosis (ST)," stroke, myocardial infarction (MI), "randomized controlled trial," "random," "random allocation," "double-blind," and "single-blind" were included for database search. We hand searched references of identified studies. The search period took place from 1 January, 2002 to November 30, 2016. No language restrictions were applied. The corresponding authors of the relevant studies were queried for required quantitative details not in the published manuscripts.

### 2.3 | Data extraction

Two reviewers (AS, AG) independently screened the titles and abstracts for relevance. The manuscripts of selected titles/abstracts were reviewed for inclusion or exclusion using the above mentioned selection criteria. Two reviewers (AS, AG) independently determined the articles to be included and excluded, and data from the relevant articles were extracted using pre-defined extraction forms. Any disagreements in data extraction were discussed until consensus was reached. Baseline patients characteristics and following data was extracted from selected studies at the end
<table><caption>TABLE 1 Baseline characteristics of studies included in analysis</caption><thead><tr><td>Study</td><td>Design</td><td>Time to randomization</td><td>Inclusion criteria</td><td>Exclusion criteria</td><td>Primary end-point</td></tr></thead><tbody><tr><td>SECURITY</td><td>Randomized, multicenter</td><td>At index PCI</td><td>Stable angina, unstable angina, silent ischemia, treated with at least 1 sec generation DES in the target lesion in the past 24 hr; ≥1 ≥70% stenosis in a native coronary artery</td><td>SVGs lesions; ISRs; UP-LMCA; STEMI in the prior 48 hr; NSTEMI in the previous 6 months; CKD (creat >2); active bleeding or high bleeding risk.; hypersensitivity to aspirin, thienopyridines</td><td>Composite of cardiac death, MI, stroke, ST or BARC 3 or 5 bleeding at 12 months after PCI</td></tr><tr><td>PRODIGY</td><td>Randomized, open label, multicenter</td><td>1 month after index PCI</td><td>≥18 years old; ≥1 50% coronary artery lesion; PCI suitability; chronic stable coronary artery disease or ACS (NSTEMI or STEMI)</td><td>History of bleeding diathesis; major surgery within 15 days; planned surgery within 24 months requiring DAPT interruption; Active bleeding or stroke in the past 6 months; concomitant anti-oagulation therapy</td><td>Composite of death, MI or cerebrovascular accidents at 24 months after PCI</td></tr><tr><td>DES-LATE</td><td>Randomized, open label, multicenter</td><td>12 months after index PCI</td><td>DES within 12 months; on DAPT; no MACE (MI, stroke, repeat PCI) or major bleeding since PCI.</td><td>CI to antiplatelet drugs, concomitant vascular disease or recent ACS requiring clopidogrel use</td><td>Composite of cardiac death, MI or stroke at 24 months after PCI</td></tr><tr><td>OPTIDUAL</td><td>Randomized, open label, multicenter</td><td>12 months after index PCI</td><td>Stable angina, silent ischemia, or acute coronary syndrome with ≥1 lesion with stenosis >50% located in a native vessel implanted with ≥1 DES of any type</td><td>Requirement for oral anti-oagulation, DES implantation in an unprotected left main coronary artery, and malignancies or other coexisting conditions associated with a life expectancy of <2 years</td><td>Composite of all-cause mortality, non-fatal myocardial infarction, stroke, or major bleeding</td></tr><tr><td>DAPT</td><td>Randomized, double-blind, multicenter</td><td>12 months after index PCI</td><td>>18 years undergoing FDA-approved PCI with DES or BMS; No MACE or bleeding within 12 months after procedure</td><td>Planned major surgery within the 30 months post enrollment; OAC; Both BMS and DES during index procedure; PCI or surgery between 6 weeks post-PCI and randomization</td><td>ST; composite of death, MI, stroke; and moderate or severe GUSTO bleeding</td></tr></tbody></table>

Abbreviations: ACS, acute coronary syndrome; BMS, bare metal stent; CKD, chronic kidney disease; CTO, chronic total occlusion; ECG, electrocardiogram; FDA, Food and Drug Administration; LM, left main; TVR, target vessel revascularization; STEMI, ST segment elevation myocardial infarction; NSTEMI, non ST segment elevation myocardial infarction; PCI, percutaneous coronary interventions; MI, myocardial infarction; DES, drug eluting stents; OAC, oral anticoagulant; MACE, major adverse cardiac event; GUSTO, global utilization of streptokinase and tpa for occluded arteries; SVG, saphenous venous grafts; UPLMA, unprotected left main artery; DAPT, the dual antiplatelet therapy study; DES-LATE, the optimal duration of clopidogrel therapy with DES to reduce late coronary arterial thrombotic event; PRODIGY, prolonging dual antiplatelet treatment after grading stent-induced intimal hyperplasia study; SECURITY, second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy; OPTIDUAL, optimal duration of dual antiplatelet therapy after drug-eluting stent implantation; RESET, REal Safety and Efficacy of 3-month dual antiplatelet Therapy following endeavor zotarolimus-eluting stent implantation.

of follow up period: all-cause mortality, cardiac mortality, MI, stent ST, target vessel revascularization (TVR), major bleeding (as defined by thrombolysis in myocardial infarction [TIMI] classification], and stroke.

neity was considered significant if the *P* value was less than 0.05. Publication bias was assessed by Begg's test and Egger's regression test.

## 2.4 | Data analysis

The statistical analysis was performed according to the recommendations from the Cochrane Collaboration using Review Manager Version 5.1 (The Nordic Cochrane Center, The Cochrane Collaboration, 2008, Copenhagen) was used. A random-effects model with inverse variance weighting was used to calculate odds ratio (OR) and 95% confidence interval (CI), associated with S-DAPT versus L-DAPT for above end points. Forest plot was used to observe the overall effect of studies. Heterogeneity between studies was assessed using Cochrane's Q test and I² statistic, which denotes the percentage of total variation across studies that is a result of heterogeneity rather than chance. Heterogeneity was considered significant if the *P* value was less than 0.05. Publication bias was assessed by Begg's test and Egger's regression test.

# 3 | RESULTS

## 3.1 | Study outlines and characteristics

Our initial search identified 2,692 publications. After careful assessment of titles and abstracts, 11 studies were identified for review of full-text manuscripts. Five RCTs that met all inclusion criteria of this meta-analysis were finally included (Figure 1) [3,5,6,9,10]. In these studies a total of 19,760 patients were randomized to S-DAPT (N = 9,810) and L-DAPT (n = 9,950). Mean follow up was 29.4 months.

Descriptors of included studies and baseline characteristics of patients enrolled in these studies are summarized in Tables 1 and 2. Mean age of enrolled patients ranged from 62 to 68 years. Male patients
<table><caption>TABLE 2 Baseline patient characteristics in the studies included in the analysis</caption><thead><tr><th>STUDY</th><th>N</th><th>Follow-up (months)</th><th>Age (years)</th><th>Male (%)</th><th>DM (%)</th><th>ACS (%)</th><th>Clopidogrel/ Prasugrel/Ticagrelor</th><th>First generation DES (%)/second generation DES (%)</th><th>Prior MI (%)</th></tr></thead><tbody><tr><td>SECURITY</td><td>1399</td><td>12</td><td>65</td><td>77</td><td>31</td><td>38</td><td>100/0/0</td><td>0/100</td><td>20</td></tr><tr><td>PRODIGY</td><td>1478</td><td>24</td><td>68</td><td>77</td><td>24</td><td>74</td><td>100/0/0</td><td>24.9/50.1</td><td>27</td></tr><tr><td>DES-LATE</td><td>5045</td><td>36</td><td>62</td><td>69</td><td>28</td><td>60</td><td>100/0/0</td><td>64/36</td><td>4</td></tr><tr><td>OPTIDUAL</td><td>1385</td><td>33</td><td>64</td><td>81</td><td>31</td><td>36</td><td>100/0/0</td><td>34.3/65.7</td><td>17</td></tr><tr><td>DAPT</td><td>9751</td><td>18</td><td>62</td><td>75</td><td>31</td><td>42</td><td>65.3/34.7/0</td><td>40.1/59.9</td><td>22</td></tr></tbody></table>

Abbreviations: ACS, acute coronary syndrome; N, number of patients; DES, drug eluting stents; DM, diabetes mellitus; MI, myocardial infarction; DAPT, the dual antiplatelet therapy study; DES-LATE, the optimal duration of clopidogrel therapy With DES to reduce late coronary arterial thrombotic event; PRODIGY, prolonging dual antiplatelet treatment after grading stent-induced intimal hyperplasia study; SECURITY, second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy; OPTIDUAL, optimal duration of dual antiplatelet therapy after drug-eluting stent implantation.

<table><caption>TABLE 3 Clinical outcomes with S-DAPT compared with L-DAPT</caption><thead><tr><th></th><th>Odds ratio (95% confidence interval)</th><th>P<sub>interaction</sub></th><th>Hetero-geneity (I<sup>2</sup>)</th></tr></thead><tbody><tr><td>All-cause mortality</td><td>0.90 [0.73, 1.12]</td><td>0.36</td><td>16%</td></tr><tr><td>Cardiac mortality</td><td>1.02 [0.80, 1.30]</td><td>0.89</td><td>0%</td></tr><tr><td>MI</td><td>1.48 [1.04, 2.10]</td><td>0.003</td><td>61%</td></tr><tr><td>ST</td><td>1.59 [0.77, 3.27]</td><td>0.21</td><td>63%</td></tr><tr><td>TVR</td><td>0.87 [0.67, 1.14]</td><td>0.31</td><td>0%</td></tr><tr><td>Stroke</td><td>1.08 [0.81, 1.46]</td><td>0.59</td><td>0%</td></tr><tr><td>TIMI major bleeding</td><td>0.64 [0.41, 0.99]</td><td>0.04</td><td>0%</td></tr></tbody></table>

Abbreviations: MI, myocardial infarction; NACE, net adverse clinical events; ST, Stent thrombosis; TIMI, thrombolysis in myocardial infarction; TVR, target vessel revascularization.

<figure><img src="image_3.png" /><figcaption>FIGURE 2 Forest plot for stent thrombosis with S-DAPT and L-DAPT [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>FIGURE 3 Forest plot for all cause mortality with S-DAPT and L-DAPT [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>FIGURE 4 Forest plot for cardiac mortality with S-DAPT and L-DAPT [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>

constituted 69–81% of included patients. Diabetes mellitus was reported in 24–31% patients. Proportion of patients with stable coronary disease at time of DES implantation was 26–64% in the included trials. Use of second generation ranged from 36% to 100%. Clopidogrel was the predominant P2Y12 inhibitor used for DAPT while prasugrel and ticagrelor were used in varying proportions in these trials.

## 3.2 | Clinical outcomes

Clinical outcomes with S-DAPT compared with L-DAPT are summarized in Table 3. Compared to L-DAPT, use of S-DAPT did not significantly increase the rate of ST (0.45% vs. 0.99%, OR 1.59, 95%: 0.77–3.27). Heterogeneity among the five studies reporting on this outcome was moderate ($I^2$ = 63%) (Figure 2). Similarly, there was no significant difference in the rate of all-cause mortality (2.41% vs. 2.19%, OR 0.90, 95% CI: 0.73–1.12) (Figure 3) or cardiac mortality (1.30% vs. 1.34%, OR 1.03, 95% CI: 0.81–1.31) (Figure 4) with L-DAPT and S-DAPT. Heterogeneity among studies was low for either outcome.

S-DAPT compared to L-DAPT was associated with a higher rate of MI (3.12% vs. 1.88%, OR 1.48, 95% CI: 1.04–2.10) (Figure 5) but a lower rate of TIMI major bleeding (0.81% vs. 1.28%, OR 0.64, 95% CI: 0.41–0.99) (Figure 6). Heterogeneity was moderate for the outcome of MI ($I^2$ = 61%) but low for TIMI major bleeding ($I^2$ = 0%). Rate of TVR was reported in three of five RCTs and there was no significant difference with S-DAPT versus L-DAPT (2.68% vs. 3.04%, OR 0.87, 95% CI: 0.67–1.14) (Supporting Information Figure 1). Similarly, rate of stroke, which was reported in 5 of 6 studies, was not statistically different in S-DAPT and L-DAPT arm (0.95% vs. 0.87%, OR 1.08, 95% CI: 0.81–1.46) (Supporting Information Figure 2).

# 4 | DISCUSSION

In the current analysis of five RCTs with approximately 20,000 patients with 2 years or longer follow up S-DAPT compared to L-DAPT was associated with significant increase in rates MI, and reduction in the rate of major bleeding. However, there was no significant difference in rate of all-cause mortality, cardiac mortality, ST, TVR, and stroke between S-DAPT and L-DAPT.

Optimal duration of DAPT after DES implantation remains a subject of ongoing debate. The previously recommended minimum 12 month duration of DAPT in patients treated with DES was based primarily on observational data [12]. Following recent randomized data from trials comparing either shorter (3 or 6 months) or longer (18–30 months) duration with the traditional 12 month DAPT duration, a focused update of the ACCF/AHA recommendations [13] gave a Class I recommendation for a reduced period of time of 6 months in patients treated with DES for stable ischemic heart disease compared to 12 months previously. The former recommendation of DAPT for at least 12 months in patients treated with DES for an ACS was upheld as a Class I indication but also suggested recommended consideration of longer durations of DAPT (Class IIa).

The risk of ST, especially late (1 month to 1 year) and very late (>1 year) ST with newer-generation DES is low [14]. Such delayed ST events seem to result largely from impaired vessel healing and delayed endothelial coverage [15], and a late hypersensitivity reaction to the drug-eluting polymer [16]. The most important independent predictor of ST is antiplatelet therapy discontinuation, especially when premature [17]. Extending duration of DAPT beyond 6–12 months might therefore reduce late and very late ST as well the small risk of non-stent

<figure><img src="image_6.png" /><figcaption>FIGURE 5 Forest plot for myocardial infarction with S-DAPT and L-DAPT [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>
<figure><img src="image_7.png" /><figcaption>FIGURE 6 Forest plot for major bleeding with S-DAPT and L-DAPT [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>

related MI, and other atherosclerotic events that exists beyond 1 year in patients treated with coronary stents [18]. In the Dual Antiplatelet Therapy (DAPT) study [9], DES treated patients (n = 9,961) were randomized to an additional 18 months of DAPT or to aspirin monotherapy if they were free of ischemic or bleeding events on DAPT for 12 months previously. Extending DAPT resulted in significant reductions in rates of very late stent thrombosis and non-stent related thrombotic events paired with an increase in major bleeding. In the most recent OPTImal DUAL Antiplatelet Therapy (OPTIDUAL) trial [10] (n = 1,385), outcomes in patients in whom clopidogrel was continued were compared with those in whom it was stopped 12 months after DES placement. There was a nominally lower rate of ischemic outcomes (combination of death, MI, or stroke) with prolonged DAPT but no difference in ST between the two groups. Similarly, in our meta-analysis of longer follow up studies there was no significant reduction in ST with L-DAPT compared with S-DAPT.

An unexpected finding in the DAPT study was a borderline-significant increase in all-cause mortality rate in patients treated with prolonged DAPT. Subsequent meta-analyses have found significant increase in risk of all-cause but not cardiovascular death with prolonged duration of DAPT in patients treated with predominantly newer DES, a finding largely driven by events in the DAPT trial [19–21]. A cause of death sub-analysis of the DAPT study [22] had previously found that the increase in all-cause mortality rates in the extended DAPT arm was driven entirely by an increase in non-cardiovascular deaths, and bleeding related deaths were few (0.3% vs. 0.2% continued DAPT vs. aspirin monotherapy, respectively). Rather, the difference was primarily attributed to a higher proportion of cancer at recruitment and cancer-related deaths among those randomized to the extended DAPT arm. Findings of our meta-analysis of no increase in either all-cause or cardiovascular death are similar to those of a Food and Drug Administration drug safety communication [23] as well as of another analysis, both of which had concluded that long-term treatment with DAPT did not increase the risk of all-cause death or cardiovascular death [13]. The risk reduction in MI with L-DAPT in our study did not translate into a reduction in all-cause or cardiovascular mortality benefit. The thrombotic benefit of L-DAPT may have been counterbalanced by an increase in clinically significant major bleeding seen in our study. Such bleeding increases mortality risk in patients treated with PCI, with suggestions from some studies that the hazard may indeed exceed that associated with an MI [24]. Therefore it is likely that no single DAPT duration is clearly superior in all patients with DES and decisions about duration of DAPT need to be individualized after incorporating an assessment of the risks of ischemia and bleeding. The “DAPT score”

derived from the DAPT study [25] provides a simple clinical tool to assess risk/benefit of extending DAPT in patients treated with a coronary stent. A score of ≥2 predicts a favorable benefit/risk ratio for continuing DAPT in patients treated for 1 year with DAPT without significant bleeding or ischemic events. Conversely, in those with a DAPT score <2, the risk/benefit ratio does not favor prolonged DAPT.

The current meta-analysis is the first to compare outcomes between S-DAPT and L-DAPT in a meta-analysis restricted to trials with patient follow-up of 24 months or longer and found no significant difference in the rate of ST with S-DAPT and L-DAPT. A major limitation of most RCTs and previous meta-analyses was a short period of follow up. Between the small number of ST events due to the low risk of ST with newer generation DES and the possibility that very-late ST events were not captured due to inadequate follow up, individual trials and even previous meta-analysis were probably underpowered to detect a definitive difference in reduction of very-late ST with L-DAPT.

Our study has several limitations. First, the current analysis is based on trial-level data, which precludes identification of causal association or factors related with recurrent ischemia and bleeding events. Second, the trials included in this study differed in terms of design and enrollment criteria. Specifically, there was heterogeneity in terms of proportion of stable versus unstable patients and time of randomization. Third, the clinical trials included in the current meta-analysis have mostly employed use of clopidogrel. With increasing adoption of more potent P2Y12 inhibitors in clinical practice, the relative benefit-to-risk profile of S-DAPT versus L-DAPT remains to be established. Finally, the current analysis is lacking in evaluation of interaction effects of stent generation type, novel P2Y12 inhibitors or clinical setting.

## 5 | CONCLUSIONS

In the present analysis of RCTs with longer follow up (2 years or longer), S-DAPT compared with L-DAPT, was associated with higher rate of MI and lower rate of major bleeding without any significant difference in the rates of all cause mortality, cardiac mortality, ST, TVR, and stroke.

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**How to cite this article:** Sharma A, Agrawal S, Garg A, Vallakati A, Lavie CJ, GeraldHelft CJ. Duration of dual antiplatelet therapy following drug-eluting stent implantation: A systemic review and meta-analysis of randomized controlled trials with longer follow up. *Catheter Cardiovasc Interv.* 2017;90:31-37. https://doi.org/10.1002/ccd.27123