Extended dual antiplatelet therapy (DAPT) beyond 12 months reduces risks of stent thrombosis and cardiovascular events after drug-eluting stent placement compared to aspirin alone. In a trial of nearly 10,000 patients who tolerated 12 months of DAPT, continued DAPT for an additional 18 months led to a 71% reduction in stent thrombosis, a 29% reduction in death, heart attack or stroke, but a 61% increase in moderate or severe bleeding. The benefits of extended DAPT must be weighed against the increased bleeding risks for individual patients.

1. ROOTs JOURNAL CLUB
Mauri LM, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy (DAPT) after drug-eluting
stents (DES). N Engl J Med. 2014;371:2155-66.
Amy Yeh, PharmD Candidate 2015
Relevance
- Study Rationale:
o DES: coated with medication to stop excess tissue growth responsible for restenosis
 lower risk of revascularization, higher risk of in-stent thrombosis (compared to that of BMS)
o BASKET-LATE study: Increased risk for cardiac death/MI in DES vs. BMS (7-18 months), twice the risk of late
stent thrombosis after discontinuation of DAPT (clopidogrel + ASA)
o Thus, 2011 ACCF/AHA/SCAI guidelines for PCI recommend 12 months of DAPT post-DES PCI to mitigate the risk
of stent-related complications
o Optimal duration of DAPT post-DES PCI is unknown
- Study Objective:
o Evaluate whether continued DAPT beyond one year of drug-eluting stent PCI reduces the risk of stent
thrombosis and death, MI, or stroke (as compared to low-dose ASA) without an increased risk of bleeding
- Null hypothesis: There is no relationship between continued DAPT beyond one year of drug-eluting stent PCI and the
occurrence of thrombotic complications
- Patients: 9961 pts who tolerated 12 months of DAPT following drug-eluting stent PCI
- Intervention: [prasugrel 10 mg or clopidogrel 75 mg] + ASA 75-162 mg daily
- Comparison: Placebo + ASA 75-162 mg daily
- Outcome(s):
o Primary
 Efficacy
 stent thrombosis
 composite of all-cause mortality, MI or stroke
 Safety
 moderate or severe bleeding (GUSTO)
o moderate: requires blood transfusion, no hemodynamic instability
o severe: intracranial hemorrhage or presence of hemodynamic instability
o Secondary: all-cause mortality, MI, stroke, bleeding
- Key Inclusion Criteria:
o At time of PCI:
 age > 18, undergoing PCI with stent, or had PCI with stent in past 3 days, no DAPT contraindications
o At month 12 randomization:
 event-free in prior 12 months (death, MI, stroke, repeat coronary revascularization, stent thrombosis,
or moderate/severe bleeding
 medication compliance with DAPT in past 12 months
- Key Exclusion Criteria: stent diameter < 2.25 mm or > 4 mm, pregnancy, planned surgery requiring > 14 days of DAPT
discontinuation, life expectancy < 3 yrs, oral anticoagulation (increases bleed risk), hypersensitivity, switched
thienopyridine type in prior 10.5 months (indicator of intolerance)
- Key Baseline Characteristics: 62 yrs old, 75% male, weight 92 kg, BMI 31, 91% white, 9% non-white, 3% Hispanic/Latino,
90% North America, 8% Europe, 25% current/former smoker
- PMH: 31% diabetes, 75% HTN, 3% stroke/TIA, 5% HF, 6% PAD, 22% MI, 10% cancer
- Prior PCI 31%, prior CABG 11.5%, any risk for stent thrombosis 51%,
- Indication for PCI: 38% stable angina, 17% UA, 16% NSTEMI, 11% STEMI
- At start of open-label period: 65% clopidogrel, 35% prasugrel
- DES type: everolimus 47%, paclitaxel 27%, zotarolimus 11%, sirolimus 11%, multiple 2%
- PCI: 1.3 treated lesions, 1.1 treated vessels, 1.5 stents, stent length 28 mm
- Treated vessel: 97% native coronary-artery lesions, 3% venous or arterial graft
Observe validity
-Study design:
NI/Sup/Equivalence? superiority Run in or washout none
Prospective/Retrospective? Prospective Randomized? Yes (DAPT vs.ASA), computer system
No (prasugrel vs.clopidogrel)
Observational or
interventional?
interventional Blinded? yes
Independent/Dependent? independent Single or multi-center? multicenter

2. Parallel or cross-over? parallel ITT? PP? ITT
Placebo or active control? placebo LOCF? yes
Statistical analysis:
PARAMETRIC NON-PARAMETRIC
Independent/Dependent
#Groups_____2________
#Comparisons___MANY
Interval/Ratio
(e.g., ht, wt, age, etc)
Ordinal
(e.g., scales, rankings)
Nominal
(e.g., Gender, Y/N)
List all study outcomes (include
baseline characteristics,
outcomes and ADRs)
Age
Weight
BMI
# of treated lesions,vessels,stents
Total stent length
Gender
Ethnicity
Region of study
PMH
Current or recent smoker
Prior PCI or CABG or MI
Indication for PCI
Risk of thrombosis
Thienopyridinetype
Type of DES
# of lesions,vessels
stent diameter (< 3 or ≥3
mm)
Type of treated vessel
Lesion class
Occurrence/Type of stent
thrombosis
Occurrence/Type of major
adverse CV and CBV events
Occurrence/Type of
GUSTO bleeding
Occurrence/Type of BARC
bleeding
All-causemortality
MI
Stroke
List statistical tests used in
study
Not explicitly stated
t-test, per Supplementary
appendix
Log-rank test
Hochberg-Benjamini
Farrington-Manningrisk-
difference
Chi square
Fisher’s exact
Kaplan Meier
List ALL possible appropriate
tests
ANOVA/ANCOVA
Mann-Whitney U
Wilcoxon rank sum
Kruskal-Wallis
Mann-Whitney U
Wilcoxon rank sum
Kruskal-Wallis
Same as above
Were stats appropriate? No N/A Yes/No
-Critique: Because the t-test should only be used to make one comparison between 2 groups,it wasn’t appropriatefor evaluating
the baselinecharacteristics(7 comparisons).Doingso increases theprobability of makinga Type I error (concludingthere i s a
significantdifferencewhen there really isn’tone). However, we didn’t want to find a significantdifferencein the baseline
characteristics,so itwas okay. The tests used for non-parametric data (primary outcome) were appropriate.
-NNT and NNH application
o NNT
o 100 pts need to be treated with DAPT (clopidogrel 75 mg or prasugrel 10 mg, plus ASA 75-162 mg daily) for 30
months to prevent one occurrence of stent thrombosis
o 62 pts need to be treated with DAPT (clopidogrel 75 mg or prasugrel 10 mg, plus ASA 75-162 mg daily) for 30
months to prevent one occurrence of all-cause mortality, MI, or stroke
o NNH

3. o 111 pts need to be treated with DAPT (clopidogrel 75 mg or prasugrel 10 mg, plus ASA 75-162 mg daily) for 30
months for one pt to experience moderate or severe bleeding (GUSTO) as an ADR
Obtain clinically significant results
o The numbers
o Enrolled: 25,682 pts who received stents
o 22,866 received DES (2816 on BMS were removed)
o 9961 randomized after 12 months of DAPT
o Assigned to tx grps: 5020 (ASA + thienopyridine) vs. 4941 (ASA + placebo)
o Included in f/u at 30 months: 4783 (DAPT) vs. 4716 (ASA)
o Included in f/u at 33 months: 4732 (94.3%, DAPT) vs. 4658 (94.3%, ASA)
 Reasons for drop-outs: withdrew consent (76%), lost to follow up (24%)
Safety (DAPT vs. ASA)
o Moderate or severe bleeding (GUSTO): 2.5% vs. 1.6% (HR 1.61; 95% CI 1.21-2.16; 2-sided p = 0.001; NNH 111)
o Difference: 1.0%; 95% CI 0.4-1.5%; 2-sided p = 0.001
Efficacy (DAPT vs. ASA)
o Stent thrombosis: 0.4% vs. 1.4% (HR 0.29; 95% CI 0.17-0.48; p < 0.001; NNT 100)
o All-cause mortality, MI, or stroke: 4.3% vs. 5.9% (HR 0.71; 95% CI 0.59-0.85; p < 0.001; NNT 62)
Cost: Average Wholesale Price of 30 pills
 For pts without insurance, adding clopidogrel or prasugrel to their monthly budget may not be feasible
o clopidogrel 75 mg: $208.80
o Plavix® 75 mg: $232.04
o Effient® (prasugrel) 10 mg: $388.08
o ASA 81 mg: $0.64
Convenience
o DAPT requires the administration of two pills instead of just one
o ASA 81 mg comes as tablets, caplets, and chewables, but clopidogrel and prasugrel are tablets only
o Prasugrel may be crushed or chewed, but has a bitter taste
o ASA is OTC; prasugrel and clopidogrel require prescriptions + time away from work for costly office visits
Clinical Guidelines (place in therapy)
 Per 2011 ACCF/AHA/SCAI guidelines, continuing DAPT beyond the first year can be considered (based on physician
discretion)
 The results of this trial have not been published in the guidelines
Major trial inconsistencies
 Trial excluded pts who didn’t tolerate DAPT well initially  selected for compliant, low bleed risk pts
 No details on how medication adherence was assessed
 Did not randomize to thienopyridine, so cannot compare efficacy of clopidogrel vs. prasugrel
 Unclear if results would apply to other types of DES
o However, the 4 types used are the only ones available in the USA
Translate Results into Practice
Conclusions
o Large, well-designed,adequately powered (85%) study
o Among patients who completed one year of DAPT after drug-elutingstent PCI, continued DAPT (for a total of 30 months)
reduces the rate of stent thrombosis and death, MI, or stroke atthe costof increased bleeding,as compared to ASA 75-
162 mg daily
Recommendations
o Continue DAPT for another 18 months post-DES PCI (for a total of 30 months) in these patients
o No increased risk of bleeding (hemophilia, oral anticoagulation, etc)
o No major ADRs on the first 12 months of DAPT
o Great with medication adherence
o Cost is not a concern
References
o Mauri LM, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy(DAPT) after drug-eluting stents (DES). N Engl J
Med. 2014;371:2155-66.
o Levine GN, BatesER, BlankenshipJC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronaryintervention. Circulation.
2011;124(23):e574-651.
o Lexicompwebsite. Accessed at http://online.lexi.com.proxy.pba.edu/on June 11, 2015