Dual Antiplatelet Therapy for 12 or 30 months (DAPT Study)

1. Dual Antiplatelet Therapy for 12 or 30 Months
After Drug-Eluting Stents
The DAPT Study

2. Background
• Studies suggesting an increased risk of stent thrombosis with drug-eluting
stent (DES) prompted the US Food and Drug Administration (FDA) to
convene a meeting of its Circulatory System Device Advisory Panel in
December 2006, to examine DES safety.
• Cessation of DAPT with Aspirin and Thienopyridine is associated with an
increased risk of stent thrombosis.

3. Background
• The American College of Cardiology & The American Heart Association
guidelines recommend 12 months of DAPT after DES. The European
Society of Cardiology recommends DAPT for 6 months or less following
DES.
• The FDA requested a trial to evaluate the optimal duration of DAPT.

4. Background
• The DAPT study was performed through a private-public collaboration
involving the FDA, stent and pharmaceutical manufacturers, and Harvard
Clinical Research Institute.

5. Methods
• Prospective, international (11 countries), multicenter (452 sites), randomized,
double-blind trial
• Subjects: Adults (> 18 yrs.) enrolled within 72 hours of stent placement and
prescribed 12 months of open-label Thienopyridine plus aspirin

6. Methods
• Eligibility: Patients without major adverse cardiovascular and cerebrovascular events
(MACCE), repeat revascularization, or moderate/severe bleeding demonstrating
adherence to Thienopyridine during the 12 month open label period
• Excluded: Warfarin or similar anticoagulant, planned surgery requiring antiplatelet
discontinuation, having both DES and bare-metal stent (BMS) during index
procedure, stent diameter < 2.25mm or > 4.0mm
• Note: Patient who received BMS were not included in this analysis

7. Methods
• Patients were randomly assigned 1:1
 Continued Clopidogrel 75mg daily or Prasugrel 10mg daily for 18 months (n=5020)
 Placebo for 18 months (n=4941)
• All patients continued Aspirin 75-162mg daily
• Primary efficacy endpoints
 Cumulative incidence of definite or probable stent thrombosis
 MACCE (composite of death, myocardial infarction or stroke)

8. Methods
• Primary safety endpoint
 Moderate or severe bleeding
• After the 30 month randomization treatment period ended, patients
continued taking Aspirin alone and were followed for a 3 month observation

9. DAPT Study Flow
Figure 1: Enrolment, Randomization, and Follow-up. Patients
were enrolled within 72 hours after stent placement. They were
followed for 12 months while they received open-label
treatment with Thienopyridine plus aspirin and were then
randomly assigned to receive Thienopyridine therapy or
placebo (each in addition to aspirin) for an additional 18
months. The randomized treatment period ended at 30 months;
thereafter, patients continued taking aspirin only and were
followed for another 3 months. Although the number of patients
with available data on clinical follow-up is reported in each
group, the co-primary efficacy end points were analysed with
the last available follow-up information in the intention-to-treat
population, which included all patients who underwent
randomization. GUSTO denotes Global Utilization of
Streptokinase and Tissue Plasminogen Activator for Occluded
Arteries.

10. Drugs and DES Types at Randomization
Thienopyridine
(n=5020)
Placebo
(n=4941)
Thienopyridine (%):
Clopidogrel
Prasugrel
65.2
34.8
65.4
34.6
DES Type (%):
Xienca/Promus (Everolimus)
TAXUS (Paclitaxel)
Endeavor (Zotarolimus)
Cypher (Sirolimus)
>1 type
46.7
26.9
12.8
11.5
2.1
47.7
26.6
12.6
10.9
2.1

11. Primary Efficacy Endpoints
Bleeding End Point during Month 12 to
Month 30.

12. Stent Thrombosis &
MACCE
Groups + _ Total Incidence
Placebo 665 4276 4941 13.46%
Thienopyridine 464 4556 5020 9.24%
Total 1129 8832 9961
Risk with placebo treatment = 0.13
Risk with Thienopyridine = 0.09
Absolute Reduction Risk = 0.04
Number Needed To Treat = 25
- for every 25 patients treated 1 patient will see a benefit
Relative Risk = 0.69
- RR< 1 therefore the event is less likely to occur in the Thienopyridine
group than in the placebo group
Relative Risk Reduction = 0.31
- there is an approximately 31% decrease risk of MCCE in the Thienopyridine
group as opposed to the placebo group

13. Cumulative Incidence of
Stent Thrombosis, According
to Study Group
Figure 2: Cumulative Incidence of Stent Thrombosis, According to Study
Group. Cumulative incidence curves are shown for the primary efficacy end
point of probable or definite stent thrombosis, as assessed according to the
criteria of the Academic Research Consortium, in the intention-to-treat
population. Randomization occurred at 12 months after stenting. The primary-
analysis period was the period from month 12 to month 30 after percutaneous
coronary intervention (i.e., the 18 months after randomization, during which
subjects received the randomized study drug). Patients were followed for an
observational period of an additional 3 months after discontinuation of the
study drug (i.e., to 33 months after enrolment and 21 months after
randomization). P values were calculated with the use of a stratified log-rank
test. The number at risk was defined as the number of patients who had not
had the event of interest and who were available for subsequent follow-up.
The final 33-month assessment visit took place between 20 and 21 months
after randomization. The figure shows the numbers at risk at the end of that
period (i.e., 21 months after randomization). The numbers at risk at the start
of that period (i.e., 20 months after randomization) were 4438 in the group
that had been assigned to continued Thienopyridine therapy versus 4362 in
the group that had been assigned to placebo. The inset shows the same data
on an enlarged y axis.

14. Cumulative Incidence of
MACCE, According to Study
Group
Figure 3: Cumulative Incidence of Major Adverse
Cardiovascular and Cerebrovascular Events, According
to Study Group. Cumulative incidence curves are shown
for the primary effectiveness outcome of major adverse
cardiovascular and cerebrovascular events (a composite
of death, myocardial infarction, or stroke) in the intention-
to-treat population. P values were calculated with the use
of the stratified log-rank test. The number at risk was
defined as the number of subjects who had not had the
event of interest and who were available for subsequent
follow-up. The numbers at risk at the start of final 33-
month visit (i.e., 20 months after randomization) were
4336 in the group that had been assigned to continued
Thienopyridine therapy and 4217 in the group that had
been assigned to placebo. The inset shows the same
data on an enlarged y axis.

15. Primary & Secondary Safety
Endpoints

16. Bleeding End Point During
Month 12 To Month 30
Risk with placebo treatment = 0.05
Risk with Thienopyridine = 0.08
Absolute Reduction Risk = - 0.03
Number Needed To Harm = 33.3
- for every 34 patients treated 1 patient will be harmed
Relative Risk = 1.6
- RR >1 therefore the event is more likely to occur in the
Thienopyridine group than in the placebo group
Relative Risk Reduction = - 0.6
- there is an approximately 60% increase risk of bleeding in the
Thienopyridine group as opposed to the placebo group
Groups + _ Total Incidence
Placebo 210 4439 4649 0.05%
Thienopyridine 382 4328 4710 0.08%
Total 592 8767 9359

17. Efficacy Outcomes at 12-33
Months
Thienopyridine
(n=5020)
Placebo
(n=4941)
Stratified
Hazard Ratio
Stratified log-
rank P value
Stent
Thrombosis (%):
Definite
Probable
0.7
0.6
0.1
1.4
1.3
0.2
0.45
0.42
0.85
< 0.001
< 0.001
0.77
MACCE (%):
MI
Stroke
Death
Cardiac
Vascular
Non-CV
5.6
3.0
1.0
2.3
1.1
0.1
1.1
6.5
4.5
1.1
1.8
1.0
0.1
0.6
0.82
0.61
0.86
1.36
1.13
1.15
1.80
0.02
< 0.001
0.48
0.04
0.53
0.81
0.01

18. Summary & Conclusion
• DAPT for 30 months after DES reduced risk for stent thrombosis and
MACCE compared with Aspirin alone
• Risk reduction was consistent across stent types and drug types
• 30 months DAPT was associated with an increased risk of bleeding
compared with Aspirin alone

19. Summary & Conclusion
• All-cause mortality was numerically higher with continued DAPT, driven by
Non-CV deaths which seemed to reflect a chance imbalance in patients with
known cancer prior to enrollment
• DAPT beyond 1 year is an effective and relatively safe option for reduction
of stent thrombosis risk in patients with DES

20. Thank You