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Duration of DAPT After PCI in Stable CAD
Prof. Dr. Helmut Schühlen, FESC, FACC
Vivantes Auguste-Viktoria-Klinikum
Berlin, Germany
Conflict of Interest Statement
Prof. Dr. Helmut Schühlen, FESC, FACC
Research support, speaker‘s or consulting honoraria from:
Astra Zeneca Abbott
Bayer Biotronik
Boehringer Ingelheim Bristol Myers-Squibb
Correvio Daiichi-Sankyo
Lilly Novartis
Pivotal Trials Establishing DAPT After BMS- DAPT Mandated for 4 Weeks - Event Rates at 30 Days -
Prof. Dr. Helmut Schühlen, FESC, FACC
0.7 0,5
5,4
2,72.9
0
1
2
3
4
5
6
ISAR STARSS
ten
t th
rom
bo
sis
(%)
n = 517 n = 1652
p < 0.005p = 0.004
aspirin +
ticlopidineaspirin + coumadin(+ overlapping heparin)
aspirin
monotherapy
A Schömig et al., N Engl J Med 1996 M Leon et al., N Engl J Med 1998
Incidence of Adverse Cardiac Events in Pivotal Early DAPT Trials
Prof. Dr. Helmut Schühlen, FESC, FACC
ISAR STARS
DAPT (aspirin + ticlopidine) aspirin + anticoagulation
A Schömig et al., N Engl J Med 1996 M Leon et al., N Engl J Med 1998
5,4
0,7
1,6
0,00
2
4
6
8
10
week 1+2 week 3+4
%
2,7
0,00,5
0,00
2
4
6
8
10
week 1+2 week 3+4
%
Late Stent Thrombosis in the Era of BMS + DAPT with Ticlopidine
Prof. Dr. Helmut Schühlen, FESC, FACC
B Doyle et al., Circulation 2007
Analysis of 4503 patients with aspirin + ticlopidinefor 4 wks.
30-day SAT rate:
0.5%
Early & Late Stent Thrombosis of BMSWith a 4-Week DAPT
Prof. Dr. Helmut Schühlen, FESC, FACC
Stent Thrombosis (%)Registry of18,334 pts
with BMS or DES
246 definite SAT
T Tada et al., JACC Intv 2013
years
0
0.5
1.0
2.0
3.0
0 1 2 3
1.5
2.5
BMS
1 month
Summary of First Part
Prof. Dr. Helmut Schühlen, FESC, FACC
After DAPT became standard after BMS placement, the optimal duration was never tested comprehensively.
Current data suggest that 4 weeks of DAPT after BMS might have been too short (and still may be).
DAPT Duration in Pivotal Trials of 1G-DES
Prof. Dr. Helmut Schühlen, FESC, FACC
RAVEL 8 wks.SIRIUS 3 mo.E- & C-SIRIUS 2 mo.
TAXUS I, II, IV-VI 6 mo.
Cypher ®
sirolimus-eluting, permanent polymer
Taxus ®
paclitaxel-eluting, permanent polymer
The Debate at ESC 2006
Prof. Dr. Helmut Schühlen, FESC, FACC
Mechanistic Insights into the Excess Risk ofLate Stent Thrombosis After 1G DES
Prof. Dr. Helmut Schühlen, FESC, FACC
AquiredMalapposition
Incomplete Endothelializationand Chronic Inflammation
Guagliumi et al., JACC Interv 2012
Guagliumi et al, Circulation 2003
18 mo. after implantation
Continuous Risk for Stent Thrombosis with 1st Gen. DES
Prof. Dr. Helmut Schühlen, FESC, FACC
Stent Thrombosis (%)
Registry of18,334 pts
with BMS or DES
246 definite SAT
T Tada et al., JACC Intv 2013
years
0
0.5
1.0
2.0
3.0
0 1 2 3
1.5
2.5
BMS
1st Gen. DES
Independent Predictors forStent Thrombosis with 1st Gen. DES
Prof. Dr. Helmut Schühlen, FESC, FACC
I Iakovou et al., JAMA 2005
2229 pts. with 1st gen. DESClopidogrel for >3 mo. (Cypher) or >6 mo. (Taxus)
* > 30 days, up to 9 mo.
* n=15.
n=14.
Lower Risk for Stent Thrombosiswith 2nd-Gen. DES
Prof. Dr. Helmut Schühlen, FESC, FACC
E Kedhi et al., Lancet 2010
COMPARE Trial: 1800 patients, 60% ACS
stent thrombosis
Xience
Taxus
RR 0.26 (95% CI 0.11-0.64)
Late Stent Thrombosis with BMS, 1st-Gen. & 2nd-Gen. DES
Prof. Dr. Helmut Schühlen, FESC, FACC
1st-G. DES
BMS
2nd-G. DES
Registry of18,334 pts
with BMS or DES
246 definite SAT
T Tada et al., JACC Intv 2013
DAPT Interruption & Stent ThrombosisAfter 2nd Gen. DES (Xience V)
Prof. Dr. Helmut Schühlen, FESC, FACC
P Généreux et al., Circ Cardiovasc
Interv 2015
Pooled data from 3 randomized trials & 4 registries11219 patients with 2 yr FU after Xience V placement
Prof. Dr. Helmut Schühlen, FESC, FACC
Data for ENDEAVOR RESOLUTE Stent to obtain CE Mark for 1 Mo. DAPT (3/2013)
Data from the RESOLUTE trial program with 5003 patients
S Silber, TCT 2012
Prof. Dr. Helmut Schühlen, FESC, FACC
DES vs. BMS in Patients withHigh Bleeding Risk & DAPT for 1 Mo.
Stent Thrombosisdefinite or probable
Primary EPdeath, MI or TVR
BMS
DES (Endeavor)
Randomization to Endeavor or BMSSubgroup of 828 patients (~48% ACS) with ≥1 bleeding risk criterion
Bleeding Risk Criteria
age > 80 yrs indication for oral anticoagulation other pro-hemorrhagic medication
(steroids, NSAID) recent bleeding episode known anemia (<10 mg/dl)
S Ariotti et al.,JACC Intv 2016
Prof. Dr. Helmut Schühlen, FESC, FACC
Polymer-Free BIOFREEDOM DES
P Urban et al., TCT 2015
N Engl J Med 2015
2466 patients with clinical indication for PCI& 1 or more inclusion criteria (high bleeding risk)
BMS(n=1227)
BioFreedom(n=1239)
DAPT for 4 wks.new P2Y12 inhibitors ~6%
triple Rx ~33%
Primary Safety EP: cardiac death, MI or stent thrombosisPrimary Efficacy EP: clinically-driven TLR (both at 1 yr.)
Polymer-Free BIOFREEDOM DES
Primary Safety EPcardiac death, MI or stent thrombosis
Primary Efficacy EPclinically-driven TLR
P Urban et al., TCT 2015 & N Engl J Med 2015
Prof. Dr. Helmut Schühlen, FESC, FACC
Summary After Second Part
Prof. Dr. Helmut Schühlen, FESC, FACC
After DAPT became standard after BMS placement, the optimal duration was never tested comprehensively.
Current data suggest that 4 weeks of DAPT after BMS might have been too short (and still may be).
First-generation DES were limited by delayed and/orincomplete healing, with a continuous thrombotic risk.
Data for 2G DES suggest that DAPT for 3 mo. may be safe.
… and 1 mo. DAPT may be safe with “3G“ DES.
Dedicated Randomized Trials on DAPT Duration After DES
Prof. Dr. Helmut Schühlen, FESC, FACC
SECURITY
ISAR-SAFE
REAL/ZEST LATE
Randomized Trials on the Duration of DAPT
Prof. Dr. Helmut Schühlen, FESC, FACC
Trial or Subgroup Patients, n Diabetics, % ACS, % Newer DES, % Thienopyridines
DAPT up to 12 mo.
EXCELLENT 1,443 38.2 51.1 74.8 Clopi
ISAR SAFE 4,000 24.5 40.0 88.6 Clopi
OPTIMIZE 3,119 35.3 5.4 N/A Clopi
RESET 2,148 29.3 58.6 44.8 Clopi
SECURITY 1,399 30.9 38.4 100 Clopi
DAPT >12 mo.
ARCTIC-Interruption 1,259 33.5 N/R 63.0 Clopi, Prasu
DAPT (DES) 9,961 30.6 42.6 47.2 Clopi, Prasu, Tica
DES LATE (extended) 5,045 28.1 60.7 34.2 Clopi
ITALIC/ITALIC plus 1,850 38.0 23.4 100 Clopi, Prasu, Tica
PRODIGY 1,970 24.2 74.4 50.2 Clopi
Randomized Trials on the Duration of DAPT
Prof. Dr. Helmut Schühlen, FESC, FACC
Randomization at Time ofPotential DAPT Interruption
DAPT
ISAR-SAFE
ARCTIC interruption
REAL / ZEST LATE
DES LATE
ITALIC
Randomization at Time ofStent Placement
EXCELLENT
PRODIGY
OPTIMIZE
RESET
SECURITY
Prof. Dr. Helmut Schühlen, FESC, FACC
all have a composite primary endpointnone was powered for mortality
* Placebo-controlled & blinded, all others are open-label
Randomization at Time ofStent Placement
Randomization at Time ofPotential DAPT Interruption
DAPT*
ISAR-SAFE*
ARCTIC interruption
REAL / ZEST LATE
DES LATE
ITALIC
EXCELLENT
PRODIGY
OPTIMIZE
RESET
SECURITY
Randomized Trials on the Duration of DAPT
… it‘s Time for Metaanalyses !
Prof. Dr. Helmut Schühlen, FESC, FACC
Prof. Dr. Helmut Schühlen, FESC, FACC
Lancet June 2015
shorter versus longer DAPTn=31666)
definite or probable SAT
major bleeding
all-cause death
HR 2.04 (1.48-2.80)
HR 0.58 (0.47-0.72)
HR 0.82 (0.69-0.98)
myocardial infarction HR 1.51 (1.28-1.77)
cardiac death HR 0.93 (0.73-1.17)
non-cardiac death HR 0.67 (0.51-0.89)
Prof. Dr. Helmut Schühlen, FESC, FACC
definite or probable SAT
major bleeding
all-cause death
myocardial infarction
cardiac death
Br Med J online 350:h1618
shorter DAPT
versus 12 mo.
n=15995)
OR 1.32 (0.83-2.08)
OR 0.58 (0.36-0.92)
OR 0.91 (0.71-1.18)
OR 1.11 (0.87-1.43)
OR 0.95 (0.68-1.33)
longer DAPT
versus 12 mo.
(n=16282)
OR 0.33 (0.21-0.51)
OR 1.62 (1.26-2.09)
OR 1.30 (1.02-1.66)
OR 0.53 (0.42-0.66)
OR 1.09 (0.79-1.50)
Prof. Dr. Helmut Schühlen, FESC, FACC
L Mauri et al., Eur Heart J 2016
DAPT Trial - Causes of Death
█ continued thienopyridine
█ placebo
ACS versus Non-ACS Patients
Prof. Dr. Helmut Schühlen, FESC, FACC
RW Yeh et al., ACC 2015 &
J Am Coll Cardiol 2015
Prof. Dr. Helmut Schühlen, FESC, FACC
DAPT Score
RW Yeh et al., AHA 2015
www.daptstudy.org
Prof. Dr. Helmut Schühlen, FESC, FACC
RW Yeh et al., J Am Coll Cardiol 2015
Does Prolonged DAPT MerelyDelay Stent Thrombosis ?
Post-Hoc Analysis
of theDAPT trial
after discontinuationof study drug
Final Summary
Prof. Dr. Helmut Schühlen, FESC, FACC
After DAPT became standard after BMS placement, the optimal duration was never tested comprehensively.
Current data suggest that 4 weeks of DAPT after BMS might have been too short (and still may be).
First-generation DES were limited by delayed and/orincomplete healing, with a continuous thrombotic risk.
Data for 2G DES suggest that DAPT for 3 mo. is safe.
… and 1 mo. DAPT may be safe with “3G“ DES.
Prolonging DAPT after 2G DES >6 mo. may decreaseischemic events, but increase bleeding & mortality.
Prof. Dr. Helmut Schühlen, FESC, FACC