Robert C. Welsh, MD, FRCPCProfessor of Medicine, University of Alberta
Zone Clinical Department Head, Cardiac Sciences
Current Status of Antiplatelet Therapy in Acute Coronary Syndromes:
Duration of DAPT in 2016
Inspiring Innovation and KnowledgeLeaders in Patient Care
Robert C. Welsh, MD, FRCPC
Inspiring Innovation and KnowledgeLeaders in Patient Care
Faculty Disclosure (12 months):• Research and Clinical Trials: Abbott Vascular, Alere, Astra Zeneca, Bayer,
BMS, Boehringer Ingelheim, CIHR, CSL Behring LLC, Edwards Lifesciences, Eli Lilly, Jansen, Johnson and Johnson, Matrizyme Pharma, Pfizer, Population Health Research Institute, University of Alberta Hospital Foundation
• Honoraria: Astra Zeneca, Bayer
• Advisory Board: Astra Zeneca, Bayer, Bristol Myers-Squibb/Pfizer
• Other: University of Alberta (employee), Alberta Health Services (Clinical privileges) and President, The Canadian Centre for Clinicians and Scientists
Reflections on DAPT therapy
We have to consider patients with Acute Coronary Syndromes separately from those with Elective Revascularization.
1. With available data – is it fair to discuss DAPT as a therapy versus C-DAPT, P-DAPT, T-DAPT?
2. Can we identify patients for prolonged versus short duration of therapy?
3. With upcoming trials – is DAPT going to remain the standard of care versus ticagrelor monotherapy, or dual pathway strategies?
Inspiring Innovation and KnowledgeLeaders in Patient Care
Antiplatelet Therapy with ASA and Clopidogrel Improves Major Outcomes in NSTE ACS
CURE Yusuf S, et al. NEJM. 2001;345:494
Cu
mu
lati
ve H
azar
d R
ate
(%)
Months of Follow-Up
Clopidogrel+ ASA
(n=6,259)
0 3 6 9 12
Placebo+ ASA
(n=6,303) 20% RRR
Primary Endpoint: MI/Stroke/CV Death Major Bleeding
3.7
2.7
RR 1.38 95% CI 1.13–1.67
p<0.001
+ ASA
PlaceboClopidogrel0
1
2
3
4
Inci
den
ce (
%)
RR 0.8095% CI 0.72–0.90p<0.001
11.4
9.3
0
2
4
6
8
12
10
All patients received ASA and UFH or LMWH
Timing of Randomization and Treatment in Dual Oral Antiplatelet Trials
< 24 hrs
NSTE ACS < 72 hrsSTEMI < 12 hrs
CUREClopidogrel
PLATOTicagrelor
Presentation
Selective Invasive
Early Invasive
CoronaryAngiography
CABG
PCI
Medical Management
TRITONPrasugrel
SymptomOnset
James SK et al. BMJ 2011;342:d3527.
Wiviott SD et al. N Engl J Med 2007;357(20):2001–2015. Yusuf S et al. N Engl J Med 2001;345(7):494–502.
CURRENTClopidogrel
Medical
TRILOGYPrasugrel
Timing of Randomization and Treatment in Dual Oral Antiplatelet Trials
< 24 hrs
NSTE ACS < 72 hrsSTEMI < 12 hrs
CUREClopidogrel
PLATOTicagrelor
Presentation
Selective Invasive
Early Invasive
CoronaryAngiography
CABG
PCI
Medical Management
TRITONPrasugrel
SymptomOnset
James SK et al. BMJ 2011;342:d3527.
Wiviott SD et al. N Engl J Med 2007;357(20):2001–2015. Yusuf S et al. N Engl J Med 2001;345(7):494–502.
CURRENTClopidogrel
Medical
TRILOGYPrasugrel
Collet et al Lancet 2014;384:1577-85
Mortality According to Continuation vs.
Interruption of DAPT After PCI
Major Adverse Cardiac Events: 1.05 (0.87-1.25); p=0.62
Stent Thrombosis: 0.86 (0.53-1.39); p=0.41
Stroke : 1.43 (0.93-2.21); p=0.10
MI: 1.03 (0.79-1.34); p=0.84
Collet et al Lancet 2014;384:1577-85
Major Bleeding According to Continuation vs.
Interruption of DAPT After PCI
“…no apparent benefit but instead harm with extension of DAPT…after stenting. The
consistency between findings from all trials of such interruption suggests the need for a
reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of
treatment.”
Study Design and Patient Population
Enrolled: Subjects treated with FDA-approved DES or BMS
(16% NSTEMI, 10% STEMI)Excluded: Subjects on oral anticoagulant therapy or with life expectancy < 3 years
Randomized: Free from MI, stroke, repeat revascularization, and
moderate or severe bleeding, and adherent with thienopyridine (80% to
120% of doses taken and no interruption > 14 days)
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66
Stent and Drug Types
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66
Co-Primary Effectiveness End Point Stent
Thrombosis
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66
65 vs. 19
Co-Primary Effectiveness End Point: Major Adverse
Cardiovascular and Cerebrovascular Events
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66
285 vs. 211
Non-Stent Thrombosis Myocardial Infarction
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66
All-Cause Mortality
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66
Primary Safety Endpoint
GUSTO
Moderate or
severe
bleeding 12-30
Months
Mauri et al for the DAPT Study Investigators N Engl J Med 2014;371:2155-66
All cause mortality
Sammy Elmariah , Laura Mauri et al; The Lancet, 2014
Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis
Figure 3 Bayesian meta-analysis of cardiovascular and non-cardiovascular mortality associated with extended duration DAPT
versus short duration or no DAPT Hazard ratio for cardiovascular mortality, and (B) non-cardiovascular mortality. Results are
present...Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis
Sammy Elmariah , Laura Mauri et al; The Lancet, 2014
■ “Extended” DAPT therapy
■ Decreases the risk of ischemic events -especially stent thrombosis and MI
■Consistent with previous observational findings and randomized clinical trial evidence
■ Increases the risk of bleeding
■ Clopidogrel based DAPT does not improve mortality
Interpretation
PLATO Comparison of Ticagrelor and Clopidogrel in Patients with ACS
Major Bleeding*CV Death/MI/Stroke
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057
Cu
mu
lati
ve In
cid
ence
( %
)
0 6 0 120 180 240 300 360
0
2
4
6
8
10
12 Clopidogrel (n=9,291)
Ticagrelor(n=9,333)
Days after randomization
Median follow-up9.1 months
HR 0.8495% CI 0.77–0.92p<0.001
11.7
9.8
Clopidogrel(n=9186)
Ticagrelor(n=9235)
7.4
HR 0.9595% CI 0.85-1.06p=0.32
7.9
4.5 3.8
HR 1.1995% CI 1.02–1.38p=0.03
CABG Major Bleed Non-CABG Major Bleed
0
2
4
6
8
10
*Total major bleeding (study criteria) for ticagrelor vs clopidogrel 11.6% vs 11.2%, HR 1.04 (0.95–1.13), p=0.43.
Inci
den
ce (
%)
Cardiovascular Death All-Cause Mortality
Wallentin L, et al. N Engl J Med. 2009;361:1045-1057
Clopidogrel (n=9,291)
Ticagrelor(n=9,333)
5.94.5
Incidence at 1 year (%)
HR 0.7895% CI 0.69–0.89
p<0.001(nominal)
Cu
mu
lative
in
cid
en
ce (
%)
Months After Randomization
Clopidogrel (n=9,291)
Ticagrelor(n=9,333)
HR 0.7995% CI 0.69–0.91p=0.001
0 2 4 6 8 1210
0
1
2
3
4
5
6
7
21%RRR
PLATO: Secondary Efficacy OutcomesTicagrelor Reduced Mortality in ACS
Incid
en
ce
(%
)
0
1
2
3
4
5
6
Stable pts with history of MI 1-3 yrs prior
+ 1 additional atherothrombosis risk factor*
Ticagrelor
90 mg bidPlacebo
RANDOMIZE
DOUBLE BLIND
Follow-up Visits
Q4 mos for 1st yr, then Q6 mos
Planned treatment with ASA 75 – 150 mg &
Standard background care
* Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD,
or chronic non-end stage renal dysfunction
Event-driven trial
Ticagrelor
60 mg bid
Trial Design
Bonaca MP et al., NEJM 2015
Months from Randomization
Ticagrelor 60 mg
HR 0.84 (95% CI 0.74 – 0.95)
P=0.004
CV
Death
, M
I, o
r S
troke (
%)
3 6 9 120 15 18 21 24 27 30 33 36
Ticagrelor 90 mg
HR 0.85 (95% CI 0.75 – 0.96)
P=0.008
Placebo (9.0%)
Ticagrelor 90 (7.8%)Ticagrelor 60 (7.8%)
Primary Endpoint
6
5
4
3
10
9
8
7
2
1
0
N = 21,162
Median follow-up 33 months
Bonaca MP et al., NEJM 2015
P value Ticagrelor 90 mg 0.008 0.15 0.01 0.14 0.43 <0.001
Ticagrelor 60 mg 0.004 0.07 0.03 0.03 0.47 <0.001
Ticagrelor 90 mg bid
Ticagrelor 60 mg bid
Outcomes over 1 Year for 10,000 Patients
with Prior MI Initiated on Ticagrelor
Events extrapolated from 3-yr KM rates from ITT population
P values based on Cox regression
Irreversible Damage
Bonaca MP et al., NEJM 2015
PEGASUSPrimary endpoint – landmark (ITT)
3.4%
2.8%
2.9%
2.6%
2.8%
2.4%
Ticagrelor pooled
HR 0.84
(95% CI 0.71 – 0.98)
P=0.029
Ticagrelor pooled
HR 0.86
(95% CI 0.72 –1.03)
P=0.094
Ticagrelor pooled
HR 0.83
(95% CI 0.68 – 1.02)
P=0.084
Median 1.7 y
from index MI
(1.2 – 2.3)
Median 2.7 y
from index MI
(2.2 – 3.3)
Median 3.7 y
from index MI
(3.2 – 4.3)
Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 383)
0
1
2
3
4
0 90 180 270 360 366 456 546 636 726 731 821 911 1001
CV
D/M
I/s
tro
ke
(%
)
0
1
2
3
4
0
1
2
3
4
Time (days) from randomization
Placebo
Ticagrelor pooled doses
Adverse events leading to discontinuationN
um
be
r o
f p
atie
nts
P=NS each for D/C for
arrhythmia or other
AE, adverse event; D/C, discontinuation; NS, not significantBonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)
Treatment arm Any AE Bleeding Dyspnoea
Ticagrelor 90 mg bid 19.0% 7.8% 6.5%
Ticagrelor 60 mg bid 16.4% 6.2% 4.6%
Placebo 8.9% 1.5% 0.8%
3 year KM rate (%) – P value for each dose vs. Placebo <0.001
Discontinuation over time for dyspnoea by randomization group
Dashed lines represent median time (days) to discontinuation
Bonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)
Days from randomization
Nu
mb
er o
f p
atie
nts
dis
con
tin
ued
fo
r d
ysp
no
ea
500
450
400
350
300
250
200
150
50
0
0 90 180 270 360
100
450 540 630 720 810 900 990
8
11
P<0.01 for each
dose vs placebo
Ticagrelor 90 mg twice daily
Ticagrelor 60 mg twice daily
Placebo
53
Median days to discontinuation
Discontinuation over time for bleeding by randomization group
Days from randomization
500
450
400
350
300
250
200
150
50
0
0 90 180 270 360
100
450 540 630 720 810 900 990 1080
86
156
344
Ticagrelor 90 mg twice daily
Ticagrelor 60 mg twice daily
Placebo
P<0.01 for each
dose vs placebo
Dashed lines represent median time (days) to discontinuation
Bonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)
Median days to discontinuationN
um
ber
of
pat
ien
ts
dis
con
tin
ued
fo
r b
leed
ing
PEGASUSEfficacy of ticagrelor – on treatment*
CV, cardiovascular; CVD, CV deathBonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)
Pooled
Ticagrelor 60 mg bid
Ticagrelor 90 mg bid
*N=20,942 patients who received at least one dose of study drug including events through 7 days from the last dose of study drug.
Results consistent after propensity score adjustment
Ticagrelor better Placebo better1.0
6.6 8.4 0.79 (0.68, 0.91) <0.001
6.8 0.78 (0.68, 0.90) <0.001
6.7 0.78 (0.70, 0.88) <0.001
1.9 2.4 0.78 (0.60, 1.03) 0.076
1.8 0.74 (0.57, 0.97) 0.031
1.9 0.76 (0.61, 0.96) 0.019
1.3 1.6 0.75 (0.54, 1.04) 0.087
1.2 0.72 (0.52, 1.00) 0.052
1.3 0.74 (0.56, 0.97) 0.029
3.8 4.9 0.78 (0.65, 0.94) 0.0080
4.1 0.81 (0.68, 0.97) 0.0236
4.0 0.80 (0.68, 0.93) 0.0036
1.4 1.8 0.77 (0.56, 1.05) 0.094
1.4 0.73 (0.53, 1.00) 0.048
1.4 0.75 (0.58, 0.97) 0.029
Ticagrelor Placebo HR (95% Cl) P value
CVD, MI, stroke
CV death
Coronary heart disease death
Myocardial infarction
Stroke
3-year Kaplan Meier (%)
METHODS: MODELS TO PREDICT ISCHEMIC AND BLEEDING EVENTS
Development of 2 Prediction Models within the randomized DAPT Study population (N=11648).
• Ischemic Model | Myocardial infarction or stent thrombosis between 12-30 months after index PCI. Includes fatal events.
• Bleeding Model | GUSTO moderate or severe bleeding between 12-30 months after index PCI. Includes fatal events.
• Cox regression, stepwise selection among 37 candidate variables, including randomization treatment arm. In addition, several interaction terms with treatment arm evaluated. P value of 0.05 for retention.
• Validated externally within the PROTECT trial population*
AHA 2015, November 10, 2015, Orlando, FL , *Camenzind, Wijns, Mauri et al. Lancet. 380; 9851:1396-1405.
INDIVIDUALIZING TREATMENT DURATION OF DUAL ANTIPLATELET THERAPY AFTER PERCUTANEOUS CORONARY
INTERVENTION: AN ANALYSIS FROM THE DAPT STUDY
THE DAPT SCORE and Distribution within the DAPT Study
AHA 2015, November 10, 2015, Orlando, FL
Variable PatientCharacteristics
Points
Age ≥ 75 -2
Age 65 - < 75 -1
Age < 65 0
Diabetes Mellitus 1
Current Cigarette Smoker 1
Prior PCI or Prior MI 1
CHF or LVEF <30% 2
Index Procedure Characteristic
MI at Presentation 1
Vein Graft PCI 2
Stent Diameter < 3 mm 1
DISTRIBUTION OF DAPT SCORES AMONG ALL RANDOMIZED SUBJECTS IN THE DAT STUDY
CONTINUED THIENOPYRIDINE VS. PLACEBODAPT SCORE <2 (LOW); N=5731
AHA 2015, November 10, 2015, Orlando, FL
INSERCONTINUED THIENOPYRIDINE VS. PLACEBODAPT SCORE ≥ 2 (HIGH); N=5917
AHA 2015, November 10, 2015, Orlando, FL
CONCLUSION
AHA 2015, November 10, 2015, Orlando, FL
Among patients who have not had a major ischemic or bleeding event within the first year after PCI:
The DAPT Score identified patients for whom ischemic benefits outweighed bleeding risks, and patients for whom
bleeding risks outweighed ischemic benefits.
Low DAPT Score (< 2)
NNT to prevent ischemic = 153
NNH to cause bleeding = 64
High DAPT Score (≥ 2)
NNT to prevent ischemic = 34
NNH to cause bleeding = 272
-2 10
DAPT Score may help clinicians decide who should and who should not be treated with extended DAPT.
CONCLUSION
AHA 2015, November 10, 2015, Orlando, FL
Among patients who have not had a major ischemic or bleeding event within the first year after PCI:
The DAPT Score identified patients for whom ischemic benefits outweighed bleeding risks, and patients for whom
bleeding risks outweighed ischemic benefits.
Low DAPT Score (< 2)
NNT to prevent ischemic = 153
NNH to cause bleeding = 64
High DAPT Score (≥ 2)
NNT to prevent ischemic = 34
NNH to cause bleeding = 272
-2 10
DAPT Score may help clinicians decide who should and who should not be treated with extended DAPT.
Applies to a selected population treated with C-DAPT or P-DAPTACS patients start with a score of 1
Interventional focused – all patients previous PCI
Scores – need to be developed in ACS specific patient population
Novel strategies to improve secondary prevention following ACS
DAPTDiagnosis
One month
Twelve months
OAC
Atrial
Fibrillation
Dual Pathway
or OAC
Ticagrelormonotherapy
Dual pathwayRivaroxaban
+ ADP Rantagonist
http://clinicaltrials.gov/show/NCT01813435
GLOBAL LEADERS Trial
Dual Pathway Strategies
Phase 2 - Study designRecent ACS
Stabilised >48 hours & <10 days from hospitalisation for index event
PRIMARY ENDPOINT: TIMI clinically significant bleeding
EXPLORATORY EFFICACY ENDPOINT: Composite of CV death, MI, ischaemic stroke or stent thrombosis
Stratify by MD decision to use either clopidogrel or ticagrelor
ASA
Ticagrelor
90 mg bid
+
Rivaroxaban
2.5 mg bid
Ticagrelor (n=1500)Clopidogrel (n=1500)
Minimum 180; Maximum 360, Day F/U
R R
ClinicalTrials.gov Identifier: NCT02293395.
Available at: https://clinicaltrials.gov/ct2/show/NCT02293395 (accessed October
2015).
Clopidogrel
75 mg od
+
Rivaroxaban
2.5 mg bid
ACS=acute coronary syndrome; ASA=acetylsalicylic acid; od=once daily; bid=twice daily; F/U=follow up; TIMI=Thrombolysis In Myocardial Infarction; CV=cardiovascular;
MI=myocardial infarction.
Clopidogrel
75 mg od
+
ASA
100 mg od
Ticagrelor
90 mg bid
+
ASA
100 mg od
SummaryConsider patients with Acute
Coronary Syndromes separately from those with Elective Revascularization
1. In appropriately selected patients DAPT should be considered beyond 12 months – focus on ACS.
2. Further academic investment is required to develop scores to assist clinical decision for prolonged therapy.
3. The current trials may further adapt the ACS anti-thrombotic landscape.