Duration of DAPT after ACS - European Society of … › static_file › Escardio ›...
Transcript of Duration of DAPT after ACS - European Society of … › static_file › Escardio ›...
1
Duration of DAPT after ACS
Robert Storey
Professor of Cardiology, University of Sheffield
and
Academic Director and Honorary Consultant Cardiologist,
Cardiology and Cardiothoracic Surgery Directorate,
Sheffield Teaching Hospitals NHS Foundation Trust,
Sheffield, United Kingdom
Disclosures
Company name Relationship
• AstraZeneca Research grant, honoraria, consultant
• Avacta Consultant
• Bayer Consultant
• BMS/Pfizer Consultant
• PlaqueTec Research grant, consultant
• Aspen Consultant
• ThermoFisher Scientific Consultant
• The Medicines Company Consultant
No. at risk
Clopidogrel
Ticagrelor
9291
9333
8560
8678
8405
8520
8177
Days after randomization
6703
6796
5136
5210
4109
4191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7
Cu
mu
lative
in
cid
en
ce
(%
)
Clopidogrel
Ticagrelor
5.8
6.9
8279
HR 0.84 (95% CI 0.75–0.95), p=0.005
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9291
9333
8865
8294
8780
8822
8589
Days after randomization
7079
7119
5441
5482
4364
44198626
Myocardial infarction Cardiovascular death
Cu
mu
lative
in
cid
en
ce
(%
)
PLATO Secondary efficacy endpoints
Wallentin L et al. N Eng J Med. 2009
PEGASUS-TIMI 54 study design
4
Stable patients >50 years old with history of MI 1–3 years prior + ≥1
additional atherothrombotic risk factor*
n ~21,000
Ticagrelor
60 mg BID
Placebo
BID
Ticagrelor
90 mg BID
Follow-up visits: 4-monthly for first year, then 6-monthly
Duration: Minimum 12 months, up to ~44 months (median 30 months)
Event-driven trial: n ~ 1360 events
Primary efficacy endpoint: CV death, MI or stroke
Primary safety endpoint: TIMI major bleeding
Randomized, double-blind
Planned treatment with ASA 75–150 mg
+ standard background care
*Age ≥65 years, diabetes, second prior MI, multivessel
CAD or chronic non-end-stage renal dysfunction
BID, twice daily; CAD, coronary artery disease; TIMI, thrombolysis in myocardial infarction
PEGASUS-TIMI 54: Primary endpoint
p<0.026 indicates statistical significance; CI, confidence interval; HR, hazard ratio
Bonaca MP et al. N Engl J Med. 2015;372:1791–1800.
No. at risk
Placebo
90 mg bid
60 mg bid
7067
7050
7045
6979
6973
6969
6892
6899
6905
6823
6827
6842
6761
6769
6784
6681
6719
6733
6508
6550
6557
6236
6272
6270
5876
5921
5904
5157
5243
5222
4343
4401
4424
3360
3368
3392
2028
2038
2055
Eve
nt
rate
(%
)
Months from randomization
Ticagrelor 60 mg vs placebo
HR 0.84 (95% CI 0.74–0.95) p=0.004
Ticagrelor 90 mg vs placebo
HR 0.85 (95% CI 0.75–0.96) p=0.008
Placebo
Ticagrelor 90 mg bid
Ticagrelor 60 mg bid
9.04% Placebo
7.85% 90 mg bid
7.77% 60 mg bid
0 3 6 9 12 15 18 21 24 27 30 33 36
0
1
2
3
4
5
6
7
8
9
10
Rates are presented as 3-year Kaplan-Meier estimates
Bonaca MP et al. N Engl J Med 2015;372:1791–1800
0.6 0.70.6 0.6 0.6
0.5
0.10.3 0.3
P=NS P=NS P=NS
Fatal bleeding or
ICH
ICH Fatal bleeding
PEGASUS-TIMI 54: Bleeding3-y
ea
r K
M e
ve
nt ra
te
2.6
2.3
1.11.3
1.2
0.4
P<0.001
P<0.001
TIMI major
bleeding
TIMI minor
bleeding
5
4
3
2
1
0
Ticagrelor 90 mg bid
Ticagrelor 60 mg bid
Placebo
PEGASUS-TIMI 54 platelet function substudy
VerifyNow PRU
Storey RF et al. J Am Coll Cardiol. 2016
p=0.34
Placebo Ticagrelor
60 mg
Ticagrelor
90 mg
Placebo Ticagrelor
60 mg
Ticagrelor
90 mg
0
100
200
300
400
PR
U
Pre-dose Post-dose
PRU=208
p=0.73
Primary endpoint – landmark (ITT)
8
Median 1.7 y
(1.2–2.3)
Median 2.7 y
(2.2–3.3)
Median 4.7 y
(4.2–5.3)
Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 383).
CV
D/M
I/s
tro
ke
(%
)
3.2%
2.8%
2.7%
5.9%
5.2%
5.1%
First year of treatment Subsequent 2 years of treatment
Ticagrelor 60 mg
HR 0.82
(95% CI 0.67–0.99)
p=0.037
Ticagrelor 90 mg
HR 0.86
(95% CI 0.71–1.03)
p=0.10
Ticagrelor 60 mg
HR 0.85
(95% CI 0.73–0.998)
p=0.047
Ticagrelor 90 mg
HR 0.85
(95% CI 0.72–0.99)
p=0.036
3.1%
2.8%
2.5%
0
1
2
3
4
5
6
7
0 90 180 270 360
0
1
2
3
4
5
6
7
366 456 546 636 726 816 906 996 1086
Placebo, N=6750
Ticagrelor 90 mg, N=6763
Ticagrelor 60 mg, N=6779
Placebo, N=7067
Ticagrelor 90 mg, N=7050
Ticagrelor 60 mg, N=7045
Time (days) from randomization
PEGASUS-TIMI 54: Efficacy
endpoints
*Indicates nominal p-value; p<0.026 indicates statistical significance.
Bonaca MP et al. N Engl J Med. 2015;372:1791–1800.
Ticagrelor better Placebo better
0.4 0.6 0.8 1 1.25 1.67
Primary – CV death, MI
or stroke (1558 events)
CV death
(566 events)
MI
(898 events)
Stroke
(313 events)
Endpoint3-year KM event
rates (%)
HR (95% CI) P-valueTicagrelor Placebo
7.85 9.04 0.85 (0.75–0.96) 0.008
7.77 9.04 0.84 (0.74–0.95) 0.004
7.81 9.04 0.84 (0.76–0.94) 0.001
2.94 3.39 0.87 (0.71–1.06) 0.15
2.86 3.39 0.83 (0.68–1.01) 0.07
2.90 3.39 0.85 (0.71–1.00) 0.06
4.40 5.25 0.81 (0.69–0.95) 0.01*
4.53 5.25 0.84 (0.72–0.98) 0.03*
4.47 5.25 0.83 (0.72–0.95) 0.005*
1.61 1.94 0.82 (0.63–1.07) 0.14*
1.47 1.94 0.75 (0.57–0.98) 0.03*
1.54 1.94 0.78 (0.62–0.98) 0.03*
Ticagrelor 90 mg bid
Ticagrelor 60 mg bid
Ticagrelor pooled
Effect of ticagrelor on CAD-related death
Death due to acute MI
Ticagrelor better Placebo better1.0
Ticagrelor vs placebo p-value
0.210.72 (0.43, 1.20)
HR (95% CI)
Ticagrelor doses pooled1.25 2.000.750.50
Sudden cardiac death 0.0190.77 (0.62, 0.96)
Coronary death 0.0480.78 (0.61, 0.9975)
Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 891).
Effect of ticagrelor on STEMI
Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 891).
0
0
0.5
1.0
1.5
2.0
Days from randomization
ST
EM
I (%
)
90 180 270 360 450 540 630 720 810 900 990 1080
Placebo
Ticagrelor 60 mg
Ticagrelor 90 mg
Ticagrelor 60 mg
HR 0.62
(95% CI 0.45, 0.86)
p=0.0016
Ticagrelor 90 mg
HR 0.57
(95% CI 0.41, 0.79)
p=0.0008
Effect of ticagrelor 60mg on stroke
Bonaca MP et al. Circulation 2016
Effect of ticagrelor 60mg on stroke
Bonaca MP et al. Circulation 2016
Adverse eventTicagrelor 90 mg bid
N=7050; n (%)
Ticagrelor 60 mg bid
N=7045; n (%)
Placebo
N=7067; n (%)
All-cause death 336 (4.8) 299 (4.2) 336 (4.8)
Non-CV death 145 (2.1) 117 (1.7) 115 (1.6)
Accident/trauma 6 (0.09) 2 (0.03) 4 (0.06)
Infection/sepsis 31 (0.44) 25 (0.36) 24 (0.34)
Malignancy 77 (1.10) 64 (0.92) 53 (0.76)
Pulmonary failure 10 (0.14) 9 (0.13) 9 (0.13)
Renal failure 2 (0.03) 4 (0.06) 4 (0.06)
Other 19 (0.27) 13 (0.19) 21 (0.30)
PEGASUS-TIMI 54: Non-CV deaths
Includes deaths occurring after the common study end date (safety window).
Data presented as proportions.
n=number of patients with events, not the number of events.
Bonaca MP et al. N Engl J Med. 2015, Supplementary Appendix [Epub ahead of print].
PEGASUS TIMI 54: MACE in patients randomized to
placebo by time from P2Y12 inhibitor withdrawal
0%
2%
4%
6%
8%
10%
12%
0 90 180 270 360 450 540 630 720 810 900 990 1080
0,0%
0,5%
1,0%
1,5%
2,0%
0 30 60 90
CV
D/M
I/str
oke (
%)
Days from randomization
1.46%
0.60%0.55%
9.9%
8.7%
6.9%
≤30 days
30 days–≤1 Year>1 Year
Adj. HR 1.47
(95% CI
1.12–1.93)
Adj. HR 1.28
(95% CI
0.98–1.67)
Ref.
p-trend 0.0097
Adjusted for baseline characteristics that differed between
groups including age, sex, race, region, time from qualifying
MI, diabetes, multivessel disease, hypertension,
hypercholesterolemia and history of PCI/stent.
Bonaca M et al. Eur Heart J. 2015 online.
Reduction in CV death, MI or stroke with ticagrelor
by time from P2Y12 inhibitor withdrawal
Ticagrelor 90 mg
Ticagrelor 60 mg
PooledPlacebo betterTicagrelor better
0.70 (0.57, 0.87)
0.75 (0.61, 0.92)
0.73 (0.61, 0.87) <0.001
0.90 (0.72, 1.12)
0.82 (0.65, 1.02)
0.86 (0.71, 1.04) 0.11
0.96 (0.73, 1.26)
1.06 (0.81, 1.38)
1.01 (0.80, 1.27) 0.96
1.0
HR (95% CI) p-value
≤30 days
n=7181
>30 days
to 1 year
n=6501
>1 year
n=5079
Time from P2Y12 inhibitor
withdrawal to randomization
Bonaca MP. Presented at ESC Congress 2015 (Abstract 3918).
p-interaction 0.0097
27% RRR
14% RRR
RRR
0.7 0.9 1.1
Efficacy of ticagrelor by eGFR
0
2
4
6
8
10
0 12 24 36
Months since randomization
3-y
ear
Kap
lan
-Meie
r %
13.99%
11.29%
7.43%
6.80%
HR (95% CI)
0.81 (0.68, 0.96)
ARR=2.70%
12
14
16
eGFR ≥60 ticagrelor pooled (n=10 713)
eGFR <60 placebo (n=1649)
eGFR <60 ticagrelor pooled (n=3200)
HR (95% CI)
0.88 (0.77, 1.00)
ARR=0.63%
eGFR ≥60 placebo (n=5336)
Primary endpoint: CV death, MI, stroke
ARR, absolute risk reduction.
Magnani G. Presented at ESC Congress 2015 (Abstract P3032).
Days from randomization
Benefit in diabetic vs non-diabetic patients:
Interaction p=0.21
3.4%
2.3%
1.5%
1.4%
Ticagrelor in non-diabetic patients
HR 0.88 (95% CI 0.65–1.19)
ARR 0.1%; p=0.39
Ticagrelor in diabetic patients
HR 0.66 (95% CI 0.48–0.91)
ARR 1.1%; p=0.01
Ticagrelor (doses pooled)
Placebo
Bhatt DL et al. J Am Coll Cardiol. 2016.
PEGASUS-TIMI 54 diabetes substudy:
CAD-related death
Co
ron
ary
death
PEGASUS-TIMI 54: Estimates of first efficacy
and bleeding events prevented and caused
Rates are annualised from 3-year Kaplan-Meier event rates in the intention-to-treat population.
Bonaca MP et al. N Engl J Med. 2015, Supplementary Appendix [Epub ahead of print].
Ticagrelor 90 mg bid
Ticagrelor 60 mg bid
CV death, MI or stroke
TIMI major bleeding
Nu
mb
er
of
eve
nts
pe
r 1
0 0
00
pa
tie
nts
init
iate
d o
n t
rea
tme
nt
for
1 y
ea
r
–40–42
41
31
Total events: efficacy and safety
20
Murphy SA et al. Presented at AHA Congress 2015 (Abstract 742).
p-value 0.006 0.07 0.07 0.11 <0.001 0.99
0
Events from ITT population
and predicted incidence rates
p-values based on negative
binomial regression
0
Adverse events leading to
discontinuation
86
35451
297
96
103
388
385
0
200
400
600
800
1000
1200
Placebo Ticagrelor 60 mg BID
Other
Arrhythmia
Dyspnoea
Bleeding
Nu
mb
er
of p
atie
nts
p=NS each for D/C for
arrhythmia or other
AE, adverse event; D/C, discontinuation; NS, not significant.
Bonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial).
Treatment arm Any AE Bleeding Dyspnoea
Ticagrelor 60 mg bid 16.4% 6.2% 4.6%
Placebo 8.9% 1.5% 0.8%
3 year KM rate (%) – p-value for 60 mg ticagrelor versus placebo <0.001
Drug discontinuation for AE by treatment arm
Days from randomization
Ka
pla
n-M
eie
r ra
te (
%)
First year Years 2 + 3
18
16
14
12
10
8
6
4
2
0
0 90 180 270 360
6.0%
4.5%
18
16
14
12
10
8
6
4
2
0
366 456 546 636 816 1086996906726
13%
6%
22Bonaca MP et al. Presented at AHA Congress 2015 (Late Breaking Clinical Trial)
P value for each
dose vs placebo
< 0.01
P<0.01 for each dose
vs placebo
DAPT study: Continuation or withdrawal of
thienopyridine 12 months after coronary stenting
Mauri et al. NEJM 2014
~ 26% with MI
Death, MI or stroke
Withdrawal of
P2Y12
Inhibition
Withdrawal of
P2Y12
Inhibition
Individual CV Endpoints
6,4
2,3
3,5
1,4
0,6
7,5
2,6
4,4
1,71,4
0
1
2
3
4
5
6
7
8
9
10
MACE CV Death MI Stroke Stent Thrombosis (Def/Prob)
Eve
nt
Ra
te (
%)
Extended DAPT
Aspirin Alone
RR 0.78
P = 0.001
RR 0.85
P = 0.03
RR 0.70
P = 0.003
RR 0.81
P = 0.02RR 0.50
P = 0.02
Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.
Long-term DAPT post MI: meta-analysis (n=33,435)
1,9
0,4 0,1
1,7
4,0
1,1
0,3 0,2
1,6
4,2
0
1
2
3
4
5
6
7
8
9
10
Major Bleeding
ICH Fatal Bleeding
Non-CV Death
All-Cause Death
Eve
nt
Ra
te (
%)
Extended DAPT
Aspirin Alone
RR 1.73
P = 0.004
P = NS
RR 1.03
P = NS
RR 0.92
P = NS
Major Bleeding Events and Safety
P = NS
Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.
Long-term DAPT post MI: meta-analysis (n=33,435)
Conclusions
• Extended DAPT post-MI reduces risks of stent thrombosis
and ischaemic events at the expense of increased risk of non-
fatal major bleeding
• The higher the ischaemic risk, the greater the absolute risk
reduction with extended DAPT post MI e.g. CKD, DM, PAD
• Extended ticagrelor-based DAPT associated with numerically
lower rates of all-cause death in the 60 mg bid group due to
lower rates of CV death, particularly CAD-related death, and
no excess of non-CV death
• Extended thienopyridine-based DAPT may be an alternative
to ticagrelor-based DAPT but relative efficacy and safety of
the regimens is uncertain
• Efficacy data for aspirin/NOAC combination awaited with
interest
My personal opinion
• Long-term ticagrelor 60 mg bid and aspirin 75 mg od is
recommended in post-MI patients at high risk of CAD-
related death who do not have high risk of fatal bleeding
• Long-term thienopyridine-based DAPT may be
considered in ticagrelor-intolerant patients at high risk of
CAD-related death
• Coronary anatomy should be considered along with
clinical variables when deciding on duration of DAPT
post-MI in order to guide risk of CAD-related death
• Duration of DAPT can be recommended following the
coronary angiography procedure but reviewed at any
stage should complications arise
Example of discharge letter
advice….
Follow-up by GP: Please continue ticagrelor 90 mg bd for 1 year
and then downtitrate to 60 mg bd long term, if tolerated, in view
of extent of coronary artery disease and clinical risk factors.
Continue aspirin, statin and other secondary prevention
medication long term.
x
ThromboxaneA
2
5HT
P2Y12
ADP ADPADP
5HT
P2Y15HT2A
PAR-1
PAR-4
Dense
granule
Thrombin
generation
Shape
change
aIIbb3
aIIbb3
FibrinogenaIIbb3
Aggregation
AmplificationAlpha
granule
Coagulation factors
Inflammatory mediators
TPa
Coagulation
GPVI
Collagen
ATPATP
P2X1
ASPIRIN
x TICLOPIDINE
CLOPIDOGREL
PRASUGREL
ACTIVE
METABOLITE
x TICAGRELOR
CANGRELOR
GP IIb/IIIa ANTAGONISTS
xx
VORAPAXAR
x
HEPARINS
FONDAPARINUX
BIVALIRUDIN
RIVAROXABAN
APIXABAN
DABIGATRANThrombin
?
Discussion
ADP, adenosine diphosphate; ATP, adenosine triphosphate; GP = glycoprotein; PAR = protease-activated receptor; TP, thromboxane A2/prostaglandin H2.Storey RF. Curr Pharm Des. 2006.
29