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VII CONGRESSO REGIONALE SIMEU LAZIOOVERVIEW IN EMERGENCY MEDICINE
Roma, Hotel Villa Pamphili5-6 Novembre 2015
Quale, Quando e per Quanto DAPT in NSTE-ACS?Leonardo De Luca, MD, PhD, FACC, FESC
Department of Cardiovascular SciencesDepartment of Cardiovascular SciencesInterventional Cardiology UnitEuropean HospitalRome, ItalyRome, [email protected]
Conflicts of Interestof Interest
I’ve received honoraria for advisory boards or as speaker/chairman at scientific congresses from thespeaker/chairman at scientific congresses from the following companies:
Abbott Vascular, AstraZeneca, Bayer, BoehringerIngelheim, Correvio, Daiichi Sankyo, Eli Lilly, Menarini, The Medicines Company
~1 in 5 Pts who are Event-free for the First Year Post-MI, will Suffer an MI, Stroke or Death within 3 yrsMI, will Suffer an MI, Stroke or Death within 3 yrs
APOLLO 4-country analysis: adjusted incidence*y y j
MI/stroke/all-cause deathAdjusted risk (%)
Shaded areas correspond to 95% confidence intervals
*Adjusted for differences in study populations; MI, myocardial infarction. Shaded areas / figures in brackets [95%CI]Rapsomaniki E et al. ESC Late Breaking Registry presentation 2014.
PEGASUS:Study DesignStudy Design
Patients with history of prior MI within 1–3 years + ≥1 additional atherothrombotic risk factor(age ≥65 years, >1 prior MI, multivessel CAD, diabetes, or chronic non-end-stage renal dysfunction)
N ~21,000
Concurrent treatment with ASA 75–150 mg + standard background care
Randomized, double-blind
Placebo BID
Ticagrelor90 mg BID
Ticagrelor60 mg BID
Duration: Minimum 12 months up to ~44 months (median ~34 months)Duration: Minimum 12 months up to 44 months (median 34 months)
Primary efficacy endpoint: CV death, non-fatal MI or non-fatal strokeP i f t d i t TIMI j bl diPrimary safety endpoint: TIMI major bleeding
Bonaca MP, et al. Am Heart J 2014;167:437
PEGASUS-TIMI 54: Primary EndpointPrimary Endpoint
9.04% PlaceboPlaceboTicagrelor 90 mg bid
10
7.85% 90 mg bid
Ticagrelor 90 mg bidTicagrelor 60 mg bid
7
8
9
rate
(%)
7.77% 60 mg bid
5
6
7
Eve
nt r
Ticagrelor 90 mg vs placebo3
4
5
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
1
2
No. at riskPl b
Months from randomisation
0 3 6 9 12 15 18 21 24 27 30 33 360
Placebo90 mg bid60 mg bid
706770507045
697969736969
689268996905
682368276842
676167696784
668167196733
650865506557
623662726270
587659215904
515752435222
434344014424
336033683392
202820382055
Bonaca MP, et al. N Engl J Med 2015;372:1791
PEGASUS-TIMI 54: Efficacy Endpoints
Ticagrelor Ticagrelor
Efficacy Endpoints
EndpointTicagrelor 90 mg bid
N=7050; n (%)
Ticagrelor 60 mg bid
N=7045; n (%)
PlaceboN=7067; n (%)
Ticagrelor 90 mg bid vs
placeboHR (95% CI)
Ticagrelor 60 mg bid vs
placeboHR (95% CI)
P i d i tPrimary endpoint
CV death, MI or stroke 493 (7.85) 487 (7.77) 578 (9.04)
0.85 (0.75–0.96)P=0.008
0.84 (0.74–0.95)P=0.004
Secondary endpointsy p
CV death 182 (2.94) 174 (2.86) 210 (3.39)0.87 (0.71–1.06)
P=0.150.83 (0.68–1.01)
P=0.07
Death from any cause 326 (5.15) 289 (4.69) 326 (5.16)
1.00 (0.86–1.16)P 0 99
0.89 (0.76–1.04)P 0 14cause P=0.99 P=0.14
Other efficacy endpoints
MI 275 (4.40) 285 (4.53) 338 (5.25)0.81 (0.69–0.95)
P=0.010.84 (0.72–0.98)
P=0.03
All stroke 100 (1.61) 91 (1.47) 122 (1.94)0.82 (0.63–1.07)
P=0.140.75 (0.57–0.98)
P=0.03
Ischaemic stroke 88 (1.41) 78 (1.28) 103 (1.65)0.85 (0.64–1.14)
P=0.280.76 (0.56–1.02)
P=0.06
Bonaca MP, et al. N Engl J Med 2015;372:1791
Evidence-Based Pharmacological Therapies in MI Survivors
Agent ASA β-blockers ACE-I/ARB Statins Aldost. Ant. ADP Ant.
in MI Survivors
Pivotal Trial ATT BHAT SMILE CARE EPHESUS** PEGASUS
Year ‘70-’80 1982 1995 1996 2003 2015Year 70- 80 1982 1995 1996 2003 2015
Duration 4,5 y 25 m 6 w 5 y 16 m 3 y
Background Rx ~None Aspirin (21%) Aspirin (53%) Aspirin (83%) Aspirin (88%) Aspirin (99%)Background Rx None Aspirin (21%) Aspirin (53%) Aspirin (83%) Aspirin (88%) Aspirin (99%)β-block (18%) β-block (41%) β-block (75%) β-block (83%)CCBs (10%) CCBs (40%) ACE-I (87%) ACE-I (81%)
ACE-I (15%) Statins (47%) Statins (93%)
PCI None None None* 32% 24% 83%
Mortality 23%p<.02
26%p<.005
29%p<.01
15%p<.008
11%P=NS
Reinfarction
p
34%p<.02
p
16%p=NS
p
37%p<.01
24%p<.003
p
16%P=.003N/A
@1y
@1y
* Pts not eligible for thrombolysis** Pts with LV dysfunction or HF
@1y
Long-term DAPT in patients with previous MI: a collaborative meta-analysis of RCTscollaborative meta analysis of RCTs
Udell JA, et al. Eur Heart J 2015, in press
PEGASUS-TIMI 54: Analysis of Net Clinical Benefit
Ti l 90 bid Ti l 60 bid
Analysis of Net Clinical Benefit
Ticagrelor 90 mg bid versus placebo
Ticagrelor 60 mg bid versus placebo
Characteristic RRR HR (95%CI) P value RRR HR (95%CI) P valueCharacteristic RRR HR (95%CI) P value RRR HR (95%CI) P value
Irreversible harm: CV death, MI, stroke,
12% 0.88 (0.78–0.99)
0.0372 14% 0.86 (0.77–0.97)
0.0160, , ,
ICH and fatal bleeding
( ) ( )
Bonaca MP, et al. N Engl J Med 2015;372:1791
‘the superiority of a drug involves the irreversible harm’
FDA Rivaroxaban package approvalFDA Cangrelor package approval
Reduction in MACE with Ticagrelor by Time from P2Y12Inhibitor Withdrawal
P-valueHR (95% CI)
Time fromP2Y12 Inhibitorwithdrawal to
0.70 (0.57 – 0.87)0.75 (0.61 – 0.92)
≤ 30 daysN=7 181
randomization
<0.0010.73 (0.61 – 0.87)
0.90 (0.72 – 1.12)
N=7,181
>30 days
27% RRR
0.110.82 (0.65 – 1.02)0.86 (0.71 – 1.04)
yto 1 yearN=6,501 14% RRR
0.96
0.96 (0.73 – 1.26)1.06 (0.81 – 1.38)1.01 (0.80 – 1.27)
>1 yearN=5079 ∅ RRR
Ticagrelor 60 mgTicagrelor 90 mg
P-interaction 0.0097
0.70 0.90 1.10Ticagrelor Better Placebo Better1.0
Ticagrelor 60 mgPooled
MACE in Patients Randomized to Placebo by Time from P2Y12Inhibitor Withdrawal
1.46%
≤ 30 days30 days – ≤1 Year>1 Year
Adj. HR 1.47 (95% CI
)
0.60%0.55%
9.9%
8.7%
>1 Year 1.12 – 1.93)
Adj. HR 1.28 (95% CI
0 98 1 67)
P-trend 0.0097
Stro
ke (%
6.9%
0.98 – 1.67)
Ref.
CV
D/M
I/S
Adjusted for baseline characteristics that differed betweenAdjusted 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.
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
Days from Randomization
PLATO NSTE-ACS:Composite of CV death, MI or strokeComposite of CV death, MI or stroke
Lindholm D, et al. Eur Heart J, 2014 in press
TRITON TIMI-38NSTE-ACS Population
HR for the Primary Endpoint
NSTE ACS Population
HR for the Primary Endpoint
De Servi S, et al. Eur Heart J:ACC 2014
New ESC Guidelines for NSTE-ACSOral Antiplatelet TherapyOral Antiplatelet Therapy
Eur Heart J 2015; doi:10.1093/eurheartj/ehv320
Pre-Treatment in Phase III Trialson Novel P2Y12 Inhibitorson Novel P2Y12 Inhibitors
Trial Study Drug Pre-Rx PCI CABG Conserv.
1
Ticagrelor
Prasugrel2
g
Confidential for AstraZeneca Discussion Purposes Only151. Wallentin L, et al. N Engl J Med. 2009;361:1045
2. Wiviott SD, et al. N Engl J Med 2007;357:2001
Comparison of Ticagrelor Versus Prasugrel to Prevent Periprocedural Myonecrosis in ACS
213 patients with NSTE-ACS @ intermediate-high risk randomized to a 180 f ti l LD i ibl ft d i i d b f PCI (LD PCI 13 4 h )
Prevent Periprocedural Myonecrosis in ACS
180 mg of ticagrelor LD given as soon as possible after admission and before PCI (LD-PCI: 13.4 hrs) or to a 60 mg LD of prasugrel given at the time of PCI (admission-PCI: 17.8 hrs for tica vs 18.2 hrs for prasu)
Bonello L, et al. Am J Cardiol 2015, in press
Patients Presenting withNSTE-ACS in the United StatesNSTE-ACS in the United States
Burke MA, et al. Am Heart J 2011;161:832
CABG-Related Bleeding Complications in Patients Treated with Ticagrelor or ClopidogrelTreated with Ticagrelor or Clopidogrel
All ACS patients in Sweden on dual antiplatelet therapy with aspirin and ticagrelor (n=1266) or clopidogrel (n=978) who underwent CABG during 2012–13 were included in a
retrospective observational studyretrospective observational study.
Hansson EC, et al. Eur Heart J 2015, in press
Time to Coronary Angiography
PCI CURE
y g g p y
FRISC IIRITA 3
APTOR EYESHOTFAST‐MIGRACETACTICS
ACUITY
CRUSADETACTICSTIMI‐18
SYNERGY
CHAMPION
FUTURA/OASIS‐8
CURRENT/PLATFORM
PLATO
ACCOASTCURRENT/OASIS‐7
RCTRegistries
Year of publication De Luca L, et al. Am J Cardiol 2015;116:660
EYESHOT
Pre-Treatmentwith DAPT
Registrywith DAPT
79 3% (1807/2280)79.3% (1807/2280)
79.5% (1395/1755)
De Luca L, et al. Eur Heart J: ACC 2015,;4:441
Population Trends in Percutaneous Coronary Intervention
20-Year Results From theSCAAR (S di h C A i h d A i l t R i t )
Percutaneous Coronary Intervention
SCAAR (Swedish Coronary Angiography and Angioplasty Registry)
%
Fokkema ML, et al. J Am Coll Cardiol 2013;61:1222
Conclusioni
DAPT in NSTE ACSDAPT in NSTE-ACS
Quale: Ticagrelor o Prasugrel (in assenza di controindicazioni)controindicazioni)
Quando: Non appena facciamo diagnosi certapp g
Per quanto: Sino a quando riteniamo ragionevole proseguire (non meno di 12 mesi)