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, Italyleo.deluca@libero.it

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)