Quale, Quando e per Quanto DAPT in NSTE-ACS? Leonardo De Luca, MD, - - PowerPoint PPT Presentation

VII CONGRESSO REGIONALE SIMEU LAZIO OVERVIEW IN EMERGENCY MEDICINE

Roma, Hotel Villa Pamphili 5-6 Novembre 2015

Quale, Quando e per Quanto DAPT in NSTE-ACS?

Leonardo De Luca, MD, PhD, FACC, FESC

Department of Cardiovascular Sciences Department of Cardiovascular Sciences Interventional Cardiology Unit European Hospital Rome, Italy Rome, Italy

leo.deluca@libero.it

Conflicts

• f Interest
• f Interest

I’ve received honoraria for advisory boards or as speaker/chairman at scientific congresses from the speaker/chairman at scientific congresses from the following companies: Abbott Vascular, AstraZeneca, Bayer, Boehringer Ingelheim, 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 yrs MI, will Suffer an MI, Stroke or Death within 3 yrs

APOLLO 4-country analysis: adjusted incidence* y y j

MI/stroke/all-cause death

Adjusted 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 Design Study 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 Ticagrelor 90 mg BID Ticagrelor 60 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 stroke P i f t d i t TIMI j bl di Primary safety endpoint: TIMI major bleeding

Bonaca MP, et al. Am Heart J 2014;167:437

PEGASUS-TIMI 54: Primary Endpoint Primary Endpoint

9.04% Placebo Placebo Ticagrelor 90 mg bid 10 7.85% 90 mg bid Ticagrelor 90 mg bid Ticagrelor 60 mg bid 7 8 9 rate (%) 7.77% 60 mg bid 5 6 7 Event r Ticagrelor 90 mg vs placebo 3 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 risk

Pl b

Months from randomisation 3 6 9 12 15 18 21 24 27 30 33 36

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

Bonaca MP, et al. N Engl J Med 2015;372:1791

PEGASUS-TIMI 54: Efficacy Endpoints

Ticagrelor Ticagrelor

Efficacy Endpoints

Endpoint Ticagrelor 90 mg bid N=7050; n (%) Ticagrelor 60 mg bid N=7045; n (%) Placebo N=7067; n (%) Ticagrelor 90 mg bid vs placebo HR (95% CI) Ticagrelor 60 mg bid vs placebo HR (95% CI)

P i d i t Primary 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 endpoints y p CV death 182 (2.94) 174 (2.86) 210 (3.39) 0.87 (0.71–1.06) P=0.15 0.83 (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 14 cause 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=0.01 0.84 (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=0.14 0.75 (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=0.28 0.76 (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 2015 Year 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=.003

N/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 RCTs collaborative 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 value Characteristic 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 approval FDA Cangrelor package approval

Reduction in MACE with Ticagrelor by Time from P2Y12 Inhibitor Withdrawal

P-value HR (95% CI)

Time from P2Y12 Inhibitor withdrawal to

0.70 (0.57 – 0.87) 0.75 (0.61 – 0.92)

≤ 30 days N=7 181

randomization

<0.001 0.73 (0.61 – 0.87) 0.90 (0.72 – 1.12)

N=7,181 >30 days 27% RRR

0.11 0.82 (0.65 – 1.02) 0.86 (0.71 – 1.04)

y to 1 year N=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 year N=5079 ∅ RRR

Ticagrelor 60 mg Ticagrelor 90 mg P-interaction 0.0097

0.70 0.90 1.10

Ticagrelor Better Placebo Better 1.0 Ticagrelor 60 mg Pooled

MACE in Patients Randomized to Placebo by Time from P2Y12 Inhibitor Withdrawal

1.46%

≤ 30 days 30 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 Stroke (%

6.9%

0.98 – 1.67) Ref.

CVD/MI/S

Adjusted for baseline characteristics that differed between 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.

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 stroke Composite of CV death, MI or stroke

Lindholm D, et al. Eur Heart J, 2014 in press

TRITON TIMI-38 NSTE-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-ACS Oral Antiplatelet Therapy Oral Antiplatelet Therapy

Eur Heart J 2015; doi:10.1093/eurheartj/ehv320

Pre-Treatment in Phase III Trials

• n Novel P2Y12 Inhibitors
• n Novel P2Y12 Inhibitors

Trial Study Drug Pre-Rx PCI CABG Conserv.

1

Ticagrelor Prasugrel

2

g

Confidential for AstraZeneca Discussion Purposes Only

15

• 1. 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)

• r 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 with NSTE-ACS in the United States NSTE-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 Clopidogrel Treated 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 study retrospective observational study.

Hansson EC, et al. Eur Heart J 2015, in press

Time to Coronary Angiography

PCI CURE

y g g p y

FRISC II RITA 3 APTOR EYESHOT FAST‐MI GRACE TACTICS ACUITY CRUSADE TACTICS TIMI‐18 SYNERGY CHAMPION FUTURA/ OASIS‐8 CURRENT/ PLATFORM PLATO ACCOAST CURRENT/ OASIS‐7 RCT Registries

Year of publication

De Luca L, et al. Am J Cardiol 2015;116:660

EYESHOT

Pre-Treatment with DAPT

Registry

with 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 the SCAAR (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 ACS DAPT in NSTE-ACS

Quale: Ticagrelor o Prasugrel (in assenza di controindicazioni) controindicazioni) Quando: Non appena facciamo diagnosi certa pp g Per quanto: Sino a quando riteniamo ragionevole proseguire (non meno di 12 mesi)