Lo studio Pegasus: il ruolo di Ticagrelor dopo i primi 12 mesi di trattamento. C. Cavallini Perugia

Transcription

1 Lo studio Pegasus: il ruolo di Ticagrelor dopo i primi 12 mesi di trattamento C. Cavallini Perugia

2 PEGASUS-TIMI 54: Aspetti qualificanti Tutti Pazienti Post-MI Tutti Pazienti stabili (>1 anno) STUDIO DI PREVENZIONE SECONDARIA NEL POST-INFARTO Tutti Pazienti ad alto rischio (età; diabete, multivasali, IRC...) Pazienti PCI e medically managed Obiettivo: Eventi ischemici anzichè stent thrombosis Ticagrelor ON TOP OF BEST MEDICAL THERAPY Ampia durata di trattamento (3 anni) CrCl, creatinine clearance Bonaca MP et al. Am Heart J 2014;167: Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print] 2

3 PEGASUS-TIMI 54: Inclusion Criteria Age 50 years old History of a spontaneous MI 1 3 years prior to enrolment and one additional high-risk feature Age 65 years old Diabetes mellitus requiring medication A second prior spontaneous MI Angiographic evidence of multivessel CAD Chronic, non-end-stage renal dysfunction (CrCl <60 ml/min) Prescribed and tolerating ASA at the time of enrolment FOR REACTIVE MEDICAL USE ONLY 3

4 Bonaca MP et al. N Engl J Med 2015 March 14

5 Bonaca MP et al. N Engl J Med 2015 March 14

6 PEGASUS-TIMI 54: Safety Endpoints Endpoint Ticagrelor 90 mg bid N=6988; n (%) Ticagrelor 60 mg bid N=6958; n (%) Placebo N=6996; n (%) Ticagrelor 90 mg bid vs placebo HR (95% CI) Ticagrelor 60 mg bid vs placebo HR (95% CI) Primary safety endpoint TIMI major bleeding 127 (2.60) 115 (2.30) 54 (1.06) 2.69 ( ) P< ( ) P<0.001 Secondary safety endpoints ICH 29 (0.56) 28 (0.61) 23 (0.47) 1.44 ( ) P=0.19 Haemorrhagic stroke 4 (0.07) 8 (0.19) 9 (0.19) 0.51 ( ) P=0.26 Fatal bleeding 6 (0.11) 11 (0.25) 12 (0.26) 0.58 ( ) P=0.27 Fatal bleeding or nonfatal ICH 32 (0.63) 33 (0.71) 30 (0.60) 1.22 ( ) P= ( ) P= ( ) P= ( ) P= ( ) P=0.47 Rates are presented as 3-year Kaplan-Meier estimates n = number of patients with events, not the number of events P<0.026 indicates statistical significance Bonaca MP et al. N Engl J Med 2015 [Epub ahead of print] FOR REACTIVE MEDICAL USE ONLY 6

7 Number of events per 10,000 patients initiated on treatment for 1 year PEGASUS-TIMI 54: Estimates of First Efficacy and Bleeding Events Prevented and Caused CV death, MI or stroke 0-10 TIMI major bleeding Ticagrelor 90 mg bid 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] FOR REACTIVE MEDICAL USE ONLY Ticagrelor 60 mg bid 7

8 Questo rapporto rischio-beneficio è accettabile? Di quali complicanze emorragiche parliamo?

9 3-Year KM Event Rate (%) Bleeding 5 4 Ticag 90: HR 2.69 ( ) Ticag 60: HR 2.32 ( ) P<0.001 Ticagrelor 90 mg Ticagrelor 60 mg Placebo P< TIMI Major TIMI Minor Fatal bleeding or ICH P=NS P=NS P=NS ICH Fatal Bleeding Bonaca MP et al. N Engl J Med 2015 March 14 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

10 Il rapporto rischio-beneficio è accettabile? Di quali complicanze emorragiche parliamo? Quali sono gli eventi ischemici prevenuti?

11 Components of Primary Endpoint Endpoint HR (95% CI) P value 0.85 ( ) CV Death, MI, or Stroke 0.84 ( ) (1558 events) 0.84 ( ) ( ) 0.15 CV Death 0.83 ( ) 0.07 (566 events) 0.85 ( ) ( ) 0.01 Myocardial Infarction 0.84 ( ) 0.03 (898 events) 0.83 ( ) ( ) 0.14 Stroke 0.75 ( ) 0.03 (313 events) 0.78 ( ) An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Ticagrelor better Placebo better Ticagrelor 90 mg Ticagrelor 60 mg Pooled

12 Proportion of MI events (%) Type and sizes of MI 13% 1042 total myocardial infarctions occurring a median of 440 days after randomization (IQR 198 to 705) Type 1 Type 2 Type 3 Type 4 * Type 5 Spontaneous Demand Fatal prior to PCI CABG Tn testing 13% 1% 1% 10% 10% 0% 0% 30% 25% 20% 15% 21% 13% 50% > 10x ULN 15% 18% 24% 10% 9% 5% 76% 76% 0% *Six type 4a, 95 type 4b Fold elevation of Tn CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; Tn, troponin Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 891)

13 Myocardial infarction size with ticagrelor 3 Year KM rate (%) Ticagrelor Placebo HR (95% CI) P value Any MI (0.69, 0.95) 0.84 (0.72, 0.98) 0.83 (0.72, 0.95) MI with Tn 25 x ULN (0.60, 0.98) 0.71 (0.55, 0.92) 0.74 (0.60, 0.91) MI with Tn 50 x ULN (0.53, 0.94) 0.70 (0.53, 0.93) 0.71 (0.55, 0.90) MI with Tn 100 x ULN (0.55, 1.04) 0.64 (0.45, 0.89) 0.70 (0.53, 0.92) MI with Tn 200 x ULN (0.47, 1.07) 0.62 (0.40, 0.95) 0.66 (0.47, 0.94) Ticagrelor better Placebo better Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 891) Ticagrelor 90 mg Ticagrelor 60 mg Pooled

14 STEMI (%) Effect of ticagrelor on STEMI Ticagrelor 90 mg HR 0.57 (95% CI 0.41, 0.79) P= Ticagrelor 60 mg HR 0.62 (95% CI 0.45, 0.86) P= Placebo Ticagrelor 60 mg Ticagrelor 90 mg Days from randomization Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 891)

15 Effect of ticagrelor on coronary death HR (95% CI) Ticagrelor vs placebo P value Death due to acute MI 0.72 (0.43, 1.20) 0.21 Sudden cardiac death 0.77 (0.62, 0.96) Coronary death 0.78 (0.61, ) Ticagrelor better Placebo better Ticagrelor doses pooled Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 891)

16 Ischemic Vs Bleeding Events Time for a New Clinical Appraisal Increased Risk Irreversable Harm Ischemia Death Periprocedural MI Stroke Spontaneous MI Bleeding Fatal Bleed ICH Instrumental bleed Instrumental nuisance bleed Spontaneous Major bleed Spontaneous Minor bleed

17 Ischemic Vs Bleeding Events In PEGASUS Increased Risk Irreversable Harm Ischemia Death Periprocedural MI Stroke Spontaneous MI Bleeding Fatal Bleed ICH Instrumental bleed Instrumental nuisance bleed Spontaneous Major bleed Spontaneous Minor bleed

18 PEGASUS-TIMI 54: 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 Irreversible harm: CV death, MI, stroke, ICH and fatal bleeding 12% 0.88 ( ) % 0.86 ( ) 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

19 Il rapporto rischio-beneficio è accettabile? Di quali complicanze emorragiche parliamo? Quali sono gli eventi ischemici prevenuti? Il rapporto rischio/beneficio è variabile nel tempo?

20 CVD/MI/stroke (%) Primary endpoint landmark (ITT) 4 3 Ticagrelor pooled HR 0.84 (95% CI ) P= % 3 2.8% Ticagrelor pooled HR 0.86 (95% CI ) P= % 3 2.6% Ticagrelor pooled HR 0.83 (95% CI ) P= % 2.4% Time (days) from randomization 0 Placebo Ticagrelor pooled doses Median 1.7 y from index MI ( ) Median 2.7 y from index MI ( ) Median 3.7 y from index MI ( ) Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 383) FOR REACTIVE MEDICAL USE ONLY 27

21 Annualized rate of TIMI major bleeding Annualized rate of TIMI major bleeding Placebo Ticagrelor 90 mg BID Ticagrelor 60 mg BID 3,0% 2,5% 2,5% 2,0% 2,0% 1,5% 1,5% Ticagrelor 90 mg ARI = 0.67% HR 3.71 (95% CI ) P<0.001 Ticagrelor 60 mg ARI = 0.57% HR 3.22 (95% CI ) P<0.001 Ticagrelor 90 mg ARI = 0.43% HR 2.21 (95% CI ) P<0.001 Ticagrelor 60 mg ARI = 0.34% HR 1.91 (95% CI ) P= ,0% 1,0% 0.94% 0.84% 0.82% 0.73% 0,5% 0.27% 0.39% 0,0% 0% First First year year After After first first year year Time from randomization Bonaca MP et al. Presented at AHA Congress 2015 (Abstract 383) FOR REACTIVE MEDICAL USE ONLY 28

22 Reduction in MACE with Ticagrelor by Time from P2Y 12 Inhibitor Withdrawal Time from P2Y 12 Inhibitor withdrawal to randomization HR (95% CI) P-value 30 days N=7,181 27% RRR 0.70 ( ) 0.75 ( ) 0.73 ( ) <0.001 >30 days to 1 year N=6,501 14% RRR 0.90 ( ) 0.82 ( ) 0.86 ( ) 0.11 >1 year N=5079 RRR 0.96 ( ) 1.06 ( ) 1.01 ( ) 0.96 P-interaction Ticagrelor Better 1.0 Placebo Better Ticagrelor 90 mg Ticagrelor 60 mg Pooled Bonaca MP, et al. Eur Heart J 2015, doi: /eurheartj/ehv531

23 Il rapporto rischio-beneficio è accettabile? Di quali complicanze emorragiche parliamo Quali sono gli eventi ischemici prevenuti? Il rapporto rischio/beneficio è variabile nel tempo? E possibile identificare sottogruppi di pazienti privilegiati?

24 3-year Kaplan-Meier % Efficacy of ticagrelor by egfr 16% Primary endpoint: CV death, MI, stroke 14% 12% egfr <60 placebo (n=1649) egfr <60 ticagrelor pooled (n=3200) egfr 60 placebo (n=5336) egfr 60 ticagrelor pooled (n=10,713) 13.99% HR (95% CI) 0.81 (0.68, 0.96) ARR = 2.70% 10% 11.29% 8% 6% 7.43% 6.80% HR (95% CI) 0.88 (0.77, 1.00) ARR = 0.63% 4% 2% 0% ARR, absolute risk reduction Months since randomization Magnani G. Presented at ESC Congress 2015 (Abstract P3032) FOR REACTIVE MEDICAL USE ONLY 32

25 PEGASUS : Renal Function Analysis Effect of Ticagrelor on TIMI Major Bleeding by egfr P int = 0.38

26 Coronary Death (%) Coronary Death Ticagrelor (doses pooled) Placebo Ticagrelor in Diabetic Patients HR 0.66 (95% CI ) ARR 1.1%; P= % Benefit in Diabetic vs. Non-Diabetic Patients: Interaction P= % 1.5% 1.4% Ticagrelor in Non-Diabetic Patients HR 0.88 (95% CI ) ARR 0.1%; P=0.39 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Days from Randomization

27 Safety of Ticagrelor Diabetic Patients 3-Year KM Rate (%) Ticagrelor Placebo HR (95% CI) P-value ( ) TIMI Major Bleeding ( ) ( ) ( ) <0.001 TIMI Major or Minor Bleeding ( ) ( ) < ( ) 0.69 ICH or Fatal Bleeding ( ) ( ) ( ) 0.30 All-Cause mortality ( ) ( ) 0.15 Ticagrelor Better Placebo Better Based on N=6735 patients Ticagrelor 90 mg Ticagrelor 60 mg Pooled

28 E nei pazienti con fattori multipli di rischio?

29 FOR REACTIVE MEDICAL USE ONLY

30 FOR REACTIVE MEDICAL USE ONLY

31 FOR REACTIVE MEDICAL USE ONLY

32 FOR REACTIVE MEDICAL USE ONLY

33 Conclusioni L aggiunta di Ticagrelor all ASA dopo il primo anno dall infarto riduce significativamente il rischio di eventi ischemici nei mesi e negli anni successivi. Questo beneficio è parzialmente mitigato da un incremento di eventi emorragici ( no ICH, no emorragie fatali). Una adeguata valutazione del rapporto rischio/beneficio del trattamento nel singolo paziente è cruciale. Sebbene rischio ischemico e rischio emorragico spesso si sovrappongano, alcune categorie di pazienti sembrano beneficiare maggiormente dal trattamento (IRC, Diabete Mellito, PAD,...). Il rapporto rischio/beneficio appare favorevole soprattutto nei pazienti che, dopo 12 mesi di DAPT, utilizzano subito la terapia con ASA e Ticagrelor 60 mg.

34 New 2015 ESC guidelines for the management of NSTEMI DAPT Duration Personalized options for Ticagrelor long term therapy

35 ~1 in 5 Pts who are Event-free for the First Year Post- MI, will Suffer an MI, Stroke or Death within 3 yrs APOLLO 4-country analysis: adjusted incidence* Adjusted risk (%) MI/stroke/all-cause death Shaded areas correspond to 95% confidence intervals *Adjusted for differences in study populations; MI, myocardial infarction. Shaded areas / figures in brackets [95%CI] FOR REACTIVE MEDICAL USE ONLY Rapsomaniki E et al. ESC Late Breaking Registry presentation 2014.

36 Adjusted* 3-year incidence of death, MI or stroke (%) ~1 in 5 patients who are event free for the first year post- MI, will suffer an MI, stroke or death within 3 years APOLLO 4-country analysis : Adjusted Incidence* ,8 21,3 16,7 18, Sweden (n=77,976) UK (n=7238) France (n=1757) US (n=53,909) *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: In press.

37 CHARISMA Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category Population RR (95% CI) p value Documented AT 0.88 (0.77, 0.998) (n=12153) Risk Factors Only 1.20 (0.91, 1.59) 0.20 (n=3284) Overall Population* 0.93 (0.83, 1.05) 0.22 (n=15603) 0.4 Clopidogrel + ASA Better Placebo + ASA Better * A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for the pre-specified subgroups of symptomatic and asymptomatic patients AT=Atherothrombosis Adapted from Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006 In press 1.6

38 Benefits of Extended DAPT in Patients with Previous MI Yen RW, et al. J Am Coll Cardiol 2015;65:2211