Aktueller Stand der dualen Plättchenhemmung nach akutem Koronarsyndrom und PCI: Wie lange, für wen?

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1 Aktueller Stand der dualen Plättchenhemmung nach akutem Koronarsyndrom und PCI: Wie lange, für wen? Uwe Zeymer Herzzentrum Ludwigshafen Institut für Herzinfarktforschung Ludwigshafen Gründungssymposium Universitäres Herzzentrum Lübeck Lübeck

2 Interessenkonflikte Astra Zeneca, B. Braun, BMS, Boehringer Ingelheim, Bayer Healtcare, Correvio, Daiichi Sankyo, Eli Lilly, Medtronic, Medicines Company, MSD, Novartis, Pfizer, Sanofi

3 Koronare Herzkrankheit Stabile KHK mit PCI - Stentthrombose Akutes Koronarsyndrom mit und ohne Revaskularization - rezidivierende ischämische Ereignisse (CV Tod und Myokardinfarkt, Stentthrombose)

4 Einfluß der PCI auf das Überleben bei stabiler KHK

5 Stentthrombose Initial Problem bei BMS, Senkung durch duale Thrombozytenhemmung Erhöhte Rate von Stentthrombosen nach DES der 1. Generation Hohe Ereignisrate durch subakute und späte Stentthrombosen Bei DES der neuesten Generation deutlich weniger Stentthrombosen nach elektiver PCI

6 Restenose versus Stent-Thrombose BMS versus DES im SCAAR-Register

7 6-Monate versus 24 Monate DAPT nach elektivem DES in der PRODIGY Studie Stentthrombose Blutung

8 MACE following PCI is equally attributable to culprit and non-culprit lesions PROSPECT study: Prospective study of the natural history of atherosclerosis over 3 years in patients with ACS who underwent PCI (n=697) Cumulative rate of MACE (%) All events Culprit lesion-related events Non-culprit lesion-related events Indeterminate events Time from PCI (years) MACE, major adverse cardiac events; PROSPECT, Providing Regional Observations to Study Predictors of Events in the Coronary Tree Stone GW et al. N Engl J Med 2011;364: % 12.9% 11.6% 2.7%

9 ESC-Leitlinien NSTE-ACS, Hamm et al, Eur Heart J 2011 STEMI, Steg et al, Eur Heart J 2012

10 CURE: Early and long-term benefits of clopidogrel in ACS Patients 0.14 Placebo b (n=6303) 20% Relative risk reduction: (p<0.001) Cumulative hazard rate a Clopidogrel b (n=6259) Months of follow-up a MI, stroke or cardiovascular death b On a background of standard therapy including aspirin) The CURE Investigators. N Engl J Med 2001;345:

11 Clopidogrel after STEMI: Mortality between discharge and 12 months Entire group Fibrinolysis No reperfusion Primary PCI Zeymer U, et al. Eur Heart J 2006;27:2661-6

12 Duale Thrombozytenhemmung nach ACS Nachgewiesen nur für NSTE-ACS in CURE, mittlere Therapie-Dauer 9 Monate Aber ist der Patient nach 9-12 Monaten geheilt?

13 Mortalität nach ACS im GRACE-Register Cumulative mortality (%) Hospital 6-month 1-year 2-year 3-year 4-year Tang et al, Am Heart J 2007; 153: 29-35

14 MACCE im REACH Register bei Patienten mit Z.n. Herzinfarkt Bangalore S, et al, JAMA 2012

15 Ongoing risk > 1-year after MI even in clinical trials Days 0 to 360 Day 360 to % 7% 6.5% 6% 6% Placebo CV Death /MI/Stroke (%) 5% 4% 3% 2% Placebo 4.0% 5% 4% 3% 2% 1% 1% 0% Days since randomization 0% Days since randomization

16 Duale Thrombozytenhemmung nach ACS Pro: Verhinderung von ischämischen Ereignissen, Reduktion der Sterblichkeit Contra: Blutungskomplikationen, Compliance

17 CHARISMA-Studie Clopidogrel versus Placebo bei stabiler Arteriosklerose Primärer Wirksamkeitsendpunkt (MI, Schlaganfall oder kardiovaskulärer Tod) nach präspezifizierten Subgruppen Population N RR (95% CI) p-wert Dokumentierte AT ,88 (0,77, 0,998) 0,046 koronar ,86 (0,71, 1,05) 0,13 zerebrovaskulär ,84 (0,69, 1,03) 0,09 PAVK ,87 (0,67, 1,13) 0,29 Multiple RF ,20 (0,91, 1,59) 0,20 Gesamtpopulation ,93 (0,83, 1,05) 0,22 0,4 0,6 0,8 1,2 1,4 1,6 Clopidogrel + ASS besser Plazebo + ASS besser Erstes Auftreten von MI (tödlich oder nicht tödlich) Schlaganfall (tödlich oder nicht tödlich), kardiovaskulärer Tod; RF= Risikofaktoren AT= Atherothrombose Bhatt DL. Oral presentation at ACC 2006.

18 CHARISMA Ereignisraten in Patienten mit Z.n. Infarkt (Median 24 Monate vor Randomisierung)

19 PEGASUS study design Patients >50 years old with history of MI 1 3 years prior + 1 additional atherothrombotic risk factor* n ~21,000 Planned treatment with ASA mg + standard background care *Age 65 years, diabetes, second prior MI, multivessel CAD or chronic non-end-stage renal dysfunction Randomized, double-blind Ticagrelor 90 mg BID Ticagrelor 60 mg BID Placebo BID Follow-up visits: Q4 months for first year, then Q6 months Duration: Minimum 12 months up to ~44 months (median 30 months) Event-driven trial Primary efficacy endpoint: CV death, MI or stroke Primary safety endpoint: TIMI major bleeding BID, twice daily; CAD, coronary artery disease; TIMI, Thrombolysis in Myocardial Infarction [trial]

20 Components of Primary Endpoint Endpoint HR (95% CI) P value CV Death, MI, or Stroke (1558 events) 0.85 ( ) ( ) ( ) CV Death (566 events) 0.87 ( ) ( ) ( ) 0.06 Myocardial Infarction (898 events) 0.81 ( ) ( ) ( ) Stroke (313 events) 0.82 ( ) ( ) ( ) 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

21 Long-term DAPT for 2 nd prevention of cardiovascular events in the subgroup of patients with previous MI Collaborative meta-analysis of randomized trials 33,435 patients, FU mean 31 months among one trial of patients with prior MI (63.3% of total) and 5 trials with a subgroup of patients that presented with, or had a history of, a prior MI (36.7% of total) Risk of MACE Study or Subgroup Extended DAPT Aspirin Alone Weight Events Total Events Total RR,IV, Random, 95%CI Risk ratio IV, Random, 95%CI 2006 CHARISMA MI cohort % 0.77 ( ) 2012 PRODIGY % 0.91 ( ) 2014 ARCTIC- Interruption % 0.79 ( ) 2014 DAPT % 0.52 ( ) 2014 DES-LATE % 0.85 ( ) 2015 PEGASUS- TIMI % 0.84 ( ) Total (95% CI) % 0.78 ( ) Total events Heterogeneity: Tau 2 =0.01; Chi 2 =8.36, df=5 (P=0.14); I 2 =40%; Test for overall effect: Z=3.28 (P=0.001) Udell J, Clinical Trial Update II 3913 Udell J et al, Eur Hear J August 2015, doi: /eurheartj/ehv443

22 Long-term DAPT: results Major adverse cardiovascular events Risk ratio (95%CI) P 0.78 ( ) D Cardiovascular death 0.85 ( ) 0.03 Myocardial infarction 0.70 ( ) Stroke 0.81 ( ) 0.02 Stent thrombosis (definite/probable) 0.50 ( ) 0.02 Major bleeding 1.73 ( ) Non-cardiovascular death 1.03 ( ) 0.76 All-cause death 0.92 ( ) Favors extended DAPT Favors aspirin alone 22 Udell J, Clinical Trial Update II 3913 Udell J et al, Eur Hear J August 2015, doi: /eurheartj/ehv443

23 Zeitpunkt der schweren Blutung in CHARISMA

24 ESC Guideline NSTE-ACS 2015 Recommendations for platelet inhibition Oral antiplatelet therapy Class Level A P2Y 12 inhibitor is recommended, in addition to aspirin, for 12 months unless there are contraindications such as excessive risk of bleeds. P2Y 12 inhibitor administration for a shorter duration of 3 6 months after DES implantation may be considered in patients deemed at high bleeding risk Long-term P2Y 12 inhibition P2Y 12 inhibitor administration in addition to aspirin beyond 1 year may be considered after careful assessment of the ischemic and bleeding risks of the patient. I IIb IIb A A A Roffi M, ESC Guidelines Roffi M et al., Eur Heart J, August 2015, doi: /eurheartj/ehv320,

25 The DAPT Score Variable Patient Characteristic Age Points Distribution of DAPT Scores among all randomized subjects in the DAPT Study <75-1 < 65 0 Diabetes Mellitus 1 Current Cigarette Smoker 1 Prior PCI or Prior MI 1 CHF or LVEF < 30% 2 Index Procedure Characteristic MI at Presentation 1 Vein Graft PCI 2 Stent Diameter < 3mm 1 25

26 Continued Thienopyridine vs. Placebo DAPT Score 2 (High); N=5917 Myocardial Infarction or Stent Thrombosis Cumulative Incidence of ST/MI 10% 8% 6% 4% 2% 0% Continued Thienopyridine Placebo 2.7% vs. 5.7% P< Months After Enrollment GUSTO Moderate/ Severe Bleeding Cumulative Incidence of GUSTO Moderate/ Severe Bleed 10% 8% 6% 4% 2% 1.8% vs. 1.4% P=0.26 Cumulative Incidence of MACCE Continued Thienopyridine Placebo Death, MI or Stroke (MACCE) 10% 8% 6% 4% 2% Continued Thienopyridine Placebo 4.9% vs. 7.6% P< % Months After Enrollment 0% Months After Enrollment 26

27 PEGASUS renal function: results by therapy 16 Primary Endpoint: CV death, MI, stroke egfr < 60 Placebo (N=1,649) egfr < 60 Ticagrelor Pooled (N=3,200) egfr 60 Placebo (N=5,336) egfr 60 Ticagrelor Pooled (N=10,713) 13.99% 11.29% HR 95% CI 0.81 ( ) ARR = 2.70% 3-yr KM % % 6.80% HR 95% CI 0.88 ( ) ARR = 0.63% Months since randomization 27 Magnani G, Antithrombotic Drugs an ongoing story, 3032 Congress Update Cardiology ESC 2015

28 Zusammenfassung Patienten mit ACS sind nicht nach 12 Monaten geheilt Wir behandeln nicht den Stent, sondern einen Patienten mit ACS Elektive PCI mit 3. Generations DES: < 6 Monate DAPT PEGASUS und die Meta-Analyse sprechen für eine längere duale Thrombozytenhemmung nach ACS Identifizierung von Patienten mit größtem Netto- Nutzen: Diabetiker, Niereninsuffizienz, hoher DAPT-Score, rez. Ereignisse