DAPT Management 2015 Michael Rinaldi, MD

Transcription

1 DAPT Management 2015 Michael Rinaldi, MD The Sanger Heart and Vascular Institute Carolinas HealthCare System Charlotte NC

2 Disclosures Advisory Board: Abbott, BSc Advisory Board: Abbott, BSc Speaker: Abbott, BSc, Edwards

3 Background Optimal duration of DAPT after stenting has been uncertain Initial labeling SES (3m) and PES (6m) CURE data suggested benefit up to 12m in ACS patients with or without stents Registry data suggested late stent thrombosis was a persistent problem Data from second generation DES studies suggest that this late ST issue may have been mitigated Current guidelines are primarily consensus driven

4 Where did we get DAPT therapy from? Leon, MB. N EJM;1998 Dec 3;339(23): Schomig, A NEJM;334:

5 Cure Trial 12m of DAPT benefits ACS patients Yusef, NEJM, 2001 Aug 16;345(7):

6 SCAAR Registry 2007 Concern for late ST and Mortality with DES

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8 Current ACC/AHA Guidelines for DAPT Duration

9 If 12m DAPT is recommended why not longer?

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19 DAPT Trial Subsets ACS vs. non-acs DES vs. BMS

20 Treatment Effect According to ACS Status at Months: Primary Endpoints All Randomized Subjects (N=11648) Stent Thrombosis Moderate/Severe Bleeding MACCE 8% 7% Continued Thienopyridine P< % P=0.08 Placebo 6% 5.3% 5% 4.4% 3.9% 4% P= % P< % 2.6% P< % 2% 1.9% 1.1% 0.5% P= % 0.8% 0.4% 0% ACS No ACS Interaction P=0.69 ACS No ACS Interaction P=0.03 ACS No ACS Interaction P=

21 Treatment Effect According to ACS Status at Months Secondary Endpoints All Randomized Subjects (N=11648) Death BARC 2, 3, or 5 Bleeding 8% 7% P<0.001 BARC 5 Bleeding (Fatal Bleeding) P<0.001 Continued Thienopyridine Placebo 5.7% 6% 5% 4.3% 4% P=0.61 P= % 3% 2% 2.1% 1.4% 1.6% 1% 2.1% 1.1% P= % 0.2% 0.1% 0.1% ACS No ACS 0% ACS No ACS Interaction P=0.13 ACS No ACS Interaction P=0.67 P=0.42 Interaction P=

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23 Conclusions The DAPT study demonstrates continued benefit through reduction in ST and MACE from 12m-30m The benefit was consistent through all subgroups True for BMS as well as DES True for non-acs as well as ACS Longer DAPT was associated with increased bleeding and possibly mortality

24 Conclusions Higher mortality seen in the DAPT arm may be related to play of chance but prolonged DAPT certainly does not appear to lower mortality Likely related to small absolute event numbers which brings into question the clinical relevance of the benefit of prolonged DAPT

25 So if >12m DAPT does not confer much benefit what is the right duration for DAPT?

26 DES is getting safer Network Meta-Analysis of Stents Types 1st gen DES probably worse than BMS for Late ST 2nd gen DES better than 1st gen and BMS for Late ST Palmerini, Stone, JACC, 2015;65:

27 2nd Gen DES Short DAPT Safety RESOLUTE DAPT Interruption Analysis Pooled DAPT Pooled Patient-Level Data from More Than 7000 Patients RESOLUTE All Comers RESOLUTE Int RESOLUTE US RESOLUTE Japan N = 1140 N = 2349 N = 1402 N = 100 RESOLUTE Japan SVS N = 65 R-China RCT N = 198 RESOLUTE Asia 38 mm RESOLUTE US 38 mm N = 223 China Registry N = 1800 A robust post-hoc analysis on the high-quality RESOLUTE Pooled DAPT interruption data was performed: Every Resolute DES study patient with available DAPT usage data was included (N = 7131) High degree of data monitoring was performed in all studies The ST rates through one year were assessed based on: The timing of the first DAPT interruption: no interruption; 0 1 month interruption; 1 12 month interruption The duration of the first DAPT interruption: interruption >1 day; interruption >14 days; permanent discontinuation

28 2nd Gen DES Short DAPT Safety RESOLUTE DAPT Interruption Analysis Pooled Patient-Level Data from More Than 7000 Patients No Increased Risk of ST in ZES DES Patients Interrupting DAPT Beyond One Month Subsequent ST (ARC Def/Prob) (%) Timing of First DAPT Interruption and ST Through 1 Year Interrupted 1 12 mo Interruption duration >1 day Interruption duration breakout Never 1 Interrupted Patients at risk 0.09 Interrupted 0-1 Mo Interrupted 1-12 Mo 0.09 > 1-Day Interruption 0.0 > 14-Day Interruption Discontinuation No. of events Median days to interruption NA Bhatt. Relation of stent thrombosis to interruption of dual antiplatelet therapy after Resolute zotarolimus-eluting stent Implantation. TCT Post-hoc RESOLUTE Pooled DAPT analysis was not powered for the analysis shown.

29 Bioabsorbable Polymers? Chronic inflammation of Various Stent Types Inflammation at 180d Swine Model Inflammation Area (mm2) 2.0 * P<0.05 vs BMS & SYNERGY * * PtCr BMS Juan Granada, MD EuroPCR 2014 Bioabsorbable Polymer (Synergy) DES Durable Polymer ZES (Resolute) DES Durable Polymer DES EES (Xience) DES

30 Pooled Analysis of Short DAPT RCTs No difference in ST 3m vs. 12m Montalescot, JACC 2015;66:832-47

31 Short DAPT Lower Bleeding Rates Montalescot, JACC 2015;66:832-47

32 Post PCI Bleeding Associated with Mortality (ADAPT DES) Genereux, JACC 2015;66:

33 DAPT Bleeding and Estimating Risk (ADAPT-DES) Genereux, JACC 2015;66:

34 Net Clinical Benefit Favors Short DAPT Montalescot, JACC 2015;66:832-47

35 Tailored Approach to DAPT In favor of Long DAPT Risk Factors for Late ST 1st gen DES Two stent bifurcation technique Two layers of DES for ISR Long stented area Under-expanded stent Previous ST STEMI / ACS indication DM Montalescot, JACC 2015;66: High Consequence of ST LM stent Proximal vessel stent with large territory Last remaining vessel

36 Tailored Approach to DAPT Favors Short DAPT Risk for Bleeding Previous bleeding Anemia Advanced age/frailty/female gender Thrombocytopenia Oral AC Chronic NSAID use High HASBLED score Montalescot, JACC 2015;66:832-47

37 Conclusions There is a reduction in ST and non-stent related MI with prolonged DAPT (possibly indefinitely) But the absolute benefit is small, increases bleeding, and does not reduce mortality Current Guidelines suggest 12m DAPT but duration of therapy should be tailored to the individual patient Discuss with patient and document reasoning DAPT <12m Class IIa (B) for bleeding risk (ACC/AHA 2011) DAPT >12m Class IIb (C) (ACC/AHH 2011 likely to be updated)

38 What DAPT Regimen Is Preferred? Clopidogrel? Prasugrel? Ticagrelor?

39 ADAPT-DES: Relationship between ACS and stent thrombosis 1 year Def/Prob Stent Thrombosis (n=70) 3.0% 2.5% 1.85% 2.0% 1.5% p= % 1.0% 0.5% 0.0% 1.20% 1.13% 0.48% 20/4147 No ACS 50/4436 ACS 20/2373 UA, biomarker negative 15/ /813 NSTEMI STEMI

40 Efficacy Trade Offs High PRU is associated with ST Low PRU is Associated with Bleeding Incidence of events (%) 50 Ischemic end point (iep) Bleeding end point (bep) 40 p< PRU 85 PRU PRU (25%) pts 1 (1.3%) iep 15 (20%) bep 185 (62%) pts 3 (1.6%) iep 3 (1.6%) bep 40 (13%) pts 17 (42.5%) iep 1 (2.5%) bep Campo et al. J Am Coll Cardiol 2011;57:

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47 PLATO: primary endpoint: Cumulative incidence (%) K-M estimate of time to major CV event (composite of CV death, MI or stroke) Clopidogrel 9.8 Ticagrelor (HR, 0.84; 95% CI, ; P<0.001) ΝΝΤ Months after randomization No. at risk Ticagrelor Clopidogrel Wallentin L, et al. N Engl J Med. 2009;361:1045.

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50 Non-ACS Patients

51 GRAVITAS Primary Endpoint: CV Death, MI, Stent Thrombosis Observed event rates are listed; P value by log rank test. Price MJ et al, JAMA. 2011;305(11):

52 ARCTIC Trial 2440 patients undergoing DES (70% elective, 30% ACS) 34% high platelet reactivity (HPR) to testing HPR patients all treated until suppression Monitored Standard p valve Stent Thrombosis 4.9% 4.6% 0.77 MACE 34.6% 31.1% 0.10 Major Bleeding 2.3% 3.3% 0.15

53 ACS Patients Medically Managed

54 TRILOGY ACS Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months (Overall population) HR (95% CI): 0.96 (0.86, 1.07) P = 0.45 HR (95% CI): 1.23 (0.84, 1.81) P = 0.29

55 Summary Prasugrel/Ticagrelor (P/T) preferred in ACS Prasugrel contraindicated in prior TIA/stroke Clopidogrel (C) preferred in non-acs and medically managed ACS pts If ACS pts can not afford P/T or are at high bleeding risk a strategy of one month of P/T (free) followed by maintenance C could be considered

56 PPI to reduce bleeding in DAPT therapy

57 ASA: Proton Pump Inhibitors and GI Effects PPIs substantially reduce gastric acidity1: Treatment with PPIs significantly reduces the rate of recurrence of ulcer complications in patients using long-term ASA1, Ulcer 3 mm, % 10 Placebo 12 PPI 10 Recurrent Ulcer, % ASA ( mg) Nexium ASA ( mg) ± 1 Nexium (esomeprazole) After 6 Months of Therapy ± Placebo PPI ASA (100 mg) Prevacid ASA (100 mg) ± ± 2 Prevacid (lansoprazole) 2 12 Months Median Follow-up 1. Yeomans N, et al. Am J Gastroenterol. 2008;103: Lai KC, et al. N Engl J Med. 2002;346:

58 Do Proton Pump Inhibitors Interact With Clopidogrel? Insights From ADAPT-DES Michael Rinaldi, Giora Weisz, Ajay J. Kirtane, Ke Xu, Thomas Stuckey, Bernhard Witzenbichler, Franz-Josef Neumann, Chris Metzger, Timothy Henry, David Cox, Peter Duffy, Bruce Brodie, Ernest Mazzaferri, Helen Parise, Roxana Mehran, Gregg W. Stone

59 Out of hospital to 1-yr Events PPI No--PPI No All (n=2163) (n=6419) (n=8582) 2.1% 1.7% 1.8% 0.26 Q-wave 0.5% 0.3% 0.3% 0.20 Non Q-wave 1.6% 1.4% 1.5% % 1.5% 1.9% < Cardiac 1.7% 1.0% 1.2% Non-cardiac 1.2% 0.6% 0.7% Death/MI 4.5% 3.1% 3.4% MACE 6.9% 5.2% 5.6% Any 2.1% 1.1% 1.4% Definite/Probable 1.1% 0.6% 0.7% TLR 4.4% 3.5% 3.7% TVR 7.8% 6.2% 6.6% MI Death P-value Stent Thrombosis

60 Adjusted Hazard-Ratios of Use of PPI Propensity Score Models Results Event (Out of hospital to 1 yr) Adj HR [95%CI] P-value MACE 1.23 [ 1.00, 1.51] Death 1.52 [ 1.09, 2.12] Cardiovascular death 1.52 [ 1.00, 2.33] Non-cardiovascular death 1.51 [ 0.89, 2.58] 0.13 MI 1.02 [ 0.71, 1.47] 0.92 Death/MI 1.19 [ 0.92, 1.53] 0.18 Def/Prob Stent Thrombosis 1.43 [ 0.82, 2.47] 0.21 Bleeding 0.99 [ 0.69, 1.42] 0.95 Clinically driven TVR 0.99 [ 0.69, 1.42] 0.95

61 COGENT Trial RCT of PPI in DAPT GI Bleeding MACE Bhatt, D. NEJM. 2010;363:

62 ACC/AHA Guidelines 2011 PPI and DAPT CLASS I PPIs should be used in patients with a history of prior gastrointestinal (GI) bleeding who require DAPT (794). (Level of Evidence: C) CLASS IIa Use of PPIs is reasonable in patients with an increased risk of GI bleeding (e.g., advanced age, concomitant use of warfarin, steroids, nonsteroidal anti-inflammatory drugs, Helicobacter pylori infection) who require DAPT (794). (Level of Evidence: C) CLASS III: NO BENEFIT Routine use of a PPI is not recommended for patients at low risk of GI bleeding, who have much less potential to benefit from prophylactic therapy (794). (Level ofevidence: C)

63 Summary of PPI use in DAPT Remains controversial Appears to reduce bleeding Theoretical reduced efficacy with Clopidogrel but should have less of an effect on Prasugrel/Ticangrelor Conflicting data on if this translates into higher ST with C Protonix (pantoprasole) interacts less (may be preferred PPI) We know even less about H2 blockers Like DAPT duration, PPI use probably best tailored to the individual pts risk profile

64 Aspirin safe in non-cardiac surgery Absolute risk of major bleeding 1.2% if ASA started on day of surgery

65 Incremental Risk of Non-cardiac Surgery on Adverse Cardiac Events Following Coronary Stenting Retrospective cohort analysis of 20,590 surgical vs. 41,180 nonsurgical patients J Am Coll Cardiol. 2014;64(25):

66 5054 real world patients at 162 US sites % ACS % multi-vessel % DM % AMI % CKD J Am Coll Cardiol Intv 2011;4:

67 Ischemic Events Around Thienopyridine Discontinuation from the DAPT study (Also noted in PEGASUS-TIMI 54 with Ticangrelor after 1 year) Months Months Months* Cumulative Incidence (%) 4.5% 4.0% 4.0% 3.5% < % 2.5% < % 2.0% <0.001 < % 1.3% 1.1% 0.9% 1.0% 0.5% 0.0% 0.4% 0.4% 0.5% 0.4% 0.3% 0.1% 0.0% Stent Thrombosis Myocardial Infarction Stent Thrombosis Thienopyridine (N=5862) Myocardial Infarction Stent Thrombosis Myocardial Infarction Placebo (N=5786) Mauri et al. N Engl J Med Dec;371(23): Yeh, Mauri, Kereiakes. JACC 2015 Online ahead of print. *Subjects randomized at 12m and discontinued study drug at 30 months. TIMI 54 data presented at ESC

68 DAPT and Surgery Conclusions Wait at least 3-6m post DES if possible before stopping thienopyridine ASA safe for most surgeries Increases bleeding (but only 1.2%) but reduces ST more Can t safely be used in some surgeries (Neurosurgery) Bridging with 2b3a or Cangrelor? No great data Selected high risk for ST pts only and is unavailable immediately post-op Is there a rebound effect and should we instead stop thienopyridine a month or more before surgery?

69 DAPT in pts with an indication for Oral AC

70 Recall Oral AC does not reduce ST Risk Leon, MB. N EJM;1998 Dec 3;339(23): Schomig, A NEJM;334:

71 NOACs do not reduce ST either but increase bleeding Data from APPRAISE-2 Hess, C. JACC 2015;66:777-87

72 ACTIVE-W Trial DAPT vs. Warfarin for stroke prevention in AF Mean CHADS 2 Median f/u 1.3y Connolly, S. Lancet Jun 10;367(9526):

73 ACTIVE-W Trial (CHADS=2) Warfarin less ischemic stroke/embolism (1.4%/y less events) Warfarin not more severe bleeding Warfarin more IC bleeding (0.2%/y more events) Warfarin/DAPT equal mortality Connolly, S. Lancet Jun 10;367(9526):

74 ACTIVE-W Trial Outcomes based on status of oral AC therapy in lead in to study Lead In Oral AC No Lead In Oral AC Stroke/embolism Major Bleeding Connolly, S. Lancet Jun 10;367(9526):

75 ACTIVE-W Trial In pts previously on oral AC NNT to prevent 1 stroke = 100 (1y treatment) (CHADS=2) Connolly, S. Lancet Jun 10;367(9526):

76 WOEST Trial Plavix/Warfarin vs. Triple Therapy Only 30% ACS, CHADS>3 in 70%, 40% continuation of baseline oral AC MACE Bleeding Dewilde, W. Lancet 2013;381:

77 ISAR Triple ASA/Warfarin with Clopidogrel 6wks vs. 6m Only 20% ACS, CHADS>3 in 50% MACE Landmark Analysis Bleeding Bleeding Fiedler, K. JACC 2015;65:

78 Options C/Oral AC (WOEST Strategy) ST risk/consequence low, Stroke risk high A/C/Oral AC for 6wks the C/Oral AC (ISAR Triple / WOEST Hybrid Strategy) ST risk/consequence high, Stroke risk high DAPT (hold oral AC) for first month then C/Oral AC thereafter (Time Dependent Risk Strategy) ST risk/consequence high, Stroke risk low * Use of Prasugrel/Ticagrelor not recommending with oral AC

79 Tailored Approach to DAPT and Oral AC Risk Factors for Late ST 1st gen DES Two stent bifurcation technique Two layers of stent for ISR Long stented area Under-expanded stent Previous ST STEMI / ACS indication DM High Consequence of ST LM stent Proximal vessel stent with large territory Last remaining vessel Montalescot, JACC 2015;66: Risk for Bleeding Previous bleeding Anemia Advanced age/frailty/female gender Thrombocytopenia Oral AC Chronic NSAID use High HASBLED score

80 Summary Low Risk/Consequence ST High Risk/Consequence ST High Bleeding Risk DAPT DAPT DAPT CHADS VASC 2 C/Oral AC TT 1m then C/Oral AC DAPT + Watchman!!! CHADS VASC >3 C/Oral AC TT 1m then C/Oral AC DAPT + Watchman!!! CHADS VASC 0-1

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82 Conclusions Duration of DAPT therapy should be per current ACC/AHA guidelines For most patients 12m of DAPT But should be tailored to fit individual patient risks (3m DAPT to indefinite) Similarly DAPT and Oral AC should be tailored to the individual patient to fit the balance of thrombotic, embolic, and bleeding risks

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