Dual Antithrombotic Therapy in AF Patients Undergoing PCI - Dr. ten Berg
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The document discusses the management of patients requiring oral anticoagulation during acute coronary syndrome (ACS) treatment and percutaneous coronary intervention (PCI). It emphasizes the importance of antithrombotic therapy, highlighting the risks of bleeding with various combinations of medications, and reviews guidelines for dual and triple therapy options. The findings suggest that dual therapy with NOACs may be safer than triple therapy involving VKAs, although further investigation is needed to understand the underlying effects.
Dual Antithrombotic Therapy in AF Patients Undergoing PCI - Dr. ten Berg
- 2. Setting new standards for AF patients who require oral anticoagulation admitted with ACS or undergoing PCI Jur ten Berg PhD, MSc, FESC, FACC St. Antonius Hospital, Nieuwegein, the Netherlands;
- 3. Disclosures • Advisory/consulting/speakers fees: AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, Accumetrics, Boehringer Ingelheim, BMS, Pfizer, Bayer, Ferrer • Research grants: ZonMw, AstraZeneca • Scientific committee RE-DUAL trial
- 4. Personal information Sex Male Age 85 years Blood pressure 161/89 mmHg Pulse 69 bpm Oxygen saturation 97% Patient: Johan Patient history Medical history • Hypertension (2002) • Type 2 diabetes mellitus (2003) • Peripheral artery disease • Renal impairment (GFR = 45 mL/min) • TIA (2011) • Paroxysmal NVAF (diagnosed 2011; CHA2DS2-VASc: 7) Medications • Beta blocker • Statin • ACE inhibitor • Antidiabetics • NOAC since 2013 (because of labile INR) Presentation management • Heavy chest pain (40 min, previous night) • Pain-free at presentation • ST-T changes and positive troponin • Grace risk score 149 • Scheduled for CAG next day Patient presentation Patient details have been altered to protect patient confidentiality. Hb, haemoglobin; TIA, transient ischaemic attack; TTR, time in therapeutic range
- 5. Roffi et al. Eur Heart J 2015 Antiplatelet therapy at admittance What do the 2015 ESC guidelines recommend? Patients undergoing coronary stenting1 Class Level Antiplatelet therapy Initial dual antiplatelet therapy with ASA plus a P2Y12 inhibitor in addition to OAC before coronary angiography is not recommended III C Management of ACS in patients with Non-STEMI requiring chronic oral anticoagulation1 Guidelines: ASA added to (N)OAC Local practice: Clopidogrel added to (N)OAC
- 6. Roffi et al. Eur Heart J 2015 How to handle the (N)OAC What do the 2015 ESC guidelines recommend? Therapeutic anticoagulation Uninterrupted therapeutic anticoagulation with VKA or NOACs should be considered during the periprocedural phase* IIa C Parenteral anticoagulation During PCI, additional parenteral anticoagulation (e.g. enoxaparin 0.5 mg/kg i.v. or UFH 60 IU/kg) is recommended, irrespective of the timing of the last dose of all NOACs and if INR is <2.5 in VKA-treated patients I C Management of ACS in patients with Non-STEMI requiring chronic oral anticoagulation1
- 7. • Clopidogrel started at CCU; ASA withheld • NOAC continued during CAG • Radial coronary angiography next day with additional low-dose UFH (60 IU/KG) • Before PCI single bolus 300 mg ASA Our patient Johan: coronary angiography Outcome: • PCI successful but bifurcation stent • Patient with CHA2DS2-VASc = 7 and high bleeding risk (HAS-BLED =4)
- 8. Q What is the optimal antithrombotic regimen after stenting? 1. Dual or triple therapy 2. NOAC or VKA 3. Full dose or lower dose NOAC 4. Which antiplatelet drug(s): clopidogrel or ticagrelor or ASA
- 9. OAC plus APT: bleeds increase especially early 1.Sorensen R, Hansen ML, Abildstrom SZ,et al. Risk of . bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet 2009;374:1967–1974. 2.Hansen ML, Sorensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy . with warfarin, aspirin, and clopidogrel in patients with atri fibrillation. Arch . Intern Med 2010;170:1433–1441. 3. Dans AL, Connolly SJ, Wallentin L,et al. Concomitant use of . antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation . of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation . 2013;127:634–640. 4.Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase . II trial. Eur Heart J 2011;32:2781–2789. 5. Dewilde, ten Berg et al. Lancet. 2013;381:1107–1115. TT HR 3-4 as compared to ASA TT as compared to DT
- 10. 573 patients receiving OAC (any indication, 69% for AF/atrial flutter/DAPT one year/low PPI) and undergoing PCI in open-label, randomized WOEST trial ASA, acetylsalicylic acid; ST, stent thrombosis; TIMI, Thrombolysis In Myocardial Infarction; TVR, target vessel revascularization. Dewilde, ten Berg et al. Lancet 2013 1. DT vs. TT WOEST: VKA + clopidogrel (excluding ASA) reduces bleeding risk vs triple therapy without compromise on efficacy Triple-therapy group Double-therapy group Any bleeding Cumulativeincidence(%) Death, MI, TVR, stroke, ST Time (days) 100 80 60 40 30 0 30 60 120 180 270 365 19.4% 44.4% HR: 0.36 (95% CI: 0.26‒0.50) P<0.0001 90 70 50 10 20 0 90 17.6% 11.1% HR: 0.60 (95% CI: 0.38‒0.94) P=0.025100 80 60 40 30 0 30 60 120 180 270 365 90 70 50 10 20 0 90 Time (days) Cumulativeincidence(%)
- 11. R A N D O M I Z E 1 mo: 16% 6 mos: 35% 12 mos: 49% XARELTO® 15 mg qd* Clopi 95%, Ticag 4%, Prasugrel 1% XARELTO® 15mg QD Aspirin 75-100 mg qd XARELTO® 2.5 mg bid Clopi 95%, Ticag 4%, Prasugrel 1% Aspirin 75-100 mg qd‡ VKA (target INR 2.0-3.0) Aspirin 75-100 mg qd TTR 65% VKA (target INR 2.0-3.0) Clopi 95%, Ticag 4%, Prasugrel 1% Aspirin 75-100 mg qd ≤ 72 hours After Sheath removal WOEST Like ATLAS Like Triple Therapy 1 mo: 16% 6 mos: 35% 12 mos: 49% ◆ 2100 patients with NVAF ◆ Coronary stenting ◆ No prior stroke/TIA, GI bleeding, Hb<10, CrCl<30 • Primary endpoint: TIMI major + minor + bleeding requiring medical attention • Secondary endpoint: CV death, MI, and stroke (Ischemic, Hemorrhagic, or Uncertain Origin) Gibson M et al 2016 Dec 22;375(25):2423-2434. doi: 10.1056/NEJMoa1611594. Epub 2016 Nov 14. 2 DT vs. TT
- 12. Kaplan-Meier Estimates of First Occurrence of Clinically Significant Bleeding Events TIMIMajor,TIMIMinor,orBleeding RequiringMedicalAttention(%) 697 Days 593 555 521 461 426 329VKA + DAPT No. at risk VKA + DAPT 26.7% VKA + DAPT Riva + DAPT 18.0% p<0.00018 HR = 0.63 (95% CI 0.50-0.80) ARR = 8.7 NNT = 12 706 697 636 593 600 555 579 521 543 461 509 426 409 329 Riva + DAPT VKA + DAPT VKA + DAPT Riva + P2Y12 16.8% p<0.000013 HR = 0.59 (95% CI 0.47-0.76) ARR = 9.9 NNT = 11 696 697 628 593 606 555 585 521 543 461 510 426 383 329 Riva + P2Y12 VKA + DAPT Riva + P2Y12 VKA + DAPT Riva + DAPT Riva + P2Y12 v. VKA + DAPT HR=0.59 (95% CI: 0.47-0.76) p <0.000013 ARR=9.9 NNT=11 Riva + DAPT v. VKA + DAPT HR=0.63 (95% CI: 0.50-0.80) p <0.00018 ARR=8.7 NNT=12 696 706 697 628 636 593 606 600 555 585 579 521 543 543 461 510 509 426 383 409 329 Riva + P2Y12 Riva + DAPT VKA + DAPT Gibson M et al 2016 Dec 22;375(25):2423-2434. doi: 10.1056/NEJMoa1611594. Epub 2016 Nov 14.
- 13. Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke (underpowered!) CardiovascularDeath,Myocardial Infarction,orStroke(%) Days Riva + P2Y12 Riva + DAPT VKA + DAPT 694 704 695 648 662 635 633 640 607 621 628 579 590 596 543 562 570 514 430 457 408 VKA + DAPT Riva + DAPT Riva + P2Y12 Riva + P2Y12 v. VKA + DAPT HR=1.08 (95% CI: 0.69-1.68) p=0.750 Riva + DAPT v. VKA + DAPT HR=0.93 (95% CI: 0.59-1.48) p=0.765 6.5% 5.6% 6.0% No. at risk Gibson M et al 2016 Dec 22;375(25):2423-2434. doi: 10.1056/NEJMoa1611594. Epub 2016 Nov 14.
- 14. Non-US patients aged ≥80 years (for Japan ≥70 years) were assigned to dabigatran 110 dual-therapy or warfarin triple-therapy 1:1. Study drug should be administered 6 hours after sheath removal and no later than ≤120 hrs post-PCI (≤72 hrs is preferable). PROBE, prospective, randomized, open, blinded end-point; R, randomization; BMS, bare metal stent; DES, drug-eluting stent. ClinicalTrials.gov: NCT02164864; Cannon et al. Clin Cardiol 2016 3 DT vs. TT Multicenter, randomized, open-label trial PROBE design R Randomization ≤120 hours post-PCI* 6-month minimum treatment duration with visits every 3 months for the first year, then visits and telephone contact alternating every 3 months and a 1-month post-treatment visit Patients with AF undergoing succesful PCI with stenting no recent < 1 m ICH, stroke, surgery, bleeding CrCl <30mL/min Dabigatran 150 mg BID + P2Y12 inhibitor Dabigatran 110 mg BID + P2Y12 inhibitor Warfarin (INR 2.0–3.0) + P2Y12 inhibitor + ASA Dabigatran (110 or 150 mg) Warfarin 1 month of ASA (BMS) 3 months of ASA (DES) N=2725 Mean duration of follow-up: ~14 months P2Y12 inhibitor P2Y12 inhibitor
- 15. Full analysis set presented. HRs and Wald CIs from Cox proportional-hazard model. For the dabigatran 110 mg vs warfarin comparison, the model is stratified by age, non-elderly vs elderly (<70 or ≥70 in Japan and <80 or ≥80 years old elsewhere). For the dabigatran 150 mg vs warfarin comparison, an unstratified model is used, elderly patients outside the USA are excluded. Non-inferiority P value is one sided (alpha=0.025). Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=0.05) Time to first major bleeding event or clinically relevant non-major bleeding event Probabilityofevent(%) 0 0 90 180 270 360 450 540 630 720 Time to first event (days) 40 35 30 25 20 15 10 5 Warfarin triple therapy Dabigatran 110 mg dual therapy HR: 0.52 (95% CI: 0.42–0.63) Non-inferiority P<0.0001 P<0.0001 0 90 180 270 360 450 540 630 720 Time to first event (days) 40 35 30 25 20 15 10 5 0 Dabigatran 150 mg dual therapy Warfarin triple therapy HR: 0.72 (95% CI: 0.58–0.88) Non-inferiority P<0.0001 P=0.002
- 16. Non-inferiority P value is one sided (alpha=0.025). Results presented are Step 3 of hierarchical testing procedure, testing non-inferiority of dabigatran dual therapy (combined doses) to warfarin triple therapy in death or thromboembolic event and unplanned revascularization Time to death or thromboembolic event, or unplanned revascularization 35 30 25 20 15 10 5 0 Probabilityofevent(%) 0 90 180 270 360 450 540 630 720 Time to first event (days) Dabigatran (combined doses) dual therapy Warfarin triple therapy
- 17. What do we know so far? • Dual therapy is safer than triple therapy with VKA 1. VKA plus clopidogrel 2. Lower dose rivaroxaban plus clopidogrel 3. Full dose dabigatran plus clopidogrel • But, Is this effect due to removal of aspirin or the use of NOAC?
- 18. VKA (INR 2–3) Apixaban 5 mg BID Apixaban 2.5 mg BID in selected patients Primary outcome: ISTH major / CRNM bleeding Secondary outcome(s): death / hospitalization, death / ischemic events Randomize <14 D n=4600 patients INCLUSION • Atrial fibrillation (prior, persistent, >6 hr) –Physician decision for OAC • Acute coronary syndrome or PCI –Planned P2Y12 inhibitor for ≥6 months EXCLUSION • Contraindication to DAPT • Other reason for VKA (prosthetic valve, moderate / severe mitral stenosis) AUGUSTUS Trial Aspirin for all on the day of ACS or PCI Aspirin versus placebo after randomization Open Label Aspirin Placebo Double Blind Aspirin Placebo Double Blind Lopes RD, et al. Am Heart J. 2018;200:17-23. N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.1056/NEJMoa1817083 4 DT vs. TT
- 19. VKA: 14.7% Apixaban: 10.5% Major / CRNM Bleeding Apixaban vs. VKA HR 0.69, 95% CI 0.58–0.81 P<0.001 for non-inferiority P<0.001 for superiority ARR=4.2% NNT=24 ARR: absolute risk reduction NNT: number needed to treat
- 20. Placebo: 9.0% Aspirin: 16.1% Major / CRNM Bleeding Aspirin vs. Placebo HR 1.89, 95% CI 1.59–2.24 P<0.001 ARI=7.1% NNH=14 ARI: absolute risk increase NNH: number needed to harm
- 21. VKA + Aspirin (18.7%) Apixaban + Aspirin (13.8%) Apixaban + Placebo (7.3%) VKA + Placebo (10.9%) Major / CRNM Bleeding Apixaban + Placebo vs. VKA + Aspirin: 11.4% absolute risk reduction (NNT=9)
- 22. Ischemic Outcomes Apixaban vs. VKA not powered for individual ischemic outcomes Endpoint Apixaban (N=2306) VKA (N=2308) HR (95% CI) Death / Ischemic Events (%) 6.7 7.1 0.93 (0.75–1.16) Death (%) 3.3 3.2 1.03 (0.75–1.42) CV Death (%) 2.5 2.3 1.05 (0.72–1.52) Stroke (%) 0.6 1.1 0.50 (0.26–0.97) Myocardial Infarction (%) 3.1 3.5 0.89 (0.65–1.23) Definite or Probable Stent Thrombosis (%) 0.6 0.8 0.77 (0.38–1.56) Urgent Revascularization (%) 1.7 1.9 0.90 (0.59–1.38) Hospitalization (%) 22.5 26.3 0.83 (0.74–0.93)
- 23. Ischemic Outcomes Aspirin vs. Placebo not powered for individual ischemic outcomes Endpoint Aspirin (N=2307) Placebo (N=2307) HR (95% CI) Death / Ischemic Events (%) 6.5 7.3 0.89 (0.71–1.11) Death (%) 3.1 3.4 0.91 (0.66–1.26) CV Death (%) 2.3 2.5 0.92 (0.63–1.33) Stroke (%) 0.9 0.8 1.06 (0.56–1.98) Myocardial Infarction (%) 2.9 3.6 0.81 (0.59–1.12) Definite or Probable Stent Thrombosis (%) 0.5 0.9 0.52 (0.25–1.08) Urgent Revascularization (%) 1.6 2.0 0.79 (0.51–1.21) Hospitalization (%) 25.4 23.4 1.10 (0.98–1.24)
- 24. Conclusion AUGUSTUS In patients with atrial fibrillation and ACS or PCI treated with a P2Y12 inhibitor: apixaban and no aspirin resulted in less bleeding and fewer hospitalizations without significant differences in ischemic events than VKA, aspirin, or both
- 25. Screening Randomization (1:1) Edoxaban 60 mg once dailya P2Y12 antagonistb (without aspirin) VKA (INR 2.0–3.0) P2Y12 antagonistb (Aspirin 1–12 months)c 4h - 5d after sheath removal EOT: 12 months Final follow-up: 30 d post-EOT R Phase 3b PROBE design: Prospective, randomized, open-label, blinded outcome evaluation of edoxaban-based regimen vs VKA-based regimen following successful PCI Primary Outcome: ISTH-defined Major or CRNM Bleeding ACS or stable CAD N = 1506 ACS = acute coronary syndrome; CAD = coronary artery disease; EOT = end of treatment; INR = international normalized ratio; ISTH = International Society on Thrombosis and Haemostasis; PCI = percutaneous coronary intervention Vranckx P et al. Am Heart J. 2018 Feb;196:105-112; Vranckx P et al. Lancet; September 03,2019 a30 mg QD if CrCl 15–50 mL/min, body weight ≤60 kg, or concomitant therapy with certain P-gp inhibitors. bClopidogrel 75 mg QD (or, in the presence of a documented clinical need, either prasugrel 5 or 10 mg QD or ticagrelor 90 mg BID). cAspirin 100 mg QD for 1–12 months guided by the clinical presentation (ACS or stable coronary disease), and upon the CHA2DS2-VASc and HAS-BLED scores. Successful PCI Edoxaban in Dual Therapy 5 DT vs.TT
- 26. Primary outcome: major or CRNM bleeding ITT analysis CI = confidence interval; CRNM = clinically relevant non major; ITT = intention to treat Vranckx P et al. Lancet; September 03,2019 Edoxaban-based regimen n/N (%):128/751 (17%) VKA-based regimen n/N (%): 152/755 (20%) Edoxaban-based regimen VKA-based regimen Hazard ratio (2-sided 95% CI) P-value Intent-to-treat analysis Number of patients 751 755 Number of patients with event (%) 128 (17) 152 (20) Annualized event rate (% per year) 20.7 25.6 0.83 (0.65; 1.05) non-inferiority: p = 0.0010 superiority: p = 0.1154 • Fatal bleeding 1 vs 7 • Intracranial bleed 4 (0.6%/year) vs 9 (1.3%/year)
- 27. Main secondary efficacy outcome CV = cardiovascular; CI = confidence interval; ITT = intention to treat; MI = myocardial infarction; SEE = systemic embolic event Vranckx P et al. Lancet; September 03,2019 VKA-based regimen n/N (%): 46/755 (6%) Edoxaban-based regimen VKA-based regimen Hazard ratio (2-sided 95% CI) Intent-to-treat analysis Number of patients 751 755 Number of patients with event (%) 49 (7) 46 (6) Annualized event rate (% per year) 7.3 6.9 1.06 (0.71; 1.69) composite of CV death, stroke, SEE, MI or definite stent thrombosis; ITT analysis Edoxaban-based regimen n/N (%): 49/751 (7%)
- 28. Q What is the optimal antithrombotic regimen after stenting? 1. Dual or triple therapy (WOEST, PIONEER, RE-DUAL, AUGUSTUS, ENTRUST) 2. NOAC or VKA (AUGUSTUS) 3. Full dose or lower dose NOAC (RE-DUAL, AUGUSTUS, ENTRUST) 4. Which antiplatelet drug to use clopidogrel or ticagrelor (all trials clopidogrel 90%) Local practise: full dose NOAC plus clopidogrel
- 29. Setting new standards for AF patients who require oral anticoagulation admitted with ACS or undergoing PCI Triple therapy preferred: it is going to be a bloody mess Takes off his glasses and puts in some hair-gel
- 30. “It is only a short period of TT” • True: most stent thromboses occur in first months • Not true: short period of TT is safe • Bleeding also occurs in the first months • Bleeding with TT is high in the RCTs, not even including the highest risk
- 31. Major bleeding event or clinically relevant non-major bleeding event 0 90 180 270 360 450 540 630 720 Time to first event (days) 40 35 30 25 20 15 10 5 0 Dabigatran 150 mg dual therapy Warfarin triple therapy HR: 0.72 (95% CI: 0.58–0.88) Non-inferiority P<0.0001 P=0.002 RE-DUAL 150 mgAUGUSTUS Successful PCI and no (recent) ICH, stroke, surgery, bleeding, CrCl <30mL/min
- 32. Valgimigli et al. European Heart Journal (2017) 0, 1–48 doi:10.1093/eurheartj/ehx419 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease. Update 2018 NOAC preferred. no RE-DUAL/AUGUSTUS Valgimigli et al. European Heart Journal (2017) 0, 1–48 doi:10.1093/eurheartj/ehx419 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease. Update 2018 NOAC preferred. no RE-DUAL/AUGUSTUS
- 34. Meta-analysis of NOACs vs VKA in PCI
- 35. Meta-analysis of NOACs vs VKA in PCI
- 36. Results presented are times to event. Stent thrombosis is time to definite stent thrombosis Does the dose of the NOAC matter? Dabigatran 110 mg dual therapy (n=981) n (%) Warfarin triple therapy (n=981) n (%) D110 DT vs warfarin TT Dabigatran 150 mg dual therapy (n=763) n (%) Warfarin triple therapy (n=764) n (%) D150 DT vs warfarin TT HR (95% CI) P value HR (95% CI) P value All-cause death 55 (5.6) 48 (4.9) 1.12 (0.76–1.65) 0.56 30 (3.9) 35 (4.6) 0.83 (0.51–1.34) 0.44 Stroke 17 (1.7) 13 (1.3) 1.30 (0.63–2.67) 0.48 9 (1.2) 8 (1.0) 1.09 (0.42–2.83) 0.85 Unplanned revascularization 76 (7.7) 69 (7.0) 1.09 (0.79–1.51) 0.61 51 (6.7) 52 (6.8) 0.96 (0.65–1.41) 0.83 MI 44 (4.5) 29 (3.0) 1.51 (0.94–2.41) 0.09 26 (3.4) 22 (2.9) 1.16 (0.66–2.04) 0.61 Stent thrombosis 15 (1.5) 8 (0.8) 1.86 (0.79–4.40) 0.15 7 (0.9) 7 (0.9) 0.99 (0.35–2.81) 0.98 Dabigatran 110 = full dose but in combination with clopidogrel numerically higher thromboembolic risk
- 37. Q What is the optimal antithrombotic regimen after stenting? And the winner is: Local practise: full dose NOAC plus clopidogrel