Angelika Cyganska, PharmD Austin T. Wilson, MS, PharmD Candidate 2017

Transcription

1 Angelika Cyganska, PharmD Austin T. Wilson, MS, PharmD Candidate 2017

2 Explain the efficacy and safety of triple therapy, in regards to thromboembolic and bleeding risk Summarize the guideline recommendations and relevant medical literature on triple antithrombotic therapy Formulate an evidence based recommendation for the management of triple therapy

3 Prevention of ischemic stroke High risk patients based on CHA 2 DS 2 VASc score Score 2: Benefit of anticoagulation outweighs the bleed risk Low risk patients Aspirin alone Europace Oct;14(10): Epub 2012 Aug 24.

4 Stent thrombosis (ST)- an abrupt thrombotic occlusion Usually within first 30 days after bare metal stent (BMS) DAPT (aspirin plus platelet P2Y 12 receptor blocker) significantly lowers the risk of MI or cardiac death Restenosis- gradual re-narrowing of the stent Presents as recurrent angina but can present as acute MI in 10% of patients Antiplatelet therapy after coronary artery stenting. Cutlip D. UpToDate. www. UpToDate.com

5 Premature discontinuation of DAPT Inflammatory changes Development of neoatherosclerosis Predictors of coronary stent thrombosis. The Dutch Stent Thrombosis Registry. J Am Coll Cardiol. 2009;53(16):1399.

6 Aspirin 75 to 100 mg daily plus clopidogrel 75 mg daily for at least 12 months Patients at high bleeding risk while on DAPT are considered for treatment of less than 12 months 1 month after BMS 6 months after DES 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention.

7 Irreversibly inhibits COX-1 and 2 enzymes Decreases formation of prostaglandin precursors; irreversibly inhibits formation of thromboxane A 2, via acetylation of platelet cyclooxygenase Inhibition of platelet activation

8 Active metabolite irreversibly blocks P2Y 12 on ADP receptors on the platelet surface Prevents platelet activation

9 Elective PCI BMS - At least 1 month of clopidogrel therapy DES - At least 6 months of clopidogrel therapy Beyond 6 months Consider treatment if no high risk of bleeding on DAPT CABG 12 months clopidogrel may be reasonable J Am Coll Cardiol Sep 6;68(10):

10 All indications require at least 12 months DAPT More than 12 months may be reasonable in patients without high risk of bleeding Medical therapy Clopidogrel or ticagrelor Thrombolytic therapy (STEMI) At least 14 days, ideally 12 months of clopidogrel J Am Coll Cardiol Sep 6;68(10):

11 PCI (BMS or DES) Clopidogrel, prasugrel, or ticagrelor CABG Resume P2Y 12 inhibitor to finish 1 year of DAPT J Am Coll Cardiol Sep 6;68(10):

12 Estimated 5-10% patients undergoing PCI have an indication for chronic anticoagulation, most commonly Afib Mean age of patients undergoing PCI is increasing Risk factor for atrial fibrillation Clinical controversy: Optimal management of patients requiring DAPT and long-term oral anticoagulation is still undefined Thromb Haemost 2011; 106:

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14 Global ischemic risk factors Advanced age ACS presentation History of Myocardial Infarction (MI) Extensive Coronary Artery Disease (CAD) Diabetes mellitus Chronic Kidney Disease (CKD) J Am Coll Cardiol Sep 6;68(10):

15 Increased risk of stent thrombosis ACS presentation Diabetes mellitus Left ventricular ejection fraction <40% First-generation drug-eluting stent Stent placement and properties J Am Coll Cardiol Sep 6;68(10):

16 Increased bleeding risk History of prior bleeding Oral anticoagulant therapy Female sex Advanced age Low body weight CKD Diabetes mellitus Anemia Chronic steroid or NSAID use J Am Coll Cardiol Sep 6;68(10):

17 2012 Antithrombotic therapy and prevention of thrombosis 9th edition: ACCP CHADS 2 > 2: BMS: 1 month triple therapy then VKA + Antiplatelet DES: 3-6 months triple therapy then VKA + Antiplatelet CHADS 2 < 2: BMS/DES: 12 months DAPT Chest Feb;141(2 Suppl):7S-47S

18 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes Duration of triple therapy should be minimized to the extent possible to limit the risk of bleeding (Class I, Level of Evidence: C) Proton pump inhibitors should be prescribed in those with a history of gastrointestinal bleeding (Class IIa, Level of Evidence: C) May be reasonable in those without known GI bleeding Targeting INR may be reasonable (Class IIb, Level of Evidence: C) J Am Coll Cardiol Dec 23;64(24):e

19 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation For patients with ACS and atrial fibrillation with CHA 2 DS 2 VASc > 2; anticoagulation with warfarin is recommended No firm statement on duration/agent use for antithrombotic management An option is to consider oral anticoagulation plus clopidogrel with or without aspirin J Am Coll Cardiol Dec 2;64(21):e1-76

20 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease J Thorac Cardiovasc Surg Nov;152(5):

21 Objective Trial Design Patient Population Treatment Groups Primary Endpoint Secondary Endpoints In patients on oral anticoagulation undergoing PCI, does using clopidogrel alone reduce the risk of bleeding compared with clopidogrel plus aspirin? Open label randomized trial 563 patients yo with an indication for OAC 1 year and PCI Double therapy with OAC and clopidogrel (n=279) or Triple therapy with OAC, ASA and clopidogrel (n=284) Occurrence of any bleeding episode during 1 year follow up Death, MI, stroke, target-vessel revascularization, and stent thrombosis

22 Baseline Characteristics General: Mean age 70, 77% male, >50% CHADS 2 2 or 3 Severe coronary lesion (at least 75% stenosis) OAC Indication: 69% Afib/Aflutter, 10% mechanical valve, 20% other (apical aneurysm or PE) Results Any bleeding by year % vs. 44.4% (HR 0.36; 95% CI ; P<0.0001; NNT 4) Bleeding episodes were seen in less patients receiving double therapy than in those receiving triple therapy Limitations Unclear why bleed rates uncharacteristically high in triple therapy group (>40%) Low use of PPIs Bleeding differences were mainly driven by minor bleeding, which may not represent clinically meaningful bleeding Underpowered to detect differences in stent thrombosis Conclusion Use of clopidogrel without aspirin was associated with significant reduction in bleeding without an increase in rate of thrombotic events

23 Objective Trial Design Patient Population Treatment Groups Primary Endpoint To assess whether shorter duration of triple therapy is associated with superior outcomes in patients with indication for anticoagulation who undergo DES placement after coronary intervention Prospective randomized open label trial in Europe 614 patients 18 yo and older with indication for OAC and DES implantation 6 weeks of clopidogrel therapy in addition to OAC and aspirin (n=307) or 6 months of clopidogrel therapy in addition to OAC and aspirin (n=307) Net clinical benefit (composite): Death MI Stent thrombosis Stroke Thrombolysis In Myocardial Infarction (TIMI) major bleeding at 9 months

24 Baseline characteristics General: Mean age 74, 25% female, >50% CHADSVASc 4 or 5 Presentation: 66% Stable angina, 16% Unstable angina, 16% NSTEMI, 1% STEMI OAC Indication: 82% Afib, 5% mechanical valve, 7.5% VTE Results No detectable difference between primary endpoint in 6 week versus 6 month clopidogrel therapy; HR 1.14 ( , p=0.63) No detectable difference between groups in secondary ischemic or bleeding endpoints Limitations Conclusion Only 9 months of follow up Underpowered to detect thrombotic difference between groups Nearly 2/3 of patients received DES for chronic stable angina 6 weeks of triple therapy was not superior to 6 months J Am Coll Cardiol. 2015;65(16): Am Heart J 2014;167: e1

25 Objective Among patients with non-valvular AF undergoing PCI with stent placement, does low-dose rivaroxaban plus either single or dual antiplatelet therapy reduce risk of bleeding when compared to warfarin plus dual antiplatelet therapy? Trial Design Multicenter, open label, 3-parallel group, randomized controlled trial in 26 countries Patient Population 2,214 patients with non-valvular AF who had just undergone PCI with stent Treatment Groups Primary Endpoint Three treatment groups: Group 1: Rivaroxaban mg daily + P2Y 12 inhibitor x12 mo Group 2: Rivaroxaban 2.5 mg BID + DAPT x1, 6, or 12 mo Group 3: Warfarin + DAPT x1, 6, or 12 mo Clinically significant bleeding TIMI major/or minor bleeding or bleeding requiring medical attention

26 Baseline Characteristics Results Limitations Conclusion General: Mean age 70, 25% female, Mean CrCl 78 ml/min, 29% 30-60mL/min 21% Unstable angina, 18% NSTEMI, 12% STEMI 65% DES, 33% BMS, 2% DES and BMS AF type: 21% Persistent, 37% permanent, 42% paroxysmal Primary endpoint Group 1: 16.8% vs. Group 2: 18.0% vs. Group 3: 26.7% Group 1 vs. 3: HR 0.59; 95% CI ; P<0.001 Assigned to DAPT for 1 mo: 19.4% vs. 25.7% (HR 0.68; ; P=0.20) Assigned to DAPT for 6 mo: 17.5% vs. 31.2% (HR 0.51; ; P<0.001) Assigned to DAPT for 12 mo: 17.9% vs. 23.9% (HR 0.74; ; P=0.08) Group 2 vs. 3: HR 0.63; 95% CI ; P<0.001 Not blinded, not powered for efficacy Little ethnic/racial diversity Use of low-dose rivaroxaban plus a P2Y 12 inhibitor or very-low-dose rivaroxaban plus DAPT for 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy (VKA + DAPT)

27 Decisions about treatment with and duration of DAPT require assessment of individual patient factors Clinical judgment Benefit/risk ratio Consideration of patient preference

28 Variable Points Age > 75-2 Age 65 to < 75-1 Age < 65 0 Current cigarette smoker 1 Diabetes mellitus 1 MI at presentation 1 Prior PCI or prior MI 1 Stent diameter < 3 mm 1 Paclitaxel-eluting stent 1 CHF or LVEF < 30 % 2 Saphenous vein graft PCI 2 Score >2 associated with a favorable benefit/risk ratio for prolonged DAPT

29 1. Eur Heart J 2011; 32: ClinicalTrials.gov; REDUAL PCI 3. N Engl J Med 2012; 366: N Engl J Med 2016; Not yet in print 5. N Engl J Med 2011; 365: J Am Coll Cardiol 2013;61(20): JAMA 2016;315(16): Use of novel oral anticoagulants Dabigatran 1,2 Xarelto 3,4 Apixaban 5 Use of newer P2Y12 inhibitors 6 Optimal duration of dual antiplatelet therapy 7 Evolution of stent technology

30 Appropriate use of PPIs Reassess use of antiplatelet agents upon admission Counsel patients on importance of adherence, signs and symptoms of bleeding, monitoring parameters

31 Questions? Angelika Cyganska, PharmD Saint Luke s Hospital acyganska@saint-lukes.org Austin T. Wilson, MS, PharmD Candidate 2017 University of Kansas School of Pharmacy AustinWilson@ku.edu