Anticoagulation Update David J. Moliterno, MD

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1 David J., MD Anticoagulant Agents n Cardiovascular Medicine: An Update David J., MD Professor and Chairman Division of Cardiovascular Medicine The University of Kentucky Linda and Jack Gill Heart nstitute Plaque Rupture Subendothelial Components von Willebrand factor Fibronectin Thrombospondin Collagen Laminin Vitronectin Tissue factor Fibrinogen Platelet Activation Coagulation Cascade Xa+Va+ PA-1 PF 4 Fibrinogen vwf Thromboxane PDGF ADP Serotonin CD4L ntrinsic Pathway (Surface Contact) X Xa Platelet surface Xa Xa Extrinsic Pathway (Tissue Factor) V Fibrin-boundbound Monitoring Anticoagulants Anticoagulants ntrinsic Pathway (Surface Contact) X aptt Xa PT aptt/pt /a Rx Platelet surface Xa Xa Fibrin-boundbound Extrinsic Pathway V (Tissue Factor) Heparins Hirudins Anti-platelets Aspirin Thienopyridines Ticlopidine Clopidogrel Prasugrel Ticagrelor GP /a Abciximab Eptifibatide Tirofiban Anti-thrombinsthrombins Heparin LMWH Dalteparin aparin Fondaparinux DT Lepirudin Bivalirudin Argatroban Dabigatran

2 David J., MD Aspirin Antiplatelet Meta-Analysis First synthesized in pure form by Felix Hoffman of Friedr. Bayer & Co. in First pharmaceutical agent ever sold in pill form in early 19s. Bayer lost rights to Aspirin in United States following WW ASA No. of Dose (mg) Trials < 75 Any Aspirin Vascular Death, M, CVA Odds Ratio & 95% C Odds : 19% 2 32% 13% Treatment effect P <.1 23% N = Antiplatelet Better Antiplatelet Worse Anti- platelet 14.5% 11.5% 1.9% 17.3% 12.9% Control 17.2% 14.8% 15.2% 19.4% 16.% Antithrombotic Trialists Collaboration, BMJ 324:71 86, 22 Heparin LMWH Pentasaccharide LMWH in ACS Death or M AT Follow-Up Day 2 Odds Ratio & 95% C.8 ( ) LMWH 1.8% 1.4% Fractionated Day 8 77(62.77 ( ).95) 5.3% 53% 41% 4.1% Anti Xa: Day14.79 ( ).96) 6.5% 5.2% Bioavailability Required monitoring Sensitive to PF4 Day ( ).97) LMWH Better Better Antman EM et al. Circulation 1999;1: % SYNERGY STEEPLE 2% 3-Day Death or M N=1,27 Bleeding aparin Death, M, utvr, & Mj Bleeding Death, M, utvr 1% 5% 14.5% aparin 14.% 9% 3% P= % 9.1% 12.3% 12.5% 14.% 1% 8% 4% 8.2 1% 8% % 5.8 Hazard Ratio,.96 (95% C, ) Days from Randomization TM Major TM Minor 2% U 2% U SYNERGY Trial nvestigators. JAMA 24;292: Montalescot et al. N Engl J Med 26;355:

3 David J., MD OASS V Death, M, or Stroke OASS V All PC Subgroup 3-Day Clinical Outcome zard Cumulative Haz 14% 1% 8% 4% aparin 12.5% Fondaparinux 11.3% 2% Hazard ratio.89 (95% C ).97) P< Days End point aparin Fondaparinux n = 389 (%) n = 3118 (%) Death Myocardial infarction Death or M Major bleeding <.1 Death, M, Mj bleeding <.1 P OASS-5. N Engl J Med 26;354: Yusuf et al. N Engl J Med 26;354: OASS V PC Subgroup 9% 3-Day Peri-PC PC Complications HR=2.44 P<.1 aparin (n=389) Fondaparinux (n=3118) ACC/AHA ACS Guidelines Antithrombins nvasive Strategy (Class, LOE:A) enoxaparin or or (Class, LOE:B) bivalirudin or fondaparinux nitiate one (Class, LOE:A) or both (Class, LOE:B) Clopidogrel and/or GP /a Likely or Definite UA/NSTEM ASA (Class ; LOE A) or Clopidogrel if ASA intolerant (Class ; LOE A) Conservative Strategy (Class, LOE:A) enoxaparin or or (LOE:B) fondaparinux (Class, LOE:B) enoxaparin, fondaparinux preferred (Class, LOE:A) Clopidogrel Consider adding (Class, LOE:B) SM GP /a 8.1 HR=2.72 P<.1 CABG PC Evaluation: Not Low Risk Medical Therapy Evaluation: Low Risk 3% 3.3 Access Site Complication HR=1.54 P= HR=.34 P= * Large Arterial Catheter Hematoma Pseudoaneurysm Thrombus Yusuf et al. N Engl J Med 26;354: Continue ASA; Discontinue clopidogrel; Discontinue V GP /a 4h prior to CABG Continue ; discontinue enoxaparin 12-24h prior to CABG; discontinue fondaparinux 24h prior to CABG; discontinue bivalirudin 3h prior to CABG and dose with per institutional practice Continue ASA; LD of clopidogrel; V GP/a* Continue current antithrombin for PC; Discontinue antithrombin after PC CAD Continue ASA; LD of clopidogrel; Discontinue V GP/a after 12h Continue V 48h or enoxaparin or fondaparinux for hospital duration; discontinue bivalirudin or continue at a dose of.25 mg/kg/hr 72h at physician s discretion No significant CAD Antiplatelet and Antithrombin therapy at physician s discretion Continue ASA and clopidogrel; Discontinue V GP/a; Discontinue antithrombin ACC/AHA ACS Guidelines ACC/AHA/SCA PC Guidelines nvasive or Conservative Strategy, enoxaparin nvasive or Conservative Strategy fondaparinux nvasive Strategy bivalirudin Conservative Strategy enoxaparin, fondaparinux preferred Warfarin (27 Recommendations) Managing warfarin to an NR equal to 2. to 3. for paroxysmal or chronic atrial fibrillation or flutter is recommended, and in most-m patients when clinically indicated (e.g., atrial fibrillation, left ventricular thrombus. Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely. n patients requiring warfarin, clopidogrel, and aspirin therapy after PC, an NR of 2. to 2.5 is recommended with low dose aspirin (75-81 mg) and a 75-mg dose of clopidogrel. COR(LOE) (A) (B) (C)

4 David J., MD HT Definitions HT Type Transient, mild, nonimmune-mediated mediated Early onset (<4 d of heparin treatment) Reversible, asymptomatic HT Type Not transient, severe, immune-mediated mediated Typically 4-14 d after start of heparin Can occur within 12 h with recent exposure Associated with thromboembolic complications (also known as HTTS) Thrombocytopenia HT vs /a Onset of thrombocytopenia Typical HT onset: 4-14 days Rapid HT onset with re-exposure exposure (<24 hrs) GP /a inhibitors: usually rapid onset (2-48 hrs) Abciximab (2-4% and within 2-4 hrs) Eptifibatide, Tirofiban (<1% and within hrs) Severity of thrombocytopenia GP /a inhibitors are more likely to cause rapid and severe thrombocytopenia (<2,/mm3) HT thrombosis, vs. GP /a bleeding Avoid platelet transfusions HT TreatmentTreatment Stop heparin immediately upon suspicion Consider other causes of thrombocytopenia Send heparin antibody assay; confirm SRA or ELSA Begin direct thrombin inhibitor (usually needed) Begin warfarin if appropriate once DT dosing stable and platelet count has increased to at least 1-15K 15K Consider hematology consultation Do not re-challenge with heparin for at least months, preferably more than a 1 year, or longer. CURRENT Study Design 25,87 ACS Patients (UA/NSTEM 7.8%, STEM 29.2%) Planned Early (<24 h) nvasive Management with intended PC schemic ECG Δ (8.8%) or cardiac biomarker (42%) Randomized to receive (2 X 2 factorial): Clopidogrel: Double-dose (6 mg then15 mg/d x 7d then 75 mg/d) vs Standard dose (3 mg then 75 mg/d) ASA: High Dose (3-325 mg/d) vs Low dose (75-1 mg/d) Compliance: Clop in 1 st 7d (median) PC 17,232 (7%) Angio 24,769 (99%) No PC 7,855 (3%) No Sig. CAD 3,616 CABG 1,89 CAD 2,43 7 d 7 d 2 d 7 d Complete follow-up 99.8% Efficacy Outcomes: CV Death, M or stroke at day 3 and Stent Thrombosis at day 3 Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TM Major) Key Subgroup: PC v No PC CURRENT ASA Dose Primary Outcome and Bleeding ASA 75-1 mg ASA mg HR 95% C P CV Death/M/Stroke PC (2N=17,232) No PC (2N=7855) Overall (2N=25,87) Stent Thrombosis TM Major Bleed CURRENT Major Bleed CURRENT Severe Bleed G Bleeds: 3 (.24%) v 47 (.38%), P=.51 No other significant differences between ASA dose groups CURRENT ClopidogrelClopidogrel Dose zard Cumulative Haz Definite Stent Thrombosis Days Standard Dose Double Dose % RRR HR.58 95% C P=.1

5 David J., MD CURRENT Clopidogrel Clopidogrel Dose zard Cumulative Haz PC Patients: CV Death, M, Stroke Standard Dose Double Dose Days RRR HR.85 95% C P=.36 Future Perspective: P2Y 12 Menu Oral irreversible Ticlopidine Clopidogrel Prasugrel V reversible Cangrelor BX48 NS5589 Oral reversible Ticagrelor PRT128 BX667 TRTON-TM TM 38 Design ACS (STEM or UA/NSTEM) & Planned PC N = 13, Double-blind blind TRTON-TM TM Month Primary Endpoint Components 12.1 P<.1 P<.1 Clopidogrel (N = 6795) Prasugrel (N = 6813) Prasugrel Clopidogrel 9% P=.2 Median duration of therapy - 12 months 3% P=.31 P= o endpoint: CV death, M, Stroke 2 o endpoints: CV death, M, Stroke, Re-ischemia CV death, M, UTVR Composite Death M Stroke Major / Minor Bleeding Wiviott et al. N Engl J Med 27;357: RE-LY RE-LY Dabigatran etexilate Oral, prodrug, serum esterase Competitive thrombin inhibitor 8% renal excretion hour half-lifelife Monitoring not required Atrial Fibrillation N = 18,113 Warfarin NR Dabigatran 11-mg BD Dabigatran 15-mg BD 2-Year median follow-up for stroke or systemic embolization Connolly et al. N Engl J Med 29;361: Connolly et al. N Engl J Med 29;361:

6 David J., MD PLATO PLATO Dabigatran etexilate Oral, prodrug, serum esterase Competitive thrombin inhibitor 8% renal excretion hour half-lifelife Monitoring not required Death, M, CVA Clopidogrel 11.7% Ticagrelor 9.8% Major Bleeding Ticagrelor 11. Clopidogrel 11.2% NSTEM + STEM N = 18,624 Ticagrelor 18 mg 9 mg BD Clopidogrel 3-6 mg 75 mg daily 1-Year death, M, stroke HR.84 (95% C ).92) P <.1 HR 1.4 (95% C ) P =.43 Wallentin et al. N Engl J Med 29;361: Wallentin et al. N Engl J Med 29;361: Anticoagulation Update Summary ASA 325 mg acutely; 75mg lifelong Dual antiplatelet therapy 1 year after DES Fondaparinux = LMWH > for medical Rx Fondaparinux least bleeding; not for PC > LMWH > control as cause of HT, LMWH, and DT: renal clearance Prasugrel > clopidogrel, but slightly more bleeding in light weight, elderly, prior CVA f polypharmacy (triple therapy), slightly lower (.5) NR target Dabigatran as effective as warfarin with less bleeding and no monitoring