Disclosure Slide. Controversies in Anticoagulation. Presenter Disclosure Information. Challenges in Anticoagulation

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1 1:15 2:15 PM Challenges in Anticoagulation SPEAKER Nasser Lakkis, MD, FACC, FSCAI Presenter Disclosure Information The following relationships exist related to this presentation: Nasser Lakkis, MD, FACC, FSCAI: No financial relationships to disclose. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Disclosure Slide Controversies in Anticoagulation Dr. Nasser Lakkis has reported no interest or other relationship(s) with commercial interests (drug/device companies) that may relate to the educational content of this activity Nasser Lakkis, MD Professor of Medicine Baylor College of Medicine

2 Learning Objectives Atherothrombosis 1. review mechanism of action of antiplatelet and anticoagulant agents 2. Review evidence for indications and efficacy of anticoagulants 3. Discuss combined use of antiplatelet and antithrombin agents 4. Management of anticoagulants in patients requiring invasive procedures Modified from the REACH Registry Investigators. JAMA 26;295(2): Antithrombin Drug Targets Aspirin for Primary Prevention Antithrombotic Trialists (ATT) Collaboration Non fatal MI Any stroke Vascular Mortality Rate Ratios for Vascular Events P value P<.1 P=.4 P=.7 Major extracranial bleed P<.1 Serious Vascular Events P= Antiplatelet Better Antiplatelet Worse Aspirin reduces the risk of MI and vascular events at the expense of bleeding Lancet 29;373:

3 Aspirin for Secondary Prevention Effect of antiplatelet treatment* on vascular events** Category Acute MI Acute CVA Prior MI Prior CVA/TIA Other high risk CVD (e.g. unstable angina, heart failure) PAD (e.g. intermittent claudication) High risk of embolism (e.g. Afib) Other (e.g. DM) All trials % Odds Reduction Antiplatelet better Control better Aspirin reduces the risk of adverse cardiovascular events Clopidogrel for Secondary Prevention Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial 19,185 patients with ischemic CVA, MI, or PAD randomized to daily aspirin (325 mg) or clopidogrel (75 mg) for 2 years Cumulative risk* (%) Months of follow-up Aspirin Clopidogrel 8.7% RRR, p=.43 Clopidogrel provides slightly greater risk reduction than aspirin. BMJ 22;324:71 86 Lancet 1996;348: Clopidogrel for Secondary Prevention Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial 12,562 patients with a NSTE ACS randomized to daily aspirin ( mg) or clopidogrel (3 mg load, 75 mg thereafter) plus aspirin ( mg) for 9 months Rate of CV death, myocardial infarction, or stroke Aspirin + Placebo Aspirin + Clopidogrel P< Months of Follow Up Dual antiplatelet therapy is more efficacious in a NSTE ACS Clopidogrel for Secondary Prevention Clopidogrel for the Reduction of Events during Observation (CREDO) Trial 2,116 patients undergoing PCI randomized to 4 weeks of DAPT* followed by aspirin ( mg) monotherapy vs. persistent DAPT* for 1 year Risk of MI, stroke, or death (%) 15 4 weeks of DAPT* Months from Randomization 1 year of DAPT* 27% RRR, P=.2 DAPT produces greater benefit when used for 1 year 12. NEJM 21;345: JAMA 22;288:

4 Death, MI, or Stroke, % Clopidogrel for Secondary Prevention Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) 45,852 patients presenting within 24 hours of a STEMI treated medically and randomized to clopidogrel (75 mg daily) vs. placebo 1 (1.1%) (9.2%) 8 (8.1%) (7.5%) % relative risk reduction (P=.2) 1 7% relative risk reduction (P=.3) Days Since Randomization (up to 28 days) Days Since Randomization (up to 28 days) DAPT produces greater benefit in medically managed STEMI patients In-Hospital Mortality, % Clopidogrel for Secondary Prevention Clopidogrel as Adjunctive Reperfusion Therapy in Thrombolysis in Myocardial Infarction (CLARITY) Trial 3,491 patients (<75 years of age) presenting within 12 hours of a STEMI treated with fibrinolytic, aspirin, and heparin and randomized to clopidogrel (3 mg load followed by 75 mg daily) vs. placebo End Point (%)* % RRR Aspirin + Clopidogrel Aspirin + Placebo P= Days DAPT benefits STEMI patients treated with fibrinolytic therapy Lancet 25;366: NEJM 25; 352: Clopidogrel for Secondary Prevention Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial 15,63 patients with multiple CV risk factors or known CVD randomized to aspirin ( mg) or aspirin ( mg) & clopidogrel (75 mg) for a mean of 3 months Incidence of CV death, MI, or CVA (%) Placebo Clopidogrel P = Months Routine DAP therapy offers little long term benefit Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events (CURRENT) OASIS 7 Trial CV death, MI, or stroke 25,87 patients with an ACS randomized in a 2 x 2 factorial trial to double dose clopidogrel (6 mg LD, 15 mg x 7 days, then 75 mg MD) vs. standard dose clopidogrel (3 mg LD and 75 mg MD) and high dose aspirin (3 325 mg) vs. low dose aspirin (75 1 mg)..2.4 Clopidogrel Secondary Prevention Clopidogrel Standard Clopidogrel Double HR.95, P= Days Type of Bleeding High dose clopidogrel does not provide benefit in ACS D (%) S (%) TIMI Major CURRENT Major* Fatal ICH.3.5 CABGrelated 1..9 *p=.1 NEJM 26;354: NEJM 21;363:93-942

5 Prasugrel for Secondary Prevention Primary Efficacy Endpoint and TIMI Major Bleeding Through 3 Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38) 13,68 patients with high-risk ACS scheduled for PCI randomized to clopidogrel (3 mg LD and 75 mg MD) or prasugrel (6 mg LD and 1 mg MD) for a median of 12 months Months (TRITON TIMI 38) (Age < 75 years, N = 7243) CV death, MI, or stroke % 12.1 HR.81, P=.4 11 Clopidogrel 9.9 Bleeding Events 9 C (%) P (%) P-value Prasugrel TIMI major Life threatening Nonfatal HR.77 HR.8 Fatal P=.1 P=.1 ICH Days Endpoint (%) HR (95% CI):.91 (.79, 1.5) P =.21 HR (95% CI): 1.31 (.81, 2.11) P =.27 Prasugrel reduces ischemic events with a higher rate of bleeding NEJM 27;357: Roe MT NEJM 212 Platelet Inhibition and Patient Outcomes (PLATO) Study 18,624 patients with a moderate to high risk ACS randomized to clopidogrel (3 6 mg LD and 75 mg MD) or ticagrelor (18 mg LD and 9 mg twice daily MD) for 12 months CV Death, MI, or Stroke (%) PLATO: Ticagrelor Secondary Prevention Clopidogrel Ticagrelor Days after randomization 11.7 HR.84, p= Bleeding Events * C (%) T (%) TIMI major/year PLATO major/year Life threatening/year Fatal/year.3.3 Ticagrelor reduces ischemic events with no higher rate of bleeding overall *No statistically significant differences were observed in bleeding rates overall NEJM 29;361: CV Death, MI, or Stroke (%) PEGASUS TIMI 54: Primary Endpoint 21,162 patients with MI 1 3 years prior and treated with low dose aspirin Months from Randomization Ticagrelor 9 mg HR.85 (95% CI.75.96) P=.8 Ticagrelor 6 mg HR.84 (95% CI.74.95) P= Placebo (9.%) Ticagrelor 9 (7.8%) Ticagrelor 6 (7.8%) NEJM 215;372:1791-8

6 PEGASUS TIMI 54: Adverse Events Leading to Discontinuation Number of Patients Year KM Rate (%) p value for each dose vs. placebo <.1 Treatment Arm Any AE Bleeding Dyspnea Ticagrelor 9 19.% 7.8% 6.5% Ticagrelor % 6.2% 4.6% Placebo 8.9% 1.5%.8% Placebo Ticagrelor 9 mg Ticagrelor 6 mg BID BID NEJM 215;372: Other Arrhythmia Dyspnea Bleeding P=NS each for D/C for arrhythmia or other Euclid: Ticagrelor in PAD N Engl J Med 217; 376:32 4 EUCLID Trial design: Patients with peripheral arterial disease (PAD) were randomized to ticagrelor 9 mg twice daily (n = 6,93) vs. clopidogrel 75 mg daily (n = 6,955). % (p =.65) Results CV death, MI, or ischemic stroke: 1.8% of the ticagrelor group vs. 1.6% of the clopidogrel group (p =.65) Acute limb ischemia: 1.7% with ticagrelor vs. 1.7% with clopidogrel Major bleeding: 1.6% with ticagrelor vs. 1.6% with clopidogrel Dyspnea resulting in drug discontinuation: 4.8% with ticagrelor vs..8% with clopidogrel (p <.1) Conclusions Among patients with symptomatic PAD, ticagrelor was not superior to clopidogrel in preventing major adverse cardiac events Ticagrelor Clopidogrel Acute limb ischemia and major bleeding were also similar between treatment groups N Engl J Med 217;376:32-4 TRILOGY

7 Indications of Anticoagulant Therapy Treatment and Prevention of Deep Venous Thrombosis Treatment of Pulmonary Emboli Prevention and treatment of stroke in patients with atrial fibrillation, artificial heart valves, cardiac thrombus. Ischemic heart disease Drug/Trial Efficacy: Stroke/ Thromboembolism Hemorrhagic Stroke Major Bleeding Dabigatran in RE-LY 34% reduction 74% reduction Similar Rivaroxaban in ROCKET Apixaban in ARISOTLE Edoxaban ENGAGE AF TIMI48 Major Results of Trials Comparing NOACs to Warfarin in AF Noninferior to warfarin 4% reduction Similar 2% reduction 5% reduction 3% reduction Noninferior to warfarin 46% reduction 2% reduction N Engl J Med 213;369: Stroke. 214;45: NOACs in DVT/PE: EINSTEIN DVT (Rivaroxaban vs. Warfarin) Comparative Effectiveness of Warfarin and NOACs for long term prevention of arterial and thromboembolism N Engl J Med 21; 363: JAMA 215;:314: 76 7.

8 Summary of NOACs vs. Warfarin Non inferior for prevention of stroke/embolism in Afib Non inferior for treatment of DVT/PE Probable reduced hemorrhagic stroke rate Reduced rate of fatal bleeding events Increased incidence of GI bleeds Cost issues JAMA 215;:314: Drug Class Mechanis m of Action Indication Warfarin (Coumadin ) Anticoagulant (vitamin K antagonist) Depletes vitamin K inhibiting factors II, VII, IX, X DVT/PE/AF: INR (mechanical mitral valve) Dabigatran (Pradaxa ) Anticoagulant (direct thrombin inhibitor) Reversible direct thrombin inhibitor (PRODRUG) DVT/PE/NVAF: 15 mg BID (CrCl > 3 ml/min) 75 mg twice daily PO (CrCl 15-3 ml/min) Not recommended in CrCl < 15 ml/min Rivaroxaban (Xarelto ) Anticoagulant (factor Xa inhibitor) Selective inhibition of factor Xa Apixaban (Eliquis ) Anticoagulant (factor Xa inhibitor) Selective inhibition of factor Xa DVT/PE: DVT/PE: 15 mg BID with food for 3 weeks followed by 2 mg once daily Orthopedic prophylaxis: 1 mg once daily Nonvalvular atrial fibrillation*: 2 mg once daily with food PO; 15 mg once daily for CrCl 15-5 ml/min 1 mg BID followed by 5 mg BID for 6 months Nonvalvular atrial fibrillation: 5 mg twice daily PO; 2.5 mg BID if >2 of the following: 8 yo, 6kg, Cr 1.5 mg/dl Edoxaban (Savaysa ) Anticoagulant (factor Xa inhibitor) Selective inhibition of factor Xa DVT/PE/NVAF: 6 mg/d 3 mg/d: patients with CrCl 3-5 ml/min, weight 6 kg, or concomitant use of PgP inhibitors NOACs in CAD: COMPASS Trial COMPASS Primary: CV death, stroke, MI Stable CAD or PAD 2,2 with a primary outcome event Rivaroxaban 2.5 mg bid + aspirin 1 mg od Run-in (aspirin) R Rivaroxaban 5 mg bid Aspirin 1 mg od follow up 3-4 years N Engl J Med 217; 377: N Engl J Med 217; 377:

9 Outcome Major bleeding Fatal Non fatal ICH* Non fatal other critical organ* *symptomatic R + A N=9,152 COMPASS: Major bleeding R N=9,117 A N=9,126 Rivaroxaban + Aspirin vs. Aspirin N (%) N (%) N (%) HR (95% CI) P 3.1% 2.8% 1.9% 1.7 ( ) <.1.2%.2%.1% 1.49 ( ).32.2%.4%.2% 1.1 ( ).77.5%.5%.3% 1.43 ( ).14 Rivaroxaban vs. Aspirin HR (95% P CI) 1.51 ( ) < ( ) ( ) 1.57 ( ).6 Placebo N=5,176 ASA + Thieno, n=4,821 ASA, n=355 Recent ACS: STEMI, NSTEMI, UA No increased bleeding risk, No warfarin, No ICH, No prior stroke if on ASA + Thienopyridine Stabilized 1 7 Days Post Index Event Stratified by Thienopyridine use at MD Discretion RIVAROXABAN 2.5 mg BID n=5,174 ASA + Thieno, n=4,825 ASA, n=349 PRIMARY ENDPOINT: EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemo) SAFETY: TIMI major bleeding not associated with CABG Event driven trial of 1,2 events in 15,342 patients** + ASA 75 to 1 mg/day RIVAROXABAN 5. mg BID N=5,176 ASA + Thieno, n=4,827 ASA, n=349 N Engl J Med 217; 377: N Engl J Med. 212;366:9 19 Primary Efficacy Endpoint CV Death / MI / Stroke* (Ischemic + Hemg.) Serious Bleeding Complications Estimated Cumulative Rate (%) No. at Risk Placebo Rivaroxaban Months After Randomization Placebo Rivaroxaban (both doses) % 8.9% HR.84 (.74.96) ARR 1.7% mitt p =.8 ITT p =.2 NNT = 59 p=ns for Riva vs Placebo p=.44 for 2.5 mg vs 5. mg * n=9 n=6 n=15 p=.9 Riva Vs Placebo n=5 n=14 n=18 p=ns for Riva vs Placebo n=4 n=5 n=8 N Engl J Med 212; 366:9 19 N Engl J Med 212; 366:9 19

10 21 patients with NVAF Coronary stenting No prior stroke/tia, No GI bleeding, Hb<1, CrCl<3 Patients With Atrial Fibrillation Undergoing Coronary Stent Placement: PIONEER AF PCI 72 hours After Sheath removal R A N D O M I Z E 1,6, or 12 months Pre randomization MD Choice Rivaroxaban 2.5 mg bid Clopidogrel 75 mg qd Aspirin 75 1 mg qd 1,6, or 12 months Pre randomization MD Choice VKA (target INR 2. 3.) Clopidogrel 75 mg qd Aspirin 75 1 mg qd Rivaroxaban 15 mg qd* Clopidogrel 75 mg qd Rivaroxaban 15mg QD Aspirin 75 1 mg qd VKA (target INR 2. 3.) Aspirin 75 1 mg qd Primary endpoint: TIMI major + minor + bleeding requiring medical attention Secondary endpoint: CV death, MI, and stroke (Ischemic, Hemorrhagic, or Uncertain Origin) End of treatment 12 months WOEST Like ATLAS Like Triple Therapy TIMI Major, TIMI Minor, or Bleeding Requiring Medical Attention (%) No. at risk Riva + P2Y 12 Riva + DAPT VKA + DAPT Kaplan Meier Estimates of First Occurrence of Clinically Significant Bleeding Events Days 26.7% p<.13 p< % VKA VKA + DAPT + DAPT 16.8% Riva + DAPT Riva + P2Y 12 HR =.63 (95% CI.5-.8) HR ARR =.59 = (95% 8.7 Riva + P2Y 12 v. VKA + DAPT CI ) Riva + DAPT v. VKA + DAPT ARR NNT = 9.9 = 12 HR=.59 (95% CI: ) HR=.63 (95% CI:.5-.8) p <.13 NNT = 11 p <.18 RR=9.9 RR=8.7 NNT=11 NNT= * Gibson et al. AHA 216 Gibson et al. AHA 216 Kaplan Meier Estimates of First Occurrence of CV Death, MI or Stroke Cardiovascular Death, Myocardial Infarction, or Stroke (%) VKA + DAPT Riva + P2Y 12 Riva + DAPT 6.5% 6.% 5.6% Riva + P2Y 12 v. VKA + DAPT HR=1.8 (95% CI: ) p=.75 Riva + DAPT v. VKA + DAPT HR=.93 (95% CI: ) p=.765 No. at risk Riva + P2Y 12 Riva + DAPT VKA + DAPT Days Gibson et al. AHA 216

11 APPRAISE 2: Primary Outcome CV Death, MI, Ischemic Stroke in ACS patients Apixaban 5 mg bid 279 (7.5%) Placebo 293 (7.9%) HR.95; 95% CI ; p=.59

12 APPRAISE 2: TIMI Major Bleeding Apixaban 48 (1.3%) Placebo 18 (.5%) HR 2.59; 95% CI ; p=.1 Triple Therapy Circulation 21;121:267 7 Lancet 213;381: Eur Heart J 216;37: To hold or not to hold for Procedures Delays procedure Longer in-hospital stay and costs Increased risk of cardiovascular complications Thromboembolic events Increased risk of Post procedural Bleeding Class/type of medication anticoagulant drugs antiplatelet agents Patient comorbidities Factors influencing decision Indication for procedure elective urgent/emergency Hold Continue Considerations: Risk of thromboembolism vs Risk inherent in the procedure TRILOGY Type of procedure high risk vs low risk Patient wishes decision must include patient in high risk cases

13 High Risk Patients ACS or STEMI h/o multi vessel PCI Drug eluting stents 12 months Bare metal coronary stents without ACS 1 month with history of ACS, 12 months prior history of stent thrombosis diffuse coronary artery disease renal failure h/o venous thromboembolism (VTE)/PE mechanical heart valves (but not bio prosthetic valves, which are low risk) Atrial Fibrillation with prior stroke/elderly Class/Type Drug Duration of Action Vitamin K antagonist Warfarin (Coumadin) 5 days Heparin & derivatives Direct Factor Xa inhibitor (oral) Direct Thrombin inhibitor Antithrombotic Drugs Unfractionated Heparin LMWHs Enoxeparin (Lovenox) Dalteparin (Fragmin) Fondaparinux (Arixtra) Rivaroxiban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Oral: Dabigatran (Pradaxa) IV: Bivalirudin IV 2-6 h SQ h 24 h h 1-4 days* (*depends on egfr) 1-6 days* (*depends on egfr) 2-3 hours ASGE Standards of Practice Committee Gastrointest Endosc. 216 Jan;83(1):3 16. Management of DAPT in Elective Cases Management of Antithrombotics in Elective Cases DAPT Aspirin ADP blockers If patient has recently placed coronary stent and/or ACS Low risk procedures High risk procedures Continue Discontinue x 5-7 days prior or switch to bridge therapy Defer procedure until minimum DAPT completed Any short-term anticoagulation therapy Warfarin and NOACs High thrombosis risk Low thrombosis risk Defer procedure High risk procedure High risk procedure Low risk procedure Bridge therapy Stop for prescribed period Continue

14 DAPT in Emergency Procedures Anticothrombotics in Emergency Procedures INR <2.5 Do not delay procedure Emergency Procedures Life threatening bleeding High thrombosis risk patients Withhold after discussion with cardiologist Stop only after consultation with prescribing physician Bleeding or Emergency Surgery NOACs INR>2.5 4-Factor PCC + Vit K *ACCP recommended Fresh Frozen Plasma Antidotes After hemostasis achieved Start UFH for rapid onset Re-initiate previous medication Resumption of Therapy Warfarin should generally be resumed: hours after surgery Unless substantial risk of delayed bleeding or reoperation anticipated NOACs should generally be resumed: hours after a minor procedure hours after major surgery Bridging Therapy: (UFH or LMWH in high risk patients) NOAC should be resumed 1 hr before UFH infusion is discontinued or 1 12 hours after the last scheduled dose of LMWH Am J Health-Syst Pharm. 213; 7 (Suppl1):S3-11. J Cardivasc Electrophysiol. 211(8): N Engl J Med 213;368: