Challenges with Current Antiplatelet & Anticoagulant Therapies CAROLYN HEMPEL, PHARMD, BCPS CLINICAL ASSISTANT PROFESSOR UNIVERSITY AT BUFFALO SCHOOL OF PHARMACY.
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Challenges with Current Antiplatelet & Anticoagulant Therapies CAROLYN HEMPEL, PHARMD, BCPS CLINICAL ASSISTANT PROFESSOR UNIVERSITY AT BUFFALO SCHOOL OF PHARMACY Disclosures No financial conflicts of interests to disclose. Objectives Assess the advantages and disadvantages of the different antiplatelet and oral anticoagulants (OACs) agents Review the evidence regarding oral antiplatelets and NOACs Evaluate the literature surrounding the use of “triple therapy” (aspirin, antiplatelet, and OAC) Recommend antiplatelet or anticoagulant regimens for a specific patient case AJ is a 65yo M who arrives to the ER with substernal 10/10 chest pain. HPI: AJ describes his CP as pressure like pain that lasts for 5 minutes and gets worse with exertion. This pain has been getting worse over the last few days until today he had the worst pain yet. He then called 911, his EKG revealed STelevations and he was emergently brought to the cath lab. 1 DES was placed in his mid-LAD. PMH of HTN, ischemic stroke (2 years ago), hyperlipidemia, GERD. Vitals: BP 138/70 HR 80 PE: No significant findings Home medications: Aspirin 81mg Oral Daily Omeprazole 20mg Oral Daily Lisinopril 20mg Oral Daily Atorvastatin 40mg Oral Daily What antiplatelet regimen would you recommend for this patient? Aspirin 81mg Oral Daily Aspirin 81mg Oral Daily + Clopidogrel 75mg Oral Daily Aspirin 81mg Oral Daily + Prasugrel 10mg Oral Daily Aspirin 81mg Oral Daily + Ticagrelor 90mg Oral BID AJ is a 65yo M who arrives to the ER with substernal 10/10 chest pain. HPI: AJ describes his CP as pressure like pain that lasts for 5 minutes and gets worse with exertion. This pain has been getting worse over the last few days until today he had the worst pain yet. He then called 911, his EKG revealed STelevations and he was emergently brought to the cath lab. 1 DES was placed in his mid-LAD. PMH of HTN, ischemic stroke (2 years ago), hyperlipidemia, GERD, atrial fibrillation Vitals: BP 138/70 HR 80 PE: No significant findings Home medications: Aspirin 81mg Oral Daily Pantoprazole 40mg Oral Daily Lisinopril 20mg Oral Daily Atorvastatin 40mg Oral Daily Metoprolol succinate 100mg Oral daily Warfarin 4mg Oral Daily What antiplatelet regimen would you recommend for this patient? Aspirin 81mg Oral Daily Aspirin 81mg Oral Daily + Clopidogrel 75mg Oral Daily Aspirin 81mg Oral Daily + Prasugrel 10mg Oral Daily Aspirin 81mg Oral Daily + Ticagrelor 90mg Oral BID What would you recommend for AJ’s anticoagulation regimen? Discontinue warfarin until antiplatelet regimen is discontinued, then restart warfarin Discontinue warfarin and begin rivaroxaban 20mg oral daily Continue warfarin and P2Y12 inhibitor, discontinue aspirin Discontinue warfarin and begin rivaroxaban 20mg oral daily, discontinue aspirin Continue warfarin, P2Y12 inhibitor, and aspirin for 6 months, then discontinue aspirin Acute Coronary Syndromes Standard of Care: Dual Anti Platelet Therapy (DAPT) Aspirin + P2Y12 Inhibitor Goal of Treatment: Reduce recurrent ischemic events or reinfarction and improve survival Goal of Treatment for Stents: Bare Metal Stent (BMS) reduce stent restenosis Drug Eluting Stents (DES) reduce in-stent thrombosis 2013 ACC/AHA STEMI Guidelines Antiplatelet Recommendations for Primary PCI O’Gara PT et al JACC 2013; 61:e78-140 2014 AHA/ACC NSTE-ACS Guidelines Antiplatelet Recommendations for Primary PCI Amsterdam EZ et al Circulation 2014 Seems easy enough, what are the challenges?? Challenges with current antiplatelet therapies New available agents Different efficacy and safety data Lack of education Lack of long-term data Drugs come with adverse effects High bleeding risk Cost Optimal Duration?? Antiplatelet Agents P2Y12 Inhibitors Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) PAR-1 Antagonists Vorapaxar (Zontivity®) Challenges with Clopidogrel Variability in platelet inhibition Drug-Drug interactions Up to 30% Non responders Genetic polymorphisms in metabolism Prodrug that must undergo two CYP450 enzymes conversion steps (CYP 2C19) Heterozygous vs. homozygous Connection of clinical outcomes debated Role of platelet function tests or genetic testing? Prasugrel TRITON-TIMI Ticagrelor PLATO Age 61 62 STEMI 26% 38% PCI 99% 61% MACE Superior Superior Death No difference Superior Major Bleeding Increased No difference Fatal Increased No difference Similar Similar (increased fatal) Demographic Results ICH Wallentin L et al.NEJM 2009;361:1045-57 Wiviott S et al. NEJM 2007; 357:2001-15 Clopidogrel Prasugrel Ticagrelor Vorapaxar Class Thienopyridine Thienopyridine Triazolopyrimidine PAR-1 antagonist “Reversibility” Irreversible Irreversible Reversible Reversible Activation Prodrug-limited by metabolism Prodrug-not limited by metabolism Active drug Active drug Onset of Effect 2-4hours 30min 30min 30min Duration of Effect 3-10 days 5-10 days 2-4 days 5-13days 600 mg loading dose (not FDA approved) provides faster, greater, and more reliable platelet inhibition Contraindicated in patients with hx CVA/TIA Concomitant ASA dose should be <100 mg Contraindicated in pts with history of stroke, TIA or intracranial hemorrhage Contraindications/ Caveats CYP2C19 *2 or *3 alleles are poor metabolizers and have reduced antiplatelet effects Generally not recommended in patients age >75 years (bleeding risk) Increased bleeding risk if body weight <60 kg Contraindicated if severe hepatic impairment Avoid use with strong CYP3A inhibitors* or CYP3A inducers** BBW Increase risk of fatal bleeding Has only been studied on background antiplatelet therapies Clopidogrel Package Insert. Bristol-Meyers Squib 2015 Prasugrel Package Insert. Eli Lilly and Company 2015 Ticagrelor Package Insert. Astra Zeneca 2015 Vorapaxar Pakcage Insert. Merck. 2015 What is the optimal duration of DAPT? Capodanno D, et al. Circulation 2013;238:2785-2798. Atrial Fibrillation Treatment for stroke prevention is therapeutic anticoagulation with a vitamin K antagonist or nonvitamin K antagonist Multiple new therapies available Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Edoxaban (Savaysa®) MOA Factor IIa inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor FDA approval stroke prevention 2010 2011 2012 2015 FDA approval VTE 2014 2012 2014 2015 2014 AHA/ACC/HRS Recommendations CHA2DS2-VASc ≥2 1 0 Recommended antithrombotic therapy OAC (2B) No therapy OR OAC OR aspirin (2B) No AT therapy (2B) RECOMMENDATIONS FOR NON-VALVULAR ATRIAL FIBRILLATION OAC: Oral Anticoagulant including warfarin, dabigatran, rivaroxaban, apixaban) Warfarin: Target INR (2—3) Aspirin: 75mg—325mg January CT, et al. J Am Coll Cardiol 2014;64:e1-76. January CT, et al. J Am Coll Cardiol 2014;64:e1-76. Challenges with Vitamin K Antagonists Bleeding risk Narrow therapeutic window Routine monitoring Slow onset/slow offset Drug-Drug/Drug-Food Interactions NOACs Pros Cons Wide therapeutic window No specific antidote (yet) Predictable anticoagulant response No routine monitoring Non compliance No coagulation assay available Cost No food interactions Less drug interactions Rapid onset Shorter half lives Dabigatran Rivaroxaban Apixaban Edoxaban Tmax 1.25—3hrs 2—4hrs 1—3hrs 1—2 hours T1/2 12—14 hrs 5—9 hrs 8—15 hrs 10—14 hours Pro-drug Yes No No No Metabolism Conjugation Oxidation & hydrolysis Oxidation and conjugation Conjugation and Oxidation Elimination 80% Renal excretion 66% renal excretion 25% renal excretion 50% renal excretion Protein Binding 35% >90% 87% ~55% Drug Interactions Pgp substrate CYP3A4 CYP3A4 CYP 3A4 substrate substrate substrate Pgp substrate Pgp substrate (minimal) Pgp substrate Dabigatran RE-LY Rivaroxaban ROCKET-AF Apixaban ARISTOTLE Edoxaban ENGAGE-AF Demographic Data Age 71 73 70 72 CHADS2 2.1 3.5 2.1 2.8 Mean TTR 64% 55% 62% 68% Superior Non-inferior Superior Non-inferior Similar Similar Decreased Decreased GI Bleeding Increased Increased Similar Increased ICH Decreased Decreased Decreased Decreased Trial Result Data Stroke and SE Major Bleeding Connolley S et al. NEJM. 2010; 361:1139-51 Patel MR et al. NEJM. 2011; 365:883-91 Granger CB et al. NEJM. 2011; 365:981-92 Giugliano RP et al. NEJM. 2013; 369: 2093-104 SAME-TT2R2 Scoring System Risk Factor Risk Scoring System to predict which patients will have good TTR on warfarin TTR >70% 0-2: Predicted to do well on warfarin (i.e. maintain good TTR) ≥ 3: Predicted to not do well on warfarin (i.e. maintain poor TTR) Points Sex category (Female) 1 Age <60 years 1 Medical history (≥2 of following: HTN, DM, CAD/MI, PAD, HF, previous stroke, pulmonary/hepatic/renal disease 1 Treatment with interacting drugs (e.g. amiodarone) 1 Tobacco use (within 2 years) 2 Race (i.e. non-Caucasian) 2 Poli D, et al. Intern Emerg Med. 2014; 9:443-7 What do we do with those patients with atrial fibrillation & ACS (or CAD with PCI)? “Triple therapy” Acute Coronary Syndrome Atrial Fibrillation 2-21% of ACS patients Optimal Management of Atrial Fibrillation and ACS Differ Why not use DAPT for stroke prevention in atrial fibrillation? ACTIVE W ACTIVE W Investigators Lancet 2006; 367:1903-12 Optimal Management of Atrial Fibrillation and ACS Differ Why not use OAC therapy for treatment of ACS in patients with stents? STARS trial Leon MB NEJM 1998; 339: 1665-71 Possible Combinations Approximately 3,000 combinations of dual or triple therapy with differing durations Antiplatelet +Therapy ASA + warfarin Clopidogrel + warfarin Prasugrel + warfarin Ticagrelor + warfarin ASA + NOAC Clopidogrel + NOAC (low dose) Clopidogrel + NOAC (high dose) Prasugrel + NOAC Ticagrelor + NOAC Triple Therapy ASA + clodidogrel + warfarin ASA + prasugrel + warfarin ASA + Ticagrelor + warfarin ASA + clopidogrel + NOAC (low dose) ASA + clopidogrel + NOAC (high dose) ASA + prasugrel + NOAC ASA + Ttcagrelor + NOAC Where’s the data? 30 non-randomized prospective observational trials or retrospective registry data 1 randomized controlled trial 0 trials of NOACs and antiplatelet therapy in this population 2 Randomized placebo controlled trials in ACS population Ongoing future studies Triple Therapy Increases Bleeding Adjusted risk of nonfatal and fatal bleeding in patients treated with aspirin, clopidogrel, and/or vitamin K antagonists after first MI Compared with aspirin alone, triple therapy is associated with 3-4 fold increased risk of fatal and nonfatal bleeding Sorensen R Lancet 2009; 374:1967-74 WOEST Trial: What is the optimal antiplatelet and anticoagulant therapy in patients with OAC and stenting Open label, multicenter, randomized trial Long term OAC + indication for PCI N=573 Double therapy Triple therapy N=279 N=284 Primary Endpoint: Any bleeding episode within 1 year Secondary Endpoint: Composite endpoint of death, MI, or stroke Median Duration Follow up = 365 days Dewilde WM Lancet 2013; 381:1107-1115 WOEST: Primary Endpoint Results 19.4% versus 44.4% in the double versus triple therapy group Statistically significant This was mainly driven by minor bleeds (no difference in severe or major bleeds) Dewilde WM Lancet 2013; 381:1107-1115 WOEST: Secondary Endpoints Dewilde WM Lancet 2013; 381:1107-1115 WEOST: Limitations Small study—unable to assess differences in ischemic events/outcomes Only 70% percent of patients had AF 85% of patients had a CHADS2 ≥ 2 73% Femoral approach for PCI 65% Patients with drug eluting stent Dewilde WM Lancet 2013; 381:1107-1115 What about “triple therapy” using NOACs? 4 Phase II Dose ranging studies in ACS Patients (dabigatran, rivaroxaban, apixaban, darexaban) lead to 2 Phase III studies ATLAST-ACS 2 TIMI 51: Study Design Randomized, Placebo controlled ACS with either DM or previous MI N=15,526 Rivaroxaban 2.5mg BID Rivaroxaban 5mg BID N=5174 N=5176 Placebo N=5176 Primary Efficacy Endpoint: Composite death from CV causes, MI or stroke Primary Safety Endpoint: Non-CABG TIMI related major bleeding Median Duration Follow up = 13.1 months Mega JL. NEJM. 2012; 366:9-19 ATLAS ACS: Primary Efficacy Endpoint Rivaroxaban significantly reduced the primary efficacy end point with rates of 8.9% and 10.7% (p=0.008) Cardiovascular death was significantly different with no difference in MI or stroke NNT = 56 patients over 2 years Mega JL. NEJM. 2012; 366:9-19 ATLAST ACS: Primary Safety Rivaroxaban significantly increased rate of TIMI major bleeding that was not CABG related 2.1% versus 0.6% (p<0.001) There was increased TIMI minor bleeding and TIMI bleeding that required medical attention in both rivaroxaban groups Similar rates of fatal bleeding in both rivaroxaban groups compared to placebo Mega JL. NEJM. 2012; 366:9-19 APPRAISE-2: Study Design Randomized, Double blind, placebo controlled ACS patients with 2 additional risk factors N=7,392 Apixaban 5mg BID Placebo N=3,705 N=3,687 Primary Efficacy Endpoint: Cardiovascular death, MI or stroke Primary Safety Endpoint: TIMI Major bleeding Median Duration Follow up = 241 days (terminated early) Alexander JH. NEJM. 2011; 367:699-708 APPRAISE-2: Primary Efficacy Endpoint A total of 279 patients (7.5%) assigned to apixaban A total of 293 patients (7.9%) assigned to placebo group No statistical difference (p=0.52) Alexander JH. NEJM. 2011; 367:699-708 APPRAISE-2: Primary Safety Endpoint A total of 46 patients (1.3%) in apixaban group NNH=125 A total of 18 patients (0.5%) in apixaban group A greater number of fatal and intracranial bleeding occurred in the apixaban group Alexander JH. NEJM. 2011; 367:699-708 Other Differences: Full dose versus low dose of therapy Higher risk population in APPRAISE-2 Which population is more similar to our AF high risk population? Caterina RD. JACC. 2012; 59:1413-1425 Limitations with current data No actual studies to assess the risk of stroke in AF patients post MI with NOACS The only P2Y12 inhibitor that was studied was clopidogrel Multiple different algorithms Drug therapies Duration Population included/excluded Bare metal stents versus Drug eluting stents Future Studies? RE-DUAL PCI Evaluation of Dual Therapy with Dabigatran versus Triple Therapy with Warfarin in patients with AF that undergo PCI with stenting Dates July 2014—July 2017 Study Type Prospective, randomized, open-label, blinded endpoint (PROBE) trial Primary endpoint Time to death of first thrombotic event (composite) Time to first TIMI major bleeding Secondary endpoint Time to event for individual outcomes (CV death, all death, Stroke, stent thrombosis, MI) Trial Arms Dabigatran 110mg BID + Clopidogrel/Ticagrelor Dabigatran 150mg BID + Clopidogrel/Ticagrelor Warfarin (goal INR 2-3) + Clopidogrel/Ticagrelor + ASA (ASA discontinued at 1 or 3 months for BMS or DES) PIONEER AF-PCI Evaluation of Dual Therapy with Rivaroxaban in patients with AF undergoing PCI Dates March 2013—August 2016 Study Type Open label, randomized, controlled, multicenter trial Primary endpoint Composite of TIMI major, minor, and bleeding requiring medical attention Secondary endpoint Composite of CV death, MI, stroke, and stent thrombosis Trial Arms Rivaroxaban 15mg + P2Y12 inhibitor for 12 months Rivaroxaban 2.5mg BID + P2Y12 inhibitor + ASA for 1/6/12 months followed by Rivaroxaban 15mg daily + ASA (low dose) Warfarin (goal INR 2-3) + P2Y12 inhibitor + ASA for 1,6, or 12 months then Warfarin (goal INR 2-3) plus ASA (low dose) 2014 AHA ACC NSTE-ACS Guidelines Recommendations Regarding “Triple Therapy” Class I Level of Evidence C Duration of vitamin K antagonist, aspirin, and P2Y12 inhibitor should be minimized to the shortest time to limit excessive bleeding Proton pump inhibitors should be used in patients with history of GI bleed Class IIa Level of Evidence C Proton pump inhibitors for patients who don’t have a history of GI bleed Class IIb Level of Evidence C It is reasonable to target an INR of 2-2.5 2014 European Consensus Document Patients with non-valvular atrial fibrillation STEP 1 Stroke risk CHA2DS2-VASc STEP 2 Bleeding risk HAS-BLED STEP 3 Clinical setting CAD/PCI or ACS STEP 4 Antithrombotic therapy Lip GYH. Eur Heart Journal 2014; 35:3155-3179 CHA2DS2-VASc for estimating risk of stroke CHA2DS2-VASc: Maximum 9 points Score TE rate C = CHF/LV dysfunction (1 point) 0 0 H = HTN (1 point) 1 0.6% A = Age >75 yo (2 points) 2 1.6% D = Diabetes (1 point) 3 3.9% S = Stroke/TIA (2 points) 4 1.9% V = Vascular disease (1 point) 5 3.2% A = Age 65-74 (1 point) 6 3.6% S = Sex—female (1 point) 7 8% 8 11% 9 100% Lip GYH. Chest 2010; 137:263-272 HAS-BLED Score for Estimating Bleeding HAS-BLED: Maximum 7 points Score Major bleeding rate 0 0.9% 1 3.4% 2 4.1% H = Hypertension (uncontrolled) A = Abnormal renal/liver function S = Stroke B = Bleeding history/predisposition L = Labile INR (TTR <60%) E = Elderly >65yo 3 5.8% D = Drugs/alcohol 4 8.9% 5 9.1% Lip GYH et al. J Am All Cardiology 2011; 57: 173-80 Pisters et al. Chest 2010; 138(5):1093-100 Lip GYH. Eur Heart Journal 2014; 35:3155-3179 What is the Pharmacists Role? Question the physician Educate the patients of bleeding risk Discuss optimal Duration Transitions of Care Ensure these drugs are prescribed by the same provider Ensure patient’s are going to the follow up appointments Ensure that these patient’s aren’t on lifetime “triple therapy” AJ is a 65yo M who arrives to the ER with substernal 10/10 chest pain. HPI: AJ describes his CP as pressure like pain that lasts for 5 minutes and gets worse with exertion. This pain has been getting worse over the last few days until today he had the worst pain yet. He then called 911, his EKG revealed STelevations and he was emergently brought to the cath lab. 1 DES was placed in his mid-LAD. PMH of HTN, ischemic stroke (2 years ago), hyperlipidemia, GERD. Vitals: BP 138/70 HR 80 PE: No significant findings Home medications: Aspirin 81mg Oral Daily Omeprazole 20mg Oral Daily Lisinopril 20mg Oral Daily Atorvastatin 40mg Oral Daily What antiplatelet regimen would you recommend for this patient? Aspirin 81mg Oral Daily Aspirin 81mg Oral Daily + Clopidogrel 75mg Oral Daily Aspirin 81mg Oral Daily + Prasugrel 10mg Oral Daily Aspirin 81mg Oral Daily + Ticagrelor 90mg Oral BID AJ is a 65yo M who arrives to the ER with substernal 10/10 chest pain. HPI: AJ describes his CP as pressure like pain that lasts for 5 minutes and gets worse with exertion. This pain has been getting worse over the last few days until today he had the worst pain yet. He then called 911, his EKG revealed STelevations and he was emergently brought to the cath lab. 1 DES was placed in his mid-LAD. PMH of HTN, ischemic stroke (2 years ago), hyperlipidemia, GERD, atrial fibrillation Vitals: BP 138/70 HR 80 PE: No significant findings Home medications: Aspirin 81mg Oral Daily Pantoprazole 40mg Oral Daily Lisinopril 20mg Oral Daily Atorvastatin 40mg Oral Daily Metoprolol succinate 100mg Oral daily Warfarin 4mg Oral Daily What antiplatelet regimen would you recommend for this patient? Aspirin 81mg Oral Daily Aspirin 81mg Oral Daily + Clopidogrel 75mg Oral Daily Aspirin 81mg Oral Daily + Prasugrel 10mg Oral Daily Aspirin 81mg Oral Daily + Ticagrelor 90mg Oral BID What would you recommend for AJ’s anticoagulation regimen? Discontinue warfarin until antiplatelet regimen is discontinued, then restart warfarin Discontinue warfarin and begin rivaroxaban 20mg oral daily Continue warfarin and P2Y12 inhibitor, discontinue aspirin Discontinue warfarin and begin rivaroxaban 20mg oral daily, discontinue aspirin Continue warfarin, P2Y12 inhibitor, and aspirin for 6 months, then discontinue aspirin CHA2DS2-VASc for estimating risk of stroke CHA2DS2-VASc: Maximum 9 points Score TE rate C = CHF/LV dysfunction (1 point) 0 0 H = HTN (1 point) 1 0.6% A = Age >75 yo (2 points) 2 1.6% D = Diabetes (1 point) 3 3.9% S = Stroke/TIA (2 points) 4 1.9% V = Vascular disease (1 point) 5 3.2% A = Age 65-74 (1 point) 6 3.6% S = Sex—female (1 point) 7 8% 8 11% 9 100% Lip GYH. Chest 2010; 137:263-272 HAS-BLED Score for Estimating Bleeding HAS-BLED: Maximum 7 points Score Major bleeding rate 0 0.9% 1 3.4% 2 4.1% H = Hypertension (uncontrolled) A = Abnormal renal/liver function S = Stroke B = Bleeding history/predisposition L = Labile INR (TTR <60%) E = Elderly >65yo 3 5.8% D = Drugs/alcohol 4 8.9% 5 9.1% Lip GYH et al. J Am All Cardiology 2011; 57: 173-80 Pisters et al. Chest 2010; 138(5):1093-100 Lip GYH. Eur Heart Journal 2014; 35:3155-3179 What would you recommend for AJ’s anticoagulation regimen? Discontinue warfarin until antiplatelet regimen is discontinued, then restart warfarin Discontinue warfarin and begin rivaroxaban 20mg oral daily Continue warfarin and P2Y12 inhibitor, discontinue aspirin Discontinue warfarin and begin rivaroxaban 20mg oral daily, discontinue aspirin Summary Challenges with or original antiplatelet and anticoagulant therapies (clopidogrel and warfarin) have led to the development of new and novel therapies New therapies have introduced medications with similar better efficacy results BUT each agent has their own caveats and specific population tested The use of “triple therapy” has a lot of conflicting data Need additional randomized controlled trial data for this AF + ACS population No evidence for “triple therapy” using any antiplatelet agent besides clopidogrel