Challenges with Current Antiplatelet & Anticoagulant TherapiesCAROLYN 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 ST-elevations 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 ST-elevations 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
TicagrelorPLATO
Demographic
Age 61 62
STEMI 26% 38%
PCI 99% 61%
Results
MACE Superior Superior
Death No difference Superior
Major Bleeding
Increased No difference
Fatal Increased No difference
ICH Similar Similar (increased fatal)
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
Contraindications/Caveats
600 mg loading dose (not FDA approved) provides faster, greater, and more reliable platelet inhibition
CYP2C19 *2 or *3 alleles are poor metabolizers and have reduced antiplatelet effects
Contraindicated in patients with hx CVA/TIA
Generally not recommended in patients age >75 years (bleeding risk)
Increased bleeding risk if body weight <60 kg
Concomitant ASA dose should be <100 mg
Contraindicated if severe hepatic impairment
Avoid use with strong CYP3A inhibitors* or CYP3A inducers**
Contraindicated in pts with history of stroke, TIA or intracranial hemorrhage
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 non-vitamin 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 RecommendationsCHA2DS2-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 FIBRILLATIONOAC: 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 Wide therapeutic window
Predictable anticoagulant response
No food interactions
Less drug interactions
Rapid onset
Shorter half lives
Cons No specific antidote (yet)
No routine monitoring
Non compliance
No coagulation assay available
Cost
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
Pgpsubstrate
CYP3A4 substrate
Pgp substrate
CYP3A4 substrate
Pgp substrate
CYP 3A4 substrate (minimal)
Pgp substrate
DabigatranRE-LY
Rivaroxaban
ROCKET-AF
ApixabanARISTOTLE
EdoxabanENGAGE-AF
Demographic Data
Age 71 73 70 72
CHADS2 2.1 3.5 2.1 2.8
Mean TTR 64% 55% 62% 68%
Trial Result Data
Stroke and SE
Superior Non-inferior Superior Non-inferior
Major Bleeding
Similar Similar Decreased Decreased
GI Bleeding Increased Increased Similar Increased
ICH Decreased Decreased Decreased Decreased
Connolley S et al. NEJM. 2010; 361:1139-51Patel MR et al. NEJM. 2011; 365:883-91
Granger CB et al. NEJM. 2011; 365:981-92Giugliano RP et al. NEJM. 2013; 369: 2093-104
SAME-TT2R2 Scoring System
Risk Factor 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
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)
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 +TherapyASA + warfarinClopidogrel + warfarinPrasugrel + warfarinTicagrelor + warfarinASA + NOACClopidogrel + NOAC (low dose)Clopidogrel + NOAC (high dose)Prasugrel + NOACTicagrelor + NOAC
Triple TherapyASA + clodidogrel + warfarinASA + prasugrel + warfarinASA + Ticagrelor + warfarinASA + clopidogrel + NOAC (low dose)ASA + clopidogrel + NOAC (high dose)ASA + prasugrel + NOACASA + 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
Sorensen R Lancet 2009; 374:1967-74
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
WOEST Trial: What is the optimal antiplatelet and anticoagulant therapy in patients with OAC and stenting
Dewilde WM Lancet 2013; 381:1107-1115
Open label, multicenter, randomized trialLong term OAC + indication for PCI
N=573
Double therapyN=279
Triple therapyN=284
Primary Endpoint: Any bleeding episode within 1 year Secondary Endpoint: Composite endpoint of death, MI, or stroke
Median Duration Follow up = 365 days
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 controlledACS with either DM or previous MI
N=15,526
Rivaroxaban 2.5mg BIDN=5174
Rivaroxaban 5mg BIDN=5176
PlaceboN=5176
Primary Efficacy Endpoint: Composite death from CV causes, MI or strokePrimary 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 BIDN=3,705
PlaceboN=3,687
Primary Efficacy Endpoint: Cardiovascular death, MI or strokePrimary 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
A total of 18 patients (0.5%) in apixaban group
A greater number of fatal and intracranial bleeding occurred in the apixaban group
NNH=125
Alexander JH. NEJM. 2011; 367:699-708
Caterina RD. JACC. 2012; 59:1413-1425
Other Differences: Full dose versus low dose of therapyHigher risk population in APPRAISE-2Which population is more similar to our AF high risk population?
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
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
Recommendations Regarding “Triple Therapy”
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
C = CHF/LV dysfunction (1 point)
H = HTN (1 point)
A = Age >75 yo (2 points)
D = Diabetes (1 point)
S = Stroke/TIA (2 points)
V = Vascular disease (1 point)
A = Age 65-74 (1 point)
S = Sex—female (1 point)
Score TE rate
0 0
1 0.6%
2 1.6%
3 3.9%
4 1.9%
5 3.2%
6 3.6%
7 8%
8 11%
9 100%Lip GYH. Chest 2010; 137:263-272
HAS-BLED Score for Estimating Bleeding
HAS-BLED: Maximum 7 points
H = Hypertension (uncontrolled)
A = Abnormal renal/liver function
S = Stroke
B = Bleeding history/predisposition
L = Labile INR (TTR <60%)
E = Elderly >65yo
D = Drugs/alcohol
Lip GYH et al. J Am All Cardiology 2011; 57: 173-80Pisters et al. Chest 2010; 138(5):1093-100
Score Major bleeding
rate
0 0.9%
1 3.4%
2 4.1%
3 5.8%
4 8.9%
5 9.1%
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 ST-elevations 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 ST-elevations 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
C = CHF/LV dysfunction (1 point)
H = HTN (1 point)
A = Age >75 yo (2 points)
D = Diabetes (1 point)
S = Stroke/TIA (2 points)
V = Vascular disease (1 point)
A = Age 65-74 (1 point)
S = Sex—female (1 point)
Score TE rate
0 0
1 0.6%
2 1.6%
3 3.9%
4 1.9%
5 3.2%
6 3.6%
7 8%
8 11%
9 100%Lip GYH. Chest 2010; 137:263-272
HAS-BLED Score for Estimating Bleeding
HAS-BLED: Maximum 7 points
H = Hypertension (uncontrolled)
A = Abnormal renal/liver function
S = Stroke
B = Bleeding history/predisposition
L = Labile INR (TTR <60%)
E = Elderly >65yo
D = Drugs/alcohol
Lip GYH et al. J Am All Cardiology 2011; 57: 173-80Pisters et al. Chest 2010; 138(5):1093-100
Score Major bleeding
rate
0 0.9%
1 3.4%
2 4.1%
3 5.8%
4 8.9%
5 9.1%
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
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