challenges with current antiplatelet & anticoagulant therapies carolyn hempel, pharmd, bcps...

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 + Clopidogrel 75mg Oral Daily

Aspirin 81mg Oral Daily + Prasugrel 10mg Oral Daily

Aspirin 81mg Oral Daily + Ticagrelor 90mg Oral BID



PMH of HTN, ischemic stroke (2 years ago), hyperlipidemia, GERD, atrial fibrillation


Home medications:


Pantoprazole 40mg Oral Daily



Metoprolol succinate 100mg Oral daily

Warfarin 4mg Oral Daily

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)


WOEST: Secondary Endpoints


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


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%

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”



PMH of HTN, ischemic stroke (2 years ago), hyperlipidemia, GERD.


Home medications:


Omeprazole 20mg Oral Daily





PMH of HTN, ischemic stroke (2 years ago), hyperlipidemia, GERD, atrial fibrillation


Home medications:


Pantoprazole 40mg Oral Daily



Metoprolol succinate 100mg Oral daily

Warfarin 4mg Oral Daily






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%

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

challenges with current antiplatelet & anticoagulant therapies carolyn hempel, pharmd, bcps...

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