Pharmacology – What’s New in Anticoagulation Medications James B. Groce III, PharmD, CACP Professor Campbell University College of Pharmacy and Health

Pharmacology – What’s New in Anticoagulation Medications

James B. Groce III, PharmD, CACPProfessor

Campbell University College of Pharmacy and Health SciencesClinical Assistant Professor of Medicine, UNCClinical Pharmacy Specialist-Anticoagulation

Cone Health, Greensboro, NC

Faculty Disclosure

• The speaker reported the following financial relationships or relationships to products or devices he or his spouse has with commercial interests related to the content of this CME activity:

– James B. Groce III, PharmD, CACP• Fees for non-CME services received directly from a

commercial interest or their agents:• Boehringer Ingelheim Pharmaceuticals, Inc., • Bristol-Myers Squibb• Eisai Pharmaceuticals, Inc.• Janssen Pharmaceuticals, Inc.• Sanofi-aventis• Stago-Diagnostica• The Joint Commission

Objectives

• Review the cardiology focused indications of the new anticoagulant medications.

• Discuss the benefits and shortcomings of the new anticoagulant medications—compared to the traditional comparator.

• Identify key opportunities in the management of patients using the new anticoagulants.

Atrial Fibrillation and Anticoagulation

• An estimated 2.6 million Americans have AF– Prevalence of AF is increasing—estimated to be 12

million patients by 2050• AF is responsible for 15-20% of all strokes

– Untreated stroke risk with AF is approximately 5% – AF strokes are severe: causing death and disability

• Anticoagulation therapy– Effectively lowers the incidence and severity of AF

stroke• Fewer than 60% of eligible patients with AF have

received anticoagulation with warfarin– Many patients with AF have INRs below the

recommended therapeutic rangeOgilvie IM, et al. Am J Med. 2010;123:638-645.Hylek E et al. N Engl J Med. 2003; 349:1019-1026.

AF=atrial fibrillation.INR=international normalized ratio.

warfarin (INR 2.0 to 3.0, target 2.5),* ordabigatran †

Any high-risk factor ormore than 1 moderate-risk factor(Previous stroke, TIA or embolism, mitral stenosis, and Prosthetic heart valve*)

aspirin, 81-325 mg daily, orwarfarin (INR 2.0-3.0, target 2.5), ordabigatran†

One moderate-risk factor(Age ≥75 yrs, HTN, CHF, LVEF ≤35%, and diabetes)

aspirin, 81-325 mg dailyNo risk factors

Recommended TherapyRisk Category

*If mechanical valve, target INR >2.5. † dabigatran is useful as an alternative to warfarin in patients with AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure, or advanced liver disease.

Fuster V, et al. J Am Coll Cardiol. 2006;48:e149-e246. Wann SL, et al. Heart Rhythm. 2011;8:e1-e8.

ACCF/AHA/HRS Focus Update 2011 Guidelines for Antithrombotic Therapy to Prevent Stroke

HTN=hypertension.INR=international normalized ratio.CHF=congestive heart failure.LVEF=left ventricular ejection fraction.

Therapies to Prevent Thrombotic Stroke

Anticoagulants Antiplatelet Agents

New Anticoagulants

aspirin +/-

Non-warfarinVitamin K Antagonists• tecarfarin

Direct Thrombin Inhibitors• ximelagatran• dabigatran• AZD 0837

Factor XaInhibitors• apixaban • rivaroxaban• idraparinux• edoxaban• YM150• betrixaban • LY517717

Non-antithrombotic Drugs

Anti-hypertensive

Statin Anti-arrhythmic

Vitamin K Antagonist

warfarin

Left Atrial Appendage Occlusion or Excision

• Umbrella device• External clip• Surgical excision

clopidogrel

Characteristics of an Ideal Anticoagulant

Hirsh J et al. Blood. 2005;105(2):453-461.

Predictable dose response (no need for

monitoring)

Minimal non-anticoagulant

side effects

Minimal

drug-drug interactions

Parenteraland oral

administrationAntidote

High efficacy-to-safety index

Rapid onset of action

Newer Oral Anticoagulants

dabigatran1,4* rivaroxaban2 apixaban3

Manufacturer Boehringer Ingelheim Bayer with Ortho-McNeilBristol-Myers Squibb

with Pfizer

Brand Name Pradaxa® Xarelto® Eliquis®

Approval Status

•Approved in U.S. 2010 • Approved in U.S. 2011 • Approved in the EU

2011

Indication•Stroke prevention in

patients with AF

• Thromboembolism in adult patients undergoing elective hip or knee replacement surgery

• Stroke prevention in patients with AF

• Not approved in US• EU indication:

Prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery

Dosage Recommendation

150mg bid (Clcr > 30mL/min)

75mg bid (Clcr 15 – 30mL/min)

75mg bid (Clcr 30 – 50mL/min)*

10mg qd Ortho20mg qd Afib Clcr >

50mL/min15mg qd Afib (Clcr 15-

50mL/min)

5 mg bid

Mechanism of Action

Direct factor IIa inhibitor Direct factor Xa inhibitorDirect factor Xa

inhibitor

1. dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. 2011.

2. rivaroxaban prescribing information. Janssen Pharmaceuticals, Inc. 2011.

3. apixaban European Union summary of product characteristics. Pfizer and Bristol-Myers Squibb. 2011.4. *dronedarone, systemic ketoconazole

Pharmacokinetic Properties of the New Oral Anticoagulants

dabigatran rivaroxaban apixaban

T1/2 12-14 hours 5-9 hours 8-15 hours

Metabolism

Conjugation (esterase catalyzed

hydrolysis in liver or plasma)

Oxidation (mainly via

CYP3A4) and hydrolysis

70% unchanged

30% Inactive metabolites

Renal Excretion 80% 36% 30%

Substrate for p-glycoprotein

Yes Yes Yes

Metabolized by CYP3A4 No Yes Yes

Wittkowsky AK. J Thromb Thrombolysis. 2010;29:182-191.Ufer M. Thrombosis and Haemostasis. 2010;103:572-585.

Differences Between New Oral Anticoagulants and Warfarin

ParameterOral

Anticoagulants Warfarin

Onset/Offset of action Rapid Slow

Dose–anticoagulant effect relationship

Linear Predictable

Food–drug interactions

Low probability of interaction

Moderate probability of

interaction

Monitoring for anticoagulant effect

Not requiredNot available

Required POCT and PST Available

POCT=point-of-care testingPST=patient self-testing

AF Stroke Risk

Stroke Risk Stratification in AF

CHADS2 CHA2DS2-VAScRisk Factor ScoreCardiac Failure 1

HTN 1Age ≥75 y 1Diabetes 1

Stroke 2

Risk Factor ScoreCardiac Failure 1

HTN 1Age ≥75 y 2Diabetes 1

Stroke 2Vascular Disease (MI, PAD, Aortic Atherosclerosis)

1

Age 65-74 y 1

Sex Category (Female) 1

Lip GY, Halperin JL. Am J Med. 2010;123(6):484-488.Camm AJ, et al. Eur Heart J. 2010;31(19):2369-2429.

Total Score Annual Risk of Stroke (%) 0 1.9 0 1 2.8 1.3 2 4.0 2.2 3 5.9 3.2 4 8.5 4.0 5 12.5 6.7 6 18.2 9.8 7 9.6 8 6.7 9 15.2

CHADS2 CHA2DS2-VASc

HTN=hypertension.MI=myocardial infarction.PAD=peripheral artery disease.

RE-LY: Study Design

Atrial fibrillation ≥1 Risk FactorAbsence of contra-indications951 centers in 44 countries

R

warfarin(INR 2.0-3.0)n=6000

dabigatran etexilate 110 mg bidn=6000

dabigatran etexilate 150 mg bidn=6000

10 efficacy outcome=stroke or systemic embolism

10 safety outcome=major bleedingNon-inferiority margin=1.46

Open Blinded

Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151.

bid=twice daily.INR=international normalized ratio.RE-LY=Randomized Evaluation of Long-Term Anticoagulation Therapy.

• Performed December 2005-March 2009• Median follow-up: 2.0 years• Follow-up 99.9% complete• Mean TTR=64% (patients on warfarin)

Stroke/systemic embolism1

0.65 (0.52-0.81)

Myocardial Infarction1

1.27 (0.94-1.71)

Vascular death1

0.85 (0.72-0.99)

Intracranial Hemorrhage (ICH)1

0.41 (0.28-0.60)

Major GI bleeding2

1.47 (1.17-1.84)

Major bleeding1

0.93 (0.81-1.07)

Total bleeding1

0.91 (0.85-0.96)

Eff

icac

y O

utc

om

es

Saf

ety

Ou

tco

mes

Relative risk

0.0 0.5 1.0 1.5 2.0

dabigatran 150 mgbetter

warfarinbetter

0.90 (0.74-1.10)

1.29 (0.96-1.75)

0.90 (0.77-1.06)

0.30 (0.19-0.45)

1.06 (0.83-1.35)

0.80 (0.70-0.93)

0.78 (0.73-0.83)

1. dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. March 2011.

2. Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151.RE-LY=Randomized Evaluation of Long-term Anticoagulation Therapy.

RE-LY Trial: Primary Efficacy & Safety Outcomes

ROCKET AF Study Design

Enrollment of subjects without prior stroke, TIA, or systemic embolism and only 2 factors capped at 10%

CHADS2 Risk Factors• Prior stroke, TIA, or non-CNS

systemic embolus – OR –

• CHF or LVEF ≤35% • Hypertension • Age ≥75 years • Diabetes

At least 2 required

Abbreviations: CHADS2 = congestive heart failure, hypertension, age, diabetes, prior stroke or TIA; CHF = congestive heart failure; CrCl = creatinine clearance; INR = international normalized ratio.

*Patients seen at weeks 1, 2, and 4, then as clinically indicated but at least monthly thereafter.

1. Patel MR et al. N Engl J Med. 2011;365(10):883-891. 2. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347. 15

rivaroxaban 20 mg/d

(15 mg/d for CrCl 30 to <50 mL/min)

warfarinINR target:

2.0 to 3.0 inclusive

NVAF

Monthly assessments*warfarin management was determined by

clinician

Randomizeddouble-blind/

double-dummy(N=14,264)

*Included all randomized subjects followed for events both on and off study drug until end of study site notification (N=14171). Patel MR et al. N Engl J Med. 2011;365(10):883-891.

No. at risk

Rivaroxaban 7081 6879 6683 6470 5264 4105 2951 1785 768 155

Warfarin 7090 6871 6656 6440 5225 4087 2944 1783 776 154

rivaroxaban warfarin

Rate/100 PTY 2.12 2.42

HR (95% CI): 0.88 (0.74-1.03)Noninferiority P value <.001

Days From Randomization

Cu

mu

lati

ve E

ven

t R

ate

(%)

0 120 240 360 480 600 720 840 960 10800

1

2

3

4

5

6

rivaroxabanwarfarin

Rocket-AF Primary Efficacy OutcomeStroke and Non–CNS Embolism

Rocket-AF Primary Safety Outcomes

Events, No. (Rate/100 PTY)

rivaroxaban(n=7061)*

warfarin(n=7082)*

HR(95% CI) P value

Major bleeding (any) 395 (3.60) 386 (3.45) 1.04 (0.90-1.20) .576

Bleeding causing death

27 (0.24)

55 (0.48) 0.50 (0.31-0.79) .003

Critical organ bleeding†

91 (0.82) 133 (1.18) 0.69 (0.53-0.91) .007

Hgb drop ≥2 g/dL 305 (2.77) 254 (2.26) 1.22 (1.03-1.44) .019

Transfusion (>2 units) 183 (1.65) 149 (1.32) 1.25 (1.01-1.55) .044

Bleeding site

Intracranial hemorrhage‡ 55 (0.49)

84 (0.74) 0.67 (0.47-0.94) .019

GI bleeding§224 (---) 154 (---) --- .001

Abbreviations: GI, gastrointestinal; hgb, hemoglobin.*Safety population on-treatment.†Critical bleeding sites included intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome or retroperitoneal.

‡Intracranial hemorrhage included intraparenchymal, intraventricular, subarachnoid, subdural hematoma, and epidural hematoma.§GI hemorrhage included upper GI, lower GI, and rectal bleeds.

Patel MR et al. N Engl J Med. 2011;365(10):883-891.

warfarin (target INR 2-3)

apixaban 5 mg oral twice daily(2.5 mg BID in selected patients)

Primary outcome: stroke or systemic embolism

Granger CB, et al. N Engl J Med. 2011 [Aug 28]. ePub ahead of print. doi: 10.1056/NEJMoa1107039.

Randomizedouble blind,

double dummy(n = 18,201)

Inclusion risk factors Age ≥ 75 years Prior stroke, TIA or SE HF or LVEF ≤ 40% Diabetes mellitus Hypertension

warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device

Exclusion Mechanical prosthetic

valve Severe renal insufficiency Need for aspirin plus

thienopyridine

ARISTOTLE: Study Design

ARISTOTLE Main Trial Results

21% RRR 31% RRR

ISTH major bleedingStroke or systemic embolism

Median TTR 66%

apixaban 212 patients, 1.27% per year warfarin 265 patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P=0.011

apixaban 327 patients, 2.13% per year warfarin 462 patients, 3.09% per yearHR 0.69 (95% CI, 0.60–0.80); P<0.001

Granger CB, et al. N Engl J Med. 2011 [Aug 28]. ePub ahead of print. doi: 10.1056/NEJMoa1107039.

What Is the Impact of Time in Target Range (TTR)?

Time in Target Range (TTR)

• What is the TTR for the patient below?

3 Methods for Calculating TTR:Percentage of Visits in Range• For an individual patient, the number of visits “in

range” is divided by the number of visits

3 Patient Visits with INR in range

5 Total Patient Visits

= 60% TTR

3 Methods for Calculating TTR:Cross Section of Patients In Range• For a group of patients, a date is selected and all

patients are evaluated on the last reading prior to that date.

Sept 30, 2011 is selected to assess TTR for 100 patients • Patients are evaluated using last INR

readings prior to Sept 30, 2011• Out of 100 patients, 71 had readings in

therapeutic range

71 Patient with INR in range

100 Total Patients

=71% TTR

As of Sept 30, 2011

• More complicated methodology which looks at the amount of time between visits to determine how long the patient might have been within their therapeutic range– Between measurements on May 1 and May 31, it is

assumed that the patient slowly moved from 2.5 to 3.5 over 30 days

– On May 15th, the patient was probably over 3.0

Apr 29, 2011 May 1, 2011 May 31, 20110

0.51

1.52

2.53

3.54

2.8 2.5

3.5

INR

Level

3 Methods for Calculating TTR: % Days in Range (Rosendaal Method)

15 days In range

15 days Out of range

Patient was in range 50% of the time

Phase 3 Trials in Atrial Fibrillation:TTR and warfarin Efficacy

Study Mean

TTR (%)

MeanCHADS2

Score

CHADS2 ≥3Patients

(%)

Primary Efficacy Rate (warfarin Arm)*

Overall CHADS2 2CHADS2

≥3

ROCKET AF1 55 3.5 87.0 2.2 1.3 2.3

RE-LY2 64 2.1 32.5 1.7 1.4 2.7

ARISTOTLE3 62 2.1 30.2 1.6 1.4 2.8

*Rate per 100 patient-years.

1. Patel MR et al. N Engl J Med. 2011;365(10):883-8912. Connolly SJ, et al. N Engl J Med. 2009;361:1139-51. doi: 10.1056/NEJMoa0905561.3. Granger CB, et al. N Engl J Med. 2011 [Aug 28]. ePub ahead of print. doi: 10.1056/NEJMoa1107039 .

♦ ROCKET AF enrolled a population of patients with AF at higher risk of stroke

♦ The overall event rate for the warfarin arm in ROCKET AF was higher than those reported in RE-LY and ARISTOTLE

♦ This difference may have been driven by the greater proportion of CHADS2 ≥3 patients enrolled in ROCKET AF/

Benefits and shortcomings of the new anticoagulant

medications—compared to the traditional comparator.

• New oral anticoagulants– No coagulation testing

• Less time and travel• No finger stick or venipuncture

– Fixed dose: no dose finding– Primary Care or Cardiology

• Simplifies responsibility– Fewer strengths

• Possible decease in dosing errors– Diet

• Less effect

Benefits and shortcomings of the currently available anticoagulant therapies.

• Given the challenges associated with warfarin, an oral anticoagulant is especially attractive

• Features of oral anticoagulants that may be associated with greater adherence include– Do not require monitoring– Fewer adverse effects, drug-drug, and drug-food

interactions• Improved adherence may reduce the risk of

subtherapeutic INR and may lead to better treatment outcomes and possibly lower costs

Kirsch B. Manag Care. 2011;20(2):33-36.

Benefits and shortcomings of the currently available anticoagulant therapies.

Identify key opportunities in the management of patients using

the new anticoagulants

• Review appropriateness prior to dispensing• CBC q72h while inpatient• Recommend CBC 7-10 days post discharge• Discharge counseling

Moses Cone Health System Pharmacy & Therapeutics Formulary Review. January 2011. Approved.

CBC=complete blood count.

Key opportunities in the management of patients

Creatinine ClearanceRecommended Dose of

Dabigatran

>30 mL/min 150 mg twice daily*

15 – 30 mL/min30 – 50 mL/min

75 mg twice daily†

75mg twice daily‡

<15 mL/min Dosing recommendations cannot be provided

* With or without food.† Based upon pharmacokinetic modeling, estimated exposure to dabigatran increases with the severity of renal function impairment. ‡For patients on P-gp inhibitors (dronedarone or systemic ketoconazole)

dabigatran etexilate prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. 2011.


• Converting from warfarin to dabigatran– Discontinue warfarin– Start with dabigatran when INR <2.0

• Converting from dabigatran to warfarin

Creatinine Clearance

Recommended Starting Time of Warfarin

>50 mL/min 3 days before discontinuing dabigatran

31-50 mL/min 2 days before discontinuing dabigatran

15-30 mL/min 1 day before discontinuing dabigatran

<15 mL/min No recommendations can be made


INR=international normalized ratio.


Administration of Parenteral Anticoagulant

Recommended Starting Time of Dabigatran

Intermittent dosing 0-2 hours before time of next dose

Continuous infusion At time of discontinuation



Creatinine Clearance

Recommended Starting Time of Parenteral Anticoagulant

CrCl ≥30 mL/min12 hours after last dose of

dabigatran

CrCl ≤30 mL/min24 hours after last dose of

dabigatran

CrCl=creatinine clearance.



Discontinue warfarin

Initiate rivaroxaban when the INR is below

3.0 to avoid inadequate anticoagulation

♦ There are no clinical trial datato guide converting from rivaroxaban to warfarin

♦ Rivaroxaban may affect INR, so INR measurements made during coadministration of rivaroxaban with warfarin may not be useful

♦ One approach is to discontnue rivaroxaban and begin both a parenteral anticoagulant and warfarin when the next rivaroxaban dose would have been taken*

warfarin rivaroxaban rivaroxaban warfarin

*The recommendation to use a parenteral anticoagulant together with warfarin after discontinuing rivaroxabanis analogous to the bridging protocol recommended for starting moderate- to high-risk patients on warfarin. 1

Fuster V et al. J Am Coll Cardiol. 2011;57(11):e101-e198.


rivaroxaban(n=4637)

warfarin(n=4691)

No.

of

Str

okes

• Anticoagulation after discontinuation was not stipulated in ROCKET AF

• Warfarin patients who completed the study were generally maintained on warfarin

• Rivaroxaban patients were generally switched to warfarin – There was no

coadministration of warfarin and rivaroxaban

– This resulted in inadequate anticoagulation after stopping rivaroxaban until attaining a therapeutic INR

Patel MR et al. N Engl J Med. 2011;365(10):883-891.


• Short half-life of oral anticoagulants makes adherence important

• Reduced monitoring may deny the physician the opportunity for patient education and the earlier detection of problems– Denies the practitioner the opportunity to tailor the

intensity of anticoagulant therapy for patient-specific factors

• Acquisition costs associated with oral anticoagulants will be greater than for warfarin– Payers may erect barriers to access– Cost-sharing may decrease adherence

Ansell J. Hematology. 2010;221-228.


• Protocol development for use and management– Short half-life of oral anticoagulants makes

adherence important• Protocol development for use and

management of life-threatening/catastrophic bleed(s)– No validated tests to measure anticoagulation

effect– No antidote for most agents– Assessment of compliance more difficult than

with vitamin K antagonistsSobieraj-Teague M, et al. Semin Thromb Hemost. 2009;35:515-524.


• The successful use of (anticoagulation) depends on an “essential triad” which includes a– Vigilant clinician– Cooperative (well educated) patient– Readily available and reliable laboratory

• If these factors are present, continuous use of anticoagulation is practical...and effective; if not, the use of the drug is dangerous…

Foley WT, Wright IS. Am J Med Sci. 1949;217:136-144.Aske JM, Cherry CB. J Am Med Assoc. 1950;144:97-100.


• Availability of new oral anticoagulants will impact the way we think about care delivery and management for patients with atrial fibrillation– We must STOP focusing upon INRs—and instead, as

practitioners—focus upon assuring:• The impact these new drugs have upon reduction of

stroke and intracranial hemorrhage!• Compliance, patient education—regarding their

disease state as well as their drug therapies• Continuing to deliver a “systematic means of

oversight” for drug therapies and disease states—for which at their extremes—patients may either bleed to death—or clot to death:– Baseline and periodic assessment of renal function– Evaluation of drug-drug/drug-disease interactions


• Anticoagulation therapy lowers the incidence and severity of AF stroke

• Less than 60% of eligible AF patients have received anticoagulation therapy

• Newer oral anticoagulants exhibit a rapid onset of action, linear kinetics, low probability of drug and food interactions, and do not require monitoring—and, relative to warfarin—have further reduced the liklihood of stroke in the setting of non-valvular atrial fibrillation


Summary

• Current cardiology indications of the new anticoagulant medications include prevention of stroke in setting of NVAF.

• Benefits and shortcomings– New oral agents eliminate a requirement of

traditional monitoring and reduce stroke—when compared to warfarin—but lack a means of reversal

• Key opportunities for practitioner involvement in the management of patients:– Will remain: provision of a systematic means of

oversight• Appropriateness of drug relative to the approved

indication(s)• Focus upon renal function and Rx-Rx interaction

prevention for new agents

Pharmacology – What’s New in Anticoagulation Medications

James B. Groce III, PharmD, CACPProfessor

Campbell University College of Pharmacy and Health SciencesClinical Assistant Professor of Medicine, UNCClinical Pharmacy Specialist-Anticoagulation

Cone Health, Greensboro, NC

Documents

Pharmacology – What’s New in Anticoagulation Medications James B. Groce III, PharmD, CACP Professor Campbell University College of Pharmacy and Health