Adult Medicine PRN Focus Session—Update on Anticoagulant ... · 1:15 p.m. Secondary Stroke Prevention: What’s New? ... anticoagulation with a vitamin K antagonist (target INR

Annual Meeting

Adult Medicine PRN Focus Session—Update on Anticoagulant Use in Stroke Patients Activity No. 0217-0000-11-095-L01-P (Knowledge-Based Activity) Tuesday, October 18 1:15 p.m.–3:15 p.m. Convention Center: Rooms 317 & 318 Moderator: Nancy Yunker, Pharm.D., BCPS Assistant Professor of Pharmacy, Clinical Specialist, Internal Medicine, Virginia Commonwealth University, Richmond, Virginia Agenda 1:15 p.m. Secondary Stroke Prevention: What’s New? A Review of

Secondary Stroke Prevention Guidelines and the Evidence that Supports the Drug Therapy Susan C. Fagan, Pharm.D., FCCP, BCPS Jowdy Professor, Associate Head, Assistant Dean, University of Georgia College of Pharmacy, Augusta, Georgia

2:05 p.m. When Is a New Medication Better than the Tried and True? Use of Dabigatran in Atrial Fibrillation for Stroke Prevention Asha L. Tata, Pharm.D., BCPS Internal Medicine Clinical Specialist; Clinical Assistant Professor, University of Maryland School of Pharmacy, University of Maryland Medical Center Department of Pharmacy Services, Baltimore, Maryland

2:35 p.m. Quality Initiatives of Anticoagulation Safety: Attacking the Coagulation Cascade, Safely William E. Dager, Pharm.D., FCCP, BCPS Pharmacist Specialist, Department of Pharmaceutical Services, University of California Davis Medical Center, Sacramento, California

3:05 p.m. Panel Discussion William E. Dager, Pharm.D., FCCP, BCPS Susan C. Fagan, Pharm.D., FCCP, BCPS Asha L. Tata, Pharm.D., BCPS

Faculty Conflict of Interest Disclosures William E. Dager: no conflicts to disclose. Susan C. Fagan: serves as a consultant/member of advisory board for Pfizer, Inc, and Genentech, Inc. Asha L. Tata: no conflicts to disclose.

Update on Anticoagulant Use in Stroke Patients 1

Annual Meeting

Learning Objectives

1. Discuss the changes to the 2010 secondary prevention stroke guidelines. 2. Examine the literature supporting these changes. 3. Evaluate recommendations for stroke prevention in specific disease states/conditions. 4. Compare and contrast the pharmacology of dabigatran versus warfarin. 5. Summarize efficacy, safety, and pharmacoeconomic data for dabigatran. 6. Describe the role of therapy for dabigatran in the treatment of atrial fibrillation. 7. Improve medication management in secondary stroke prevention and in patient with atrial

fibrillation. 8. Describe the pharmacist’s role in enhancing anticoagulation safety in the hospital. 9. Provide dosing guidelines or protocols for the management of antithrombotic therapy.

Self-Assessment Questions Self-assessment questions are available online at www.accp.com/am


Secondary Stroke Prevention: What’s New?

Susan C. Fagan, Pharm.D., FCCP

Jowdy Professor / Associate Head / Assistant Dean

University of Georgia

Conflicts of Interest

Dr. Fagan is a consultant for Pfizer, Inc and Genentech, Inc.Dr. Fagan receives research funding from NINDS and VA Merit Review

Objectives

Discuss changes in Acute Stroke Treatment and the 2010 Secondary Stroke Prevention Guidelines.

Examine the literature supporting these Examine the literature supporting these changes.

Make recommendations for stroke prevention in specific disease states/ conditions.

Stroke Facts

795,000 strokes per year in U.S.

Every 40 seconds, someone in the US has a stroke

87% ischemic

Blacks and Mexican Americans have higher stroke incidence than whites.

More women than men die of stroke each year

Heart Disease and Stroke Statistics – 2010 Update, American Heart Association

Self Assessment Question

What is the NEW treatment window for use of intravenous tPA in ischemic stroke?

a. < 3 hours

b < 6 hoursb. < 6 hours

c. < 4.5 hours

d. < 3.5 hours

The Story of tPA: Bench to Bedside in Record Time (7 years!)

1979: Purification of tPA from Bowes melanoma cell line 1981: Renal allograft patients treated with melanoma tPA 1982: Cloning of tPA and expression in mammalian line

(CHO) by Diane Pennica PhD at Genentech(CHO) by Diane Pennica, PhD, at Genentech 1983: Acute MI patients treated with melanoma tPA 1984: First patient treated with FDA-approved tPA (CHO) 1980s: Large clinical trials in acute MI patients 1987: FDA approval of tPA for acute MI 1996: FDA approval of tPA for acute ischemic stroke

tPA, tissue plasminogen activator; CHO, Chinese hamster ovary; MI, myocardial infarction.Collen D, Lijnen HR. Arterioscler Thromb Vasc Biol. 2009;29:1151-1155.

2011 ACCP Annual Meeting


The One FDA-Approved Drug (1996): Tissue Plasminogen Activator (tPA)

3-hour window (FDA label)

Only 2% to 4% of patients with ischemic stroke receive it

Leads to recanalization in only about 50% of patients

Can the Time Window for tPAbe Extended Beyond 3 Hrs?

OR, odds ratio; CI, confidence interval.Bernstein R, Futterer S. Lancet. 2004;363:368-374.

ECASS III(3.0 to 4.5–hour window)

Inclusion Criteria• Acute ischemic stroke• Age: 18 to 80 years• 3.0 to 4.5 hours• Stroke symptoms present for 30 minutes

ECASS, European Cooperative Acute Stroke Study.Hacke W et al. N Engl J Med. 2008;359:1317-1329.

ECASS III ICH

ICH, intracranial hemorrhage; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study; NINDS, National Institute of Neurological Disorders.Hacke W et al. N Engl J Med. 2008;359:1317-1329.

Expansion of the Time Window for Treatment of Acute Ischemic Stroke With IV tPA

A Science Advisory From the American Heart Association/American Stroke Association

rtPA should be administered to eligible patients who can be treated in the time period of 3.0 to 4.5 hours after stroke (Class I Recommendation, Level of Evidence B) Exclude patients with previous stroke and diabetes, age > 80 years, oral

anticoagulation, NIHSS > 25

IV, intravenous; rtPA, recombinant tissue plasminogen activator; NIHSS, National Institutes of Health Stroke Scale.del Zoppo GJ et al. Stroke. 2009;40:2945-2948.

Still: Earlier the Better



Strategies to Increase Recanalization Rates

IV Pharmacological tPA (FDA-approved)1

Tenecteplase,2 desmoteplase3

Monoclonal antibodies to antiplasmin4 Monoclonal antibodies to antiplasmin4

Intra-Arterial (Invasive) Pharmacological5

Mechanical6

Merci (FDA device approval)

Penumbra (FDA device approval)1. Wolpert S et al. AJNR Am J Neuroradiol. 1993;14:3-13. 2. Hacke W et al. Stroke. 2005;36:66-73. 3. Haley E et al. Stroke. 2005;36:607-612. 4. Nagai N et al. Blood. 2001;97:3086-3092.5. IMS Study Investigators. Stroke. 2004;35:904-911. 6. Gupta R et al. AJNR Am J Neuroradiol. 2006;27:521-523.

Secondary Prevention of Ischemic Stroke and TIA

Risk of Recurrent Stroke

• People who have already suffered an ischemic stroke or TIA are at highest risk of a second stroke or death

• Approximately 17% of strokes are second strokes

• Second stroke risk is highest in the 7 daysfollowing the event

American Heart Association. Heart Disease and Stroke Statistics 2003 update.Sacco RL et al. Stroke. 1998; 29(10): 2118-24.

German Stroke Databank.

Recurrent Vascular Events

Patients who suffer ischemic strokes who have a recurrent vascular event in the first 3 years, 80% of time will have a stroke, 20% an MI

Patients who suffer an MI, who have a recurrent vascular event in the first 3 years, 80% of the time will have a recurrent MI, 20% of the time a stroke

Stroke published online October 21, 2010; Stroke 2011;42:00-00

Components of Secondary Prevention

Blood pressure control

Diabetes management

Lipid management

Smoking cessation

Alcohol moderation

Weight reduction / Physical activity

Carotid Artery Interventions

Antiplatelet agents / anticoagulants

Statins

Diuretics +/- ACE inhibitors



Self Assessment Question

Which comorbidity would lead to a recommendation (ASA guidelines) of warfarinfor secondary stroke prevention?

a Vertebral dissectiona. Vertebral dissection

b. Atrial fibrillation

c. Patent foramen ovale (PFO)

d. Diabetes

2010 Guidelines: New

BP: choice of agents based on co-morbidities

Diabetes: use existing id li (i t d f

Intracranial stenosis: ASA 50-325 mg daily with risk factor reduction

Atrial fib: noguidelines (instead of <7%)

Lipids: reduce LDL at least 50% or target <70

Metabolic syndrome: risk reduction

Atrial fib: no clopidogrel + ASA; bridging OK

Antiplatelet: no new recs; removal of preference statements

Furie et al. Stroke published online October 21, 2010; Stroke 2011;42:00-00

2010 Guidelines: New

Dissection and PFO: antiplatelet vs anticoag unknown

Fabry’s disease:

Anticoag after ICH: restart warfarin after 7-10 days in high risk patientsy

alpha galactosidase enzyme replacement


Stroke Prevention - NoncardioembolicASA 2010 Recommendations

For patients with noncardioembolic ischemic stroke or TIA, antiplatelet agents are recommended rather than oral anticoagulation to reduce the risk

f t t k d th di l tof recurrent stroke and other cardiovascular events (Class I, Evidence A).


IMPACT OF PROFESSIMPACT OF PROFESS

Sacco RL et al. N Engl J Med 2008;359:1238-1251





PROFESS Outcomes

Recurrent stroke rate Clopidogrel: 8.8% IS: 7.9%; Hem: 0.4%

Aggrenox: 9.0% IS: 7.7%; Hem: 0.8%

Composite outcomes: Composite outcomes: stroke, stroke/death, death

Clopidogrel: 13.1%

Aggrenox 13.1%


Atrial FibrillationASA 2010 Recommendations

For patients with ischemic stroke or TIA with persistent or paroxysmal (intermittent) AF, anticoagulation with a vitamin K antagonist (target INR 2.5, range 2.0 to 3.0) is recommended (Class , g ) (I, Evidence A).

For patients unable to take oral anticoagulants, aspirin alone is recommended (Class I Evidence A).


Updated Atrial Fibrillation Guidelines - 2011 Dabigatran is an alternative to warfarin (Class

I, Level of Evidence B)

NOT for patients with prosthetic valves or hemodynamically significant valve diseasehemodynamically significant valve disease

NOT for patients with CrCl <15 mL/min

NOT for patients with advanced liver disease (altered clotting fxn)

Wann LS et al. Circulation 2011;123:1144-1150

Evidence

Original ArticleDabigatran versus Warfarin in Patients with Atrial Fibrillation

Stuart J. Connolly, M.D., Michael D. Ezekowitz, M.B., Ch.B., D.Phil., y, , , , , ,Salim Yusuf, F.R.C.P.C., D.Phil., John Eikelboom, M.D., Jonas Oldgren, M.D., Ph.D., Amit Parekh, M.D., Janice Pogue, M.Sc., Paul A. Reilly, Ph.D., Ellison Themeles, B.A., Jeanne Varrone, M.D., Susan Wang, Ph.D., Marco Alings, M.D., Ph.D., Denis Xavier, M.D., Jun Zhu, M.D., Rafael Diaz, M.D., Basil S. Lewis, M.D., Harald Darius, M.D., Hans-Christoph Diener, M.D., Ph.D., Campbell D. Joyner, M.D., Lars Wallentin, M.D., Ph.D., and the RE-LY Steering Committee and InvestigatorsN Engl J Med 2009; 361:1139-1151September 17, 2009



Dabigatran vs. warfarin for A. Fib

Connolly SJ et al. N Engl J Med 2009;361, August 30, 2009

Dabigatran and stroke prevention May offer options for secondary prevention

(20% of patients in RELY had prior stroke or TIA)

150 mg twice daily 150 mg twice daily

What about patients having an event on dabigatran? Thrombolysis?

Connolly SJ et al. N Engl J Med 2009;361, August 30, 2009

Self Assessment QuestionWhich surgical procedure has been shown to

reduce the risk of stroke recurrence ?

a. Carotid endarterectomy

b PFO closureb. PFO closure

c. Carotid stenting

d. Intracranial stenting

e. A and C

Stenting versus Endarterectomyfor treatment of Carotid Artery Stenosis 2502 patients with symptomatic or asymptomatic

carotid artery stenosis randomized and followed for a median of 2.5 y

Primary endpoint: stroke, MI or death within the periprocedural period OR ipsilateral stroke withinperiprocedural period OR ipsilateral stroke within 4 years of follow up

No difference in primary endpoint: 7.2 vs 6.8% (stenting vs CEA, resp) (p=0.51)

More strokes in stenting group, more periprocedural MIs in the CEA group

Brott TG et al. N Engl J Med 2010; May 26

Brott TG et al. N Engl J Med 2010; May 26

Summary

Window for IV tPA is now 4.5 hours, with additional exclusion criteria

Many patients receive endovascular interventions acutely

Emphasis on neurorestoration Emphasis on neurorestoration Antiplatelet preference leaning back toward ASA High intensity statin therapy favored Dabigatran offers new options for a.fib patients Carotid endarterectomy still preferred for

patients with carotid stenosis but stenting an option (esp in younger patients)



When is a new medication better than the tried and true? Use of dabigatran in atrial fibrillation for stroke prevention

Asha L. Tata, Pharm.D. BCPSInternal Medicine Clinical Pharmacy Specialist

University of Maryland Medical Center

Conflicts of Interest

No conflicts to disclose

Objectives

Compare and contrast the pharmacology of dabigatran versus warfarin

Summarize efficacy, safety, and Summarize efficacy, safety, and pharmacoeconomic data for dabigatran

Describe the place in therapy for dabigatran in the treatment of atrial fibrillation

Atrial Fibrillation (AF)

Affects more than 1% of general population with prevalence increasing with age

Independent risk factor for ischemic stroke Increased morbidity and mortality compared with non-AF Increased morbidity and mortality compared with non AF

related strokes

Economic burden Estimated indirect and direct costs $66 billion annually

Antiplatelet agents and vitamin K antagonists mainstay of anticoagulation therapy in AF

J Am Coll Cardiol 2010;56:2067-76.

Risk Assessment: Stroke

CHADS2

Risk Factor Score

CHF 1

HTN 1

DM 1

CHA2DS2-VAScRisk Factor Score

CHF 1

HTN 1

Age ≥ 75 2DM 1

Age > 75 1

Stroke/TIA 2

Maximum score 6

Age ≥ 75 2

DM 1

Stroke, TIA, or thromboembolism

2

Vascular disease 1

Age 65-74 years 1

Sex category 1

Maximum score 9

0 – No antithrombotic therapy1 – Oral anticoagulation or antiplatelet therapy≥2 – Oral anticoagulation

Stroke 2010;41:2705-13.Curr Cardiol Rep 2011;13:9-17.

Risk Assessment: Bleeding

HAS-BLEDRisk Factor Score

HTN 1

Abnormal renal and liver function (1 point each)

1 or 2

Stroke 1Stroke 1

Bleeding tendency 1

Labile INRs (if on warfarin) 1

Elderly (age > 65 years) 1

Drugs or alcohol (1 point each) 1 or 2

Maximum score 9≥4 – High risk2-3 – Moderate risk0-1 – Low risk

Curr Cardiol Rep 2011;13:9-17.



Vitamin K Antagonists for AF

Superior to placebo and antiplatelet agents in patients at moderate-high risk of stroke

Underutilized, especially in elderly patientsp y y p Fear of bleeding

Fall risk

Patient with CHADS2 score of 3 would have to fall ~295 times in a year to outweigh warfarin benefit

Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA) indicates that elderly patients benefit from anticoagulation therapy

Stroke 2010;41:2705-13.Curr Cardiol Rep 2011;13:9-17.

New Anticoagulants

VTE prophylaxis post orthopedic surgery

VTE treatment

Atrialfibrillation

Arterial disease

Other potential indications

Dabigatran: Ideal Anticoagulant?

Ideal Anticoagulant Warfarin Dabigatran

Oral administration + +

Fixed dosing - +

Predictable PK - +

Rapid onset/offset of action - +

N d f d i t tiNo drug or food interactions - +

No routine monitoring - +

Low risk of hemorrhage - +/-

Use in severe liver disease

- ?

Use in severe renal disease

+ ?

Available antidote + -

Inexpensive + -

Circulation 2011;123:1436-50.

Dabigatran (Pradaxa®)

Approved by FDA October 2010 for non-valvular AF

Mechanism of action

Prodrug

P t t titi ibl di t i hibit f th Potent, competitive, reversible direct inhibitor of the active site of thrombin

Formulation

Capsule containing tartaric acid pellets

Dispense in original manufacturer’s bottle and use within 30 days

Pradaxa® Product Information.Circulation 2011;123:1436-50.Am J Health-Syst Pharm 2011;68:1506-19.Ann Pharmacother 2011;45:603-14.

Dabigatran (Pradaxa®)Pharmacokinetics

Absorption Time to peak 0.5-2 hours

Time to steady state ~ 3 days

Bioavailability 3-7%

Distribution 35% protein bound

Vd 50-70L

M t b li Bioavailability 3-7% Ingestion of pellets can

increase by 75%

High-fat meal delays time to Cmax by 2 hours

Metabolism Not mediated by CYP450

P-gp substrate

Elimination 80% renal

T1/2 12-17 hoursPradaxa® Product Information.Circulation 2011;123:1436-50.Am J Health-Syst Pharm 2011;68:1506-19.Ann Pharmacother 2011;45:603-14.

Dabigatran (Pradaxa®)

Dosing CrCl > 30 mL/min – 150 mg orally twice daily

CrCl 15-30 mL/min – 75 mg orally twice daily

CrCl < 15 mL/min or dialysis – no recommendations

D i t ti Drug interactions Avoid with P-gp substrate inducers

No dose adjustments required for P-gp inhibitors

Proton pump inhibitor interaction not clinically significant

Adverse reactions Dyspepsia

Gastrointestinal bleeding

Pradaxa® Product Information.Circulation 2011;123:1436-50.Am J Health-Syst Pharm 2011;68:1506-19.Ann Pharmacother 2011;45:603-14.



Dabigatran (Pradaxa®)Conversion

Conversion Recommendation

From warfarin Discontinue warfarin and start dabigatran when INR < 2

CrCl > 50 mL/min start warfarin 3 days before discontinuing dabigatran

CrCl 31-50 mL/min start warfarin 2 days before discontinuing dabigatran

To warfarindiscontinuing dabigatran

CrCl 15-30 start warfarin 1 day before discontinuing dabigatran

CrCl < 15 mL/min no available recommendations

From parenteral anticoagulantStart dabigatran 0-2 hours before next dose of SC

parenteral agent or at time of discontinuation of continuously administered parenteral agent

To parenteral anticoagulantWait 12 hours (CrCl ≥ 30 mL/min) or 24 hours

(CrCl < 30 mL/min) after last dose of dabigatran

Pradaxa® Product Information.

Dabigatran (Pradaxa®)Anticoagulant Effects

PT aPTT TT ECT

Coagulationactivity

Extrinsic pathway

Intrinsicpathway

Direct thrombin activity in plasma

Thrombin generation

R l ti hi tRelationship to concentration

Linear Curvilinear Linear Linear

Sensitivity Lacks Less Extreme Precise

Commercialavailability

Yes Yes Yes No

Circulation 2011;123:1436-50.Am J Health-Syst Pharm 2011;68:1506-19.Neurocrit Care. 2011 Jul 12. [Epub ahead of print]

PT – prothrombin timeaPTT – activated partial thromboplastin time

TT – thrombin timeECT – ecarin clotting time

Dabigatran (Pradaxa®)Reversal

Mild bleeding Moderate-severe bleeding

Life-threatening bleeding

Delay dose or discontinue as appropriate

Symptomatic treatment

Mechanical compression

Surgical intervention

Fluid replacement

Hemodynamic support

Blood product transfusion

Oral charcoal

Hemodialysis

rFVIIA

PCC

Charcoal filtration

Circulation 2011;123:1436-50.Neurocrit Care. 2011 Jul 12. [Epub ahead of print]

Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)

Multicenter

Prospective 18 113 ti t

Dabigatran 110mg BIDProspective

Open-label

Randomized

Blinded evaluation

Noninferiority

18, 113 patients with non-valvular AF and at least 1 stroke risk factor

BID

Dabigatran 150mg BID

Warfarin INR 2-3

Primary study outcome: stroke or systemic embolismPrimary safety outcome: major hemorrhage2 year duration

Am Heart J 2009;157:805-10.N Engl J Med 2009;361:1139-51.

RE-LYPrimary Efficacy and Safety Outcomes

EventDabigatran

110 mg(n = 6015)

Dabigatran 150 mg

(n = 6076)

Warfarin (n = 6022)

Dabigatran 110 mg vs.

warfarin

Dabigatran 150mg vs. warfarin

%/year Relative risk, p-value

Stroke or 0 90 0 65Stroke or systemic embolism

1.54 1.11 1.710.90

(0.74-1.10), 0.30

0.65 (0.52-0.81),

<0.001

Major bleeding

2.87 3.32 3.570.80

(0.70-0.93),0.003

0.93 (0.81-1.07),

0.32

Myocardial infarction

0.82 0.81 0.641.29

(0.96-1.75), 0.09

1.27 (0.94-1.71),

0.12

N Engl J Med 2010;363:1875-76.

RE-LYSecondary Outcomes

Hemorrhagic stroke significantly lower in dabigatran groups

Death from any cause similar among all groups

Life-threatening, intracranial, and major or minor bleeding significantly l i d bi tlower in dabigatran groups

Gastrointestinal bleeding significantly higher in dabigatran 150mg group

Dyspepsia more common in the dabigatran groups

Rates of discontinuation at 1 and 2 years higher in dabigatran groups

N Engl J Med 2009;361:1139-51.



RE-LYConclusions

Rates of stroke and systemic embolism with both doses of dabigatran noninferior compared to warfarin

Dabigatran 110mg dose noninferior to warfarin with lower rates of major hemorrhagelower rates of major hemorrhage

Dabigatran 150mg dose superior to warfarin with similar rates of major hemorrhage but higher rates of gastrointestinal bleeding

N Engl J Med 2009;361:1139-51.

RE-LY Sub-analyses

Sub-group Findings

Previous TIA or strokePrimary efficacy and safety outcomes consistent with RE-LY in patients with

previous TIA or stroke

Previous vitamin K antagonistVitamin K antagonistnaïve vs. experienced

Previous vitamin K antagonist exposure does not influence benefits of dabigatran compared with warfarin

Cardioversion

Frequencies of stroke and major bleeding within 30 days of

cardioversion on dabigatran comparable to those on warfarin

Lancet Neurol 2010;9:1157-63.Circulation 2010;122:2246-53.Circulation 2011;123:141-136.

RE-LY Sub-analyses

Sub-group Findings

Time in therapeutic range (TTR)

For all vascular events, non-hemorrhagic events, and mortality

advantages of dabigatran greater at sites with poor INR control illustrating

local standards affect treatment choice

Bleeding risk in older vs. younger Patients

Both dabigatran doses have lower risks of intracranial and extracranial

bleeding in patients <75 years;In those ≥75 years, intracranial

bleeding risk is lower but extracranial bleeding similar with dabigatran

110mg and higher with dabigatran 150mg

Lancet 2010;376:975-83.Circulation 2011;123:2363-72.

Pharmacoeconomic Data

Outcome WarfarinDabigatran

110mgDabigatran

150mg

Quality-adjustedlife-years (QALYs)

10.28 10.70 10.84

Direct Costs (2008 U.S. dollars)

$143,193 $164,576 $168,398( )

Incremental cost-effectiveness

Ratios (ICERs) compared with

warfarin

NA $51,229 $45,372

Cost-effective alternative to warfarin if dabigatran 150 mg BID treatment daily cost < $13.70

Ann Intern Med 2011;154:1-11.

Pharmacoeconomic Data

Hypothetical cohort of 70- year old patients with AF using cost-effectiveness threshold of $50,000/QALY

Estimated dabigatran cost $9/day with average risk of major hemorrhage ~3%/year

CHADS2 score 0 – aspirin cost-effective

CHADS2 score 1-2 – warfarin cost-effective unless risk of hemorrhage high or INR TTR < 57.1%

CHADS2 score ≥ 3 - dabigatran 150mg BID cost-effective unless INR TTR >72.6%

Circulation 2011;123:2562-2570.

Current Challenges

Administration in hospitalized patients

Acute kidney injury

Non-adherent patients

Cost



Unresolved Issues

Long term efficacy Attainment of therapeutic

INRs in real life compared to clinical trials

Long term safety

Underweight/obese patients

Severe renal and hepatic impairment

Drug interactions Long term safety Rebound thrombosis

Myocardial infarction

Hepatotoxicity

Reversal

Drug interactions

Role of 75mg and 110mg doses

Use in other indications

Comparison to oral Factor Xa inhibitors

Circulation 2011;123:1436-50.Am J Health-Syst Pharm 2011;68:1506-9.Ann Pharmacother 2011;45:603-14.

Patient Case

82 yo AAF with PMH significant for HTN, AF, and severe dementia. Patient’s laboratory values are all WNL. Patient had been stable on warfarin for the past 10 years but over the past month has been refusing bloodwork. Your physician colleagues ask you your opinion in p y g y y pmanaging her anticoagulation. What is your recommendation?

A) Switch to aspirin 81mg daily

B) Switch to aspirin 81mg daily + clopidogrel 75 mg daily

C) Switch to dabigatran 150 mg twice daily

D) Discontinue anticoagulation given patient’s age and dementia

Place in Therapy

ACCF/AHA/HRS 2011 focused update recommendation Dabigatran is useful as an alternative to warfarin for the

prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent 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 (C Cl 15 L/ i ) d d li di (i i d b li(CrCl <15 mL/min), or advanced liver disease (impaired baseline clotting function). (Level of Evidence: B)

Alternative to warfarin in moderate-high risk patients with: Difficulty achieving therapeutic INRs

Inability obtaining regular INR monitoring

Low risk for gastrointestinal bleeding

Low risk for cardiovascular events

Circulation 2011;123:1144-50.

Conclusions

Anticoagulation is the mainstay of treatment in AF with risk assessment for stroke and bleeding essential in individualizing therapy

Warfarin should continue to be used as the first line anticoagulant in most patients

Dabigatran offers an alternative in a small niche of patients who are poor candidates for warfarin

When is a new medication better than the tried and true? Use of dabigatran in atrial fibrillation for stroke prevention

Asha L. Tata, PharmD BCPSInternal Medicine Clinical Pharmacy Specialist

University of Maryland Medical Center



Quality initiatives of anticoagulant safety: attacking the coagulation cascade,

SAFELY

William Dager, Pharm.D., BCPS (AQ Cardiology) g , , ( Q gy)FCCP, FCSHP, FCCM, FASHP

Pharmacist Specialist, UC Davis Medical Center

Clinical Professor of Pharmacy, UC San Francisco School of Pharmacy

Clinical Professor of Medicine, UC Davis School of Medicine

Affiliate Faculty, ACLS American Heart Association

Objectives

Improve medication management in secondary stroke prevention and in patient with atrial fibrillation

Describe the pharmacist’s role in enhancing anticoagulation safety in the hospital

Provide dosing guidelines or protocols for the management of antithrombotic therapy

Thrombosis Management and Prevention: Why is Anticoagulation therapy oversight important?

ADE / Safety Concerns• UFH/Warfarin/LMWH → High incidence of Medication errors

Growing Science/Options Multi-disciplinary Component Financial Impact Pay for Performance: SCIP guidelines The Joint Commission

• VTE and Stroke Measures• Safety Goal 3E

Expanding Management Considerations• CMS outpatient follow-up

Challenges Faced in providing safe anticoagulation

Unfunded mandates

Budgets are shrinking

Prioritizing resources to meet basic patient carePrioritizing resources to meet basic patient care services

Creating successful systems, and identifying/training healthcare professionals to provide optimal, safe anticoagulation management

Stroke Core Initiatives

STK-1 - # of patients with stroke who have VTE prophylaxis or documentation of reason for no prophylaxis

STK-3 - # of ischemic stroke patients with a fib/flutter discharged home on anticoagulation

Patient Safety Goals

NPSG.03.05.01 Reduce the likelihood of patient harm associated with the use of anticoagulant therapy.

Note: This requirement applies only to hospitals that provide anticoagulant therapy and/or long-term anticoagulation prophylaxis (i.e. Atrial Fibrillation) where the clinical expectation is that the patient’s laboratory values for coagulation will remain outside y gnormal values.

This requirement does not apply to routine short-term prophylactic anticoagulation against VTE if the clinical expectation is that the patient’s laboratory values for coagulation will remain within, or close to, normal values.

Pre-Publication Version © 2009 by the Joint Commission on Accreditation of Healthcare Organizationshttp://www.jointcommission.org/NR/rdonlyres/122D9A33-6540-4B73-9D7A-F8B26C32A8CA/0/HAP_2010NationalPatientSafetyGoals_PrePub_20090909.pdf



Anticoagulation Safety GoalsChanges for 2010 Deleted requirement for written description (policy) of the program

Changed requirement for a baseline INR to a baseline assessment of anticoagulation status

Changed requirement for dietary notification to use of “authoritative ”resources”

Clarified educational requirements

Changes for 2011 A written policy addresses baseline and ongoing laboratory tests that

are required for heparin and low molecular weight heparin therapies anticoagulants.

• Applies to Warfarin, UFH and LMWH only

Joint Commission Perspectives®, August 2010, Volume 30, Issue 8 Copyright 2010 Joint Commission on Accreditation of Healthcare Organizations

NPS.03.05.01 2. Use approved protocols for the initiation and maintenance of anticoagulant therapy.

Is it drug dosing specific, or systems approach?

- How are anticoagulant orders initiated and managed

Challenges with warfarin dosing protocolsA patient (CHADS2 = 5 and CKD IV) arrives with a small GI

Bleed, gets 10mg SQ vitamin K x 3 days. INR = 1.2 after doubling the home warfarin dose for 5 days.

A AF patient with a recent ischemic stroke and ICH requiring a heparin drip. Baseline INR of 1.8

A patient gets 5mg of warfarin and has a INR of 1.5 the next day (with aPTT > 150). 3mg of warfarin is given and the next day INR is 1.0. Amiodarone and Metronidazole are ordered.

Proposed Stroke CMS measures Future CMS measures - Collection begins in 2013 FY2015 Proposed additions from CMS

Stroke Measure set STK-1 VTE Prophylaxis

STK 2 A i h b i h f i h i k STK-2 Antithrombotic therapy for ischemic stroke STK-3 Anticoagulation therapy for A fib/flutter STK-4 Thrombolytic therapy for acute ischemic stroke STK-5 Antithrombotic therapy by the end of hospital

day 2 STK-6 Discharged on statin STK-8 Stroke education STK-10 Assessed for rehab

ACCP 2008 Guidelines for Stroke Prevention in AF

Risk category Prior ischemic stroke, TIA, or

systemic embolism, or history of mitral stenosis (valvularAF) or prosthetic

≥ 2 stroke risk

factors†

Only 1 stroke risk

factor†

Age ≤ 75 years and no other stroke risk

factors†

AF), or prosthetic heart valve*

Recommended therapy

Warfarin (INR 2-3)

Warfarin (INR 2-3)

Warfarin (INR 2-3) or daily ASA 75–325 mg

Daily ASA 75-325 mg

*INR target may be higher than 2-3 for patients with prosthetic heart valves†Stroke risk factors—age > 75 years, history of hypertension, diabetes mellitus, and moderately or severely impaired left ventricular systolic function and/or heart failure

Singer DE, et al. Chest 2008;133:546S-592S.

ACC/AHA/ESC 2006 Guidelines for the Management of Patients

with AF Risk category Any high-risk factor* or more

than 1 moderate-risk factor†

One moderate-risk factor†

No risk factors

R d d W f i W f i (INR D il ASARecommended therapy

Warfarin (INR 2-3)

Warfarin (INR 2-3) or daily

ASA 81–325 mg

Daily ASA 81–325 mg

*High-risk factors—previous stroke/TIA/embolism, mitral stenosis, prosthetic heart valve (INR target may be higher than 2-3)†Moderate-risk factors—age ≥ 75 years, hypertension, heart failure, left ventricular ejection fraction ≤ 35%, diabetes mellitusDabigatran: Alt to Warf. (Persistent/Paroxysmal AF) and CVA risk but no prosthetic heart valve or severe renal/hepatic Dz)

Fuster V, et al. Circulation 2006;114:e257-e354; Wann LS et al. Heart Rhythm 2011;8:e1-8.

AHA 2010 Stroke Guidelines for the Management of Patients with AF

CVA plus AF High Risk (CHADS – 5-6)

Thrombus on ECHO

Recommended VKA LMWH Bridge VKAtherapy (INR 2-3)

gto VKA is reasonable

(INR 2-3)

Ref. Furie KL Circulation 2010



Centralizing Experience: Financial Impact

Need for Hospitalization LOS ADE Cost of care

• Over-reversalH h• Home therapy

• Drug acquisition• Excessive Assays

Billing for service: Internist for surgical patients

Implementing and Assessing Anticoagulation Therapy

Patient/Condition

Outcomes

ProphylaxisTreatment

Thrombosis BleedingADECosts

DosingInteractionsDual-Triple therapyE id l/S i l

Ordering

UFH

LMWH

DTI

Monitoring

Pump SettingsCompatibilityAdministration Schedule (q___ “hr”)

IV Admixture ProcessRelease to Pyxis

aPTT , INRHgb, PltTiming

Epidural/Spinal Baseline Labs

Administration

aPTT = activated partial thromboplastin time; Hgb = hemoglobin; INR = International Normalized Ratio; Plt = platelets.

Preparation

ASA

ANTI-PLATELET

Improving medication management in secondary stroke prevention

Risk of thrombosis

Risk assessment Score: CHADS, CHA2DS2VASc ECHO observationsECHO observations

• Not studied as a independent factor

Plan for Therapy• Cardioversion, Ablation, Rate, Rate/Rhythm or Rhythm

control

Gage B et al JAMA. 2001;285: 2864-2870Lip GY, et al. Chest 2010;137:263-272

Improving medication management in secondary stroke prevention

Risk for Bleeding

HASBLED Score HASBLED Score Use of a anticoagulant How falls is to high of a risk Are independent factors for falls considered?

Lip G Chest 2010; 138(5):1093–1100

AF: Considerations for Bridging Having a Stroke on my watch is a very bad thing!

• → Clinicians tend to thus “bridge” to warfarin

• Careful planning for invasive procedures

Thrombus typically develops in the cardiac chamber• Aspirin?

• LMWH: What dose?

• UFH: Do I need to bolus? aPTT target?

Is the patient in sinus rhythm?

What is the risk for bleeding?• Any critical issues?

Atrial Fibrillation: LMWH or UFH RCT’s

Stroke: 14 day recurrent stroke rate AF but no warfarin (CHEST 2008: Bridge for high risk patients)

HAEST Dalteparin ASA OR

100 u/kg BID 160mg/day

8.5% 7.5% 1.1 (0.6-2.2)

Saxena UFH 12,500 BID No UFH

2.3% 4.9% 0.5 (0.3-0.8)

HAEST: Lancet 2000; Saxena Stroke 2001



Warfarin Management Considerations in AF

Does the dose need to be aggressive?

Was the INR elevated secondary to a clinical situation?• Considerations with any requested reversal therapy• Considerations with any requested reversal therapy

Is bridging necessary?

Was medication reconciliation accurate to the most recent regimen?

What was given in the hospital?

Potential drug interactions

Quality of Warfarin Management Considerations in AF

Hard outcomes: • Stroke, Bleeding, Hospitalizations, Mortality

Defining good practice• Time in therapeutic range (TTR)

• Standard Deviation of transformed INR etc

Trial RE-LY Rocket AF ARISTOLTE

Drug Dabigatran Rivaroxaban Apixaban

TTR 64% 55% 62%

Lind M et al. Thromb Res 2011; Connolly SJ NEJM 2009;361:1139-51; Ahrens I et al. Thromb Haemost 2011; Granger CB NEJM 2011

Why should AC programs include reversal therapies

Bleeding concern is very high or present• During Procedures (Ablation etc)

The cost of the reversal agent and prolonged length of staylength of stay

Inadequate reversal:• Cost of delayed surgery or avoidable bleeding

• Incorrect use or exposure to short acting agents

Over reversal has risks for:• Prolonged anticoagulation free period

• Need for dual anticoagulants

ASA vs Warfarin to prevent AF related stroke

ASA provides little protection against stroke in AF and is markedly inferior to adjusted-dose (INR 2-3) warfarin therapy

ASA vs Placebo: Pooled analysis of trials

ASA RRR f 21%• ASA – RRR of 21%

• WARFARIN - RRR of 68%

ASA + WARFARIN:

• ↑ major bleeding risk of major bleeding

• No additional protection against ischemic stroke in AF– Possible exception: AF and prosthetic heart valve

replacement Singer DE, et al. Chest 2008;133:546S-592S

Non-Pharmacologic Management Approaches

Procedure Anticoagulation therapy considerations

Cardioversion-TEE

Warf (INR 2-3) x 1-2 months; Bridging

Cardiac Ablation Warfarin - INR 2-3 before, during and post procedureEnoxaparin 0.5 to 1mg/kg Bridge post procedureDabigatran: Avoid during procedure

Cox-Maze III Procedure

Watchman Device May still require anticoagulation

Tying off atrial appendage May still require anticoagulation

How is AC balanced with any reversal strategy

What happens with new anticoagulants

Is the dose correct for the indication?

Any unidentified or missed special populations?• Renal/Age adjustments

• Combined TherapiesCombined Therapies

• Compliance

Drug interactions

Non-Compliance

How do we “…reduce the risk of adverse events associated with the use of these agents.”



Role of Pharmacists in Optimizing Outcomes in AF

Gatekeepers of safe medication use

Medication management• Keep the big picture in mind

.

• Anticoagulation services

• Treat the Patient, not the INR

• Monitor: Antiarrhythmic therapy, Heart Failure, Medications creating fall or bleeding risk

Role of Pharmacists in Optimizing Outcomes in AF

Development of clinical pathways• Optimize patient outcomes

• Standardize where possible, but allow for individualized therapy

.

• Inpatient ↔ Transition ↔ Outpatient

Formulary management• Timely review of new therapies and appropriate

restrictions to ensure therapies are prescribed appropriately and for the right patient based on efficacy, safety, and cost



Documents

Adult Medicine PRN Focus Session—Update on Anticoagulant ... · 1:15 p.m. Secondary Stroke Prevention: What’s New? ... anticoagulation with a vitamin K antagonist (target INR