William E. Dager, Pharm.D., BCPS (AQ-Cardiology), FCCP, FCSHP, FCCM, FASHP

UC Davis Medical CenterSacramento, California

Preventing Stroke in Atrial Fibrillation: Pharmacist Roles in Optimizing Therapy

and Ensuring Patient Safety

• The following faculty and planners report no relationships pertinent to this activity– William E. Dager, Pharm.D., BCPS (AQ-Cardiology), FCCP,

FCSHP, FCCM, FASHP, Faculty– James S. Kalus, Pharm.D., BCPS (AQ-Cardiology), FASHP,

Faculty– Angela R. Raval, Pharm.D., Staff– Carla J. Brink, M.S., B.S.Pharm., Staff

ASHP Advantage staff have no relevant financial relationships to disclose

Disclosures

‒ Assess or reassess the need for anticoagulation therapy and bleeding risk in patients with atrial fibrillation.

‒ Recommend an appropriate target-specific oral anticoagulant for patients with atrial fibrillation, based on critical differences among the options and patient needs.

‒ Develop a plan for ongoing assessment of patients with clinical challenges who are receiving oral anticoagulation for atrial fibrillation.

Learning Objectives

Atrial Fibrillation(AF)

• Most common arrhythmia in U.S.– 9% of patients over age 65 years in the U.S.

• Prevalence increases with age• Risk factors

– Age– Hypertension (HTN)– Heart failure (HF)

• Complications: frequent hospitalizations, hemodynamic abnormalities, and thromboembolic events

January CT et al. J Am Coll Cardiol. 2014 Mar 28. [Epub ahead of print]

Stroke in AF

• AF → Stroke risk 5x higher

• Stroke risk increases with age

• AF-related stroke frequently more severe

January CT et al. J Am Coll Cardiol. 2014 Mar 28. [Epub ahead of print]

Impact of AF on Cost of Treating Stroke

Patients with AF Patients without AFAcute hospitalization $7190 ± 4439* $5838 ± 3662Readmission $1936 ± 5908 $1118 ± 4256Inpatient rehab $2058 ± 3637 $1733 ± 2809Total direct costs $15,575 ± 10,945* $11,638 ± 9571

Mean Cost Per Patient

*p<0.05

Brüggenjürgen B et al. Value Health. 2007; 10:137-43.

‒ Indirect costs (due to loss of productivity) accounted for 18% of total costs

‒ But what about the impact on quality of life?

Therapy Considerations

• Rate and/or rhythm control- Antithrombotic therapy - Regulatory considerations

• Clinical quality measures (VTE prophylaxis)• Stroke core measures• Joint Commission: (2012) Extra care for blood

thinners

• Management of co-morbidities

Regulatory ConsiderationsMeasure DescriptionSTK - 1 Ischemic/hemorrhagic: venous thromboembolism (VTE)

prophylaxis received or documentation why not the day of and day after hospital admission

STK – 2 Ischemic: discharged on antithrombotic therapy(no preferred agent, includes new oral anticoagulants)

STK - 3 Ischemic stroke with AF: prescribed anticoagulation therapy at hospital discharge (new anticoagulants included)

STK - 4 Acute ischemic stroke arriving within 2 hours of onset: IV-tPA (tissue plasminogen activator) initiated within 3 hours of stroke onset

STK - 5 Ischemic stroke received antithrombotic therapy by end of hospital day 2

STK - 6 Discharged on statin medicationSTK - 8 Stroke education providedSTK - 10 Assessed for rehabilitation Related CQM for 2014 - STK 2, STK3, STK 4 (must report 16 of the 29)

http://www.jointcommission.org/assets/1/6/Stroke.pdf (accessed 2014 Jun 25).

Question

Which of the following are included in the CHA2DS2-VASc, but not CHADS2?

a. Female genderb. Prior myocardial infarction (MI)c. Age 65-74 yearsd. All the above

AF Anticoagulation: Risk/Benefit Assessment

Risk for Thrombosis• Stroke Risk Assessment

‒ CHADS2‒ CHA2DS2-VASc‒ Other factors not included

- e.g. Thrombus seen on echo (Smoke), renal impairment

• Other Indications for AnticoagulationRisk for Bleeding Event• Scoring

‒ HAS-BLED‒ HEMORR2HAGES

• Presence of Antiplatelet Agents• Fall Risk

Stroke Risk Stratification in AF

Gage BF et al. JAMA. 2001; 285:2864-70.Lip GYH et al. Stroke. 2010; 41:2731-8.

TIA = transient ischemic attackPAD = peripheral artery diseaseLV = left ventricular

CHADS2 CHA2DS2-VAScHeart Failure (1) CHF/LV dysfunction (1)Hypertension (1) Hypertension (1)Age ≥75 years (1) Age ≥75 years (2)Diabetes (1) Diabetes (1)Stroke/TIA (2) Stroke/TIA (2)

Vascular disease (1)[Prior MI, PAD, or aortic plaque]Age 65 – 74 years (1)Sex Female (1)

CHADS2 CHA2DS2-VASc

2 (4/100 ptyears)

2(2.2%/yr)

4 (8.5/100 pt years)

4 (4%/yr)

2014 AHA/ACC/HRS Atrial Fibrillation Guidelines

Risk Category RecommendationCHA2DS2-VASc = 0 No therapy CHA2DS2-VASc = 1 OAC or ASA or no therapyCHA2DS2-VASc ≥ 2 OACUnstable INR Dabigatran, rivaroxaban, or apixaban

OAC = oral anticoagulant = warfarin, dabigatran, rivaroxaban, apixabanASA = aspirin

January CT et al. J Am Coll Cardiol. 2014 Mar 28. [Epub ahead of print]

Major Hemorrhage in AF:HEMORR2HAGES

• Hepatic or renal disease• Ethanol abuse• Malignancy• Older (> 75 years)• Reduced platelet count/function• Rebleeding risk (2 points) • Hypertension (uncontrolled)• Anemia• Genetic factors (CYP2C9 polymorphisms)• Excessive fall risk• Stroke

*CYP=cytochrome P450

Gage et al. Am Heart J. 2006; 151:713-9.

Total Points 0 1 2 3 4 5 Any Score

Adjusted Risk 1.9 2.5 5.3 8.4 10.4 12.3 18.2

Bleeds per 100 patient years

HAS-BLED Score for Estimating Bleeding Risk in AF

Events Score Major Bleeding H: HTN 1 point 0 points 0.9%

A: Abnormal renal/liver function 1 point each 1 point 3.4%

S: Stroke 1 point 2 points 4.1%

B: Bleeding history/predisposition 1 point 3 points 5.8%

L: Labile INR (TTR <60%) 1 point 4 points 8.9%

E: Elderly (>65 yr) 1 point 5 points 9.1%

D: Drugs†/alcohol 1 point each

TOTAL

Lip GYH et al. J Am Coll Cardiol. 2011; 57:173-80.

†Antiplatelets, NSAIDS, or steroidsTTR - time in therapeutic range

n = 3,665 patients taking warfarin from SPORTIF cohort

Case: Atrial Fibrillation (CHA2DS2-VASc score = 4)

• 85-year-old female patient• New onset AF > 48 hours• ESRD on hemodialysis • Cardiac stent placed 8 weeks ago‒ Taking clopidogrel 75 mg daily and aspirin

325 mg daily

Case Discussion Questions

• Would this patient’s stroke risk be high enough for anticoagulation?

• What agents (including doses) could be used for stroke prophylaxis?

• How would you manage risk associated with the need for antiplatelet therapy?

Anticoagulant Sites of Action on the Common Pathway

X X

Xa

ThrombinProthrombin

Fibrinogen Fibrin

Direct Thrombin InhibitorsDabigatran, ArgatrobanBivalirudin, Lepirudin

Direct Xa Inhibitors (Free and bound Xa)Rivaroxaban , Apixaban,

Edoxaban

Indirect Xa InhibitorsUFH, LMWH

Fondaparinux

Clot Formation

Extrinsic activation pathway Intrinsic activation pathwayVII IXVKA

VKA

VKA

Facilitating Optimal Antithrombotic Therapy

• Cost of therapy (coverage and copay)• Management support• Adherence• Compliance with follow up• Other indications for anticoagulation• Drug/food interactions

– Including antiplatelet agents• Organ function (kidneys, liver)• Quality of life• Success/failure of past therapies• Bleeding risks/needs for reversal

Question Which statement is true?a. Opened dabigatran capsules have no impact on

bioavailabilityb. RE-LY assessed dabigatran 75 mg dosing for renal

dysfunctionc. Rivaroxaban renal dose adjustment depends on indicated

used. Treat paroxysmal AF more aggressively with antithrombotic

therapy than persistent AF

AHA/ACC/HRS 2014 RecommendationsI C Individualized antithrombotic therapy  (stroke, bleeding, patient values/preferences)

I B Antithrombotic selection based on thromboembolism risk, not type of AFI B CHA2DS2‐VASc score preferred

I B Use warfarin if mechanical heart valve present (Avoid dabigatran [III B])

I A Warfarin: INR weekly initially, then monthlyI C Unable to maintain Tx INR on warfarin ‐ use dabigatran, rivaroxaban, apixabanI C Periodic revaluation for stroke to bleeding riskI C AF and mechanical heart valve and procedure: Bridge UFH, LMWH based on risk of 

thrombosis and bleedingI B Assess renal fxn initially and periodically when using for DTI or anti‐Factor Xa agentI C Atrial flutter therapy same as atrial fibrillationIIa B CKD ‐ CrCl < 15 mL/min or hemodialysis – warfarin preferred (NOAC not 

recommended [III C])IIb C CKD – Moderate to severe + CHA2DS2‐VASc ≥ 2 – reduced dose NOAC –

safety/efficacy unknownIIb C PCI required – Consider Bare Metal Stent to minimize dual antiplatelet therapy

Can interrupt during PCI January CT et al. J Am Coll Cardiol. 2014 Mar 28. [Epub ahead of print]UFH – Unfractionated heparin, LMWH – Low molecular weight heparin, INR – International

Normalized Ratio, fxn – function, DTI – direct thrombin inhibitor, CKD – chronic kidney disease, PCI- percutaneous coronary intervention; NOAC – New oral anticoagulant

Warfarin Management Considerations in AF

• Availability and quality of management resources– Other factors: Drug interactions, diet, testing barriers

• Does the dose need to be aggressive?• Was the INR elevated secondary to other factors?

– Considerations with any requested reversal therapy• Is bridging necessary?• Was medication reconciliation accurate to the most recent

regimen, including adherence?• What was given in the hospital?

Antithrombotic Therapy

Aspirin vs. control

Warfarin vs. aspirin

0.73 [0.53 – 1.00]

0.68 [0.54 – 0.85]

0.72 [0.52 – 0.99]

0.53 [0.51 – 0.68]

1.0 2.0 5.0 10.00.50.20.1

Warfarin vs. aspirin

Aspirin vs. control

Stroke or Intracranial Hemorrhage

Ischemic Stroke

0.78 [0.59 – 1.02]

0.99 [0.83 – 1.18]Warfarin vs. aspirin

Aspirin vs. control

Mortality

Aguilar MI et al. Cochrane Database Syst Rev. 2007; (3):CD006186.Aguilar MI et al. Cochrane Database Syst Rev. 2005; (4):CD001925.

Favors aspirin

Favors aspirin

Favors warfarin

Favors warfarin

Pharmacokinetic Comparison: Target Specific Oral Anticoagulants (TSOAs)

Dabigatran Rivaroxaban Apixaban Edoxaban*Target for activity Thrombin (II) Anti-Xa Anti-Xa Anti-XaProdrug Yes No No NoBioavailability 6% (> 80% capsule

opened)> 80% > 50% 62%

Time to peak Cp 2 hr (Delayed by food) 3 hr (Delayed by food) 3 hr 1.5 hr

Half-life 14-17 hr 5-9 hr (Elderly 11-13hr) 9-14 hr 8-10 hrDosing interval Once or twice daily Once daily Twice daily Once dailyRenal excretion 80% 36% 25% 35%Drug interactions P-gp inhibitors or

inducers, PPICYP 3A4P-gp modifiers

CYP 3A4; P-gp modifiers

P-gp modifiers

Gross PL et al. Arterioscler Thromb Vasc Biol. 2008; 28: 380-6.Plitt A et al. J Cardiovasc Pharmacol Ther. 2014 [Epub ahead of print]

*Currently only approved in Japan, review in U.S. is pendingCYP - cytochrome P450; P-gp - P glycoprotein; PPI - proton pump inhibitors; hr – hours; Cp = peak plasma concentration

Atrial Fibrillation TrialsRE-LY

(18,113)ROCKET-AF

(14,264)ARISTOTLE

(18,201)ENGAGE( 21,108)

Agent Dabigatran Rivaroxaban Apixaban Edoxaban*Design Open-label

Non-inferiorityDouble-blindNon-inferiority

Double-blindNon-inferiority

Double-blindNon-inferiority

Inclusion Non-valvular AFCHADS2 > 1

Non-valvular AFCHADS2 > 2

Non-valvular AFCHADS2 > 1

Non-valvular AFCHADS2 > 2

Kidney fxnexclusion criteria

CrCl < 30 mL/min

CrCl < 30 mL/min

Serum creatinine > 2.5 mg/dL or CrCl < 25 mL/min

CrCl ≤ 30 mL/min

Normal dose

150 mg twice daily

20 mg daily 5 mg twice daily High – 60 mg/dayLow – 30 mg/day

Renal dose adjustment

NONE 75-mg dose not studied in patients

CrCl = 30 – 49 mL/min15 mg daily

2.5 mg twice daily if 2 or more of the following: Age > 80 years, body weight <60 kg, SCr > 1.5 mg/dL

½ dose if CrCl 30-50 mL/min or weight < 60 kg

Connolly SJ et al. N Engl J Med. 2009; 361:1139-51; Patel MR et al. N Engl J Med. 2011; 365:883-91.Granger CB et al. N Engl J Med. 2011; 365:981-92; Giugliano RP et al. N Engl J Med. 2013; 369:2093-104.

*Currently only approved in Japan, review in U.S. is pending

Atrial Fibrillation TrialsTrial(N)

RE-LY (18,113)

ROCKET-AF (14,264)

ARISTOTLE (18,201)

ENGAGE( 21,108)

Agent Dabigatran Rivaroxaban Apixaban Edoxaban*Age – mean years 71 73 70 72

CHADS2 ≥ 3 (%) 33 87 30 23

Prior stroke/TIA (%) 20 55 20 28

Heart failure (%) 32 17 15 25Diabetes (%) 23 40 25 36Warfarin use (%) 50 62 57 59ASA randomization (%) ~40 36 31 29ASA concurrently (%) ~ 20 36 NR NR

Connolly SJ et al. N Engl J Med. 2009; 361:1139-51; Patel MR et al. N Engl J Med. 2011;365:883-91; Granger CB et al. N Engl J Med. 2011; 365:981-92; Giugliano RP et al. N Engl J

Med. 2013;369:2093-104; Rosanio S et al. Int J Cardiol. 2014; 174:471-83.

* Currently only approved in Japan, review in U.S. is pendingNR – Not reported

Stroke or Systemic Embolism

1.00.80.60.40.2 1.81.61.41.2

RE-LY150 mg BID arm

RR (95% CI)

0.79 (0.66 – 0.95)

0.66 (0.53 – 0.82)

ROCKET-AF Intention-to-treat analysis presented

0.88 (0.74 – 1.03)

ARISTOTLEEfficacy results driven by reduction in hemorrhagic stroke

non-inferior & superior

non-inferior only

non-inferior & superior

Connolly SJ et al. N Engl J Med. 2009; 361:1139-51; Patel MR et al. N Engl J Med. 2011; 365: 883-91. Granger CB et al. N Engl J Med. 2011; 365: 981-92.

Stroke or Systemic Embolism

1.00.80.60.40.2 1.81.61.41.2

1.38

Low Dose Edoxaban (30mg) vs. Warfarin

GFR 30-50 mL/min, Wt < 60 kg, potent PG inhibitor

RR (95% CI)

0.87 (0.73 – 1.04)

1.13 (0.96 – 1.34)

High Dose Edoxaban (60mg) vs. Warfarin

non-inferior

ENGAGE AF-TIMI 48

non-inferior

Giugliano RP et al. N Engl J Med. 2013; 369: 2093-104.

Quality of Warfarin Management in AF• Hard outcomes

‒ Stroke, bleeding, hospitalizations, mortality • Defining good practice

‒ Time in therapeutic range (TTR)‒ Standard deviation of transformed INR

Trial RE‐LY ROCKET‐AF ARISTOTLE ENGAGEDrug Dabigatran Rivaroxaban Apixaban EdoxabanTTR 64% 

(U.S. 67%)55% (U.S. 63%)

62% 65%

Lind M et al. Thromb Res. 2011; Connolly SJ et al. NEJM. 2009; 361:1139-51; Ahrens I et al. Thromb Haemost. 2011; Granger CB et al. NEJM. 2011; 365:981-92; Giugliano RP et al. NEJM.

2013; 369:2093-104; Wallentin L et al. Lancet. 2010; 376:975-83; Fleming TR et al. NEJM. 2011; FDA.gov; FDA.gov-rivaroxaban and dabigatran reviews.

ROCKET: Different method for calculating TTR; Compliance Warfarin Arm 95%Impact on stroke similar across all TTR ranges in ROCKET-AF and RE-LYDabigatran – greatest benefit over warfarin in centers where INR control was poor

Major Bleeding Rates

2.1

3.09 3.60 3.452.75

3.433.11 3.36

0123456789

10

%/1

00 p

atie

nt y

ears

Apixaban Rivaroxaban Edoxaban Dabigatran

New Agent Warfarin

p < 0.001 p = 0.576 p = 0.31p < 0.001

Connolly SJ et al. N Engl J Med. 2009; 361:1139-51. Patel MR et al. N Engl J Med. 2011; 365:883-91.

Granger CB et al. N Engl J Med. 2011; 365:981-92.Giugliano RP et al. N Engl J Med. 2013; 369:2093-104.

Trial ConclusionsTrial Drug Conclusion  (vs. warfarin)

RE‐LY Dabigatran 150 mg more effective in preventing stroke or systemic embolism without significantly increasing major bleeding

ROCKET‐AF

Rivaroxaban Non‐inferior for preventing stroke or major embolism without significantly increasing major bleeding

ARISTOTLE Apixaban Superior to warfarin in preventing stroke or systemic embolism, reducing bleeding and mortality

ENGAGE Edoxaban 30 mg and 60 mg non‐inferior for the prevention of stroke or systemic embolism, reduced the risk of major bleeding and cardiovascular death

AVERROES Apixaban Apixaban 5 mg BID superior to aspirin 81‐325 mg/dayin warfarin unsuitable patients

Chan NC et al. Thromb Haemost. 2014; 111:798-807.

Indications for UseIndication Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban*

Atrial fibrillation √ √ √ √ Seeking approval

VTE treatment √ √ √ Pending Seeking approval

VTE prophylaxis √ √ (Ortho) √ (Ortho) Seeking Approval (Ortho)

Mechanical valve √ (Avoid)

PAD √

Pediatrics √

Morbid obesity √

Hemodialysis √ √

Ability to reverse √

*Currently only approved in Japan, review in U.S. is pending

PAD – peripheral arterial disease; Ortho – elective orthopedic hip and knee surgery; VTE – venous thromboembolism

Managing Oral Anticoagulants in Selected Clinical Challenges

• What happens in acute illness or organ system changes?

• What is the impact of an interacting drug?‒ Do you make a change if it is started or stopped?

• Need for invasive procedure‒ Type/associated risks

• Switching between agents• Underweight or overweight; organ failure adjustments• Follow-up plans• What should be monitored/measured?• Is there a way to reverse the effects?

Concurrent Antiplatelet TherapyRisk vs. benefit- Are 1-2 antiplatelet agents + oral anticoagulant required?

• Increased risk for bleeding• Shorten duration of triple therapy?

‒WOEST/PRODIGY: Higher rate of any bleeding with triple therapy, no increase in rate of cardiac events with single antiplatelet therapy after 6 months – 1 year

‒Exception may be PCI for in-stent thrombosis• Use lower aspirin doses?

Dewilde WJM et al. Lancet. 2013; 381:1107-15; Valgimigli M et al. Circulation. 2012; 125:2015-26; Campo G et al. J Am Coll Cardiol. 2014; 63:506-12.

Dose Adjustments with AF and Organ Dysfunction

Pradaxa (dabigatran etexilate mesylate) prescribing information (PI). Boehringer Ingelheim Pharmaceuticals, Inc.; 2014 Apr; Xarelto (rivaroxaban) PI. Janssen

Pharmaceuticals, Inc; 2014 Mar; Eliquis (apixaban) PI. Bristol-Myers Squibb Company. 2014 Mar.

Kidney LiverWarfarin Possible small (20%) dose reduction Multiple challengesDabigatran 15 – 30 mL/min – reduced dose (75 mg twice

daily)< 15 mL/min – not recommended

No major issues

Rivaroxaban(indication dependent)

15 – 49 mL/min – reduced dose (15 mg daily)< 15 mL/min – not recommended

Avoid in moderate to severe liver impairment

Apixaban Not specifically: reduced dose (2.5 mg twice daily) if 2 or more of the following – age > 80 years, body weight < 60 kg, serum creatinine > 1.5 mg/dL

Avoid in moderate to severe liver impairment

Apixaban (ESRD on hemodialysis)

5 mg twice daily, reduced to 2.5 mg twice daily if age > 80 years OR body weight < 60 kg

Heart failure?

Drug Interactions• Some have been identified – others never explored• What happens when stacked on other factors influencing the drug? • How should the dose be changed or interacting agent stopped?

Dabigatran Interacting Agents↑ Serum conc. Amiodarone, quinidine, ketoconazole, verapamil, clopidogrel↓ Serum conc. Antacids, atorvastatin, proton pump inhibitors, rifampin (Avoid)

Rivaroxaban Interacting Agents↑ Serum conc. Ketoconazole (160%), ritonavir (150%), clarithromycin (50%), erythromycin (30%);

Others - Conivaptan, diltiazem, verapamil, quinidine, ranolazine, dronedarone, amiodarone, felodipine, itraconazole

↓ Serum conc. Carbamazepine, phenytoin, rifampin, St. John’s wort

Apixaban Interacting Agents↑ Serum conc. Ketoconazole (2x increase in AUC), diltiazem (1.4x AUC increase), naproxen (1.3x

increase in AUC). Not recommended with azoles (ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (ritonavir)

↓ Serum conc. Carbamazepine, phenytoin, rifampin (~50% decrease in AUC), St. John’s wort

Pradaxa (dabigatran etexilate mesylate) prescribing information (PI). Boehringer Ingelheim Pharmaceuticals, Inc.; 2014 Apr; Xarelto (rivaroxaban) PI. Janssen Pharmaceuticals, Inc; 2014 Mar;

Eliquis (apixaban) PI. Bristol-Myers Squibb Company. 2014 Mar.

Question

Which of the following is true?

a. Switching heparin infusion to NOAC requires 12-hr overlap

b. Thrombin time can effectively assess dabigatran presence

c. Vit K immediately reduces prothrombin time elevated by NOAC

d. Place epidural catheter 2-4 hr after administration of NOAC

Surgery/Invasive Procedures • Ability to reverse effects

- Dialysis: dabigatran only

• Laboratory measures to assess adequate loss of activity- Is there a safe measured value to operate?

What can I do?• Medication history• Urgency of surgery• Awareness for complications• Consider bridge therapies as needed

Measuring newer oral anticoagulants

Note: INR/aPTT - Potential for normal values at trough/active levels

What does a value mean?‒ Is it too high where the dose should be lowered?

Dabigatran Rivaroxaban and Apixaban (?Edoxaban)Drug present Thrombin time(TT) ? Chromogenic anti-factor Xa

Quantitative test

? Dilute thrombin time or chromogenic Ecarin clotting time (ECT)

Chromogenic anti-factor Xa

Sensitivity:PT vs. aPTT

aPTT > PT(point-of-care INR > central lab)

Prothrombin time (PT) > aPTT

No or limited effect

ECT, TT

Lindhoff-Last E et al. Ther Drug Monit. 2010; 32; 673-9; Lindahl TL et al. Thromb Haemost. 2011; 105:371-8; van Ryn J et al. Am J Med. 2012; 125:417-20.

van Ryn J et al. Thromb Haemost. 2010; 103:1116-27.

AF: Considerations for Bridging

• Having a stroke on my watch is a very bad thing!‒ But what is the risk of an acute stroke happening?

• 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?• LMWH cost coverage (warfarin patients)?• What is the risk for bleeding?

‒ Any critical issues?

How should I switch between agents?• Rapid acting → rapid acting (switch is rapid)

‒ Consider time to Cp max ‒ NOAC/LMWH: Give when next dose due‒ Eliminate dual effects (avoid stacking)

• Slow acting → rapid acting (warfarin → new agent)‒ Start when there is moderate loss of effect (e.g.,? INR <

1.8/2.0) Note: INR may be elevated by new agent

‒ To UFH/LMWH: Wait 2-5 estimated half-lives• Rapid acting → slow acting (new agent to warfarin)

‒ Measure INR just before next dose‒ Stop new agent when INR at trough > 2.0 or slightly

higher if agent is increasing it (assay dependent)

41

Considerations for Reversing a (2nd Generation) Oral Anticoagulant in Bleeding Patients

Several proposed guidelines – data limited and evolving‒ How much anticoagulation is present, how fast, and degree of reversal‒ Hold drug, monitor and assess, labs (Coag and CBC etc)‒ Activated charcoal if recent ingestion‒ Prothrombin complex concentrate (PCC) may depend on what is available – Reassess 5-10 min

post administration - If time available, start with lower doses and repeat if necessary

Dabigatran Rivaroxaban & ApixabanNo rush, minor bleeding

• Monitor – re-check labs • Monitor – re-check labs

Expedited (1-24 hr), majorbleeding

• Consider PCC4 (25 units/kg) or low dose factor VIII inhibitor bypassing activity (aPCC)

• Consider hemodialysis – and approach to catheter placement (? 8 units/kg aPCCjust prior to placement)

• Evaluate if PCC needed. Consider PCC4 or PCC3 if clinically necessary

• Option: low dose aPCC

Emergent (< 1 hr), majorbleeding

• aPCC 25 units/kg, have next dose ready • Option: PCC4 25-50 units/kg• Arrange hemodialysis

• aPCC 25 units/kg or• PCC4 or PCC3 25-50 units/kg

Nutescu EA et al. Am J Health-Syst Pharm. 2013; 70:1914-29.

Dialysis and Dabigatran• Develop plan for placing dialysis catheter

‒ Site Placement‒ Minimize bleeding risk (? aPCC 8 units/kg)

• Dialyze for several hours at tolerable blood flow (depends on initial INR) – (2/3rd may not be removed in 2-3 hours)

• Slow rate until TT, INR, dabigatran Cp normal to catch tissue re-distribution

Cp

Time

Dialysis

Tissue Rebound

Stangier J et al. Clin Pharmacokinet. 2010; 49:259-68. Wanek MR et al. Ann Pharmacother. 2012; 46:e21. Singh T et al. Clin J Am Soc Nephrol. 2013; 8:1533-9. Khadzhynov D et al. Thromb Haemost. 2013; 109:596-605; Chen BC et al. Am J Kidney Dis. 2013; 62:591-4. Lisenfeld KH et al. Clin Pharmacokinet 2013; 52:453-62.

Importance of Patient Receiving Intended Therapy

• ComplianceAdherence to chronic medications: 43% - 78%ROCKET-AF - Warfarin 95% compliance, no provision

for short bridging to warfarin! Last 2 days of rivaroxaban to 30 days after last dose: 22 vs. 6 strokes

Highlights the importance of patient compliance with the target specific oral anticoagulant (TSOAs), particularly rivaroxaban

• Was warfarin stopped?Avoid “doubling up”Drug alerts

• Medication management‒ Anticoagulation services‒ Monitoring of antiarrhythmic therapy‒ Resolve cost issues

• Development of clinical pathways‒ Optimize patient outcomes ‒ Standardize where possible, but allow for individualized therapy‒ Inpatient ↔ Transition ↔ Outpatient

• Educate patients and providers• 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

Role of Pharmacists in Optimizing Outcomes in AF