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Anticoagulation & Atrial Fibrillation

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Scott Bragg

on 22 September 2016

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Transcript of Anticoagulation & Atrial Fibrillation

Anticoagulation &
Atrial Fibrillation

Presented by: Scott Bragg, PharmD
Trident/MUSC Family Medicine Residency
9/22/16

Objectives
Recall important clinical trial evidence for the novel oral anticoagulants (NOACs)

Analyze treatment options to optimize patient outcomes and population based care

Design evidence based regimens for individual patients

What questions do you have?
Dabigatran (Pradaxa)
Reversible, direct thrombin inhibitor

Approved for:
Nonvalvular a fib
DVT/PE treatment and prevention
Hip replacement prophylaxis

Contraindicated with mechanical prosthetic heart valves
Rivaroxaban (Xarelto)
Reversible, direct factor Xa inhibitor

Approved for:
Nonvalvular a fib
Hip and knee replacement prophylaxis
DVT/PE treatment
Long term risk reduction post DVT/PE

No FDA approved reversal agent currently
Apixaban (Eliqius)
Reversible, direct factor Xa inhibitor

Approved for:
Nonvalvular a fib
Hip and knee replacement prophylaxis
DVT/PE treatment
Long term risk reduction post DVT/PE

No FDA approved reversal agent currently
Edoxaban
(Savaysa)
Reversible, direct factor Xa inhibitor

Approved for:
Nonvalvular a fib if GFR is 15–95 mL/min
DVT/PE treatment
Warfarin Clinical Pearls
Anticoagulation Take-aways
Prefer warfarin with: cost issues, heart valves, GFR < 25–30, some bad interactions, med compliance

Prefer apixaban with: labile INR, inconsistent diet, monitoring compliance or need to monitor, some drug interactions

Use CHA2DS2-VASc and HAS-BLED appropriately

Look up when to hold for surgery, bridging, and conversions
Anticoagulation Timeline
NOAC trial data
NOAC
Clinical Pearls
Warfarin Pearls
Anticoagulation take-aways
A fib risk calculation
CHA2DS2-VASc

HAS-BLED
So what do we do...
CHA2DS2-VASc
0 nothing
1 debatable (anticoagulation vs. aspirin/clopidogrel vs. aspirin alone)
≥ 2 anticoagulation
HAS-BLED
≥3 Use caution, review risk regularly, correct reversible factors
Connolly SJ, et al.
NEJM
2009;362:1139-51.
Eikelboom JW, et al.
NEJM
2013;369:1206-14.
What does the evidence tell us?
Connolly SJ, et al.
NEJM
2009;362:1139-51.
Dabigatran 150 mg twice daily showed non-inferiority to dose adjusted warfarin for stroke or systemic embolism

Stroke or systemic embolism was reduced on dabigatran (RR 0.66 95% CI 0.53-0.82)
Hemorrhagic stroke was reduced on dabigatran (RR 0.26 95% CI 0.14-0.49)
MI was increased on dabigatran (RR 1.38 95% CI 1.00-1.91, p=0.048)
Mortality was similar (RR 0.88 95% CI 0.77-1.00, p=0.051)
Major bleeding was similiar (RR 0.93 95% CI 0.81-1.07)
GI bleeding was increased on dabigatran (RR 1.50 95% CI 1.19-1.89)
Important Trial Points
Average CHADS2 score=2.1

Patients on warfarin had 64% of INRs between 2-3

110 mg twice daily dose was not FDA approved

75 mg twice daily dose has no data for safety or efficacy

Study in mechanical heart valves showed increased VTE and bleeding compared to warfarin
Connolly SJ, et al.
NEJM
2009;362:1139-51.
Eikelboom JW, et al.
NEJM
2013;369:1206-14.
Patel MR, et al.
NEJM
2011;365:883-91.
What does the evidence tell us?
Patel MR, et al.
NEJM
2011;365:883-91.
Rivaroxaban 20 mg daily showed non-inferiority to dose adjusted warfarin for stroke or systemic embolism

Stroke or systemic embolism was similiar (HR 0.88 95% CI 0.75-1.03)
Hemorraghic stroke was reduced on rivaroxaban (HR 0.67 95% CI 0.47-0.93)
MI was similiar (HR 0.81 95% CI 0.63-1.06)
Mortality was similiar (HR 0.85 95% CI 0.70-1.02)
Major bleeding was similiar (HR 1.04 95% CI 0.90-1.20)
GI bleeding was increased on rivaroxaban (3.2% vs 2.2%, p<0.001)
Important Trial Points
Average CHADS2 score=3.47

Patients on warfarin had inaccurate INR measurements

Patients with CrCl 30-49 mL/min given 15 mg daily

No trial data for CrCl <30 mL/min
Patel MR, et al.
NEJM
2011;365:883-91.
Granger CB, et al.
NEJM
2011;365:981-92.
What does the evidence tell us?
Aristotle
Apixaban 5mg twice daily showed non-inferiority to dose adjusted warfarin for stroke or systemic embolism

Stroke or systemic embolism was reduced on apixaban (HR 0.79 95% CI 0.66-0.95)
Hemorraghic stroke was reduced on apixaban (HR 0.51 95% CI 0.35-0.75)
MI was similiar (HR 0.88 95% CI 0.66-1.17)
Mortality was reduced on apixaban (HR 0.89 95% CI 0.80-0.998)
Bleeding on apixaban
Major bleeding was reduced on apixaban (HR 0.68 95% CI 0.61-0.75)
GI bleeding was similiar (HR 0.89 95% CI 0.70-1.15)
Granger CB, et al.
NEJM
2011;365:981-92.
Granger CB, et al.
NEJM
2011;365:981-92.
Important Trial Points
Granger CB, et al.
NEJM
2011;365:981-92.
Average CHADS2 score=2.1

Patients on warfarin had 62% of INRs between 2-3

Excluded patients with Scr >2.5 mg/dL or CrCl <25 mL/min

Dose was reduced to 2.5 mg twice daily with 2/3 of the following:
Age ≥80
Body weight ≤60 kg
Scr ≥1.5 mg/dL
What does the evidence tell us?
Edoxaban 60 mg daily & 30 mg daily showed non-inferiority to dose adjusted warfarin for stroke or systemic embolism

Stroke or systemic embolism was similiar: 60 mg (HR 0.87 95% CI 0.73-1.04) & 30 mg (HR 1.13 95% CI 0.96-1.34)
Hemorraghic stroke was reduced: 60 mg (HR 0.54 95% CI 0.38-0.77) & 30 mg (HR 0.33 95% CI 0.22-0.50)
MI was similiar: 60 mg (HR 0.94 95% CI 0.74-1.19) & 30 mg (HR 1.19 95% CI 0.95-1.49)
Mortality was similiar and reduced: 60 mg (HR 0.92 95% CI 0.83-1.01) & 30 mg (HR 0.87 95% CI 0.79-0.96)
Bleeding on edoxaban
Giugliano RP, et al.
NEJM
2013;369:2093-104.
Giugliano RP, et al.
NEJM
2013;369:2093-104.
Giugliano RP, et al.
NEJM
2013;369:2093-104.
Major bleeding was reduced: 60 mg (HR 0.80 95% CI 0.71-0.91) & 30 mg (HR 0.47 95% CI 0.41-0.55)
GI bleeding was increased and reduced: 60 mg (HR 1.23 95% CI 1.02-1.50) & 30 mg (HR 0.67 95% CI 0.53-0.83)
Important Trial Points
Giugliano RP, et al.
NEJM
2013;369:2093-104
.
Average CHADS2 score=2.8

Patients on warfarin had 65% of INRs between 2-3

Excluded patients with CrCl <30 mL/min & not approved w/ GFR > 95 mL/min

Dose was reduced to 1/2 the regular dose:
CrCl 30-50 mL/min
Body weight ≤60 kg
Concomitant potent P-glycoprotein inhibitors
Indirect inhibitor on coagulation factors II, VII, IX, X, protein C, and protein S

Affects PT and thus INR, titrate to goal INRs

Chronic monitoring required every 4-6 weeks
Warfarin Dosing
Initial dosing 2.5-10 mg depending on the patient (use nomogram)

Dose adjust up or down 5-15% of the total weekly dose in chronic anticoagulation

When starting a new med check drug interactions with Lexi-comp or Micromedex

Beware of smoking, EtOH, vitamin K consumption, compliance, and other drugs
INR Monitoring
Always know goal INR (may individualize)

May be affected by other drugs, lupus anticoagulant, etc.

When making changes the drug steady state won't be reflected with INR for 2 weeks

In low risk patients, 10 mg LD x 2 days will decrease time to goal INR by 1.4 days on average
Anticoagulants are like walking on thin ice!
Dosing with liver disease
Use caution with drug-drug interactions
Each label slightly different (effects CYP3A4 and P-glycoprotein)

Bad inducers: rifampin, pheyntoin, St. Johns Wort, carbamazepine

Bad inhibitors: ritonavir, ketoconazole, itraconazole, conivaptan, dronedarone, clarithromycin
Missed doses and stability
Take as soon as possible; if close to next dose ≤6 hours skip (Do not double dose)
Dabigatran has short stability (use open bottle within 4 months)
Surgery recommendations
Conversions
When is warfarin preferred?
Lowest cost
Mechanical heart valves
Bad renal function (GFR< 25–30)
Significant drug interactions with NOACs
Clotting on a NOAC
Diagnosis and Testing
D-dimer
High sensitivity/negative predictive value
AAFP does not recommend with intermediate or high pre-test probability
Confirmatory testing
Helical CT
Ventilation/perfusion scan
Lower extremity ultrasound
Can patients with acute PE be treated safely as an outpatient?
YES!
Compared outpatient vs inpatient treatment in 344 patients

PE severity index of I or II (low risk of death)

No difference in recurrent DVT/PE, bleeding, or death
Aujesky D, et al.
Lancet
2011;378:41-48.
?
Pradaxa
Approved for DVT/PE treatment

Dose 150 mg twice daily
(5-10 days after parental anticoagulation)

Some data on extended DVT/PE treatment, but not approved
Important Trial Points
Xarelto
Approved for DVT/PE treatment and risk reduction for extended DVT/PE treatment

Dose 15 mg twice daily for 21 days, then 20 mg daily
Extended 6-12 months in select patients
Important Trial Points
Apixaban
Approved for DVT/PE treatment and risk reduction for extended DVT/PE treatment

Studied 10 mg twice daily for 7 days, then 5 mg twice daily

Extended for 12 months in select patiets with 2.5 mg or 5 mg twice daily
Important Trial Points
Questions?
The end, for now anyways...
So based on the evidence, which would you choose?
Recurrent DVT/PE prevention with aspirin?
WARFASA (aspirin 100 mg vs placebo)
403 patients with median follow-up 24.6 months
Recurrent VTE was reduced with aspirin (6.6% vs 11.2% per year; HR 0.58; 95% CI 0.36-0.93)
Bleeding was similar (HR 0.98; 95% CI 0.24-3.96)
Becattini C, et al.
NEJM
2012;366:1959-67.
Brighton TA, et al.
NEJM
2012;367:1979-87.
RE-MEDY and RE-SONATE (dabigatran vs warfarin vs placebo)
Recurrent VTE similar to warfarin (HR 1.44; 95% CI 0.79-2.64)
Major bleeding was similar to warfarin (HR 0.52; 95% CI 0.27-1.02)
Pooled analysis of RE-COVER (dabigatran vs warfarin)
Recurrent VTE or death similar with dabigatran (HR 1.09; 95% CI 0.76-1.57)
Major bleeding was similar (HR 0.73; 95% CI 0.48-1.11
Schulman S, et al.
NEJM
2013;368:709-718.
Schulman S, et al.
Circulation
2014;129:764-772.
Bauersachs R, et al.
NEJM
2010;363:2499-2510.
Buller HR, et al.
NEJM
2012;366:1287-1297.
EINSTEIN-EXTENDED (rivaroxaban vs placebo)
Recurrent VTE was reduced (1.3% vs 7.1%; HR 0.18; 95% CI 0.09-0.39)
Bleeding was increased (6% vs 1.2%; HR 5.19; 95% CI 2.311.7)
EINSTEIN-DVT (rivaroxaban vs warfarin)
Recurrent VTE was similar with rivaroxaban (HR 0.68 95% CI 0.44-1.04)
Major bleeding was similar (HR 0.65 95% CI 0.33-1.30)
EINSTEIN-PE (rivaroxaban vs warfarin)
Recurrent VTE was similar (HR 1.12; 95% CI 0.75-1.68)
Major bleeding was reduced (1.1% vs 2.2%; HR 0.49; 95% CI 0.31-0.79)
ASPIRE (aspirin 100 mg vs placebo)
822 patients with median follow-up 37.2 months
Recurrent VTE was similar (HR 0.74; 95% CI 0.52-1.05)
Secondary composite outcome reduced (6% vs 9%; HR 0.67; 95% CI 0.49-0.91)
Bleeding was similar (HR 1.73; 95% CI 0.72-4.11)
Agnelli G, et al.
NEJM
2013;368:699-708.
Agnelli G, et al.
NEJM
2013;369:799-808.
AMPLIFY (apixaban vs coumadin)
Recurrent VTE or death was similar with apixaban (RR 0.84 95% CI 0.60-1.18)
Major bleeding was reduced (0.6% vs 1.8%; RR 0.31 95% CI 0.17-0.55)
AMPLIFY-EXT (apixaban 2.5 mg vs apixaban 5 mg vs placebo)
Recurrent VTE or death was reduced (3.8% vs 4.2% vs 11.6%; HR 0.33 95% CI 0.22-0.48 & HR 0.36 95% CI 0.25-0.53)
Major bleeding was similiar (HR 0.49 95% CI 0.09-2.64 & HR 0.25 95% CI 0.03-2.24)
Category B: enoxaparin, apixaban

Category C: dabigatran, edoxaban, rivaroxaban

Category X: warfarin
Pregnancy Categories
Effects on Hypercoagulable Factors
Effects on Anticoagulant Tests
How Do We Treat Upper Extremity DVT?
Monitoring INR in patients with lupus anticoagulant
> 10% of patients with lupus anticoagulant have false elevations in INR measurements

Chromogenic factor X assay is helpful with erratic INRs
Measures anticoagulation by enzymatic activity of factor X

Can correlate to a specific INR range and thus level of anticoagulation
Rosborough TK, et al. Pharmacotherapy. 2004;24(7):838-842.
No specific recommendations with dabigatran

Don't use rivaroxaban or edoxaban with Child Pugh classes B or C and with any hepatic coagulopathy

Don't use apixaban in Child Pugh class C
Warfarin hold 5 days prior to surgery & check INR (prefer INR<1.4)

Apixaban hold 48 hours prior to major surgery and 24 hours prior to minor surgery

Dabigatran hold 1-2 days with CrCl >50 mL/min and 3-5 days with CrCl <50 mL/min

Rivaroxaban and edoxaban hold at least 24 hours prior to surgery
Warfarin to NOAC:
Start apixaban or dabigatran with INR <2
Start edoxaban with INR ≤2.5
Start rivaroxaban with INR <3
NOAC to warfarin:
Apixaban or rivaroxaban-bridge with LMWH or heparin
Dabigatran-bridge with dabigatran base on renal function
Edoxaban-bridge with edoxaban, dose reduce from 60 to 30 mg or 30 to 15 mg and stop with INR ≥2
NOAC to parental or vice versa: start within 0-2 hours of next scheduled dose
Photo credit: Vincent JL et al: Textbook of critical care, ed 6, Philadelphia, 2011, Saunders.
If symptomatic treat like a lower extremity clot
Do not screen asymptomatic patients
Treatment duration is debatable
Risk of PE varies between 1 to 10%
Photo credit: Mai C, et al. Radiol Clin North Am. 2007;45:513-524.
Savaysa
Approved for DVT/PE treatment

Dose 60 mg daily
(5-10 days after parental anticoagulation)

Dose 30 mg daily if
Patient weigh ≤ 60 kg
Prescribed P-glycoprotein inhibitors (e.g., verapamil, macrolides, azole antifungals)
Individualize treatment duration
Keep an eye out for new guidelines
Consider long-term treatment with: warfarin vs. apixaban vs. rivaroxaban vs. aspirin 81 mg
Duration of Therapy
HAS-BLED should not be used on its own to exclude patients from anticoagulation

Highlights bleeding risk factors that are modifiable (i.e., control BP; remove concomitant antiplatelets, NSAIDs, etc.; maintain stable INRs; counsel on reducing alcohol intake)

Use caution with anticoagulation and review regularly
HAS-BLED Misconceptions
Lane DA, et al.
Circulation. 2012;126:860–865.
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