Oral Anticoagulation in Patients with Atrial Fibrillation ...cme.uthscsa.edu/Courses/CardioRenal/2017/Online Syllabus/042817/4... · Oral Anticoagulation in Patients with Atrial Fibrillation

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Oral Anticoagulationin Patients with Atrial Fibrillation

and End Stage Renal Disease

Manoj M. Panday, M.D.Head, Section of Cardiac Electrophysiology

Division of CardiologyUT Health San Antonio

Disclosures

• Current consultant agreements with Janssen, Pfizer, Bristol Myers Squibb, Daiichi Sankyo, and Abbott

• Prior consultant agreements with Sanofi-Aventis, Medtronic, Boston Scientific, and Biotronik


Objectives

• Provide a concise review of the indications for thromboembolism prophylaxis in atrial fibrillation

• Discuss the pros and cons of using oral anticoagulation in patients with end stage renal disease

• Provide an overview of the treatment options in patients with atrial fibrillation who are on dialysis

Definition

“AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function.”

Bellet. Clinical Disorders of the Heart Beat. 1971.

AF is characterized by rapid fibrillatory waves that vary in amplitude, shape, and timing, associated with an irregular ventricular response.

Fuster et al. ACC/AHA/ESC Atrial Fibrillation Guidelines. 2006.


Age-Specific Prevalence

Feinberg et al. Prevalence, Age Distribution, and Gender ofPatients with Atrial Fibrillation. Arch Intern Med 1995.

Natural Time Course of AF

ESC Guidelines. European Heart Journal. 2010;31:2369-2429.


Coumadin Clinics23+ million visits

Primary Care Providers

AfibPatients

3.2 millionCardiologists

Emergency Room Strokes/TIAs

NeurologistsStrokes (15%)

Electrophysiologists

CT SurgeonsSleep ClinicsOSA (50%)

Geriatrics

Spectrum of Health Care Professionals

2014 Atrial Fibrillation Guideline


AF Definitions: A Simplified Scheme

Term Definition

Paroxysmal AF • AF that terminates spontaneously or with intervention within 7 days of onset

Persistent AF • Continuous AF that is sustained for > 7 days

Longstanding persistent AF • Continuous AF of > 12 months duration

Permanent AF • Used when there has been a joint decision by the patient and clinician to cease further attempts to restore and/or maintain SR

• Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than a pathophysiological attribute of the AF

Nonvalvular AF • AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair

2014 AHA/ACC/HRS Atrial Fibrillation Guideline.

Selected Risk Factors for AF

• Increasing age

• Hypertension

• Diabetes mellitus

• MI

• Valvular HD

• HF

• Obesity

• Obstructive sleep apnea

• Chronic kidney disease

• Cardiothoracic surgery

• Smoking

• Alcohol use

• Hyperthyroidism

• Increased pulse pressure

• European ancestry

• Family history

• Genetic variants

• LVH

• LA enlargement

• Increased CRP

• Increased BNP


Diet and Clinical Risk• Alcohol

– Consistently increased risk of AF in heavy alcohol drinkers, but no risk associated with moderate alcohol intake

• Caffeine– High coffee intake was not clearly associated with an increased

risk of AF, and a potential lower AF risk in moderate drinkers could exist

• Fish-derived n-3 polyunsaturated fatty acids– High intake from diet or supplements might prevent AF episodes

following cardiovascular events, but no consistent evidence supports an effect in primary prevention

• Ascorbic acid– Oral doses pre and post-CABG reduced AF occurrence from

25% to 4% compared to beta-blockers alone

Gronroos and Alonso. Diet and Risk of Atrial Fibrillation –Epidemiologic and Clinical Evidence. Circ J 2010 Oct.

Dietary Exposures and Pathophysiology

Gronroos and Alonso. Diet and Risk of Atrial Fibrillation –Epidemiologic and Clinical Evidence. Circ J 2010 Oct.


Mechanisms of Atrial Fibrillation

2014 AHA/ACC/HRS Atrial Fibrillation Guideline.

Clinical Case

• 76 yo female with CHF, HTN, DM, ESRD on HD, prior CVA, and CAD

• Patient had a major GIB requiring blood transfusion while in therapeutic range on warfarin

• She had a recurrent GIB on a NOAC

• She has a history of unsteady gait and prior falls


Keskar et al. ClinJ Am SocNephrol. 11: 2085-2092, 2016.

CHADS2 versus CHA2DS2-VASc Score

CHA2DS2-VASc Score

Congestive HF 1

Hypertension 1

Age ≥ 75 2

Diabetes 1

Stroke/TIA/TE 2

Vascular disease (prior MI, PAD, or aortic plaque)

1

Age 65-74 years 1

Sex category (female) 1

Maximum score 9

CHADS2 Score

Congestive HF 1

Hypertension 1

Age ≥ 75 1

Diabetes 1

Stroke/TIA/TE 2

Maximum score 6


CHADS2 versus CHA2DS2-VASc Score

CHA2DS2-VASc Score

Congestive HF 1

Hypertension 1

Age ≥ 75 2

Diabetes 1

Stroke/TIA/TE 2

Vascular disease (prior MI, PAD, or aortic plaque)

1

Age 65-74 years 1

Sex category (female) 1

Maximum score 9

CHADS2 Score

Congestive HF 1

Hypertension 1

Age ≥ 75 1

Diabetes 1

Stroke/TIA/TE 2

Maximum score 6

Our patient: CHA2DS2-VASc score = 9!

Stroke Risk Stratification

CHADS2Score

Adjusted stroke rate(% per year)

0 1.9

1 2.8

2 4.0

3 5.9

4 8.5

5 12.5

6 18.2

CHA2DS2-VAScScore

Adjusted stroke rate(% per year)

0 0

1 1.3

2 2.2

3 3.2

4 4.0

5 6.7

6 9.8

7 9.6

8 6.7

9 15.2

Gage et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864-70. Lip et al. Atrial fibrillation. Lancet.

2012;379:648-61.


HAS-BLED Bleeding Risk Score

*Hypertension is defined as systolic blood pressure > 160 mmHg.

HAS-BLED Bleeding Risk Score

*Hypertension is defined as systolic blood pressure > 160 mmHg.

Our patient: HAS-BLED score = 5


Thromboembolism Prophylaxis

Left Atrial Thrombus

LA Thrombus Video.avi


Risk of Thromboembolism

• AF conveys a 5-fold increase in stroke risk compared with the general population

• 90% of the thrombi found in nonvalvularAF patients and 57% found in valvular AF are in the LAA



Medication Options for Thromboembolism

Prophylaxis

Vitamin K Antagonist – Warfarin


Warfarin Therapy

• Subtherapeutic INR levels (< 2.0) raised the incidence of stroke (RR: 2.39) and arterial thromboembolism (RR: 5.68) compared with therapeutic INR levels.

• Supratherapeutic INR levels (> 3.0) doubled the incidence of intracranial hemorrhage (RR: 2.11).

Walker and Bennett. Epidemiology and Outcomes in Patientswith Atrial Fibrillation in the US. Heart Rhythm 2008 Oct.

Stroke vs. Bleeding with Warfarin Therapy

Hylek and Singer. Risk Factors for Intracranial Hemorrhage in Outpatients Taking Warfarin. Ann Intern Med 1994. Data from Odén et al. Optimal INR for Prevention of

Stroke and Death in Atrial Fibrillation: A Critical Appraisal. Thromb Res 2006.


Aspirin Plus Clopidogrel

• ACTIVE-W (AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events)

– Primary endpoint of stroke, systemic embolism, MI, or vascular death in patients with an average of two risk factors

– 3.93% annual risk with warfarin and 5.60% with aspirin + clopidogrel (RR = 1.44, P = 0.0003)

– Rates of hemorrhage were similar between two groups– Significantly greater minor and total bleeds with aspirin + clopidogrel


• ACTIVE-A (Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation)

– For patients who were deemed unsuitable for warfarin due to specific risk of bleeding, patient preference, or physician preference

– Similar primary endpoint to ACTIVE-W– 3.6 year average follow-up– 6.8% annual risk with aspirin + clopidogrel and 7.6% with aspirin + placebo (RR

= 0.89, P = 0.01)– Difference was primarily due to reduction of stroke by clopidogrel (2.4% versus

3.3%, RR = 0.72, P < 0.001)– Major bleeding occurred in 2.0% with aspirin + clopidogrel versus 1.3% with

aspirin + placebo (RR = 1.57, P < 0.001)



2011 Focused Update Recommendations

Class IIb (Level of evidence B)

The addition of clopidogrel to aspirin to reduce the risk of major vascular events, including stroke, might be

considered in patients with AF in whom oral anticoagulation with warfarin is considered unsuitable due to patient

preference or the physician’s assessment of the patient’s ability to safely sustain anticoagulation.

Wann et al. 2011 ACCF/AHA/HRS Focused Update on the Guidelines for the Management of Patients with AF.

RivaroxabanApixabanEdoxaban

Dabigatran


Coagulation Cascade

De Caterina et al. JACC. Vol. 59, No. 16, 2012.

McCullough et al. Clin J Am SocNephrol. 11: 2079-2084, 2016.



Dabigatran (RE-LY)

RE-LY (Randomized Evaluation of Long term anticoagulant therapY) trial was a prospective, randomized, open-label clinical phase III trial.

Comparing 2 blinded doses of dabigatranetexilate (110 mg B.I.D. [D110] or 150 mg B.I.D. [D150]) with open-label, adjusted-dose warfarin aiming for a target international normalized ratio (INR) of 2.0 to 3.0

Dabigatran (RE-LY)

A total of 18,113 patients with NVAF and at least one risk factor for stroke were included.

Patients with a stroke during the last 14 days or with a CrCl of 30 mL/min were excluded.

The mean CHADS2 score was 2.1, and 31.9% of the patients had a CHADS2 score of 0 to 1, 35.6% had a score of 2, and 32.5% had a score of 3 to 6.

Median treatment duration was 2 years.


Dabigatran (RE-LY)

The results showed a reduction of the primary outcome of stroke or systemic embolism from 1.71% in the warfarin group to 1.54% per year in the D110 group (HR = 0.90; 95% CI = 0.74 to 1.10; p = 0.001 for non-inferiority).

There was a reduction of 1.11% per year in the D150 group (HR = 0.65; 95% CI = 0.52 to 0.81; p = 0.001 for superiority).

Dabigatran (RE-LY)

The rate of major bleeding was 3.57% per year in the warfarin group compared with 2.87% per year in the D110 group (p = 0.003) and 3.32% in the D150 group (p = 0.31).

Rates of hemorrhagic stroke and intracranial bleeding were lower with both doses of dabigatran (annual intracranial bleeding rate = 0.1% with both D110 and D150 vs. 0.4% with warfarin; p = 0.001).


Dabigatran (RE-LY)

• Gastrointestinal bleeding, however, was increased from 1.0% per year on warfarin to 1.5% per year with the D150 group (p = 0.001).

• The rates of discontinuation at 2 years were higher with D150 (20.7%) and D110 (21.2%) than with warfarin (16.6%).


Rivaroxaban (ROCKET-AF)

Annual rate of major bleeding was 3.60% in the rivaroxaban group and 3.45% in the warfarin group (p = 0.58).

There was a lower rate of intracranial bleeding (0.5%/year vs. 0.7%/year; p = 0.02) and fewer fatal bleeding events (0.2%/year vs. 0.5%/year; p = 0.003) with rivaroxaban.

More patients with bleeding that required transfusion and more GI bleeding with rivaroxaban.

Apixaban (ARISTOTLE)

18,201 patients

Apixaban 5 mg bid versus warfarin

Primary efficacy endpoint: stroke and systemic embolism

Primary safety endpoint: major bleeding

Key secondary endpoint: all-cause mortality

Median age 70

Mean CHADS2 score = 2.1


Apixaban (ARISTOTLE)

Treatment discontinuation of 1.7% with apixaban versus 2.5% with warfarin

21% RRR of stroke and systemic embolism versus warfarin

31% RRR of major bleeding events versus warfarin

11% RRR in all-cause mortality versus warfarin

McCullough et al. Clin J Am SocNephrol. 11: 2079-2084, 2016.


Rivaroxaban (ROCKET AF)

• Included patients with nonvalvular atrial fibrillation at high risk of stroke.

• Randomized 14,264 patients to double-blind treatment with rivaroxaban 20 mg QD (15 mg daily for CrCl of 30 to 50 ml/min) or warfarin.

• Mean CHADS2 score of 3.5.



55% had a history of stroke, TIA, or systemic embolism.

The warfarin treatment aimed at an INR level between 2.0 and 3.0. The mean time in therapeutic range was 55% (median 58%).

Primary objective was to demonstrate non-inferiority versus warfarin for the occurrence of stroke or systemic embolism.


• The annual rate of stroke and systemic embolism was 2.12% in the rivaroxaban group and 2.42% in the warfarin group (HR = 0.88; 95% CI = 0.74 to 1.03; p = 0.001 for non-inferiority and p = 0.117 for superiority).

• No reduction in ischemic stroke.


Dias et al. Am J Nephrol. 43: 229-236, 2016.


Phase III Trial Comparison

RE-LY ROCKET-AF

ARISTOTLE ENGAGE AF-TIMI 48

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

Dose (mg)

Frequency

150, 110

BID

20 (15*)

QD

5 (2.5*)

BID

60*, 30*

QD

N 18,113 14,266 18,206 >21,000

Design PROBE 2x blind 2x blind 2x blind

AF Criteria AF x 1

< 6 months

AF x 2

(>1 in <30 d)

AF or AFl x 2

< 12 months

AF x 1

< 12 months

% VKA naïve 50% 38% 43% 40% goal

RELY Dabigatran 110 mg

Dabigatran 150 mg

Warfarin

CHADS2 Mean0-1 (%)2 (%)3+ (%)

2.132.634.732.7

2.232.235.232.6

2.130.937.032.1

ROCKET -AF Rivaroxaban Warfarin

CHADS2 Mean2 (%)3 (%)4 (%)5 (%)6 (%)

3.5134329132

3.5134428122

ARISTOTLE Rivaroxaban Warfarin

CHADS2 Mean0-1 (%)2 (%)3+ (%)

2.134

35.830.2

2.134

35.830.2


RE-LY ROCKET AF ARISTOTLE

Time in Therapeutic Range (TTR)

64%67% warfarin-experienced

61% warfarin-naïve

Mean 55%Median 58%

Mean 62%Median 66%

RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

ROCKET AFRivaroxaban 20mg 1.7% per yearWarfarin 2.2% per year

ARISTOTLEApixaban 5 mg 1.27% per yearWarfarin 1.60% per year

Primary Endpoint of Stroke or Systemic Embolism: Non-Inferiority Analysis

Antithrombotic Therapy RecommendationsClass I

• Selection of antithrombotic therapy should be based on the risk of thromboembolism irrespective of whether the AF pattern is paroxysmal, persistent, or permanent.

• In patient with nonvalvular AF, the CHA2DS2-VASc score is recommended for assessment of stroke risk.



• For patient with mechanical heart valves, warfarin is recommended.

• For patients with nonvalvular HF with prior stroke, TIA, or a CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended (warfarin: level of evidence A; dabigatran, rivaroxaban, or apixaban: level of evidence B).


• For patients with nonvalvular AF unable to maintain a therapeutic INR level with warfarin, use of a direct thrombin inhibitor or factor Xainhibitor is recommended.

• For patients with atrial flutter, antithrombotic therapy is recommended according to the same risk profile used for AF.


Antithrombotic Therapy Recommendations

• Class IIa– For patients with nonvalvular AF and a

CHA2DS2-VASc score of 0, it is reasonable to omit antithrombotic therapy.

• Class IIb– For patients with nonvalvular AF and a

CHA2DS2-VASc score of 1, no antithrombotic therapy or treatment with an oral anticoagulant or aspirin may be considered.

Antithrombotic Therapy RecommendationsCKD

• Class I– Renal function should be evaluated prior to

initiation of direct thrombin or factor Xainhibitors and should be re-evaluated as needed and at least annually.

• Class IIa– For patients with nonvalvular AF with a

CHA2DS2-VASc score of ≥ 2 and who have ESRD (CrCl < 15) or are on HD, it is reasonable to prescribe warfarin.


Dose Selection in CKD

Renal Function Warfarin Dabigatran Rivaroxaban Apixaban

Normal/mild

impairment

Dose adjusted for

INR 2.0‐3.0

150 mg bid

(CrCl > 30)

20 mg qd with evening meals

(CrCl > 50)

5 or 2.5 mg bid (unless 2 of

3:

age > 80,

weight < 60 kg,

Cr > 1.5)

Moderate impairment 15 mg qd

(CrCl 30‐50)

Severe impairment 75 mg bid

(CrCl 15‐30)

15 mg qd

(CrCl 15‐30)

End‐stage but not on

Dialysis

May be continued

(CrCl < 15)

May be continued

(CrCl < 15)

May be continued

(CrCl < 15)

End‐stage but on

dialysis

Antithrombotic Therapy RecommendationsClass III – No Benefit

• Dabigatran and rivaroxaban are not recommended in patients with AF and end-stage CKD or on hemodialysis b/c of lack of evidence from clinical trials.

• Dabigatran should not be used in patients with AF and a mechanical heart valve.


Table from McCullough et al. Clin J Am SocNephrol. 11: 2079-2084, 2016.

Data from Kaatzet al. Stroke. 45: 2497-2505, 2014.

Back to Our Patient…

• 76 yo female with CHF, HTN, DM, ESRD, prior CVA, and CAD

• Patient had a major GIB requiring blood transfusion while in therapeutic range on warfarin

• She had a recurrent GIB on a NOAC

• She has a history of unsteady gait and prior falls


Non-Medication Options for Thromboembolism

Prophylaxis

Surgical Excision of Left Atrial Appendage


AtriCure AtriClip® LAA Occlusion System

Antithrombotic Therapy RecommendationsClass IIb

• Surgical excision of the LAA may be considered in patients undergoing cardiac surgery (level of evidence: C).


Percutaneous Left Atrial Appendage Closure Techniques

ev3 PLAATO ® System


Boston Scientific WATCHMAN® Device

St. Jude Medical Amplatzer® Cardiac Plug


SentreHeart LARIAT® Suture Delivery Device

Status of Available Devices

• The surgical AtriClip device was FDA-approved since 2009 and is currently the most widely used LAA exclusion device placed through an epicardial approach.

• The Lariat device received 510K clearance by the FDA for tissue approximation but not LAA exclusion and has been the target of some criticism due to procedural safety concerns, incomplete closure rates, and lack of stroke prevention data.


Status of Available Devices

• The Watchman device was shown to be noninferior to warfarin for stroke prevention in nonvalvular atrial fibrillation, and this device has gained approval from the FDA following lengthy delays and two randomized studies (PROTECT AF and PREVAIL).

Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients with Atrial

Fibrillation Versus Long-Term Warfarin TherapyThe PREVAIL Trial

• LAA occlusion was noninferior to warfarin for ischemic stroke prevention or systemic embolism >7 days post-procedure.

• Noninferiority was not achieved for overall efficacy, but event rates were low and numerically comparable in both arms.

• Procedural safety has significantly improved, and the trial provides additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with NVAF who do not have an absolute contraindication to short-term warfarin therapy.



Summary

• Atrial fibrillation is a prevalent disease in patients with end stage renal disease and carries a significant risk for thromboembolic events.

• There is considerable debate on the risk-benefit profile of using warfarin in patients with atrial fibrillation on dialysis.

• Direct oral anticoagulants and new surgical and percutaneous approaches to left atrial appendage closure are options with great potential, but there is a lack of data in patients with ESRD.

• A new era of treatment options in this difficult patient population is now here.

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Oral Anticoagulation in Patients with Atrial Fibrillation ...cme.uthscsa.edu/Courses/CardioRenal/2017/Online Syllabus/042817/4... · Oral Anticoagulation in Patients with Atrial Fibrillation