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DOACsDosing, Compliance, Renal Function, Common

Questions and What to do with Warfarin

U Q CEN T RE

S T L U C I A

2 8 O C T O B E R 2 0 1 7

A S S O C I A T E P R O F E S S O R D A V I D C O L Q U H O U N

D . C O L Q U H O U N @ U Q . E D U . A U

W W W . C O R E R E S E A R C H G R O U P . C O M

U N I V E R S I T Y O F Q U E E N S L A N D , W E S L E Y & G R E E N S L O P E S H O S P I T A L S

B R I S B A N E , A U S T R A L I A

CARDIOGENIC EMBOLISM IS THEMOST COMMON CAUSE OF STROKE

o Leyden JM et al. Stroke. 2013;44(5):1226-31.

Figure 3: Age-Specific incidence rates for all ischemic stroke subtypes in Adelaide (2009-2010)

Antiplatelet Agents

2014 AHA/ACC/HRS Guideline for the

Management of Patients with Atrial Fibrillation

A report of the American College

of Cardiology/American Heart

Association Task Force on

Practice Guidelinesand the

Heart Rhythm Society

(Circulation, 2014;130:e199-e267) December 2014

“No studies, with the exception of the SPAF-1(Stroke Prevention in Atrial Fibrillation) show benefit for aspirin alone in preventing stroke among patients with AF”

“Antiplatelet therapy was compared with placebo or no treatment in 8 trials with a total of 4876 subjects”

“It is important to recognise that the 19% reduction instroke incident observed in this meta-analysis was drivenby positive results from only 1 of these RCTs”

“Aspirin was ineffective in preventing strokes in those >75 years of age and did not prevent severe strokes. Moreover, aspirin has not been studied in a population at low risk of AF”.

Anticoagulants

2014 AHA/ACC/HRS Guideline for the

Management of Patients with Atrial Fibrillation

A report of the American College

of Cardiology/American Heart

Association Task Force on

Practice Guidelinesand the

Heart Rhythm Society

(Circulation, 2014;130:e199-e267) December 2014

“All 3 new oral anticoagulants represent important advances OVER warfarin because they have more predictable pharmacological profiles, fewer drug-drug interactions, an absence of major dietary effects, and less risk of intracranial bleeding than warfarin”

“If patients are stable … and they are satisfied with warfarin therapy… it is important to discuss this option with patients who are candidates for the new agents”

New Anticoagulants

Coagulationcascade

Drug

Initiation

Propagation

Thrombin activity

TF/VIIa

VIIa

IXa

IXX

Xa

Va

II

IIa

Fibrinogen Fibrin

TFPINAPc2

Fondaparinux

Idraparinux

Razaxaban

Rivaroxaban

Apixiban

XimelagatranDabigatran

Adapted with permission from Weitz J,, Hirsh J. Chest. 2001;119:95S-107S.

Properties of the New Oral Anticoagulants

Property Apixaban1Dabigatran2

(as etexilate)Rivaroxaban3

Target Factor Xa IIa (Thrombin) Factor Xa

Bioavailability 50% 6.5% 66%

Cmax (hrs) 3-4 0.5-2.0 2 – 4

t½ (hrs) 12 12 – 14 11 – 13

Dosing bid bid qd

Renal Excretion 27% 85% 66%

t½ (hrs) AUC* t½ (hrs) AUC* t½ (hrs) AUC*

CrCl >80CrCl >50 to ≤80CrCl ≥30 to ≤50

CrCl

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RECENT ORAL ANTICOAGULATION TRIALS

ARISTOTLEa

Warfarin Apixaban RR (95% CI) P

3.94 3.52 0.89 (0.80-0.998) .047

RE-LYb

Warfarin Dabigatran 110 mg RR (95% CI) P Dabigatran 150 mg RR (95% CI) P

4.13 3.75 0.91 (0.80-1.03) .13 3.64 0.88 (0.77-1.00) .51

ROCKET AFc

Warfarin Rivaroxaban RR (95% CI) P

As treated: 2.2 1.9 0.85 (0.70-1.07) .07

ITT: 4.9 4.5 0.92 (0.82-1.03) .15ENGAGE AF-TIMI 48d

Warfarin Edoxaban 30 mg RR (95% CI) P Edoxaban 60 mg RR (95% CI) P

4.35 3.80 0.87 (0.79-0.96) .006 3.99 0.92 (0.83-1.01) .08

POOLEDe

Warfarin NOACs RR (95% CI) P

3.94 3.52 0.90 (0.85-0.95) .0003

a. Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151[8]; b. Patel MR, et al. N Engl J Med. 2011;365:883-891[9]; c. Granger CB, et al. N Engl J Med. 2011;365:981-992[10]; d. Giugliano RP, et al. N Engl J Med. 2013;369:2093-2104.[11]; e. Ruff CT, et al. Lancet. 2013. 2014;383:955-962.[12]

NOAC Trials Mortality

Anticoagulation for Atrial Fibrillation and Renal Disease

As creatinine clearance decreases from 60mls/min (Cockcroft-Gault Formula)

• Risk of stroke increases markedly

• Risk of bleeding increases markedly

Superiority of NOACs more marked as renal function deteriorates

Dr Charles Everett Koop - Surgeon General USA 1982-89

“Drugs don’t work in patients who don’t take them”

Persistence curve for patients in Australia initiated to NOAC drugs and warfarin - 2014

Improved persistence with non-vitamin K oral anticoagulants compared with warfarin in patients with atrial fibrillation: recent Australian experience. Simons L, Ortiz M, Freedman B, Waterhouse B, Colquhoun D, Thomas G. CSANZ 2015 Melbourne.

0

20

40

60

80

100

0 2 4 6 8 10 12Pe

rs

iste

nc

e %

Months of therapy

NOAC drugs Warfarin

o Healey et al. ESC 2011

USE OF ORAL ANTICOAGULATION IN AF:RESULTS FROM A GLOBAL REGISTRY

65.1

44.8

63.5

38.7

55.8

36.939.9

10.5

43.6

0

20

40

60

80

100

OAC USE IN CHADS2≥2

APPROPRIATE U SE OF OAC CONTINU ES TO REM AIN LOW.

➢ WHEN OAC IS USED , INR CONTROL IS SUBOPTIMAL.

BASED ON 15,174 PATIENTS PRESENTING TO AN EMERGENCY DEPARTMENTWITH AF/AFL BETWEEN JAN. 2008 AND APR. 2011

53.543.5

66.959.1

46.839.533.936.138.4

0

20

40

60

80

100

TIME IN THERAPEUTICRANGE*

*BASED ON 3 MOST RECENT

INR VALUES

(%)

(%)

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Causes of Poor Persistence with Therapy

INCONVENIENCE – DIFFICULT, PAINFUL, TIMECONSUMING

DEPRESSION

SIDE EFFECTS PERCEIVED OR REAL, FEAR OFBLEEDING WITH ANTICOAGULANTS

FREQUENCY OF DOSING, NUMBER OF TABLETS, COST, BELIEFS IN EFFICACY, MEDIA ETC

Depression (%) - 56 (34.8%) / 40 (23.0%) p = 0.017Women versus Men with Chronic Atrial Fibrillation

Figure 3: Typical socio-demographic and risk profiles of women versus men with chronic Atrial Fibrillation

in the SAFETY cohort 1

National Heart Foundation of AustraliaRecommended Screening Tool

Patient Health Questionnaire (PHQ-2)

YES/NO Version

1. During the past month, have you often been bothered by feeling down, depressed or hopeless?

2. During the past month, have you often been bothered by little interest or pleasure in doing things?

* Yes to either question is sufficient for a provisional diagnosis of depression.

Colquhoun D, Bunker ST, Clarke DM et al. Med J Aust 2013;198(9):483-484

Fear of Bleeding

The major reason for non-prescription:- initiation and follow-up

DOCTORS: Overestimate bleeding risk per se Overestimate bleeding risk with falls Still equate “no symptoms” with “no need for OAC” Skew “therapeutic range” that increases sub-therapeutic INR

PATIENTS: Overestimate bleeding risk (“rat poison”) Correctly believe INR testing is frequent

MYTH: Warfarin can be relatively easily reversed

Risk of Major Bleeding in Key Subgroups in RE-LY Trial

Dabigatran 110 %

(n/N)

Dabigatran 150 %

(n/N)

Warfarin %

(n/N)

Urgent Surgery 17.8 (19/107) 17.7 (25/141) 21.6 (24/111)

Elective Surgery 2.8 (38.1380) 3.8 (53/1405) 3.3 (48/1447)

Major Surgery 6.1 (29/473) 6.5 (33/511) 7.8 (39/498)

Healey JS, Eikelboom J, et al. Circulation 2012;126:343-348

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

“The fact that bleeding was similar (in fact numerically higher)

with Warfarin compared with Dabigatran for urgent surgery

should serve as a reassurance to those who are concerned both

about the lack of standard way to measure anticoagulation effect

of Dabigatran and about the absence of a specific antidote for

Dabigatran”.

Garcia DA, Granger CB, Editorial. Anticoagulation, Novel Agents and Procedures. Can We Pardon the Interruption? Circulation 2012;126:255-257

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Thank you to all the investigators and patients involved in this studydTT diluted thrombin time

Results: Diluted Thrombin Time Assessment of Dabigatran Reversal

Mrs ZS 30/06/1930

06/2017 PCH with now cardiac chest pain

28/07/2017 Wesley A&E same chest painConstant central chest pain at least 3 weeks + SOB at rest

No response to TNG Exam no CCF

Poor response to antacids BP 130/-Bloods, CXR ECG paced

28/07/2017 Echo Done at noon – Dr Cross gave me an urgent call

LVED 3.6cm (3.5 - 5.6)

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Mrs ZS 30/06/1930

Usual pradexa dose 110mg given 8am

Praxbind 50mg IVI given 4pm

Pericardiocentesis 5pm in catheter lab with no complications

Procedure done under echo guidance

Over the next few days - no bleeding, no bruising and pericardial drain removed

CHOICE OF ANTICOAGULANT BASEDON PATIENT CHARACTERISTICS

01.03.2016 Update Major adaptation from Weitz & Gross, Hematology 2012:536-40

CHARACTERISTIC DRUG CHOICE RATIONALE

Mechanical or valvular AF Warfarin Only Dabigatran has been studied and trial stopped early

Liver dysfunction with elevated INR

? Any drug Depending on degree of liver failure

At risk of bleed and need for reversal

Dabigatran Idarucizumab (Praxbind) antidote available

Poor compliance NOACWarfarin persistence less than NOAC. Address compliance (egdepression screen PHQ2)

Stable on Warfarin Warfarin or a NOACSuperiority of NOACs needs to be discussed (AHA Guidelines 2014)

CrCl 30mls/min for dabigatran, rivaroxaban> 25mls/min for apixaban

DVT treatment and prophylaxis allowed for:> 15mls/min

• Warfarin should now only be used for mechanical valves, Rheumatic heart disease associated atrial fibrillation, when creatinine clearance is below TGA limits.

“Satisfaction with warfarin” is not a valid reason

NO. BEST LEFT FOR OUR RODENT FRIENDS!