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ATRIAL FIBRILLATION

IN WOMEN AND ASSOCIATED DISEASES

A N N U A L W O M E N ’ S & C H I L D R E N ’ S H E A L T H U P D A T E

A D E L A I D E

1 4 M A Y 2 0 1 6

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

S L I D E S P R E P A R E D B Y D A V I D C O L Q U H O U N & C I N D Y T A M S O N

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

ATRIAL FIBRILLATION

GOALS OF MANAGEMENT IN AF

MANAGEMENT OF AF HAS THREE BROAD OBJECTIVES:

1. Relief of symptoms.

2. Prevention of thromboembolism (particular stroke).

3. Minimising bleeding risk and inconvenience of anticoagulation.

THESE OBJECTIVES CAN BE ACHIEVED BY:

1. Rate control and rhythm control.

2. Antithrombotic therapy.

Anti-platelet drugs are similar to placebo in efficacy but bleeding risk similar to

anticoagulants.

THE KEY CLINICAL QUESTION IS:

WHO DOES NOT NEED ANTICOAGULANT THERAPY?

STROKE INCIDENCE BY AGE

o NEMESIS (Thrift et al, 2009), Thrift et al, 2012 Deloitte Access Economics Calculations

AUSTRALIA 2012

AGE MALE FEMALE TOTAL

0-74 9,784 7,441 17,255

75-84 9,128 6,103 15,231

>85 6,920 9,690 16,610

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)

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INCIDENCE OF ATRIAL FIBRILLATIONACCORDING TO AGE AND GENDER (2004-2012)

o Haim M et al. J Am Heart Assoc 2015;4:e001486 © 2015 Haim M et al

INCIDENCE OF STROKE AMONG INCIDENTATRIAL FIBRILLATION PATIENTS

ACCORDING TO AGE AND GENDER

o Haim M et al. J Am Heart Assoc 2015;4:e001486 © 2015 Haim M et al

AN AGE-RELATED RISK-TREATMENTPARADOX WITH WARFARIN USE IN SPAF

o Go AS, et al. Ann Intern Med 1999; 131: 927-934

44.3

58.1 60.757.3

35.4

0

10

20

30

40

50

60

70

80

90

100

<55 55-64 65-74 75-84 >85

AGE (YEARS)

RISK OF STROKE IN AF PATIENTS INCREASES WITH AGE

1.5% per year in 50-59 year olds.

23.5% in 80-89 year olds.

WA

RF

AR

INU

SE

(%)

RATE OF WARFARIN USE WITHIN 3 MONTHS OF DIAGNOSIS OF AF Adelaide Stroke Study:

Only 27% of those with known atrial fibrillation prior to CVA were on warfarin

Of these patients 66% of the rest were on aspirin

Canada (2003-2007):

In patients with first stroke and known atrial fibrillation:

Only 40% on warfarin (3/4 had INR <2.0)

30% on antiplatelet therapy

29% no treatment

Anticoagulant underutilizationin atrial fibrillation

in Australia and Overseas

S. Ben Freeman, Bernard J Gersh and Gregory Y H Lip. European Heart Journal (2015) 36, 653-656

o Hylek EM, et al. N Eng J Med 2003; 349:1019-1026

0

20

40

60

80

100

<1.5 1.5-1.9 2.0-2.5 2.6-3.0 3.1-3.5 3.6-4.0 4.1-4.5 >4.5

Ischaemic Stroke

Intracranial Haemorrhage

EV

EN

TS

/ 10

00

PA

TIE

NT

YE

AR

S

INTERNATIONAL NORMALISED RATIO (INR)

NARROW THERAPEUTIC RANGE WITH VKA FOR AF

The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range

TargetINR

(2.0-3.0)

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 USE OF OAC CONTINUES TO REMAIN LOW.

WHEN OAC IS USED, INR CONTROL IS SUBOPTIMAL.

BASED ON 15,174 PATIENTS PRESENTING TO AN EMERGENCY DEPARTMENT

WITH AF/AFL BETWEEN JAN. 2008 AND APR. 2011

53.5

43.5

66.9

59.1

46.8

39.533.9 36.1 38.4

0

20

40

60

80

100

TIME IN THERAPEUTIC RANGE*

*BASED ON3 MOSTRECENT

INR VALUES

(%)

(%)

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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

Happy patient having his dabigatran reversed

while being prepared for emergent coronary angiography

with view to revascularisation

(Nursing staff very happy too!)

ANTICOAGULATION AND RISK OF FALLS IN ELDERLYPATIENTS WITH ATRIAL FIBRILLATION

o Arch Intern Med 1999; 159:677-685

PATIENT WITH A 5% PER YEAR STROKE RISK NEEDS TO FALL 295 TIMES PER YEAR

FOR RISK OF SUBDURAL HEMATOMA TO OUTWEIGH STROKE REDUCTION BENEFIT.

Antiplatelet Agents2014 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 Guidelines

and 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”.

Anticoagulants2014 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 Guidelines

and 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”

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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 Australiainitiated 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 12

Pe

rs

iste

nc

e %

Months of therapy

NOAC drugs Warfarin

PROPERTIES OF THE NEW ORAL ANTICOAGULANTS

PROPERTY APIXABAN1 DABIGATRAN2

(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 <30

12 1.01.21.31.4

131518

1.01.53.2

11-13 1.01.41.51.6

1Product information, Eliquis® (apixaban ), most recent amendment 29th of April, 20132Product information, Pradaxa® (dabigatran etexilate), most recent amendment 25th January, 20133Product information, Xarelto® (rivaroxaban), most recent amendment 3rd of April, 2012

DRUG

ARISTOTLE1 RE-LY2 ROCKET-AF3

APIXABAN

ANTI-XA

DABIGATRAN

ANTI-II A

RIVAROXABAN

ANTI-XA

Dose (mg)Freq

5 (2.5**)BID

150, 110BID

20 (15*)QD

N 18,206 18,113 14,266

Design 2x blindNon-inferiority

PROBENon-inferiority

2x blindNon-inferiority

AF criteria AF or AFl x 2<12 mths

AF x 1<6 mths

AF x 2(>1 in <30d)

% VKA naive 43% 50% 38%

Dose (mg)Freq

5 (2.5**)BID

150, 110BID

20 (15*)QD

1Granger CB, et al. N Engl J Med. 2011;365(11):981-9922Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-11513Patel MR, et al. N Engl J Med. 2011;365(10):883-891

PHASE III AF TRIALS

*DOSE ADJUSTED IN PATIENTS WITH↓DRUG CLEARANCE.

**DOSE ADJUSTED IN PATIENTS WITH TWO OR MORE OF:

↓DRUG CLEARANCE / LOW BODY WEIGHT / ELDERLY

P.R.O.B.E. = PROSPECTIVE, RANDOMIZED, OPEN-LABEL, BLINDED, END-POINT EVALUATION

RECENT ORAL ANTICOAGULATION TRIALS

Dragos Vinereanu; Susanna R. Stevens; John H. Alexander; Sana M. Al-Khatib;

Alvaro Avezum; M. Cecilia Bahit; Christopher B. Granger; Renato D. Lopes; Sigrun Halvorsen; Michael Hanna; Steen Husted; Elaine M. Hylek; Andrei D. Margulescu;

Lars Wallentin; Dan Atar

Efficacy and Safety of Apixaban in Patients with

Atrial Fibrillation According to Sex:

Results from the ARISTOTLE Trial

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WOMEN IN ARISTOTLE TRIAL

o Granger C.B., Alexander J.H. et al. ARISTOTLE N Engl J Med 2011; 365: 981-92

APIXABAN WARFARINVS.n = 9,120 n = 9081

MEDIAN FOLLOW-UP: 1.8 YEARS

AGE MEDIAN: 70 YEARS

35% OF WOMEN…

Prior stroke: 20%

Prior AMI: 15%

Baseline characteristics (1)

• All patients enrolled in the ARISTOTLE trial (11785 men, 6416 women) were analyzed.

N Men N Women p-value

Age, yrs 11785 69 (62-75) 6416 72 (65-77) <0.0001

BMI at baseline 11727 28.4 (25.4-32.1) 6380 28.7 (24.8-33.5) 0.0887

Smoking status 11767 6413 <0.0001

Never 39.0 (4590) 77.0 (4936)

Current 10.6 (1246) 3.9 (248)

Former 50.4 (5931) 19.2 (1229)

Alcohol consumption 11768 6414 <0.0001

None 48.1 (5658) 76.9 (4935)

≤ 2 drinks per day 48.3 (5686) 22.6 (1449)

3+ drinks per day 3.6 (424) 0.5 (30)

Baseline characteristics (2)

N Men N Women p-value

Type of AF 11783 6415 <0.0001

Paroxysmal 13.7 (1620) 18.2 (1166)

Persistent or permanent 86.3 (10163) 81.8 (5249)

Heart rate while in AF 10147 78 (68-90) 5221 80 (70-93) <0.0001

Prior warfarin/VKA status 11785 59.6 (7024) 6416 52.6 (3377) <0.0001

CHADS2 score 11785 2 (1-3) 6416 2 (1-3) <0.0001

≤1 36.5 (4307) 29.2 (1876)

2 35.3 (4161) 36.7 (2355)

≥3 28.1 (3317) 34.1 (2185)

CHA2DS2-Vasc score 11785 3 (2-4) 6416 4 (3-5) <0.0001

HAS-BLED score 11785 2 (1-2) 6416 2 (1-2) 0.0541

The efficacy and safety benefit of apixaban compared to warfarin

in AF is independent of sex.

Effect of treatment: Apixaban vs Warfarin

Rate (%/yr) Adjusted

HR (95% CI) Interaction

P-ValueEndpoint Apixaban Warfarin

Stroke or systemic embolism 0.45

Male 1.22 1.49 0.84 (0.66, 1.05)

Female 1.35 1.81 0.73 (0.54, 0.97)

All-cause death 0.83

Male 3.75 4.22 0.89 (0.78, 1.02)

Female 3.11 3.41 0.87 (0.71, 1.06)

CV death 0.64

Male 1.99 2.20 0.88 (0.73, 1.06)

Female 1.45 1.71 0.81 (0.61, 1.08)

Major bleeding 0.06

Male 2.26 2.98 0.76 (0.64, 0.9)

Female 1.91 3.29 0.56 (0.44, 0.72)

Major or non-major clinically relevant bleeding 0.48

Male 4.17 6.00 0.69 (0.61, 0.79)

Female 3.88 6.03 0.64 (0.53, 0.76)

Intracranial bleeding 0.76

Male 0.34 0.80 0.43 (0.29, 0.64)

Female 0.33 0.81 0.38 (0.22, 0.67)

Men

Women

0.50.250.125 1 2

Prevalence of Heart Failure in 3 Index Cardiovascular Conditions

Arnett DK, Goodman RA et al. AHA/ACC/HHS Strategies to Enhance Application… Cardiovascular Disease and Comorbid Conditions. CIRC 2014;130:1662-1667

2012 Data Medicare patients ≥ 65 years USA

“A beneficiary with cardiovascular disease but without at least one

comorbid chronic condition is the exception rather than the rule”

“… particularly important for some older adults, because clinicians must select from among treatments on the basis of evidence for risk and benefit”

IschaemicHeart

Disease

Atrial Fibrillation

Stroke

n = 8,678,060 n = 2,556,839 n = 1,145,714

Heart Failure 36% 51% 37%

Iron DeficiencyIdentification

• Ferritin < 100μg/L + Chronic disease with pro-

inflammatory activation

= iron deficiency

• Ferritin 100 – 300

• and Transferrin Saturation < 20%

=functional iron deficiency

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Incidence of Iron Deficiency in HF

• Occurs in up to 1/3 of

non-HF population

• Prevalence of 30 -

50% in the absence

of anaemia

• Prevalence of 73% in

presence of anaemia

E Jankowska et al: European Heart Journal (2010) 31, 1872–1880

Exercise tolerance In Iron Deficient Heart Failure Patients

E A Jankowska et al: J Cardiac Fail 2011;17:899-906

Depression In Iron Deficient Heart Failure Patients

• Moderate Depression:

– In 48% of iron deficient men with HF vs 25% of

iron replete men with HF

– Lack of depression symptoms:

• 13% of men with Iron Deficiency

• 51% of men without Iron Deficiency

E. Jankowska et al: European Heart Journal (2013) 34, 816–826

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

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 <25 mL/min Warfarin NOACs not TGA approved

CrCl <25-30 mL/min Apixaban Only NOAC TGA approved

CrCl 15-30 mL/min (USA)Dabigatran 75 mg bd

Rivaroxaban 15 mg/day

CrCl > 30 mL/minRivaroxaban, Apixaban or

DabigatranAll TGA approved

Heartburn or upper GI complaints

Rivaroxaban or Apixaban Heartburn occurs in about 10% of patients on Dabigatran

Recent GI bleed Apixaban Lowest GI bleeding rates

Recent ischemic stroke on Warfarin

Dabigatran 150 mg, Rivaroxaban or Apixaban

All are superior to warfarin ?Dabigatran greater benefit

Recent acute coronary syndrome and atrial fibrillation

Unknown Await ongoing AUGUSTUS and REDUAL trial

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CONCLUSIONS

Higher stroke rate related to atrial fibrillation in women.

Women less likely to be given anticoagulation.

In randomised NOAC trials (n > 60,000), women have greater stroke rates but greater absolute benefit with NOACs.

Aspirin as a single agent or added to NOAC/Warfarin causes harm and no benefit.

Co-morbidities in atrial fibrillation eg iron deficiency, depression

Women, like men, are grossly undertreated which is related to the slow uptake of the science and guidelines, as well as fear of possible side effects and perhaps even ageism and sexism.

Antidote to dabigatran now on PBS – idarucizumab.

Medico-legal implications should not be underestimated for non -treatment and choosing less effective therapy.

NO. BEST LEFT FOR OUR RODENT FRIENDS!