ATRIAL FIBRILLATION ATRIAL IN WOMEN AND · PDF file24-may-16 1 atrial fibrillation in women...
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24-May-16
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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!