af and increased mortality: causation or association?€¦ · af and increased mortality: causation...

AF and increased mortality:

causation or association?

Antonio Raviele, MD, FESC, FHRS

AP-HRS 2015– Melbourne, Australia– 19/22 November 2015

ALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, Italy

Eur Heart J 2013; 34: 1061-1067

Andersson T et al. Eur Heart J 2013;34:1061-1067

Andersson T et al. Eur Heart J 2013;34:1061-1067

ALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, Italy

Andersson T et al. Eur Heart J 2013;34:1061-1067

All-cause mortality in AF patients vs controls

Andersson T et al. Eur Heart J 2013;34:1061-1067

AF patients

Controls

ALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, Italy

Unadjusted all-cause mortality risk

All-cause mortality risk adjusted for concomitant diseases

Age < 65 yrs Age 65-74 yrs Age 75-85

All patients

- Women 3,57

2.15

2,55

1,72

1,94

1,44

- Men 2,80

1,76

2,03

1,36

1,72

1,24

Patients with primary

diagnosis of AF

- Women 2,20

1,63

1,76

1,46

1,43

1,28

- Men 1,91

1,45

1,44

1,17

1,25

1,10

Andersson T et al. Eur Heart J 2013;34:1061-1067

Andersson T et al. Eur Heart J 2013;34:1061-1067

Impact of Atrial Fibrillation on the Risk of Death

Emelia J. Benjamin, Philip A. Wolf, Ralph B. D’Agostino, Halit Silbershatz, William B. Kannel, and Daniel Levy

Circulation 1998; 98: 946-952

(Benjamin EJ et al. Circulation 1998; 98: 946-952)

Impact of AF on the risk of death: the Framingham study

N = 5209; follow-up: 40 years

80

60

40

0 0 2 4 6 8 10

% o

f su

bje

cts

dead

in

th

e f

oll

ow

-up

Follow-up (years)

70

50

20

30

10

9 7 5 3 1

Men without AF

Women without AF

Women with AF

Men with AF HR = 1.5

HR = 1.9

General Population

Specific clinical situations

Relationship between AF & mortality

- Heart failure

- Myocardial infarction

- Renal failure

- Stroke

- Hypertension

- Diabetes mellitus

- Post-cardiac surgery period

Circulation 2003;107:2920-2925

Wang TJ et al. Circulation 2003; 107: 2920-25

Risk of Death and Cardiovascular Events in Initially

Healthy Women With New-Onset Atrial Fibrillation

David Conen, MD, MPH; Claudia U. Chae, MD, MPH; Robert J. Glynn, ScD; Usha B.

Tedrow, MD, MSc; Brendan M. Everett, MD, MPH; Julie E. Buring, ScD; Christine M. Albert,

MD, MPH

JAMA. 2011; 305: 2080-2087

Women’s Healthy Study

FU = 15.4 years

Conen DT et al. JAMA. 2011; 305: 2080-2087

AF & ↑ Mortality

• Direct cause of death ?

• Marker of an increased risk ?

It is important to determine whether the

excess mortality observed in patients with AF

is directly due to AF or is just an association

Considerations

AF is a largely diffuse clinical condition and the

mortality due to this pathology is increasingly growing

If AF directly causes excess mortality, then the use of

therapies that specifically and successfully eliminate

AF – rather than just prevent its symptoms – are

preferable

Considerations

Eur Heart J 2013; 34: 1027-1030

Leong DP et al. Eur Heart J 2013; 34: 1027-1030

Incident AF & Overall Mortality

HR = 1.5 – 2.0

Andersson T et al. Eur Heart J 2013;34:1061-1067

Ferrie JE et al. Heart 2009 ;95 :1250-1257

In a 40-year prospective cohort study, smoking exhibited a similar hazard ratio of about 1.5

Leong DP et al. Eur Heart J 2013; 34: 1027-1030

Leong DP et al. Eur Heart J 2013; 34: 1027-1030

Despite adjustment for co-morbidities, all the studies

are observational and subject to the potential for

confounding factors that were not measured, such as

myocardial fibrosis, digoxin use, obesity, obstructive

sleep apnoea, control of hypertension, patient

adherence to heart failure and other therapies, etc.

Consideration

Leong DP et al. Eur Heart J 2013; 34: 1027-1030

J Am Heart Assoc 2013; doi: 10.1161/JAHA 113000126

Lubitz SA et al. J Am Heart Assoc 2013; doi: 10.1161/JAHA 113000126

Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial

Steinberg BA, Hellkamp AS, Lokhnygina Y, Patel MR, Breithardt G, Hankey GJ, Becker RC,

Singer DE, Halperin JL, Hacke W, Nessel CC, Berkowitz SD, Mahaffey KW, Fox KA, Califf RM,

Piccini JP; ROCKET-AF Steering Committee and investigators

Eur Heart J. 2015; 36: 288-96

Steinberg BA et al. Eur Heart J. 2015; 36: 288-96

Leong DP et al. Eur Heart J 2013; 34: 1027-1030

Stroke / Thromboembolic events

Worsening of Heart failure

Plausible mechanisms of death in AF pts

Stroke appears to account for a very small

proportion of the deaths in AF patients.

In the AF-CHF study, reducing atrial fibrillation in

heart failure patients did not mortality

Considerations

Marijon E et al. Circulation 2013;128:2192-2201

Stroke appears to account for a very small

proportion of the deaths in AF patients.

In the AF-CHF study, reducing atrial fibrillation in

heart failure patients did not decrease mortality

Considerations

Roy D et al. N Engl J Med 2008; 358: 2667-2677

Death from cardiovascular cause (primary endpoint)

Leong DP et al. Eur Heart J 2013; 34: 1027-1030

Represent the strongest support

to the causation hypothesis

Randomized clinical trials

PIAF, Lancet 2000

AFFIRM, N Engl J Med 2002

RACE, N Engl J Med 2002

STAF, JACC 2003

HOT- CAFE, Chest 2004

AF-CHF, N Engl J Med 2008

J-RHYTHM, Circ J 2009

AF Randomized Trials / Rhythm Control vs Rate Control

Trial Age, y

Mean Follow - up

Throm bo- em bolic

com plicat ions %

Mortality %

Modified from Falk, RH. Circulat ion (2005) 111: 3141

Rate vs Rhythm Trials n

PI AF 1 2 m

Rate cont rol

Rhythm cont rol

1 2 5

1 2 7

6 1

6 0

1 0

5 6

1 0 0

1 0 0

NR

NR

1 .6

1 .6

AFFI RM 4 2 m

Rate cont rol

Rhythm cont rol

2 0 2 7

2 0 3 3

7 0

7 0

3 5

6 3

8 5

7 0

6

7 .5

2 1

2 4

RACE 2 7 m

Rate cont rol

Rhythm cont rol

2 5 6

2 6 6

6 8

6 8

1 0

3 9

9 6 - 9 9

8 6 - 9 9

5 .5

7 .9

1 7

1 3

STAF 2 2 m

Rate cont rol

Rhythm cont rol

1 0 0

1 0 0

6 5

6 6

0

NR

NR

NR

0 .6

3 .1

5 .0

2 .5

Hot Cafe 2 0 m

Rate cont rol

Rhythm cont rol

1 0 1

1 0 4

6 1

6 0

NR

6 3 .5

7 4

NR

1

2 .9

1 .0

2 .9

AF- CHF 3 7 m

Rate cont rol

Rhythm cont rol

6 9 4

6 8 2

6 7

6 6

3 0 - 4 1

7 3

9 2

8 8

4

3

3 3

3 2

J- RHYTHM 1 9 m

Rate cont rol

Rhythm cont rol

4 0 4

4 1 9

6 4 .5

6 5

4 4

7 3

5 9

6 0

2 .9

2 .3

0 .7

1 .0

Sinus rhythm

( % )

W arfarin ( % )

Circulation 2004; 109: 1509-13

AFFIRM Circulation 2004; 109: 1509-13

These data suggest that any beneficial

antiarrhythmic effects of AADs are offset by

their adverse effects, and that if an effective

method for maintaining SR with fewer adverse

effects were available, it might be beneficial in

reducing the increased mortality of AF patients

Considerations

Leong DP et al. Eur Heart J 2013; 34: 1027-1030

Consistent evidence indicates that AF is

associated with increased mortality, but the

extent to which this is a direct effect of AF itself

or is related to the numerous serious associated

conditions remains a puzzle.

Conclusions (1)

It is likely that AF itself directly increases the

risk of death in some patients; and it is also a

marker of worsening of heart failure,

hypertension, valvular disease, and other

associated conditions.

Conclusions (2)

Improving our understanding of how AF is

associated with mortality may offer the potential

for new treatments that reduce the risk of

premature death.

Conclusions (3)

Clinical approach to atrial fibrillation

Mont L Eur Heart J 2014;eurheartj.ehu099