Atrial fibrillation and increased mortality: causation or association? Mexico City 2016 final version

AF and increased mortality: AF and increased mortality: causation or association?causation or association?

Antonio Raviele, MD, FESC, FHRSAntonio Raviele, MD, FESC, FHRS

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

Curso de Actualizaciòn en Arritmias, Mexico City, Mexico - 16-18 November, 2016

Eur Heart J 2013; 34: 1061-1067

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



All-cause mortality in AF patients vs controls


AF patients

Controls

ALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, ItalyALFA – 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 3,572.15

2,551,72

1,941,44

- Men 2,801,76

2,031,36

1,721,24

Patients with primary diagnosis of AF

- Women 2,201,63

1,761,46

1,431,28

- Men 1,911,45

1,441,17

1,251,10



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

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

N = 5209; follow-up: 40 yearsN = 5209; follow-up: 40 years

8080

6060

4040

0000 22 44 66 88 1010

% o

f su

bje

cts

dea

d i

n t

he

foll

ow

-up

% o

f su

bje

cts

dea

d i

n t

he

foll

ow

-up

Follow-up (years)Follow-up (years)

7070

5050

2020

3030

1010

9977553311

Men without AF Men without AF

Women without AFWomen without AF

Women with AFWomen with AFMen with AFMen with AF HR = 1.5

HR = 1.9

General Population

Specific clinical situations

Relationship between AF & mortalityRelationship 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 AF & & ↑ MortalityMortality

• 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

ConsiderationsConsiderations

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


Eur Heart J 2013; 34: 1027-1030

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

Incident AF & Overall MortalityIncident AF & Overall Mortality

HR = 1.5 – 2.0HR = 1.5 – 2.0


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



All these studies were observational and, despite

adjustment for co-morbidities, they are 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.

ConsiderationConsideration


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


Stroke / Thromboembolic events

Worsening of Heart failure

Plausible mechanisms of death Plausible mechanisms of death in AF ptsin 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


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


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

Death from cardiovascular cause (primary endpoint)


Represent the strongest support

to the causation hypothesis

Randomized clinical trialsRandomized clinical trials

PIAF, Lancet 2000PIAF, Lancet 2000

AFFIRM, N Engl J Med 2002 AFFIRM, N Engl J Med 2002

RACE, N Engl J Med 2002RACE, N Engl J Med 2002

STAF, JACC 2003STAF, JACC 2003

HOT- CAFE, Chest 2004HOT- CAFE, Chest 2004

AF-CHF, N Engl J Med 2008 AF-CHF, N Engl J Med 2008

J-RHYTHM, Circ J 2009J-RHYTHM, Circ J 2009

AF Randomized Trials AF Randomized Trials / Rhythm Control vs Rate Control/ Rhythm Control vs Rate Control

Trial Age, yMean

Follow-up

Thrombo-emboliccomplications

%Mortality

%

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

RateRate vs vs Rhythm TrialsRhythm Trialsn

PIAFPIAF 12m

Rate control Rhythm control

125127

6160

1056

100100

NRNR

1.61.6

AFFIRMAFFIRM 42m


20272033

7070

3563

8570

67.5

2124

RACERACE 27m


256266

6868

1039

96-9986-99

5.57.9

1713

STAFSTAF 22m


100100

6566

0NR

NRNR

0.63.1

5.02.5

Hot CafeHot Cafe 20m


101104

6160

NR63.5

74NR

12.9

1.02.9

AF-CHFAF-CHF 37m


694682

6766

30-4173

9288

43

3332

JJ-RHYTHM-RHYTHM 19m


404419

64.565

4473

5960

2.92.3

0.71.0

Sinus rhythm

(%)Warfarin

(%)

Circulation 2004; 109: 1509-13

AFFIRM Circulat ion 2004; 109: 1509-13AFFIRM Circulat ion 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 Considerations


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)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.


Improving our understanding of how AF is

associated with mortality may offer the potential

for new treatments that reduce the risk of

premature death.


Health & Medicine

Atrial fibrillation and increased mortality: causation or association? Mexico City 2016 final version