Transcript Heart Rhythm Disorders in Older Adults

Michael W Rich, MD
Professor of Medicine
Washington University School of Medicine
St. Louis, Missouri
Disclosures: None
Outline
 Effects of aging on the cardiac conduction system
 Bradyarrhythmias and pacemakers
 Supraventricular arrhythmias: Focus on atrial fibrillation
 Ventricular arrhythmias: Focus on ICDs
 Research directions: Unmet needs
Effects of Aging on the
Cardiac Conduction System
Sinus node
 Progressive decline in number of pacemaker cells
(<10% remain by age 75)
 Increased fat and collagen deposition surrounding the
node contributing to sinus node exit block
 Decreased parasympathetic activity
 Decreased HR variability
 No change in resting heart rate (HR) but decreased
maximum HR with exercise: peak HR = 220 – age
Effects of Aging on the
Cardiac Conduction System
Atrioventricular (AV) conduction
 Fibrosis and calcification of the cardiac skeleton
 10-20% increase in PR interval (proximal to His bundle)
 Increased prevalence of 1st degree AV-block but not 2nd
or 3rd degree block (in the absence of CV disease)
 No change in QRS duration but axis shifts to the left
 Increased incidence and prevalence of LAHB, RBBB, and
LBBB (the latter due primarily to concomitant CVD)
Effects of Aging on the
Cardiac Conduction System
 Increased prevalence and frequency of APDs
 Increased prevalence and frequency of short runs of
SVT
 Markedly increased incidence and prevalence of atrial
fibrillation and atrial flutter
 Increased prevalence and frequency of VPDs
 Non-sustained VT (≥ 5 beats) rare in absence of CVD
 With the exception of AF/AFL, the age-related
increase in ectopy is generally benign in older adults
without structural heart disease
Bradyarrhythmias and Pacemakers
Sinoatrial dysfunction (“sick sinus syndrome”)
 Clinical features
 Symptoms: fatigue, exercise intolerance, light-headedness, falls,
pre-syncope/syncope
 Inappropriate sinus bradycardia
 Chronotropic incompetence
 Sinus pauses (≥ 3 sec, may be up to 20 sec or longer)
 AV block
 Brady-tachy syndrome (alt. brady and tachyarrhythmias)
 Diagnosis: correlation of symptoms with arrhythmia
 Treatment: permanent pacemaker (PPM)
 Prognosis: favorable with PPM, but increased risk of stroke in
patients with brady-tachy syndrome (due to AF)
Bradyarrhythmias and Pacemakers
Pacemaker Selection
 Compared to single-chamber ventricular pacing (VVI),
dual-chamber pacing reduces AF, PM syndrome, and
HF admissions, but has no effect on stroke or mortality;
procedural complications and costs are higher
 Atrial pacing preferred in patients with preserved AV
conduction (with back-up V-pacing if needed)
 VVI in patients with persistent/permanent AF
 Role of biventricular pacing in SND remains undefined
Supraventricular arrhythmias:
Focus on atrial fibrillation
Prevalence of Atrial Fibrillation
by Age and Gender in the U.S.
Among octogenarians with HF, the prevalence of AF is ~ 30%.
JAMA 2001;285:2370-2375
Distribution of AF by Age
Over 50% of AF occurs in the 6% of the
population ≥ 75 years of age.
Arch Intern Med 1995;155:469-73
Projected Age and Sex Distribution of Adults
with Atrial Fibrillation in the U.S. – 2000-2050
Women
Age group
< 65
65-79
≥ 80
2000
48.6%
2025
46.3%
2050
47.4%
18.0%
45.3%
36.7%
15.5%
48.7%
35.8%
11.5%
35.9%
52.6%
JAMA 2001;285:2370-75
Attributable Risk of AF for Stroke:
The Framingham Heart Study
23.5%
25%
20%
15%
9.9%
10%
2.8%
5%
1.5%
0%
50-59
60-69
70-79
80-89
Stroke 1991;22:983-8
Stroke Rates in Patients with Atrial Fibrillation
without Anti-thrombotic Therapy
Arch Intern Med 1994;154:1449–57
Aging and the Hemostatic System
• Increase in coagulation factors V, VIII, IX, XIIIa, vWF, and
•
•
•
•
fibrinogen
Increase in platelet activity
Rise in IL-6: increases fibrinogen, PAI-1, CRP, and platelet
aggregability
Increase no. of adipocytes: increases PAI-1, IL-6, TNF-α,
angiotensinogen, complement
Increase in endogenous inhibitors of angiogenesis: PAI-1,
PF 4, α2-antiplasmin
Net effect: shift in balance between thrombosis
and fibrinolysis in favor of thrombosis
Stroke Risk in Patients with Non-valvular
Atrial Fibrillation: the CHADS2 Index
Risk factor
Score
Congestive heart failure
Hypertension
Age ≥ 75 years
Diabetes
Stroke or TIA
1
1
1
1
2
JAMA 2001;285:2864-2870
Annual Stroke Rate By CHADS2 Score in Patients
Not Receiving Anti-thrombotic Therapy
N=1733, mean age 81 yrs, 58% women
20%
18%
16%
14%
12%
10%
8%
6%
4%
2%
0%
0
1
4
3
2
CHADS2 Score
5
6
JAMA 2001;285:2864-2870
Effect of Gender on Risk of Ischemic Stroke and
Peripheral Embolism in Atrial Fibrillation
N=13,559, 57.3% men
Circulation 2005;112:1687-1691
CHA2DS2-VASc
Risk factor
Congestive heart failure
Hypertension
Age ≥ 75 years
Diabetes
Stroke or TIA
Vascular disease (CAD, PAD)
Age ≥ 65 years
Sex category = female
Score
1
1
2
1
2
1
1
1
Meta-Analysis of Anti-thrombotic Therapy for
Stroke Prevention in Atrial Fibrillation
Warfarin
68%
Aspirin
21%
W vs. A
52%
Prog Cardiovasc Dis 2005;48(2):108-124
Birmingham Atrial Fibrillation
Treatment of the Aged Study: BAFTA
 973 pts ≥ 75 yrs (mean 81.5 yrs, 55% male)
 Randomized to warfarin (INR 2.0-3.0) or aspirin 75
mg/day
 Mean follow-up: 2.7 yrs
 Primary endpoint: fatal or disabling stroke, ICH, or
arterial embolism
Lancet 2007;370:493-503
BAFTA: Primary Endpoint
RR 0.48, (0.28-0.80)
P=0.003
Similar effects in men
and women, and in pts
75-79, 80-84, and ≥ 85
years of age
Lancet 2007;370:493-503
Atrial Fibrillation Follow-up Investigation
of Rhythm Management: AFFIRM
 4080 pts, mean age 69.7 yrs, 39.3% female, with
paroxysmal or persistent atrial fibrillation
 All pts treated with warfarin
 Randomized to “rate control” or “rhythm control”
strategy
 Primary outcome: all-cause mortality
 Mean follow-up: 3.5 years
N Engl J Med 2002;347:1825-33
AFFIRM Results: All-cause Mortality
HR for rhythm vs. rate control:
1.15 (0.99-1.34) P=0.08
N Engl J Med 2002;347:1825-33
AFFIRM Results: Secondary Endpoints
 No difference between groups in strokes, other
neurological events, or systemic emboli
 Rhythm control was associated with significantly
greater number of hospital admissions and medication
side effects
 In both groups, most strokes occurred after warfarin
was discontinued
AFFIRM: Subgroup Analysis by Age
N Engl J Med 2002;347:1825-33
RACE-2 Study Design
 614 pts with permanent AF
 Mean age 68 yrs, 34% female, mean CHADS2 1.4
 Randomized to lenient rate control (resting HR <
110/min) or strict rate control (resting HR < 80/min,
exercise HR < 110/min)
 Primary outcome: death from CV causes, HF
admission, stroke or systemic embolism, bleeding, or
life-threatening arrhythmic event
 Follow-up: 2-3 years
NEJM 2010;362:1363-73
RACE-2 Primary Results
NEJM 2010;362:1363-73
HAS-BLED Bleeding Risk Score
Hypertension
Age ≥ 65 or abnormal renal or
hepatic function
Stroke history
Bleeding history or tendency
Labile INRs
Ethanol use
Drugs (ASA, NSAIDs)
1
1 each
1
1
1
1
1
Score: 0-9; a score of 3 or more indicates increased
1-year risk for serious bleeding (incl. ICH)
Fall Risk and Intracranial Hemorrhage in
Elderly Patients with Atrial Fibrillation
 1245 pts at high-fall risk (mean 83 yrs, 60% female) compared
to 18,261 other pts with atrial fibrillation (mean 79 yrs, 56%
female)
 High-fall risk associated with 6-fold increase in the risk of
traumatic intracranial hemorrhage (ICH) but no increased
risk of non-traumatic ICH
 Warfarin associated with increased mortality in pts with
ICH, but was not a risk factor for ICH
 In pts with CHADS 2 2-6, warfarin associated with a 25%
reduction in death, stroke, MI, or major hemorrhage
Am J Med 2005;118:612-617
New Drug Therapies
for Atrial Fibrillation
 Dronedarone (ATHENA, ANDROMEDA, others)
 Aspirin + clopidogrel (ACTIVE-A)
 Dabigatran (RE-LY)
 Rivaroxaban (ROCKET-AF)
 Apixaban (ARISTOTLE)
RE-LY Study Design
 18,113 pts with AF at risk for stroke
 Mean age 71.5 yrs, 63.5% women, CHADS2 2.1
 Randomized to blinded dabigatran 110 mg or 150 mg
BID or to unblinded adjusted dose warfarin (INR 2-3)
 Primary outcome: stroke or systemic embolization
 Median follow-up 2.0 years
NEJM 2009;361:1139-51
RE-LY: Primary Outcome
No interactions
across subgroups
for either dose
but age subgroups
were not reported.
NEJM 2009;361:1139-51
Bleeding Risk with Dabigatran
in the Frail Elderly
 44 episodes of bleeding on dabigatran over a 2
mo period
 12 episodes considered “major”, incl. 2 SDH
 66% ≥ 80yrs, 50% < 60kg, 58% CrCl < 50 ml/min
 RE-LY: mean age 71.2 yrs, mean weight 83 kg,
mean CrCl 68 ml/min
NEJM 2012;366:864-6
ROCKET-AF Study Design
 14,264 pts with AF at risk for stroke
 Median age 73 yrs, 39.7% women, CHADS2 3.5
 Randomized double-blind to rivaroxaban 20 mg daily
(15 mg if eGFR 30-49 ml/min) or to adjusted dose
warfarin (INR 2-3)
 Primary outcome: stroke or systemic embolization
 Median follow-up 1.9 years
NEJM 2011;365:883-91
ROCKET-AF Primary Outcome
AHR 0.88 (0.74-1.03)
P<0.001 for non-inferiority
P=0.12 for superiority
No interactions across
subgroups
NEJM 2011;365:883-91
ARISTOTLE Study Design
 18,201 pts with AF at risk for stroke
 Median age 70 yrs, 35% women, CHADS2 2.1
 Randomized double-blind to apixaban 5 mg BID (2.5
mg BID if ≥ 2 of: age ≥ 80, weight ≤ 60 kg, creatinine ≥
1.5 mg/dl) or to adjusted dose warfarin (INR 2-3)
 Primary outcome: stroke or systemic embolization
 Median follow-up 1.8 years
NEJM 2011;365:981-92
ARISTOTLE Primary Outcome
and Major Bleeding
AHR 0.79 (0.66-0.95)
P=0.01 for superiority
AHR 0.69 (0.60-0.80)
P<0.001
NEJM 2011;365:981-92
ARISTOTLE Subgroup Analysis
NEJM 2011;365:981-92
Mechanical Interventions
 AV-node ablation with VVI pacing (ablate and pace)
 AF ablation (pulmonary vein isolation)
 Cox maze procedure
Ventricular Arrhythmias:
Focus on ICDs
Criteria for ICD Implantation
Class I indications:
 NYHA class II-III symptoms
 LVEF ≤ 30-35%
 Life expectancy > 1 year
 “Good functional status”
ACC/AHA/HRS Guidelines for Device-Based Therapy
J Am Coll Cardiol 2008;51:e1-e62
ICDs in Patients ≥ 75 Years:
Pooled Results from AVID, CASH, and CIDS
N=252
Eur Heart J 2007;28:1746-9
Age and Effectiveness of ICDs for Primary
Prevention of SCD: Meta-analysis of RCTs
 5783 pts from 5 RCTs (MADIT-II, DINAMIT,
DEFINITE, SCD-HeFT, IRIS)
 44% “elderly” (defined as age ≥ 60-65 yrs)
 Mean follow-up: 32 months
 Impact of ICD therapy on all-cause mortality:


Younger pts: HR 0.65 (95% CI 0.50-0.83, p < 0.001)
Older pts: HR 0.81 (95% CI 0.62-1.05, p = 0.11)
 Exclusion of DINAMIT and IRIS did not change results
Ann Intern Med 2010; 153:592-9
ICD Considerations in Older Adults
 With increasing age, the relative likelihood of dying from
VT/VF decreases, while the likelihood of dying from
worsening HF, MI, or other non-cardiac causes increases
 The risk for “inappropriate” shocks may be higher in older
adults due to increasing incidence of AF/RVR
 Procedural complications increase with age, esp. after 80 yrs
 Therefore, the benefit/risk ratio of ICD implantation
decreases with age
 “Routine” generator replacement at end of battery life is not
warranted and must be considered on an individual basis
ICDs Implanted in US: 1995-2008
Age at Implant
Under 20
20-29
30-39
40-49
50-59
60-69
70-79
80-89
90-99
100 and over
Unknown
Total
Number
1,290
2,250
5,450
16,500
39,100
63,150
74,350
24,600
665
10
1,850
229,215
% of total
0.6
1.0
2.4
7.2
17.0
27.6
32.4
10.7
43.4%
0.3
0.0
0.8
100.0
ICDs and End-of-Life Care
 Terminally ill patients with previously implanted ICDs often
receive 1 or more shocks in the last 30 days of life
 Given the choice, many patients and families prefer
disabling the ICD to allow a natural death rather than
suffering unwanted shocks (but this almost never happens!)
 Device disablement is consistent with patient autonomy
(the right to refuse treatment) and is considered legal and
ethical in all states
 All patients with ICDs should be asked about preferences
for device disablement in the event of terminal illness
Heart Rhythm 2010;7:1008-26
Research Directions: Unmet Needs
 Effects of aging on the conduction system
 Elucidate mechanisms
 Develop interventions for attenuating age-related effects
 Bradyarrhythmias and pacemakers
 Prevention of age-associated bradyarrhythmias
 Pacemaker selection and mode optimization
 Novel therapies (e.g. stem cells, other devices)
 Atrial fibrillation
 Primary prevention
 Develop safer and more effective anti-thrombotic and anti-arrhythmic agents
 Define role of AF ablation and other interventions (e.g. LAA occluders)
 Ventricular arrhythmias and ICDs
 Patient selection (i.e. improved risk stratification)
 Refine criteria for generator replacement
 Enhance communication about risks/benefits
 Incorporate patient preferences and goals of care into decision-making
Question 1
All of the following changes in the cardiac conduction system
occur with normal aging EXCEPT:
A. Marked decrease in the number of functioning sinus node
pacemaker cells
B. Impaired conduction from the sinus node to the atrial
conduction system
C. Gradual decline in resting heart rate
D. Slowing of conduction through the AV node
E. Increased prevalence of both left bundle branch block and
right bundle branch block
Question 2
All of the following statements about atrial fibrillation in older
adults are true EXCEPT:
A. More than 50% of all patients in the U.S. with atrial
fibrillation are ≥ 75 years of age
B. The incidence of atrial fibrillation is higher in older women
than in older men
C. The proportion of ischemic strokes attributable to atrial
fibrillation increases exponentially with age
D. In older patients with atrial fibrillation, the risk of stroke
is higher in women than in men
E. In most cases, high fall risk is not a contraindication to
warfarin in older adults with atrial fibrillation
Question 3
All of the following statements about implantable cardioverterdefibrillators (ICDs) in patients 80 years of age or older are
true EXCEPT:
A. The efficacy of ICDs in terminating life-threatening
ventricular tachyarrhythmias declines with increasing age
(esp. after age 80)
B. Compared to younger patients, older patients with ICDs are
at increased risk for ‘inappropriate’ shocks (i.e. in the
absence of a life-threatening ventricular tachyarrhythmia)
C. ICDs have been shown to reduce mortality in appropriately
selected octogenarians
D. It is legal and ethical for a physician to disable an ICD in an
older patient approaching the end-of-life
E. In the absence of shocks (appropriate or inappropriate), ICDs
have minimal impact on quality of life in older adults
Am J Cardiol 1996;77:1185-90
Epidemiology of AF in the U.S.
 Most common arrhythmia in clinical practice
 Estimated 2.5 million Americans affected
 Accounts for ~ 1/3 of hospitalizations for heart rhythm
disorders
 66% increase in hospitalizations for AF over the past 20
yrs
 Annual cost/pt ~ $3600 (total cost ~ $9 billion)
 AF is associated with ~ 10-15% increase in mortality in
men, ~ 20-25% increase in women
 Median age 75 yrs, ~ 50% women (60% after age 75)
Epidemiology of AF in the U.S.
 Prevalence: 2.7 million, with projected increase to 5.5-6






million by 2050 due to population aging
Incidence > 75,000 new cases per year
Incidence & prevalence increase progressively with age
Incidence is higher in men than in women, but women
comprise over 50% of cases
66% increase in hospitalizations for AF over the past 20 yrs
Annual cost/pt ~ $3600 (total cost ~ $9 billion)
AF is associated with ~ 10-15% increase in mortality in men,
~ 20-25% increase in women
Circulation 2011;123:e18-e209
Incidence of Atrial Fibrillation:
The Framingham Heart Study
Am J Cardiol 1998;82(8A):2N-9N
Age-Related CV Changes that Increase AF Risk
 Increased arterial stiffness (↑ systolic BP)
 Increased myocardial stiffness and impaired relaxation
(altered diastolic filling, ↑ LVEDP)
 Increased LA size and fibrosis
 Degenerative changes in the conduction system, esp.
SA node (sick sinus; tachy-brady)
Co-existing Conditions that Increase AF Risk
 Hypertension
 Coronary artery disease
 Valve disease (esp. AS & MR)
 Pulmonary disease
 Subclinical hyperthyroidism
Warfarin vs. Aspirin: SPAF-II
Subgroup Analysis by Age
Among patients > 75 yrs
(N=385) all-cause CVA with
residual deficit occurred in
4.6% of pts on warfarin
vs. 4.3% of pts on aspirin.
P=0.39
Lancet 1994;343:687-691
BAFTA: Subgroup Analysis
Lancet 2007;370:493-503
Incidence of Major Extracranial Bleeding in
13,559 Patients with Atrial Fibrillation
J Am Geriatr Soc 2006;54:1231-1236
Incidence of Intracranial Hemorrhage in 13,559
Patients with Atrial Fibrillation
J Am Geriatr Soc 2006;54:1231-1236
Risk of Major Bleeding Events in Patients
at High vs. Low Risk for Falls
Prospective study of 515 pts
on oral anticoagulants
Median 71.2 yrs, 64% male
High fall risk: 59.8%
Follow-up: 12 mo
Incidence of major bleeds:
7.5 per 100 pt-yrs
Predictors of major bleeds:
female, # of medications
AHR: 1.09 (o.54-2.21)
Am J Med 2012;125:773-8
“In NVAF, what may matter most to
patients is not the risk of stroke or
bleeding but rather the risks of
functional and cognitive disability.”
Arch Intern Med 2010;170:566-569
Emerging Therapies for Atrial Fibrillation
 Dronedarone
- ATHENA: N Engl J Med 2009;360:668-78
- Similar results in pts < 75 and ≥ 75
 Dabigatron (direct thrombin inhibitor)
- RE-LY: N Engl J Med 2009;361:1139-51
- No subgroup analysis by age
 Aspirin + clopidogrel (vs. aspirin alone)
- ACTIVE-A: N Engl J Med 2009; 360:2066-78
- No benefit in pts ≥ 75
ACTIVE-A Study Design
 7554 pts with AF, increased stroke risk, and
contraindications to vitamin K antagonists
 Mean age 71 yrs, 42% female, mean CHADS2 score 2.0
 Randomized to ASA 75-100 mg/day plus either
clopidogrel 75 mg/day or placebo (double-blind)
 Primary endpoint: CV death, stroke, MI, systemic
embolism
 Median follow-up 3.6 years
NEJM 2009;360:2066-78
ACTIVE-A: Primary Results
RR 0.89, P=0.01
NEJM 2009;360:2066-78
ACTIVE-A: Stroke
RR 0.72, P<0.001
NEJM 2009;360:2066-78
ANDROMEDA Study Design
 627 patients hospitalized with HF, NYHA class III-IV,
and LVEF ≤ 35%
 Median age 71.5 yrs, 25% female, 38% h/o AF/AFL
 Randomized to dronedarone 400 mg BID or placebo
(double-blind)
 Primary endpoint: all-cause mortality or HF admission
 Study discontinued after a median follow-up of 2 mo
due to increased mortality in the dronedarone group
(8.1% vs. 3.8%, HR 2.13, p=0.03)
NEJM 2008;358:2678-87
ANDROMEDA Main Results
NEJM 2008;358:2678-87
ATHENA Study Design
 4628 pts with paroxysmal or persistent AF/AFL within
6 mo and additional risk factors for death
 Mean age 71.6 yrs, 47% women
 Randomized to dronedarone 400 mg BID or placebo
(double-blind)
 Primary endpoint: all-cause mortality or CV admission
 Mean follow-up: 21 months
NEJM 2009;360:668-78
ATHENA: Primary Endpoint
NEJM 2009;360:668-78
ATHENA: CV Hospitalizations
NEJM 2009;360:668-78
ICD vs. Placebo in Selected Subgroups:
SCD-HeFT
* Also no benefit in diabetics, NYHA class III
patients, or patients with LVEF > 30%
NEJM 2005;352:225-37
All-Cause Mortality: SCD-HeFT
ICD vs. Amiodarone vs. Placebo
Placebo
Amio
ICD
NEJM 2005;352:225-37
ECG Manifestations of Sinus Node Dysfunction