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Michael W Rich, MD Professor of Medicine Washington University School of Medicine St. Louis, Missouri Disclosures: None

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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

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Effects of Aging on the Cardiac Conduction System Sinus node Progressive decline in number of pacemaker cells (

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

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ICDs in Patients 75 Years: Pooled Results from AVID, CASH, and CIDS Eur Heart J 2007;28:1746-9 N=252

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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

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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

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ICDs Implanted in US: 1995-2008 Age at ImplantNumber% of total Under 201,2900.6 20-292,2501.0 30-395,4502.4 40-4916,5007.2 50-5939,10017.0 60-6963,15027.6 70-7974,35032.4 80-8924,60010.7 90-996650.3 100 and over100.0 Unknown1,8500.8 Total229,215100.0 43.4%

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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

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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

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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

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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

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Question 3 All of the following statements about implantable cardioverter- defibrillators (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

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Am J Cardiol 1996;77:1185-90

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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)

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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

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Incidence of Atrial Fibrillation: The Framingham Heart Study Am J Cardiol 1998;82(8A):2N-9N

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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)

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Co-existing Conditions that Increase AF Risk Hypertension Coronary artery disease Valve disease (esp. AS & MR) Pulmonary disease Subclinical hyperthyroidism

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Warfarin vs. Aspirin: SPAF-II Subgroup Analysis by Age Lancet 1994;343:687-691 P=0.39 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.

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BAFTA: Subgroup Analysis Lancet 2007;370:493-503

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Incidence of Major Extracranial Bleeding in 13,559 Patients with Atrial Fibrillation J Am Geriatr Soc 2006;54:1231-1236

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Incidence of Intracranial Hemorrhage in 13,559 Patients with Atrial Fibrillation J Am Geriatr Soc 2006;54:1231-1236

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Risk of Major Bleeding Events in Patients at High vs. Low Risk for Falls Am J Med 2012;125:773-8 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)

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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

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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

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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

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ACTIVE-A: Primary Results NEJM 2009;360:2066-78 RR 0.89, P=0.01

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ACTIVE-A: Stroke NEJM 2009;360:2066-78 RR 0.72, P

* Also no benefit in diabetics, NYHA class III patients, or patients with LVEF > 30% NEJM 2005;352:225-37 ICD vs. Placebo in Selected Subgroups: SCD-HeFT

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All-Cause Mortality: SCD-HeFT ICD vs. Amiodarone vs. Placebo NEJM 2005;352:225-37 ICD Placebo Amio

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ECG Manifestations of Sinus Node Dysfunction