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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