IMPLANTABLE DEVICE THERAPY FOR HEART FAILURE

IMPLANTABLE DEVICE THERAPY FOR HEART FAILURE Nora Goldschlager, M.D. MACP, FACC, FAHA, FHRS Cardiology San Francisco General Hospital UCSF Disclosures: None LEADING CAUSES OF DEATH IN US Sudden cardiac death 375, Stroke 16, Lung cancer 9,1 Automobile accidents 5, Breast cancer 4,2 AIDS 16, American Heart Association 2 National Cancer Institute 21 National Transportation Safety Board 2 Center for Disease Control 21 NFPA, US Facts & Figures 2 emedicine http://emedicine.com/me/topic276.htm Aug.22 Definition SUDDEN CARDIAC DEATH Death occurs within minutes Unwitnessed death Incidence 375, per year (approximately 43 every hour) 75, (2%) survive

UNDERLYING ARRHYTHMIA OF SUDDEN CARDIAC ARREST VT 62% Primary VF 8% Torsades de Pointes 13% Bradycardia 17% SUDDEN CARDIAC DEATH AND PROGRESSIVE HF Mortality in NYHA Class IV 3 to 7% 33% SCD, 56% HF NYHA Class III 2 to 5% 59% SCD, 26% HF NYHA Class II 5 to 15% 64% SCD, 12% HF PHARMACOLOGICAL THERAPY Classes of drugs evaluated for ability to prevent SCD in high-risk patients ACE inhibitors Beta blockers Class I antiarrhythmics d-sotalol Amiodarone Adapted from Bayés de Luna A. Am Heart J. 1989;117:151-159.

HIGH RISK GROUPS: DEPRESSED EJECTION FRACTION AND VENTRICULAR ECTOPY Survivorship 1..8.6.4.2 Survival After Acute MI N EF VPD 536 3% <1/hr 113 3% 1/hr 8 <3% <1/hr 37 <3% 1/hr Bigger, JT. Am J Cardiol. 1986;57:128. 1 Year 2 3 HIGH RISK GROUPS: DEPRESSED EJECTION FRACTION, VENTRICULAR ECTOPY 1 Survival.96.92.88 No PVBs 1-1/h >1/h p =.2 p =.1 6 12 18 6 12 18 Patients without LV dysfunction Risk of Sudden Death: Data from GISSI-2 Trial Maggioni AP Circ 1993;87:312-322 Days Patients Patients with with LV Dysfunction LV dysfunction CAST I (1987-1989) CARDIAC ARRHYTHMIA SUPRESSION TRIAL Objective Test hypothesis that suppression of PVCs post-mi would reduce mortality Inclusion Post MI, > 1 PVCs per hour Patients 1,727 randomized to placebo vs active therapy with Encainide, Flecainide, or Moricizine Results After mean follow-up of 1 months, Encainide and Flecainide arms terminated prematurely due to excess death or cardiac arrest N Engl J Med 1989, 321:46-412

Survival 1 9 8 7 6 5 CAST SURVIVAL CURVES Placebo (n-1371) Active Rx (n=138) p =.6 N Engl J Med 1989, 321:46-412. 4 8 12 16 2 Months PRIMARY SUDDEN DEATH PREVENTION IN HEART FAILURE ACE Inhibitors Beta Blockers Amiodarone ACE INHIBITORS ACE inhibitors reduce mortality in LV dysfunction do they alter the risk of arrhythmic death? SOLVD and CONSENSUS trials no significant effect on SCD V-HeFT II mortality benefit attributable to decreased incidence of SCD Circulation 1998;97 N Engl J Med 1987;316(23):1429-1435 N Engl J Med 1991;325:33-31

Trials of Beta Blockers for Heart Failure: Effects on Sudden Cardiac Death CIBIS II 1999 MERIT-HF 1999 Meta- Analysis (17 Trials) Number 2,647 3,991 3,39 Lancet 1999;353:9-13 Lancet 1999;353:21-7 Circulation 1998;98:1184-1 Drug Bisoprolol 1.25-3.125 mg or Placebo Metoprolol 12.5-25 mg or Placebo -- LVEF 35% 4% 23% Study Period (days) 475 365 -- Mortality Risk Reduction All- Cause -34% P=.1-35% P=.6-31% Heart Failure -- -49% P=.1-32% Sudden Cardiac -44% P=.1-41% P=.2-16% CHF-STAT: CONGESTIVE HEART FAILURE SURVIVAL TRIAL OF ANTIARRHYTHMIC THERAPY Hypothesis: Amiodarone will reduce mortality in patients with HF and ventricular arrhythmias HF Class II, III, or IV EF 4% 1 PVCs/hour May be on ACE inhibitors, hydralazine, or nitrates Circulation 1996;2128-2134 Probability of survival CHF-STAT: ALL-CAUSE MORTALITY 1..8.6 Ischemic Contr Clin Trials. 1992;13:339-35 Non-ischemic.4 Amiodarone.2 Placebo p =.61 p =.7 12 24 36 48 12 24 36 48 Month Amiodarone 242 184 12 67 24 94 76 55 34 9 Placebo 239 1854 121 66 29 99 78 57 29 1

ICD CLINICAL TRIALS AVID CABG Patch CASH MADIT II CIDS DEFINITE MADIT DINAMIT MUSTT SCD-HEFT MADIT (199-1996) MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL Objective ICDs vs conventional medical Rx in high risk patients Inclusion MI 3+ weeks prior to study, asymptomatic non-sustained VT, EF <35%, NYHA Class I-III, and no indication for coronary revascularization Exclusion previous cardiac arrest, VT, CABG within past 2 months, PTCA in past 3 months, NYHA Class IV, or major noncardiac comorbidity N Engl J Med 1996;335:1933-4 MADIT Patients 196 enrolled & randomized (95 ICD, 11 AARx therapy) Choice of conventional medical Rx left to the patient s attending Results ICDs reduced cardiac mortality by 57% in high risk patients relative to best conventional Rx MADIT was the first randomized ICD trial to show that the ICD save lives in the narrowly defined population of patients described in this study * N Engl J Med 1996;335:1933-4 * Moss, Arthur J Cardiac Electrophysiology Review 1998; 2:6-7

% 4 3 2 1 New Eng J Med 1996;335:1933-4 MADIT: MORTALITY 15.8% 38.6% All-Cause Mortality ICD (95 pts) Conventional (11 pts) 11.6% 26.7% Cardiac Death ICD vs. Drugs:Reported Mortality Results Prospective Randomized Studies % Mortality 4 3 2 1 38.6% 15.8% 35.9% Drugs ICDs MADIT AVID CIDS CASH 2 3 1 MADIT Study: 196 post MI patients, <.35 EF, inducible VT/VF despite procainamide; ICD vs. Drugs (74% Amiodarone); 2 year survival data. 2 AVID Study: 116 VT/VF patients; ICDs vs. Amiodarone/Sotalol; 3 year survival data. 3 CIDS Study: 659 VT/VF; ICDs vs. Amiodarone; 3 year survival data. 4 CASH Study: 346 VF patients; ICDs vs. Amiodarone/Metoprolol; 2 year survival data. 3.% 24.6% 25.% 19.6% 12.1% 1 4 CABG PATCH (1992-1997) CORONARY ARTERY BYPASS GRAFT PATCH TRIAL Objective test ICD prophylaxis against sudden death Inclusion ischemic patients, with coronary heart disease, depressed EF, abnormal SAECG undergoing non-emergency coronary bypass graft surgery Exclusion Patients with prior history of sustained ventricular arrhythmia Patients 71,864 patients screened, 1422 eligible, 9 were randomized Results no significant mortality difference likely due to benefits of revascularization Bigger et al. N Engl J Med 1997;337:1569-75

CABG-PATCH: ALL-CAUSE MORTALITY Cumulative Mortality (%) 3 2 1 ICD group 445 Control group 454 12 384 399 Bigger et al. N Engl J Med 1997; 337:1569-75 Defibrillator group Control group 24 Month 313 38 36 213 199 48 51 57 MADIT II (1997-22) MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTATION TRIAL II Objective evaluate ICD vs. medical therapy in patients with left ventricular dysfunction and MI Inclusion post MI patients with EF < 3%. No prior assessment of VT in EP lab Exclusion approved indication for an ICD; Coronary revascularization within 3 months; MI within the past 1 month Ann Noninvasive Electrocardiol 1999;4:83-1 MADIT II Patients 1,232 randomized in a 3:2 ratio to receive an ICD (752) or conventional medical therapy (49) Results over a 4-yr period with average follow-up of 2 months, ICD group resulted in a 5.6% absolute and 31% relative risk reduction in mortality over conventional group (14.2% vs. 19.8%) respectively Study terminated early due to this favorable result Ann Noninvasive Electrocardiol 1999;4:83-1

Probability of survival No. at risk Defibrillator Conventional 1.8 742 49 MADIT II Conventional.6 1 2 3 4 53 329 Moss, A. et. al. N Engl J Med 22;877-83 Year 274 17 Defibrillator 11 65 9 3 Mortality (%) MADIT II: Comparison with Other Landmark Trials 3 15 1 JAMA 1982, 247:177-1714. 2 N Engl J Med 1984, 31:75-758. 3 Pfeffer, et al. N Engl J Med 1992, 327:669-677. 4 Moss, et al. N Engl J Med 22, 346:877-883 P <.1 9.8 7.2 BHAT 1 n = 3837 HR =.74 Conv Rx Test Rx P = NS 9. 8. CASS 2 n = 78 HR =.89 P =.19 24.6 P =.16 2.4 19.8 SAVE 3 n = 2231 HR =.81 14.2 MADIT II 4 n = 1232 HR =.69 MADIT II: Time from MI and ICD Benefit

DEFINITE (1998-28) DEFibrillator IN NON-ISCHEMIC CARDIOMYOPATHY TREATMENT EVALUATION Objective determine effectiveness of ICD in preventing death due to VT/VF in at-risk patients Inclusion non-ischemic cardiomyopathy, EF < 35%, symptomatic CHF, and NSVT or > 1 PVCs per hour Exclusion patients with no previous resuscitation from SCD or who have not yet experienced sustained ventricular arrhythmias CenterWatch Clinical Trials Listing Service Clinical Trial #12395 DEFINITE Patients 458 patients ICD vs drug therapy, all receive standard drug therapy for heart failure and beta blockers if tolerated Results 13.8 overall mortality in control vs 8.1% in ICD; RR cardiac arrest.26 in ICD arm CenterWatch Clinical Trials Listing Service Clinical Trial #12395 SCD-HeFT (1997-28) SUDDEN CARDIAC DEATH-HEART FAILURE Objective compare all-cause mortality between ICDs, amiodarone, and placebo in patients without clinically evident arrhythmias who are being treated for Class II or III HF Inclusion NYHA Class II or III CHF for > 3 months, and EF < 35% with no record of sustained ventricular arrhythmias Exclusion asymptomatic patients with EF > 35%, history of cardiac arrest or patients requiring AARx Patients 2,521 patients randomized to ICDs (shock only), amiodarone, or placebo Results at 2.5 years, ICD decreased mortality by 23%. Amiodarone did not improve survival http://www.sicr.org/scdheft/index.html

MORTALITY BY INTENTION-TO-TREAT Mortality.4.3.2.1 Placebo vs: HR 97.5% CI P-Value Amio 1.6.86, 1.3.529 ICD.77.86,.96.7 Months of follow-up Amiodarone ICD therapy Placebo 12 24 36 48 6 ISSUES IN ICD Rx FOR 1º SCD PREVENTION Only 5-7% absolute mortality over 2-4yrs Only about 2% receive shocks in 3-5 yrs (2x the mortality in controls); only 1% of 1º prevention patients receive Rx 9% of patients exposed to Risk of infection Psychological Inappropriate trauma shocks Post-shock PEA? Proarrhythmia Most life-saving shocks occur in low-risk groups, in whom overall mortality is < 1% From Tung, Swerdlow. Circulation 29;12

CARDIAC RESYNCHRONIZATION THERAPY (CRT) EFFECTS OF RV APICAL PACING (VENTRICULAR DYSSYNCHRONY DUE TO FUNCTIONAL LBBB) Ventricular remodeling, wall motion abnormalities ischemia scores, reflecting alterations in blood flow or depolarization sequences LVEDD, LVESD, LA size LV fractional shortening MR AF CHF DUAL CHAMBER AND VVI ICD (DAVID) TRIAL Inclusion criteria: Pts requiring ICD but without bradycardia requiring pacing Endpoint: Death or hospitalization for CHF Pts: N = 56, 83% men, avg EF 27% Study stopped prematurely at FU 8.4 mos 4 2 New or worse CHF 4.2% Hazard ratio: 1.61.8% DDDR VVI 7 bpm 4 bpm (No pacing) JAMA 22;288:3155

DUAL CHAMBER AND VVI ICD (DAVID) TRIAL 1 8 6 4 2 73% 84% Survival free of composite endpoint one year 1% 6.5% 22% 13% Death JAMA 22;288:3155 DDDR VVI 7 bpm 4 bpm CHF hospitalization Implication: RV (apical) pacing may be detrimental in ICD pts with poor LV function g g g g MOST SUBSTUDY: % RV PACING CORRELATES WITH ADVERSE ENDPOINTS Risk of hospitalization for HF in DDDR group Increases exponentially as RV pacing increases from to 4% 2.6 x in HF hospitalizations if RVP >4% (vs RVP < 4%) Levels off at RV pacing between 4-1% Average HF hospitalization risk = 1% over a 33 month follow up Lowest risk of HF hospitalization = 2% in DDDR group paced <1% of the time Risk of AF =1% with each 1% increase in V pacing (VVIR or DDDR) Circulation 23;17:2932 % RV PACING AND OUTCOME: DAVID* TRIAL % primary endpoint: death or hospitalization for HF 1-yr survival free of endpoint: 84% VVI 4 vs 73% DDDR 7 3 2 1 6 12 18 Months * ICD pts s brady indication Heart Rhythm 25;2:83 DDDR > 4% N = 126 VVI unpaced N = 195 DDDR 4% N = 58 p =.3 p =.7

RV PACING IN ICD PATIENTS: PROBABILITY OF CHF HOSPITALIZATION OR DEATH MADIT II Trend toward CHF JCE 25;16:359.4 MADIT II substudy % % RV pacing.2 relating to CHF, death, ICD shocks Most pts either paced <1% or >9% of time Unadjusted p <.1 VP 5% N = 198 N = 368 VP < 5% 1 2 3 Years RV PACING AND VENTRICULAR ARRHYTHMIAS: PROBABILITY OF APPROPRIATE ICD Rx.4.2 Unadjusted p <.1 VP 5% VP < 5% 1 2 3 Years MADIT substudy JCE 25;16:359 CARDIAC RESYNCHRONIZATION THERAPY: WEIGHT OF EVIDENCE More than 4 patients evaluated in randomized controlled trials Consistent improvement in quality of life, functional status, and exercise capacity Strong evidence for reverse remodeling LV volumes and dimensions LV ejection fraction Mitral regurgitation Reduction in heart failure (CRT) and allcause morbidity and mortality (CRT-D) Abraham WT, 23

CRT IMPROVES CARDIAC FUNCTION AT DIMINISHED ENERGY COST.24 MVO 2 / hr (relative units).22.2.18.16 p <.5 Dobutamine.14 5 6 7 8 9 1 dp / dt max (mmhg/s) Nelson et Circulation 2;12:353-359 LV pacing NE Level pg/ml NE Levels: CRT a positive impact on NE levels 12 8 4 Baseline Paced 12 wk N = 71 N = 15 P = NS N = 35 P = NS < 4 4-8 > 8 Norepinephrine levels Saxon et al. PACE. 1999;22:4(pt II):83. Abstract 519. N = 21 P =.1 % improving 1 NYHA class > 1 8 6 4 2 NYHA FUNCTIONAL CLASS 1 yr p <.1 PATH- CHF 1 yr p <.5 6 mo p <.5 6 mo p <.3 MUSTIC MIRACLE CONTAK CD (advanced HF)

74 mm 7 66 62 71.27 68 Path CHF ECHO LVEDD Echo data (LVEDD).1 74 69 MUSTIC SR 7 NS 68 MUSTIC AF.1 73 69 MIRACLE Pre-CRT CRT 71.1 67 CONTAK CD Improvement (ml / kg / min) 2 16 12 8 4 3 mo p =.3 PATH- CHF PEAK VO 2 No CRT 3 mo p =.3 6 mo p =.6 CRT 6 mo p =.4 MUSTIC MIRACLE CONTAK CD (advanced HF) Mean improvement in peak VO 2 ~ 2 ml / kg / min Improvement (meters) 5 4 3 2 1 6-MINUTE WALK PATH- CHF No CRT 3 mo 3 mo p =.1 6 mo p =.3 CRT 6 mo p =.2 MUSTIC MIRACLE CONTAK CD (advanced HF) Mean improvement in meters walked ~ 6+ meters

Improvment QOL score (points) 6 4 2 3 mo p =.3 PATH- CHF QUALITY OF LIFE No CRT 3 mo p <.1 CRT 6 mo p =.2 6 mo p =.2 MUSTIC MIRACLE CONTAK CD (advanced HF) Mean improvement ~ 17 points HF HOSPITALIZATION AMONG PTS RANDOMIZED TO CARDIAC RESYNCHRONIZATION vs NO RESYNCHRONIZATION Favors CR Favors No CR Contak CD OR.79 InSync ICD.81 Miracle.48 Total.71.1.5 1. 2. Odds ratio (95% Cl) *Meta-analysis of RCT Miracle (N = 263), Contak CD (N = 245), InSync ICD (N = 272) Bradley et al JAMA 2.12.3 CARDIAC RESYNCHRONIZATION AND HOSPITALIZATION RISK Hospital admissions per patient 2 1 Cardiac 1. Anand et al JACC 29; 119:964 N = 152 p-value vs OPT OPT CRT-P p <.1 CRT-D p <.1 HF 12 24 36 12 24 36 Time post randomization (mos).5

CRT AND ATRIAL FIBRILLATION Meta-Analysis of observational studies: 5 studies, total of 1164 subjects with CRT Findings (comparing CRT subjects with AF vs NSR): Similar NYHA class improvements after CRT Mortality not statistically different RR 1.57; 95% Cl,.87 2.8 NSR: Greater improvements with 6- min walk and QOL AF: slightly greater improvement in LVEF Upadhyay GA et al, JACC 28;52:1247-9 APPROPRIATE CANDIDATES FOR CRT BASED ON RANDOMIZED CLINICAL TRIALS: 28 Symptomatic heart failure despite stable, optimal medical therapy Moderate to severe heart failure (NYHA Class III/IV) LV ejection fraction 4% QRS 12 ms (intrinsic or paced) REVERSE TRIAL: Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction Patients: N=61, EF 4%, QRS d 12 ms, NYHA I and II, LVEDD 55 nn CRT on ± ICD 419 off 191 1º Endpoint: Composite HF morbidity, mortality; 1 st hospitalization, QOL Results: (1 year) Worse (disease progression surrogate): on 16%, off 21% (p=.1) LVEDV: on 18.4%, off 1.3 ml/m 2 (p <.1) Longer time to 1 st HF hospitalization (53% relative reduction) Linde et al JACC 28;52:1834 Multicenter

% CRT IN MILD HF (CLASS I, II) Clinical Composite at 1 yr 1 8 6 4 2 21% 16% 79% 84% CRT-OFF CRT-ON Worsened Improved/ unchanged CRT-off CRT-on 11 1 9 8 CRT IN MILD HF (CLASS I, II LVESVI (ml/m 2 ) P <.1 15 13 11 LVEDVI (ml/m 2 ) P <.1 7 9 2 Base 12 Mo Base 12 Mo Base 12 Mo 32 28 24 LVEF (ml/m 2 ) P <.1 % Patients Hospitalized for HF CRT IN MILD HF (CLASS I, II) 15 1 5 Hazard ratio =.47 P =.3 CRT-OFF CRT-ON 3 6 9 12 Months since randomization No. at risk CRT-OFF 191 187 181 176 119 CRT-ON 419 415 411 49 251 Linde et al JACC 28; 52:1834 N - 61 CRT on/off Linde et al JACC 28; 52:1834 N - 61 CRT on/off Linde et al JACC 28; 52:1834 N - 61 CRT on/off

MADIT-CRT (24-29) Primary Hypothesis: in minimally symptomatic cardiac pts. (NYHA I/II) with ischemic or nonischemic cardiomyopathy, decreased EF, and wide QRS, CRT-D will reduce mortality or HF event (which ever comes first) when compared to ICD-only therapy. It was anticipated in this prevention trial that there would be a low annual mortality rate in both Rx groups, with CRT-D benefit dominated by reduction in HF events.. MADIT-CRT Eligibility IHD NYHA class I or II NIHD NYHA class II EF <.3 QRS >13ms Meet AHA/ACC guideline indications for ICD Receiving optimal medical therapy Exclusion CABG, PCI, MI, NYHA III/IV within 3 months - AF within 1 month - Existing indication for CRT Having an implanted pacemaker, ICD, or CRT MADIT-CRT: PRIMARY END POINT First Occurrence 1. All-cause Mortality or 2. Heart-failure Event:* S & S or HF with response to RX involving a) IV decongestive therapy in an outpatient setting or b) augmented decongestive IV or oral therapy during in-hospital stay * Adjudicated by Independent Blinded End Point Review Committees

MADIT-CRT: Kaplan-Meier Estimate of Heart-failure Free Survival Probability N = 182 Hazard Ratio =.66 P<.1 Average FU = 2.4 yrs. MADIT-CRT: COX ANALYSES End Point Hazard ICD CRT Ratio P-Value 1 Analysis Death/HF.66.1 (n=182) 25.3% 17.2% Heart Failure 22.8% 13.9%.59 <.1 Death (any time) 1..99 7.3% 6.8% (mortality <3% per year) Variable Age <65 yr >65 yr Sex* Male Female NYHA Class Ischemic I Ischemia II Nonischemic II QRS ms* <15 >15 LVEF <.25 >.25 LVEDV <24ml >24ml LVESV <17 >17 All patients CRT-D:ICD Hazard Ratios for Prespecified Subgroups Hazard Ratio Significant Sex-Rx Interaction Significant QRS-Rx Interaction.2.4.6.8 1. 1.2 1.4 1.6 CRT-D Better ICD-only Better

Mean Changes in Echo LV Volumes and EF from Baseline to 1-year by Treatment Group ml - 4-8 P<.1 P<.1 = -37ml ml = -39ml EF = +.8 15 ml vs. 52 ml in LVEDV from baseline - 4-8 18 ml vs. 57ml in LVESV from baseline +.1 +.5 LVEDV LVESV LVEF N=62 N=746 ICD-only P<.1 CRT-D.3 vs..11 in LVEF from baseline CRT-D associated with significant reduction in heart size and improvement in heart function. MADIT-CRT: SUMMARY CRT-D: 34% reduction in death or HF in minimally symptomatic patients with ischemic or non-ischemic cardiomyopathy ( EF and QRS) CRT-D benefit: driven by improvement in LV function with 41% reduction in HF events CRT-D: more effective in women than men, and in patients with wider than narrower QRS complexes