ICD’s: Current Roles and Evidence Shariff Attaya M.D. Senior Talk Case Western Reserve University

Learning Objectives Brief history of the ICD Review of the prevalence of Sudden Cardiac Death. Gaining familiarity with major trials that went into the current guidelines of ICD placement. Secondary Prevention Primary prevention in Heart Failure Ischemic Non Ischemic Familiarity with the latest guidelines for ICD placement. Briefly discuss CRT We will not talk about ethical or economic issues.

History and Idea Pioneered by the work of Dr. Michael Mirowski and his colleagues at Sinai Hospital in Baltimore (Hopkins affiliate). Began thinking of the idea after his mentor died suddenly after having ventricular tachycardia just a few weeks earlier. Worked on his Defibrillator from 1968-1980.

The first ICD Because of Dr. Mirowski: In 1980, the first patient received an ICD at Johns Hopkins Hospital. 1985: FDA approves sale and use of ICD’s

Dr. Mirowski (1924 – 1990)

Evolution of ICD’s First ICD’s required a thoracotomy and used epicardial leads. The device was so large, that it needed to placed in the abdomen. Invention of transvenous defibrillator in 1969 allowed for a great reduction in ICD size, and made Mirowski’s idea practicle.

First ICD’s

ICD

Road to ICDs Point out that the time span from the first concept of the device (1966) to FDA approval (1985) was nearly 20 years! 9

Principles The idea behind ICD’s recognizes that Vfib or Vtach degenerating into Vfib is responsible for a large percentage of sudden cardiac death. Thought to be 85% VF/Vtach 15% bradyarrythmias While CPR can temporarily maintain perfusion to the brain, the only effective treatment is prompt defibrillation or cardioversion.

The Problem: Sudden Cardiac Death In the United States, accounts for 325,000 deaths per year. Often the first presentation of heart disease. More often than not, occur in people with structural heart or coronary disease. Out of hospital cardiac arrests are unlikely to survive (rates from 1.4 - 20%). Those who do survive are often not neurologically intact.

SCD

10 minute moment of silence To all those we have lost in the fight against Sudden Cardiac Death

Secondary Prevention ICD’s first treatment group to be studied were those had already suffered a VF or VT event. Important trial AVID Preceding AVID (smaller trials) CASH - Cardiac Arrest Survival in Hamburg (349 subjects) CIDS – Canadian Implantable Defibrillator Study (659 subjects) The above two showed trends, but not signifcance towards less mortality with ICD’s (underpowered)

AVID Trial Antiarrhythmics Versus Implantable Defibrillators (AVID) Multicenter Randomized Controlled Study. 1993 - 1997 NEJM Nov 1997 Secondary prevention trial VF survivors Vtach w/ syncope Vtach w/ LVEF <40%

AVID trial 1013 study subjects received either an ICD or medical thearpy (sotalol or amiodarone) There was crossover both ways of 20% (either ICD’s or antiarrythmics added). Study terminated early due greatly improved outcome in ICD group. Survival Antiarrythmics ICD Year 1 82.3 % 89.3 % Year 2 74.7 % 81.6 % Year 3 64.1% 75.4 %

AVID trial

Important Observation From the AVID and other secondary prevention trials, those with a low EF actually did much better w/ ICD’s than patients with preserved EF’s.

Primary Prevention As so many patients do not survive SCD neurologically intact or at all, there was a focus to investigate which groups of patients would benefit from ICD’s as primary prevention. Focus of investigation High risk (Brugada syndrome, long qt syndrome, Arrythmogenic Right Ventricular dysplasia) Cardiomyopathy (Ischemic or Nonischemic)

ICD’s as primary prevention: Ischemic Cardiomyopathy

MADIT I MULTICENTER AUTOMATIC DEFIBRILLATOR IMPLANTAINO TRIAL 1996. From University of Rochester. Notice Dr. Waldo, also an author.

MADIT I 196 patients who had Prior MI AND NYHA class I, II, or III AND NSVT AND LV dysfunction (LVEF 35%) AND Inducible VT despite procainamide Randomly assigned to ICD, antiarrythmic drug.

MADIT I 196 patients enrolled 15 deaths in ICD group (N = 101) vs 39 in conventional therapy (N=95). ICD reduced overall mortality by 54% and arrhythmic mortality by 75% compared to antiarrythmic therapy Mean followup was 27 months

MADIT I Subset analysis found survival benefit in ICD only in high risk patients LVEF < 26% Clinical heart failure QRS > or equal to .12 sec

MADIT I - criticisms By selecting amongst pt’s with inducible VTACH on procainamide, they selected a population that would be less likely to respond to anti-arrythmics. Higher beta blocker use in ICD group (26 v 8%) The prerequesite of NSVT doesn’t seem appropriate as NSVT is not a great marker for inducible VT.

MADIT II 1232 patients Criteria No longer used EPS study as criteria. MI > 30 days prior LVEF ≤ 30% No longer used EPS study as criteria. Randomized to ICD or medical therapy

MADIT II Study prematurely terminated after 20 months ICD reduced all cause mortality 14.2% vs 19.8% Showed pretty clearly that patients with Ischemic Cardiomyopathy (evidence of an MI and an LVEF of ≤ 30%) would benefit from ICD.

DINAMIT Prior studies had looked and found survival benefit in patients > 3 weeks post MI. This study aimed to study whether soon after an MI (less than 40 days), implantation of an ICD would improve survival. Defibrillator in Acute Myocardial Infarction Trial

DINAMIT Good thought behind the study. Pt’s with an MI are at a high risk of ventricular arrhythmias. Prior studies showed decreased mortality in high risk groups, but no study had looked at ICD’s in such recent MI’s.

DINAMIT About the Study Criteria: Age 18-80 Suffered an MI 6-40 days prior LV EF of .35 or less Needed to have impaired autonomic dysfunction. Either elevated 24 hour heart rate, or depressed heart rate variability on Holter. Previously shown to be risk for arrhythmia

DINAMIT: RESULTS 332 pts in ICD group and 342 in No ICD group

DINAMIT

DINAMIT Conclusions “Prophylactic ICD therapy does not reduce overall mortality in high-risk patients who have recently had a myocardial infarction” “Although ICD therapy was associated with a reduction in the rate of death due to arrhythmia, that was offset by an increase in the rate of death from nonarrhythmic causes” Unclear why this is. Perhaps, that ICD’s in some pt’s do not prevent SCD  pump failure, and a more prolonged death. No signs that it was actually related to the implantation of the devices. Helped in framing the guideline that ICD should not be placed until at least 40 days after an MI.

ICD’s as primary prevention: Nonischemic Cardiomyopathy

SCD HeFT Sudden Cardiac Death in Heart Failure Trial Looked at pt’s w/ Heart failure from both ischemic and nonischemic causes. We will talk about the nonischemic results in the next section. Compared Placebo, Amiodarone, or ICD. Cut off LVEF was 35% NYHA Class II or III

SCD HeFT 2521 Patietns Class II or III Heart failure LVEF of 35% 52% with ischemic heart failure, 48% with nonischemic cardiomyopathy.

SCD HEFT ICD Amiodarone Placebo Overall 28%* 34% 36% Ischemic CM 35%* 41% 43% NICM 21%* 26% 28%

SCD HEFT Overall

SCD HEFT Ischemic

SCD HeFT: nonischemic

Class dependent effects

SCD HEFT Conclusion “In patients with NYHA class II or III CHF and LVEF of 35 percent or less, amiodarone has no favourable effect on survival, whereas single-lead, shock-only ICD therapy reduces overall mortality by 23 percent” This conclusion was accurate across both ischemic and nonischemic subgroups.

Take Home Point ICD’S can save lives in patients the heart failure arising from BOTH ischemic AND nonischemic causes.

Definite Trial Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation

DEFINITE TRIAL 458 Patients Followed for Mean of 29 months LVEF <36%, h/o of pvc’s or nsvt pts only with NON ischemic Cardiomyopathy Randomized to medical therapy or medical therapy + ICD. Followed for Mean of 29 months Good compliance w/ good medical therapy including ace (86%) and beta blockers (

DEFINITE TRIAL

DEFINITE TRIAL: NYHA III BENEFIT This is an opposite finding from SCD-HeFT

DEFINITE TRIAL Conclusions “In patients with severe, nonischemic dilated cardiomyopathy who were treated with ACE inhibitors and beta-blockers, the implantation of a cardioverter-defibrillator significantly reduced the risk of sudden death from arrhythmia and was associated with a nonsignificant reduction in the risk of death from any cause”

Take Home Point - Again ICD’S can save lives in patients the heart failure arising from BOTH ischemic AND nonischemic causes.

Who should have an ICD? According to these guys … EVERYONE !

ACC guidelines on Secondary Prevention and ICD’s

ACC: Secondary Prevention ICD therapy is indicated in patients who are survivors of cardiac arrest due to ventricular fibrillation or hemodynamically unstable sustained VT after evaluation to define the cause of the event and to exclude any completely reversible causes. ICD therapy is indicated in patients with structural heart disease and spontaneous sustained VT, whether hemodynamically stable or unstable. ICD therapy is indicated in patients with syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or VF induced at electrophysiological study. I IIa IIb III A I IIa IIb III B I IIa IIb III B All primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than 1 year.

Primary Prevention B B I IIa IIb III ICD therapy is indicated in patients with LVEF less than or equal to 35% due to prior MI who are at least 40 days post-MI and are in NYHA functional Class II or III. ICD therapy is indicated in patients with nonischemic DCM who have an LVEF less than or equal to 35% and who are in NYHA functional Class II or III. ICD therapy is indicated in patients with LV dysfunction due to prior MI who are at least 40 days post-MI, have an LVEF less than or equal to 30%, and are in NYHA functional Class I. ICD therapy is indicated in patients with nonsustained VT due to prior MI, LVEF less than or equal to 40%, and inducible VF or sustained VT at electrophysiological study. I IIa IIb III B I IIa IIb III A I IIa IIb III B All primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than 1 year.

Contraindications to ICD placement: The IC Don’ts

Implantable Cardioverter-Defibrillators IIa IIb III C ICD therapy is not indicated for patients who do not have a reasonable expectation of survival with an acceptable functional status for at least 1 year, even if they meet ICD implantation criteria specified in the Class I, IIa, and IIb recommendations above. ICD therapy is not indicated for patients with incessant VT or VF. ICD therapy is not indicated in patients with significant psychiatric illnesses that may be aggravated by device implantation or that may preclude systematic follow-up. ICD therapy is not indicated for NYHA Class IV patients with drug-refractory congestive heart failure who are not candidates for cardiac transplantation or cardiac resynchronization therapy defibrillators (CRT-D). I IIa IIb III C I IIa IIb III C I IIa IIb III C All primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than 1 year.

Implantable Cardioverter-Defibrillators IIa IIb III C ICD therapy is not indicated for syncope of undetermined cause in a patient without inducible ventricular tachyarrhythmias and without structural heart disease. ICD therapy is not indicated when VF or VT is amenable to surgical or catheter ablation (e.g., atrial arrhythmias associated with the Wolff-Parkinson-White syndrome, RV or LV outflow tract VT, idiopathic VT, or fascicular VT in the absence of structural heart disease). ICD therapy is not indicated for patients with ventricular tachyarrhythmias due to a completely reversible disorder in the absence of structural heart disease (e.g., electrolyte imbalance, drugs, or trauma). I IIa IIb III C I IIa IIb III B All primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than 1 year.

Evolution of ICD Therapy: 1980 to Present 2002 2000 MADIT-II ICDs with Cardiac Resynch 2004 SCD-HeFT 1997/8 Number of Worldwide ICD Implants Per Year COMPANION Dual-Chamber ICDs Size Reduction AVID CASH CIDS 1980 1989 First Human Implant Transvenous Leads Biphasic Waveform 1985 FDA Approval of ICDs 1993 1999 Smaller Devices Major milestones in ICD therapy evolution: 1985: First FDA approval of basic implantable defibrillator. Implants are reserved for the highest risk patients. 1988: Introduction of tiered-therapy: painless antitachycardia pacing, low-energy cardioversion, and high-energy defibrillation. 1989: Transvenous leads eliminate the need for open heart procedures in most cases. Biphasic waveforms allow more effective defibrillation and greater patient safety. 1993: The beginning of the reductions in size which allow pectoral implants (shorten procedure times and hospital stays). 1996: Steroid-eluting leads are introduced, which minimize tissue inflammation and provide up to 48% greater ICD longevity. MADIT is also published: the first prospective study to prove that ICD therapy improves survival in high-risk post-MI patients who have not experienced VT/VF. 1997: Dual-chamber ICDs receive FDA approval: one device can provide multiple therapy options. 1997/1998: Large randomized studies AVID, CASH and CIDS prove that ICD therapy improves VT/VF patient survival compared to antiarrhythmic drug therapy. 1998: Actual worldwide implant volume 55,000 ICDs. AT therapies introduced in Europe. 1999: MUSTT data point to significant reductions in mortality for high-risk post-MI patients. 2000: By the year 2000, it is expected that more VT/VF and high-risk patients will have access to ICD therapy, bringing the projected worldwide implant volume to over 80,000 implants/year. AT Therapies MUSTT 1988 Tiered Therapy 1996 MADIT Steroid-eluting Leads Increased Diagnostic and Memory Capacity

Cardiac Resynchronization Therapy BiVentricular Pacing

Cardiac Dysynchrony Some Heart failure patients will suffer from dysynchrony. It is thought that this dysynchrony can further impair their overall cardiac function. IF the ventricles beat together, the thought is that there will be less regional loading disparities. As upgraded, ICD’s, with coronary sinus leads have the capability of pacing both ventricles, we should see which patients benefit from BiV pacing.

MIRACLE ICD Multicenter InSync Randomized Clinical Evaluation JAMA 2003 Small study, using a survey to look at symptoms. Not powered to detect a mortality difference.

MIRACLE ICD

COMPANION Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure 2004 NEJM Looks at biv pacing in addition to an ICD.

COMPANION 1527 patients Assigned to one of three groups NYHA III or IV (ischemic or nonischemic) QRS >120 Assigned to one of three groups Pharamcologic therapy alone Above + CRT Above + CRT + ICD Primary endpoint: composite of death or hospitalization for any cause.

Companion Results After 12 months 68% composite end point in pharacological group. 56% in BIV alone 56% in ICD + BIV group. Secondary endpoint (death from any cause) Pharmacological 19% BIV (hazard ration of .76, CI of .58 to 1.01, p 0.059) – near significant BIV ICD: 36% reduction, Hazard ratio .64, CI .48 to .86, P0.004

Companion Conclusion “In patients with advanced heart failure and a prolonged QRS interval, cardiac-resynchronization therapy decreases the combined risk of death from any cause or first hospitalization and, when combined with an implantable defibrillator, significantly reduces mortality”

CARE HF CArdiac REsynchronization in Heart Failure Study Looked at the effect on mortality and morbitity by CRT in patients with evidence of dysyncrhony and heart failure. THIS STUDY IS WITHOUT DEFIBRILLATORS. NYHA Class III or IV LVEF < 35% QRS > 150, or 120 w/ other signs of dyssynchrony by echo. NEJM: 2005

CARE HF Not a blinded study. Primary end point was MACE Secondary endpoint all casue mortality @ 28 months Reduction in MACE in 39 vs 55% This benefit does increase over time Also a reduction in overall mortaliyt of 20% vs 30%. Biggest finding is that this drop was found to mostly be in less deaths from worsening heart failure. Shows the benefits of Bi Ventricular pacing and CRT alone in survival in HF.

Kaplan-Meier Estimates of the Time to the Primary End Point (Panel A) and the Principal Secondary Outcome (Panel B) Cleland, J. et al. N Engl J Med 2005;352:1539-1549

CARE HF Hemodynamic, Echocardiographic, and Biochemical Assessments Cleland, J. et al. N Engl J Med 2005;352:1539-1549

CRT guideline Class I Recommendation for CRT Therapy “Patients with LVEF less than or equal to 35%, sinus rhythm, and NYHA functional class III or ambulatory class IV symptoms despite recommended, optimal medical therapy and who have cardiac dyssynchrony, which is currently defined as a QRS duration greater than 120 ms, should receive cardiac resynchronization therapy unless contraindicated.” (Level of Evidence: A)

Cardiac Resynchronization Therapy Cardiac Resynchronization Therapy* in Patients With Severe Systolic Heart Failure For patients who have left ventricular ejection fraction (LVEF) less than or equal to 35%, a QRS duration greater than or equal to 0.12 seconds, and sinus rhythm, cardiac resynchronization therapy (CRT) with or without an ICD is indicated for the treatment of New York Heart Association (NYHA) functional Class III or ambulatory Class IV heart failure symptoms on optimal recommended medical therapy. For patients who have LVEF less than or equal to 35%, a QRS duration greater than or equal to 0.12 seconds, and AF, CRT with or without an ICD is reasonable for the treatment of NYHA functional Class III or ambulatory Class IV heart failure symptoms on optimal recommended medical therapy. For patients with LVEF less than or equal to 35% with NYHA functional Class III or ambulatory Class IV symptoms who are receiving optimal recommended medical therapy and who have frequent dependence on ventricular pacing, CRT is reasonable. I IIa IIb III A I IIa IIb III B I IIa IIb III *All primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than 1 year.

Cardiac Resynchronization Therapy Cardiac Resynchronization Therapy* in Patients With Severe Systolic Heart Failure For patients with LVEF less than or equal to 35% with NYHA functional Class I or II symptoms who are receiving optimal recommended medical therapy and who are undergoing implantation of a permanent pacemaker and/or ICD with anticipated frequent ventricular pacing, CRT may be considered. CRT is not indicated for asymptomatic patients with reduced LVEF in the absence of other indications for pacing. CRT is not indicated for patients whose functional status and life expectancy are limited predominantly by chronic noncardiac conditions. I IIa IIb III C I IIa IIb III B I IIa IIb III C *All primary SCD prevention ICD recommendations apply only to patients who are receiving optimal medical therapy and have reasonable expectation of survival with good functional capacity for more than 1 year.

That’s all I have to say about ICD’s and CRT

Reference

Just Kidding ACC Guidelines: Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation 2006; 114:e385-484 UptoDate AVID: The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337:1576-1583 . MADIT I: Moss AJ, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335:1933-1940 MADIT II: Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877-83. SCD-HeFT: Bardy GH, Lee KL et al. DEFINITE: Kadish A, Eyer A et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. NEJM 2004: 350:211-2158