MADIT II Multicenter Automatic Defibrillator Implantation Trial II

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MADIT II Multicenter Automatic Defibrillator Implantation Trial II Status: Completed in 2001 First trial to show the life-saving benefits of ICDs without requiring patients to have a documented history of abnormal heart rhythms

Design 1 Patients were randomized into two treatment arms in a 3: 2 ratio. Patients in the first arm were treated with conventional drug treatment and also implanted with an ICD. The second group was treated exclusively with conventional drug treatment, as prescribed by the patient's attending physician (control arm). Patients were seen in the follow-up clinic at 1 month after randomization, and then at 3 -month intervals until the termination date of the study or death.

Patient Population • Eligible study participants included both male and female patients over 21 years of age that had experienced an MI at least 30 days prior to study enrollment and demonstrated an ejection fraction (EF) < 30%. • Some of the exclusion criteria were – – prior cardiac arrest syncope unrelated to an acute MI NYHA Class IV CABG or non-CABG revascularization less than 3 months prior to enrollment – use of antiarrhythmic agents, except for atrial arrhythmias – Comorbidity associated with decreased survival for trial duration. • 76 Centers worldwide – 71 US – 5 European • 1232 patients enrolled

Clinical Relevance • To evaluate the effect of prophylactic ICD therapy on survival in patients with prior MI and LV dysfunction. • The primary endpoint was death from any cause • First trial to show the life-saving benefits of ICDs without requiring patients to have a documented history of abnormal heart rhythms

Results 2 Mortality over an average follow-up of 20 months Conventional Group (n=490) ICD Group (n=742) Hazard Ratio (95% CI) P-value 19. 8 (97) 14. 2 (105) . 69 (0. 51 -0. 93) 0. 016 • 31% reduction in the risk of death at any interval among patients in the defibrillator group as compared with patients in the conventional-therapy group • The cumulative survival curves represent a decrease in death rates in the defibrillator group (95% confidence limits; P-value) of 12% at 1 year (27 to 40%), 28% at 2 years (4 to 46%), and 29% at 3 years (5 to 46%).

Additional Results – MADIT II 8 -Year Data 3 Mortality over an average of 7. 6 years* post-enrollment Cumulative Probability of Mortality (n=1232) ICD No ICD (Conventional Therapy) 49% 62% • 34% relative reduction in the risk of death at any interval among patients with a defibrillator as compared with patients without an ICD • Number needed to treat (NNT) • 8 at 8 years • 17 at 2 years • Analysis showed sustained benefit with primary ICD therapy in the MADIT II study population *median Hazard Ratio (95% CI) p-value 0. 66 (0. 56 -0. 78) <0. 001

References 1 Moss A, Cannom D, Daubert J et al. Multicenter Automatic Defibrillator Implantation Trial II (MADIT II): Design and Clinical Protocol. Ann Noninvasive Electrocardiol 1999; 4: 83 -91. 2 Moss A, Zareba W, Hall W, et al, for the Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346: 877 -883. 3 Goldenberg I, Moss A, Hall W, et al. Long-Term Benefit of Primary Prevention with an Implantable Cardioverter Defibrillator: An Extended 8 -Year Follow-Up Study of the Multicenter Automatic Defibrillator Implantation Trial II. Circulation. 2010; xxxx

Brief Summary ICD Systems from Boston Scientific CRM ICD Indications and Usage ICDs are intended to provide ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life-threatening ventricular arrhythmias. ICDs with atrial therapies are also intended to provide atrial antitachycardia pacing and atrial defibrillation treatment in patients who have or are at risk of developing atrial tachyarrhythmias. Contraindications Use of ICD systems are contraindicated in: Patients whose ventricular tachyarrhythmias may have reversible cause, such as 1) digitalis intoxication, 2) electrolyte imbalance, 3) hypoxia, or 4) sepsis, or whose ventricular tachyarrhythmias have a transient cause, such as 1) acute myocardial infarction, 2) electrocution, or 3) drowning. Patients who have a unipolar pacemaker. Warnings Read the product labeling thoroughly before implanting the pulse generator to avoid damage to the ICD system. Such damage can result in patient injury or death. Program the pulse generator ventricular Tachy Mode to Off during implant, explant or post-mortem procedures to avoid inadvertent high voltage shocks. Always have sterile external and internal defibrillator protection available during implant. If not terminated in a timely fashion, an induced tachyarrhythmia can result in the patient’s death. Ensure that an external defibrillator and medical personnel skilled in cardiopulmonary resuscitation (CPR) are present during post-implant device testing should the patient require external rescue. Patients should seek medical guidance before entering environments that could adversely affect the operation of the active implantable medical device, including areas protected by a warning notice that prevents entry by patients who have a pulse generator. Do not expose a patient to MRI device scanning. Strong magnetic fields may damage the device and cause injury to the patient. Do not subject a patient with an implanted pulse generator to diathermy since diathermy may cause fibrillation, burning of the myocardium, and irreversible damage to the pulse generator because of induced currents. Do not use atrial tracking modes (or an AVT device) in patients with chronic refractory atrial tachyarrhythmias. Tracking of atrial arrhythmias could result in VT or VF. (Applies to dual-chamber devices only. ) Do not use this pulse generator with another pulse generator. This combination could cause pulse generator interaction resulting in patient injury or lack of therapy delivery. Do not kink leads. Kinking leads may cause additional stress on the leads, possibly resulting in lead fracture. For specific models, when using a subpectoral implantation, place the pulse generator with the serial number facing away from the ribs. Implanting the pulse generator subpectorally with the serial number facing the ribs may cause repetitive mechanical stress to a specific area of the titanium case, potentially leading to a component failure and device malfunction. Precautions For information on precautions, refer to the following sections of the product labeling: clinical considerations; sterilization, storage and handling; implantation and device programming; follow-up testing; explant and disposal; environmental and medical therapy hazards; home and occupational environments. Advise patients to avoid sources of electromagnetic interference (EMI) because EMI may cause the pulse generator to deliver inappropriate therapy or inhibit appropriate therapy. Potential Adverse Events Potential adverse events from implantation of the ICD system include, but are not limited to, the following: allergic/physical/physiologic reaction, death, erosion/migration, fibrillation or other arrhythmias, lead or accessory breakage (fracture/insulation/lead tip), hematoma/seroma, inappropriate or inability to provide therapy (shocks/pacing/sensing), infection, procedure related, psychologic intolerance to an ICD system patients susceptible to frequent shocks despite antiarrhythmic medical management/imagined shocking, and component failure. In rare cases severe complications or device failures can occur. Refer to the product labeling for specific indications, contraindications, warnings/ precautions and adverse events. Rx only. (Rev. M)