Telemedicine To Detect Recurrent MI C. Michael Gibson, M.S., M.D. Chief, Clinical Research, Beth Israel Deaconess CV Division Chairman, PERFUSE Study Group Senior Trialist TIMI Study Group, Brigham and Women’s Hospital Chairman of the Board of WikiDoc Foundation, www.wikidoc.org The World’s Largest Textbook of Medicine with 6,900 Contributors Viewed 150 Million Times Each Year Harvard Medical School

C. Michael Gibson, MD Consulting: Bristol-Myers Squibb Daiichi Sankyo Eli Lilly and Company Portola Pharmaceuticals, Inc. St. Jude Medical, Inc. Cytori Therapeutics The Medicines Company

C. Michael Gibson, MD Grant Support: Bayer Corporation, Angel Medical Systems, Inc., Atrium Medical Corporation, Ikaria, Inc., Lantheus Medical Imaging, Portola Pharmaceuticals, Inc., St. Jude Medical, Inc., Genentech, Inc., Stealth Peptides, Inc., Volcano Therapeutics, Inc, Johnson and Johnson, Walk Vascular, Merck and Company, Inc. and Sanofi-Aventis

C. Michael Gibson, MD Honoraria: Merck and Company, Inc. Regado Bio-Sciences Baxter International, Inc. Sanofi-Aventis Cardiovascular Research Foundation Consensus Medical Communications

Median Time (hrs) Between Symptom Onset and Treatment 2.9 2.8 2.8 2.7 2.7 2.7 In large, randomized trials, the duration of symptoms before reaching the hospital has been fairly constant at 2.7 hours Median Time (hrs) Between Symptom Onset and Treatment GUSTO I 90-93 GUSTO III 95-97 InTIME II 97-99 ASSENT II 97-98 GUSTO V 99-01 ASSENT 3 00-01 Gibson CM, Circulation 2001;104:2632-2634 5

Time to Door for Recurrent MI Having a prior heart attack does not shorten time to presentation for new event Patient History Avg. Time to Door (Hr) Median Time to Door Those With First MI (n=17,602) 3.40** 3.25 Those With Previous MI (n=2,633) 3.38* Analysis performed by C. Michael Gibson using TIMI database of 20,235 patients

Symptom-to-Balloon Time Every 30 minute delay increased: 1-year mortality by 7.5% Risk of pre-discharge EF < 30% by 8.7% De Luca et al. Circulation. 2004;109:1223-5

Time Is Muscle and the Importance of Preserving Muscle Slide by C. Michael Gibson, M.S., M.D.

Atypical Pain or No Pain is Frequent Among Patients with MI ~30% of AMIs are silent or without typical chest symptoms 1,2 Kannel WB . "Silent myocardial ischemia and infarction: insights from the Framingham Study". Cardiol Clin 1986; 4 (4): 583–91. Davis TM, Fortun P, Mulder J, Davis WA, Bruce DG . "Silent myocardial infarction and its prognosis in a community-based cohort of Type 2 diabetic patients: the Fremantle Diabetes Study". Diabetologia 2004; 47 (3): 395–9.

Unrecognized Myocardial Infarction Study Patients # MI % silent MRFIT (1987) 12,866 460 25 Framingham (1990) 5070 363 30 CVS (1990) 5888 901 22 Rekjavik (1995-8) - Men - Women 9141 13,000 237 641 35 33

BARI 2D 2368 pts with angiographically proven CAD 279 - 1st MIs (12.4% at 5 yrs) 243 - Non-fatal 1st MIs MI Type N (%) 3 yr Cardiac Mortality HR Type I sympt 169 (69.5) 16.1% 8.2 Silent 23 (9.4) 10.7% 4.8 Peri-PCI 51 (21.0) 9.6% 3.4 No MI 2.4% - Chaitman BR. Circulation. 2009;120:2529-2540

Reinfarction and Mortality in 20,101 patients Reinfarction was associated with a 2-fold increase in 30-day and 2-year mortality Gibson CM et al. JACC. 2003;42;7-16

Reinfarction and Incident Heart Failure GUSTO (n = 56,080): Risk of HF 31.9% subjects with reinfarction vs. 13.9% without reinfarction*. German registry (n = 22,613): Reinfarction associated with 87% increase in relative risk of LVEF < 40%#. VALIANT trial (n = 10,599): In subjects with known LV dysfunction and/or HF, reinfarction increased the 1-year risk of mortality or new heart failure by > 2-fold¶. *Hudson et al. Circulation. 2001;104:1229-35.; #Donges et al. Am J Cardiol. 2001;87:1039-44. ¶Thune et al., Eur J Heart Fail. 2011’13:148-53.

Barriers to Patients Seeking Care for STEMI Reliance on symptoms: There can be none Can be atypical Can be confused with GI symptoms Denial What if, instead of a symptom, there was a sign, or a signal, that was objective and detected true ischemia?

Intracardiac ST Segment Deviation: LAD Injury Yields ST Depression + + + RV APEX RV APEX R T R T P P S S Q Q

DETECT Patient 5 – Confirmed STEMI LCX - Sep 2007 LCX - Jul 2008 Baseline Electrogram Alarm Electrogram At home 6:30am 21-Jul-08 Intracardiac Electrogram ST Changes of Inferior and “True” Posterior STEMI ECG IN ER 7:20am External EKG

Symptom to Door Time: First MI vs Second MI vs In The Presence of An Alarming System Mean Time: Symptom(?) To Hospital Door (In Minutes) With Guardian Alarm After First MI First Heart Attack After First Heart Attack 240 120 60 90% Reduction 180 195** At 7.5% improvement per 30 minutes this would mean a 37.5% reduction in mortality 2/3 of our alerts in trial patients occur 9 hours or more before the actual heart attack which will create even greater potential life savings All of the AngelMed trial patients are still living, having been treated early in spite of more than 15 ruptured plaque clinical events in our implanted population 196** 26.5† By C. Michael Gibson using TIMI database of 20,235 patients *n= 17,602; **n=2633; Presentation at 2009 HRS meeting; Boston, MA †Fischell TA, et al. (2010). Initial Clinical Results Using Intracardiac Electrogram Monitoring to Detect and Alert Patients During Coronary Plaque Rupture and Ischemia. JACC;56(14):1089-98. 17

Completed Studies DETECT: US Feasibility study completed 5/08, 2 plaque ruptures detected Pivotal protocol approved by FDA 7/08, now enrolling CardioSaver: Brazilin study completed in Oct. 2007, 2 plaque ruptures detected and no STEMI false positives/negatives with current algorithm. Median symptom to door time only 19.5 minutes in these two studies. J Am Coll Cardiol, 2010; 56:1089-1098

Randomization at 7-14 Day visit ALERT AMI PI: CM Gibson Co-PI: D Holmes 3,000 acute coronary syndrome patients with either: Diabetes (Type I or Type II), compromised renal function (Cr > 1.2 mg/dl or creatinine clearance less than 50), or TIMI Risk Score > 3 Implant 7-14 Day Follow-Up Alerts turned ON 1 Month Follow-Up Alerts remain ON 3 Month Follow-Up 6 Month Follow-Up Alerts turned OFF Alerts remain OFF At 14 days ETT performed to max heart rate to train device re anticipated ST deviation at different heart rate bins Randomization at 7-14 Day visit Primary Endpoint: Cardiac or unexplained death, new Q-wave MI, time to door > 2 hours for a thrombotic coronary occlusion event

Conclusions Time is muscle Greatest improvements in salvage are when improvements in delivery of care are made during the earliest phase of symptoms Improvements in door to data, and decision to drug/device times have improved outcomes Symptom to door and data to decision times are two targets for further improvements in the timely delivery of STEMI care