Is it possible to develop universal bleeding definition? By Victor Serebruany, MD, PhD

Victor Serebruany, MD, PhD DISCLOSURES Victor Serebruany, MD, PhD Receipt of Intellectual Property Rights/Patent Holder British Technology Group, Novartis AG, Boehringer Ingelheim, Eli Lilly and Company, Pfizer, Inc., AtheroGenics, Inc., Eisai, Inx., AstraZeneca Consulting Fees Pfizer, Inc., Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, McNeil, NPS Pharmaceuticals, Bayer AG, Eisai, Inc. Speakers’ Bureau Pfizer, Inc., Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership Grants/Contracted Research Pfizer, Inc., Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Novartis AG, Lundbeck A/S, Boehringer Ingelheim, Eli Lilly and Company, AtheroGenics, Inc., Guilford, Johnson & Johnson, Bayer AG, Merck & Co., Inc., FIBREX Medical, Cardax Pharmaceuticals, Inc., Eisai, Inc., Pronova BioPharma ASA Ownership Interest (Stocks, Stock Options or Other Ownership Interest) HeartDrug™ Research, LLC

Why Do We Need a Universal Bleeding Definition? Bleeding is deadly Vascular benefits are not impressive Drug approval based on safety

Impact of Bleeding on Outcomes in 34,146 ACS Patients Pooled from OASIS, OASIS-2, and CURE Variable Major Bleed, n (%) No Major Bleed, n (%) HR (95% Cl) Unadjusted P HR (95% Cl) Death <30 d 12.8 2.5 9.77 (7.50—12.72) <0.0001 5.37 (3.97—7.26) Death 30 d – 6 m 4.6 2.9 1.86 (1.26—2.75) 0.002 1.54 ((1.01—2.36) 0.047 MI <30 d 10.6 4.1 6.98 (5.19—9.39) 4.44 (3.16—6.24) MI 30 d – 6 m 1.6 1.8 1.15 (0.60—2.23) 0.67 1.14 (0.59—2.21) 0.69 Stroke < 30 d 2.6 0.56 8.63 (4.80—15.53) 6.46 (3.54—11.79) Stroke 30 d– 6 m 0.8 0.6 1.70 (0.70—4.13) 0.24 1.30 (0.48—3.54) 0.60 Eikelboom Circ 2006;114:774-782

Type of Bleeding and Mortality 30 60 90 120 150 180 5.0 20.0 25.0 10.0 15.0 Life Threatening Major Mortality (%) Minor No Bleeding Days No. at Risk Life Threaten 200 185 172 163 152 141 130 Major 132 129 125 121 117 112 107 Minor 379 375 370 368 349 326 308 No Bleeding 11851 11612 11514 11465 10790 10105 9368 EikelboomCirc 2006;114:774-782

Bleeding and Outcomes in 10,974 PCI Patients from Washington Hospital Center (1991-2000) Bleeding Complication In-Hospital Clinical Events Major (n=588) Minor (n=1,394) None (n=8,992) Death 7.5%*† 1.8%* 0.6% Q-wave myocardial infarction 1.2%* 0.7%‡ 0.2% Non-Q-wave myocardial infarction 30.7%*† 16.8%* 11.8% Repeat lesion angioplasty 1.9%*§ 0.8%‡ 0.3% Major adverse cardiac event 6.6%*† 2.2%* Kinnaird TD et al. AM J Cardiol 2003;92:930-5

Days after Randomization Association of Blood Transfusion and Mortality 10% 4% 2% 6% 8% Transfusion No Transfusion Log rank P<0.001 N=24,112 5 10 15 20 25 30 Days after Randomization Rao et al. JAMA 2004;292:1555-62

Association of PCI-related Bleeding and Mortality 10% 4% 2% 6% 8% p<.0001 With Major Hemorrhage 8.7% Without Major Hemorrhage 1.9% 60 120 180 240 300 360 Days after Randomization Feit et al. Am J Cardiol 2007;100:1364-69

“Optimal Anticoagulation” Myth Bleeding Thrombosis

Preception versus Cold ”Bloody” Facts ”Until recently, bleeding was thought to be inherent to the modern therapeutic approach to ACS, and was seen as the price to pay for an improvement in outcome.” “Bleeding complications were more or less considered to be a non-event that could easily be fixed with appropriate measures, and blood transfusion if needed.” Bassand JP: Heart 2008;94:661–666

Reporting Bleeding Events in Modern Antithrombotic Trials Postulates The medical community is lulled by the ever-appearing and obligatory refrain: “low incidence of bleeding events”, even in studies testing aggressive combination regimens Bleeding is considered as an unfortunate but unavoidable shortcoming of antithrombotic therapy

Bleeding Classifications TIMI ISTH GUSTO CURE ACUITY PLUTO REPLACE BleedScore™ STEEPLE

What is Wrong with Current Classifications? Descriptive, avoiding cause Ignoring nuisance events Hiding rather than fairly scaling events Justifying the ”net clinical benefit” concept

Timing of Event Adjudications in TRITON

Myths and Realities of Bleeding After Conventional Clopidogrel Event Myth Reality Any Bleeding 1.5 -4.0% 7.5-9.0% Nucent Bleeding Can be ignored Observed in 50-60% Non-compliance after 2-3 episodes Relation to IPA Direct Only for moderate, but not major events Serebruany EHJ 2010; 31:227-235

Conclusions Some critical data on bleeding (incidence, causes, and associated hazards) are lacking Development of universal bleeding scale is extremely important for the success of future antithrombotics A combined effort from academia, industry, regulatory, and clinical trialists is needed This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 16