Devilish Definitions: Bleeding, Procedural Outcomes and Other Key Endpoints/Variables. US ACADEMIC View

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1 Devilish Definitions: Bleeding, Procedural Outcomes and Other Key Endpoints/Variables US ACADEMIC View Roxana Mehran, MD Columbia University Medical Center Cardiovascular Research Foundation Shifting the Balance of Potency and Bleeding Risk for Anti Coagulant and Anti Platelet Agents Through Radial Arteriotomy June 23, 2010 FDA Headquarters

2 Disclosures: Roxana Mehran Clinical Research Support: Sanofi/Aventis, BMS Educational Support to CRF: The Medicines Company, Boston Scientific, Abbott, Medtronic, and Cordis Consultant/Advisory: TMC, Abbott, Medtronic, Sanofi/Aventis, Astra Zeneca, Cordis, Bracco, Guerbert, Regado

3 The BALANCE ischemic events Thrombosis bleeding Bleeding

4 Bleeding and Mortality Major Bleeding Hypotension Cessation of ASA/Clop Transfusion Ischemia Stent Thrombosis Inflammation Mortality Bhatt DL. In Braunwald EB, Harrison s Online

5 Definitions of Major Bleeding in Clinical Trials: Main Components Clinical Events Intracranial / intracerebral bleeding Intraocular bleeding Bleeding causing hemodynamic compromise Cardiac tamponade Retroperitoneal hematoma Hematoma Surgical intervention for bleeding Blood product transfusion Laboratory Parameters Decrease in Hgb 3 g/dl with overt source of bleeding Decrease in Hgb 4 g/dl w/o overt source of bleeding Decrease in Hgb 5 g/dl with or w/o overt source of bleeding Decrease in Hct 15% with overt source of bleeding

6 Definitions of Major/Severe Bleeding in Randomized Controlled Clinical Trials Type of bleeding GUSTO TIMI phase I TIMI phase II REPLACE2 OASIS5 ESSENCE CURE STEEPLE ACUITY HORIZONS PLATO Intracranial/intracerebral Intraocular Retroperitoneal Bleeding causing hemodynamic compromise Cardiac tamponade Bleeding requiring surgical intervention Hematoma >5cm at the puncture site Transfusion, units Decrease in Hgb with overt bleeding, g/dl 5.0* Decrease in Hgb without overt bleeding, g/dl *Or decrease in Hct 15%

7 Bleeding Definitions TIMI Major Bleeding with >5 g/dl fall in hgb Intracranial bleeding Intraocular bleeding Access site bleed requiring intervention 5 cm hematoma at puncture site Reoperation for bleeding Blood product transfusion ACUITY and HORIZONS Major Bleeding Hgb 3g/dL with an overt source TIMI Minor Hgb 4g/dL w/o overt source Retroperitoneal bleeding Gross hematuria or hematemesis Rao AK et al. JACC 1988;11:111; 11; Stone GW et al. NEJM 2006;355:220316

8 Hierarchical Incidence of Major Bleeding Within 30 Days After PCI REPLACE2 (N=5894) ACUITY (N=7760) HORIZONS (N=3348) Total (n=17,002*) TIMI major bleed 35 (0.6%) 135 (1.7%) 79 (2.4%) 249 (1.5%) ACUITY major (non TIMI major) bleed with blood transfusion** ACUITY major (non TIMI major) bleed without blood transfusion** 81 (1.4%) 120 (1.5%) 41 (1.2%) 242 (1.4%) 73 (1.2%) 125 (1.6%) 95 (2.8%) 293 (1.7%) Large hematoma only 100 (1.7%) 82 (1.1%) 13 (0.4%) 195 (1.1%) Total 289 (4.9%) 462 (6.0%) 228 (6.8%) 979 (5.8%) * Excluding patients with any bleed prior to the PCI ; ** Excluding hematomas if the only criteria Not related to CABG. Each patient is represented only once according to their most severe bleed

9 Influence of Bleeding Severity within 30 Days After PCI on the Risk of Death Over 1 Year Baseline covariateadjusted adjusted timeupdated Cox multivariable model Type of Bleed HR (95% CI) P value Attributable deaths within 1 yr TIMI major bleed 4.85 ( ) 6.60) < ACUITY major (non TIMI major) bleed with transfusion* ACUITY major (non TIMI major) bleed without transfusion* 2.98 ( ) < ( ) Hematoma 5 5 cm only 1.30 ( ) HR (95%CI) * Excluding hematomas if the only criteria Each patient is represented only once according to their most severe bleed

10 ARC Academic Research Consortium: Charter

11 ARC Mission Statement To promote informed and collaborative dialogue across stakeholders supporting the development of consensus definitions and nomenclature for targeted areas of new medical device development, and to disseminate such definitions in the public domain. Krucoff, M. et al ARC Charter. (as yet unpublished).

12 BARC Bleeding Academic Research Consortium

13 BARC Major bleeding has been identified as a powerful independent predictor of mortality in patients undergoing PCI. Currently there is a disturbing heterogeneity of bleeding definitions currently in use Lack of standardization creates difficulty in the interpretation of clinical study results and limits effective comparison of results between studies. New antiplatelet & antithrombotic agents emerging onto the market, older agents undergoing postmarket surveillance Bleeding continues to be a safety endpoint of paramount importance, and a standardized definition is vital

14 Trial MI, Bleeding and AllCause Mortality Large RCTs with significant reductions in death MI Major bleed* Death (time) OASIS5 5 (n=20,078) 6 months Enoxaparin 4.1% 5.0% 6.5% Fondaparinux 3.9% 3.1% 5.8% HORIZONS (n=3,602) 1 year UFH/GPI 1.8% 10.8% 4.8% Bivalirudin 1.8% 6.8% 3.5% PLATO (n=18,624) 1 year Clopidogrel 6.9% 11.2% 5.9% Ticagrelor 5.8% 11.6% 4.5% *TIMI major minor or protocol major

15 MI, Bleeding and AllCause Mortality Large RCTs without significant reductions in death Trial MI Major bleed* Death (time) CHARISMA (n=15,603) 28 mos Placebo 2.0% 1.3% 4.8% Clopidogrel 1.9% 1.7% 4.8% CURRENT (n=25,807) 30 days (CV) LD Clopidogrel 2.2% 2.0% 2.2% HD Clopidogrel 1.9% 2.5% 2.1% SYNERGY (n=10,027) 1 year UFH 12.7% 7.6% 7.3% Enoxaparin 11.7% 9.1% 7.7% REPLACE2 2 (n=6,010) 1 year UFH/GPI 6.2% 4.1% 1.4% Bivalirudin 7.0% 2.4% 1.0% ACUITY (n=9,215) 1 year UFH/GPI 4.9% 11.8% 3.9% Bivalirudin 5.4% 9.1% 3.8% CURE (N=12,562) 1 year Placebo 6.7% 2.7% 6.2% Clopidogrel 5.2% 3.7% 5.8% TRITON (n=13,608) 15 mos Clopidogrel 9.5% 3.8% 3.2% Prasugrel 7.3% 5.0% 3.0% *TIMI major minor or protocol major