Important Data Elements, Definitions and Metrics for Meaningful Results

Transcription

1 Important Data Elements, Definitions and Metrics for Meaningful Results Roxana Mehran, MD Professor of Medicine (Cardiology) Director, Interventional Cardiovascular Research and Clinical Trials Mount Sinai School of Medicine

2 Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Grant/Research Support Consulting Fees/Honoraria Company Sanofi/BMS Significant Astra Zeneca, Cardiva, Cordis, The Medicines Company, Regado Biosciences

3 Challenges with PCI in Women Later diagnosis elderly with more comorbidities More diabetes restenosis Smaller coronaries restenosis More CKD on presentation, more CIN Coronary tortuosity difficulty tracking equipment, dissections, rigid stents straighten vessels and may fracture Hemodynamics: low cardiac output despite normal EF unable to tolerate coronary occlusion Bleeding and Vascular complications

4 6 independent RF for noncabg bleeding (n=17421, from HORIZONS and ACUITY) 1. female sex 2. advanced age 3. elevated serum creatinine 4. white blood cell count 5. anemia 6. nonstsegment elevation MI or STsegment elevation MI Mehran R. JACC 2010;55:

5 Considerations for Radial Access Learning curve Procedure success Smaller radial arteries, more spasm in women compared to men Procedural Time Fluro time and radiation dosage to the pt and operators Contrast Media Use Volume matters for CIN Incidence of AKI should be collected Much less Access site bleeding, what about nonaccess bleeding? Operators may be more likely to use potent antiplatelets, anticoagulants Medication use should be collected

6 Must haves Collection of nonaccess bleeding complications Collection of Radial artery failure/successcrossover. Understanding the learning curvecollection of operator experience with radial approach Enrollment of CKD, DM for meaningful conclusions in these subgroups Collection of adjunct medications in both arms Evaluation of both ischemic and bleeding events

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

8 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

9 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%

10 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; Stone GW et al. NEJM 2006;355:220316

11 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

12 Influence of Bleeding Severity within 30 Days After PCI on the Risk of Death Over 1 Year Baseline covariateadjusted timeupdated Cox multivariable model Type of Bleed HR (95% CI) P value Attributable deaths within 1 yr TIMI major bleed 4.85 ( ) < ACUITY major (non TIMI major) bleed with transfusion* ACUITY major (non TIMI major) bleed without transfusion* 2.98 ( ) < ( ) Hematoma 5 cm only 1.30 ( ) HR (95%CI) Mehran, et al. JACC Int 2011 InPress * Excluding hematomas if the only criteria Each patient is represented only once according to their most severe bleed

13 How Does Access Site Impact Major Bleeding Rates in PCI Patients? Metaanalysis of 18 randomized trials (5 had no bleeding events) of femoral versus radial access involving 4,458 patients undergoing angiography or PCI Major Bleeding Radial access reduced major bleeding by 73%, with a trend for reductions in the composite of death, MI, or stroke (2.5% vs 3.8%, P =.058) Jolly SS. Am Heart J 2009;157:13240.

14 Percent Protocol Major Bleed NonCABG Major Bleeding in PCITreated ACS Patients % Femoral Access 84% Radial Access ACUITY 30 Days TRITON 3 Days EARLY ACS 120 hours SYNERGY 30 Days OASIS 5 9 Days ABOARD 30 Days

15 Analysis Population: All PCI patients (ITT) from: REPLACE2 N = 6,002 ACUITY N = 7,789 HORIZONS N = 3,602 N = 17,393 For antithrombotic comparisons the bivalirudin GPIIb/IIIa arm (n=2609) of ACUITY was excluded, N= 14,784 patients Verheugt JACC Cardio Interv 2011;4:1917:

16 Sources of Bleeding Access/puncture Retroperitoneal 1. Access Site Only 2. Both Access and NonAccess 3. NonAccess Site Only 4. No Identified Location Bleeding location was determined locally by the investigators and recorded on the case report form Intracranial Intraocular Gastrointestinal Genitourinary Pleural Pulmonary Head and Neck Epistaxis Hemoptysis Hematemasis Gingival Other Verheugt JACC Cardio Interv 2011;4:1917:

17 Percentage (%) Sources and Incidence of Bleeding Among 17,393 PCI Patients No Location Both 5.2% % NonAccess Site Only Access Site Only 5.3% (n=925) 1.6 (281) 3.3% 0.8 (142) 0.8 (145) Non access site bleeds are 61.4% of TIMI bleeding events % 0.7 Protocol Major TIMI Major TIMI Major Minor Access site only accounts for 38.6% Verheugt JACC Cardio Interv 2011;4:1917:

18 GU GI Head and Neck Pulmonar y Intracrani al Other No Location % of Patients Incidence and source of bleeding excluding access site GU GI Head/Neck Pulmonary ICH Other No site Axis Title Verheugt JACC Cardio Interv 2011;4:1917:

19 Relative Risk 1Year Mortality Relative Risk of 1year Mortality Associated with Bleeding and Source (unadjusted) 6.0 P< for all bleeding versus none Access Only Both NonAccess Only No Location All NonAccess Verheugt JACC Cardio Interv 2011;4:1917:

20 Risk for 1 year mortality 1year mortality risk from nonaccess site bleeding vs access site = HR 2.27 (95%CI ), p= Relative Risk PValue Unadjusted Access site 2.33 ( ) < Nonaccess site 5.40 ( ) < Adjusted Hazard ratio Access site 1.82 ( ) Nonaccess site 3.94 ( ) < No Bleed TIMI Major Minor Bleed Verheugt JACC Cardio Interv 2011;4:1917:

21 Impact of Antithrombotic Therapy on Bleeding by Source Relative Risk PValue TIMI Major Minor Bleeding Access Only 0.45 ( ) < Both 0.31 ( ) < Non Access Only 0.70 ( ) 0.08 No Location 0.75 ( ) 0.02 All nonaccess 0.62 ( ) < Bivalirudin better Hep GPI better Verheugt JACC Cardio Interv 2011;4:1917:

22 Impact of Randomized Antithrombotic Therapy on TIMI Bleeding by Location Hep GPI (%) Bivalirudi n (%) Relative Risk Intracranial ( ) GI ( ) GU ( ) NEENT ( ) Pulmonary ( ) Other ( ) No location bleed ( ) All NonAccess ( ) Bivalirudin better Hep GPI better Verheugt JACC Cardio Interv 2011;4:1917:

23 BARC Type 0: No evidence of bleeding. Type 1: Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health care professional. Examples include, but are not limited to, bruising, hematoma, nosebleeds, or hemorrhoidal bleeding for which the patient does not seek medical attention. Type I bleeding may include episodes that lead to discontinuation of medications by the patient because of bleeding without visiting a health care provider. Circulation 2011 Inpress

24 BARC Type 2: Any clinically overt sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance; including bleeding found by imaging alone) that is actionable, but does not meet criteria for Type 3 BARC bleeding, The bleeding must require diagnostic studies, hospitalization or treatment by a health care professional. In particular, the bleeding must meet at least one of the following criteria: 1) Requiring intervention: defined as a health care professionalguided medical treatment or percutaneous intervention to stop or treat bleeding, including temporarily or permanently discontinuing a medication or study drug. 2) Leading to hospitalization or an increased level of care: defined as leading to or prolonging hospitalization or transfer to a hospital unit capable of providing a higher level of care; or 3) Prompting evaluation: defined as leading to an unscheduled visit to a healthcare professional resulting in diagnostic testing (laboratory or imaging). Circulation 2011 Inpress

25 BARC Type 3: Clinical, laboratory, and/or imaging evidence of bleeding with specific healthcare provider responses, as listed below: a. BARC Type 3a Bleeding Any transfusion with overt bleeding; Overt bleeding plus hemoglobin drop 3 to <5 g/dl* (provided hemoglobin drop is related to bleeding) b. BARC Type 3b Bleeding Overt bleeding plus hemoglobin drop 5 g/dl* (provided hemoglobin drop is related to bleed), Cardiac tamponade, Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid), Bleeding requiring intravenous vasoactive drugs c. BARC Type 3c Bleeding Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation; does include intraspinal). Intraocular bleed compromising vision Circulation 2011 Inpress

26 BARC Type 4: CABGRelated Bleeding. Perioperative intracranial bleeding within 48 hours Reoperation following closure of sternotomy for the purpose of controlling bleeding Transfusion of 5 units of whole blood or packed red blood cells within a 48 hour period* Chest tube output 2L within a 24 hour period. Notes: If a CABGrelated bleed is not adjudicated as at least a Type 3 severity event, it will be classified as not a bleeding event. If a bleeding event occurs with a clear temporal relationship to CABG (i.e. within a 48 hour timeframe) but does not meet Type 4 severity criteria, it will be classified as not a bleeding event. * only allogenic transfusions are considered as transfusions for CABGrelated bleeds Circulation 2011 Inpress

27 BARC Type 5: Fatal Bleeding. Fatal bleeding is bleeding that directly causes death with no other explainable cause. BARC Fatal Bleeding is categorized as either definite or probable as follows: a) Probable fatal bleeding (Type 5a) is bleeding that is clinically suspicious as the cause of death, but the bleeding is not directly observed and there is no autopsy or confirmatory imaging. b) Definite fatal bleeding (Type 5b) is bleeding that is directly observed (either by clinical specimen blood, emesis, stool, etc. or by imaging) or confirmed on autopsy. Circulation 2011 Inpress

28 Impact of Transfusion in ACS 30Day Survival by Transfusion Group GUSTO IIb, PURSUIT, PARAGON B trials N=24,111 Rao SV et. al. JAMA 2004;292:

29 Discharge Medication Use in Patients who Bleed: PREMIER Registry (STEMI) 1433 STEMI pts treated with primary stenting P=0.001 P=0.002 P<0.001 P=0.05 Wang TY et. al. Circulation 2008;118:

30 Discharge Medication Use in Patients who Bleed: HORIZONSAMI (STEMI) 3,345 STEMI pts in whom primary PCI was performed P=0.12 P=0.05 P< P<0.0001

31 Women CRF for CVD Regulatory Research History with potential of association with CVD Menopause Age, surgical (before or after natural menopause) or natural, post menopausal depression syndrome Comorbidities Migraines, lupus, raynaud disease, known hypercoagulable state, antiphospholipid syndrome Medications HRT, oral contraceptives, infertility, endometriosis, female sexual dysfunction (testosterone), hot flashes, weight loss

32 Conclusions Data elements in Safe PCI are crucial for our understanding of the impact of radial access in women undergoing PCI These data elements should include not only primary, but important secondary endpoints like: Radiation dose to the pt and operator, Contrast Dose; etc The net balance of ischemia and bleeding may vary tremendously with the risk profile of the individual pt for each complication, and the followup duration Using a unified Bleeding definition will allow for a more comprehensive and standardized evaluation of