CLI: Patient level Risk Factors and CLI Outcomes

Transcription

1 Disclosures CLI: Patient level Risk Factors and CLI Outcomes CHRISTOPHER D. OWENS MD, MSC UCSF VASCULAR SURGERY I am paid to talk about peripheral interventions by BARD and Medtronic CLI Natural Evolution: Competing Risk. 54% mortality, 46% amputation at 1y for untreated CLI Survival of 4,061 Veteran s undergoing amputation 3642 produced 17,694 re-admissions 1559 patients were admitted 5 times 1097 additional bypass grafting procedures Lepäntalo M, Mätzke S. Outcome of unreconstructed chronic critical leg ischaemia. Eur J Vasc Endovasc Surg. 1996;11: J Vasc Surg

2 From: Functional Outcomes After Lower Extremity Revascularization in Nursing Home Residents: A National Cohort Study JAMA Intern Med. Published online April 06, doi: /jamainternmed Risk score in patients with CLI Figure Legend: Mortality After Surgery, Stratified by Ambulatory Status Date of download: 4/18/2015 Copyright 2015 American Medical Association. All rights reserved. J Vasc Surg 2009 Risks prediction scores in patients with CLI are not helpful Confirm what we already know Have modest discriminatory ability They are not generalizable What is the full denominator Developed on patients that were selected for surgery already We need an all-comer trial that would have to happen at the level of the primary provider Regarding the biochemistry of the CLI patient, which is false? A. Characterized by inflammation B. CRP is the strongest risk predictor C. Have low total cholesterol, LDL cholesterol, and HDL cholesterol D. Albumin is the strongest risk predictor C h a r a c t e r i z e d b y i n f l a m... 5% C R P i s t h e s t r o n g e s t r i s k... 27% H a v e l o w t o t a l c h o l e s t e r o.. 36% A l b u m i n i s t h e s t r o n g e s t... 32% 2

3 The Cachexia of Critical Limb Ischemia The cytokinemia are higher in PAD patient than in CHF heart failure PAD 2 0 IL6 (pg/ml) TNFaR2 (ng/ml) Biomarker (mean, SD) Overall, N=225 Claudication, N=92 CLI, N=133 P-value Albumin, g/dl ± ± Hemoglobin, g/dl ± ± 1.65 < WBC, 10 3 /mm ,83 ± ± egfr, ml min m ± ± Apolipoprotein A1, mg/dl ± ± Apolipoprotein B100, mg/dl ± ± Triglycerides, mg/dl ± ± Total cholesterol, mg/dl (mean ± SD Overall, N=225 T. cholesterol ± Claudication, N=92 CLI, N=133 P-value ± ± ± LDL, mg/dl ± ± ± HDL, mg/dl ± ± ± Apolipoprotein A1, mg/dl Apolipoprotein B100, mg/dl ± ± ± ± ± ± Lp(a), mg/dl ± ± ± Triglycerides, mg/dl + Statin - statin P-value ± ± ± ± LDL ± ± HDL ± ±

4 Biomarker (median, IQR) Overall, N=225 Claudication, N=92 Coagulation and Fibrinolytic Factors CLI, N=133 P-value PAI-1, ng/ml Fibrinogen, mg/dl Soluble Cell Adhesion Molecules and Receptors P-Selectin, ng/ml VCAM-1, ng/ml ( ).0001 stnfr2, ng/ml 2.80 ( ) 2.28 ( ) 3.41 ( ).0001 Inflammatory cytokines and pentraxins IL6, pg/ml 4.74 ( ) 2.78 ( ) 6.67 ( ).0001 CRP, mg/l 2.98 ( ( ) 5.53 ( ).0001 MCP-1, pg/ml Lower albumin worse Albumin = 4.19 (.24) Albumin = 3.65 (.10) Albumin = 3.06 (.29) Higher VCAM worse VCAM-1 = (70.03) VCAM-1 = (93.58) VCAM-1 = (637.99) Lower cholesterol worse Total cholesterol 94.0 (13.4) Total Cholesterol = (31.2) Higher IL-6 worse IL-6 = 1.53 (.62) IL-6 = 4.82 (1.27) IL-6 = (32.26) Cox model C-statistic for all-cause mortality at full follow up (median 2.3 years) Risk markers C-statistic AIC Clinical model risk factors (rf) Clinical model rf + egfr Clinical model rf + egfr + albumin Clinical model rf + egfr + albumin + hscrp > 5 mg/l Integrated discrimination improvement (IDI) Estimate P-value IDI adding egfr to clinical model rf IDI adding albumin to clinical model rf +egfr IDI adding hscrp to clinical model rf + egfr + albumin Inflammation and Mortality in Bypass Patients Sensitivity Sensitivity Clinical model + egfr + Albumin (tertile) + hscrp > 5mg/L Clinical Model = Age, DM, CAD, CLI Area Area under ROC ROC curve curve =.8127 = Specificity Specificity Remember WIFI in these patients FI=0 Clinical model risk factors (rf) include age, diabetes mellitus, coronary artery disease, critical limb ischemia. J Vasc Surg 2012 Sep;56(3):

5 Malnutrition (albumin < 3.5mg/dl) Renal impairment (egfr <60 ml/min) 18 HR= HR=6.7 HR= HR= HR=5.65 HR= INJURY Stretching Recoil Denudation Injury response programs Inflammation Inflammation Leukocyte adherence Recruitment Progenitor cell differentiation Negative remodeling Phenotypic switch: quiescent prolifera ve and synthetic Proliferation Myofibroblast proliferation Lumen loss Neointima Fibrosis Fibrosis Media Lumen Adventitia 57 HR=4.54 Inflammation (hscrp> 5mg/L) Microvascular networks Paracrine factors Animal models suggest cells migrate from here Restenosis Summary Perivascular tissue The Bullfrog Micro-Infusion Device (Mercator MedSystems) Bullfrog Infusion (DANCE Trial of Adventitial Dexamethasone) Pre-Revascularization Post-Revascularization Post-Infusion Without Angio With Angio 20% contrast, 80% drug

6 PAD Trials of Adventitial Dexamethasone Baseline angiogram and biomarker blood draw (1/3 of pts) 150 PTA DANCE 150 atherectomy SFA and Popliteal N=300 Long lesions ISR Rutherford 5 N 1,000 DANCE-R Revascularization N=240 Below the Knee LIMBO (2 Trials) Beginning Q Baseline angiogram and biomarker blood draw 120 PTA and 120 ATX revascularization (2 trials) Interim DANCE Biomarker Data Goal: limit production of C-reactive protein from baseline to 24 hours based on anti-inflammatory activity of dexamethasone Adventitial DEX treatment Adventitial DEX treatment 60 controls (each) 60 DEX treatment (each) 24-hour blood draw for biomarkers (1/3 of pts) 1-month blood draw for biomarkers (1/3 of pts) Clinical, hemodynamic and duplex U/S followup at 12 months 24-hour blood draw for biomarkers 1-month blood draw for biomarkers Clinical, hemodynamic and duplex U/S follow-up at 6, 12, 18, 24 months Clinical, hemodynamic and angiographic followup at 6 months 21 Inflammation (CRP) Conceptual Framework for Vascular Surgeons Baseline Pre Peri Post JUPITER IL-1 β inhibition Methotrexate Omega FA Risk prediction High dose Omega FA Pulsed steroids VH dose vitamin D Dexamethasone Resolvins Lipoxins Nab-Rapamycin Target Level Avoid metal implants? statins ACEi Conclusions CLI patients have 2 primary competing risks. Death and Amputation Critical limb ischemia (CLI) = Critical patient ischemia (CPI) A subset actually have vascular cachexia Current risk models add little benefit over intuition but may be important in comparative risk evaluations, creating O/E, research, etc Current risk models are not modifiable Biochemical model may be more accurate, C-statistic.82 Biochemical models may be modifiable - 30 days Angioplasty +??? days Time 6

7 Thank You Michael Conte Joe Rapp Alexander Reyzelman Linda Reilly Warren Gasper Marlene Grenon Sandre Perez Christine Hall Beverly Scott Hugh Alley Christine Patton 7