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12/1/17 Disclosures § Grant support from NIH § Grant support from Pfizer § Honoraria received from Gilead Inflammation and Cardiovascular Disease: 2017 Updates Priscilla Hsue, MD FACC William Watt Kerr Professor of Medicine Division of Cardiology Zuckerberg San Francisco General University of California, San Francisco Inflammation and CVD • Inflammatory biomarkers are predictive of CV events • Inflammation and atherosclerosis: pathophysiology • Benefit of statins on CV events most pronounced among individuals who lower LDL and inflammatory biomarkers • Can targeted anti-inflammatory therapies reduce CV events and prolong life (with effects on cancer)? – CIRT – CANTOS • Inflammation and heart failure (HFrEF and HFpEF) • Special populations: DM, HIV, and RA 1

12/1/17 Role of inflammation in atherothrombosis: Inflammation in Atherosclerosis: From Pathophysiology to Practice Innate Immunity Adaptive Immunity Hansson GK et al NEJM 2005 Hansson GK Circulation 2017 Libby P et al JACC 2009 Residual inflammatory risk: what are options after statin How Common is Residual Inflammatory Risk? treatment? IMPROVE-IT PROVE-IT 40mg Pravastatin vs 80mg Atorvastatin in 3745 ACS pts 40mg Simvastatin vs. 40mg Dr. Phan to simvastatin+ 10mg discuss ezetimibe in 15179 ACS pts tomorrow! Residual Inflammatory Risk Residual Cholesterol Risk Both Neither hsCRP > 2 mg/L hsCRP < 2 mg/L hsCRP > 2 mg/L hsCRP < 2 mg/L LDLC < 70 mg/dL LDLC > 70 mg/dL LDLC > 70 mg/dL LDLC < 70 mg/dL Ridker PM European Heart Journal 2016 Ridker PM. Circulation Res 2017;120:617-9. 2

12/1/17 • Inflammatory biomarkers predict CV events 543 healthy men randomized to asa vs. placebo Take home: Baseline hsCRP predicts risk of future MI and stroke in short/long term Physicians Health Study: Benefit of aspirin is modified by IL-6, a crucial inflammatory cytokine, is a strong predictor underlying inflammation of future heart attack and stroke Nested case control in P Trend = 0.001 Physicians Health Study For each quartile increase 4 P= 0.01 in IL-6, there was as 38% P =0.003 The role of aspirin increase in risk, P=0.001 Relative Risk of MI Benefit of aspirin is highest among pts with highest quartile of baseline hsCRP as an anti-inflammatory 3 agent for protection (Risk Reduction 55.7%, p=0.02) Relative Risk against cardiovascular P =0.3 No benefit of aspirin among individuals with hsCRP in lowest quartile events Myocardial 2 Infarction (Risk reduction 13.9%, p=0.77) Take home: benefit of aspirin directly related to hsCRP level 1 1 0 0 Placebo 1 2 3 4 4 3 Aspirin £ 1.04 1.04-1.46 1.47-2.28 ³ 2.28 2 1 Quartile of hsCRP Quartile of IL-6 (range, pg/dL) Ridker et al N Engl J Med 1997;336:973-9 16 Ridker et al Circulation 2000;101:1767-1772 3

12/1/17 Meta-analysis of 54 Prospective Cohort Studies Meta-analysis of 54 Prospective Cohort Studies Inflammation and risk of future cardiovascular events: 2010 The magnitude of independent risk associated with inflammation is at least as large, if not larger, than that of BP and cholesterol. However, in contrast to BP and cholesterol, no clinical trials have been completed to see if lowering inflammation can lower cardiac event rates. Coronary Heart Disease All Vascular Deaths Risk Ratio (95%CI) 3.0 3.0 Risk ratio (95% CI) hsCRP 1.37 (1.27-1.48) 2.5 2.5 2.0 2.0 Systolic BP 1.35 (1.25-1.45) 1.5 1.5 1.0 1.0 T otal cholesterol 1.16 (1.06-1.28) Non-HDLC 1.28 (1.16-1.40) 0.5 1.0 2.0 4.0 8.0 0.5 1.0 2.0 4.0 8.0 0.5 1.0 1.2 1.4 1.8 hsCRP concentration (mg/L) Risk Ratio (95%CI) per 1-SD higher usual values Emerging Risk Factor Collaborators, Lancet January 2010 Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hsCRP Emerging Risk Factor Collaborators, Lancet January 2010 Cardiovascular Inflammation Reduction Trial (CIRT) Translation to clinical practice Ridker PM JAMA 2007 www.reynoldsriskscore.org Ridker PM Circulation 2008 • Individuals benefit the most from statins who reduce LDL and Reynolds Risk reduce inflammatory markers Score Age Smoking SBP TC HDLC hsCRP Family History HbA1c hsCRP (mg/L) is not CRP (mg/dL) 4

12/1/17 PROVE IT-TIMI 22: 80mg atorvastatin vs. 40mg pravastatin after ACS Statin treatment, hsCRP, and CV events 0.10 CARE: Secondary prevention using 40mg Median hsCRP was 21.6% lower in those on LDL > 70 mg/dL, hsCRP > 2 mg/L pravastatin pravastatin at 5 years 0.08 LDL > 70 mg/dL, hsCRP < 2 mg/L LDL < 70 mg/dL, hsCRP > 2 mg/L 0.06 LDL < 70 mg/dL, hsCRP < 2 mg/L 0.04 0.02 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Follow-Up (Y ears) Ridker P at al Circulation 1998 Ridker P et al Circulation 1999 Ridker et al NEJM 2005;352:20-28. JUPITER Lower is better not only for LDL but also inflammation Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP Rosuvastatin 20 mg (N=8901) No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL Placebo (N=8901) 4-week hsCRP >2 mg/L run-in Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany , Israel, Mexico, Netherlands, Norway , Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay , United States, Venezuela Mean LDLC 104 mg/dL, Mean HDLC 50 mg/dL, hsCRP 4 mg/L Ridker P European Heart Journal 2016 5

12/1/17 JUPITER (MI, CVA, UA/Revascularization, CV Death Benefit of JUPITER in all subgroups, most among those with low LDL and low hsCRP 251/8901 -44% HR 0.56, 95%CI 0.46-0.69 P<0.00001 142/8901 NNT = 25 Libby P et al JACC 2009 Ridker P et al NEJM 2008 Cardiovascular Inflammation Reduction Trial (CIRT) JUPITER: Are statins anti-inflammatory? 140 120 • Studies of anti-inflammatory agents used in RA LDL (mg/dL) 100 80 Is the large benefit 60 40 observed in the 20 LDL DL decr crease 50 per ercent at 12 mo months hs JUPITER Trial due to 0 lipid lowering, to 5 inflammation inhibition, hsCRP (mg/L) 4 or to a combination of 3 these two processes? 2 1 hsCRP RP de decrease se 37 pe percent at 12 mo months 0 0 12 24 36 48 Months 6

12/1/17 Cardiovascular Inflammation Reduction Trial (CIRT) Atherothrombosis in rheumatic diseases Why Low Dose Methotrexate (LDM)? II. Observational evidence strongly suggests a reduction in vascular events Cohort Group HR * (95 % CI) Endpoint Exposure Wichita RA 0.4 (0.2 - 0.8) Total Mortality LDM Choi 2002 0.3 (0.2 - 0.7) CV Mortality LDM 0.4 (0.3 – 0.8) CV Mortality LDM < 15 mg/wk Netherlands RA 0.3 (0.1 – 0.7) CVD LDM only van Helm 2006 0.2 (0.1 – 0.5) CVD LDM + SSZ 0.2 (0.1 – 1.2) CVD LDM + HCQ 0.2 (0.1 – 0.5) CVD LDM + SSZ + HCQ Miami VA PsA 0.7 (0.6 – 0.9) CVD LDM Pradanovich 2005 0.5 (0.3 – 0.8) CVD LDM < 15 mg/wk RA 0.8 (0.7 – 1.0) CVD LDM 0.6 (0.5 – 0.8) CVD LDM < 15 mg/wk CORRONA RA 0.6 (0.3 – 1.2) CVD LDM Solomon 2008 0.4 (0.2 – 0.8) CVD TNF-inhibitor QUEST-RA RA 0.85 (0.8 – 0.9) CVD LDM Narango 2008 0.82 (0.7 – 0.9) MI LDM 0.89 (0.8 - 1.0) Stroke LDM UK Norfolk RA, PsA 0.6 (0.4 – 1.0) Total Mortality LDM Mason JC et al Eur Heart Journal 2015 2008 0.5 (0.3 – 1.1) CV Mortality LDM Cardiovascular Inflammation Reduction Trial (CIRT) Colchicine as an anti-inflammatory agent in CAD Overall Design and Primary Aim Low Dose Colchicine for 2 o Prevention Plaque stabilization in ACS Stable CAD, Reduced CV events Stable CAD (past history of MI or • To directly test the inflammatory multi-vessel CAD on angiogram) hypothesis of atherothrombosis. On Statin, ACE/ARB, BB, ASA To evaluate in a randomized, • double-blind, placebo-controlled trial whether LDM given at a target Persistent Evidence of Inflammation dose of 15 to 20 mg po weekly will Diabetes or Metabolic Syndrome reduce rates of myocardial Pre-Colchicine infarction, stroke, or cardiovascular death among patients with stable coronary artery disease and either type 2 diabetes or metabolic LDM 15-20 mg po LDM placebo po syndrome. once weekly once weekly + daily folate + daily folate Post-Colchicine Nonfatal MI, Nonfatal Stroke, N = 7,000 NHLBI-Sponsored Cardiovascular Death 350- 400 US and Canadian Sites Vaidya K JACC CV Imaging 2017 Nidorf SM et al JACC 2013 7

12/1/17 Targeting inflammation: Moving upstream • Moving upstream in the inflammatory pathway: IL-1β Ridker P Circulation Research 2016 IL-1β inhibition using canakinumab • Canakinumab is a human monoclonal IL-1β antibody indicated for treatment inflammatory disorders such as CAPS and Muckle-Wells syndrome – Dosing is quarterly subcutaneous injection • Binds IL-1β and blocks interaction of cytokine with type I and II receptors • Produces a rapid and sustained inhibition of inflammation with only modest effects on lipids Ridker P et al Lancet August 27, 2017 8