Subodh Verma, MD PhD FRCSC

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2 CIRT and CANTOS Targeting g Inflammation at in Atherosclerosis e s Subodh Verma, MD PhD FRCSC Cardiac Surgeon, St. Michael s Hospital Associate Professor, Surgery & Pharmacology Canada Research Chair in Atherosclerosis Director Traineeship in Atherosclerosis University of Toronto Toronto, Canada

3 Disclosures: Subodh Verma Honoraria and Consulting Fees AstraZeneca Actelion Abbott Medtronic Servier Sorin Novartis Roche GSK Takeda Merck BMS Sanofi-Aventis Amgen Lilly Nutrasource

4 Historical Perspective 1. Aging g Hypothesis 2. Lipid Hypothesis 3. Response to Injury Hypothesis 4. Inflammatory Hypothesis

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7 Role of MMP and TIMPs in Plaque Stability Matrix Degradation Altered Cell-Matrix Contacts (integrins) Cytokine Activation

8 Inflammation Regulates Metabolism of Fibrillar Collagen influencing vulnerability Libby P, in Contemporary Cardiology, 2006

9 Atherosclerosis is a Complex, Heterogeneous and Multifactorial Disease Various Cell Types Endothelial Cells Macrophages Vascular Smooth Muscle Cells Dendritic cells Immune Activation and Cytokine Production Innate Immunity Adaptive Immunity Multiple Transducers AP-1 NFkB Multiple Genes and Genetic Susceptibilities Multiple Risk Factors Environmental Hemodynamic

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11 Innate Immunity in Atherosclerosis Libby et al. JACC 2009

12 Adaptive Immune Cells in Atherosclerosis Libby et al. JACC 2009

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23 The Cardiovascular Inflammation Reduction Trial (CIRT) Scientific Rationale and Trial Overview Slide Set for Investigators

24 Chair: Paul M Ridker, MD, MPH Robert J. Glynn, ScD Brendan M. Everett, MD, MPH Aruna D. Pradhan, MD, MPH Ahmed Hasan, MD, PhD Daniel H. Solomon, MD Peter Libby, MD Michael Clearfield, DO Milan Gupta, MD Subodh Verma, MD PhD Nina Paynter, PhD Julie Buring, ScD Jean MacFadyen, BA Elaine Zaharris, BA

25 Cardiovascular Inflammation Reduction Trial (CIRT) What is CIRT? CIRT is an NHLBI-funded randomized double-blind placebo-controlled trial designed to: directly test the inflammatory hypothesis of atherothrombosis determine whether the common anti-inflammatory drug low-dose methotrexate (LDM, target dose of 15 to 20 mg po weekly) will reduce rates of recurrent myocardial infarction, stroke, or cardiovascular death among patients with a prior history of myocardial infarction and either type 2 diabetes or metabolic syndrome determine whether LDM will reduce the rate of new onset type 2 diabetes among those with metabolic syndrome at study entry N = 7,000 NHLBI-Sponsored Enrollment to Start March US and Canadian Sites

26 Cardiovascular Inflammation Reduction Trial (CIRT) Why is the NHLBI funding CIRT? Like rheumatoid arthritis and psoriasis [two inflammatory disorders successfully treated with low-dose methotrexate (LDM)], atherothrombosis is an inflammatory disease. Yet, to date, no clinical trial has been completed that addresses whether inhibiting inflammation may reduce cardiovascular event rates.

27 Cardiovascular Inflammation Reduction Trial (CIRT) Inflammation as a predictor of future heart attack and stroke Meta-analysis of 54 Prospective Cohort Studies Inflammation and risk of future cardiovascular events: 2010 Coronary Heart Disease All Vascular Deaths Risk ra atio (95% CI) hscrp concentration (mg/l) Emerging g Risk Factor Collaborators, Lancet January 2010

28 Cardiovascular Inflammation Reduction Trial (CIRT) Meta-analysis of 54 Prospective Cohort Studies 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. Risk Ratio (95%CI) hscrp Systolic BP Total cholesterol Non-HDLC 1.37 ( ) 1.35 ( ) 1.16 ( ) 1.28 ( ) Risk Ratio (95%CI) per 1-SD higher usual values Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hscrp Emerging Risk Factor Collaborators, Lancet January 2010 CR-153

29 Cardiovascular Inflammation Reduction Trial (CIRT) The fundamental question Can Targeted Anti-Inflammatory Therapy Reduce Cardiovascular Event Rates and Prolong Life? 154

30 Cardiovascular Inflammation Reduction Trial (CIRT) Can targeted anti-inflammatory therapies reduce cardiovascular event rates and prolong life? 4 The role of aspirin as an anti-inflammatory agent for protection against cardiovascular events 3 2 Relative Risk Myocardial Infarction 1 Placebo Aspirin 1 2 Quartile of hscrp Ridker et al N Engl J Med 1997;336:

31 Cardiovascular Inflammation Reduction Trial (CIRT) Inflammation and Statin Therapy - Part I Rela ative Risk 3 2 Trend = (P= ) 004) P Trend = dl) Median hs scrp (mg/ Placebo 1 Pravastatin 0 Pravastatin Placebo Pravastatin Placebo Inflammation Absent Inflammation Present Baseline 5 Years Ridker et al Circulation. 1998;98: Ridker et al Circulation. 1999;100:

32 Cardiovascular Inflammation Reduction Trial (CIRT) JUPITER: Are statins anti-inflammatory? 0.08 HR 0.56, 95% CI P < Placebo 251 / 8901 Cumula ative Incide ence Number Needed to Treat (NNT 5 ) = % Rosuvastatin 142 / Follow-up (years) Ridker et al NEJM 2008;359:

33 Cardiovascular Inflammation Reduction Trial (CIRT) JUPITER: Are statins anti-inflammatory? LD DL (mg/dl L) hscrp (mg/l) LDL decrease 50 percent at 12 months hscrp decrease 37 percent at 12 months Months Is the large benefit observed in the JUPITER trial due to lipid lowering, to inflammation inhibition, or to a combination of these two processes?

34 Cardiovascular Inflammation Reduction Trial (CIRT) JUPITER: LDL reduction and inflammation reduction both contribute to clinical benefits N Rate Placebo LDL>70mg/dL,hsCRP>2 mg/l LDL<70mg/dL,hsCRP>2 mg/l LDL 70mg/dL,hsCRP 2 mg/l LDL<70mg/dL,hsCRP<2 mg/l LDL>70mg/dL,hsCRP<2 mg/l P < Placebo LDL>70mg/dL,hsCRP>1 mg/l LDL<70mg/dL,hsCRP>1 mg/l LDL>70mg/dL,hsCRP<1 mg/l LDL<70mg/dL,hsCRP<1 mg/l P < Rosuvastatin Rosuvastatin Fully Adjusted Hazard Ratio Better Worse 0.21, 95% CI , P < Ridker et al Lancet 2009;373:

35 Cardiovascular Inflammation Reduction Trial (CIRT) Design considerations Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Evidence of Inflammation How to define? DM or MetSyn What agent to study? Low Dose Methotrexate Anti-Inflammatory Intervention Placebo Nonfatal MI, Nonfatal Stroke, Cardiovascular Death Ridker P. Thromb Haemost 2009

36 Cardiovascular Inflammation Reduction Trial (CIRT) Issues in the selection of anti-inflammatory agents for trials of cardiovascular inflammation inhibition Statins TC LDL HDL TG Chylo CRP / IL-6

37 Cardiovascular Inflammation Reduction Trial (CIRT) Issues in the selection of anti-inflammatory agents for trials of cardiovascular inflammation inhibition Statins TNF Inhibition IL-6 Inhibition TC LDL HDL TG Chylo CRP / IL-6

38 Cardiovascular Inflammation Reduction Trial (CIRT) Issues in the selection of anti-inflammatory agents for trials of cardiovascular inflammation inhibition Statins TNF Inhibition IL-6 Inhibition Low Dose Methotrexate TC LDL HDL TG Chylo CRP / IL-6

39 Cardiovascular Inflammation Reduction Trial (CIRT) Why low-dose methotrexate? I. Extensive clinical experience and well-known safety yprofile Low Dose Methotrexate (15 to 20 mg po weekly + folic acid) Used weekly by millions of Americans and Canadians as first line therapy for rheumatoid arthritis and psoriasis. Enviable safety record with over 40 years of use among older individuals with similar co-morbidities as those who have suffered a prior heart attack. Inexpensive and widely used, unlikely to have any unknown off-target effects. Guidelines for safe use already exist and are strictly followed in the CIRT protocol and in its inclusion and exclusion criteria.

40 Cardiovascular Inflammation Reduction Trial (CIRT) Why Low Dose Methotrexate (LDM)? II. Observational evidence strongly gysuggests a reduction in vascular events Cohort Group HR * (95 % CI) Endpoint Exposure Wichita RA 0.4 ( ) Total Mortality LDM Choi (0.2-07) 0.7) CV Mortality LDM 0.4 ( ) CV Mortality LDM < 15 mg/wk Netherlands RA 0.3 ( ) CVD LDM only van Helm ( ) CVD LDM + SSZ 0.2 ( ) CVD LDM + HCQ 0.2 ( ) CVD LDM + SSZ + HCQ Miami VA PsA 0.7 ( ) CVD LDM Pradanovich (0.3 08) 0.8) CVD LDM < 15 mg/wk RA 0.8 ( ) CVD LDM 0.6 ( ) CVD LDM < 15 mg/wk CORRONA RA 0.6 ( ) CVD LDM Solomon ( ) CVD TNF-inhibitor QUEST-RA RA 0.85 ( ) CVD LDM Narango ( ) MI LDM (0.8-10) 1.0) Stroke LDM UK Norfolk RA, PsA 0.6 ( ) Total Mortality LDM ( ) CV Mortality LDM

41 Cardiovascular Inflammation Reduction Trial (CIRT) Why Low Dose Methotrexate (LDM)? III. Methotrexate Inhibits Atherogenesis in Cholesterol-fed Rabbits H&E Anti-VSMC Anti-rabbit macrophage Anti-rabbit MMP-9 MTX Control MTX Control Bulgarelli et al, J Cardiovasc Pharmacol 2012;59:308-14

42 Cardiovascular Inflammation Reduction Trial (CIRT) Overall Design and Primary Aim Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Evidence of Inflammation Diabetes or Metabolic Syndrome LDM mg po once weekly + daily folate LDM placebo po once weekly + daily folate To directly test the inflammatory hypothesis of atherothrombosis. To evaluate in a randomized, double-blind, placebo-controlled trial whether LDM given at a target dose of 15 to 20 mg po weekly will reduce rates of recurrent myocardial infarction, stroke, or cardiovascular death among patients with a prior history of myocardial infarction and either type 2 diabetes or metabolic syndrome. Nonfatal MI, Nonfatal Stroke, Cardiovascular Death N = 7,000 NHLBI-Sponsored Enrollment to Start March US and Canadian Sites

43 Cardiovascular Inflammation Reduction Trial (CIRT) Secondary Aims To determine in a randomized, double-blind, placebo-controlled trial whether LDM will reduce rates of: all-cause mortality hospitalization for unstable angina incident congestive heart failure deep vein thrombosis and/or pulmonary embolism percutaneous revascularization or coronary artery bypass procedures atrial fibrillation new onset diabetes among those with metabolic syndrome but not tdiabetes at study entry progression of peripheral vascular disease aortic stenosis

44 Cardiovascular Inflammation Reduction Trial (CIRT) Study Population and Basic Inclusion Criteria CIRT will include approximately 7,000 men and women aged 18 years and over have suffered a documented myocardial infarction in the past five years have completed any planned coronary revascularization a a procedures es associated a with the qualifying event have been on a stable secondary prevention regimen for a minimum i of 60 days have either type 2 diabetes or metabolic syndrome no contraindication to LDM

45 Cardiovascular Inflammation Reduction Trial (CIRT) Exclusion Criteria I. Contraindications to Methotrexate Chronic infectious disease tuberculosis severe fungal disease chronic hepatitis B or C known HIV infection Renal insufficiency Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis Non-basal cell malignancy or treated lymphoproliferative disease within the past 5 years Abnormal baseline blood counts or LFTs History of alcohol abuse or unwillingness to limit alcohol consumption to less than 4 drinks weekly Women of child bearing potential or those intending to breastfeed Class IV heart failure

46 Cardiovascular Inflammation Reduction Trial (CIRT) Exclusion Criteria II. Concomitant Medications Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazol) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible Currently taking methotrexate, oral steroids, or other immunosuppressive or biologic response modifiers Eligible study participants will be encouraged to have up to date pneumococcal and influenza vaccinations as recommended based on their age and underlying medical conditions All of these inclusion and exclusion criteria are consistent with or more conservative than those recommended by the American College of Rheumatology for the use of methotrexate in rheumatoid arthritis or psoriasis

47 Cardiovascular Inflammation Reduction Trial (CIRT) LDM Complications Will Be Minimized Regular monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose reductions while maintaining the study blind, and provide an efficient method to address issues of compliance and follow-up on a cost-effective centralized basis. All dose adjustments will be made centrally following simple clinical algorithms Medical monitors with methorexate expertise available at all times Study drug will be dispensed in child-safe monthly calendar packs to improve safety and compliance

48 Cardiovascular Inflammation Reduction Trial (CIRT) thecirt.org website

49 Inflammation, Atherothrombosis, and Vascular Prevention: Three Crucial Questions Is there evidence that individuals with elevated levels of inflammatory biomarkers are at high vascular risk even when other risk factors are acceptable? YES Is there evidence that individuals identified at increased risk due to inflammation benefit from a therapy they otherwise would not have received? YES Is there evidence that reducing inflammation per se will reduce vascular events? LET S FIND OUT CIRT/CANTOS

50 Annals Int Med 1961;55:33-50