Biomarkers, Cardiovascular Outcomes & Effect of Ezetimibe after - PowerPoint PPT Presentation

Biomarkers, Cardiovascular Outcomes & Effect of Ezetimibe after ACS in the IMPROVE-IT Trial Arman Qamar , Robert P. Giugliano, Michael A. Blazing, Jeong-Gun Park, Sabina A. Murphy, Christopher P. Cannon, Eugene Braunwald, David A. Morrow On behalf of the IMPROVE IT Investigators American Heart Association Scientific Sessions November 13, 2017 An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Study Design Patients stabilized post ACS ≤ 10 days: LDL-C 50 – 125 mg/dL (or 50 – 100 mg/dL if prior lipid-lowering Rx) Standard Medical & Interventional Therapy N=18,144 Simvastatin Ezetimibe / Simvastatin 40 mg 10 / 40 mg Follow-up Visit Day 30, every 4 months Duration: Minimum 2 ½-year follow-up (Median f/u 6 yrs) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization (≥ 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

Background Addition of ezetimibe to statin therapy reduces the risk of recurrent CV events in patients with prior ACS KM Rate of CVD/MI/Stroke at 7 yr (%) HR 0.90 CI (0.84, 0.97) Simva — 22.2% p=0.003 1.8% ARR NNT 56 EZ/Simva — 20.4% Cannon CP, Blazing MA, Giugliano RP, et. al. N Engl J Med 2015

Background Biomarkers improve risk stratification of patients with CAD Kragelund C, et al. NEJM, 2005 Omland T, et al. NEJM, 2009

Objectives To assess the application of available cardiac biomarkers for: 1. Long-term risk stratification 2. Therapeutic decision-making with ezetimibe Qamar AHA 2017

Methods • Prespecified biomarker analysis ( hsTnT, NT-proBNP, GDF-15 & hsCRP [Roche Diagnostics])) in stable phase after ACS (1 month after randomization; N=7,327 pts) • Pts with recurrent CV events prior to biomarker analyses were excluded • Outcomes of interest: CVD/MI/Stroke; CVD/HF at 7 yrs Qamar AHA 2017

Results High % of established CAD pts have elevated biomarkers hsTnT NT-proBNP hsCRP GDF-15 36.2% 63.8% 33.5% 66.5% 25.9% 74.1% 45.6% 54.4% ≥2 <2 ≥14 ≥450 <14 <450 <1800 >1800 NT-proBNP (pg/mL) hsTnT (ng/L) GDF-15 (pg/mL) hsCRP (mg/L) Qamar AHA 2017

Results Significant correlation between biomarkers representing different pathobiological axes NT-proBNP hsTnT GDF-15 hsCRP NT-proBNP - 0.65* 0.60* 0.24 hsTnT - 0.91* 0.48* GDF-15 - 0.45 hsCRP - *= p<0.05 Qamar AHA 2017

Biomarkers & Risk of MACE Graded in risk of MACE across levels of each biomarker P-trend <0.001* Q1 Q2 Q3 Q4 40 35 34 KM Rate (%) of CVD/MI/Stroke at 7 yr 32 33 30 25 25 22 20 19 19 20 18 17 16 15 16 15 15 13 10 10 5 0 hsTnT NT-proBNP GDF-15 hsCRP Qamar AHA 2017

Biomarkers & Risk of CV Death/HF Graded in risk of CV Death/HF across biomarker levels Q1 Q2 Q3 Q4 P-trend <0.001* 25 23 23 22 KM Rate (%) of CV Death/HF at 7 yr 20 15 14 10 10 9 9 9 7 6 6 5 5 5 4 3 2 0 hsTnT NT-proBNP GDF-15 hsCRP Qamar AHA 2017

Biomarkers and Adjusted Risk of CV Events Biomarkers were independently associated w/ risk of CV death, MI, stroke * (Q4 vs. Q1) Qamar AHA 2017 *Adjusted for TRS 2P: Age, DM, HTN, Smoking, PAD, Prior Stroke, Prior CABG, CHF, and Renal dysfunction.

Multimarker Strategy for Risk Stratification Incremental increase in the risk of CV events across biomarker risk categories Adj HR 30 2.6 (2.1-3.2) Low Risk (Score 0) Multimarker Score KM Rate of CVD/MI/Stroke at 6.5 yr (%) Intermediate Risk (Score 1-2) 28.4 Assign pts 1 point for the presence 25 of each elevated biomarker High Risk (Score 3-4) 20 • hsTnT>14 ng/L Adj HR • NT-proBNP>450 pg/mL 1.6 (1.4-2.0) 15 • GDF-15>1800 pg/mL 14.5 • hsCRP>2 mg/L 10 Ref. 7.9 5 *Adjusted for TRS 2P: Age, DM, HTN, Smoking, PAD, Prior Stroke, Prior CABG, CHF, and Renal dysfunction. 0 Qamar AHA 2017 N=3842 N=1916 N=1437

Biomarker-Predicted Risk & Absolute Benefit of Ezetimibe High absolute benefit from the addition of ezetimibe to statin therapy in high risk pts __ __ __ Simvastatin High Risk (Score 3-4) } __ __ __ Ezetimibe/Simvastatin KM Rate of CVD/MI/Stroke at 6.5 yr (%) 7.3% ARR NNT 14 Intermediate Risk 2.5% ARR (Score 1-2) } NNT 40 Low Risk (Score 0) } HR 1.1 Qamar AHA 2017

Conclusions • A substantial % of pts with established CAD in the stable phase have evidence of ongoing (chronic) myocardial injury, hemodynamic stress, or systemic inflammation • A biomarker based strategy identifies a gradient of risk among those with established CAD offering the potential to further personalize therapy • A multimarker approach identified high risk pts with a correspondingly high absolute benefit from the addition of ezetimibe to statin therapy Qamar AHA 2017