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

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

Ezetimibe / Simvastatin 10 / 40 mg Simvastatin 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

N=18,144

Study Design

Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

Simva — 22.2% EZ/Simva — 20.4% HR 0.90 CI (0.84, 0.97) p=0.003

Background

Cannon CP, Blazing MA, Giugliano RP, et. al. N Engl J Med 2015

KM Rate of CVD/MI/Stroke at 7 yr (%)

Addition of ezetimibe to statin therapy reduces the risk of recurrent CV events in patients with prior ACS

1.8% ARR NNT 56

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

NT-proBNP

<450 ≥450

33.5% 66.5%

NT-proBNP (pg/mL)

GDF-15

<1800 >1800

25.9% 74.1%

GDF-15 (pg/mL)

hsCRP

<2 ≥2 hsCRP (mg/L)

54.4% 45.6%

hsTnT

<14 ≥14

High % of established CAD pts have elevated biomarkers

36.2% 63.8%

hsTnT (ng/L)

Qamar AHA 2017

Results

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

Significant correlation between biomarkers representing different pathobiological axes

Qamar AHA 2017

5 10 15 20 25 30 35 40

hsTnT NT-proBNP GDF-15 hsCRP

Q1 Q2 Q3 Q4 P-trend <0.001*

Graded in risk of MACE across levels of each biomarker

KM Rate (%) of CVD/MI/Stroke at 7 yr

10 16 22 34 13 17 19 32 15 15 19 33 16 18 20 25

Biomarkers & Risk of MACE

Qamar AHA 2017

5 10 15 20 25

hsTnT NT-proBNP GDF-15 hsCRP

Q1 Q2 Q3 Q4 P-trend <0.001*

KM Rate (%) of CV Death/HF at 7 yr

Graded in risk of CV Death/HF across biomarker levels

2 6 9 23 3 5 9 23 4 5 9 22 6 7 10 14

Biomarkers & Risk of CV Death/HF

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Biomarkers and Adjusted Risk of CV Events

Biomarkers were independently associated w/ risk of CV death, MI, stroke

*Adjusted for TRS 2P: Age, DM, HTN, Smoking, PAD, Prior Stroke, Prior CABG, CHF, and Renal dysfunction.

*

(Q4 vs. Q1)

Qamar AHA 2017

Multimarker Strategy for Risk Stratification

5 10 15 20 25 30

Low Risk (Score 0) Intermediate Risk (Score 1-2) High Risk (Score 3-4)

KM Rate of CVD/MI/Stroke at 6.5 yr (%)

N=1916 N=3842 N=1437

7.9 14.5 28.4 Ref.

Incremental increase in the risk of CV events across biomarker risk categories

Adj HR 1.6 (1.4-2.0) Adj HR 2.6 (2.1-3.2)

*Adjusted for TRS 2P: Age, DM, HTN, Smoking, PAD, Prior Stroke, Prior CABG, CHF, and Renal dysfunction.

Multimarker Score Assign pts 1 point for the presence

• f each elevated biomarker
• hsTnT>14 ng/L
• NT-proBNP>450 pg/mL
• GDF-15>1800 pg/mL
• hsCRP>2 mg/L

Qamar AHA 2017

KM Rate of CVD/MI/Stroke at 6.5 yr (%)

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7.3% ARR NNT 14 2.5% ARR NNT 40 HR 1.1

High Risk (Score 3-4) Intermediate Risk (Score 1-2) Low Risk (Score 0) __ __ __ Simvastatin __ __ __ Ezetimibe/Simvastatin

High absolute benefit from the addition of ezetimibe to statin therapy in high risk pts

Biomarker-Predicted Risk & Absolute Benefit of Ezetimibe

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