Lipoprotein(a), PCSK9 Inhibition and Cardiovascular Risk: Insights from the FOURIER Trial Michelle L. O Donoghue, Robert P. Giugliano, Anthony C. Keech, Estella Kanevsky, KyungAh Im, Peter S. Sever, Terje R. Pedersen, Marc S. Sabatine European Atherosclerosis Society May 7, 218
KM Rate (%) at 3 Years Summary of Effects of PCSK9i Evolocumab LDL-C by 59% down to a median of 3 mg/dl CV outcomes in patients on statin Safe and well-tolerated Placebo 59% reduction P<.1 Absolute 56 mg/dl 15 1 HR.85 (.79-.92) P<.1 14.6 12.6 HR.8 (.73-.88) P<.1 9.9 7.9 Evolocumab (median 3 mg/dl, IQR 19-46 mg/dl) 5 CVD, MI, stroke UA, cor revasc CVD, MI, stroke Sabatine MS et al. NEJM 217;376:1713-22
Lp(a) and Risk of MI Mendelian randomization data support a causal role for Lp(a) in risk of coronary heart disease Risk of MI for Doubling in Lp(a) concentration Kamstrup et al, JAMA. 29;31(22):2331-2339
Methods Lp(a) was measured at baseline and weeks 12 and 48 at Medpace Reference Laboratories (Medpace Inc. Cincinnati, OH) using an isoform-independent immunoturbidometric assay (Polymedco, Cortlandt Manor, New York) Association between Lp(a) and CV risk Examined in placebo arm Unadjusted, and then adjusting for age, sex, race, weight, region, prior MI, history of stroke, PAD, HTN, DM, current smoking, baseline LDL-C Effect of evolocumab On Lp(a) and LDL-C CV outcomes by baseline Lp(a) concentration Association of achieved Lp(a), achieved LDL and CV risk Kaplan-Meier rates are reported at 3 years
Percent Percent 4 Descriptive Statistics N = 25,96 Mean ± Std: 94.1 ± 112.7 Median (IQR): 37 (13, 165) Min, max: 5, 1451 Baseline Distribution of Lp(a) 35 3 Descriptive Statistics N=2596 Median (IQR) = 37 (13-165) nmol/l 25 2 15 1 5 5 1 15 2 25 3 35 4 45 5 55 6 Baseline lp(a) Lp(a) in (nmol/l)
Baseline Characteristics Q1 (<14nM) Q2 (14-37nM) Q3 (38-165nM) Q4 (>165nM) P value Age, y, mean (SD) 62 (9.) 63 (9.1) 62 (9.1) 63 (8.8).8 Male sex 8% 76% 76% 68% <.1 Type of CV disease Myocardial infarction 79% 79% 81% 83% <.1 Ischemic stroke 21% 21% 2% 17% <.1 CV Risk Factor Quartiles of baseline Lp(a) PAD 13% 13% 13% 15% <.1 Hypertension 81% 81% 79% 8%.55 Diabetes Mellitus 41% 36% 36% 34% <.1 Current tobacco 3% 3% 29% 25% <.1 Baseline LDL-C, mean (SD) 93 (25) 96 (27) 98 (31) 11 (27) <.1
KM rates at 3 years (%) Baseline Lp(a) and CV Risk 12. Q1 Q2 Q3 Q4 Adjusted HR Q4:Q1 = 1.12 (95% CI.93-1.34) 11.7 1. Adjusted HR Q4:Q1 = 1.26 (95% CI 1.2-1.56) 9.5 1.3 8. 8.1 8.4 7.8 6.8 6. 6. 4. 2.. CHD death or MI CV death, MI or stroke MV model: Age, sex, race, weight, region, prior MI, history of stroke, PAD, HTN, DM, current smoking, baseline LDL-C Restricted to placebo arm
KM rates at 3 years (%) Baseline Lp(a) and CV Risk 8. Adj HR Q4:Q1 = 1.31 (95% CI 1.4-1.66) Q1 Q2 Q3 Q4 7. 7. 6.8 6. 5.5 5.5 5. Adj HR Q4:Q1 =.92 (95% CI.63-1.33) 4. 3.3 Adj HR Q4:Q1 =1.23 (95% CI.81-1.89) 3. 2. 2.4 2.1 2.4 1.6 1.3 1.5 2. 1.. Myocardial infarction Stroke Coronary death MV model: Age, sex, race, weight, region, prior MI, history of stroke, PAD, HTN, DM, current smoking, baseline LDL-C Restricted to placebo arm
nmol/l Change in Lp(a) from Baseline to Week 48 with Evolocumab % 2 Median absolute change in Lp(a) 5 Median % change in Lp(a) -2-5 -4-1 -6-15 -8-2 -1-25 -12-11 nmol/l -3-26.9% Placebo-controlled values
Percent Percent 4 Absolute Descriptive Statistics change in Lp(a) for patients N = 11,864 Mean ± Std: -22.4 ± 4.4 Median (IQR): -11. (-32., -1.) Min, max: -63, 425 on evolocumab 35 3 Descriptive Statistics N=11864 Median (IQR) = -11 (-32, -1) nmol/l 25 2 15 1 5-2 -18-16 -14-12 -1-8 -6-4 -2 2 4 6 8 1 Lp(a) Change from Baseline to 48 Weeks Absolute change from baseline to 48 weeks nmol/l
Percent Percent 2 18 % change in Lp(a) for patients on evolocumab Descriptive Statistics N = 11,864 Mean ± Std: -23.7 ± 88.7 Median (IQR): -26.9 (-46.7, -6.2) Min, max: -98.3, 6,71.4 16 14 Descriptive Statistics N=11864 Median (IQR) = -26.9 (-46.7, -6.2) % 12 1 8 6 4 2-1 -8-6 -4-2 2 4 6 8 1 12 14 16 18 2 Lp(a) Percent Change Baseline to 48 Weeks Lp(a) % change from baseline to 48 weeks
nmol/l % Change in Lp(a) by Quartile of Baseline Lp(a) with Evolocumab Median absolute change in Lp(a) Median % change in Lp(a) 5 Q1 Q2 Q3 Q4 5 Q1 Q2 Q3 Q4-5 -1-5 -1-15 -2-9 -1-15 -2-25 -9.1-16 -25-24 -3-3 -35-32.5-35 -4-36 -4-45 -41.9 *Reflects change from baseline to week 48 Placebo-controlled values
Absolute change in LDL-C (mg/dl) Absolute change in Lp(a) versus LDL for patients on evolocumab 25 2 r =.21 15 1 Change in LDL-C, mg/dl 5-5 -1-15 -2-25 -25-2 -15-1 -5 5 1 15 2 25 Change in Lp(a), nmol/l) Absolute change in Lp(a) (nmol/l) Change from baseline to week 48
% change in Lp(a) versus LDL for patients on evolocumab 1 r =.37 8 6 Change LDL-C inin LDL-C change % Percent 4 2-2 -4-6 -8-1 -1-8 -6-4 -2 2 4 6 8 1 Percent Change in Lp(a) % change in Lp(a) Change from baseline to week 48
CV death, MI or stroke (3y KM rate, %) Efficacy by Baseline Lp(a) 12 1 Evolocumab Placebo HR.85 (95% CI.73-.97) ARR=1.26% NNT=79 HR.76 (95% CI.66-.86) ARR=2.8% NNT=36 1.97 P interaction=.26 8 7.48 8.74 8.17 6 4 2 Lp(a) <=median Lp(a) >median
CV death, MI or stroke beyond week 12 (%) Achieved Lp(a), LDL and CV Risk P<.1 1 9 9.43% 8.45% 8 7 6 7.88% 6.57% 5 4 3 2 LDL-C>median 1 Lp(a) >median Lp(a) <=median LDL-C <=median KM rate at 3 years
Summary Evolocumab significantly reduces Lp(a) concentration Patients starting with higher Lp(a) levels appear to derive greater absolute benefit from PCSK9 inhibition. Patients who achieve lower levels of both LDL-C and Lp(a) have the lowest subsequent risk of CV events.