FOURIER: Enough Evidence to Justify Widespread Use? Did It fulfill Its Expectations? CVCT Washington, DC November 3, 2017 Marc S. Sabatine, MD, MPH Chairman, TIMI Study Group Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine, BWH Professor of Medicine, HMS
Disclosures Research Grant Support through BWH: Amgen; AstraZeneca; Daiichi-Sankyo; Eisai; GlaxoSmithKline; Intarcia; Janssen Research Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Poxel; Takeda Scientific Advisory Boards & Consulting: Amgen; Bristol-Myers Squibb; CVS Caremark; Esperion; Intarcia; Janssen Research Development; MedImmune; Merck; Novartis
Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C 70 mg/dl (1.8 mmol/l) or non-hdl-c 100 mg/dl (2.6 mmol/l) Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks Median f/up 2.2 yrs Sabatine MS et al. Am Heart J 2016;173:94-101
LDL Cholesterol (mg/dl) KM Rate (%) at 3 Years 100 80 60 40 Summary of Effects of PCSK9i Evolocumab LDL-C by 59% down to a median of 30 mg/dl CV outcomes in patients on statin Safe and well-tolerated Placebo 59% reduction P<0.00001 Absolute 56 mg/dl 15 10 HR 0.85 (0.79-0.92) P<0.0001 14,6 12,6 HR 0.80 (0.73-0.88) P<0.0001 9,9 7,9 20 Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) 5 0 0 24 48 72 96 120 144 168 Weeks after randomization 0 CVD, MI, stroke UA, cor revasc CVD, MI, stroke Sabatine MS et al. NEJM 2017;376:1713-22
# Events Total Primary Endpoint Events 3000 2714 Total Events RR 0.82 (95%CI 0.75-0.90) P<0.001 2000 1151 Additional Events RR 0.74 (0.65-0.85) 2192 848-522 -303 1000 1563 1st Event HR 0.85 (0.79-0.92) 1344-219 0 Placebo Evolocumab Murphy SA. AHA 2017
Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) 3-yr Kaplan-Meier rate HR (95% CI) CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88) Cardiovascular death 2.5 2.4 1.05 (0.88-1.25) Death due to acute MI 0.26 0.32 0.84 (0.49-1.42) Death due to stroke 0.29 0.30 0.94 (0.58-1.54) Other CV death 1.9 1.8 1.10 (0.90-1.35) Fatal or nonfatal MI 4.4 6.3 0.73 (0.65-0.82) Fatal or nonfatal stroke 2.2 2.6 0.79 (0.66-0.95) 60% of MIs w/ peak Tn 10x ULN 34% in MIs with peak Tn 10x ULN 29% in MIs with peak Tn 100x ULN 34% in STEMI Wiviott SD. AHA 2017 Sabatine MS et al. NEJM 2017;376:1713-22
LDL-C Lowering & CV Death Benefit on mortality was not apparent early, even in trials in which it was the primary endpoint 4S LIPID Lancet 1994;344:1383-89 NEJM 1998;339:1349-57
Genetic Variants and CV Outcomes 112,772 individuals from 14 studies w/ 14,120 major CV events 7 variants in PCSK9 & 6 variants in HMGCR Outcome No. Genetic OR (95%CI) Events Score per 10 mg/dl lower LDL-C Coronary death or MI 10,401 PCSK9 HMGCR 0.81 (0.74-0.89) 0.81 (0.72-0.90) Major coronary event 12,303 Major vascular event 14,120 Coronary death, MI, or stroke 12,073 MI 8,642 Coronary death 2,603 PCSK9 HMGCR PCSK9 HMGCR PCSK9 HMGCR PCSK9 HMGCR PCSK9 HMGCR 0.79 (0.72-0.86) 0.79 (0.69-0.91) 0.80 (0.74-0.86) 0.80 (0.71-0.90) 0.83 (0.76-0.91) 0.82 (0.72-0.92) 0.76 (0.68-0.86) 0.77 (0.65-0.92) 0.85 (0.70-1.00) 0.86 (0.72-1.00) Ference BA et al. & Sabatine MS. NEJM 2016;375:2144-53
Timing of Benefit of LDL-C Lowering Data from CTTC Meta-Analysis of Statin Trials Collins R et al. Lancet 2016;388:2532-61
CV Death, MI, Stroke Landmark Analysis 8% 16% RRR 8% 25% RRR 6% HR 0.84 (95%CI 0.74-0.96) P=0.008 6% HR 0.75 (95%CI 0.66-0.85) P<0.00001 4% 4% Placebo 2% 2% Evolocumab 0% 0% 0 3 6 9 12 12 18 24 30 36 Months from Randomization Sabatine MS et al. NEJM 2017;376:1713-22
Comparison to Cholesterol Treatment Trialists Collaboration Hazard Ratio (CI) per 1 mmol/l reduction in LDL-C Major Coronary Events 0.78 (0.70-0.86) Stroke 0.77 (0.66-0.91) CTTC Meta-analysis Year 2 Coronary revascularization 0.75 (0.67-0.84) Major Vascular Events 0.77 (0.73-0.82) 0.5 Lipid-lowering therapy better 1.0 Lipid-lowering therapy worse 2.0 CIs are 99% for individual outcomes and 95% for MVE CTTC data from Lancet 2010;376:1670-81
Comparison to Cholesterol Treatment Trialists Collaboration Hazard Ratio (CI) per 1 mmol/l reduction in LDL-C Major Coronary Events 0.78 (0.70-0.86) 0.80 (0.71-0.90) Stroke Coronary revascularization Urgent Elective 0.77 (0.66-0.91) 0.77 (0.63-0.94) 0.75 (0.67-0.84) 0.73 (0.62-0.86) 0.84 (0.73-0.98) CTTC Meta-analysis Year 2 FOURIER Year 2 Major Vascular Events 0.77 (0.73-0.82) 0.83 (0.76-0.90) 0.5 Lipid-lowering therapy better 1.0 Lipid-lowering therapy worse 2.0 CIs are 99% for individual outcomes and 95% for MVE for CTTC and 95% for FOURIER Sabatine MS et al. NEJM 2017;376:1713-22
Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any 77.4 77.4 Serious 24.8 24.7 Allergic reaction 3.1 2.9 Injection-site reaction 2.1 1.6 Treatment-related and led to d/c of study drug 1.6 1.5 Muscle-related 5.0 4.8 Cataract 1.7 1.8 Diabetes (new-onset) 8.1 7.7 Neurocognitive 1.6 1.5 Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC Sabatine MS et al. NEJM 2017;376:1713-22
Triaging PCSK9 Inhibition Patient w/ prior MI 65 yo M w/ diabetes and HTN Sabatine & Giugliano. JAMA Cardiol 2017;2:935-6
CV Death, MI, or Stroke Benefit of EvoMab Based on # of High-Risk MI Features High-risk feature: <2 yrs from qualifying MI, 2 prior MIs, or residual multivessel disease Placebo Evolocumab 0 Features 6% RRR 0.5% ARR N=8343 (37% of prior MI trial population) 0 6 12 18 24 30 36 Months after Randomization Sabatine MS. AHA 2017
CV Death, MI, or Stroke Benefit of EvoMab Based on # of High-Risk MI Features High-risk feature: <2 yrs from qualifying MI, 2 prior MIs, or residual multivessel disease Placebo Evolocumab 1 Feature 22% RRR 2.5% ARR P interaction =0.11 N=13,973 (63% of prior MI trial population) 0 6 12 18 24 30 36 Months after Randomization Sabatine MS. AHA 2017
CV Death, MI or Stroke in Patients w/ & w/o Peripheral Artery Disease Bonaca MP et al. & Sabatine MS. Circulation 2017;epub ahead of print
Major Adverse Limb Events Bonaca MP et al. & Sabatine MS. Circulation 2017;epub ahead of print
LDL Cholesterol (mg/dl) LDL Cholesterol In 2034 Pts w/ baseline LDL-C <70 mg/dl 100 90 80 70 60 50 40 30 Placebo (median 66 mg/dl, IQR 56-78 mg/dl) 66% mean reduction (95%CI 62-69), P<0.00001 20 10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Weeks Evolocumab (median 21 mg/dl, IQR 11.5-37 mg/dl) Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;epub ahead of print
Clinical Outcomes by Baseline LDL-C CVD, MI, stroke, UA, or cor revasc HR (95% CI) P interaction All Patients 0.85 (0.79-0.92) Baseline LDL-C <70 mg/dl 0.80 (0.60-1.07) Baseline LDL-C 70 mg/dl 0.86 (0.79-0.92) 0.65 CVD, MI, or stroke 0.4 1.0 2.5 All Patients 0.80 (0.73-0.88) Baseline LDL-C <70 mg/dl 0.70 (0.48-1.01) Baseline LDL-C 70 mg/dl 0.81 (0.73-0.89) 0.44 0.4 1.0 2.5 EvoMab better Pbo better Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;epub ahead of print
CV Death, MI, Stroke LDL-C (mm) Adj HR (95% CI) <0.5 0.69 (0.56-0.85) 0.5-1.3 0.75 (0.64-0.86) 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 referent P = 0.0001 mm 19 39 58 77 97 116 135 155 174 mg/dl LDL-C at 4 weeks Giugliano RP et al. & Sabatine MS. Lancet 2017;309:1962-71
% pts Safety Events by Achieved LDL-C 25 % Patients (n/n) 10 LDL-C (mg/dl) 20 Adj P-values for trend 8 >0.10 for each comparison <20 20-49 15 6 50-69 70-99 10 4 100 5 2 0 SAE AE->Discon New DM Cancer Cataract 0 Neurocog AST/ALT CK Non-CV death Hem stroke Giugliano RP et al. & Sabatine MS. Lancet 2017;309:1962-71
Conclusions 1. PCSK9 inhibition with evolocumab significantly & safely major cardiovascular events when added to statin therapy 2. The achieved benefit further validates the LDL-C hypothesis, now down to ~20 mg/dl 3. We should strive to achieve very low levels of LDL-C early in individuals to maximize cardiovascular benefit