6/30/2018. Cholesterol Management in the 21 st Century: Who Do We Treat? How Low Do We Go? DISCLOSURES

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1 holesterol Management in the 21 st entury: Who Do We Treat? How Low Do We Go? Theodore Feldman MD FA FAP Head of ardiology, FIU Wertheim School of Medicine Medical Director, Prevention and ommunity Health Miami ardiac and Vascular Institute Baptist Health South Florida DISLOSURES SPEAKERS BUREAU: SANOFI, REGENERON, BOERINGER INGELHEIM, ELI LILLY, NOVO NORDISK, NOVARTIS, AKEA, PORTOLA, MERK 2013 A/AHA Guideline on the Treatment of Blood holesterol to Reduce Atherosclerotic ardiovascular Risk in Adults Endorsed by the American Association of ardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American Society for Preventive ardiology, Association of Black ardiologists, Preventive ardiovascular Nurses Association, and WomenHeart: The National oalition for Women with Heart Disease 1

2 itation This slide set is adapted from the 2013 A/AHA Guideline on the Treatment of Blood holesterol to Reduce Atherosclerotic ardiovascular Risk in Adults. E-Published on November 12, 2013, available at: [ 016/j.jacc and NHLBI harge to the Expert Panel Evaluate higher quality randomized controlled trial (RT) evidence for cholesterol-lowering drug therapy to reduce ASVD risk Use ritical Questions (Qs) to create the evidence search from which the guideline is developed holesterol Panel: 3 Qs Risk Assessment Work Group: 2 Qs Lifestyle Management Work Group: 3 Qs RTs and systematic reviews/meta-analyses of RTs independently assessed as fair-to-good quality Develop recommendations based on RT evidence Less expert opinion than in prior guidelines lassification of Recommendations and Levels of Evidence A recommendation with Level of Evidence B or does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/ efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (lass I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. 2

3 4 Statin Benefit Groups linical ASVD* LDL >190 mg/dl, Age >21 years Primary prevention Diabetes: Age years, LDL mg/dl Primary prevention - No Diabetes : 7.5% 10-year ASVD risk, Age years, LDL mg/dl, *Atherosclerotic cardiovascular disease Requires risk discussion between clinician and patient before statin initiation. Statin therapy may be considered if risk decision is uncertain after use of ASVD risk calculator. Guideline Scope Focus on treatment of blood cholesterol to reduce ASVD risk in adults Emphasize adherence to a heart healthy lifestyle as foundation of ASVD risk reduction See Lifestyle Management Guideline Identify individuals most likely to benefit from cholesterol-lowering therapy 4 statin benefit groups Identify safety issues New Perspective on LDL & Non-HDL Goals Lack of RT evidence to support titration of drug therapy to specific LDL and/or non-hdl goals Strong evidence that appropriate intensity of statin therapy should be used to reduce ASVD risk in those most likely to benefit Quantitative comparison of statin benefits with statin risk Nonstatin therapies did not provide ASVD risk reduction benefits or safety profiles comparable to statin therapy 3

4 Why Not ontinue to Treat to Target? Major difficulties: 1. urrent RT data do not indicate what the target should be 2. Unknown magnitude of additional ASVD risk reduction with one target compared to another 3. Unknown rate of additional adverse effects from multidrug therapy used to achieve a specific goal 4. Therefore, unknown net benefit from treat-totarget approach 4 Statin Benefit Groups (Revised Figure) IA IA IB IA IIaB 1 linical Flow (Revised Figure-con t) 4

5 Intensity of Statin Therapy *Individual responses to statin therapy varied in the RTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response. Evidence from 1 RT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al). Although simvastatin 80 mg was evaluated in RTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis. linical ASVD Initiating Statin therapy *Fasting lipid panel preferred. In a nonfasting individual, a nonfasting non-hdl >220 mg/dl may indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are >500 mg/dl, a fasting lipid panel is required. It is reasonable to evaluate the potential for ASVD benefits and for adverse effects, and to consider patient preferences, in initiating or continuing a moderate- or high-intensity statin, in individuals with ASVD >75 years of age. Primary Prevention Global Risk Assessment To estimate 10-year ASVD* risk New Pooled ohort Risk Equations White and black men and women More accurately identifies higher risk individuals for statin therapy Focuses statin therapy on those most likely to benefit You may wish to avoid initiating statin therapy in high-risk groups found not to benefit (higher grades of heart failure and hemodialysis) 5

6 Primary Prevention Statin Therapy Thresholds for initiating statin therapy derived from 3 exclusively primary prevention RTs Before initiating statin therapy, clinicians and patients engage in a discussion of the potential for ASVD risk reduction benefits, potential for adverse effects, drug-drug interactions, and patient preferences alculators don t write Rx, physicians do! Individuals Not in a Statin Benefit Group In those for whom a risk decision is uncertain: These factors may inform clinical decision making: Family history of premature ASVD Elevated lifetime risk of ASVD LDL 160 mg/dl hs-rp 2.0 mg/l oronary artery calcium (A) score 300 Agaston units Ankle brachial index (ABI)<0.9 Their use still requires discussion between clinician and patient Statin Therapy: Monitoring Response- Adherence *Fasting lipid panel preferred. In a nonfasting individual, a nonfasting non-hdl >220 mg/dl may indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are >500 mg/dl, a fasting lipid panel is required. In those already on a statin, in whom baseline LDL is unknown, an LDL <100 mg/dl was observed in most individuals receiving high-intensity statin therapy in RTs. See guideline text 6

7 Safety RTs & meta-analyses of RTs used to identify important safety considerations Allow estimation of net benefit from statin therapy o ASVD risk reduction versus adverse effects Expert guidance on management of statin-associated adverse effects, including muscle symptoms Advise use of additional information including pharmacists, manufacturers prescribing information, & drug information centers for complex cases Management of Muscle Symptoms on Statin Therapy It is reasonable to evaluate and treat muscle symptoms including pain, cramping, weakness, or fatigue in statin-treated patients according to the management algorithm To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiating statin therapy 7

8 Management of Muscle Symptoms on Statin Therapy (con t) If unexplained severe muscle symptoms or fatigue develop during statin therapy: Promptly discontinue the statin Address possibility of rhabdomyolysis with: K reatinine urine analysis for myoglobinuria Management of Muscle Symptoms on Statin Therapy (con t) If mild-to-moderate muscle symptoms develop during statin therapy: Discontinue the statin until the symptoms are evaluated Evaluate the patient for other conditions* that might increase the risk for muscle symptoms If after 2 months without statin Rx, muscle symptoms or elevated K levels do not resolve completely, consider other causes of muscle symptoms *Hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency or primary muscle diseases Statin-Treated Individuals Nonstatin Therapy onsiderations Use the maximum tolerated intensity of statin onsider addition of a nonstatin cholesterol-lowering drug(s) If a less-than-anticipated therapeutic response persists Only if ASVD risk-reduction benefits outweigh the potential for adverse effects in higher-risk persons: linical ASVD <75 years of age Baseline LDL 190 mg/dl Diabetes mellitus 40 to 75 years of age Nonstatin cholesterol-lowering drugs shown to reduce ASVD events in RTs are preferred 8

9 Three Principles Do not focus on LDL or non-hdl- cholesterol levels as treatment goals o Lipid panel to monitor adherence For those shown to benefit, use statins inexpensive (5 of 7 generic) medications proven to reduce ASVD risk In primary prevention decisions, use a clinicianpatient discussion to determine: global risk reduction strategy potential for benefit and harms of statin therapy Patient preferences (shared decision making) Future Updates to the Blood holesterol Guideline This is a comprehensive guideline for the evidencebased treatment of blood cholesterol to reduce ASVD risk These guidelines represent a change from previous guidelines that aligns recommendations closely to the evidence For primary prevention, they are patient-centered Guidelines will change in the future as high-quality data will improve future cholesterol treatment guidelines Educational Objectives 1. Summarize results of clinical trials of PSK9 inhibition 2. ompare risks and benefits of available lipid-lowering agents 3. ompare LDL- lowering efficacy of available lipidmodifying agents 4. Identify patients who may benefit from PSK9 inhibition 9

10 IMPROVE-IT: Primary Endpoint ITT ardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke HR I (0.887, 0.988) p=0.016 Simva 34.7% 2742 events NNT= 50 EZ/Simva 32.7% 2572 events 7-year event rates annon P et al. N Engl J Med. 2015;372: PSK9i: Rapid Progress From Discovery to linic PSK9i = PSK9 inhibition. Seidah NG. Proc Natl Acad Sci US. 2003;100(3): Abifadel M. Nat Genet. 2003;34(2): Maxwell KN. Proc Natl Acad Sci US. 2004;101(18): Rashid S. Proc Natl Acad Sci US. 2005;102(15): Lagace TA et al. JI. 2006;116: ohen J. N Engl J Med. 2006;354(12): Zhao Z. Am J Hum Genet. 2006;79(3): Hooper AJ. Atherosderosis. 2007;193(2): han J. Proc Natl Acad Sci US. 2009;106(24): Stein et al. N Engl J Med. 2012;366: European Medicines Agency. Available at: Global Assessment of Plaque Regression with a PSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) Phase 3 study 970 patients with coronary artery disease, taking lipid-lowering therapy, and undergoing coronary catheterization Randomized to receive evolocumab or placebo every 4 weeks for 78 weeks Primary endpoint: hange in percent atheroma volume (assessed by IVUS) from baseline to week

11 GLAGOV: Primary Endpoint Percent Atheroma Volume Nicholls SJ, et al. JAMA. 2016; 316: PSK9 Outcome Trials FOURIER (evolocumab) N = 22,500 Duration 5 years SPIRE-1 (bococizumab)* N = 12,000, LDL- 70 and <100 mg/dl SPIRE-2 (bococizumab)* N = 6,300, LDL- 100 mg/dl ODYSSEY Outcomes (alirocumab) N = 18,000 Duration 5 6 years * Discontinued 1 November Trial Design 27,564 high-risk, stable patients with established V disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Run-in High or moderate intensity statin therapy (± ezetimibe) Evolocumab S 140 mg Q2W or 420 mg QM LDL- 70 mg/dl or non-hdl- 100 mg/dl RANDOMIZED DOUBLE BLIND S Q2W or QM Sabatine MS, et al. Am Heart J. 2016; 173: Follow-up Q 12 weeks 11

12 Summary of Effects of PSK9i Evolocumab LDL- by 59% First V outcomes in patients on statin Safe and well-tolerated 59% reduction P< Absolute 56 mg/dl HR 0.85 ( ) P< HR 0.80 ( ) P< Evolocumab (median 30 mg/dl, IQR mg/dl) VD, MI, stroke UA, cor revasc VD, MI, stroke Sabatine MS et al. NEJM. 2017; 376: Total Primary Endpoint Events # Events 1st Event HR ( ) Evolocumab Murphy SA et al. Presented at AHA Total Primary Endpoint Events 2714 Total Events RR 0.82 (95%I ) P<0.001 # Events Addition al Events RR 0.74 ( ) st Event HR ( ) Evolocumab Murphy SA et al. Presented at AHA

13 Primary Endpoint Events: Wei, Lin, Weissfeld Model HR (95% I) 1 Event (n=2907) 2 Events (n=1333) 3 Events (n=373) 4+ Events (n=152) HR 0.60 HR 0.76 HR 0.74 HR Evolocumab 1. Better 0 Better Murphy SA et al. Presented at AHA Total Primary Endpoint Events Number of Events Prevented for 1,000 Patients Treated with Evolocumab for 3 Years Events per 1,000 Patients First Event Only Total Events Murphy SA et al. Presented at AHA Giugliano RP et al. Lancet 2017;390:

14 Giugliano RP et al. Lancet 2017;390: Benefit of EvoMab Based on Time from Qualifying MI V Death, MI, or Stroke Qualifying MI <2 yrs ago 24% RRR 10.8% 2.9% HR 0.76 NNT 35 (95% I ) 7.9% P<0.001 Evolocumab Qualifying MI 2 yrs ago 13% RRR HR 0.87 (95% I ) P= % 8.3% 1.0% NNT 101 P interaction= Months after Randomization Sabatine MS et al. Presented Sabatine MS. at AHA Benefit of EvoMab Based on Multivessel Disease V Death, MI, or Stroke Multivessel Disease 30% RRR HR 0.70 (95% I ) P<0.001 Evolocumab 12.6% 3.4% NNT % No Multivessel Disease 11% RRR HR 0.89 (95% I ) P= % 7.6% 1.3% NNT 78 P interaction= Months after Randomization Sabatine MS et al. Presented at AHA Sabatine MS. AHA 14

15 Adjusted for age, sex, race, BMI, diabetes, HTN, smoking, egfr, HF, prior MI, ABG/PI, and Hx stroke or TIA. VD / MI / Stroke 6% 4% 2% Peripheral Artery Disease and Risk in Patients PAD with MI/Stroke N=1036 PAD N=1784 PAD no MI/Stroke N=748 16% 16% MI or Stroke and no PAD N=11996 MI or Stroke and no PAD N= % 14% Adjusted HR 14% 13.0 P= % 12% % 10% ( ) P< % 10.3% P= % 8% 7.6% 7.6% 0% Days from Randomization VD / MI / Stroke 6% 4% 2% 0% Days from Randomization Bonaca MP et al. irculation 2018;137: Major Adverse Limb Events Major Adverse Limb Events All Patients N=27,564 Evolocumab 0.5% 42% RRR 0.45% HR % ( ) P= % 0.27% 0.2% Outcome HR 95% I 0.1% MALE 0.58 ( ) ALI or major amputation 0.52 ( ) ALI 0.55 ( ) Major amputation 0.57 ( ) 0.0% Urgent revascularization 0.69 ( ) Days from Randomization Bonaca MP et al. irculation 2018;137: MAE or MALE In Patients with and without PAD MAE or MALE PAD Evolocumab N=3,642 16% PAD 27% N=3,642 RRR 15.0% 14% PAD PAD HR HR % ARR 4.1% 95% I ( ) NNT 25 12% ( ) ARR P= P= % NNT 2.5y 10% 25 8% 7.8% No No PAD 1.5% 1.5% ARR 6% 6.3% NNT ARR 67 NNT 2.5y No PAD 4% 67 N=23,922 HR % 95% I ( ) P<0.001 p-interaction = % Days from Randomization Bonaca MP et al. irculation 2018;137:

16 MAE or MALE In Patients with PAD and no MI or Stroke Evolocumab PAD (no MI/stroke, N=1505) MAE or MALE 14% 48% RRR 12.8% 12% HR 0.52 ( ) 10% P= % 6.5% 6% 4% 2% 0% Days from Randomization PAD 6.3% ARR NNT 2.5y 16 Bonaca MP et al. irculation 2018;137: Benefit of EvoMab by Risk Strata Bohula EA et al. Presented at AHA ODYSSEY Outcomes ~18,600 men and women aged 40 years with AS 52 weeks before randomization Randomized to receive biweekly alirocumab (75 mg or 150 mg, titrated to achieve LDL- 25 mg/dl and <50 mg/dl) or placebo Primary efficacy measure: time to first occurrence of HD death, nonfatal MI, fatal or nonfatal ischemic stroke, or hospitalization for unstable angina Duration: 64 months (4-month run-in, 60 months randomized treatment; 2 years follow-up) Schwartz GG, et al. Am Heart J. 2014;168:

17 The ODYSSEY OUTOMES Trial: Topline Results Alirocumab in Patients After Acute oronary Syndrome Gregory G. Schwartz, Michael Szarek, Deepak L. Bhatt, Vera Bittner, Rafael Diaz, Jay Edelberg, Shaun G. Goodman, orinne Hanotin, Robert Harrington, J. Wouter Jukema, Guillaume Lecorps, Angèle Moryusef, Robert Pordy, Matthew Roe, Harvey D. White, Andreas Zeiher, Ph. Gabriel Steg On behalf of the ODYSSEY OUTOMES Investigators and ommittees American ollege of ardiology 67th Scientific Sessions March 10, 2018 linicaltrials.gov: NT Residual Risk After Acute oronary Syndrome A.18 Remains high despite evidence based preventive therapies Is related, in part, to levels of low density lipoprotein cholesterol (LDL ) Is reduced when LDL is lowered by Statin therapy, compared with placebo 1 High intensity, compared with moderate intensity statin therapy 2 Ezetimibe, compared with placebo, added to statin 3 1. Schwartz GG, et al. JAMA 2001;285: annon P, et al.nejm 2004;350: annon P, et al.nejm 2015;372: A.18 Alirocumab PSK9 is a validated target for risk reduction in stable atherosclerotic cardiovascular disease 1 3 A fully human monoclonal antibody against PSK9 Produces substantial and sustained reductions in LDL and other atherogenic lipoproteins 2 Has been safe and well tolerated in studies to date 4 PSK9, proprotein convertase subtilisin/kexin type 9 1. Sabatine et al, NEJM 2017;376: Robinson JG et al. NEJM 2015;372: Ridker PM et al. NEJM 2017;376: Robinson JG et al.ja 2017;69:

18 A.18 Study Hypothesis Alirocumab, versus placebo, reduces cardiovascular (V) morbidity and mortality after recent acute coronary syndrome (AS) in patients with elevated levels of atherogenic lipoproteins despite intensive or maximum tolerated statin therapy Schwartz GG, et al. Am Heart J 2014;168: e1. A.18 Main Inclusion riteria Age 40 years AS 1to12monthspriortorandomization Acute myocardialinfarction (MI) orunstable angina High intensity statin therapy* Atorvastatin 40 to 80 mg daily or Rosuvastatin 20 to 40 mg daily or Maximum tolerated dose of one of these agents for 2 weeks Inadequate control of lipids LDL 70 mg/dl (1.8 mmol/l) or Non HDL 100 mg/dl (2.6 mmol/l) or ApolipoproteinB 80 mg/dl *Patients not on statins were authorized to participate if tolerability issues were present and documented Schwartz GG, et al. Am Heart J 2014;168: e1. A.18 Key Exclusion riteria Uncontrolled hypertension NYHA class III or IV heart failure; LVEF <25% if measured History of hemorrhagic stroke Fasting triglycerides >400 mg/dl (4.52 mmol/l) Use of fibrates other than fenofibrate or fenofibric acid Recurrent AS within 2 weeks prior to randomization visit oronary revascularization performed within 2 weeks prior to randomization visit, or planned after randomization Liver transaminases >3 ULN; hepatitis B or infection reatine kinase >3 ULN egfr <30 ml/min/1.73 m 2 Positive pregnancy test egfr, estimated glomerular filtration rate; ULN, upper limit of normal Schwartz GG, et al. Am Heart J 2014;168: e1. 18

19 A.18 Primary Efficacy Outcome Time of first occurrence of: oronary heart disease (HD) death, or Non fatal MI, or Fatal or non fatal ischemic stroke, or Unstable angina requiring hospitalization* All outcomes adjudicated by the linical Events ommittee, under the auspices of the Duke linical Research Institute (DRI). Members were unaware of treatment assignment and lipid levels *Required all of the following: 1. Hospital admission >23 h for MI symptoms, tempo in prior 48 hours and/or 20 min of chest discomfort at rest 2. New EG findings consistent with ischemia or infarction 3. Angiographically significant obstructive coronary disease Schwartz GG, et al. Am Heart J 2014;168: e1. Major Secondary Efficacy Endpoints A.18 Tested in the following hierarchical sequence: HD event: HD death, non fatal MI, unstable angina requiring hospitalization, or ischemia driven coronary revascularization* Major HD event: HD death or non fatal MI V event: V death, non fatal HD event, or non fatal ischemic stroke All cause death, non fatal MI, non fatal ischemic stroke HD death V death All cause death *Revascularization performed because of recurrent AS, new or progressive symptoms of myocardial ischemia or new or progressive abnormalities on functional testing, except revascularization due to restenosis at a prior coronary intervention site. Other Secondary and Safety Endpoints A.18 Other secondary endpoints omponents of the primaryendpointconsidered individually: HD death Non fatal MI Fatalandnon fatalischemic stroke Unstable angina requiring hospitalization Ischemia driven coronary revascularization ongestive heart failurerequiringhospitalization Safety endpoints Adverse events Laboratory assessments 10 19

20 A.18 Treatment Assignment Post ASpatients(1to12months) Run in period of 2 16 weeks on high intensity or maximum tolerated dose of atorvastatin or rosuvastatin At least one lipid entry criterion met Randomization Alirocumab S Q2W S Q2W Patient and investigators remained blinded to treatment and lipid levels for the entire duration of the study Schwartz GG, et al. Am Heart J 2014;168: e1. A.18 A Target Range for LDL- We attempted to maximize the number of patients in the target range and minimize the number below target by blindly titrating alirocumab (75 or 150 mg S Q2W) or blindly switching to placebo. Below target Acceptable range Target range Alirocumab Undesirably high baseline range LDL (mg/dl) Schwartz GG, et al. Am Heart J 2014;168: e1. ODYSSEY OUTOMES: 18,924 patients randomized at 1315 A.18 sites in 57 countries, Nov 2, 2012 Nov 11, 2017 Western Europe entral/eastern Europe anada/usa anada 361 Austria 58 Bosnia Herzegovina 156 Macedonia 132 US 2511 Belgium 197 Bulgaria 333 Poland 926 Denmark 352 roatia 70 Romania 145 Finland 116 zech Republic 381 Russian Federation 1109 France 185 Estonia 216 Serbia 255 Germany 509 Georgia 131 Slovakia 340 Greece 70 Hungary 224 Slovenia 36 Italy 275 Latvia 80 Turkey 78 Netherlands 686 Lithuania 188 Ukraine 639 Norway 97 Portugal 174 Asia Spain 826 Sweden hina Hong Kong 17 Switzerland 88 UK 292 India 521 Japan 204 Korea 94 Malaysia 110 Philippines 116 Singapore 49 Sri Lanka 314 Latin America We thank the patients, Taiwan 93 Argentina 592 Thailand 161 their families, all Brazil 928 Rest of World Australia investigators and hile olombia 354 coordinators involved in Israel 582 Guatemala 25 New Zealand 257 this study, and DRI Mexico 349 South Africa 505 Peru

21 Patient Disposition Randomized 18,924 patients A. 1 8 Alirocumab Follow up*: median 2.8 (Q1 Q ) years 8242 (44%) patients with potential follow up 3 years 1955 patients experienced a primary endpoint 726 patients died Premature treatment discontinuation Blinded switch to placebo (2 consecutive LDL values<15mg/dl) Patients lost to follow up (vital status) 1343 (14.2%) 1496 (15.8%) 730 (7.7%) Not applicable 14 9 *Ascertainment was complete for 99.1% and 99.8% of potential patient years of follow up for the primary endpoint and all cause death, respectively Baseline Demographics haracteristic Alirocumab Age, years, median (Q1 Q3) 58 (52 65) 58 (52 65) Female, n (%) 2390 (25.3) 2372 (25.1) Medical history, n (%) Hypertension 6205 (65.6) 6044 (63.9) Diabetes mellitus 2693 (28.5) 2751 (29.1) urrent tobacco smoker 2282 (24.1) 2278 (24.1) Prior MI 1790 (18.9) 1843 (19.5) A. 1 8 Baseline Index Events haracteristic Alirocumab Time from index AS to randomization, 2.6 ( ) 2.6 ( ) months, median (Q1 Q3) AS type, n (%) NSTEMI 4574 (48.4) 4601 (48.7) STEMI 3301 (35.0) 3235 (34.2) Unstable angina 1568 (16.6) 1614 (17.1) Revascularization for index AS, n (%) 6798 (71.8) 6878 (72.7) A

22 A.18 Baseline Lipid haracteristics haracteristic, mg/dl, median (Q1 Q3) Alirocumab 92.5% of patients qualified on the basis of LDL 70 mg/dl LDL 87 (73 104) 87 (73 104) Non HDL 115 (99 136) 115 (99 137) Apolipoprotein B 79 (69 93) 80 (69 93) HDL 43 (37 50) 42 (36 50) Triglycerides 129 (94 181) 129 (95 183) Lipoprotein(a) 21 (7 59) 22 (7 60) BaselineLipid Lowering Therapy Therapy, n (%) Alirocumab High dose atorvastatin/rosuvastatin 8380 (88.6) 8431 (89.1) Low /moderate dose atorvastatin/rosuvastatin 830 (8.8) 777 (8.2) Other statin 19 (0.2) 27 (0.3) Ezetimibe, with or without statin 269 (2.8) 285 (3.0) No lipid lowering therapy* 87 (0.9) 91 (1.0) A. 1 8 *Patients not on statins were authorized to participate if tolerability issues were present and documented Guideline Recommended Post AS Medications A. 1 8 Medication, n (%) Alirocumab Aspirin 9050 (95.6) 9036 (95.5) P2Y 12 antagonist 8296 (87.7) 8245 (87.1) AE I/ARB 7356 (77.7) 7360 (77.8) Beta blocker 7998 (84.5) 7992 (84.5) AE I,angiotensin converting enzyme inhibitor;arb, angiotensin receptor blocker 22

23 LDL : ITT and On Treatment Analyses Mean LDL- (mg/dl) ITT On treatment* Alirocumab ITT On treatment* Months Since Randomization A. 1 8 *Excludes LDL values after premature treatment discontinuation or blinded switch to placebo All LDL values, including those after premature treatment discontinuation, blinded down titration, or blinded switch to placebo A.18 Mean LDL- (mg/dl) LDL-: On-Treatment Analysis mg/dl 62.7% mg/dl 61.0% Alirocumab Months Since Randomization Excludes LDL values after premature treatment discontinuation or blinded switch to placebo Approximately 75% of months of active treatment were at the 75 mg dose mg/dl 54.7% Primary Efficacy Endpoint: MAE ARR* 1.6% A. 1 8 MAE: HD death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization HR 0.85 (95% I 0.78, 0.93) P= *Based on cumulative incidence 31 23

24 Primary Efficacy and omponents Endpoint, n (%) Alirocumab HR (95% I) Log rank P value MAE 903 (9.5) 1052 (11.1) 0.85 (0.78, 0.93) A. 1 8 HD death 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38 Non fatal MI 626 (6.6) 722 (7.6) 0.86 (0.77, 0.96) Ischemic stroke 111 (1.2) 152 (1.6) 0.73 (0.57, 0.93) 0.01 Unstable angina 37 (0.4) 60 (0.6) 0.61 (0.41, 0.92) Main Secondary Efficacy Endpoints: Hierarchical Testing A.18 Endpoint, n (%) Alirocumab HR (95% I) Log rank P value HD event 1199 (12.7) 1349 (14.3) 0.88 (0.81, 0.95) Major HD event 793 (8.4) 899 (9.5) 0.88 (0.80, 0.96) V event 1301 (13.7) 1474 (15.6) 0.87 (0.81, 0.94) Death, MI, ischemic 973 (10.3) 1126 (11.9) 0.86 (0.79, 0.93) stroke HD death 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38 V death 240 (2.5) 271 (2.9) 0.88 (0.74, 1.05) 0.15 All cause death 334 (3.5) 392 (4.1) 0.85 (0.73, 0.98) 0.026* *Nominal P value 33 All ause Death A. 1 8 ARR 0.6% HR 0.85 (95% I 0.73, 0.98) P=0.026* *Nominal P value Based on cumulative incidence 34 24

25 Other Efficacy Endpoints Endpoint n (%) Alirocumab HR (95% I) Log rank P value A. 1 8 Ischemia driven coronary revascularization Hospitalization for HF 731 (7.7) 828 (8.8) 0.88 (0.79, 0.97) (1.9) 179 (1.9) 0.98 (0.79, 1.20) Post Hoc Analysis: All ause Death by Baseline LDL Subgroups 100 mg/dl HR=0.71 A. 1 8 <80 mg/dl HR 0.89 (95% I 0.69, 1.14) 80 to <100 mg/dl HR 1.03 (95% I 0.78, 1.36) 40 OMPARISON OF FOURIER AND ODYSSEY EVOLUAMAB ALIROUMAB TITLE FOURIER ODYSSEY TYPE OF PTS MI,VS, OR PAD (+/- 3y) 4-52 wks POST AS # PTS 27,564 18,600 HIGH INT. STATIN 69% 89% BASELINE LDL 92 MG/DL 89MG/DL PSK9 DOSING 140MG2W/420MGQ4W 75/150Q2W to LDL 25-50MG/DL LDL- HANGE 56MG/DL 66.4MG/DL DURATION 2.2Y 3Y ENDPOINT 1-VD, MI, VA, UA HOSP., OR REVAS 2-VD, MI, OR VA HD DEATH, MI, ISHEMI VA OR UA HOSP RESULTS 0.81 EP HR 0.85 ( ) 2EP HR(0.73-0,88) 0.85 ( ) 0.88 ( ) 25

26 ombination therapy for lowering LDL- Statins plus PSK9 inhibitor: >75% estimated Statins plus ezetimibe: 60 to 70% reduction with high dose atorva/rosuva Statin plus low dose/alternative day statin: 40 to 50% LDL- reduction Ezetimibe plus bempedoic acid ( experimental therapy in phase 3 trials); 45% LDL- reduction 26