Educational Objectives. Disease Trajectories and CVD Risk Reduction. Hypercholesterolemia Support for LDL-C Causality

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1 Educational Objectives At the conclusion of this activity, participants should be able to: Evaluate the extent of residual CVD risk to which ASCVD patients are exposed, and treat additional CVD risk elements as appropriate A CME-certified, MOC-eligible Activity Jointly provided by and Conduct appropriate diagnosis of familial hypercholesterolemia and implement appropriate treatment and rationale for cascade screening of the families Differentiate the clinical properties of new and emerging pharmacologic approaches to reduce LDL-C and lower CVD risk Analyze the potential utility of new LDL-C lowering agents used in combination with statins to reduce CVD risk in patients who have ASCVD This activity is supported by educational funding provided by Amgen. Hypercholesterolemia Support for LDL-C Causality Disease Trajectories and CVD Risk Reduction Four compelling lines of evidence Experimental models Observational human data Genetic studies Interventional human trials Packard CJ et al. Vasc Pharmacol. 215;71: Substantial CVD Risk Remains after ACS 43,81 Patients with ACS in GRACE Registry: 6-month Death Rate Death (%) STEMI NSTEMI UA Familial Hypercholesterolemia (FH) Diagnostic Categories ICD-1 Category Clinical Criteria With Genetic Testing Performed Heterozygous FH LDL-C 16 mg/dl for children and 19 mg/dl for adults and 1 first-degree relative similarly affected or Presence of 1 abnormal LDL-C raising (LDL receptor, apob or PCSK9) gene defect Diagnosed as heterozygous FH if LDL-C raising defect positive and LDL-C <16 mg/dl with premature CAD or with Occasionally, heterozygotes will have LDL-C >4 mg/dl; positive genetic testing for they should be treated similarly to homozygotes LDL-C raising gene defect (LDL receptor, apob, or PCSK9) Presence of both abnormal LDL-C raising (LDL receptor, apob or PCSK9) gene defect(s) and LDL-C lowering gene variant(s) with LDL-C <16 mg/dl GRACE = global registry of acute coronary events Fox KAA et al. BMJ. 26;333:191. Days Gidding SS et al. Circulation 215;132:

2 Men and Women with Familial Hypercholesterolemia Rates of CHD Death or Nonfatal MI per 1, Person-years and Underlying Observed Event Numbers FH Confers Greater CAD Risk Especially when Baseline LDL-C Level 19 mg/dl CAD Risk is ~3x with monogenic FH when LDL-C >19 3x 3x LDL Cholesterol Category (mg/dl) Perak AM et al. Circulation. 216;134:9-19. Khera AV et al. J Am Coll Cardiol. 216;67: Monogenic Drivers of Coronary Artery Disease Risk Familial Hypercholesterolemia 3-year Survival Rates in Patients with FH Implicated genes LDLR, APOB, PCSK9 Prevalence ~1 in 211 CAD risk ~4-fold increase Targeted therapies to reduce LDL-C Statins, ezetimibe, PCSK9 inhibitors Khera A, Kathiresan S. Nat Rev Genet. 217;18: Perak AM et al. Circulation. 216;134:9-19. LDL-C Reduction Cardiovascular Benefits LDL-C and ASCVD Statement from the European Atherosclerosis Society Consensus Panel Cumulative LDL arterial burden is a central determinant for the initiation and progression of ASCVD The lower the LDL-C level attained by agents that primarily target LDL receptors, the greater the clinical benefit Both relative risk reduction and absolute risk reduction relate to the magnitude of LDL-C reduction Lowering LDL-C in individuals at high cardiovascular risk earlier rather than later appears advisable, especially in those with familial hypercholesterolemia Ferense BA et al. Eur Heart J. 217; 38:

3 Treatments for Hypercholesterolemia Therapies That Lower LDL-C Lifestyle Change Physical activity Medical nutrition therapy Smoking cessation Jellinger P et al. Endocr Practice. 217;23: Pharmacologic Therapy Statins Cholesterol absorption inhibitors Bile acid sequestrants Fibrates Omega-3 fish oil PCSK9 inhibitors MTP inhibitors Antisense apo B oligonucleotide Combination therapies Ference BA et al. Eur Heart J. 217;38: Statins The Gold Standard for LDL-C Reduction and ASCVD Prevention Primary Prevention Statin Trials CHD Event Rates O Keefe JH et al. J Am Coll Cardiol. 24;43: Secondary Prevention Statin Trials CHD Event Rates Patients with Homozygous FH Efficacy of LDL-C Lowering Therapies O Keefe JH et al. J Am Coll Cardiol. 24;43: Cuchel M et al. Eur Heart J. 214;35:

4 Patients with Homozygous FH CHD Risk According to Statin Treatment Lower On-treatment LDL-C with Statins Predicts Lower ASCVD Risk LDL-C Levels and Risk of CV Events LDL-C (mg/dl) < <15 1 < <1 5 <75 < Adjusted Hazard Ratio 95% Cl Sniderman AD et al. J Am Coll Cardiol. 214;63: Boekholdt SM et al. J Am Coll Cardiol. 214;64: ACC/AHA Guidelines Four Statin Benefit Groups Clinical ASCVD secondary prevention LDL-C >19 mg/dl without secondary cause Primary prevention with diabetes Age 4-75 years; LDL-C mg/dl Primary prevention without diabetes Age 4-75 years; LDL-C mg/dl; Estimated ASCVD risk >7.5% Stone NJ et al. J Am Coll Cardiol. 214;63: Intensive Statin Therapy Reduces MACE PROVE IT - TIMI 22: Study Design Double-blind 4,162 patients with an acute coronary syndrome <1 days Standard Statin Therapy pravastatin 4 mg ASA + Standard Medical Therapy Intensive Statin Therapy atorvastatin 8 mg 2x2 factorial: gatifloxacin vs placebo Duration: mean 2-year follow-up (>925 events) Primary Endpoint: death, MI, documented UA requiring hospitalization, revascularization (>3 days after randomization), or stroke Cannon CP et al. N Engl J Med. 24;35: Intensive Statin Therapy: PROVE IT-TIMI 22 All-Cause Death or Major CV Events % of Patients with MACE Intensive Statin Therapy Pravastatin 4mg (26.3%) Standard Statin Therapy Atorvastatin 8mg (22.4%) 16% RR (P=.5) Months of Follow-up Cannon CP et al. N Engl J Med. 24;35: ACC/AHA Guideline Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults High-intensity statins recommended for: clinical ASCVD; LDL-C >19 mg/dl; DM with high-risk; 1-year ASCVD risk >7.5% Moderate-intensity possible for patients at less-elevated risk or prone to statin intolerance Low-intensity statins recommended only in patients with history of/at risk for adverse drug effects Monitoring LDL-C was recommended to assess compliance and response to therapy, but no guidance given for LDL-C goals on-treatment Shared decision making (doctor with patient) recommended for all treatment choices. Stone NJ et al. Circulation. 214;129:S1-45. Goff DC et al. Circulation. 214;129:S49-S73. 4

5 National Lipid Association Recommendations Initiate Therapy Based on Risk and Lipid Levels then Treat to Specific Goal Risk Category Criteria Initiate Drug Therapy Non-HDL-C (LDL-C) (mg/dl) Treatment Goal Non-HDL-C (LDL-C) (mg/dl) Low -1 major risk factors (RF)* >19 (>16) <13 (<1) Moderate At least 2 major RF and 1-year risk <1%* >16 (>13) <13 (<1) High At least 2 major RF and 1-year risk >1% At least 3 RF DM with -1 other RFs and no end organ damage CKD stage 3 or 4 LDL-C >19 mg/dl >13 (>1)# <13 (<1) Very High Established ASCVD DM with at least 2 other RFs or end organ damage *Consider other risk markers # Consider moderate or high intensity statin in patient with ASCVD or DM regardless of baseline lipid levels Jacobson TA. J Clin Lipidol. 215;9: >1 (>7)# <1 (<7) Efficacy of Statin Treatment to Lower LDL-C Only about 1/3 of High Risk Patients Achieve LDL-C Goal Patients Achieving LDL-C Goal (%) High-Risk Patients All Patients Jones PH et al. J Am Heart Assoc. 212;1:e CHD Patients High-Risk 1 o Prevention 3 At High-Risk 1 o Prev Goal (<1 mg/dl) 13 At High-Risk LDL-C Goal (<7 mg/dl) Secondary Prevention CHD Patients At 2 o Prev at LDL-C Goal Goal (<1 mg/dl) (<7 mg/dl) Electronic Medical Records (23-21) Considerable ASCVD Risk Remains Despite Even Intensive Statin Monotherapy Residual CHD Risk Despite Statin Monotherapy Statin-based LDL-C lowering to reduce CAD risk 2-1 Relative Risk Reduction (%) S CARE WOSCOPS LIPID AFCAPS HPS CARDS ASCOT 24% 24% 24% 29% 34% 36% 37% 37% R E S I D U A L R I S K JUPITER 44% Statins reduce CAD/CVD risk by ~24%-44% but 56% to 76% residual risk remains Adapted from Rader DJ et al Shepherd J et al. N Engl J Med. 1995;333: Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344: Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q. 5. Sacks FM et al. N Engl J Med. 1996;335: Downs JR et al. JAMA. 1998;279: LIPID Study Group. N Engl J Med. 1998;339: Brown BG. Eur Heart J Suppl. 25;7:F34-F4. 9. Grundy SM et al. Circulation. 24; 11: Ridker PM et al. N Engl J Med. 28;359: Non-statin Add-on LDL-lowering Therapies Ezetimibe Ezetimibe: IMPROVE IT Trial Design Patients stabilized post-acs 1 days LDL-C 125 mg/dl (or 1 mg/dl if prior statin) Double-blind n ~ 18, ASA + Standard Medical Therapy Simvastatin 4 mg* Follow-up visit day 3, every 4 months Ezetimibe / Simvastatin 1/4 mg* Duration: minimum 2.5-year follow-up (525 events) *up-titrated to 8 mg if LDL-C >79 mg/dl Primary Endpoint: CV death, MI, hospitalization for UA, revascularization (>3 days after randomization), or stroke Study drug is administered once daily in the evening. Cannon CP et al. Am Heart J. 28;156:

6 IMPROVE-IT Trial LDL-C and Other Lipid Effects with Ezetimibe 1-Yr Mean LDL-C TC TG HDL hscrp Simva EZ/Simva Δ in mg/dl IMPROVE IT Trial: Ezetimibe + Simvastatin Lowers ASCVD More than Simvastatin Alone ~1% relative risk after 1 st year Median Time avg 69.5 vs mg/dl Cannon CP et al. Am Heart J. 28;156: Primary endpoint: cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization Cannon CP et al. N Engl J Med. 215;372: Non-statin Add-on LDL-lowering Therapies PCSK9 Inhibitors Rationale Behind PSCK9 as a Therapeutic Target PCSK9 # of LDL Receptors LDL-C PCSK9 # of LDL Receptors LDL-C Physiology of PCSK9 Proprotein Convertase Subtilisin/Kexin Type 9 PCSK9 retains LDL-R in endosome LDL-R destruction LDL removal plasma LDL-C PCSK9 Mutations and Effect on LDL Metabolism Gain of Function LDL-R levels LDL clearance Loss of Function LDL-R levels LDL clearance LDL High risk for ASCHD) LDL Protection from atherosclerosis and CHD Sever P, Mackay J. Br J Cardiol. 214;21: Giugliano RP et al. Lancet. 212;38: Sabatine MS et al. N Engl J Med. 215;372: LDL = Low-density lipoprotein Adapted from: 1. Catapano AL and Papadopoulos N. Atherosclerosis. 213;228: Soufi M et al. Gene. 213;521:

7 PCSK9 Loss-of-Function Mutations Resulted in Lower LDL-C Levels and Reduced CHD Rates Wild-type PCSK9 degrades LDL receptors 1,2 1% to 3% of population have a lossof-function (LOF) mutation LOF mutations increase hepatic LDL receptor expression, reducing LDL-C levels by 15%-4% 2,3 CHD incidence was reduced 47%- 88% in PCSK9 loss-of-function mutation carriers compared with normal individuals 3 CHD (%) Black Subjects P= n=3278 n=85 White Subjects 11.8 P= n=9223 n=31 Normal Subject Mutation Carrier PCSK9 Inhibition Enhanced LDL-C Reduction and Reduced CVD Risk 1. Peterson AS et al. J Lipid Res. 28;49: Cohen J et al. Nature Genetics. 25;37: Cohen JC et al. N Engl J Med. 26;354: LDL-C Lowering Efficacy Dose-Response of Alirocumab and Evolocumab* ALIROCUMAB EVOLOCUMAB mab added to stable atorva dose of % Change mab added to stable statin and % Change 1-4 mg QD with LDL-C 1 mg/dl LDL-C LDL-C > ~85 mg/dl LDL-C n=183, Duration = 12 wks n=631, Duration = 12 wks 5 mg Q2W -35% 7 mg Q2W -42% 1 mg Q2W -59% 15 mg Q2W -6% 15 mg Q2W -67% 14 mg Q2W -66% 3 mg Q4W -43% 28 mg Q4W -42% 35 mg Q4W -5% 42 mg Q4W -5% *Added to Stable Statin Therapy - Week 12 Giugliano et al. Lancet. 212;38: McKenney et al. J Am Coll Cardiol. 212; Clinical Outcomes of PCSK9 Inhibitors Meta-analysis of 35 Randomized Clinical Trials End Point Fixed-effects Odds Ratio (95% CI) P Myocardial Infarction.72 ( ) <.1 Stroke.8l ( ).2 Coronary Revascularization.79 ( ) <.1 All Cause Mortality* 1. ( ).999 Cardiovascular Mortality 1.1 ( ).936 Neurocognitive Adverse Events 1.12 ( ).218 *A significant association was shown between LDL-C and benefit in all-cause mortality Karatasakis A et al. J Am Heart Assoc. 217;6:e691. Alirocumab: ODYSSEY Outcomes Evaluation of Alirocumab After ACS Clinical Data on Alirocumab Schwartz GG. Am Heart J. 214;168:

8 ODYSSEY Outcomes Design: Alirocumab Dose Adjustments to Stay within LDL-C Target Range ODYSSEY Outcomes Design: Alirocumab Dose Adjustments to Stay within LDL-C Target Range LDL-C (mg/dl) Undesirably high baseline range We attempted to maximize the number of patients in the target range and minimize the number below target by blindly titrating alirocumab (75 or 15 mg SC Q2W) or blindly switching to placebo. Below target Acceptable range Target range Alirocumab 5 7 LDL-C (mg/dl) Undesirably high baseline range Approximately 75% of months of active treatment were at the 75 mg dose Schwartz GG et al. Am Heart J 214;168: e1. Schwartz GG et al. Am Heart J. 214;168: e1. Steg G. Presented at: American College of Cardiology (ACC) Scientific Sessions; March 218. ODYSSEY Outcomes: Alirocumab Lowers LDL-C Mean LDL-C (mg/dl) Placebo mg/dl 75 mg/dl mg/dl 54.7% % 61.% Alirocumab Months Since Randomization Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo Approximately 75% of months of active treatment were at the 75 mg dose Steg G. Presented at: American College of Cardiology (ACC) Scientific Sessions; March 218. Alirocumab: ODYSSEY Outcomes Alirocumab MACE by 15% Steg G. Presented at: American College of Cardiology (ACC) Scientific Sessions; March 218. ARR* 1.6% 4-Point MACE = CHD death, Non-fatal MI, Ischemic stroke Unstable angina requiring hospitalization *Based on cumulative incidence. Alirocumab: ODYSSEY Outcomes Alirocumab MACE by 15%, same as Evolocumab Alirocumab: ODYSSEY Outcomes Alirocumab Reduces MACE ARR* 1.6% 4-Point MACE = 4-Point MACE = CHD CHD death, death, Non-fatal non-fatal MI, MI, Ischemic ischemic stroke Unstable unstable angina requiring hospitalization Steg G. Presented at: American College of Cardiology (ACC) Scientific Sessions; March 218. *Based on cumulative incidence. Steg G. Late-Breaker Presentation at: American College of Cardiology (ACC) Scientific Sessions; March

9 Alirocumab Effects on Main Secondary Efficacy Endpoints: Hierarchical Testing in ODYSSEY Outcomes Alirocumab: ODYSSEY Outcomes Alirocumab May Reduce Total Mortality* ARR.6% *Nominal P-value Based on cumulative incidence *Nominal P-value Steg G. Late-Breaker Presentation at: American College of Cardiology (ACC) Scientific Sessions; March 218. Steg G. Late-Breaker Presentation at: American College of Cardiology (ACC) Scientific Sessions; March 218. Alirocumab: ODYSSEY Outcomes Post Hoc Analysis: All-cause Death by Pre-specified Baseline LDL-C Subgroups Clinical Data on Evolocumab ARR* 1.7% P interaction =.12 Steg G. Presented at: American College of Cardiology (ACC) Scientific Sessions; March 218. Evolocumab: FOURIER LDL Cholesterol Evolocumab: FOURIER Primary Efficacy Endpoint ARR 2.% Sabatine MS et al. Am Heart J. 216;173: Sabatine MS et al. Am Heart J. 216;173:

10 Evolocumab: FOURIER Key Secondary Endpoint Evolocumab: FOURIER Landmark Analysis Sabatine MS et al. Am Heart J. 216;173: Sabatine MS et al. Am Heart J. 216;173: Lowest LDL-C is Best for ASCVD Prevention Evolocumab (FOURIER) Key 2 o Endpoint (CV Death, MI, or Stroke) LDL-C (mg/dl) Adj HR (95% CI) <2.69 ( ) ( ) ( ) ( ) 1 referent P =.1 Evolocumab Appears Effective (CVD) and Safe (SAE, D/C) to LDL-C < 1 mg/dl* CARDIOVASCULAR EFFICACY Percent HR.69 ( ) P= mg/dl <1 mg/dl HR.59 ( ) P= SAFETY Percent HR.94 ( ) P= HR 1.8 ( ) P= mg/dl <1 mg/dl Giugliano RP et al. Lancet. 217;39: LDL-C (mg/dl) 8 at 4 weeks CVD, MI, Stroke, UA, CVD, MI, Stroke Cor Revasc *Exploratory Analysis of FOURIER n = 54: Median [IQR]LDL-C: 7 [5-9] mg/dl Giugliano RP. Presented at: European Society of Cardiology (ESC) Congress, Barcelona; August, 217. Serious adverse AE -> drug event discontinued An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Ebbinghaus: Evolocumab Evaluation of Cognition with Aggressive LDL-C Lowering CANTAB Tests Adj P trend Executive function.11 Working memory.61 Episodic memory.61 Reaction Time.47 Global Everyday Score Cognition Self Survey.3 Adj P trend Memory.11 Executive function.12 Planning.27 Organization.98 Divided attention.38 Total Score.17 Even slightly better scores at lower achieved LDL-C New Guidance for PCSK9 Inhibitors and Ezetimibe In Light of Cardiovascular Outcomes Data Giugliano RP et al. N Engl J Med. 217;377:

11 216 ACC/AHA Expert Consensus Decision Pathway 217 NLA Expert Panel PCSK9-inhibitor Recommendations Bottom Line 1. LDL-C goals approved: a. <7 for 2 o prevention b. <1 for HR 1 o prev. 2. For PCSK9i, LDL-C Threshold = Goal Lloyd-Jones D et al. J Am Coll Cardiol. 216;68: Orringer C et al. J Clin Lipidology. 217;11: Focused Update: ACC Expert Consensus Decision Pathway on Therapies for LDL-C Lowering in Management of ASCVD* Patients with stable clinical ASCVD without comorbidities, on statin for secondary prevention. Patient has 5% LDL-C reduction (may consider LDL-C <7 mg/dl or non-hdl-c <1 mg/dl) on maximally tolerated statin therapy. NO 1. Address statin adherence 2. Intensify lifestyle (may consider phytosterols 3. Increase to highintensity statin if not already taking 4. Evaluate for statin intolerance if unable to tolerate moderateintensity statin. Consider referral to lipid specialist if statin intolerant 5. Control other risk factors Patient has 5% LDL-C reduction (may consider LDL-C <7 mg/dl or non-hdl-c <1 mg/dl) on maximally tolerated statin therapy. NO CLINICIAN-PATIENT DISCUSSION FACTORS TO CONSIDER 1. Potential for additional ASCVD risk reduction from addition of nonstatin therapy to lower LDL-C 2. Potential for adverse events or drug-drug interactions from addition of nonstatin therapy 3. Patient preferences Optional non-statin medications to consider 1 2 Consider ezetimibe first Consider adding or replacing with PCSK9 inhibitor second NO Patient has 5% LDL-C reduction (may consider LDL-C <7 mg/dl or non-hdl-c <1 mg/dl) on maximally tolerated statin/other medications. Algorithm for Stepwise Management of Patients with HeFH and Clinical ASCVD *Patients 21 years of age with stable clinical ASCVD without comorbidities, on statin for secondary prevention. Lloyd-Jones DM et al. J Am Coll Cardiol. 217;7: Saeed AS et al. J Clin Lipidol. 217;11: ESC/EAS Task Force on Practical Clinical Guidelines PCSK9 Inhibition in Patients with Familial Hypercholesterolemia Approval/Reimbursement Barriers Faced by Patients % of Attempts to Get a PCSK9 Inhibitor Prescription that are Successful 1.% 8.% ASCVD (N=298) FH (N=284) Responses, % 6.% 4.% 64% of respondents with ASCVD patients and 57% of respondents with FH patients were unable to get 3 out of every 4 PCSK9 inhibitor prescriptions approved, despite multiple appeals * 2.% *Confirmed on two consecutive occasions Landmesser U et al. Eur Heart J. 218;39: % None 1%-25% 26%-5% 51%-75% More Than 75% Successful approvals, % Cohen JD et al. J Clin Lipidol. 217;11:

12 Defining a Reimbursement Roadmap To Address Cumbersome Approval/Reimbursement Process More consistent criteria by payers and checklists, algorithms, apps, sharing of best practices which: Improve patient selection Help to assure that required documentation is submitted Reduce wasted time Avoid frustration by health care providers and patients in the approval/denial process CME/MOC Credit Post-activity Survey and CME Evaluation If you re seeking only CME credit, please take a moment to answer the Postactivity Survey questions on your form Your answers are important and will help us identify remaining educational gaps and shape future CME activities After the post-activity survey, please complete the rest of the Evaluation form and ensure you fill in your name and demographic information after the questions Return all forms to on-site CME staff MOC Evaluation MOC seekers do not need to complete the remainder of the paper form. Instead, follow the instructions at the top of the form to complete the online MOC evaluation. Thank you for joining us today! 12