2/26/19. Secondary Cardiovascular Risk Reduction: Incorporating Evolving Data to Individualize Care. Disclosures. Faculty

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1 Secondary Cardiovascular Risk Reduction: Incorporating Evolving Data to Individualize Care Faculty v Karol E. Watson, MD, PhD Professor of Medicine/Cardiology Co-director, UCLA Program in Preventive Cardiology Director, UCLA Barbra Streisand Women s Heart Health Program Los Angeles, CA v David N. Smith, MD Clinical Assistant Professor of Medicine, Yale University Associate Professor of Medicine, Wingate University Adjunct Professor at UNC Chapel Hill Charlotte, NC 2 Disclosures vkarol E. Watson, MD, PhD is a consultant for Amgen, Boehringer Ingelheim, Esperion and Kowa. vdavid N. Smith, MD has no relationships to disclose. 3 1

2 Learning Objectives 1. Describe the findings from recent trials of PCSK9i hypercholesterolemia treatments on cardiovascular outcomes 2. Discuss current guidelines and recommendations for the management of hyperlipidemia in high-risk patients 3. Incorporate current data into secondary prevention treatment strategies for patients with the highest cardiovascular risk 4. Recognize barriers to access for PCSK9 monoclonal antibody therapy and discuss strategies to overcome them 4 Pre-test Questions 5 Pre-test Question 1 Pre-L1: In the FOURIER and ODYSSEY outcomes trials, what was the relative reduction in risk for major cardiovascular events with PCSK9 inhibitors compared to placebo? 1. 5% 2. 15% 3. 25% 4. 30% 6 2

3 Pre-test Question 2 Pre-L2: Which of the following is a common barrier to prior authorization of PCSK9 inhibitor prescription? 1. Triglycerides <150 mg/dl 2. Patient has not tried ezetimibe 3. <100% compliance with statin therapy 4. LDL-C < 130 mg/dl with clinical ASCVD 7 Pre-test Question 3 Pre-L3: According to the 2018 Blood Cholesterol guidelines, for patients in which category of estimated 10-year ASCVD risk should risk enhancers be considered when discussing potential statin therapy for primary prevention? 1. <5% 2. 5% to 20% 3. Over 20% 4. All categories of ASCVD risk 8 Pre-test Question 4 Pre-L4: A 68-year-old woman with a history of NSTEMI (6 months ago), hypertension, dyslipidemia, and previous PCI, presents for a checkup. Her LDL-C is 89 mg/dl, HDL-C 52 mg/dl, and triglycerides 160 mg/dl. Current lipid-lowering therapy is rosuvastatin 40 mg qd. According to the 2018 Blood Cholesterol guidelines, what would be the next most appropriate step to take? 1. Add ezetimibe 2. Add PCSK9 inhibitor 3. Patient at goal; maintain current therapy 4. Switch rosuvastatin 40mg to atorvastatin 80mg 9 3

4 Pre-test Question 5 Pre-L5: A 67-year-old man with a history of NSTEMI (2 years and 6 months ago), hypertension, and dyslipidemia presents for a checkup. He is feeling well. LDL-C is 73 mg/dl. Meds: atorvastatin 80 mg qd, ezetimibe 10mg qd, metoprolol tartrate 100 mg bid, lisinopril 20 mg qd, and aspirin 81 mg qd. According to the 2018 Blood Cholesterol guidelines, which of the following is most appropriate? 1. Add bile acid sequestrant 2. No change, patient stable and at goal 3. Complete prior authorization for PCSK9 inhibitor 4. Switch from atorvastatin 80mg to rosuvastatin 40mg 10 Blood Cholesterol Guidelines 11 Statin Effects on Vascular Events Endpoint Events (%) Treatment Control Rate Ratio (CI) Non-fatal MI 2001 (4 4) 2769 (6 2) 0 74 ( ) CHD death 1548 (3 4) 1960 (4 4) 0 81 ( ) Any major coronary event 3337 (7 4) 4420 (9 8) 0 77 ( ) CABG 713 (3 3) 1006 (4 7) 0 75 ( ) PTCA 510 (2 4) 658 (3 1) 0 79 ( ) Unspecified 1397 (3 1) 1770 (3 9) 0 76 ( ) Any coronary revascularisation 2620 (5 8) 3434 (7 6) 0 76 ( ) Haemorrhagic stroke 105 (0 2) 99 (0 2) 1 05 ( ) Presumed ischaemic stroke 1235 (2 8) 1518 (3 4) 0 81 ( ) Any stroke 1340 (3 0) 1617 (3 7) 0 83 ( ) Any major vascular event 6354 (14 1) 7994 (17 8) 0 79 ( ) 12 CTT. Lancet : Favors statin 4

5 2013 ACC-AHA Cholesterol Guidelines 13 Stone NJ et al. Circulation. 2014;129:S1-45. ACC/AHA Statin Benefit Groups Secondary Prevention Clinical ASCVD Primary Prevention LDL-C > 190 mg/dl Diabetes Mellitus Primary Prevention > 7.5% 10-yr ASCVD risk Age < 75: High-intensity statin Age > 75: Moderate-intensity statin High-intensity statin 10-yr risk < 7.5%: Moderate-intensity statin 10-yr risk > 7.5%: High-intensity statin Consider moderate or high intensity statin 14 Stone NJ et al. Circulation. 2014;129:S1-45. Intensity of Statin Therapy High Intensity Statin Moderate Intensity Statin Low Intensity Statin Daily dose lowers LDL-C ~50% Daily dose lowers LDL-C 30% 50% Daily dose lowers LDL-C <30% Atorvastatin (40)- 80 mg Rosuvastatin 20 (40) mg Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2-4 mg Simvastatin 10 mg Pravastatin mg Lovastatin 20 mg Fluvastatin mg Pitavastatin 1 mg 15 Stone NJ et al. Circulation. 2014;129:S

6 2018 Blood Cholesterol Guidelines Blood Cholesterol Guidelines: Secondary Prevention 17 Grundy et al. J Am Coll Cardiol. Nov Very High-risk of Future ASCVD Events Major ASCVD Events Recent ACS (within the past 12 months) History of MI (other than recent ACS event listed above) History of ischemic stroke Symptomatic PAD (history of claudication with ABI <0.85, or previous revascularization or amputation) High-Risk Conditions Age 65 y Heterozygous familial hypercholesterolemia History of prior CABG or PCI outside of the major ASCVD event(s) Diabetes mellitus Hypertension CKD (egfr ml/min/1.73 m2) Current smoking Persistently elevated LDL-C (LDL-C 100 mg/dl) despite maximally tolerated statin therapy and ezetimibe History of congestive HF 18 Grundy et al. J Am Coll Cardiol. Nov

7 2018 Blood Cholesterol Guidelines: Primary Prevention <5% 5% - <7.5% 7.5% - <20% 20% Low Risk Borderline Risk Intermediate Risk High Risk Risk discussion: Risk discussion: Risk discussion: Risk discussion: Emphasize lifestyle to reduce risk factors (Class I) If risk enhancers present then risk discussion regarding If risk estimate + risk enhancers favor statin, initiate moderate-intensity Initiate statin to reduce LDL-C 50% moderate-intensity statin to reduce LDL-C by (Class I) statin therapy (Class IIb) 30% - 49% (Class I) If risk decision is uncertain: Consider measuring CAC in selected adults: CAC = zero (lowers risk; consider no statin, unless diabetes, family history of premature CHD, or cigarette smoking are present) CAC = 1-99 favors statin (especially after age 55) CAC = 100+ and/or 75th percentile, initiate statin therapy 19 Grundy SM et al. JACC. Nov Blood Cholesterol Guidelines: Primary Prevention <5% Low Risk Risk discussion: Emphasize lifestyle to reduce risk factors (Class I) 20 Grundy SM et al. JACC. Nov Blood Cholesterol Guidelines: Primary Prevention 5% - <7.5% Borderline Risk Risk discussion: If risk enhancers present then risk discussion regarding moderate-intensity statin therapy (Class IIb) 21 Grundy SM et al. JACC. Nov

8 2018 Blood Cholesterol Guidelines: Primary Prevention 7.5% - <20% Intermediate Risk Risk discussion: If risk estimate + risk enhancers favor statin, initiate moderate-intensity statin to reduce LDL-C by 30% - 49% (Class I) If risk decision is uncertain: Consider measuring CAC in selected adults: CAC = zero (lowers risk; consider no statin, unless diabetes, family history of premature CHD, or cigarette smoking are present) CAC = 1-99 favors statin (especially after age 55) CAC = 100+ and/or 75th percentile, initiate statin therapy 22 Grundy SM et al. JACC. Nov Blood Cholesterol Guidelines: Primary Prevention 20% High Risk Risk discussion: Initiate statin to reduce LDL-C 50% (Class I) 23 Grundy SM et al. JACC. Nov Risk-enhancing Factors v Family history of premature ASCVD (males <55 y; females <65 y) v Primary hypercholesterolemia (LDL-C mg/dl; non HDL-C mg/dl) v Metabolic syndrome v Chronic kidney disease (egfr ml/min/1.73 m 2) v Chronic inflammatory conditions (eg, psoriasis, RA, HIV/AIDS) v History of premature menopause (<40 y) and history of pregnancy-associated conditions that increase ASCVD risk (eg, preeclampsia) v High-risk race/ethnicities (eg, South Asian ancestry) v Lipid/biomarkers: v Persistently elevated, primary hypertriglyceridemia ( 175 mg/dl) v If measured: v Elevated high-sensitivity CRP ( 2.0 mg/l) v Lp(a) 50 mg/dl v apob 130 mg/dl v ABI < Grundy et al. J Am Coll Cardiol. Nov

9 Rationale for Pushing LDL-C Levels Even Lower Meta-analysis of 38,153 patients from 8 randomized statin trials <175 LDL-C Levels and Risk of CV Events Major CV and Coronary Event Rates vs Various LDL-C Levels Major Coronary Events Major CV Events 34.4 LDL-C (mg/dl) 125-< < < <75 <50 Event Rate (%) Adjusted Hazard Ratio 95% CI < >190 LDL-C (mg/dl) 25 Boekholdt SM, et al. JACC. 2014;64(5): IMPROVE-IT Trial 18,144 patients with recent ACS simvastatin 40 mg v. simvastatin 40 mg + ezetimibe 10 mg Simvastatin alone (median LDL 69 mg/dl) Simvastatin + ezetimibe (median LDL 54 mg/dl) Event rate % RRR = 6% NNT = Christopher Cannon et. al. N Engl J Med 2015; 372: PCSK9 Inhibitors 27 9

10 PCSK9 (Proprotein convertase subtilisin/kexin type 9) va secreted protein which targets the LDL receptor for degradation vgain of function mutations cause high LDL-C vloss of function mutations cause low LDL-C vinhibition lowers LDL-C levels vup-regulated by statin therapy 28 How is Cholesterol Removed from Blood? 29 The Theory Behind PCSK9 Inhibitors 30 10

11 FOURIER Trial Design - Evolocumab 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 or non-hdl-c 100 mg/dl Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up ~ 3 years 31 Sabatine MS et al. Am H J 2016; 173: FOURIER Trial Lipid Results Placebo LDL Cholesterol (mg/dl) % mean reduction, P< Absolute reduction: 56 mg/dl (95%CI 55-57) (median LDL on Evolocumab 30 mg/dl, IQR mg/dl) Weeks 32 Sabatine MS et al. Am H J 2016; 173: FOURIER Trial: Primary Outcome* 16% 14% Placebo Evolocumab 15% RRR NNT = 67 12% 10% 8% 6% 4% 2% *Primary composite end point: cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. 0% Sabatine MS et al. N Engl J Med 2017; 376: Months 11

12 FOURIER Trial: MI/Stroke/CV Death* 10% 9% 8% 7% Placebo Evolocumab 20% RRR NNT = 74 6% 5% 4% 3% 2% *Secondary composite end point: cardiovascular death, myocardial infarction, or stroke 1% 0% Months 34 Sabatine MS et al. N Engl J Med 2017; 376: ODYSSEY Outcomes Trial Design - Alirocumab 18,924 post ACS patients (1-12 months) 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 Alirocumab SC Q2W RANDOMIZED DOUBLE BLIND Placebo SC Q2W Follow-up: Event-driven 35 Schwartz, G.G., et. al. N Engl J Med 2018; 379: ODYSSEY Trial Lipid Results Upward drift likely due to protocolmandated discontinuation of therapy for LDL <30 mg/dl 36 Schwartz, G.G., et. al. N Engl J Med 2018; 379:

13 ODYSSEY Trial Primary Outcome* RRR = 15% NNT = 63 *Primary endpoint: major adverse cardiovascular events (MACE) the time to first occurrence of coronary heart disease (CHD) death, nonfatal myocardial infarction (MI), unstable angina requiring hospitalization or ischemic stroke 37 Schwartz, G.G., et. al. N Engl J Med 2018; 379: ODYSSEY: All Cause Mortality RRR = 15% NNT = Schwartz, G.G., et. al. N Engl J Med 2018; 379: FOURIER Trial Efficacy and Safety in Patients with LDL-C <10 mg/dl Cardiovascular Efficacy Safety LDL > 100 LDL < 10 LDL > 100 LDL < Percent (%) Percent (%) CV D, M I, Str oke, UA, Cor Reva sc CV D, M I, Str oke 0 Serious A E AE (Drug Discontinued) 39 Giugliano RP, et al. Lancet. 2017;390(10106):

14 Access to PCSK9 Inhibitors 40 Approved PCSK9 Inhibitors Alirocumab Evolocumab Indication Adjunct to diet and maximum-tolerated statin for adults with HeFH or clinical ASCVD who require additional lowering of LDL-C To reduce risk of CVE in adults with established CVD Adjunct to diet, alone or in combination with other LLT, for adults with primary hyperlipidemia (including HeFH) to reduce LDL-C Adjunct to diet and other LDL-lowering therapies in patients with HoFH who require additional lowering of LDL-C Dosing How supplied Side effects mg SQ Q2W 300 mg SQ monthly Single-dose prefilled pens or syringes 75-mg/mL or 150-mg/mL Nasopharyngitis Injection-site reactions Hypersensitivity reactions 140 mg SC Q2W 420 mg SC monthly Single-use prefilled syringe or autoinjector 1 ml of 140-mg/mL or 420 mg/3.5 ml Nasopharyngitis Injection-site reactions Hypersensitivity reactions 41 Accessed May 8, Accessed May When to Consider a PCSK9 Inhibitor LDL-C Reduction on Patient Type Therapy Recommendation Maximally Tolerated Statin <50% LDL-C reduction or Ezetimibe 1st Very high-risk ASCVD LDL-C >70 mg/dl PCSK9 inhibitor 2nd years of age with baseline LDL-C LDL-C >130 mg/dl on statin plus ezetimibe PCSK9 inhibitor 220 mg/dl years of age with heterozygous FH LDL-C >100 mg/dl on statin plus ezetimibe PCSK9 inhibitor and baseline LDL-C 190 mg/dl years of age with baseline LDL-C <50% LDL-C reduction or Ezetimibe 190 mg/dl LDL-C >100 mg/dl years of age with baseline LDL-C <50% LDL-C reduction and triglycerides Bile acid sequestrant 190 mg/dl 300 mg/dl on statin plus ezetimibe Diabetes and 10-year ASCVD risk 20% <50% LDL-C reduction Ezetimibe Very high-risk ASCVD: history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions 42 Grundy et al. J Am Coll Cardiol. Nov

15 Access to PCSK9 Inhibitors vbaum et al. (44,234 prescriptions) 1-83% of PCSK9 inhibitor prescription rejected initially; 57% rejected ultimately - Patients with PCSK9 prescriptions approved were more likely to be on highintensity statin + ezetimibe vnavar et al. (prescriptions for 45,029 patients) 2-79% rejected within 24 hours; 53% rejected ultimately - Rejection rates: 33% 78% for commercial payers; 38% 84% for government insurance programs; 33% 75% across PBMs - 35% of filled prescriptions were abandoned at the pharmacy 1. Baum SJ, Chen CC, Rane PB, et al. Characteristics of patients approved and denied access in PCSK9i therapy by payers. Presented at the 66 th Scientific Session of the American College of Cardiology, Washington, DC, March 17-19, Abstract Navar AM, Taylor BT, Flevitz E, et al. Early challenges for PCSK9 inhibitor prescriptions and patients: rejections and rates unfilled. Presented at the 66 th Scientific Session of the American College of Cardiology, Washington, DC. March 17-19, Abstract PCSK9 Inhibitor Support Programs - Copay cards for eligible patients with commercial insurance - Low income subsidy programs for Medicare patients - Patient assistance programs to provide free medication to eligible patients - Insurance specialists available to assist with prior authorization and coverage issues 44 Common Reasons for PCSK9 Denial: A Veritable Laundry List vpatient has not tried ezetimibe vre-challenge with statin not documented in statin-intolerant patient vpatient has not tried a bile acid sequestrant vldl <100 mg/dl with ASCVD or <130 mg/dl without ASCVD vrequires 80% compliance in fill history from pharmacy over 12- month period vnutrition intervention not documented vtriglycerides >400 mg/dl 45 15

16 Common Reasons for PCSK9 Denial, cont d vexercise and weight management regimen not documented vrequires confirmation of FH with genetic testing vcriteria for definite FH not documented vindication for PCSK9 inhibitor not clearly documented vfailure to submit office notes or labs with prior authorization request vno statement that patient will continue to receive maximally tolerated statin vascvd criteria not met 46 Strategies to Improve PCSK9 Inhibitor Access: A Team-based Approach vhave dedicated team to deal with prior authorizations, appeals, re-appeals, and peer-to-peer reviews vmultidisciplinary team of physicians, a nurse, a medical assistant, a clinical pharmacist, and a physician assistant (the PCSK9 Inhibitor Clinic ) - Coordinator oversees the approval process, provides injection training, and arranges longitudinal management and surveillance - 92% success rate (n=142/153) vkey to successful PCSK9 inhibitor PA approval vmeticulous documentation of all data required for PA 47 Statins are still the mainstay of lipid-lowering therapy 48 16

17 Meta-analysis of 14 Statin Trials (N=90,056) For each 39 mg/dl LDL-C lowering with statins v12% reduction in all-cause mortality (P<0.0001) v19% reduction in coronary mortality (P<0.0001) v23% reduction in MI and coronary death (P<0.0001) v24% reduction in revascularizations (P<0.0001) v17% reduction in fatal or non-fatal stroke (P<0.0001) v21% reduction in any major vascular event (P<0.0001) 49 Adapted from Baigent C et al. Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2005; 366: Summary 50 Summary vldl-c is the target of lipid therapy and statins are the mainstay of treatment vresponse to statins is variable and influenced by many factors including genetic factors vnew therapies are emerging for treatment of hyperlipidemia: vezetimibe, PCSK9 inhibitors vpatient populations at highest ASCVD risk may benefit greatly from such therapies 51 17

18 Post-test Questions 52 Post-test Question 1 Post-L1: In the FOURIER and ODYSSEY outcomes trials, what was the relative reduction in risk for major cardiovascular events with PCSK9 inhibitors compared to placebo? 1. 5% 2. 15% 3. 25% 4. 30% 53 Post-test Question 2 Post-L2: Which of the following is a common barrier to prior authorization of PCSK9 inhibitor prescription? 1. Triglycerides <150 mg/dl 2. Patient has not tried ezetimibe 3. <100% compliance with statin therapy 4. LDL-C < 130 mg/dl with clinical ASCVD 54 18

19 Post-test Question 3 Post-L3: According to the 2018 Blood Cholesterol guidelines, for patients in which category of estimated 10-year ASCVD risk should risk enhancers be considered when discussing potential statin therapy for primary prevention? 1. <5% 2. 5% to 20% 3. Over 20% 4. All categories of ASCVD risk 55 Post-test Question 4 Post-L4: A 68-year-old woman with a history of NSTEMI (6 months ago), hypertension, dyslipidemia, and previous PCI, presents for a checkup. Her LDL-C is 89 mg/dl, HDL-C 52 mg/dl, and triglycerides 160 mg/dl. Current lipid-lowering therapy is rosuvastatin 40 mg qd. According to the 2018 Blood Cholesterol guidelines, what would be the next most appropriate step to take? 1. Add ezetimibe 2. Add PCSK9 inhibitor 3. Patient at goal; maintain current therapy 4. Switch rosuvastatin 40mg to atorvastatin 80mg 56 Post-test Question 5 Post-L5: A 67-year-old man with a history of NSTEMI (2 years and 6 months ago), hypertension, and dyslipidemia presents for a checkup. He is feeling well. LDL-C is 73 mg/dl. Meds: atorvastatin 80 mg qd, ezetimibe 10mg qd, metoprolol tartrate 100 mg bid, lisinopril 20 mg qd, and aspirin 81 mg qd. According to the 2018 Blood Cholesterol guidelines, which of the following is most appropriate? 1. Add bile acid sequestrant 2. No change, patient stable and at goal 3. Complete prior authorization for PCSK9 inhibitor 4. Switch from atorvastatin 80mg to rosuvastatin 40mg 57 19

20 Post-test Question 6 Post-L6: Approximately how many patients with hyperlipidemia do you see on a weekly basis, in any clinical setting? 1. None >25 58 Q&A 59 20