Managing Complex Lipid Patients

Transcription

1 September 10, th Cardiology for the Primary Care Provider Conference, Salishan, OR Cezary Wójcik MD, PhD, FNLA Department of Family Medicine Diplomate, American Board of Clinical Lipidology Managing Complex Lipid Patients

2 National Cholesterol Education Program ATP National Heart, Lung, and Blood Institute (NHLBI) ATP I 1988 patients with and without CAD who had 2 or more risk factors for CAD have an LDL-C target of <130 mg/dl ATP II lowered the goal LDL-C to 100 mg/dl in patients with known CAD ATP III 2001 introduced risk stratification, LDL-C goal for high-risk patients is <100 mg/dl ATP III 2004 update - optional goal of <70 mg/dl for very high-risk patients ATP IV - aborted in 2013

3 2013 ACC/AHA Guidelines Original ATP IV panel appointed by NHLBI, transitioned to ACC/AHA Expert Panel in mid 2013

4 Cholesterol goals of therapy have been eliminated Advises initiation and maintenance of maximal statin dose (no wasting time to titrate therapy) Evidence limited to RCTs with ASCVD outcomes and systematic reviews and meta-analyses of RCTs with ASCVD outcomes

5 2013 ACC/AHA Guidelines Four Major Statin Benefit Groups Patients with: Clinical ASCVD Primary elevations of LDL C 190 mg/dl DM yo with LDL C mg/dl and without clinical ASCVD Without clinical ASCVD or diabetes with LDL C mg/dl and estimated 10-year ASCVD risk 7.5% using pooled cohort equations

6 Different statin dosages Doses not tested in RCTs are italicized

7 Case 1 63 yom w/ ASCVD 63 yo male, former smoker with established CAD: STEMI at age 55, CABGx4 at age 60, no anginal symptoms currently. Normal BMI, eating healthy, active. Taking all medications. No muscle pain. Had muscle pain on higher rosuvastatin dose, had muscle pain with any atorvastatin dose. Positive family history of heart disease, BP 130/65 Medications: ASA 81 mg daily Carvedilol 12.5 mg BID Lisinopril 20 mg daily Rosuvastatin 20 mg daily

8 Case 1-63 yom w/ ASCVD Labs normal CMP, A1C, TSH, CBC, NT-BNP Total cholesterol 200 HDL-C 35 LDL-C 129 Non-HDL-C 165 TG 180

9 Case 1-63 yom w/ ASCVD Labs normal CMP, A1C, TSH, CBC, NT-BNP Total cholesterol 200 HDL-C 35 LDL-C 129 Non-HDL-C 165 TG 180 Are we done? Does patient need other lipid lowering therapy?

10 2013 ACC/AHA Guidelines Non-Statins Clinicians treating high-risk patients who have a less-than-anticipated response to statins, who are unable to tolerate a less-thanrecommended intensity of a statin, or who are completely statin intolerant may consider the addition of a nonstatin cholesterol-lowering therapy. His untreated LDL-C was 188 mg/dl at time of NSTEMI

11 2013 ACC/AHA Guidelines Non-Statins High-risk individuals include those with ASCVD, those with LDL C 190 mg/dl and individuals with diabetes. In this situation, this guideline recommends clinicians preferentially prescribe drugs that have been shown in RCTs to provide ASCVD risk-reduction benefits that outweigh the potential for adverse effects drug-drug interaction, and patient preferences. The patient is certainly high risk

12 Currently Available Non-Statin Lipid Lowering Drugs Niacin (vitamin B3) Fibrates (PPARα agonists) Bile acid binding resins Ezetimibe (cholesterol absorption inhibitor) Omega3-PUFAs PCSK9 inhibitors

13 New Evidence Since 2013 ACC/AHA Guidelines IMPROVE-IT trial: CV benefits of ezetimibe AIM-HIGH and HPS2-THRIVE trials: Lack of CV benefits of niacin Many trials with PCSK9 inhibitors: Potent LDL-C lowering Secondary analysis show CV benefit ~48-53% Major CV outcome trials under way

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15 AIM-HIGH Results Primary Outcome 1 o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization Boden WE. N Engl J Med. epub 15 Nov 2011; doi /NEJMoa

16 HPS2 THRIVE 20 Patients suffering events (%) Risk ratio 0.96 (95% CI ) Logrank P=0.29 Placebo ERN/LRPT 15.0% 14.5% 0 NEJM Years of follow up

17 PCSK9 Inhibitors PCSK9 inhibitors available Alirocumab (Praluent) Evolocumab (Repatha) Bococizumab - in phase 3 trials Lower LDL-C 50-80% on top or without statins Post hoc analysis shows ~48-53% decrease in MACE

18 Dramatic LDL-C Lowering by PCSK9 inhibitors LDL-C Mean (±SE) % Change from Baseline Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week % -62.9% -5.1% Placebo -72.4% Alirocumab LOCF = last observation carried forward. McKenney JM. A Randomized, Double-blind, Placebo-controlled Trial of the Safety and Efficacy of a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease, REGN727/SAR236553, in Patients with Primary Hypercholesterolemia (NCT: ). American Cardiology Conference 2012, Chicago, IL.

19 Post Hoc Analysis of OSLER Trial: Effect of Evolocumab on Cardiovascular Outcomes 3 Composite Endpoint: Death, MI, UA hosp, coronary revasc, stroke, TIA, or CHF hosp Cumulative Incidence (%) 2 1 HR % CI P=0.003 Standard of care alone (n=1489) 2.18% 0.95% Evolocumab plus standard of care (n=2976) Days Since Randomization TIA = transient ischemic attack; CHF = congestive heart failure; MI = myocardial infarction; UA = unstable angina. Sabatine MS, et al. N Engl J Med. 2015;372:

20 Cardiovascular Outcomes Trials of PCSK9 Inhibitors Alirocumab Evolocumab Bococizumab Sponsor Sanofi/Regeneron Amgen Pfizer Trial ODYSSEY Outcomes FOURIER SPIRE I SPIRE II Sample Size 18,000 22,500 12, Patients 4-16 weeks post-acs MI, stroke, or PAD High risk of CV event Atorvastatin 20 mg or Statin Evidence-based Rx Lipid-lowering Rx equivalent LDL-C 70 mg/dl 70 mg/dl mg/dl 100 mg/dl PCSK9i Dosing Endpoint Every 2 weeks Every 2 or Every 4 weeks Every 2 weeks CHD death, MI, ischemic stroke, or UA hospitalization Primary: CV death, MI, stroke, UA hospitalization or coronary revascularization Key Secondary: CV death, MI, or stroke CV death, MI, stroke, or urgent revascularization Completion March 2018 December 2017 August 2017

21 Biology of PCSK9

22 Inhibition of PCSK9

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26 Definition of comorbidities Diabetes mellitus Recent (<3 months) ASCVD event ASCVD event while on statin therapy Baseline LDL-C 190 mg/dl not due to secondary causes Poorly controlled other major ASCVD risk factors Elevated lipoprotein (a) Chronic kidney disease

27 Case 1-63 yom w/ ASCVD Labs normal CMP, A1C, TSH, CBC, NT-BNP Total cholesterol 200 HDL-C 35 LDL-C 129 Non-HDL-C 165 TG 180 LDL-C 188 mg/dl before rosuvastatin 20 mg Not 50% reduction, above LDL-C goal < 100 mg/dl

28 Case 1-63 yom w/ ASCVD Ezetimibe 10 mg prescribed

29 Case 1-63 yom w/ ASCVD Ezetimibe 10 mg prescribed Insurance denies ezetimibe stating must try niacin or fenofibrate first

30 Case 1-63 yom w/ ASCVD You write a lengthy PA letter arguing that according to 2016 ACC EDCP: On the basis of currently available evidence of nonefficacy and potential harms, the committee judged that there are no clear indications for the routine use of niacin preparations as additional non-statin therapies, and niacin is therefore not recommended for use in any of the clinical situations addressed below.

31 Case 1-63 yom w/ ASCVD After 6 weeks on ezetimibe 10 mg plus rosuvastatin 20 mg Total cholesterol 173 HDL-C 35 LDL-C 103 Non-HDL-C 138 TG 175 LDL-C 188 mg/dl before therapy Still not 50% reduction, still >100 mg/dl What next?

32 Case 1-63 yom w/ ASCVD PCSK9 inhibitor prescribed

33 Case 1-63 yom w/ ASCVD PCSK9 inhibitor prescribed Insurance sends back a denial letter arguing that those are experimental drugs for the treatment of high blood fats

34 Case 1-63 yom w/ ASCVD While you are involved in letter exchange with insurance, patient gets to the ER with chest pain, diagnosed with ACS, followed by cath and placement of 2 drug eluting stents Now what?

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36 Case 1-63 yom w/ ASCVD PCSK9 inhibitor prescribed again, this time arguing that patient had an ASCVD event and needs additional LDL-C lowering (new LDL-C goal < 70 mg/dl) -Alirocumab (Praluent - Sanofi Regeneron) - 75 or 150 mg subcutaneous injection with prefilled pen q2 weeks -Evolocumab (Repatha - Amgen) mg subcutaneously with Pushtronex system monthly mg subcutaneously with prefilled pen q2 weeks

37 Case 1-63 yom w/ ASCVD PCSK9 inhibitor got approved. After 6 weeks on ezetimibe 10 mg plus rosuvastatin 20 mg plus PCSK9 inhibitor injection: Total cholesterol 80 HDL-C 36 LDL-C 25 Non-HDL-C 44 TG 170 LDL-C 188 mg/dl before therapy Now 50% reduction, <70 mg/dl What next?

38 Case 1-63 yom w/ ASCVD Patient is seen by cardiologist who told patient your LDL cholesterol is too low and suggested to stop ezetimibe. What do you tell the patient? Was the cardiologist right?

39 Case 1-63 yom w/ ASCVD

40 Lower is better

41 Case 2 52 yof w/ T2DM 52 yo female with type 2 DM, HTN, depression and chronic lower back pain. BMI of 32, not eating healthy, mostly sedentary. VS: 138/82 PE: obese female, trace BP edema, otherwise WNL Medications: ASA 81 mg daily Metformin 500 mg BID Lisinopril 20 mg daily Citalopram 20 mg daily Ibuprofen 600 mg q6h prn Hydrocodone/acetaminophen 5mg /325 mg q8h prn

42 Case 2 52 yof w/ T2DM CBC, TSH normal, A1C 6.7, CMP normal except mild AST elevation of 55 and egfr of 58. Total cholesterol 220 HDL-C 35 LDL-C 123 Non-HDL-C 185 TG 310 Based on 2013 ACC/AHA guidelines you advise starting patient on atorvastatin 80 mg (ASCVD risk 8.2%)

43 Case 2 52 yof w/ T2DM Patient calls your office in a week, reports severe muscle cramps in legs, she is attributing to statin. You advise to stop atorvastatin, wait 2 weeks for the pain to go away and try rosuvastatin 20 mg instead. Pt starts rosuvastatin and after a week calls your office that she has her leg cramps back. She tells you she never wants to be on any statin again.

44 Case 2 52 yof w/ T2DM What to do next? For statin intolerant patients consider referral to a lipid specialist according to the 2016 ACC ECDP

45 Case 2 52 yof w/ T2DM 3 mo follow up You use your magic skills convince the patient to try pravastatin 10 mg and she tolerates it. When you try to increase dose to 20 mg she develops muscle cramps. She goes back to 10 mg and is able to take it without problems. Total cholesterol 179 HDL-C 33 LDL-C 90 Non-HDL-C 146 TG 280 What next?

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47 Case 2 52 yof w/ T2DM - 3 mo follow up On pravastatin 10 mg Total cholesterol 179 HDL-C 33 LDL-C 90 Non-HDL-C 146 TG 280 What next? LDL-C not reduced by 50%, LDL-C < 100 mg/dl Non-HDL-C above goal of < 130 mg/dl

48 Case 2 52 yof w/ T2DM - 3 mo follow up You convince patient to start ezetimibe in addition to her statin. Patient is tolerating it well, has no side effects. Total cholesterol 140 HDL-C 34 LDL-C 51 Non-HDL-C 106 TG 275 Success! LDL-C reduced by 50%, LDL-C < 100 mg/dl Non-HDL-C < 130 mg/dl Other options per ECDP: Bile acid

49 Case 2 52 yof w/ T2DM - 3 mo follow up Could we have used bile acid binding resins?

50 Case 2 52 yof w/ T2DM - 3 mo follow up Could we have used bile acid binding resins? Contraindicated if triglycerides > 300 mg/dl as paradoxically it may increase TG and cholesterol concentrations

51 Case 2 52 yof w/ T2DM - 3 mo follow up How about PCSK9 inhibitors?

52 Case 2 52 yof w/ T2DM - 3 mo follow up How about PCSK9 inhibitors? They will certainly work and lower LDL-C, they will very likely also lower ASCVD risk, but there is no clinical trial data of benefit in this group of patients at the moment, therefore there is no indication for its use.

53 Case 3-22 yof 22 year old college student presents to your office for a physical. No complaints. Not taking any meds. She has been playing basketball since HS, very active, eats healthy. Non smoker, drinks socially 1-2 x per month. IUD for birth control since 2 years. Both parents alive and healthy. HR: 56 RR: 12 BP 115/65 BMI 24.5 PE: athletic female, PE findings WNL Any labs you are willing to do?

54 Case 3-22 yof Detailed Family History: Both parents well and alive. Father age 42, Mother 43. Paternal grandfather died in Vietnam at young age Paternal grandmother alive, no mayor issues. Maternal grandfather was obese and alcoholic, died in his 50s, Maternal grandmother alive, has type 2 diabetes

55 Case 2-22 yof Will you check her lipids?

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57 Case 2-22 yof What is meant by increased risk? Diabetes Previous personal history of CHD or non-coronary atherosclerosis Family history of cardiovascular disease before age 50 in male relatives or age 60 in female relatives. Tobacco use Hypertension Obesity (BMI 30)

58 American Heart Association Position (2014) If you are age 20 or older and have not been diagnosed with cardiovascular disease, the American Heart Association recommends having your cholesterol levels checked every four to six years as part of a cardiovascular risk assessment

59 Case 2-22 yof Should her pediatrician/family doctor check her lipids before age 21?

60 USPSTF 2016 Statement The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for lipid disorders in children and adolescents 20 years or younger (Grade I statement)

61 American Academy of Pediatrics 2016 Recommendations for Preventive Pediatric Health Care Universal lipid screening between ages 9 and 11 following 2011 guidelines from the National Heart Lung and Blood Institute

62 National Lipid Association Recommendations (2016) Universal screening is recommended beginning at 10 years of age (range 9 to 11). If lipid levels are acceptable, then screening should be repeated every 5 years throughout life, with earlier screening prompted by change in ASCVD risk factors

63 Case 3-22 yof w/hefh Total cholesterol 378 HDL-C 65 LDL-C 295 Non-HDL-C 313 TG 90

64 Rule out 4Ds: Secondary Causes of Hypercholesterolemia Diet : Saturated or trans fats, weight gain, anorexia Drugs: Diuretics, cyclosporine, glucocorticoids, amiodarone Diseases: Biliary obstruction, nephrotic syndrome Disorders and altered states of metabolism: Hypothyroidism, obesity, pregnancy

65 Case 3-22 yof w/hefh Total cholesterol 378 HDL-C 65 LDL-C 295 Non-HDL-C 313 TG 90 Patient does not want to take a statin. She wants to become vegan and is willing to take any natural supplements you recommend.

66 Supplements able to lower LDL-C Red Rice Yeast Plant Sterols/Stanols Berberine Soluble fiber others

67 Case 3-22 yof w/hefh back in 3 months Total cholesterol 350 HDL-C 75 LDL-C 275 Non-HDL-C 313 TG 75 Patient frustrated being vegan and taking three expensive supplements. Decides to take atorvastatin 80 mg.

68 Case 3-22 yof w/hefh back in 3 months Total cholesterol 250 HDL-C 80 LDL-C 156 Non-HDL-C 170 TG 70 Taking atorvastatin 80 mg without any problems. Are we done?

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70 Case 3-22 yof w/hefh back in 3 months Total cholesterol 250 HDL-C 80 LDL-C 156 Non-HDL-C 170 TG 70 Taking atorvastatin 80 mg without any problems. Not achieving 50% LDL-C reduction, above goal of 100 mg/dl Rx of ezetimibe

71 Case 3-22 yof w/hefh back in another 3 months Total cholesterol 210 HDL-C 77 LDL-C 117 Non-HDL-C 133 TG 80 Taking atorvastatin 80 mg and ezetimibe 10 mg without any problems. Achieving 50% LDL-C reduction, but above goal of 100 mg/dl Are we done?

72 Case 3-22 yof w/hefh The committee also notes that for patients with baseline LDL-C 190 mg/dl and without other high-risk features or comorbidities, achievement of 50% reduction in LDL-C and LDL-C <130 mg/dl is a reasonable therapeutic outcome that may not require further intensification of therapy. Does she have other high risk features or comorbidities?

73 Case 3-22 yof w/hefh EKG and treadmill EKG normal (insurance did not authorize stress ECHO) Coronary calcium score 0.2 (above 99 th percentile for age/gender) Lipoprotein(a) 150 mg/dl HS-CRP 5.0

74 Case 3-22 yof w/hefh Rx of Welchol patient called in 2 weeks that she just cann not take it: too bulky and causing severe constipation. Taking atorvastatin 80 mg and ezetimibe 10 mg without any problems. Rx for PCSK9 inhibitors Finally approved

75 Case 3-22 yof w/hefh back in another 3 months Total cholesterol 145 HDL-C 75 LDL-C 52 Non-HDL-C 133 TG 90 Taking atorvastatin 80 mg, ezetimibe 10 mg and biweekly injections of PCSK9 inhibitors without any problems. Achieving 50% LDL-C reduction, at LDL-C goal of <100 mg/dl

76 Case 4 55 yom 65 yo male, smokes ½ PPD, not eating very healthy, msotly sedentary. Taking all medications. Negative family history of heart disease, BP 115/65 Medications: ASA 81 mg daily Losartan 25 mg

77 Case 4 55 yom Labs normal CMP, A1C, TSH, CBC, NT-BNP Total cholesterol 210 HDL-C 35 LDL-C 139 Non-HDL-C 175 TG 180 You advise smoking cessation, healthy lifestyle and starting atorvastatin 40 mg based on ASCVD risk of 14.3%

78 Case 4 55 yom In 1 week patient reports muscle pain with this dose. You rechallenge him with rosuvastatin 20 mg. Also muscle pain. Muscle pain with pravastatin 10 mg. You try atorvastatin 10 mg weekly, patient able to tolerate this dose. Total cholesterol 200 HDL-C 36 LDL-C 130 Non-HDL-C 164 TG 170 What next?

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80 Case 4 55 yom Not achieving 50% LDL-C reduction, not achieving LDL-C < 100 mg/dl Rx of ezetimibe: too expensive Rx of colesevalam: too expensive Rx of cholestyramine: too bulky, patient unable to tolerate it. Anything else that can be done?

81 Cost- Effectiveness of PCSK9 Inhibitors Current price for 1 year of PCSK9 inhibitor therapy ~$14,000 Simulation model of US adults yo Adding PCSK9 inhibitor therapy to current statin regimens $423,000 per QALY pained compared with adding ezetimibe $565 billions increase of US health care costs over 5 years Price reduction needed to $4536 to reach the $100,000 QALY threshold JAMA 2016;316(7):

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