Lipids What s new? Meera Jain, MD Providence Portland Medical Center

Transcription

1 Lipids What s new? Meera Jain, MD Providence Portland Medical Center 1

2 Can I trust the ASCVD risk calculator? Do harms outweigh benefits in primary prevention? Is there anything besides a statin? Can I stop checking yearly lipids? How do I get my patients to stay on their statin? Questions Do the Pooled Cohort Equations over-estimate 10 yr ASCVD risk? Are there any other important cholesterol guidelines? Should I be using more or less statins for primary prevention? How do I keep patients with ASCVD on their statin? Is there finally some evidence for ezetimibe? What do I need to know about PCSK-9 inhibitors? 2

3 Case #1 Primary Prevention 55yo male, new to clinic. No diabetes. BP 130/85. No tobacco. Nonfasting lipids: Total cholesterol 230 HDL 40 TG 150 LDL 160 What is his 10 yr CHD risk? At what 10 yr CHD risk would you start a statin? 3

4 MESA study- Multi-Ethnic Study of Atherosclerosis MESA study- Multi-Ethnic Study of Atherosclerosis Purpose: to compare predicted vs observed 10 yr risk in various risk models Design: prospective epidemiologic study of ASCVD Setting: community-based, sex-balanced, muti-ethnic cohort in 6 US communities Patients: 4227 participants aged without diabetes 42% White, 26% African-American, 20% Hispanic, 12% Chinese Measurements: predicted and observed events over 10 yrs 4

5 MESA Study- observed 10 yr ASCVD rate less than predicted Risk score 10 yr event rate Predicted Observed AHA/ACC- ASCVD Total 9% 5% MESA Study- observed 10 yr ASCVD rate less than predicted, both sexes Risk score 10 yr event rate Predicted Observed AHA/ACC- ASCVD Total 9% 5% Men 12% 6% Women 7% 4% 5

6 MESA Study- observed 10 yr ASCVD rate less than predicted, across all risk scores in Men Risk score 10 yr event rate Predicted Observed AHA/ACC- ASCVD Men 10yr risk 0 4.9% 3% 1% 5 7.4% 6% 3% % 9% 3% > 10 % 18% 10% MESA Study- observed 10 yr ASCVD rate less than predicted, across all risk scores in Men Risk score 10 yr event rate Predicted Observed AHA/ACC- ASCVD Men 10yr risk 0 4.9% 3% 1% 5 7.4% 6% 3% Overestimation in low risk groups does not affect treatment threshold % 9% 3% > 10 % 18% 10% 6

7 MESA Study- observed 10 yr ASCVD rate less than predicted, across all risk scores in Men Risk score 10 yr event rate Predicted Observed AHA/ACC- ASCVD Men 10yr risk 0 4.9% 3% 1% 5 7.4% 6% 3% % 9% 3% Observed rate lower than treatment threshold > 10 % 18% 10% MESA Study- observed 10 yr ASCVD rate less than predicted, across all risk scores in Men Risk score 10 yr event rate Predicted Observed AHA/ACC- ASCVD Men 10yr risk 0 4.9% 3% 1% 5 7.4% 6% 3% % 9% 3% > 10 % 18% 10% Observed rate lower but still exceeds treatment threshold 7

8 MESA Study- most risk scores over-estimated 10 yr event rate Risk score 10 yr event rate Predicted Observed AHA/ACC- ASCVD 9% 5% ATPIII 7% 3% FRS-CVD 13% 11% FRS-CHD 9% 6% MESA Study- most risk scores over-estimated 10 yr event rate (except Reynold s Risk Score) Risk score 10 yr event rate Predicted Observed AHA/ACC- ASCVD 9% 5% ATPIII 7% 3% FRS-CVD 13% 11% FRS-CHD 9% 6% Reynold s Risk Score 7.4% 7.6% 8

9 MESA Study-over-estimate of 10yr risk even untreated participants Risk score 10 yr event rate in never treated (no asa,statin,bp meds) Predicted Observed AHA/ACC- ASCVD 5% 2% ACC-AHA ASCVD Pooled Cohort Equations Overprediction of 10 yr risk for men and women Across all cardiac risk Even in those without medication use (asa, bp meds, statin) 9

10 Implications from MESA study Should we use another risk calculator? Should we use a higher threshold to start statin therapy? Should we calculate 5 year or 1 year risk instead? Questions Do the Pooled Cohort Equations over-estimate 10 yr CHD risk? Are there any other important cholesterol guidelines? Should I be using more or less statins for primary prevention? How do I keep patients with ASCVD on their statin? Is there finally some evidence for ezetimibe? What do I need to know about PCSK-9 inhibitors? 10

11 2013 AHA/ACC and 2015 VA/DOD Cholesterol Guidelines Treatment based on risk Use of risk calculator to determine risk in primary prevention Treatment with statins No goal LDL 11

12 Primary prevention- 10 yr ASCVD risk for which statin recommended ACC/AHA > 7.5% 10 yr CHD risk VA/DOD > 12% 10 yr CHD risk Consider with 6-12% 10yr CHD risk Measure Fasting or nonfasting lipids? ACC/AHA Fasting preferred VA/DOD Non-fasting sufficient 12

13 Use a CHD risk calculator ACC/AHA Use Pooled Cohort Equations VA/DOD Use a 10 yr risk calculator Use of hs-crp, coronary artery calcium testing to help with CVD risk ACC/AHA Consider use to help increase or decrease risk to guide statin treatment VA/DOD Not recommended 13

14 Labs prior to starting statin Labs after starting statin ACC/AHA VA/DOD ALT, fasting lipid, A1c (if DM ALT, CPK, nonfasting lipid status unknown) CPK (if indicated) Labs prior to starting statin r/o secondary causes Lipids 1-3mo later and then Q 3-12months Labs after starting statin None except LFTs if on high dose statin LDL can be measured to assess adherence or to see if too low/statin reduction CPK if myalgias Secondary Prevention Dose of statin starting dose ACC/AHA High dose VA/DOD Moderate dose (consider titrate up to high dose in select patients) 14

15 Moderate and high dose statins Questions Do the Pooled Cohort Equations over-estimate 10 yr CHD risk? Are there any other important cholesterol guidelines? Should I be using more or less statins for primary prevention? How do I keep patients with ASCVD on their statin? Is there finally some evidence for ezetimibe? What do I need to know about PCSK-9 inhibitors? 15

16 Case #2 Primary Prevention 55yo male with 10 yr CHD risk of 20% You would like to start a statin but patient is concerned about muscle aches and risk for diabetes. Statin associated myopathy not common in clinical trials Clinical trial data incidence is 1.5-5% -sicker patients excluded -run in phase, compliant patients -patients who tolerate statins are in trials Real life incidence is (much higher) -Nocebo effect? -sicker patients, drug interactions, statin naive 16

17 Absolute benefit of statin depends on risk Harms are fixed Benefits Major CV events: RRR: 20-30% ARR: variable NNT: variable Harms Diabetes 1 in every 200 pts Myalgias 10-30% 20% 10 yr ASCVD risk- For every 100 persons treated with statin for 5 yrs Benefits Major CV events: RRR: 20% 20% 16% ARR: 4% NNT: 25 Harms fixed Diabetes < 1 new dx of diabetes Myalgias 20 people with muscle complaints Prevent 4 major CV events 17

18 5% 10 yr ASCVD risk- For every 100 persons treated with statin for 5 yrs Benefits Major CV events: RRR: 20% ARR: 1% NNT: 100 Harms fixed Diabetes < 1 new dx of diabetes Myalgias 20 people with muscle complaints Prevent 1 major CV event Primary prevention- 10 yr ASCVD risk for which statin recommended ACC/AHA > 7.5% 10 yr CHD risk VA/DOD > 12% 10 yr CHD risk Consider with 6-12% 10yr CHD risk EBDM-Evidence-based decision making SDM- Shared-decision making 18

19 Questions Do the Pooled Cohort Equations over-estimate 10 yr CHD risk? Are there any other important cholesterol guidelines? Should I be using more or less statins for primary prevention? How do I keep patients with ASCVD on their statin? Is there finally some evidence for ezetimibe? What do I need to know about PCSK-9 inhibitors? Case #3 55yo with stable CAD/had PCI for MI 1 yr ago. On atorvastatin 80mg. Complains of muscle aches. He wants to stop atorvastatin. Do you check CPK? What are your treatment options? 19

20 Myopathy: Risk Factors Endogenous Advanced age Hypothyroidism Genetic polymorphisms/predispositions Small BMI Diabetes mellitus Renal disease Female sex Multi-system disease - liver and/or kidney Exogenous Heavy exercise Drugs effecting statin metabolism (CYP3A4) Gemfibrozil Grapefruit juice > 1 quart/day Non-dihydropyridine CCBs Amiodarone Protease inhibitors implications for HIV Warfarin Azole antifungals Macrolide antibiotics Cyclosporine Statins are not all alike Lipophilic Half-life (hours) Atorva Fluva XL Lova Pitava Prava Rosuva Simva Yes Yes Yes Yes No No Yes (most) Metabolism CYP3A4 CYP2C9 CYP3A4 Limited Sulfation Limited CYP3A4 Urinary excretion (%) Potency High Low Low High Low High Medium Therapeutic dose range (mg)

21 Statins are not all alike Lipophilic Half-life (hours) Atorva Fluva XL Lova Pitava Prava Rosuva Simva Yes Yes Yes Yes No No Yes (most) Metabolism CYP3A4 CYP2C9 CYP3A4 Limited Sulfation Limited CYP3A4 Urinary excretion (%) Potency High Low Low High Low High Medium Therapeutic dose range (mg) Statins are not all alike Lipophilic Half-life (hours) Atorva Fluva XL Lova Pitava Prava Rosuva Simva Yes Yes Yes Yes No No Yes (most) Metabolism CYP3A4 CYP2C9 CYP3A4 Limited Sulfation Limited CYP3A4 Urinary excretion (%) Potency High Low Low High Low High Medium Therapeutic dose range (mg)

22 Statins are not all alike Lipophilic Half-life (hours) Atorva Fluva XL Lova Pitava Prava Rosuva Simva Yes Yes Yes Yes No No Yes (most) Metabolism CYP3A4 CYP2C9 CYP3A4 Limited Sulfation Limited CYP3A4 Urinary excretion (%) Potency High Low Low High Low High Medium Therapeutic dose range (mg) Myopathy: varies by statin, dosing Higher risk for myopathy Lower risk for myopathy Cerivastatin (no longer available) Simvastatin (esp 80mg) High dose of statin Fluvastatin XL Pravatatin Low dose statin Lower dose atorvastatin Lower dose rosuvastatin 22

23 Myopathy Consider labs or not (CPK, TSH, vitamin D, CMP) Stop statin Resume statin at same or lower dose or a different statin (consider pravastatin or rosuvastatin) Consider 1x/week to 3-4x/week long acting statin Keep trying- any dose statin better than no statin for most Consider adding vitamin D (in future- consider ezetimibe or PCSK-9 inhibitor) Use longer acting if you d like less frequent dosing Atorvastatin: daily, every other day Rosuvastatin: daily, every other day, MWF, or even once a week 23

24 Use longer acting if you d like less frequent dosing Atorvastatin: daily, every other day Rosuvastatin: daily, every other day, MWF, or even once a week Prior to saying someone is statin intolerant I try once a week rosuvastatin Questions Do the Pooled Cohort Equations over-estimate 10 yr CHD risk? Are there any other important cholesterol guidelines? Should I be using more or less statins for primary prevention? How do I keep patients with ASCVD on their statin? Is there finally some evidence for ezetimibe? What do I need to know about PCSK-9 inhibitors? 24

25 Ezetemibe- an interesting tale Reduces cholesterol absorption by small intestine Approved by FDA in 2002 based on LDL reduction Aggressively marketed in US/millions of Rxs in US ENHANCE trial 2008 (N Engl J Med) showed no improvement in surrogate endpoint of carotid atherosclerotic burden despite impressive LDL lowering Not recommended in 2013 ACC/AHA guidelines IMPROVE-IT trial 25

26 IMPROVE-IT trial Purpose- to see if adding ezetimibe to statin therapy is beneficial Design- double-blind, randomized, multi-center, multi-country Participants- 18,144 (recent acute coronary syndrome) LDL (on statin) LDL (not on statin) Intervention- Simva 40mg + ezetimibe 10mg daily or Simva 40mg + placebo daily * *CV death or major coronary event or hosp for unstable angina or coronary revasc at >30d or nonfatal stroke 26

27 * LDL When might you use ezetimibe (zetia)? Secondary prevention -Adjunct to statin if LDL > (I do not use though) -Statin intolerant patients -Marked LDL elevations despite statin use 27

28 When might you use ezetimibe (zetia)? Secondary prevention -Adjunct to statin if LDL > (I do not use though) -Statin intolerant patients -Marked LDL elevations despite statin use I ll likely use more when off patent and generic Questions Do the Pooled Cohort Equations over-estimate 10 yr CHD risk? Are there any other important cholesterol guidelines? Should I be using more or less statins for primary prevention? How do I keep patients with ASCVD on their statin? Is there finally some evidence for ezetimibe? What do I need to know about PCSK-9 inhibitors? 28

29 PCSK9 binds to LDL receptor and LDL receptor is degraded and LDL receptor cannot be reused PCSK9 binds to LDL receptor LDL-C PCSK9 LDL receptor degraded LDL receptor LDL receptors clear LDL from blood PCSK-9 inhibitors- monoclonal antibodies help clear LDL from bloodstream Inhibitor(Ab) binds to PCSK9 LDL receptor recycled More available LDL receptors More LDL clearing from blood 29

30 PCSK-9 inhibitors SQ Q 2 weeks, expensive ($15000 per year) LDL lowering 50-60% Alirocumab (Praluent) and Evolocumab(Repatha) FDA approved Most current trial data in familial hyperlipidemia Encouraging data showering reduction in clinical outcomes in as little as 1 year Small trial showing benefit in statin intolerance Multiple large scale ongoing trials (to be completed in 2018) looking at use in ASCVD patients on statin therapy Key messages- Lipids 2016 Pooled Equations over-estimate 10yr ASCVD risk Use ACC/AHA 2013 or VA/DoD 2015 lipid guidelines 10 yr CHD risk > 12% encourage statin use 10 yr CHD risk 6-12% shared decision-making No need to order fasting lipids, yearly LDLs Prevent statin myopathy and try hard to keep patients on statin (secondary prevention) Some evidence exists for ezetimibe New class of LDL lowering drug- PCSK-9 inhibitors expensive/limited outcome data for efficacy and safety 30