Objec ves To discuss the process of formulation of guidelines and how this may differ among professional societies 5/14/15

Transcription

1 Kellie McLain, NP- C, CLS Medical University of South Carolina Cardiology Division Seinsheimer Cardiovascular Prevention and Lipid Program May 29 th, 2015 Objecves To discuss the process of formulation of guidelines and how this may differ among professional societies To provide an overview of the development, recommendations, confusions and controversies concerning the new 2013 ACC/AHA Treatment of Blood Cholesterol Guideline for ASCVD Prevention To discuss difficult lipid management case studies using current recommendations and novel lipid lowering medications. 1

2 A Year of Controversy in Guideline Development 2013 ACC/AHA Cholesterol Guidelines 2013 ACC/AHA ASCVD Risk Assessment Algorithm not JNC 8 Panel BP Guidelines Guidelines for the Management of LDL- related ASCVD Risk Significant etiologic role of low density lipoprotein in the pathogenesis of atherosclerotic cardiovascular disease Plethora of guidelines with sometimes discordant or overlapping recommendations can lead to confusion among providers, media, patients General population Special populations 2

3 Comparison of Clinical Guidelines for the Management of Risks Related to LDL in ASCVD J Am Coll Cardiol. 2014;64(2): doi: /j.jacc A Change in Strategy 3

4 2013: ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atheroscleroc Cardiovascular Risk in Adults Content/Scope: Addresses only a limited number of clinical questions (3) and does not provide comprehensive recommendations for management of dyslipidemias What is the evidence for LDL- C and non- HDL- C goals for secondary prevention of ASCVD? (19 RCTs) What is the evidence for LDL- C and non- HDL- C goals for primary prevention of ASCVD? (6 RCTs) What is the impact on lipid levels, effectiveness, and safety of specific lipid- lowering drugs in general and in selected subgroups? Succinct summary of evidence for each recommendation DOI: /01.cir a Crical Queson 1: Secondary Prevenon Publicaons screened 4D (diabetics, atorva 20 mg v. placebo: hemodialysis pts, n=1255) *A- Z (ACS, early v. delayed, simva 40 to 80 mg v. placebo to simva 20 mg, n=2265) ACCORD (diabetics, fenofibrate v. placebo on background simva mg, n=5518) ALLIANCE (CHD, usual care v. atorva 80 mg, n=2442) ASPEN (2006, T2DM+CAD baseline LDL- C 114 mg/dl, atorva 10 mg v. placebo, n=2410) AURORA (hemodialysis, rosuva 10 mg v. placebo, n=2776) CARE (MI, prava 40 mg v. placebo, n=4159) CORONA (Class II- IV ischemic syshf age >60 yrs, rosuva 10 mg v. placebo, n=5011) *GREACE (Greece CHD, usual care v. atorva titrated to LDL- C < 100 mg/dl, n=1600) HATS (CHD, simva+niacin v. placebo, n=160) HPS (UK CVD or DM, simva 40 mg v. placebo, n=20,536) IDEAL (MI, atorva 80 mg v. simva 20 mg, n=8888) LIPID (ACS, prava 40 mg v. placebo, n=9014) LIPS (s/p PCI, fluva 80 mg v. placebo, n=1677) MIRACL (ACS, atorva 80 mg v. placebo, n=3086) MUSHASHI- AMI (Japan, acute MI, any statin v. no statin, n=486) PROVE- IT (ACD, atorva 80 mg v. prava 40 mg, n=4132) SPARCL (CVA or TIA, atorva 80 mg v. placebo, n=4731) TNT (CHD, LDL<130 mg/dl, atorva 80 mg v. atorva 10 mg, n=10,001) 4

5 Crical Queson 2: Primary Prevenon Publicaons screened Publications Screened 1958 Included 20 Excluded 1938 Final total for review of CQ2: 6 RCTs Good quality 7 Fair quality 12 Poor quality 1 Total ABSTRACTED 19 Crical Queson 2: Primary Prevenon Publicaons screened AFCAPS/TexCAPS (pts. with average LDL- C levels 150 mg/dl, lova mg v. placebo, n=6605) ASPEN (diabetics, atorva 10 mg v. placebo, n=2410) AURORA (hemodialysis, rosuva 10 mg v. placebo, n=2776) CARDS (T2DM LDL- C 160 mg/dl, atorva 10 mg v. placebo, n=2838) JUPITER (hs- CRP >2 mg/dl, LDL- C <130 mg/dl, rosuva 20 mg v. placebo, n=17,802) MEGA (Japan LDL- C 157 mg/dl, prava mg v. diet alone, n=7832) 5

6 Crical Queson 3: Efficacy and Safety Publicaons screened Publications Screened 2911 Included 59 Excluded 2852 Good quality 10 Fair quality 25 Poor quality 24 Total ABSTRACTED 35 Meta-analyses used for statin efficacy and safety included data from additional studies. 2013: ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atheroscleroc Cardiovascular Risk in Adults New GLOBAL risk assessment tool: CV Risk Calculator based on the Pooled Cohort Equations Derived from large, diverse, community- based cohorts that are generally representative of US population of whites and AA (ARIC, CHS, CARDIA, Framingham original and FOS) 10- year risk of first hard ASCVD event (nonfatal MI, CHD death, fatal or nonfatal stroke) DOI: /01.cir a DOI: / 01.cir

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9 2013: ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atheroscleroc Cardiovascular Risk in Adults Provides race- and sex- specific estimates of 10- year risk Should be used in non- Hispanic whites and non- Hispanic African Americans between the ages of years of age Also provides lifetime risk for persons yr who are not at high short- term risk Recommended optional RF or screening tests: primary LDL- C >160 mg/dl, family history premature ASCVD, hs- CRP >2 mg/l, CAC >300 Agatston or >75 th percentile, ABI <0.9, elevated lifetime risk DOI: /01.cir a DOI: / 01.cir : ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atheroscleroc Cardiovascular Risk in Adults Novel new approach to the management of LDL- related ASCVD risk No RCTs available in which ALL patients were titrated to a specific LDL- C goal <70 or <100 mg/dl in primary or secondary prevention Determined that data are inadequate to identify specific lipoprotein targets of therapy Panel makes no recommendation for or against LDL- C or non- HDL- C targets for primary or secondary ASCVD prevention DOI: /01.cir a DOI: / 01.cir

10 2013: ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atheroscleroc Cardiovascular Risk in Adults Identified four groups of patients with most extensive evidence of benefit of statin therapy for ASCVD prevention 1) Individuals with clinical ASCVD 2) Individuals with primary elevations of LDL- C >190 mg/dl 3) Individuals 4-75 yrs. of age with diabetes and LDL- C mg/dl 4) Individuals without ASCVD or diabetes, yrs. of age, with LDL- C mg/dl and an estimated 10- year ASCVD risk of >7.5% by the Pooled Risk Equations DOI: /01.cir a DOI: / 01.cir

11 2013: ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atheroscleroc Cardiovascular Risk in Adults For each risk group an intensity of statin therapy is specified: moderate- or high- intensity Low- intensity statins are recommended only in patients with history of/at risk for adverse drug effects Quantitative comparison of statin risks and benefits Did not find evidence to support targets of therapy No dose titration recommended Monitoring of LDL- C to assess compliance and response to therapy DOI: /01.cir a DOI: / 01.cir : ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atheroscleroc Cardiovascular Risk in Adults Non- statin therapies did not provide ASCVD risk reduction benefits or safety profiles comparable to statin therapy (IMPROVE- IT) Insufficient evidence to make recommendations in Class II- IV heart failure or hemodialysis DOI: /01.cir a DOI: / 01.cir

12 High-, moderate, and low- intensity stan therapy used in clinical trials High- intensity statin Moderate- intensity therapy statin therapy Daily dose lowers LDL- C on average, by approximately >50% Atorvastatin 40*- 80* mg Rosuvastatin 20*- 40** mg Daily dose lowers LDL- C on average, by approximately 30 to <50% Atorvastatin 10* (20**) mg Rosuvastatin (5**) 10* mg Simvastatin 20*- 40* mg Pravastatin 40* (80**) mg Lovastatin 40* mg Fluvastatin XL 80** mg Fluvastatin 40 mg BID* Pitavastatin 2-4** mg *Statins demonstrated reduction in major CVD events **FDA approved doses not tested in clinical trials Low- intensity statin therapy Daily dose lowers LDL- C on average by approximately <30% Simvastatin 10** mg Pravastatin 10*- 20* mg Lovastatin 20* mg Fluvastatin 20**- 40** mg Pitavastatin 1** mg DOI: /01.cir a DOI: / 01.cir

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14 Monitoring Stan Therapy Initial fasting lipid panel Second panel 4-12 weeks later to determine adherence to therapy Every 3-12 months as clinically indicated Monitoring Stan Therapy Insufficient response to statin therapy Reinforce medication adherence Reinforce adherence to intensive lifestyle changes Exclude secondary causes of hyperlipidemia 14

15 Monitoring Stan Therapy Insufficient response to statin therapy Reinforce medication adherence Reinforce adherence to intense lifestyle changes Exclude secondary causes to dyslipidemia Secondary Causes of Dyslipidemia Secondary Causes- (most common) Diet Drugs Diseases Disorders and altered states of metabolism Elevated LDL- C Saturated or trans fat, weight gain or anorexia Diuretics, cyclosporine, glucocorticoids, amiodarone Biliary obstruction, nephrotic syndrome Hypothyroid, obesity, pregnancy Elevated TG Weight gain, very low- fat diets, high refined carbs, excess ETOH Oral estrogens, glucocorticoids, BAS, protease inhibitors, anabolic steroids, sirolimus, raloxifene, tamoxifen, thiazides, BB(not carvedilol) Nephrotic syndrome, Chronic renal failure, lipodystrophies Diabetes(PC), hypothyroid, obesity, pregnancy 15

16 Monitoring Stan Therapy Higher risk individuals with suboptimal response May consider addition of non- statin therapy if potential risk- reduction benefits outweigh potential adverse effects Preference should be given to drugs shown to reduce ASCVD events in RCTs Statin- intolerant patients May consider addition of non- statin therapy if potential risk- reduction benefits outweigh potential adverse effects Preference should be given to drugs shown to reduce ASCVD events in RCT Stan Safety Recommendaons Consider reduction of statin intensity Multiple comorbidities, impaired renal or hepatic function Previous statin adverse effects, muscle disorders, Unexplained ALT >3 times ULN Concomitant use of drugs affecting statin metabolism >75 yrs of age History of hemorrhagic stroke Asian ancestry 16

17 Stan Safety Recommendaons Do not routinely measure CK Reasonable to measure CK at baseline if individual at increased risk for muscle events or on therapy with muscle symptoms Measure ALT prior to initiation of statin therapy Reasonable to measure LFTs if symptoms of hepatotoxicity May consider decreasing statin dose if 2 consecutive LDL- C <40 mg/dl Do not use simvastatin 80 mg Monitor for new onset diabetes per ADA guidelines Obtain baseline history of current or previous history of muscle symptoms Change, Controversy, Confusion, Concern, Chaos? What is similar? LDL- C remains the lipoprotein of interest Very high- risk patients with FH and/or LDL- C >190 mg/dl are candidates for high- intensity statin therapy In FH combination therapy may be considered (ezetimibe, BAS, niacin, lomitapide, mipomersen, LDL apheresis) Diabetics are a high- risk group: however, intensity of therapy is now based on 10- year risk of hard ASCVD by the Pooled Risk Equations Monitoring of LDL- C, but for adherence rather than goal of therapy 17

18 Change, Controversy, Confusion, Concern, Chaos? What is different? Limited scope of current guideline 3 critical questions Fire and forget vs treat to target, lowest is best, treat level of ASCVD risk, lifetime risk Abandonment of LDL- C and non- HDL- C goals Limited monitoring of LDL- C Limited guidance <40 or >75 yrs. of age Treatment in special populations Limited discussion of management of complex patients New Pooled Risk Equations/CV Risk Calculator work in progress to validate in other populations with varying levels of risk DOI: /01.cir a DOI: / 01.cir Misconcepons What is the meaning of the panel s determination that there is inadequate evidence that lowering of LDL- C to a specific target lowers ASCVD risk? LDL- C is not important Lipid therapy is not beneficial LDL- C is not relevant in ASCVD It s all about statins, not LDL- C Reluctance to initiate therapy, discontinuation of statins DOI: /01.cir a DOI: / 01.cir

19 Misconcepons With primary focus on statins, patients with more complex dyslipidemias, statin intolerance, FH may discontinue combination regimens. Physicians reluctant to prescribe non- statin therapies in appropriate patients. Challenges Large patient population who are possible candidates for statin therapy (non- diabetics, no clinical ASCVD) require calculation of ASCVD risk by the new Pooled Risk Equations. Will providers incorporate this into busy daily practice? 19

20 ACC/AHA and collaborating societies will begin updating these guidelines in 2014 Key Points 20

21 Key Points (cont.) Case Study: Statin intolerant Alternate therapy, weekly dosing, non- statin therapy Primary prevention Alternate risk evaluation Secondary Prevention LDL- P 21

22 Stan Intolerant: 22

23 Lipo/hydrophilicity lipophilicity Log P Simvastatin Lovastatin Atorvastatin Fluvastatin Pitavastatin hydrophilicity Pravastatin Rosuvastatin 23

24 1. Case Study: SI RW 63 yo AAM with CAD, s/p CABG, AFIB, Kidney TX, DM, PVD, Htn, OSA on cpap presented on gemfibrozil 600mg bid. TG 578, HDL 25 Previous zocor 80mg/myalgias- termed Statin Intolerant - Gemfibrozil, RD, 4g O3 Tried atorvastatin(daily/weekly), rosuvastatin, pravachol, lovastatin, fluvastatin all with myalgias. Vit D low- replaced. Pitavastatin What would be next option? 1. Case Study: SI Rosuvastatin 5mg 3x week, vit D replaced/supplement Kidney and liver- nl or slightly elevated transaminases Last visit 3-15 TC 131, HDL 40, LDL 75, TG 78 Lipophilic statins easily penetrate muscle cells, hydrophilic statins penetrate at a lesser extent. 24

25 2. Case Study: Primary Prevenon MS 48 yo WM with HTN, asthma referred by wife(rn) for high cholesterol. Highest LDL 158, TG 285. No DM, thyroid, kidney/liver. FH premature CAD in father at 51 with MI and 2V CABG, deceased at 55 MI. 11 Siblings. BP well controlled. Past intolerance to pravastatin, on simva 10mg, no complaints. Losartan 50mg. Labs 6/13 LDL 135, HDL 37, TG245, TC 221, FG 119, liver nl What next? 25

26 2. Case Study: PP Obtained calcium score Total calcium score of 150, which is at the 97th percentile for age and race matched controls. This means that 97% of people of this age, race, and gender have less calcium than was detected in this CT scan What would be next step? 2. Case Study: PP Started on atorvastatin 20. Developed myalgias. Initiated rosuvastatin 10mg- tolerating well. Started couch to 5K. RD. FU 3 mo. Most recent labs: LDL 65, HDL 44, TG 123, TC 134, AST/ALT nl, FG 97 Continues to tolerate rosuvastatin 10mg. 26

27 3. Case Study: Secondary Prevenon SC 69 yo WM with CAD, s/p mult PCI s, dyslipidemia. Rf by cardiologist for lipid optimization/low HDL Initial labs TC 140, HDL 39, LDL 73, TG 140, on atorvastatin 80mg, ASA 81, toprol xl 50,multi vit. What would be your next step? 3. Case Study: Secondary Prevenon Discuss exercise (rehab), eating habits- refer to RD, low HDL- C, routine lipids ok Check LDL- P number(ideal high risk <700) LDL- P 1929, HDL- P 29.1?? 27

28 3. Case Study: Secondary Prevenon *Options* lifestyle He was started on ezetimibe 10mg and encouraged to change diet (LC) and keep up exercising. FU 3-4 months. Fasting labs at FU LDL- C 55, HDL 42, TG158, TC130 LDL- P 1489 HDL- P tolerating meds without myalgias. No diet or exercise change. Next? 3. Case Study: Secondary Prevenon FU 4 months after met with exercise physiologist and signed up for cardiac gym membership. Decided to change eating habits. Lost 8 lbs LDL- P 984! HDL- P 32.7 LDL- c 52, HDL 45, TG 110, TC 119 Continues with exercise efforts and lower carb eating. 28

29 Quesons? 29