1. 2013 ACA/AHA Blood Cholesterol Guidelines University of Southern California – Los Angeles County Hospital Journal Club Thursday, January 23 rd, 2014 José L. González, MD

2. Outline Methodology Results Adverse effects and monitoring Discussion & Controversies

3. What’s New? No specific lipid treatment goals Limited scope; focus mainly on CQs New Pooled Cohorts Equation Focus on statins and statins only

4. Methodology

5. Organization of the Panel Appointed by the NHLBI 13 members, 3-ex members: primary care, cardiology, endocrinology, experts in clinical lipidology, clinical trials cardiovascular epidemiology and guideline development 16 members from NHLBI ATP IV panel 23 expert reviewers and representatives of federal agencies

6. Methodology Data from RCTs and meta-analyses of RCTs (1995-2009 + RCTs published later) Rated fair to good quality by independent contractor Excluded poor quality RCTs, post-hoc analysis, observational studies Most studies excluded patients w/ 2° causes of hyperlipidemia Triglycerides > 500

7. 3 Critical Questions What is the evidence for LDL-C and non-HDL C goals for the SECONDARY prevention of ASCVD? What is the evidence for LDL-C and non-HDL-C goals for the PRIMARY prevention of ASCVD? What is the impact on lipid levels, effectiveness, and safety of specific drugs used for lipid management in general and in selected subgroups?

8. Evidence Rating A: strong B: moderate C: weak D: recommend against E: expert recommendation N: no recommendation

9. Lifestyle modification Heart healthy diet Regular exercise Avoidance of tobacco products Maintenance of healthy weight

10. Secondary Causes of Hyperlipidemia

11. Results

12. Findings Statins prevent both non-fatal and fatal ASCVD events High level of evidence for secondary prevention Moderate level of evidence for primary prevention Statins and statins only

13. What was NOT found? Support for treatment to specific LDL and non-HDL goals Support for use of non-statin therapy (alone or in addition to statins) Support for the idea that lower cholesterol is better Reduced risk in patients on HD or w/ CHF

14. Use of non-statin therapy No evidence that it provides benefit, but… May consider it’s use in patients on max dose therapy or w/ contraindications to statin use Do not lower the dose of a statin to safely add a non-statin

15. 4 groups that benefit Clinical ASCVD (includes TIA and stroke) LDL ≥ 190 LDL between 70-190, but 40-75 yoa and DM LDL between 70-190, but 40-75 yoa and no DM

17. Statin Intensity

19. Pooled Cohorts Equation Used to estimate 10 yr risk of ASCVD Why not lifetime ASCVD risk? Lack of data on long-term f/u of RCTs 15 years Limited safety data for > 10 years Limited data on treatment of individuals < 40 yoa

20. Pooled Cohort Equation Why a cutoff of 7.5%? The higher your absolute risk, the greater your benefit Adverse events are independent of benefit, however Net benefit if ASCVD risk 5-7.5% w/ mod dose statin, but discuss w/ pt

21. Adverse Events

22. Adverse Effects of Statins New onset diabetes: 0.1/100 for moderate intensity statins 0.3/100 for high intensity statins Myopathy: ~0.01/100 Hemorrhagic stroke: 0.01/100

23. Recommendations before starting a statin Check baseline ALT, but no need to monitor No need to check baseline CK levels Don’t use in females of childbearing age unless using contraceptives

24. Monitoring Statin Theray Check initial fasting lipid panel Check follow-up 4-12 weeks after to determine adherence Perform assessments q 3-12 months as clinically indicated (?) Caveat: percent reduction of LDL not to be used as a treatment goal, but as an indicator of response and adherence

25. Individuals w/ Predisposition to Adverse Effects: Multiple comorbidities, (impaired hepatic or renal function) Hx of previous statin intolerance or muscle disorders Unexplained ALT elevations 3x ULN Concomitant use of drugs affecting statin metabolism >75 yoa

26. What to do in case of adverse events If muscle symptoms develop, stop statin, check CK, UA and Cr Eval for other causes If a causal relationship exists, switch statins Pregnancy category X

27. Discussion & Controversies

28. Why not use specific goals? RCTs use fixed dose statins Data = ASCVD events reduced by using max-tolerated intensity LDL goals may result in under-tx, or over-tx w/ non-statin AIM-HIGH – futility of adding niacin to pts w/ high triglycerides ACCORD subgroup: fenofibrates in DM, needs further study + compare to statins Familial hyperlipidemia may be unable to achieve goal, not necessarily tx failures Type 2 DM = often have lower LDLs at baseline, under-tx

29. What about non-statins? Data do not show improved outcomes. Recommendations do include safety precautions when used. May be of use when patients cannot tolerate an indicated statin.

30. What about patients on HD or with CHF? No recommendation. Not even an E. 4 RCTs reviewed in these subgroups: no reduction in 2 Insufficient evidence on which to base recommendations for or against

31. Individuals Already on a Statin if baseline LDL is unknown, an LDL < 100 was observed in most individuals receiving high intensity statin (i.e. put them on high dose) RCT does support continuation of statins beyond 75-yoa in those already tolerating them

32. What about other tests and biomarkers? CAC score Non-HDL-C Apo-B LP(a) or LDL particles Non-invasive testing Lifetime ASCVD risk ASCVD risk 5-7.5%

33. Strengths & Limitations

34. Strengths Most of the controversies arise from lack of data Strength of recs: doesn’t include specious recommendations, few grade E Limited to very high level of evidence

35. Limitations Patients <40 yoa have a low estimated 10-yr ASCVD risk score, thus don’t qualify for treatment, yet they may have a high lifetime risk score No data on special subpopulations who are likely at high risk of ASCVD (individuals w/ HIV, rheumatologic or inflammatory dz, s/p x-plant)

36. Future Directions Adults > 75 yoa Titration of meds to specific LDL goals Combination of submaximal statins w/ non-statins Management of hypertigylceridemias Use of other markers (apo-B, non-HDL, LP(a) or LDL particles,

37. Sources Keaney JF, Curfman GD, Jarcho J. “A Pragmatic View of the New Cholesterol Treatment Guidelines.” N Engl J Med 2014; 370:275-278. January 16, 2014. Stone NJ, Robinson J, Lichtenstein AH et al “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.” J Am coll Cardiol. 2013; 90:’ doi:10.1016/j,jacc.2013.11.002.