1. Lipid Guideline Controversies in 2014: The Decision is Yours
Carl E. Orringer, MD, FACC, FNLA

2. Objectives
To provide an overview of the American College of Cardiology/American Heart Association and the National Lipid Association lipid management approaches for ASCVD prevention
To identify the similarities and differences between the two approaches
To provide the information needed to decide which approach to use and when

3. Two Different Perspectives
Two ASCVD Prevention Approaches
Two Different Perspectives
External reviewer
Author

4. US age-standardized death rates attributable to CVD, 2000 to 2010
Release of NCEP
ATP III
Release of NCEP
ATP III Update
US age-standardized death rates* attributable to CVD, 2000 to *Directly standardized to the age distribution of the 2000 US standard population. †Total CVD: International Classification of Diseases, 10th Revision (ICD-10) I00 to I99 and Q20 to Q28. §Stroke (all cerebrovascular disease): ICD-10 I60 to I69. ¶CHD: ICD-10 I20 to I25. **Other CVD: ICD-10 I00 to I15, I26 to I51, I70 to I78, I80 to I89, and I95 to I99. CHD indicates coronary heart disease; and CVD, cardiovascular disease. Source: Centers for Disease Control and Prevention, National Center for Health Statistics.5
Go A S et al. Circulation. 2014;129:e28-e292
Copyright © American Heart Association, Inc. All rights reserved.

5. Mean age-adjusted LDL-C trends 2001–2011 in the
United States: Analysis of 105 million patient records
from a single national diagnostic laboratory
/journal.pone

6. Is There a Need for a Dramatic Change in Approach to ASCVD Prevention?
ACC/AHA
CCS
IAS
EAS/ESC
JAS
NICE
NLA
Changes in:
Evidence base
Central focus
Lipid goals
Use of non-statins
Risk calculator

7. The Rules The topic will be identified
Common ground and differences will be noted
Appropriate supporting evidence will be introduced
Summary will be provided
You make the decision

8. Evidence Base ACC/AHA NLA
Randomized controlled trials (RCT) of statin therapy
Meta-analyses of RCT
RCT of statins and non-statin drug therapy
Meta-analyses of RCT
Observational epidemiologic studies
Genetic studies
Metabolic studies
Mechanistic studies

9. Randomized Controlled Trials (RCT)
Systematically test effect(s) of an intervention on pre-specified outcomes in defined populations
Their use minimizes confounding
Study populations are often not diverse and exclusion criteria may hamper physician’s ability to apply results to real-world patients
Most are designed to gain regulatory registration for pharmaceutical agents; lifestyle trials, studies of generic drugs or of those produced by smaller companies may be under-represented in RCT due to inadequate financial support

10. Observational Epidemiologic Studies
Worldwide in scope and may assess ASCVD risk across populations
Cohort studies evaluate mortality and morbidity within populations
Confounding may occur even after matching, stratification, and multivariate adjustment because of measurement error or unmeasured or unknown risk factors

11. Observational Epidemiologic Cohort Study of 2146 Patients with FH and no CHD at Baseline
Versmissen J, et al BMJ 2008; 337: a2423

12. Genetic Studies
Genetic epidemiology reduces the likelihood of confounding by focusing on single variables: genetic mutations
Identification of specific mutations may serve to generate hypotheses for other types of trials
Often limited in patient selection and costly

13. Data Demonstrating Genetic Variants Affecting ASCVD Risk
Sequence variants in the gene encoding for PCSK9 resulting in loss of function mutations are associated with 28% reduction in LDL-C, an 88% reduction in CHD risk and provide support for the value of long term low LDL-C in promoting CHD risk reduction
J Cohen et al. N Engl J Med 2006;354:

14. Evidence Base: Summary
ACC/AHA
By limiting the scope to RCT of statins and meta-analyses of RCT, only the highest level of evidence on statins in defined populations is employed to assess ASCVD outcomes
NLA
By including evidence from RCT and other sources, a broader evidence base for clinical decision making is employed . This approach is consistent with the perspective of previous NCEP ATP’s and the international community

15. Central Focus of Guideline
ACC/AHA
NLA
Identification of statin benefit groups
Initiation and maintenance of high or moderate intensity statin therapy
Abandonment of lipid goals
Avoidance of non-statin therapy because of “unfavorable risk/benefit ratio.”
Identification of an individual patient’s ASCVD risk based on clinical parameters and risk factors
Initiation of ASCVD risk-based lipid-lowering therapy
Maintenance of lipid goals to assess effective reduction of atherogenic lipoproteins and enhace adherence
Use of high or moderate dose statins, ±non-statins, if necessary, to achieve goals

16. ACC/AHA Statin Benefit Groups
H=High intensity statin; M=Moderate intensity statin
Individuals with clinical ASCVD without New York Heart Association class II-IV heart failure or receiving hemodialysis (H preferred; M if age >75 or if not candidate for H).
Individuals with primary elevations of LDL-C ≥190 mg/dl (H preferred; M if not candidate for H).
Individuals age years with diabetes, and LDL-C mg/dl without clinical ASCVD (M if 10 yr risk <7.5%; H if ≥7.5%).
Individuals without clinical ASCVD or diabetes, who are age years with LDL-C mg/dl, and have an estimated 10-year ASCVD risk of ≥ 7.5% using Pooled Cohort Equations (M or H).

17. High- and Moderate-Intensity Daily Statin Therapy
High Intensity (Lowers LDL-C ≥ 50%)
Atorvastatin mg
Rosuvastatin mg
Moderate Intensity (Lowers LDL-C 30-50%)
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20–40 mg
Simvastatin 80 mg*
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg 2x/day
Pitavastatin 2–4 mg
Bold = Tested in RCT and
reviewed by Expert Panel
Yellow= Not tested in RCT

18. Efficacy of Intensive Lowering of LDL-C in Subjects with Low Baseline LDL-C
Meta-analysis of RCT’s of >1000 participants and ≥2 years treatment duration of more versus less intense statin trials involving 169,138 subjects
The major vascular event reduction, among in those with baseline LDL-C <77mg/dL per further 39 mg/dL reduction was 29% (99% CI 2-48, p=0.007); in those with baseline LDL-C <70 mg/dl, similar reduction in LDL-C continued to demonstrate MVE reduction (RR 0.63, 99% CI , p=0.004).
Cholesterol Treatment Trialists Collaboration. Lancet 2010;376:

19. ACC/AHA Perspective on Statin Therapy
Statin intensity trials showed clear benefit for high intensity versus moderate intensity statins
Because fixed doses, not dosage titrations, were employed, one should not assume that a dosage titration strategy is correct or that addition of non-statins to achieve low LDL-C is indicated

20. ACC/AHA Perspective on Non-Statin Lipid Drug Therapy
Non-statin drugs without demonstrated ASCVD risk reduction may favorably alter lipids but have an unfavorable risk/benefit ratio
Niacin in AIM-HIGH and HPS-2 THRIVE
Fibrates in ACCORD-Lipid, FIELD
Lack of ASCVD event end-point data on ezetimibe
CETP inhibitors torcetrapib and dalcetrapib
The use of non-statin drugs should generally be avoided

21. Overview of the NLA Recommendations
All preventive therapy begins with risk assessment and a provider-patient discussion of the pros and cons of therapy
Lifestyle therapy is at the basis of all ASCVD preventive recommendations, regardless of baseline risk
Judicious use of evidence-based drug therapy, particularly moderate and high-dose statins, is associated with optimal ASCVD risk reduction
When excessive circulating atherogenic cholesterol (non-HDL-cholesterol and LDL cholesterol) persists after appropriate lifestyle and statin therapy, the use of non-statin therapy may be considered
Long-term follow-up fostered by provider-patient communication is essential for optimal ASCVD prevention
This slide provides an overview of the NLA Recommendations for the Patient-Centered Management of Dyslipidemia. You will note that it begins with and ends with provider patient interaction.

22. NLA ASCVD Risk Category Criteria
Very High
ASCVD
Diabetes mellitus (type 1 or 2)
≥2 other major ASCVD risk factors; or
Evidence of end-organ damage
High
≥3 major ASCVD risk factors
0-1 other major ASCVD risk factor, and
no evidence of end-organ damage
Chronic kidney disease Stage 3B or 4
LDL-C ≥190 or non-HDL-C ≥220 mg/dL
Moderate
2 major ASCVD risk factors
For specific clinical features, high quantitative risk score or specific biomarker levels, consider reclassification to high risk
Low
0-1 major ASCVD risk factor
For specific clinical features, consider reclassification to moderate risk
The NLA Recommendations advocate risk categorization, beginning with very-high and moving to progressively lower risk groups. Specific criteria are used for each risk category. Once the clinician defines the highest risk category applicable to a patient, the next step is discussion with the patient about risk-appropriate atherogenic cholesterol lowering therapy.

23. NLA ASCVD Risk Categories, Levels for Consideration of Drug Therapy and Treatment Goals
Risk Category
Consider Drug Therapy
Treatment Goal
Non-HDL-C /LDL-C Goal (mg/dL)
Non-HDL-C/LDL-C Goal (mg/dL)
Very-high
≥100
≥70
<100
<70
High
≥130
<130
Moderate
≥160
Low
≥190
Recognizing that lifestyle therapy is always advocated as the basis for ASCVD prevention, this slide provides the NLA perspective on non-HDL-C and LDL-C thresholds for considering drug therapy and treatment goals. The non-HDL-C and LDL-C levels at which drug therapy should be considered vary in accordance with the absolute risk of the patient. However, the treatment goals are all <130 for non-HDL-C and <100 mg/dL for LDL-C, except in the very high risk patient in whom the non-HDL-C goal is <100 and LDL-C goal <70 mg/dL.
For patients with ASCVD or diabetes mellitus, consider use of moderate or high intensity
statins, irrespective of baseline atherogenic cholesterol levels.

24. NLA Perspective on Statin Therapy
Statin therapy is the most potent and evidence-based approach to lowering atherogenic lipoproteins (non-HDL-C and LDL-C)
Statin intensity trials showed clear benefit for high-intensity versus moderate-intensity statins
Broad-based evidence supports “lower is better” concept, and provides an opportunity for clinicians to address residual risk above that addressed by appropriately-dosed statin therapy

25. NLA Perspective on Non-Statin Lipid Drug Therapy
If non-HDL-C and LDL-C goals are not achieved with maximal tolerated statin therapy, the addition of non-statin therapy should be considered to lower atherogenic cholesterol levels and to achieve goals
Doctors can be instructed not to use niacin in patients on aggressive statin regimens
As ezetimibe is safe and lowers atherogenic cholesterol, its use may be considered in selected patients with elevated non-HDL-C and/or LDL-C
Resins may be considered in selected patients
Meta-analyses of fibrate therapy in subgroups with atherogenic dyslipidemia suggest ASCVD risk reduction

26. Is High-Dose Statin Therapy the End of the Line?

27. Variability of Achieved LDL-C With High-Intensity Statin Therapy
Boekholdt SM et al. J Am Coll Cardiol 2014;64:
Meta analysis of 8 statin RCT involving 38, 153 subjects of whom 5,387 had 6,286 major CV events and had baseline and 1 year lipids and lipoproteins
Waterfall plot of
Individual values
From TNT,
SPARCL, IDEAL and
JUPITER
demonstrating
variability of
LDL-C lowering.
>40% did not achieve
LDL-C <70 mg/dl on
atorvastatin 80 or
rosuvastatin 20 mg
daily
Boekholdt’s meta-analysis of 8 statin RCT’s involving 38,153 subjects focused on 5,387 subjects who had 6,286 major CV events and had baseline and 1-year lipids and lipoproteins. In those receiving atorvastatin 80 mg daily or rosuvastatin 20 mg daily more than 40 % did not achieve LDL-C <70 mg/dl.

28. Very Low LDL-C and Non-HDL-C in Statin Trials and Major CVD Event Risk
On Treatment LDL- C, Non-HDL-C mg/dL
Boekholdt et al. JACC 2014;64:

29. Central Focus of Guidelines: Summary
ACC/AHA: define statin benefit groups; risk/benefit discussion; use moderate or high-intensity statin therapy with lifestyle change as background therapy; generally avoid non-statin drug therapy; no lipid goals
NLA: identify ASCVD risk level; risk/benefit discussion; emphasize healthy lifestyle and use moderate or high-intensity statin therapy, and if necessary, adjunctive non-statin therapy, to lower atherogenic cholesterol; maintain lipid goals (non-HDL-C is favored lipoprotein target)

30. Risk Calculators ACC/AHA NLA
Use Pooled Cohort Risk calculator in non-Hispanic Whites and non-Hispanic African Americans age without ASCVD and not on statin therapy; may be considered in other populations
Assessment of lifetime risk may be considered in those aged with no ASCVD and not at high short-term risk
Consider 10-year FRS, ACC/AHA Pooled Cohort Risk calculator, or 30-year risk in those with 2 major ASCVD risk factors; re-classify to higher risk those with ≥10% 10-year FRS, ≥15% ACC/AHA risk, or ≥45% long-term risk
One of the most contentious controversies between the ACC/AHA Guideline and the NLA Recommendations relates to the use of risk calculators. The ACC/AHA Guideline advocates the use of the Pooled Cohort Risk calculator in non-Hispanic Whites and non-Hipsanic African Americans age without ASCVD and not on stain therapy, and suggested that it could reasonably be used in other populations. The use of the lifetime risk calculator was suggested for those individuals age not found to be a high risk. The NLA Recommendations advises consideration of any of three risk calculators, including Framingham 10-year risk, Lifetime or 30 year risk, or the 10-year Pooled Cohort Risk in those with 2 major risk factors.

31. This is a screen shot of the ACC/AHA risk calculator used to demonstrate 10 year ASCVD risk using the Pooled Cohort Risk Equations calculator available on the Cardiosource.org website. The variables employed include gender, age, HDL-C, systolic blood pressure, treatment for hypertension, cigarette smoking status and diabetes mellitus. When all of these variable are entered the 10 year calculated risk appears at the top on the left. Below it there is a box that estimates the patient’s risk level if all of those risk factors were optimal. To the right of those numbers there are boxes that estimate lifetime or 30-year ASCVD risk, a calculation that is recommended for consideration for individuals between the age of 20 and 59 with 10-year risk <7.5%. The Risk Assessment Working Group of the ACC/AHA does not use lifetime risk to advise the initiation of drug therapy, but suggests that such information may be of value when counseling individuals on the value of initiating lifestyle therapy for ASCVD prevention.

32. Key Disclaimer of the ACC/AHA Pooled Cohort Risk Calculator
It does not definitively recommend statin therapy for individuals with 10-year risk ≥7.5%
It advises that for such individuals before initiating statin therapy “it is reasonable for clinicians and patients to engage in a discussion which considers the potential for ASCVD risk reduction benefits and for adverse effects, for drug-drug interactions and patient preferences for treatment.”
The ACC/AHA Expert Panel emphasizes that the finding of a 7.5% 10 year risk is not an automatic recommendation for statin therapy, but represents a level at which joint patient provider discussion should be undertaken, explaining to the patient the benefit of starting statin therapy.

33. Pooled Cohort Equations: Criticism
Early criticism of the Pooled Risk calculator centered around lack of long-term prospective validation and possible overestimation of risk
When the Pooled Risk Equation calculator was applied to 3 large, more recent primary prevention cohorts, the Women’s Health Study, the Physician’s Health Study and the Women’s Health Initiative Observational Study, it systematically overestimated observed risk by %, roughly doubling the actual observed risk
As the Pooled Cohort Equations lacked prospective long-term validation, debate ensued on the advisability of using this tool for clinical risk assessment and management reccommendations.
Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease.
Lancet /S (13) published Nov 20. PubMed
Copyright NLA 2014

34. Pooled Cohort Equations: Defense
Validation was more extensive than any other previous risk equations
The primary prevention cohorts of WHS, PHS and WHI were likely significantly healthier than the general population
In WHS and PHS some risk factors were self-reported in ranges rather than directly measured, resulting in imprecision
All 3 cohorts might have been subject to some downstream initiation of statins
The response to these criticisms were centered on potential selection of usually healthy subjects in the Women’s Health Study, Physician’s Health Study and Women’s Health Initiative populations; on the potential inaccuracy of self-reported rather than measured risk factors; and on the possibility that downstream initiation of statins may have been responsible for overestimation of risk.
Lloyd-Jones DM, Goff D and Stone N. The Lancet, Early Online
Publication, 4 December 2013 doi: /S (13)62348-X
Copyright NLA 2014

35. Pooled Cohort Equations: Criticism
An analysis of the Women’s Health Study examined data from 632 women who had an ASCVD event over a median follow-up of 10 years
After adjustment for the intervention effects of statins, revascularization and hypothetical confounding by indication the ratios of predicted to observed events were 1.8 in those with 0-<5% and 5-7.4% estimated 10-year risk and 1.3 in the groups with % and >10% estimated 10 year risk groups
A more recent analysis adjusted for intervention of statins, revascularization and hypothetical confounding and still found that the risk calculator over-estimated risk in the Women’s Health Study.
Cook NR, Ridker PM. JAMA Intern Med Published Online October 6, 2014

36. Pooled Cohort Equations: Defense
10,997 adults, ages 45-79, in the Reasons for Geographic Distribution and Racial Differences in Stroke study, without ASCVD or diabetes, with total cholesterol mg/dl and not taking statins were examined for incident ASCVD at 5 years, and additional analysis in 3,333 Medicare beneficiaries added additional ASCVD events as defined in Medicare Claims data.
There was a high degree of correlation between observed and predicted ASCVD incidence per 1,000 person-years in groups with <5%, 5-<7.5%, 7.5-<10% and ≥10% (calibration) and moderate to good ability to accurately rank-order individuals (discrimination) (C-statistic ~0.7).
Further validation of the Pooled Risk Equations was provided in this 2014 study, which demonstrated a high degree of correlation between observed and predicted ASCVD incidence in low, intermediate and high risk groups.
Muntner P et al. JAMA 2014;311:
Copyright NLA 2014

37. Pooled Cohort Equations: Criticism
Application to elderly populations
When the risk calculator was applied to 4,854 Rotterdam Heart Study participants with a mean age of 65 years, 96.4% of men and 65.8% of women would be recommended statins
The average predicted versus observed cumulative incidence of hard ASCVD events was 21.5 vs % for men and 11.6 vs. 7.9% for women (poor calibration)
There is continuing concern that the Pooled Cohort Equations recommend statin use in too many elderly patients. One example of this was noted when the Pooled Cohort Equations were applied to men and women participating in the Rotterdam Heart Study.
Kavousi M et al. JAMA 2014: 311(14):

38. ACC/AHA Risk Calculator: Possible Overtreatment in Older Patients?
Age
Total cholesterol
HDL cholesterol
Systolic BP
Treatment for HBP
Diabetes
Smoker
10-year ASCVD risk
60 AA♂
170 50
125 No
7.5%
65 AA♀
178
130
60 C ♂ 47
Examining US populations, the individuals for who the Pooled Cohort Equations were designed, this slide provides 3 examples of patients for whom clinicians might not normally consider statin therapy.

39. NLA Perspective on Risk Calculators
Although any of 3 risk calculators are suggested for consideration (10 year Framingham risk, lifetime Framingham risk, ACC/AHA Pooled Cohort Risk Calculator), risk calculators measure diverse endpoints and have limited application in various ethnic and age groups
The interpretation of a particular risk level using any risk calculator in a given patient must be done using careful clinical judgment
The NLA Expert Panel provides a more conservative approach to the use of risk calculators, suggesting consideration of their use only in intermediate risk individuals for whom the clinician feels that more information is required to make preventive lipid therapy management decisions. It recognizes that each risk calculator examines different endpoints, has its strengths and weaknesses in any given patient and that careful clinical judgment must be used in applying the results to the management of a specific patient.

40. Risk Calculators ACC/AHA NLA
Consider 10-year FRS, ACC/AHA Pooled Cohort Risk calculator, or 30-year risk in those with 2 major ASCVD risk factors; re-classify to higher risk those with ≥10% 10-year FRS, ≥15% ACC/AHA risk, or ≥45%% long-term risk
Use Pooled Cohort Risk calculator in non-Hispanic whites and non-Hispanic African Americans age without ASCVD and not on statin therapy; may be considered in other populations
Assessment of lifetime risk may be considered in those aged with no ASCVD and not at high short-term risk

41. Lipid Guideline Controversies: Common Threads Between ACC/AHA and NLA
Lifestyle therapy is warranted for ASCVD risk reduction, whether or not drug therapy is used
Patients with ASCVD, FH and diabetes are candidates for moderate or high-dose statins
Risk calculators aid in, but do not take the place of clinical judgment
Whether or not lipid goals are set, regular lipid follow-up is warranted to assess adherence
Patient engagement in preventive care decision making aids in long-term adherence

42. What’s Ahead in Guidelines?
A new app for the NLA Recommendations Part 1
New ACC/AHA performance measures related to the 2013 Blood Cholesterol Guideline and another app related to the Guideline
NLA Recommendations Part 2 on special populations (women, elderly, HIV, south Asian Indians, Hispanic, CKD, heart failure, rheumatoid arthritis)
A new NLA Self-Assessment Program on Guidelines

43. The Decision is Yours
ACC/AHA
NLA