presentation slides - National Forum for Heart Disease

Lipid Guideline Controversies in 2014:
The Decision is Yours
Carl E. Orringer, MD, FACC, FNLA
• To provide an overview of the American
College of Cardiology/American Heart
Association and the National Lipid Association
lipid management approaches for ASCVD
• To identify the similarities and differences
between the two approaches
• To provide the information needed to decide
which approach to use and when
Two ASCVD Prevention Approaches
Two Different Perspectives
External reviewer
US age-standardized death rates
attributable to CVD, 2000 to 2010
Release of NCEP
Release of NCEP
ATP III Update
Go A S et al. Circulation. 2014;129:e28-e292
Copyright © American Heart Association, Inc. All rights reserved.
Mean age-adjusted LDL-C trends 2001–2011 in the
United States: Analysis of 105 million patient records
from a single national diagnostic laboratory
Is There a Need for a Dramatic Change
in Approach to ASCVD Prevention?
Changes in:
Evidence base
Central focus
Lipid goals
Use of non-statins
Risk calculator
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
Evidence Base
• Randomized controlled
trials (RCT) of statin
• Meta-analyses of RCT
• RCT of statins and nonstatin drug therapy
• Meta-analyses of RCT
• Observational
epidemiologic studies
• Genetic studies
• Metabolic studies
• Mechanistic studies
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
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
Observational Epidemiologic Cohort Study of
2146 Patients with FH and no CHD at Baseline
Versmissen J, et al BMJ 2008; 337: a2423
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
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;354:1264-72
Evidence Base: Summary
– By limiting the scope to RCT of statins and metaanalyses of RCT, only the highest level of evidence on
statins in defined populations is employed to assess
ASCVD outcomes
– 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
Central Focus of Guideline
• 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
• Identification of an individual
patient’s ASCVD risk based on
clinical parameters and risk
• 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
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 40-75 years with diabetes, and LDL-C 70-189
mg/dl without clinical ASCVD (M if 10 yr risk <7.5%; H if
• Individuals without clinical ASCVD or diabetes, who are age 4075 years with LDL-C 70-189 mg/dl, and have an estimated 10year ASCVD risk of ≥ 7.5% using Pooled Cohort Equations (M or
High- and Moderate-Intensity
Daily Statin Therapy
• High Intensity (Lowers
LDL-C ≥ 50%)
– Atorvastatin 40-80 mg
– Rosuvastatin 20-40 mg
Bold = Tested in RCT and
reviewed by Expert Panel
Yellow= Not tested in RCT
reviewed by Expert Panel
• 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
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
0.41-0.95, p=0.004).
Cholesterol Treatment Trialists Collaboration. Lancet 2010;376:1670-81
ACC/AHA Perspective on Statin Therapy
• Statin intensity trials showed clear benefit for
high intensity versus moderate intensity
• 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
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
Overview of the NLA Recommendations
1. All preventive therapy begins with risk assessment and a
provider-patient discussion of the pros and cons of therapy
2. Lifestyle therapy is at the basis of all ASCVD preventive
recommendations, regardless of baseline risk
3. Judicious use of evidence-based drug therapy, particularly
moderate and high-dose statins, is associated with optimal
ASCVD risk reduction
4. When excessive circulating atherogenic cholesterol (nonHDL-cholesterol and LDL cholesterol) persists after
appropriate lifestyle and statin therapy, the use of nonstatin therapy may be considered
5. Long-term follow-up fostered by provider-patient
communication is essential for optimal ASCVD prevention
NLA ASCVD Risk Category Criteria
Risk Category
Very High
• Diabetes mellitus (type 1 or 2)
≥2 other major ASCVD risk factors; or
Evidence of end-organ damage
• ≥3 major ASCVD risk factors
• Diabetes mellitus (type 1 or 2)
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
• 2 major ASCVD risk factors
• For specific clinical features, high
quantitative risk score or specific
biomarker levels, consider reclassification
to high risk
• 0-1 major ASCVD risk factor
• For specific clinical features, consider
reclassification to moderate risk
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
Non-HDL-C/LDL-C Goal
For patients with ASCVD or diabetes mellitus, consider use of moderate or high intensity
statins, irrespective of baseline atherogenic cholesterol levels.
NLA Perspective on Statin Therapy
• Statin therapy is the most potent and evidencebased 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
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 nonstatin 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
Is High-Dose Statin Therapy
the End of the Line?
Variability of Achieved LDL-C
With High-Intensity Statin Therapy
Boekholdt SM et al. J Am Coll Cardiol 2014;64: 485-94
Waterfall plot of
Individual values
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
From TNT,
variability of
LDL-C lowering.
>40% did not achieve
LDL-C <70 mg/dl on
atorvastatin 80 or
rosuvastatin 20 mg
Very Low LDL-C and Non-HDL-C in
Statin Trials and Major CVD Event Risk
<50, <75
50-74, 75-99
75-99, 100-124 100-124, 125-149 125-149, 150-174 150-174, 175-199
On Treatment LDL- C, Non-HDL-C mg/dL
Boekholdt et al. JACC 2014;64:485-494
>=175, >=200
Central Focus of Guidelines:
• ACC/AHA: define statin benefit groups;
risk/benefit discussion; use moderate or highintensity 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)
Risk Calculators
• Use Pooled Cohort Risk
calculator in non-Hispanic
Whites and non-Hispanic
African Americans age 4079 without ASCVD and not
on statin therapy; may be
considered in other
• Assessment of lifetime risk
may be considered in those
aged 20-59 with no ASCVD
and not at high short-term
• Consider 10-year FRS,
ACC/AHA Pooled Cohort
Risk calculator, or 30-year
risk in those with 2 major
ASCVD risk factors; reclassify to higher risk those
with ≥10% 10-year FRS,
≥15% ACC/AHA risk, or
≥45% long-term risk
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.”
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 75-150%, roughly doubling the
actual observed risk
Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease.
Lancet 2013 10.1016/S0140-6736(13)62388-0. published Nov 20. PubMed
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
• All 3 cohorts might have been subject to some
downstream initiation of statins
Lloyd-Jones DM, Goff D and Stone N. The Lancet, Early Online
Publication, 4 December 2013 doi:10.1016/S0140-6736(13)62348-X
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 7.5-10% and >10% estimated 10 year
risk groups
Cook NR, Ridker PM. JAMA Intern Med Published Online October 6, 2014
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 70-189
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) (Cstatistic ~0.7).
Muntner P et al. JAMA 2014;311:1406-1415
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. 12.7 % for men and 11.6 vs. 7.9% for
women (poor calibration)
Kavousi M et al. JAMA 2014: 311(14): 1416-23
ACC/AHA Risk Calculator: Possible
Overtreatment in Older Patients?
Systolic BP
for HBP
ASCVD risk
60 AA♂
65 AA♀
60 C ♂
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
Risk Calculators
• Use Pooled Cohort Risk
calculator in non-Hispanic
whites and non-Hispanic
African Americans age 4079 without ASCVD and not
on statin therapy; may be
considered in other
• Assessment of lifetime risk
may be considered in those
aged 20-59 with no ASCVD
and not at high short-term
• Consider 10-year FRS,
ACC/AHA Pooled Cohort
Risk calculator, or 30-year
risk in those with 2 major
ASCVD risk factors; reclassify to higher risk those
with ≥10% 10-year FRS,
≥15% ACC/AHA risk, or
≥45%% long-term risk
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
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
• A new NLA Self-Assessment Program on
The Decision is Yours

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