Lipid Guideline Controversies

in 2014: The Decision is Yours

Carl E. Orringer, MD, FACC,

FNLA

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

Two ASCVD Prevention Approaches

Two Different Perspectives

External reviewer

Author

US age-standardized death rates

attributable to CVD, 2000 to 2010

Release of NCEP
ATP III

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 20012011

in the
United States: Analysis of 105 million
patient records
from a single national diagnostic laboratory

10.1371/journal.pone.0063416

Is There a Need for a Dramatic Change

in Approach to ASCVD Prevention?

CCS
IAS
EAS/ESC
JAS
NICE
NLA

ACC/AHA
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
ACC/AHA
Randomized
controlled trials
(RCT) of statin
therapy
Meta-analyses of
RCT

NLA
RCT of statins and
non-statin 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 physicians 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

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 ATPs and the international community

 Identification
of an
Central Focus of
Guideline

Identification of statin
ACC/AHA
benefit
groups
Initiation and
maintenance of high
or moderate intensity
statin therapy
Abandonment of lipid
goals
Avoidance of nonstatin therapy
because of
unfavorable
risk/benefit ratio.

individual patients
ASCVD risk
based on
NLA
clinical parameters and
risk factors
Initiation of ASCVD riskbased lipid-lowering
therapy
Maintenance of lipid goals
to assess effective
reduction of atherogenic
lipoproteins and enhace
adherence
Use of high or moderate
dose statins, nonstatins, 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 7.5%).
Individuals without clinical ASCVD or diabetes, who are
age 40-75 years with LDL-C 70-189 mg/dl, and have an
estimated 10-year ASCVD risk of 7.5% using Pooled
Cohort Equations (M or H).

High- and Moderate-Intensity

Moderate Intensity
Daily Statin Therapy
(Lowers LDL-C 30 High Intensity
(Lowers LDL-C
50%)
Atorvastatin 40-80
mg
Rosuvastatin 2040 mg
Bold = Tested in RCT and
reviewed by Expert Panel
Yellow= Not tested in RCT
reviewed by Expert Panel

50%)

Atorvastatin 10 (20)
mg
Rosuvastatin (5) 10
mg
Simvastatin 2040
mg
Simvastatin 80 mg*
Pravastatin 40 (80)
mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg
2x/day

Efficacy of Intensive Lowering of LDLC in Subjects with Low Baseline LDL-C

Meta-analysis of RCTs 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 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

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

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

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

Moderate

2 major ASCVD risk factors

For specific clinical features,
high quantitative risk score or

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
100

<130
<100

Moderate

160
130

<130
<100

Low

190
160

<130
<100

nts with ASCVD or diabetes mellitus, consider use of moderate or high

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
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

Is High-Dose Statin Therapy

the End of the Line?

Variability of Achieved LDL-C

With High-Intensity Statin
Boekholdt
SM et al. J Am Coll Cardiol 2014;64: 485-94
Therapy
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,
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

Very Low LDL-C and Non-HDL-C

in Statin Trials and Major CVD
Event Risk
LDL-C

Non-HDL-C
1.00 1.00
0.89

0.57

0.60
0.51

0.64
0.56

0.69
0.58

0.75
0.64

0.44

On Treatment LDL- C, Non-HDL-C mg/dL

Boekholdt et al. JACC 2014;64:485494

0.71

Central Focus of Guidelines:

Summary
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
ACC/AHA
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
populations
Assessment of lifetime risk
may be considered in those
aged 20-59 with no ASCVD
and not at high short-term
risk

NLA
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% 10year FRS, 15%
ACC/AHA risk, or
45% long-term risk

ttp://www.tools.cardiosource.org/ascvd-risk-estimator

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 Womens
Health Study, the Physicians Health Study
and the Womens Health Initiative
Observational Study, it systematically
overestimated observed risk by 75-150%,
roughly
doubling
theguidelines
actual
observed
risk
Ridker PM, Cook
NR. Statins: new American
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 imprecision
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 Womens 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 10year 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) (C-statistic ~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
calibration)
Kavousi(poor
M et al. JAMA
2014: 311(14): 1416-23

ACC/AHA Risk Calculator: Possible

Overtreatment in Older Patients?
Age

Total
cholest
erol

HDL
cholest
erol

Systolic
BP

Treatme
nt for
HBP

Diabete
s

Smoker

10-year
ASCVD
risk

60
AA

170

50

125

No

No

No

7.5%

65
AA

178

50

130

No

No

No

7.5%

60 C

170

47

125

No

No

No

7.5%

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
ACC/AHA
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
populations
Assessment of lifetime risk
may be considered in those
aged 20-59 with no ASCVD
and not at high short-term
risk

NLA

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% 10year 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

Whats 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

The Decision is Yours

ACC/AHA

NLA