The ACC/AHA recently released updated cholesterol treatment guidelines. I review them along with what I feel are their limitations. Watch my YouTube video describing these slides: http://youtu.be/2BlUhW6Zu2E

1. Update on the
New ACC/AHA
Guideline on
the Treatment
of Blood
Cholesterol to
Reduce
Atherosclerotic
Cardiovascular
Risk in Adults
Terry Shaneyfelt, MD, MPH
Gen Med Noon Conf.
December 10, 2013

2. Disclosures
o > 5yrs ago speaker for unrestricted
educational grant to Johns Hopkins School of
Medicine on cholesterol mgmt and EBM
• Funded by AstraZeneca (Rosuvastatin)
o VA P&T Committee member

3. Objectives
o Apply the new guidelines to the care of adults
at increased risk for ASCVD
o Understand limitations of new pooled cohort
risk prediction tool
o Learn a little something about guideline
limitations and prediction rules

5. Clinical practice guidelines are statements
that include recommendations intended to
optimize patient care that are informed by a
systematic review of evidence and an
assessment of the benefits and harms of
alternative care options
-- Institute of Medicine 2011

6. To be trustworthy guidelines must:
o Be based on a systematic review of the existing evidence;
o Be developed by a knowledgeable, multidisciplinary panel of experts and
representatives from key affected groups;
o Consider important patient subgroups and patient preferences, as appropriate;
o Be based on an explicit and transparent process that minimizes distortions, biases, and
conflicts of interest;
o Provide a clear explanation of the logical relationships between alternative care options
and health outcomes,
o Provide ratings of both the quality of evidence and the strength of the
recommendations; and
o Be reconsidered and revised as appropriate when important new evidence warrants
modifications of recommendations.
IOM 2011

7. o No LDL target
o Statins only
o Only considered high quality RCT data

9. o ACS, h/o
MI, angina, revascularization, TIA, stroke, peri
pheral arterial disease
o No RCTs identified that titrated drug therapy
to specific LDL goals to improve ASCVD
outcomes

11. o Often genetic (family screening)
o Consider secondary causes
– Drugs
(diuretics, cyclosporin, glucocorticoids, amiodaron
e)
– Biliary obstruction, nephrotic syndrome
– Hypothyroidism, pregnancy*
* Statins contraindicated in pregnancy & lactation

12. o Extrapolation of data for primary prevention
in high risk (≥ 7.5% 10 yr risk) who did not
have diabetes
– Expert opinion, some conflicting data (IIa, B)
o < 40 or > 75 yrs the decision to initiate statin
therapy should be individualized
– Expert opinion, divergent opinions (IIa, C)

13. o Most controversial area of guideline because of
risk equations & lower cut off
o Reasonable to offer statin therapy to those with
risk of 5-7.5% [conflicting evidence (IIa, B)]

14. Primary Prevention
JAMA 11/25/13
o Healthy individuals aged 40-75 yrs., without
serious comorbidities and who were not taking
drugs with potential for statin interaction

15. Primary Prevention
o CTT metaanalysis (Lancet 2012;380:581)
– Similar efficacy findings
– found increased risk of myopathy (NNH
2000), diabetes (NNH 200) and hemorrhagic
stroke (NNH 2000)
– No reduction in CVD events in patients with
• Heart failure
• Maintenance hemodialysis

16. Lancet 2012;380:581
1 mmol/l = 38.6 mg/dl

17. o Conflicts of interest in most panel members
o Increased in statin utilization (“statinization”)?

18. Conflicts of Interest
o 2 main types
– Financial
– Intellectual
o Per IOM 2011:
– Whenever possible GDG members should not have COIs.
– Members with COIs should represent not more than a
minority of the GDG.
– The chair or co-chairs should not be a person(s) with COIs.
– Funders should have no role in CPG development.

19. Conflicts of Interest
o COI should be disclosed
• Disclosure should reflect all current and planned commercial
(including services from which a clinician derives a substantial
proportion of income), noncommercial, intellectual, institutional, and patient– public
activities pertinent to the potential scope of the CPG.
o Members of the GDG should divest themselves of
financial investments they or their family
members have in, and not participate in marketing
activities or advisory boards of, entities whose
interests could be affected by CPG
recommendations

20. “Majority of panelists on controversial new cholesterol
guideline have current or recent ties to drug manufacturers”
- BMJ 2013;347:16989
o Neil Stone, MD (chairman)
• Abbott, AstraZeneca, Merck, Pfizer, Sanofi-Aventis and
Schering-Plough
• “I will not take industry funding for 2 years after release
of the guidelines”
o Jennifer Robinson, MD (Co-chair)
• Financial ties to several statin manufactures while on
panel from 2008-2013
o 6 of 8 panelist with financial ties during
service on the panel!

21. Conflicts of Interest
o “Members with conflicts were asked to recuse
themselves from voting on any aspect of the
guideline where a conflict might exist”
o Independent contractors performed the
systematic review of evidence

22. Increased in statin utilization
(“statinization”)?
o Risk calculator overestimates risk
o Lower thresholds to initiate statin therapy
o 101 million people in US aged 40-79 yrs
without cardiovascular disease
• 33 million expected to have ≥ 7.5% predicted risk
• 13 million expected to have 5-7.4% predicted risk
• US population 1/20th global population in this age range
– (33+13) x 20 = 920 million worldwide would be new statin
candidates (JAMA 12/2/13)

23. Is this a bad thing?
MI and stroke are leading
causes of death in the US
Health Affairs 2012

24. o Risk prediction tool overestimates risk

25. Clinical prediction rule development
Step 2. Validation
Evidence of reproducible accuracy
Step 1. Derivation
Identification of factors with
predictive power
Narrow Validation
Application of a rule
in a similar clinical
setting and population
as in Step 1
Broad Validation
Application of a rule
in multiple clinical
settings with varying
prevalence of disease
Step 3. Impact
Analysis
Evidence that rule changes
physician behavior and
improves patient outcomes

26. Why a new risk predictor?
o Previously used Framingham risk score was not felt to be
adequate because of its “derivation in an exclusively White
sample population and the limited scope of the outcome (in
determining CHD alone).”
o Other risk scores also suffered from “nonrepresentative or historically
dated populations, limited ethnic diversity, narrowly defined
endpoints, endpoints influenced by provider preferences
(e.g., revascularizations), and endpoints with poor reliability
(e.g., angina and heart failure [HF]).”
o Broader outcomes of interest
• ASCVD: first occurrence of nonfatal myocardial infarction
or CHD death, or fatal or nonfatal stroke

28. Development of the Pooled Cohort
Risk Assessment Equations
– Used several large, racially and
geographically diverse, modern
NHLBI-sponsored cohort
studies, including the ARIC
study, Cardiovascular Health
Study, and the CARDIA
study, combined with applicable
data from the Framingham
Original and Offspring Study
cohorts
– Sex-and race-specific
proportional hazards models that
included the covariates of
age, treated or untreated systolic
blood pressure (SBP), total
cholesterol, high-density
lipoprotein cholesterol (HDLC), current smoking (Y/N), and
diabetes (Y/N).
– Calculated area under the
receiver operating curve (Cstatistic) for discrimination and
the calibration chi-squared
statistic
– External validation done in
external cohorts consisting of
Whites and African Americans
from the Multi-Ethnic Study of
Atherosclerosis (MESA) and the
REasons for Geographic And
Racial Differences in Stroke study
(REGARDS) and contemporary
cohorts from ARIC and
Framingham.

29. Validation
o Discrimination
– Accurately determine if a person has or doesn’t
have disease
– C-statistic or AUC
o Calibration
– How well do predicted risk estimates match
observed risk in external populations

30. Validation
(http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437741.48606.98/suppl/DC1 )
Wom en
Algorithm
Derivation
Cohort
Men
Validation Cohorts
Contemporary
(4)
MESA
(5)
Validation Cohorts
Algorithm
REGARDS
(6)
Derivation
Cohort
Contemporary
(4)
MESA
(5)
REGARDS
(6)
White
Total N
11,240
6,509
1,273
6,333
9,098
5,041
1,184
5,296
Events(1)
683
400
37
101
1,032
539
57
218
Events(2)
722.9
426.7
38.4
120.7
1,095.2
580.9
59.7
250.2
Exp
Events(3)
723.5
549.4
49.9
153.9
1,098.5
798.9
94.9
306.4
0.8058
0.7377
0.7109
0.6599
0.7462
0.6843
0.7044
0.5950
6.43
45.50
14.56
44.93
4.86
84.45
21.43
66.71
2,641
1,367
978
5,275
1,647
735
799
2,969
Events(1)
235
127
28
126
194
107
36
136
Events(2)
248.7
131.3
30.1
147.1
213.8
114.0
38.3
162.5
Exp
Events(3)
250.6
173.5
59.4
217.5
212.5
120.8
72.3
180.7
0.8182
0.7068
0.7684
0.6625
0.7130
0.7109
0.6689
0.5564
7.25
15.96
18.51
48.22
6.71
12.62
24.40
46.23
Cstatistic
Calib.
Chi-sq
African
Am erican
Total N
Cstatistic
Calib.
Chi-sq
C statistic: range 0.5 – 1.0 (“reasonable” > 0.7, “strong” > 0.8)

31. Calibration

32. External Validation
The Lancet, Volume 382, Issue 9907, Pages 1762 - 1765
o How many of the 33 million expected to have
risk >7.5% actually have risk that is much
lower?

33. What should you do about risk
assessment?
o Use the pooled risk estimation equations
o Use other risk scores (eg Framingham, QRISK, etc)
o Ignore any risk assessment and consider that
almost everyone benefits from primary
prevention
o Use eligibility criteria of the primary prevention
trials

34. Other recommendations from the
guidelines
o In lower risk patients (5-7.5%, < 40 or > 75 yrs)
clinicians should discuss with patients:
•
•
•
•
ASCVD risk reduction benefits (30% RRR MIS, 45% HIS)
Adverse effects (diabetes NNH 200)
Drug-drug interactions
Patient preferences
o In lower risk individuals also consider:
• FH of premature CAD (< 55yo M, < 65yo F)
• hsCRP > 2
• CAC score >300 Agatston units (or >75 percentile for
age)

35. Other recommendations from the
guidelines
o CK should not be routinely measured
o Measure baseline ALT and only remeasure if
symptoms suggest hepatotoxicity
o Screen for diabetes following current diabetes
screening guidelines
o Muscle symptoms:
• Temporarily d/c statin and assess for rhabdo if severe &
other conditions that cause muscle symptoms
• Rechallenge with lower or same dose of statin
– If statin causative then give lower dose of different statin

36. Other recommendations from the
guidelines
o No recommendations for add-on therapy to
lower LDL after optimal statin dosing
o Separate guideline on triglycerides (Circul 2012)
• No gemfibrozil
• Fenofibrate only if TG > 500 mg/dl and benefits judged to
outweigh risks
o Consider rechecking lipid panel 4-12 wks after
initiation to assess for adherence but not to
adjust therapy

39. Suggested Answers
o Case 1: B
• Pt has ASCVD and should be on high intensity statin
o Case 2: A or B
• Risk is estimated at 7.2% which is below absolute
recommended cutoff to initiate statin therapy for primary
prevention
o Case 3: E (if not tolerated then D)
• Risk is estimated at 9.1% (driven by age) which is above the
7.5% threshold.

40. By Brian McFadden at DailyKos.com