- The document discusses guidelines for statin use in primary prevention from the 2014 ACC/AHA, including algorithms for determining statin eligibility based on estimated 10-year risk of atherosclerotic cardiovascular disease (ASCVD). - It notes that the guidelines lower the risk threshold for statin recommendation from greater than 7.5% 10-year ASCVD risk to greater than 5% for some patients. - Concerns raised about the guidelines include the selection of studies included in reviews and the lack of consideration of observational data or post-hoc analyses of randomized controlled trials.

1. R3 Talk
Benjamin P. Geisler, MD MPH
11/10/2014
*
* I borrowed this term from Dr. Ben Goldacre’s 2004 BMJ 2014 opinion piece

2. A long time ago in a galaxy far,
far away....

3. Vignette 1
• 66yo non-diabetic M w/ HTN (BP 125/75 on
amlodipine) and w/o known ASCVD visits you
in the primary care clinic for a well visit. He is
a never smoker and has no acute complaints.
• Lipids: TC 140; HDL 45; TG 100; LDL 79 (calc)
• You calculate his 10y ASCVD risk as 12.8%
• Should he be on a statin?

4. A Tale Of Two Types of Endpoints
• The term “surrogate marker” dates from the late
1980s, but it had been preceded by the term
“biomarker” and was succeeded and replaced by
yet another term, “surrogate endpoint”.
• A surrogate endpoint has been defined as “a
biomarker intended to substitute for a clinical
endpoint”
• A clinical [hard] endpoint is “a characteristic or
variable that reflects how a patient feels,
functions, or survives”
Brotman&Prince Vox Sang 1988; Paone et al. J Surg Oncol 1980; Boone&Kelloff J Cell Biochem Suppl 1993; NIH Definitions
Working Group. Biomarkers and Surrogate Endpoints. 2000. Cited after Aronson Br J Pharmacol 2005

5. Lipoproteins (i)
Genest & Libby. In: Bonow et al. Braunwald’s Heart Disease. Cited After Ridker Lancet 2014

6. Lipoproteins (i)
non-HDL
Genest & Libby. In: Bonow et al. Braunwald’s Heart Disease. Cited After Ridker Lancet 2014

7. Lipoproteins (ii)
Mora et al. Circ 2009. Cited After Ridker Lancet 2014

8. ATP III Lipid Goals
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary 2001

9. ATP III Algorithms
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Executive Summary 2001

10. Vignette 1
• 66yo non-diabetic M w/ HTN (BP 125/75 on
amlodipine) and w/o known ASCVD visits you
in the primary care clinic for a well visit. He is
a never smoker and has no acute complaints.
• Lipids: TC 140; HDL 45; TG 100; LDL 79 (calc)
• You calculate his 10y ASCVD risk as 12.8%
• Should he be on a statin?

12. Prevention of MACEs
• Paradigm shifted from treating the one “risk factor”
(among others) HLD to preventing Major Adverse
Cardiovascular Events (MACEs as hard endpoints):
– All-cause Mortality
– CV mortality
– MI (non-fatal, fatal, or both)
– Revascularization (CABG, PCI, lysis, all – physician-driven)
– Stroke (ischemic or total; non-fatal, fatal, or both)
• Lowering cholesterol (LDL or non-HDL or HDL/TC ratio)
vs outcomes that actually matter
• Triglycerides and other endpoints (eg, pancreatitis) not
addressed in some guidelines

13. Hayward, Hofer & Vijan Ann Int Med 2006

14. Hayward & Krumholz Circ Cardiovasc Qual Outcomes 2012

15. Stone Circ 2014

16. Proposed Statin Indications
(and changes from ATP-III)
• Secondary prevention (any prior
atherosclerotic disease including stroke that is
not believed to be embolic or hemorrhagic)
• Diabetes (unchanged, previously termed CHD
equivalent)
• LDL≥190 (unchanged)
• And … primary prevention (previously optional
drug therapy for LDL 160-189)

17. Relative Risk Does Not Depend On
ASCVD Status, T2DM, Sex, Age, or HTN
Cholesterol Treatment Trialists’ Collaboration Lancet 2010

18. Relative Risk Does Not Depend On BP,
BMI, HDL, Smoking Status, or EGFR
Cholesterol Treatment Trialists’ Collaboration Lancet 2010

19. RR Depends on ASCVD Status and Risk
Cholesterol Treatment Trialists’ Collaboration Lancet 2012

20. ACC/AHA 2014 Algorithm (i)
Stone et al. Circ 2014

21. ACC/AHA 2014 Algorithm (i)
Stone et al. Circ 2014

22. ACC/AHA 2014 Algorithm (ii)
Stone et al. Circ 2014
Primary Prevention

23. ACC/AHA 2014 Algorithm (iii)
Stone et al. Circ 2014

24. Vignette 1
• 66yo non-diabetic M w/ HTN (BP 125/75 on
amlodipine) and w/o known ASCVD visits you
in the primary care clinic for a well visit. He is
a never smoker and has no acute complaints.
• Lipids: TC 140; HDL 45; TG 100; LDL 79 (calc)
• You calculate his 10y ASCVD risk as 12.8%
• Should he be on a statin?

25. Vignette 1
• 66yo non-diabetic M w/ HTN (BP 125/75 on
amlodipine) and w/o known ASCVD visits you
in the primary care clinic for a well visit. He is
a never smoker and has no acute complaints.
• Lipids: TC 140; HDL 45; TG 100; LDL 79 (calc)
• You calculate his 10y ASCVD risk as 12.8%
• Should he be on a statin?
• What if his TC is 130 and his LDL is 69

26. Vignette 2
• 60yo normotensive, non-diabetic, non-smoking
F w/ HLD
• Lipids: TC 257; HDL 50; TG 166; LDL 180
• You calculate her 10y ASCVD risk as 4.9%
• Should she be on a statin?

27. Statins for Primary Prevention
• Age 40-75
• LDL 70-190
• 10y MACE Risk >7.5% (or even >5%)
• And … patient preference
• 33mio add’ pts w/ 10y MACE risk>7.5
• 12mio add’ pts w/ 10y MACE risk 5-7.5%

28. Factors To Weigh in the Discussion
• 10-year risk (stay tuned)
• Lifetime risk (stay tuned)
• What impact can life style changes have?
• Other risk factors (…)
– … and how well controlled they are
• Risk vs benefit
– DM
– Myalgia
– Transaminitis
– Cognitive impairment
– ICH
– Cancer?

29. Where is the 7.5% from? (i)
Benefit vs Risk
14% ↓ mortality
27% ↓ CHD (fatal and non fatal) events
22% ↓ in stroke (fatal and non fatal)
33% ↓ in nonfatal MI
38% ↓ in revascularization
18% ↑in diabetes (2.8% on statin vs. 2.4% controls)
No significant increase in short-term risk of
- Muscle adverse events
- Liver adverse events
- Cancer, memory loss
- Hemorrhagic stroke
Taylor et al. Cochrane 2013

30. Where is the 7.5% from? (ii)
Benefit vs Risk for High-intensity Statins for PP
HIGH INTENSITY STATIN TREATMENT
Assumes a 45% relative risk reduction in ASCVD from high intensity statin treatment
NNT to prevent 1 ASCVD event varies by baseline estimated 10-year ASCVD risk
NNH based on 3 excess cases of incident diabetes* per 100 individuals treated with statins for 10 years.
Stone Circ 2014 Suppl
For T2DM

31. What Exactly is a “High-Intensity Statin”?
High-Intensity Statin
Moderate-Intensity
Statin Low-Intensity Statin
Daily dose lowers LDL-C on average, by
approximately ≥50%
Daily dose lowers
LDL-C on average, by
approximately 30% to <50%
Daily dose lowers LDL-C on
average, by <30%
Atorvastatin (40†)-80 mg
Rosuvasatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg‡
Pravstatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
Simvastatin 10 mg
Pravastatin 10-20 mg
Lovastatin 20 mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a
less-than-average response.
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to
the increased risk of myopathy, including rhabdomyolysis.
Stone Circ 2014 Suppl

32. What Exactly is a “High-Intensity Statin”?
High-Intensity Statin
Moderate-Intensity
Statin Low-Intensity Statin
Daily dose lowers LDL-C on average, by
approximately ≥50%
Daily dose lowers
LDL-C on average, by
approximately 30% to <50%
Daily dose lowers LDL-C on
average, by <30%
Atorvastatin (40†)-80 mg
Rosuvasatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10 mg
Simvastatin 20-40 mg‡
Pravstatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
Simvastatin 10 mg
Pravastatin 10-20 mg
Lovastatin 20 mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a
less-than-average response.
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to
the increased risk of myopathy, including rhabdomyolysis.
Stone Circ 2014 Suppl

33. 5% for Moderate-intensity Statins –
Did You Know?
MODERATE INTENSITY STATIN TREATMENT
Assumes a 35% relative risk reduction in ASCVD from moderate intensity statin treatment
NNT to prevent 1 ASCVD event varies by baseline estimated 10-year ASCVD risk.
NNH based on 1 excess case of incident diabetes per 100 individuals* treated with statins for 10 years.
Stone Circ 2014 Suppl
For T2DM

34. MACE 10-year Risk (i)
Google “ASCVD Risk Calculator”

35. MACE Risk (ii)
Ridker & Cook Lancet 2014

36. MACE Risk (iii)
Ridker & Cook Lancet 2014

37. MACE Lifetime Risk Calculation
• Can be used in the
shared decision making
process
• Only available for ages
20-59

38. So does this mean we never have to
measure lipids again?
Follow-up lipid panel – see if anticipated response
Reinforce continued adherence
Follow-up 3-12 mo
Anticipated
therapeutic
response?
Follow-up 4-12 wk &
thereafter as indicated
Management of
statin intolerance
(Table 8, Rec 8)
Less-than-anticipated
therapeutic response
Intolerance
to recommended
dose of statin
Follow-up 4-12 wk
Yes
Yes
No
No
Reinforce improved adherence
Increase statin intensityǂ
OR
Consider addition of nonstatin drug therapy
Reinforce medical adherence
Reinforce adherence to intensive lifestyle changes
Exclude secondary causes of hypercholesterolemia (Table
6)
therapy
Treat
Initial lipid panel
to risk-stratify
Stone Circ 2014 Suppl

39. Other Problems with the New
Guidelines
• Study selection
– Important (older) RCTs seem to have been left out
– No update of the systematic review(s) for the critical
questions has been conducted since 2011; individual
studies have only been added selectively
– No observational studies, no post-hoc analyses, and expert
opinion are consider as input for the deliberations
– However, many recommendations extrapolate either from
RCTs or from observational studies (that are discussed in
much detail)
• Just because there is no evidence does not mean that
something is wrong (stay tuned)
– No trial has used ASCVD risk as an entry criterion

40. Inclusion Criteria Age and Baseline LDL
Of Studies Included In the Guidelines
Age (y)
80+
70–79 JUPITER
Stone Circ 2014 Suppl
AFCAPS
60–69
MEGA
50–59
40–49
CARDS
<40
70–99 100–129 130–159 160–189 190–229
LDL–C (mg/dL)

41. Inclusion Criteria Age and Baseline LDL
Of PP Studies In the Guidelines
Age (y)
80+
70–79 JUPITER
Stone Circ 2014 Suppl
AFCAPS
60–69
MEGA
50–59
40–49
CARDS (100% DM)
<40
70–99 100–129 130–159 160–189 190–229
LDL–C (mg/dL)

42. Inclusion Criteria Age and Baseline LDL
Of PP Studies In the Guidelines
Age (y)
80+
70–79 JUPITER
Stone Circ 2014 Suppl
AFCAPS
60–69
MEGA
50–59
40–49
<40
70–99 100–129 130–159 160–189 190–229
LDL–C (mg/dL)

43. Baseline LDL Mediates MACE Risk
– To Different Degrees
Robinson & Stone Am J Card 2006

44. 4S Posthoc: Logarithmic Relationship
between LDL Reduction and MACE
Pedersen et al. Circ 1998

45. Meta-regression Confirms Correlation
1.2 1.4 1.6 1.8
2
1
.1 .2 .3 .4
Proportion of LDL reduction
1.2 1.4 1.6 1.8
2
1
0 20 40 60 80
New analysis, based on Cholesterol Treatment Trialists’ Collaboration Lancet 2010
LDL reduction

46. CARE (Prava40 for PP) Post-Hoc
New analysis, based on Cholesterol Treatment Trialists’ Collaboration Lancet 2010

47. TNT Posthoc
Q LDL Mean ± SD At 10 At 80 Total
1 <64 54 ± 8 114 1,722 1,836
2 64-76 70 ± 4 529 1,403 1,932
3 77-89 83 ± 4 1,019 968 1,987
4 90-105 97 ± 5 1,515 515 2,030
5 ≥106 122 ± 16 1,718 266 1,984
LaRosa et al. Am J Card 2007

50. UK NICE - QRISK

51. UK NICE – Recs
• Offer atorvastatin 20 mg for the primary prevention of CVD
to people who have a 10% or greater 10-year risk of
developing CVD
• Offer atorvastatin 20 mg for the primary prevention of CVD
to people with type 2 diabetes who have a 10% or greater
10-year risk of developing CVD
• Start statin treatment in people with CVD with atorvastatin
80 mg
• Offer atorvastatin 20 mg for the primary or secondary
prevention of CVD to people with CKD
– Increase the dose if a greater than 40% reduction in non-HDL
cholesterol is not achieved and eGFR is 30 ml/min/1.73 m2 or
more

52. Misunderstandings
• Isn’t a, say >50% risk reduction a goal in itself?
– Substitute “goal” with “target level” – just semantics
• Just because there is no evidence does not mean that
something is wrong
– That is why the ACC/AHA guidelines actually do not give a
recommendation on target levels (N for no recommendation for
or against)
• The (unabridged) guidelines actually do not recommend
automatic prescriptions but rather a discussion with the
patient first
• Confusion about dosing
– Except for atorva-, rosuva-, and fluvastatin, all 10-20mg
preparations are low-intensity and almost never indicated
– For high-intensity statin, there is more evidence for atorvastatin
80 – so unless there are reasons against, do not pre

53. Future Therapies
• Ezetimibe: PROVE IT
• PCSK9 Ab: ODYSSEE, Fourier, SPIRE
• CEPT Inhibition (also raises HDL): REVAL-HPS3/
TIMI, ACCELERATE

54. Conclusions
• Statins – via decreasing LDL +/- unknown mechanisms (that
might differ between members of this class) – prevent or
probably just delay MACEs.
• Moving from surrogate to hard endpoints is interesting.
However, it is unclear if abandoning LDL/non-HDL target levels
is justified as they might be supported by post-hoc evidence.
• The guidelines greatly simplify the process for PCPs and will
help to improve patient care.
• Although the change to including more primary prevention
seems reasonable, as physicians we need to individualize our
treatment recommendations and be mindful about the
context and our patients’ preferences. Discussions will
strengthen understanding and adherence.

55. Acknowledgements
• Arnab Ghosh, MD MA
• Arthur Schwartzbard, MD FACC
• James Underberg, MD MS FACPM FACP FNLA