Supplemental Figure 1.
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Supplemental Table 1. Footnotes to Figure 1. Initiation of statin therapy
Summary of Statin Initiation Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in
Adults (See Figures Figure 3, Figure 4, and Figure 5 for More Detailed Management Information in the 2013 ACC/AHA
cholesterol guideline report)
*Percent reduction in LDL-C can be used as an indication of response and adherence to therapy, but is not in itself a
treatment goal.
†The Pooled Cohort Equations can be used to estimate 10-year ASCVD risk in individuals with and without diabetes.
The estimator within this application should be used to inform decision making in primary prevention patients not on
a statin.
‡Consider moderate-intensity statin as more appropriate in low-risk individuals.
§For those in whom a risk assessment is uncertain, consider factors such as primary LDL-C ≥160 mg/dL or other
evidence of genetic hyperlipidemias, family history of premature ASCVD with onset <55 years of age in a first-degree
male relative or <65 years of age in a first-degree female relative, hs-CRP ≥2 mg/L, CAC score ≥300 Agatston units, or
≥75th percentile for age, sex, and ethnicity (for additional information, see http://www.mesanhlbi.org/CACReference.aspx), ABI <0.9, or lifetime risk of ASCVD. Additional factors that may aid in individual risk
assessment may be identified in the future.
‖Potential ASCVD risk-reduction benefits. The absolute reduction in ASCVD events from moderate- or high-intensity
statin therapy can be approximated by multiplying the estimated 10-year ASCVD risk by the anticipated relative-risk
reduction from the intensity of statin initiated (∼30% for moderate-intensity statin or ∼45% for high-intensity statin
therapy). The net ASCVD risk-reduction benefit is estimated from the number of potential ASCVD events prevented
with a statin, compared to the number of potential excess adverse effects.
¶Potential adverse effects. The excess risk of diabetes is the main consideration in ∼0.1 excess cases per 100
individuals treated with a moderate-intensity statin for 1 year and ∼0.3 excess cases per 100 individuals treated with
a high-intensity statin for 1 year. In RCTs, both statin-treated and placebo-treated participants experienced the same
rate of muscle symptoms. The actual rate of statin-related muscle symptoms in the clinical population is unclear.
Muscle symptoms attributed to statin therapy should be evaluated (see Table 8, Safety Recommendation 8 in the
2013 ACC/AHA cholesterol guideline report).
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ABI indicates ankle-brachial index; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; and
RCT, randomized controlled trial.
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Supplemental Table 2.
Case examples for Table 1.
Examples:
1. Very high risk patient with LDL-C <100 mg/dl (2.59 mmol/L). Average patient within 10 days of acute
coronary syndrome with additional high risk factor in IMPROVE-IT [1]: 7-year event rates:
Simvastatin+placebo group had 22.2% ASCVD event rate (3.2% per year) with mean LDL-C 70 mg/dl
(1.81 mmol/L) versus Simvastatin + Ezetimibe group had 20.4% ASCVD event rate and median achieved
LDL-C 54 mg/dl (1.40 mmol/L); RRR 10% in ASCVD events
Clinical application:
Absolute CVD risk of about 15% over 5-years OR 30% over 10 years
Relative risk reduction of 10% from about an 18 mg/dl (0.47 mmol/L)
reduction in LDL-C
(LDL-C 7052 mg/dl or 8870 mg/dl)
(LDL-C 1.811.35 mmol/L or 2.281.81 mmol/L)
5-year NNT67 OR 10-year NNT33
Reasonable to consider addition of ezetimibe if patient otherwise likely to have a
good quality life expectancy for 5 years or more
2. High risk patient with LDL-C <100 mg/dl (2.59 mmol/L). Average patient with chronic CHD in TNT[2]:
Mean follow-up 5 years; Atorvastatin 10 mg group had 10.9% 5-year hard ASCVD event rate with mean
LDL-C 98 mg/dl (2.54 mmol/L) versus atorvastatin 80 mg group had 8.7% 5-year hard ASCVD event rate
with mean LDL-C 77 mg/dl (2.0 mmol/L).
Clinical application:
Absolute CVD risk of about 10% over 5-years OR 20% over 10 years
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Relative risk reduction of 15% from about an 18 mg/dl (0.47 mmol/L)
reduction in LDL-C
(LDL-C 7052 mg/dl or 8870 mg/dl)
(LDL-C 1.811.35 mmol/L or 2.281.81 mmol/L)
5-year NNT100 OR 10-year NNT50
 Clinician and patient should discuss whether this is a meaningful clinical benefit
over 5-10 year treatment period
3. High risk patient with LDL-C >130 mg/dl (3.37 mmol/L). Average patient with chronic CHD (20% 10year ASCVD risk) and LDL-C 130 mg/dl (3.37 mmol/L) on maximally tolerated statin therapy.
Clinical application:
Absolute CVD risk of about 10% over 5-years OR 20% over 10 years
Relative risk reduction of 10% from about a 26 mg/dl (0.67 mmol/L)
reduction in LDL-C
(LDL-C 130 →104 mg/dl)(LDL-C 3.372.69 mmol/L)
5-year NNT 67 OR 10-year NNT33
Reasonable to consider addition of ezetimibe if patient otherwise likely to have a
good quality life expectancy for 5 years or more
4. Patient with genetic hypercholesterolemia (untreated LDL-C >190 mg/dl; 4.92 mmol/L). All patients
with genetic hypercholesterolemia should be treated with a high intensity statin if possible, and a >50%
reduction in LDL-C is desirable. Do not estimate 10-year ASCVD risk conventional risk prediction
equations in patients with genetic hypercholesterolemia because they do not capture the high risk of
premature ASCVD in these patients. Exposure to severe hypercholesterolemia has been present since
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birth and lifetime risk of ASCVD is very high in patients with genetic hypercholesterolemia, therefore the
addition of ezetimibe would be reasonable for many of these patients.
PCSK-9 inhibitors may be particularly promising in patients with genetic hypercholesterolemia if
they are shown to reduce ASCVD outcomes and are safe in the long-term outcomes trials. These drugs
can lower LDL-C 50-65% when added to background lipid-lowering therapy. [3,4].
References
1. Cannon C, On behalf of the IMPROVE-IT study group. IMProved Reduction of OUtcomes: Vytorin
Efficacy International Trial. Presented at the American Heart Association Scientific Sessions, November
17, 2014 [serial on the Internet]. 2014
2. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart J-C, et al. Intensive lipid lowering with
atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-35.
3. Raal F, Scott R, Somaratne R, et al. Low-Density Lipoprotein Cholesterol–Lowering Effects of
AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine
Protease in Patients With Heterozygous Familial Hypercholesterolemia: The Reduction of LDL-C
with PSCK-9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD)
Randomized Trial. Circulation. 2012;126:2408-2417.
4. Robinson J, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Long-term safety, tolerability and
efficay of alirocumab versus placebo in high cardiovascular risk patients: first results from the ODYSSEY
LONG TERM study in 2,341 patients. In: Hot Topic, editor. European Society of Cardiology Congress;
August 31, 2014; Barcelona, Spain2014.
CHD: Coronary heart disease
CVD: Cardiovascular disease
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ASCVD: Atherosclerotic cardiovascular disease (hard events defined as myocardial infarction, stroke,
cardiovascular death)
NNT: Number-needed-to-treat
TNT = Treating to New Targets
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