3. ATP III Classification of Cholesterol
Concentrations
Lipoprotein Concentration (mg/dL) Interpretation
TC < 200
200-239
≥240
Desirable
Borderline high
High
LDL-c <100
100-129
130-159
160-189
≥190
Optimal
Near/above optimal
Borderline high
High
Very high
HDL-c <40
≥60
Low
High
TG <150
150-199
200-499
≥500
Normal
Borderline high
High
Very high
4. ATP III Treatment Targets
Exception: TG lowering is an immediate target if ≥ 500
mg/dL
Primary Target:
LDL-c
Secondary Target:
Non-HDL-c
(Once LDL goal met and if TG ≥200)
5. NCEP ATP III: Determining
LDL-c Goals
Yes No
Yes No
Presence of ASVD, DM
High-Risk:
<100mg/dL,
optional <70mg/dL
≥2 major CV risk factors*
10-year CHD risk: FRS
>20% 10-20% <10%
High-Risk:
<100mg/dL
Mod-high Risk:
<130mg/dL,
optional
<100mg/dL
Moderate risk
<130mg/dL
Lower risk
<160mg/dL
6. Targets for Therapy after LDL-C Goal in Patients
with TG 200 mg/dL
Patient Category
LDL-C target
(mg/dL)
Non-HDL-C
target (mg/dL)
CHD or CHD risk
equivalent
<100 <130
No CHD, 2+ RF <130 <160
No CHD, <2 RF <160 <190
10. Individuals with
clinical Atherosclerotic
Cardiovascular Disease (ASCVD)
Individuals ≥ 21 years of age
with primary LDL-C ≥ 190 mg/dl
Individuals of
40-75 years of age with Diabetes
Individuals of 40-75 years of age with
10-year ASCVD risk ≥ 7.5% or higher
Even if they have LDL-C 70-189 mg/dl without ASCVD or Diabetes
12. NCEP ATP III vs ACC/AHA
NCEP ATP III AHA/ACC – ATP IV
Year 2001 (updated in 2004) 2013
Focus Reducing CHD risk Reducing risk of
atherosclerotic CV disease
(ASCVD) – includes CHD +
TIA/stroke, PAD or
revascularisation
Risk
assessment
Framingham 10 yr risk score
(CHD death + non fatal MI
Pooled cohort equations*
(fatal & nonfatal CHD +
fatal & nonfatal stroke
*Developed by the Risk Assessment Work Group to estimate the 10-year ASCVD risk
(defined as first-occurrence nonfatal and fatal MI and nonfatal and fatal stroke) for the
identification of candidates for statin therapy
13. NCEP ATP III vs ACC/AHA
NCEP ATP III AHA/ACC – ATP IV
Risk
Categories
3 main risk categories:
CHD / CHD risk equivalent (DM,
Clinical CHD, symptomatic CAD,
PAD)
2+ risk factors & 10-yr risk ≤ 20%
0-1 risk factors & 10-yr risk <10%
4 statin benefit groups:
Clinical ASCVD
Primary LDL-C elevations ≥190
mg/dl
DM without clinical ASCVD
No DM/CVD with 10-yr ASCVD
risk ≥7.5%
Rx targets LDL-C primary target
<100mg/dl
<130mg/dl (<100 if risk 10-20%)
<160mg/dl
(in the order of categories
mentioned above)
Intensity of statin therapy
High intensity statin therapy
(LDL-C reduction ≥50%)
recommended for most
patients in 4 statin benefit
groups
Rx
recommen
dations
Statin (or bile acid sequestrants or
nicotinic acid) to achieve LDL-C
goal
Maximally tolerated statin
first-line to reduce risk of
ASCVD events
19. Drug Therapy
Nicotinic Acid
• Major actions
Lowers LDL-C 5–25%
Lowers TG 20–50%
Raises HDL-C 15–35%
• Side effects: flushing, hyperglycemia,
hyperuricemia, upper GI distress, hepatotoxicity
• Contraindications: liver disease, severe gout,
peptic ulcer
20.
21. High Triglycerides
(200–499 mg/dL) ?
• Primary goal: achieve LDL-C goal
• First-line therapy for high triglycerides: weight reduction and
increased physical activity
• Second-line therapy: drugs to achieve non-HDL-C goal
– Statins: lowers both LDL-C and VLDL-C
– Fibrates: lowers VLDL-triglycerides and VLDL-C
– Nicotinic acid: lowers VLDL-triglycerides and VLDL-C
(500 mg/dL) ?
Drug therapy for lowering non-HDL-C
– High doses of statins (lower both LDL-C and VLDL-C)
– Moderate doses of statins and triglyceride-lowering drug (fibrate or
nicotinic acid):
• Caution: increased frequency of myopathy with statins + fibrates
25. Take home massage
• ASCVD risk reduction is the main goal by reducing LDL as
much as possible at tolerated doses.
• High intensity statin therapy (LDL-C reduction ≥50%)
recommended for most patients in 4 statin benefit groups
Clinical ASCVD
Primary LDL-C elevations ≥190 mg/dl
DM without clinical ASCVD
No DM/CVD with 10-yr ASCVD risk ≥7.5%
• Pharmacological management is required if isolated TG
500 mg/dL and after LDL-C goal in patients with TG 200
mg/dL
• Guidelines are not a replacement for clinical judgment
26. Hypertension
… the most prevalent modifiable risk factor for
cardiovascular and renal disease worldwide
Editor's Notes
Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p=0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p=0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up
The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes
The relative risk of death in the simvastatin group was 0.70 (95% CI 0.58-0.85, p = 0.0003). The 6-year probabilities of survival in the placebo and simvastatin groups were 87.6% and 91.3%, respectively. There were 189 coronary deaths in the placebo group and 111 in the simvastatin group (relative risk 0.58, 95% CI 0.46-0.73), while noncardiovascular causes accounted for 49 and 46 deaths, respectively. 622 patients (28%) in the placebo group and 431 (19%) in the simvastatin group had one or more major coronary events. The relative risk was 0.66 (95% CI 0.59-0.75, p<0.00001), and the respective probabilities of escaping such events were 70.5% and 79.6%. This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged 60 or more. Other benefits of treatment included a 37% reduction (p<0.00001) in the risk of undergoing myocardial revascularisation procedures
The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan-Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen
Vital status was confirmed on all but 22 patients. Averaged over the 5 years' study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p<0.0001) commenced other lipid treatments, predominantly statins. 5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR]0.89, 95% CI 0.75-1.05; p=0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0.76, 0.62-0.94; p=0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90-1.57; p=0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; p=0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p=0.18). Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2%vs 3.6%, p=0.0003). There was a slight increase in pancreatitis (0.5%vs 0.8%, p=0.031) and pulmonary embolism (0.7%vs 1.1%, p=0.022), but no other significant adverse effects.
The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction
At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test).
Laropirant – prostaglandin receptor antagonist
During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001).
The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups
No anticipated major changes here:
ATP II HDL low was < 35, ATP III < 40, goal was set to be the same for both men and women because of the view that a given level of HDL would impart the same risk for both genders (no sources sited)
These are classification of parameters, not goals. LDL goal and treatment is individualized based on risk.
Treatment targets are our primary focus to reduce CV risk and reduce CHD event. Expected to be an area of change..
If fasting TG > 500, then TG are primary target because of the risk of pancreatitis.
In all other patients, LDL-c is primary target for initiating and titrating therapy.
Non-HDL is identified as a secondary target in patients with fasting TG > 200. Many trials have demonstrated non-HDL levels are a better predictor of CVD risk than is LDLc. LDL underestimates the burden of atherogenic, cholesterol-carrying lipoproteins
Some experts are expecting more emphasis on non-HDL as a target in ATP IV. Some have gone as far to say it may become a co-target with LDL-c. It is an easy number available with current testing practices.
A recent meta-analysis published in JAMA March 2012 (8 trials, over 60,000 patients) evaluated the strengths of associations between LDL-c, non-HDL-c and apo B with CV risk in patients receiving statins. Although LDL-c, non-HDL-c and apo B levels were each strongly associated with risk of major CV events, the strength of association of future major CV events was higher for non-HDL-c than with LDL-c and apo B. Non-HDL may be proving to be a better surrogate marker for CHD risk and risk reduction. Guidelines are anticipated to reflect this information.
Based on recent trial data and Canadian and European guidelines: it is anticipated that HDL and TG as treatment targets will be deemphasized. But are indicators of metabolic syndrome/IR and other risk factors to modify.
No specific goal for raising HDL because of lack of evidence for benefit
Current : how we assign an individual LDL goal based on risk – stratified based on level of risk
ASVD:
CHD: (MI), angina, coronary artery procedures (angioplasty, bypass)
CHD risk equivalents:
Non-coronary forms of ASVD
Peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), carotid artery disease, renal artery stenosis
Diabetes (most pts have high risk of CHD events)
Framingham Risk Score > 20%= high risk of CHD event in next 10 year.
Targets for therapy after LDL-C goal in patients with TG 200 mg/dL
Epidemiologic and clinical studies have demonstrated that high blood triglyceride level is an independent risk factor for CHD and that CHD risk is amplified in patients who have elevations in both LDL-C and triglyceride levels. An elevated triglyceride level probably does not contribute to atherogenesis per se but most likely signals the presence of a constellation of lipid abnormalities that increase atherogenic risk, including increased levels of cholesterol-carrying remnant particles, low HDL-C levels, increased numbers of particles, and increased levels of small dense LDL. Patients with these abnormalities often have multiple other CHD risk factors, including central obesity, impaired glucose tolerance, and hypertension.
To address these issues and to enhance the potential for CHD risk reduction, ATP III recommends that secondary treatment targets, defined by non-HDL-C (total cholesterol – HDL-C), be established for those who have a triglyceride level 200 mg/dL, after the LDL-C goal has been achieved. Non-HDL-C goals may be achieved by intensifying lifestyle modification, accentuating LDL-C–lowering therapy, or adding a triglyceride-lowering drug to the LDL-C–lowering regimen. Time and additional clinical trials will establish the utility of these various approaches.
Reference:
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
*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.mesa-nhlbi. 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).
ABI indicates ankle-brachial index; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; and RCT, randomized controlled trial.)
This guideline recommends using the new Pooled Cohort Risk Assessment Equations developed by the Risk Assessment Work Group to estimate the 10-year ASCVD risk (acute coronary syndromes, a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin) for the identification of candidates for statin therapy (see
http://my.americanheart.org/cvriskcalculator and http://www.cardiosource.org/en/Science-And-Quality/Practice-Guidelinesand-Quality-Standards/2013-Prevention-Guideline-Tools.aspx for risk calculator). These equations should be used to predict stroke as well as CHD events in non-Hispanic, Caucasian, and
African-American women and men 40 to 79 years of age with or without diabetes who have LDL-C levels 70 to 189 mg/dL and are not receiving statin therapy
