TRIPASS XR تري باس

 

54 Apoptosis (cell death) of smooth muscle cells in the shoulders of the

atherosclerotic cap further weakens the lesion.

55 These processes increase the chance

that the atherosclerotic lesion may rupture or erode, especially at the shoulders of the

lesion, and expose the underlying tissue to circulating blood elements.

56 Collagen in

the exposed plaque can trigger platelet activation, and tissue factor produced by

macrophages and smooth muscle cells activates the coagulation cascade. Platelets

may adhere and microthrombi may form. The resultant clot can occlude blood flow

entirely, causing MI. More commonly, only partial occlusion of blood flow occurs,

causing transient ischemic symptoms or unstable angina. The clot creates a barrier

between the underlying tissue and circulating blood and allows healing of the plaque

rupture. This process of fissuring and re-healing appears to lead to the more

complicated lesions of atherosclerosis.

Atherosclerotic lesions exist along a continuum from vulnerable lipid-rich lesions

that are prone to rupture and cause a thrombosis to more stable lipid-poor, fibrin-

and collagen-rich lesions. Younger atherosclerotic lesions occupy only the intimal

space, whereas the older lesions may protrude into the luminal space. In fact, the

culprit lesion that results in acute MI is usually not at the site of the greatest stenosis,

but distal to it.

55

CLINICAL EVALUATION AND MANAGEMENT OF

ASCVD RISK

Assessment of the Standard Lipid Panel and the Role of

Advanced Lipid Testing

The routine lipid panel includes standardized measurements of total cholesterol

(TC), HDL-C, and TGs. Although it is possible to measure LDL-C directly, it is

common for most laboratories to calculate LDL-C. TC, HDL-C, and TGs are

measured directly and then the Friedewald equation is applied to calculate LDL-C:

Because the ratio of cholesterol to TGs in VLDL is 1:5, VLDL-C is estimated by

dividing the total TG level by 5. Thus, the formula is rewritten as

If the TG level is greater than 400 mg/dLthe formula for estimating VLDL-C is not

accurate and, therefore, LDL-C cannot be calculated. An accurate LDL-C calculation

by the Friedewald equation also requires that the patient fast for 10 to 12 hours

which provides sufficient time for exogenous TGs, carried by chylomicrons, to be

cleared from the systemic circulation. Most laboratories can measure LDL-C directly

but this is necessary only when the TG level is greater than 400 mg/dL or the patient

has not fasted.

In the presence of cardiometabolic disturbances including the metabolic syndrome,

insulin resistance, impaired glucose tolerance, diabetes, hypertriglyceridemia, as

well as chronic kidney disease (CKD), the calculated or direct measurement of LDLC may not provide a complete assessment of the lipid-related cardiovascular risk.

Cardiometabolic disorders are often associated with the atherogenic dyslipidemia

described above, in which there are near-normal to modest elevations of LDL-C,

reduced HDL-C levels, elevations of TGs, and an excess of atherogenic small, dense

LDL particles. When LDL-C levels are near-normal to modestly elevated and the

LDL particle concentration (LDL-P) is elevated, the measures are considered to be

“discordant.”

There are a number of advanced lipid/lipoprotein tests to determine the

concentration and/or the relative size distribution of both LDL and HDL particles.

These include gradient gel electrophoresis, vertical automated profile, nuclear

magnetic resonance spectroscopy, and ion mobility analysis. Data from both the

Framingham Offspring Study and the Multi-Ethnic Study of Atherosclerosis

demonstrated that patients with discordantly high LDL-P compared to LDL-C had

higher CVD event rates, while patients with discordantly low LDL-P compared to

LDL-C had lower CVD event rates.

57,58 CVD risk, therefore, tracked most closely

with levels of LDL-P. Apo B is another measure of concentrations of atherogenic

lipoproteins, including remnant VLDL particles and LDL particles and is strongly

related to CVD risk.

59

Non–HDL-C provides a simple and easily calculated estimate of the excess CVD

risk associated with the atherogenic dyslipidemia.

7

p. 109

p. 110

It is a single measurement of cholesterol carried by all potentially atherogenic

particles, including VLDL, VLDL remnants, IDL, and LDL particles and can give the

clinician information regarding the patient’s CVD risk when LDL-C cannot reliably

be calculated or in the presence of excess VLDL-C and excess LDL particle

concentration. Non–HDL-C is calculated by the following formula:

As mentioned previously, non–HDL-C can be calculated in both the fasting and

non-fasting state because VLDL-C does not need to be estimated.

There are a number of guidelines for the management of lipid-related ASCVD risk

and there is considerable variation in the recommended targets and goals of therapy,

including LDL-C, non–HDL-C, LDL-P, and apo B. A recent review of guidelines

from major US and international professional societies compares recommendations

for lipid/lipoprotein targets and initiation of lipid-lowering therapies.

8

Guidelines for the Management of Dyslipidemia to

Reduce ASCVD Risk

In 2013 the ACC and the AHA published updated guidelines for management of

blood cholesterol to reduce ASCVD risk.

5 Previous guidelines have focused on the

fasting lipid panel as the initial evaluation of lipid-related risk. Within each category

of ASCVD risk, lipid goals were then specified to achieve optimal risk reduction. In

2013 experts determined that current clinical trial data do not support the previous

approach and that data are inadequate to indicate specific lipoprotein targets or goals

of therapy. Therefore, the panel made no recommendation for or against specific

targets (LDL-C or non–HDL-C) for primary or secondary ASCVD prevention.

Instead, four groups of patients were identified in which there is the most extensive

4.

1.

2.

3.

evidence of the benefit of statin therapy for prevention of ASCVD:

Individuals with clinical ASCVD,

Individuals with primary elevations of LDL-C ≥190 mg/dL,

Individuals 40 to 75 years of age with diabetes and LDL-C 70 to 189 mg/dL, and

Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age

with LDL-C 70 to 189 mg/dL and an estimated 10-year ASCVD risk of ≥7.5%.

For each risk group the guidelines recommend an intensity of statin therapy, either

moderate or high intensity (Table 8-3). Low-intensity statins are recommended only

in patients who have experienced or are at risk for adverse effects of treatment. The

guidelines do not support dose titration to achieve specific levels of LDL-C, non–

HDL-C, or apo B, as recommended in previous guidelines (Fig. 8-9). Measurement

of the lipid panel is recommended at 4 to 12 weeks after initiation of statin therapy to

assess compliance with lifestyle recommendations and medication, as well as

response to therapy. Regular monitoring of the lipid panel is then recommended

every 3 to 12 months as clinically indicated.

For primary prevention of ASCVD the recommended risk assessment tool is the

new CV Risk Calculator based on the Pooled Cohort Equations as described in the

2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk.

6 The

equations are derived from large, diverse, community-based cohorts that are

generally representative of the US population of whites and African Americans. The

calculator provides race- and sex-specific estimates of the 10-year risk of first hard

ASCVD event (nonfatal MI, CHD death, fatal or nonfatal stroke) and should be used

in non-Hispanic African American and non-Hispanic whites between 40 and 79

years of age. Lifetime- or 30-year risk is also provided for individuals aged 20 to 59

years who are not at high short-term risk. Variables considered in the risk calculation

include age, sex, race, total cholesterol, HDL-C, systolic blood pressure, treatment

for hypertension, tobacco use, and diabetes. To further refine risk assessment,

optional factors that may be considered include family history of premature ASCVD,

hs-CRP, LDL-C ≥160 mg/dL, coronary artery calcium scoring, and ankle brachial

index. The National Lipid Association Patient-Centered Recommendations: Part 2

provide recommendations for risk assessment in non-Hispanic whites and other

racial and ethnic groups which were not a part of populations used to derive the

ACC/AHA Pooled Cohort Equations.

60

Table 8-3

Intensity of the Various Statins

5

High intensity (when taken as prescribed will reduce

LDL-C by ≥50%

Atorvastatin (40 mg)

* – 80 mg

Rosuvastatin 20 (40) mg

Moderate intensity (when taken as prescribed will

reduce LDL-C by 30% < 50%)

Atorvastatin 10 (20) mg

Rosuvastatin (5) 10 mg

Simvastatin 20–40 mg

Pravastatin 40 (80) mg

Lovastatin 40 mg

Fluvastatin XL 80 mg

Fluvastatin 40 mg bid

Pitavastatin 2–4 mg

Low intensity (when taken as prescribed will reduce

LDL-C by <30% on average

Simvastatin 10 mg

Pravastatin 10–20 mg

Lovastatin 20 mg

Fluvastatin 20–40 mg

Pitavastatin 1 mg

The doses listed in parenthesis were not evaluated in randomized controlled trials.

*Evidence is from one randomized controlled trial Bold—Doses of statins that were evaluated in randomized

controlled trials

Patients with a 10-year risk of ≥7.5% should be engaged in a patient–clinician

discussion of the ASCVD risk reduction benefits of statin therapy, potential adverse

drug effects, potential drug–drug interactions, and consideration of patient

preferences to determine if statin therapy is appropriate (Fig. 8-10).

CASE 8-1

QUESTION 1: B.C. is a 46-year-old peri-menopausal white female who has recently relocated to the area

and is establishing care with a gynecologist. As part of her annual evaluation a routine lipid panel is obtained.

She takes no prescription medications but does take a number of dietary supplements and vitamins, including

krill oil, multivitamin, B-complex, and vitamin D. She has no history of tobacco use, hypertension, or diabetes.

She states she was told a number of years ago that her LDL “bad” cholesterol was elevated, but her HDL

“good” cholesterol was high and no treatment was indicated. She has enjoyed jogging and spin classes but says

that as she gets older she is more fatigued and sore with exercise. She follows a Mediterranean style diet and

has a glass of red wine daily.

Her father is alive at age 72 and takes statin therapy for hyperlipidemia, though she is uncertain of the

severity of his lipid disorder. He has no history of cardiovascular disease. Her mother is a 71-year-old diabetic

and underwent coronary stent placement last year following the onset of angina and an abnormal stress test.

She was started on statin therapy at the time of her procedure. Her brother is overweight, has hypertension and

borderline diabetes, and is also on statin therapy and fenofibrate.

On physical exam the patient has the following: normotensive (128/76 mm Hg); carotid pulses with normal

amplitude and no bruits; 2/6 crescendo/decrescendo noted at the left sternal border; no abdominal bruit;

peripheral pulses 2+; no tendon xanthomas, corneal arcus, or xanthelasmas.

Following a 12-hour fast the patient’s lipid panelshows the following results:

Total cholesterol, 290 mg/dL

HDL-C, 56 mg/dL

LDL-C calculated, 218 mg/dL

TG, 132 mg/dL

What is your assessment of B.C.’s lipid panel results?

p. 110

p. 111

Figure 8-9 Recommendations for the intensity of statin therapy based on statin benefit group diagram. (Adapted

from Stone NJ et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic

cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task

Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889–2934. doi:10.1016/j.jacc.2013.11.002.)

The NLA Recommendations for Patient-Centered Management of Dyslipidemia

were published in 2014. Similar to NCEP ATP III Guidelines, these comprehensive

recommendations for management of a variety of dyslipidemias continue to

recommend lipoprotein targets (non–HDL-C and LDL-C) and titration to achieve

goals of therapy (Table 8-4).

7

The patient’s LDL-C is very high and she would qualify for statin therapy as

defined by both the ACC/AHA and NLA recommendations for management of

hypercholesterolemia. Her HDL-C is near the average range for a woman and her TG

level is considered normal (<150 mg/dL). There has been a misconception among

some providers and patients that a normal or high HDL-C level is “protective” in the

presence of hypercholesterolemia, based on a TC/HDL-C ratio of <3.5, and that

statin therapy is not indicated. However, in the presence of very high elevations of

LDL-C levels all current and previous guidelines recommend statin therapy

regardless of baseline HDL-C.

In the presence of very high LDL-C levels it is important to consider a number of

issues prior to initiation of therapy. The patient’s lifestyle, including diet and

exercise, may play an important role in B.C.’s new diagnosis of dyslipidemia.

However, she is actually quite compliant with lifestyle recommendations for optimal

cardiovascular health and this is unlikely to be a factor in her lipid levels. Careful

review of family history of hypercholesterolemia and ASCVD by construction of a

detailed pedigree can identify patients with possible HeFH or HoFH. B.C.’s father

has dyslipidemia of uncertain severity and is on statin therapy, but he has no history

of premature ASCVD. Her mother developed ASCVD after age 65 and a long history

of diabetes. Statin therapy was not prescribed until her stent placement and FH is

unlikely. Her brother has a mixed dyslipidemia, most likely exacerbated by

overweight and poorly controlled diabetes. Thus, based on this brief pedigree the

diagnosis of FH is unlikely. Classic physical examination findings of tendon

xanthomas, corneal arcus before age 45, and xanthelasmas are often, but not always

present in FH. B.C. does not have these findings. The patient does have a systolic

murmur on cardiac examination which may be indicative of aortic valvular disease, a

very common problem in patients with HoFH.

p. 111

p. 112

Figure 8-10 Recommendations for initiating statin therapy in patients without clinical ASCVD.(Adapted from

Stone NJ et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic

cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task

Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2889–2934. doi:10.1016/j.jacc.2013.11.002.)

Mean TC is typically lower in premenopausal women than in age-matched men.

Premenopausal women have a less pro-atherogenic lipid profile with higher HDL-C

levels (average 10 mg/dL) and lower LDL-C and non–HDL-C levels than agematched men. Due to the hormonal alterations during the perimenopausal period,

LDL-C levels rise and are often higher than in age-matched men. Postmenopausal

women also have a higher incidence of high TG and low HDL-C levels, with an

increase in small, dense LDL particles. It is not uncommon for women without a

prior history of dyslipidemia to be newly diagnosed in the perimenopausal period

and B.C. may be just such a patient.

p. 112

p. 113

Table 8-4

NLA Criteria for ASCVD Risk Assessment and Treatment Goals for

Atherogenic Cholesterol, and Levels at Which Pharmacologic Therapy Should

Be Considered

7

Risk Low Moderate High Very High

Criteria 0–1 Major

ASCVD risk

factor

Consider other

known risk

factors

Major ASCVD

risk factors

Consider other risk

factors

Consider

quantitative risk

scoring

≥3 major ASCVD risk

factors

Chronic kidney disease

stage 3B or 4

a

Quantitative risk score

reaching the highrisk threshold

LDL-C ≥ 190 mg/dL

(severe

hypercholesterolemia

Diabetes mellitus

b

(type 1 or 2) with 0–

1 major ASCVD risk

factor and no

evidence of endorgan damage

ASCVD

diabetes

b

(type 1 or

2) and >2 major

ASCVD risk

factors or evidence

of end-organ

damage

Treatment Goal

Non–HDL-C

(mg/dL)

<130 <130 <130 <100

LDL-C (mg/dL) <100 <100 <100 <70

Consider Pharmacologic Therapy

Non–HDL-C

mg/dL

≥190 ≥160 ≥130 ≥100

LDL-C (mg/dL) ≥160 ≥130 ≥100 ≥70

aChronic kidney disease stage 3B or 4 = estimated glomerular filtration rate of 30 to 44 mL/minute and 15 to 29

mL/minute, respectively. Risk calculators should not be used in these patients as they underestimate risk.

bDiabetic patients plus 1 major ASCVD risk factor, treating to a non–HDL-C goal of <100 mg/dL (LDL-

C).Adapted from Jacobson TA et al. National lipid association recommendations for patient-centered management

of dyslipidemia: part 1—full report. J Clin Lipidol. 2015;9:129–169.

ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; non–HDL-C, non–

high-density lipoprotein cholesterol.

CASE 8-1, QUESTION 2: Is there any evidence for other potential causes of B.C.’s dyslipidemia?

As a routine every patient with dyslipidemia should be evaluated for secondary

causes of elevated LDL-C, non–HDL-C, or TG. Conditions that may be associated

with lipid abnormalities include diabetes, CKD and nephrotic syndrome, obstructive

liver disease, hypothyroidism, anorexia nervosa, polycystic ovarian syndrome, and

pregnancy, among others (Table 8-5).

5 Average values of total-C, LDL-C, HDL-C,

and TG steadily rise throughout pregnancy and levels peak near full-term. In

uncomplicated or “normal” pregnancies, neither total-C nor TG exceeds 250 mg/dL

at any time during pregnancy. A number of drugs are associated with dyslipidemia or

worsening of baseline lipid abnormalities, including exogenous estrogen and

progesterone therapy, and a careful review of the patient’s medication regimen is

necessary prior to initiation of lipid-lowering therapy. B.C. is currently

perimenopausal and does not take any medications associated with exacerbation of

dyslipidemia nor any form of exogenous hormone replacement therapy or oral

contraception.

Table 8-5

Classification of Secondary Causes of Dyslipidemia

5

Cause Increased LDL-C Increased TG

Drugs/medications Glucocorticoids,

amiodarone, diuretics,

cyclosporine

Hormone therapy, glucocorticoids, bile acid sequestrants,

protease inhibitors, retinoic acid, anabolic steroids, tamoxifen,

sirolimus, atypical antipsychotics (predominately olanzapine

and clozapine), raloxifene, β -blockers, thiazide diuretics

Dietary Influences Anorexia, trans fats or

saturated fats, weight gain

Very low fat diets, weight gain, high carbohydrate intake

(refined), and excessive alcohol use

Disease states Nephrotic syndrome,

biliary obstruction

Nephrotic syndrome, chronic renal failure, lipodystrophies

Disorders of

metabolism

Obesity, pregnancy,

hypothyroidism

Hypothyroidism, poorly controlled diabetes, pregnancy, and

obesity

p. 113

p. 114

CASE 8-1, QUESTION 3: Further review of B.C.’s laboratory studies showed the following:

Glucose, 92 mg/dL

Alanine aminotransferase (ALT), 24 mg/dL

Aspartate aminotransferase (AST), 18 mg/dL

Creatinine, 0.9 mg/dL

Thyroid-stimulating hormone (TSH), 57 international units (IU)/mL

Laboratory evaluation has revealed that B.C.’s fatigue and muscle soreness are likely due to hypothyroidism,

which has also exacerbated her previous dyslipidemia. She is placed on thyroid replacement therapy and with

normalization of her thyroid function her follow-up laboratory results show the following:

TSH, 1.254 IU/mL

TC, 215 mg/dL

HDL-C, 59 mg/dL

LDL-C calculated, 132 mg/dL

TG, 118 mg/dL

What is the next step in the evaluation of B.C.’s ASCVD risk?

B.C. has no other ASCVD risk factors or risk equivalents other than mild

dyslipidemia. Using the ACC/AHA Pooled Cohort Equations or CV Risk Calculator

her 10-year risk of ASCVD event is 0.9%. According to both the ACC/AHA and

NLA recommendations for lipid management there is currently no indication for

initiation of statin therapy.

The 2015 Standards of Diabetes Care of the American Diabetes Association

(ADA) were revised to recommend initiation and intensification of statin therapy

(high versus moderate) in patients with diabetes based on the individual patient’s

risk profile.

61 However, the ADA notes that the presence of diabetes confers

significant risk of ASCVD and that the ACC/AHA CV Risk Estimator is of limited

use in diabetics. Recommendations are made for patients <40, 40 to 75, and >75

years of age for moderate- or high-intensity statin therapy in the presence of ASCVD

risk factors or overt ASCVD (Table 8-6).

The 2013 Clinical Practice Guideline for Lipid Management in Chronic Kidney

Disease (CKD), published by the Kidney Disease: Improving Global Outcomes

(KDIGO) Panel, notes that in nondialysis-dependent CKD patients the relationship

between LDL-C and ASCVD events is weaker than in the general population.

62 This

is likely related to lipoprotein metabolic abnormalities characterized by lower levels

of LDL-C, elevated LDL-P, an increase in small dense LDL, reduced HDL-C, and

elevated TG. Therefore, according to KDIGO guidelines the measured LDL-C may

be less useful as a marker of coronary risk among people with advanced nondialysisdependent CKD and does not serve as an indication for pharmacologic treatment.

Instead, therapy is guided by the absolute risk of coronary events based on patient

age and stage of CKD or estimated glomerular filtration rate (eGFR). Specific doses

of individual statins are recommended for each stage of CKD or eGFR and dose

titration is not indicated. Statin therapy or combination therapy with statin and

ezetimibe is not recommended in adults with dialysis-dependent CKD due to lack of

evidence of ASCVD risk reduction in patients with stage V CKD. However, therapy

may be continued in patients already receiving therapy at the time of initiation of

dialysis (Table 8-7).

CASE 8-2

QUESTION 1: S.W. is a 51-year-old African American male with CKD due to polycystic kidney disease. He

has no history of tobacco use or diabetes, but is treated for hypertension. He is very active and works in

landscape maintenance, but does not have a program of consistent aerobic exercise. He follows a heart-healthy

diet consistent with the DASH (Dietary Approaches to Stop Hypertension) recommendations and has

maintained a normal BMI. He is referred for nephrology consultation and the following results are obtained:

eGFR, 42 mL/minute

TC, 187 mg/dL

HDL, 39 mg/dL

LDL-C calculated, 102 mg/dL

TG, 230 mg/dL

HgbA1c

, 6.8%

BP, 126/68 mm Hg

What is your assessment of S.W.’s ASCVD risk and his lipid panel results?

S.W. has stage 3b CKD defined as an eGFR between 30 and 44 mL/min/1.73 m2

.

According to the NLA Recommendations for Patient-Centered Management of

Dyslipidemia, patients with stage 3b to stage 4 CKD are at high risk for ASCVD and

should be considered for drug therapy. Statin therapy with or without ezetimibe are

recommended therapies in CKD patients who are nondialysis dependent and the

goals of therapy are non–HDL-C <130 mg/dL and/or LDL-C <100 mg/dL.

Table 8-6

ADA Recommendations for Statin Treatment in People with Diabetes

61

Age <40 years 40–75 years >75 years

Risk factors Zero risk factor(s) for

CHD

a

Overt CHD

b

Zero risk factor(s) for

CHD

Overt CHD

Zero risk factor(s) for

CHD

Overt CHD

Recommended dose of

statin

No statin if zero risk

factors

Moderate or high

intensity in presence of

CHD risk factor(s)

High if overt CHD

Moderate if no risk

factors

High intensity in

presence of CHD risk

factor(s)

High if overt CHD

Moderate if no risk

factors

Moderate or high

intensity in presence of

CHD risk factor(s)

High if overt CHD

Recommended monitoring

of lipid panel

Annually or as needed As needed to assess for

adherence

As needed to assess for

adherence

Statin therapy should be initiated as an adjunct to lifestyle modifications.

aCHD risk factors include hypertension, smoking, LDL-C ≥ 100 mg/dL, being overweight, and obesity.

bOvert CHD includes those who have had a previous cardiovascular event or an acute coronary syndrome.

CHD, coronary heart disease.

Adapted from Cromwell et al. LDL particle number and risk of future cardiovascular disease in the Framingham

Offspring Study—implications for LDL management. J Clin Lipidol. 2007;1:583–592.

p. 114

p. 115

Table 8-7

KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney

Disease

62

Chronic Kidney Disease Severity Treatment Recommendations

Age ≥ 50 years of age with eGFR <60 mL/minute/1.73

m

2 not on HD or have a history of kidney transplant

Statin or statin/ezetimibe combination

Age ≥ 50 years with CKD and eGFR >60

mL/minute/1.73 m

2

Statin

Age 18–49 years with CKD not on HD or history of

kidney transplant with one or more of the following

Diabetes mellitus

Prior stroke

Known CAD

Estimated 10-year risk of CAD death or nonfatal MI

> 10%

Statin

Dialysis-dependent CKD No initiation of therapy

CHD, coronary heart disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HD,

hemodialysis.

Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group. KDIGO Clinical

Practice Guideline for lipid management in chronic kidney disease. Kidney Int Suppl. 2013;3:259–305.

The 2013 ACC/AHA Blood Cholesterol guidelines do not consider CKD as a risk

factor in ASCVD risk assessment and do not provide specific recommendations for

statin or ezetimibe therapy in nondialysis-dependent patients. ASCVD risk

assessment is performed by the CV Risk Calculator incorporating standard risk

factors and pharmacotherapy is implemented according to the algorithm for primary

prevention. For patients on maintenance peritoneal dialysis or hemodialysis the

ACC/AHA experts felt that there was inadequate information to make a

recommendation for or against the initiation or continuation of statin therapy.

CASE 8-2, QUESTION 2: Would this patient require treatment at this time?

The 2013 KDIGO Clinical Practice Guideline for Lipid Management in Chronic

Kidney Disease provides guidance on lipid management and treatment for all patients

with CKD (nondialysis dependent, dialysis dependent, kidney transplant recipients,

and children). According to KDIGO experts, in patients with CKD who are

nondialysis dependent, the relationship between LDL-C and ASCVD events is

weaker than in the general population likely related to the atherogenic dyslipidemia

characteristic in CKD. Thus, the measured LDL-C does not serve as an indication for

treatment. KDIGO guidelines recommend that lipid therapy be guided by the absolute

risk of coronary events based on patient age and stage of CKD or eGFR, regardless

of baseline lipids. Statin or statin/ezetimibe therapy is recommended in nondialysisdependent adults age ≥50 years with eGFR <60 mL/minute/1.73 m2

. In adults age ≥50

years with CKD and eGFR ≥60 mL/minute/1.73 m2

, only statin therapy is

recommended. In adults age 18–49 years with CKD but not treated with chronic

dialysis or kidney transplantation, statin treatment is suggested if one of the following

is present: known CHD (MI or coronary revascularization), diabetes mellitus, prior

ischemic stroke, or estimated 10-year incidence of coronary death or nonfatal MI

>10% by the Framingham Risk Score. Statin therapy is also recommended in adult

kidney transplant recipients. Therefore, according to KDIGO guidelines, S.W. may

be treated with statin or statin/ezetimibe therapy.

PHARMACOLOGIC THERAPY

3-Hydroxy-3-Methyl-glutaryl Coenzyme A Inhibitors

(Statins)

MECHANISM OF ACTION

Statins competitively inhibit HMG-CoA reductase, the enzyme responsible for

converting HMG-CoA to mevalonate in an early, rate-limiting step in the biosynthetic

pathway of cholesterol (Figs. 8-1 and 8-11). This causes decreased production of

mevalonate and its subsequent conversion to cholesterol and a subsequent

compensatory increase in the synthesis of LDL receptors. The increased LDL

receptor density results in an increase in hepatic update of LDL-C, and to a lesser

extent VLDL particles, and significantly lower levels of plasma LDL-C. In addition

to the reduction in LDL-C, statins also reduce Apo B, triglyceride, and total

cholesterol concentrations.

63–67

EFFICACY

Lipid-lowering therapy for patients with ASCVD is now accepted as standard of

care.

5 Beginning in the mid-1990s, the results of clinical trials with more potent

statins were reported. Five of these (Scandinavian Simvastatin Survival Study (4S),

Cardiovascular and Recurrent Events (CARE), the Long-Term Intervention with

Pravastatin in Ischemic Disease Study (LIPID), Treating to New Targets (TNT), and

Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL))

were secondary prevention trials conducted in patients with known CHD.

68–72

In 4S,

CARE, and LIPID, CHD death and nonfatal MI occurred in 13% to 22% of placebotreated patients in the 5-year follow-up period, compared with event rates of 10% to

14% with patients on statin therapy.

68–70 Total mortality was reduced significantly in

two of these trials, 4S and LIPID, that were powered to assess total mortality.

Additionally, fewer revascularization procedures were required in patients receiving

statin therapy and 31% fewer strokes occurred.

73 The TNT and IDEAL trials

demonstrated additional cardiovascular benefit for high-intensity versus moderateintensity statin therapy in patients with stable CHD. These trials randomly assigned

patients to receive either high-dose atorvastatin 80 mg versus atorvastatin 10 mg or

simvastatin 20 mg with an approximate follow-up period of 5 years. In both trials,

more intensive lowering of LDL-C to significantly less than 100 mg/dL was

associated with a reduction in CHD.

71,72 The further reductions in the incidence of

heart attacks, revascularizations, and ischemic strokes with more intensive lowering

of LDL-C with statins compared with less-intensive statin regimens was verified in a

recent meta-analysis of randomized trials. An additional 38.6-mg/dL reduction of

LDL-C in patients on high-intensity therapy was associated with a 38% relative

reduction in major vascular events (p < 0.0001).

73

The Heart Protection Study (HPS)

74 extended the results of earlier secondary

prevention statin trials (4S,

68 CARE,

69 LIPID70

). The HPS included 20,536 patients

with a history of CHD or cerebrovascular disease (stroke or transient ischemic

attacks), peripheral vascular disease, or diabetes not considered by their general

practitioner to have a clear indication for statin therapy because of relatively low

baseline cholesterol levels (mean LDL-C 131 mg/dL).

74 A reduction in CHD events

was achieved in both men and women; in all age groups, including those aged 75 to

85 years; and regardless of the baseline LDL-C, including those with initial levels

less than 100 mg/dL.

p. 115

p. 116

Figure 8-11 Reaction catalyzed by HMG-CoA reductase. HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A;

IDL, intermediate-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; VLDL, very low-density

lipoprotein.

Trials in patients with acute coronary syndromes (ACS) have also demonstrated

CHD risk reduction. The Myocardial Ischemia Reduction with Aggressive

Cholesterol Lowering (MIRACL) study randomly assigned patients presenting to the

hospital with unstable angina or non–Q-wave MI to statin therapy or placebo for 4

months. This resulted in a 24% reduction in symptomatic ischemia requiring

emergency hospitalization and a 60% reduction in nonfatal strokes in those receiving

the statin.

75,76 More recently, the Pravastatin or Atorvastatin Evaluation and Infection

Therapy—Thrombolysis in Myocardial Infarction (PROVE-IT) is considered a

landmark trial that demonstrated superior cardiovascular event lowering when highintensity statin therapy (atorvastatin 80 mg) was implemented within 10 days of ACS

versus moderate-intensity (pravastatin 40 mg) statin therapy.