Atherosclerotic Cardiovascular Disease (ASCVD)

Primary Prevention Guideline

Major Changes as of October 2020 ........................................................................................................ 2

Definitions................................................................................................................................................ 2
Goals of Primary Prevention ................................................................................................................... 2
Lipid Screening and ASCVD Risk Calculation ........................................................................................ 3
Lifestyle Modifications ............................................................................................................................. 5
Dietary Supplements ............................................................................................................................... 6
Statin Therapy ......................................................................................................................................... 7
Shared decision-making: ASCVD risk tool ....................................................................................... 9
Antiplatelet Therapy .............................................................................................................................. 11
Patients with Diabetes: ACE Inhibitor or ARB Therapy ........................................................................ 12
Lowering Triglycerides to Prevent Pancreatitis ..................................................................................... 13
Medication Monitoring ........................................................................................................................... 14
Evidence Summary ............................................................................................................................... 15
References ............................................................................................................................................ 19
Guideline Development Process and Team ......................................................................................... 20

Last guideline approval: October 2020

Guidelines are systematically developed statements to assist patients and providers in choosing
appropriate health care for specific clinical conditions. While guidelines are useful aids to assist providers
in determining appropriate practices for many patients with specific clinical problems or prevention issues,
guidelines are not meant to replace the clinical judgment of the individual provider or establish a standard
of care. The recommendations contained in the guidelines may not be appropriate for use in all
circumstances. The inclusion of a recommendation in a guideline does not imply coverage. A decision to
adopt any particular recommendation must be made by the provider in light of the circumstances
presented by the individual patient.

© 1996 Kaiser Foundation Health Plan of Washington. All rights reserved. 1

Major Changes as of October 2020
New Previous
Updated aspirin recommendations: Previous aspirin recommendations:
• Initiating low-dose aspirin therapy is no • Aspirin is recommended for patients
longer routinely recommended for primary aged 50–59 if ≥ 10% risk of ASCVD
prevention, given new evidence that the (myocardial infarction or stroke) over
benefits do not generally outweigh the risks 10 years.
of bleeding. • Use shared decision-making for patients
• It is appropriate to discontinue aspirin aged 60–69 if ≥ 10% risk over 10 years.
therapy in many patients who are already • No recommendation on aspirin for
taking it, with the exception of patients at patients under age 50 or over age 70 due
high cardiovascular risk (10-year ASCVD to insufficient evidence.
risk ≥ 10%), who may still benefit. Shared
decision-making is encouraged.
Coronary artery calcium (CAC) scores may be Coronary artery calcium scoring is not routinely
helpful for patients at intermediate ASCVD risk recommended because it does not add
who are uncertain about taking a statin, and/or significantly to clinical decision-making in a way
for patients whose calculated risk is higher or that improves outcomes.
lower than expected.

Definitions
ASCVD, or atherosclerotic cardiovascular disease, is caused by plaque buildup in arterial walls and
refers to the following conditions:
• Coronary heart disease (CHD), such as myocardial infarction, angina, and coronary artery
stenosis > 50%.
• Cerebrovascular disease, such as transient ischemic attack, ischemic stroke, and carotid artery
stenosis > 50%.
• Peripheral artery disease, such as claudication.
• Aortic atherosclerotic disease, such as abdominal aortic aneurysm and descending thoracic
aneurysm. Patients with incidental aortic atherosclerosis should follow usual care
recommendations for ASCVD prevention (e.g., lifestyle changes, statins).
Primary prevention refers to the effort to prevent or delay the onset of ASCVD.

Secondary prevention refers to the effort to treat known, clinically significant ASCVD, and to prevent or
delay the onset of disease manifestations.

Goals of Primary Prevention

Modify risk factors or prevent their development with the aim of delaying or preventing new-onset ASCVD.
This guideline addresses the primary prevention of ASCVD in general. It does not attempt to address
screening or treatment of specific potential manifestations of ASCVD.

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Lipid Screening and ASCVD Risk Calculation
Table 1. Lipid screening for patients not already on statins
Eligible population Test Frequency
Under age 40 Routine screening is not recommended unless patient has a major
cardiovascular risk factor (e.g., diabetes, hypertension, family history,
smoking).
Age 40–75 Non-fasting lipid panel Every 5 years at a minimum 1
Over age 75 Routine screening is not Upon patient request or based on other
recommended. ASCVD risk factors
1 Consider re-screening intervals based on ASCVD risk:
• Every 5 years if ASCVD risk < 7.5% over 10 years
• Every 2 years if ASCVD risk 7.5–14.9% over 10 years
• Annually if ASCVD risk ≥ 15% over 10 years and not on statin

Lipid screening tests

Lipid panel: for most patients
The results of a lipid panel—total cholesterol, HDL, LDL, and triglycerides—ordered through KP
HealthConnect include the patient’s 10-year risk calculation for cardiovascular disease. It is
recommended that the patient be non-fasting for the lipid panel, as this is much easier for the patient and
does not require a return visit. Any patient who has a triglyceride level > 400 mg/dL (regardless of LDL
level) will need to return for a fasting lipid panel.

hs-CRP: consider for patients at 7.5–14.9% risk

For patients at 7.5–14.9% ASCVD risk over 10 years, consider testing with hs-CRP to help confirm
elevated risk when deciding whether to recommend statin therapy.

Table 2. Interpreting hs-CRP test results

Result Interpretation
< 1 mg/L Risk is lower than the ASCVD risk calculation.
1–3 mg/L Risk is close to the ASCVD risk calculation.
3.1–9.9 mg/L Risk is higher than the ASCVD risk calculation.
≥ 10 mg/L These elevations are associated with a nonspecific inflammatory
process. Cardiac risk CRP should be reevaluated after the inflammatory
condition has resolved.

Coronary artery calcium scoring: consider for patients at indeterminate risk or at

intermediate risk and undecided about statins
Coronary artery calcium (CAC) scoring is not routinely recommended. However, CAC may be helpful for
patients at intermediate ASCVD risk who are uncertain about taking a statin, and/or patients whose
calculated risk is higher or lower than expected.

Who should consider getting CAC score testing?

• Individuals at intermediate ASCVD risk (aged 40–75 years without diabetes and with LDL-C
levels ≥ 70 mg/dL, at a 10-year ASCVD risk of ≥ 7.5% and < 20%), if risk status or decision
about statin therapy is uncertain (for example, due to patient reluctance to start
pharmacotherapy). For these patients, treatment with statin therapy may be withheld or delayed if
CAC = 0, except in cigarette smokers and those with a strong family history of premature

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 ASCVD. A CAC score of 1–99 favors statin therapy, especially in those aged ≥ 55 years. For any
patient, if the CAC score is ≥ 100 or ≥ 75th percentile, statin therapy is indicated.
• Measurement of CAC may be considered in select adults with borderline elevated ASCVD risk
(5–7.4% 10-year ASCVD risk) for further risk stratification, in whom the presence of CAC may
change decision-making with regard to statin treatment and intensity of ASCVD risk factor
modification.

If patients get CAC testing but remain untreated, repeating CAC measurement in 5–10 years may
have some value in reassessing for CAC progression, but data are limited.

Who should not get CAC score testing?

• Routine CAC measurement is not recommended in patients at low (< 5% 10-year risk) or high
(≥ 20% 10-year risk) ASCVD risk, as the results are generally unlikely to change management.
• Patients who are averse to treatment and unlikely to initiate treatment even if CAC is
identified should not undergo CAC testing.

Patients should be advised to contact Member Services to determine their coverage benefit for CAC
testing, as it may incur out of pocket costs. See Clinical Review Criteria for CT Angiography and CT
Cardiography: Screening & Calcium Scores for more information.

Note: The U.S. Preventive Services Task Force (USPSTF 2018) examined whether the addition of
coronary artery calcium to the traditional risk factors improves risk classification. The report concluded
that—while CAC scoring statistically improves risk stratification—there was insufficient evidence to
determine either the benefits and harms of using CAC score testing for risk assessment, or whether
adding it to the tools currently used would reduce the incidence of CHD or mortality following statin
therapy.

Biomarker tests: not recommended

Testing for the following biomarkers of inflammation and lipid-related markers is not recommended.
Although they may be independently associated with cardiovascular disease risk, they have only a
minimal prognostic value when added to conventional risk markers:
• Fibrinogen
• Lipoprotein(a)
• Phospholipase A2
• Apolipoprotein B and A-1 combined

ASCVD risk calculation

KP Washington is now using the Pooled Cohort Equation to estimate a patient’s risk of developing an
ASCVD event (myocardial infarction or stroke) over the following 10 years. Use of this risk estimate will
help determine which patients might benefit from primary prevention interventions. The calculations will
be returned with the lipid panel results or by using a SmartLink in KP HealthConnect.

Note: ASCVD risk calculators can only estimate risk. Interpretation of ASCVD risk calculations
should always reflect informed clinical judgment.

The ASCVD calculator is available:

• On the public website for use by clinicians, contracted providers, and members.
• Through the KP HealthConnect SmartLink .ascvdrisk, which pulls information from a patient’s
record to calculate the risk.
• In the Health Profile online tool for members.
• In the Clinical Lab’s lipid panel results.

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Lifestyle Modifications
Tobacco cessation
• Ask patients about tobacco use at every office visit.
• Advise tobacco users to quit.
• Advise patients at every office visit to avoid exposure to environmental tobacco smoke at home,
work, and in public places.
• See the Tobacco and Nicotine Cessation Guideline for additional information.

Healthy diet
All patients should strive to:
• Make smart choices from every food group to meet caloric needs.
• Get the most and best nutrition from the calories consumed.

There is strong evidence that adhering to a Mediterranean-style eating plan reduces the incidence of
major cardiovascular events in people at risk for ASCVD. Adhering to a DASH eating plan can be an
alternative. Both eating plans provide similar key elements: an emphasis on plant foods (fruits,
vegetables, whole-grain breads or other forms of cereals, beans, nuts, and seeds), minimally processed
foods, and seasonally fresh foods; inclusion of fish; and minimal intake of red meat. The SmartPhrases
.avsmediterraneandiet, .avsdash, and .avsnutrition are available for after-visit summaries.

There is some evidence that consuming an average of two fish servings weekly may reduce CHD mortality.

Moderation of alcohol consumption

• Consider having patients complete the AUDIT-C (part of the Annual Mental Health
Questionnaire).
• See the Unhealthy Drinking in Adults Guideline for additional information.

Alcohol consumption is not considered to be a strategy for preventing ASCVD.

Physical activity
The American Heart Association recommends the following physical activity goals:
• At least 30 minutes of moderate-intensity aerobic activity 5 or more days per week.
• Moderate- to high-intensity muscle-strengthening activity 2 or more days per week.

An example of moderate-intensity aerobic activity is walking at a pace that makes a patient feel slightly
out of breath but still able to maintain a conversation.

For patients who have been inactive for a while, recommend that they start slowly and work up to at least
30 minutes per day at a pace that is comfortable. If they are unable to be active for 30 minutes at one
time, suggest accumulating activity over the course of the day in 10- to 15-minute sessions.

Weight management
• Encourage getting to or maintaining a healthy weight through an appropriate balance of caloric
intake and physical activity.
• See the Weight Management Guideline for additional information.

Blood pressure management

• The target the blood pressure for the general population is < 140/90 mm Hg.
• For patients who are at ≥ 10% 10-year risk of ASCVD, have chronic kidney disease (CKD), or are
age 75 or older, the blood pressure target is < 130/80 mm Hg.
• If a patient’s blood pressure is higher than goal, see the Blood Pressure Guideline for
management recommendations.

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Dietary Supplements
Calcium and vitamin D
• If a patient is taking a calcium supplement for the prevention of osteoporosis, recommend that it
be taken in combination with vitamin D and that its dose not exceed 1,200 mg per day.
• There is some evidence that calcium supplementation may be associated with increased risk of
cardiovascular events, particularly myocardial infarction. The co-administration of vitamin D with
the calcium supplement may weaken the observed adverse effects of calcium supplementation.
• The literature indicates that intake of calcium from whole foods is not associated with an
increased ASCVD risk.

Dietary supplements that are not recommended

• Multivitamins: There is evidence that daily intake of a multivitamin does not reduce major
cardiovascular events, MI, stroke, or ASCVD mortality.
• Folic acid, vitamin B12, and vitamin E: There is evidence of no benefit and/or possible harm with
the use of these supplements/vitamins in the primary prevention of ASCVD.
• Beta-carotene: There is good evidence that supplemental doses of beta-carotene do not improve
cardiovascular outcome and that they may be associated with increased cardiovascular deaths
and overall mortality.
• Vitamin C: There is evidence that vitamin C supplementation has no benefit in the primary
prevention of ASCVD.
• Fish oil: There is some evidence that fish oil supplementation has no significant benefit in
reducing cardiovascular events or mortality among individuals with no history of ASCVD.

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Statin Therapy
Table 3. Overview of statin therapy recommendations for primary prevention of ASCVD

Population Statin therapy

ASCVD risk 5–7.4% over 10 years Use shared decision-making. Consider treatment with
a moderate-intensity statin.
ASCVD risk 7.5–14.9% over 10 years Use shared decision-making. Consider treatment with
a moderate- to high-intensity statin.
ASCVD risk ≥ 15% over 10 years Initiate or continue moderate- to high-intensity statin.
People with diabetes, aged 40–75, with Initiate or continue moderate-intensity statin. Consider
ASCVD risk ≥ 7.5% over 10 years use of a high-intensity statin.
People with diabetes, aged 40–75, with Initiate or continue moderate-intensity statin.
LDL cholesterol 70–189 mg/dL
LDL cholesterol ≥ 190 mg/dL Initiate or continue high-intensity statin.

Recommended statin dosing

Most patients who are taking statins for primary prevention of ASCVD should be initiated on moderate-intensity
statins, defined as those lowering LDL cholesterol by an average of 30–49%. See Table 4.

Only patients with questionable ability to tolerate moderate-intensity statins—the frail/elderly, those taking
interacting drugs, and those with hepatic/renal impairment or untreated hypothyroidism—should be
initiated on reduced doses, as given in Table 5.

Table 4. STANDARD (moderate-intensity) statin dosing for primary prevention of ASCVD

Standard dosing applies to patients for whom there are no concerns about their ability to tolerate
moderate-intensity statin therapy.
Line Medication Initial dose Maximum dose
1st Atorvastatin 20 mg daily 80 mg daily
Rosuvastatin 5–10 mg daily 40 mg daily
2nd Simvastatin 40 mg daily at bedtime 40 mg 1 daily at bedtime
1 For patients already on simvastatin 80 mg daily, it is acceptable to maintain the dose if they have been
taking the drug for 12 months or longer, are not taking interacting medications, are at LDL goal, and are
without myopathy.

Table 5. REDUCED (low-intensity) statin dosing for primary prevention of ASCVD

Reduced dosing applies only to patients with questionable ability to tolerate moderate-intensity
statin therapy, including those who are elderly/frail, have hepatic/renal impairment or untreated
hypothyroidism, or are taking interacting drugs.
Line Medication Initial dose Maximum dose
1st Atorvastatin 10 mg daily 80 mg daily
Rosuvastatin 2.5–5 mg daily 40 mg daily
2nd Simvastatin 10–20 mg daily at 40 mg daily at
bedtime bedtime
3rd Pravastatin 1 (Alternative in cases of 20–40 mg daily at 80 mg daily at
drug interactions or side effects) bedtime bedtime
1 Pravastatin has about half the potency of simvastatin; however, it is less likely to interact with other
medications, particularly medications that are strong CYP3A4 inhibitors.

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Cholesterol and lipid goals
LDL levels

LDL goal < 100 mg/dL

Generally, LDL is 1measured only as follow-up for patients on statin therapy to assess response and
adjust dose if needed. The LDL goals listed above may not fit all patients. An alternative goal is a 30–40%
reduction from the previous LDL measure.

HDL levels
All patients on statins: no specific HDL target for therapy
A low HDL level is an independent risk factor for ASCVD, but there is no evidence to date that increasing
HDL levels reduces cardiovascular risk. Encourage patients to increase HDL levels through lifestyle
measures (e.g., increased physical activity, weight loss if overweight, and tobacco cessation).
Medications generally are not recommended.

Triglycerides and pancreatitis

All patients on statins: triglyceride target < 500 mg/dL
Evidence has shown, at most, a weak association between elevated triglycerides (TGs) and health
outcomes. Neither the threshold nor the target of therapy is known. Although there is no direct evidence,
there is consensus that TG levels of 500 mg/dL or greater warrant treatment to prevent pancreatitis. (See
Lowering Triglycerides to Prevent Pancreatitis section on page 12.) Treatment/investigation at > 1,000
mg/dL would also be reasonable; use shared decision making.

Follow-up for patients on statins

Statin therapy should be adjusted if patients are not meeting the LDL goals above. For patients on at
least moderate-intensity therapy who are above the LDL goal, consider increasing to high-intensity statin
therapy (defined as lowering LDL cholesterol by an average of ≥ 50%). On the other hand, if a patient has
achieved a very low LDL level, do not lower the intensity of statin therapy. Expert opinion is that no LDL
level is too low.

Use clinical judgment before escalating doses or changing or adding medications.

If the statin is not working (patient is not achieving LDL goal)

1. First, assess adherence to therapy. Patients often are not taking their medication regularly.
Approximately half of patients who start on statin drugs stop them on their own within 1 year.
2. If they are taking their medication regularly, consider increasing dose (if not already at maximum).
3. If the statin is still not working, use shared decision-making to decide whether to consider
switching to another statin. Consider an E-Consult with Cardiology, where available.
4. Consider adding ezetimibe 10 mg for patients who are not able to achieve an LDL < 100 mg/dL
on maximally tolerated doses of formulary statins and meet at least one of the following criteria:
o 10-year ASCVD risk ≥ 7.5% based on Pooled Cohort Equation, or
o Patient aged 40 or older with diabetes, or
o Any patient with LDL ≥ 190 mg/dL

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If the patient appears intolerant to statins
1. First, consider decreasing the dose.
2. If the patient is still intolerant, use shared decision-making to decide whether to consider
switching to another statin. Consider an E-Consult with Cardiology or Clinical Pharmacy, where
available.
3. To determine if myalgia symptoms can be attributed to use of the statin, consider using the
American College of Cardiology’s statin intolerance tool.

If the patient is still intolerant or has contraindications to statins

• For patients who are not able to achieve an LDL < 100 mg/dL and meet at least one of the
following criteria, stop the statin and consider prescribing ezetimibe:
o 10-year ASCVD risk ≥ 7.5% based on Pooled Cohort Equation, or
o Patient aged 40 or older with diabetes, or
o Any patient with LDL ≥ 190 mg/dL

What is statin intolerance?

The National Lipid Association (Guyton 2014) defines statin treatment intolerance as
…a clinical syndrome characterized by the inability to tolerate at least 2 statins: one
statin at the lowest starting daily dose AND another statin at any daily dose, due to
either objectionable symptoms (real or perceived) or abnormal lab determinations,
which are temporally related to statin treatment and reversible upon statin
discontinuation, but reproducible by re-challenge with other known determinants
being excluded (such as hypothyroidism, interacting drugs, concurrent illnesses,
significant changes in physical activity or exercise, and underlying muscle disease).
Specifically, the lowest starting statin daily dose, is defined as rosuvastatin 5 mg,
atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg, pravastatin 40 mg,
fluvastatin 40 mg, and pitavastatin 2 mg.

Shared decision-making for statin therapy

To help providers discuss the risks and benefits of taking statins for primary prevention of ASCVD, Kaiser
Permanente has developed a shared decision-making (SDM) tool that calculates ASCVD risk using pre-
populated data from KP HealthConnect. This tool is available in any KP HealthConnect encounter and
can also be accessed at https://clm.kp.org/pkc/national/cmi/programs/dyslipidemia/cadrisk/index.html.

NOTE: The SDM tool also provides recommendations on aspirin, which are based on 2018 ACC/AHA
guidance. However, these aspirin recommendations should be interpreted with caution as we
no longer recommend routine use of low-dose aspirin for primary prevention based on new evidence
showing that the increased risk of major bleeding outweighs the small benefit in risk reduction. See
the Antiplatelet Therapy section (page 11) for more information.

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ASCVD risks can also be displayed in a format that shows patients how much their risks would do down if
they added interventions such as taking a statin or aspirin or quitting smoking:

Risks of statin therapy

For patients who are concerned about the risks of statins, the following evidence summary on potential
harms of statin therapy may be helpful.

• Cognitive impairment: Per the U.S. Food and Drug Administration (FDA), rare post-marketing
reports of cognitive impairment (e.g., memory loss/impairment, forgetfulness, amnesia, confusion)
have been reported with statin use, with time to onset ranging from 1 day to years after starting statin
therapy (USFDA 2012). The incidence of cognitive-related adverse events reported to the FDA for
statins (1.9 per 1 million prescriptions) was similar to those reported for losartan (1.6 per 1 million
prescriptions) and clopidogrel (1.9 per 1 million prescriptions) (Richardson 2013). If cognitive
10
 impairment occurs, discontinue the statin (median time to symptom resolution was 3 weeks upon
statin discontinuation).

• Diabetes risk: The FDA added warnings to all statins (except pravastatin) that statin use can
increase HbA1c and fasting serum glucose levels. The absolute excess risk of new-onset diabetes is
very low, approximately 0.1% per year (number needed to harm [NNH] 255 over 4 years; Sattar
2010). The FDA (2012) also analyzed this data, and stated that the cardiovascular benefits of statins
in clinically appropriate patients outweigh this risk. Therefore, statin treatment alone does not
constitute an indication to screen for diabetes, but screening should still be considered if other risk
factors for diabetes exist.

• Myalgias/musculoskeletal injuries/decreased benefits of exercise: In a meta-analysis of 55

placebo-controlled RCTs (N=43,531), there was no significant increase in myalgia with statins
compared with control (Naci 2013), whereas observational studies have reported myalgia incidence
varying from 1 to 25% (Sathasivam 2012, Parker 2013). Keep in mind, however, that many of the
RCTs had a “run-in” period of 30 days, when patients who were intolerant of the statins were
excluded from the study. A retrospective, propensity-matched cohort study (N=13,934) reported a
0.6% per-year risk of dislocation/strain/sprain with statin use (NNH 38 over 4.7 years; Mansi 2013).
Other small RCTs have reported conflicting results of whether statin use decreases muscle strength
or exercise capacity (Parker 2013, Mikus 2013).

• Rhabdomyolysis: Very rare. A large (N=473,343) observational cohort study reported that for
commercially available statins, rates of hospitalized rhabdomyolysis events were approximately 0.3–
1.6 per 10,000 person-years of statin use (NNH 6,250–33,334 per year) (Cziraky 2013).

• Acute kidney injury (AKI): Rare. A large (N=2,067,639) retrospective observational analysis
reported that in non-CKD patients on low-dose statins, hospitalizations for acute kidney injury at 6
months ranged from 1.0 to 3.5 per 1,000 patients in those younger than 65 years and 3.1 to 4.0 per
1,000 patients in those aged 65 years and older (Dormuth 2013). Non-CKD patients on high-potency
statins versus low-potency statins were 34% more likely to be hospitalized for acute kidney injury, but
incidence remained rare, with NNH 1,700 over 120 days.

• Hepatotoxicity: Per the FDA, statins have a very low risk of serious liver injury (reported at a rate of
≤ 2 per 1 million person-years), and routine liver function monitoring is not recommended, as ALT
monitoring does not appear to detect or prevent serious liver injury (USFDA 2011).

Antiplatelet Therapy
Use of low-dose aspirin for ASCVD primary prevention is no longer routinely recommended and should
be decided on an individual basis. This is because its small benefit in preventing adverse cardiovascular
events such as myocardial infarction and stroke is generally offset by the risk of major bleeding. Based on
current data, it would also be appropriate to discontinue low-dose aspirin in many patients who are
already taking it. However, patients at high risk of ASCVD (10-year risk ≥ 10%), may still benefit from low-
dose aspirin, so shared decision-making is encouraged.

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Patients with Diabetes: ACE Inhibitor or ARB Therapy
ACE inhibitor or ARB therapy should be prescribed for patients with diabetes who have the following risk
factors:
• Hypertension (BP > 140/90 mm Hg) (type 1 or 2), or
• Elevated microalbumin to creatinine ratio (type 2 only), or
• Are aged 55 or older and have additional cardiovascular risk factors (type 2 only).

Table 6. Patients with diabetes and elevated risk: ACE inhibitor or ARB therapy for primary
prevention of ASCVD
Line Medication Initial dose Maximum dose
1st ACE inhibitor
Lisinopril 5–10 mg daily 40 mg daily
or (target dose is 20 mg daily)

Ramipril 2.5–5 mg daily 20 mg daily

(target dose is 10 mg daily)
2nd ARB 1
Losartan 25–50 mg/day in 1–2 doses 100 mg/day in 1–2 doses
1 Use an ARB (losartan) for patients who cannot tolerate an ACE inhibitor because of cough, rash, or
angioedema (rather than because of renal failure, hyperkalemia, or hypotension). In a patient who
previously developed angioedema with an ACE inhibitor, an ARB is less likely to cause angioedema, but
there is still a risk of cross-reactivity. In the CHARM-Alternative study, the ARB group had 2.6% ACE-
ARB cross-reactivity versus 0% in the placebo group (Granger 2003).

Combination therapy is not recommended

ACE inhibitor and ARB combination therapy is not recommended. There is evidence that there is harm
and no additional benefit in combining an ACE inhibitor and an ARB. Numbers needed to harm (NNH) are
33 for hypotensive symptoms, 1,000 for syncope, 250 for diarrhea, and 250 for renal impairment.

Lowering Triglycerides to Prevent Pancreatitis

Triglycerides do not require pharmacologic treatment unless they are higher than 500 mg/dL.
(Treatment/investigation at higher than 1,000 mg/dL would also be reasonable. Use shared decision-
making.) If a patient has elevated triglycerides, consider the following workup:
• HbA1c, TSH, protein/creatinine ratio, and pregnancy test (if applicable).
• Review other items that can cause triglyceride elevations:
o Obesity (review diet).
o Alcohol intake.
o Medications: estrogen replacement, oral contraceptives, tamoxifen, HIV antiretroviral
regimens, beta-blockers (excluding carvedilol), retinoids, and immunosuppressive agents
such as glucocorticoids and cyclosporine.

Consult with Endocrinology if:

• Cause of elevated triglycerides cannot be identified.
• You are not able to get triglyceride level lower than 500 mg/dL with treatment.
• You have any other questions about elevated triglycerides.

Icosapent ethyl
Icosapent ethyl has been approved by the FDA for the treatment of patients with hypertriglyceridemia (not
shown to reduce pancreatitis). The generic omega-3 fatty acids (Lovaza) and over-the-counter
alternatives are also available in this treatment category.
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 Table 7. Medications for lowering triglyceride levels to prevent possible pancreatitis
See also the prescribing notes that follow Table 7.
Medication Initial dose Maximum dose
Start with: Atorvastatin 80 mg daily 80 mg daily
or
Rosuvastatin 20 mg daily 40 mg daily
If TG not < 500 mg/dL: Add
Fenofibrate 54–160 mg daily 160 mg daily
or
Generic omega-3 2,000 mg DHA/EPA 4,000 mg DHA/EPA in
fatty acids in divided doses divided doses daily
(Lovaza) daily
If TG still not < 500 mg/dL: Add
Omega-3 fatty acids or fenofibrate per agent chosen in previous
step
or
Gemfibrozil 600 mg twice daily 600 mg twice daily
monotherapy

Prescribing notes for Table 7

Atorvastatin and rosuvastatin
Use maximum dose of atorvastatin and rosuvastatin with caution in patients at risk for statin intolerance
or adverse effects, such as those who are elderly, have kidney disease (rosuvastatin max dose =
10 mg/day with CrCl < 30 mL/min), have untreated hypothyroidism, or are taking interacting drugs.

Fenofibrate
• In patients with CKD 3 (CrCl 30–59 mL/min), do not exceed fenofibrate 54 mg per day.
• Do not use in patients with CKD 4–5.

Omega-3 fatty acids

• Use is associated with increased risk of significant bleeding and risk of atrial fibrillation/flutter
requiring hospitalization.
• Use cautiously in patients with fish allergy.

Gemfibrozil
• Gemfibrozil is contraindicated with statin therapy due to an increased risk for muscle symptoms
and rhabdomyolysis. Use caution in patients with mild to moderate renal impairment (CKD 2–3).
• Do not use in patients with severe renal impairment (serum creatinine greater than 2 mg/dL or
CKD 4–5).

13
Medication Monitoring
Table 8. Medication monitoring
Eligible population Tests Frequency of lab testing
Patients on statin Non-fasting 4–6 weeks after initiating therapy
lipoprotein panel
Patients on ACE Potassium At baseline
inhibitor or ARB and and
Creatinine 2 weeks after initiating therapy
and
With each dose increase
and
Annually
Patients on Creatinine
fenofibrate therapy At baseline
and
3 months after initiating therapy
and and
Every 6 months
ALT/AST
(Only for patients on At baseline
combo therapy with a and
statin) 4–6 weeks after initiating therapy
and
Annually

Medication monitoring that is not recommended

ALT/AST
For patients on statin monotherapy, routine baseline and periodic ALT or AST monitoring are not
recommended. Liver function tests are recommended only if clinically indicated to work up symptoms of
liver disease. Asymptomatic transaminase elevations with statin use are common but usually mild,
transient, and reversible. They do not indicate liver dysfunction. Progression to liver toxicity is exceedingly
rare and is likely due to idiosyncratic or immunoallergic reactions. The presence of chronic liver disease
other than cirrhosis is not a contraindication for statin use. However, consultation with Gastroenterology
first is recommended.

Creatine kinase (CK)

Routine CKs are not helpful and often are misleading. Check creatine kinase only if patient has symptoms
of myopathy, an extremely rare side effect.

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Evidence Summary
The Primary Prevention of ASCVD Guideline was developed using an evidence-based process,
including systematic literature search, critical appraisal, and evidence synthesis.

As part of our improvement process, the Kaiser Permanente Washington guideline team is working
towards updating our clinical guidelines every 2–3 years. To achieve this goal, we are adapting
evidence-based recommendations from high-quality external guidelines, if available and appropriate.
The external guidelines must meet several quality standards to be considered for adaptation. They
must: be developed by a multidisciplinary team with no or minimal conflicts of interest; be evidence-
based; address a population that is reasonably similar to the KPWA population; and be transparent
about the frequency of updates and the date the current version was completed.

In addition to identifying the recently published guidelines that meet the above standards, a literature
search was conducted to identify studies relevant to the key questions that are not addressed by the
external guidelines.

External guidelines meeting KPWA criteria for adaptation/adoption

2020 American Diabetes Association. Cardiovascular Disease and Risk Management: Standards of
Medical Care in Diabetes—2020. Diabetes Care. 2020;43(Suppl 1):S111-S134. doi:10.2337/dc20-S010
2020 National KP Clinical Practice Guidelines: Cholesterol and Cardiovascular Risk.
2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A
Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice
Guidelines. J Am Coll Cardiol. 2019;74(10):1376-1414. doi:10.1016/j.jacc.2019.03.009
2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce
cardiovascular risk. Eur Heart J. 2020;41(1):111-188. doi:10.1093/eurheartj/ehz455
2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration
with the EASD. Eur Heart J. 2020;41(2):255-323. doi:10.1093/eurheartj/ehz486
2018 U.S. Preventive Services Task Force. Risk Assessment for Cardiovascular Disease With
Nontraditional Risk Factors: US Preventive Services Task Force Recommendation Statement. JAMA.
2018;320(3):272-280. doi:10.1001/jama.2018.8359

Key questions addressed in the KPWA guideline

Key question 1
Coronary artery calcium (CAC) score
a) Is there an association between CAC and major cardiovascular events in asymptomatic individuals
with no history of ASCVD?
b) Is the CAC score an independent predictor of ASCVD events in asymptomatic individuals?
c) Does CAC scoring add an incremental predictive value to the traditional risk factors/calculators
currently used for risk stratification of adult asymptomatic patients with no known history of ASCVD?
d) Does CAC scoring have clinical utility in asymptomatic individuals at intermediate risk of ASCVD? In
other words, does the measurement of CAC in addition to the traditional risk factors guide the long-
term use of statin therapy and improve the clinical outcome in asymptomatic adults at intermediate
CV risk?

• There is moderate-quality evidence from large longitudinal long-term population studies, mainly
the landmark MESA (Budoff 2018), indicating that CAC may be strongly associated in a graded
fashion with 10-year risk of incident ASCVD (including stroke) in asymptomatic White, Black,
Hispanic and Chinese American men and women aged 45–84 with no known history of CHD.
MESA showed that 10-year event rates in participants with CAC = 0 were almost exclusively
below 5%, while these rates were consistently above 7.5% in participants with CAC ≥ 100.
• Moderate-quality evidence from large longitudinal long-term population studies shows that CAC
may be independently associated with ASCVD risk in asymptomatic individuals with no known
history of ASCVD (Hoffmann 2016, Lehman 2018, Mitchell 2018, Shaw 2015).
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 • Large longitudinal long-term population studies (Hoffmann 2016, Yeboah 2016) show that CAC
scoring provides additional predictive information on ASCVD events and mortality, beyond the
traditional risk factors, in men and women of different age groups, races, ethnic backgrounds, and
risk levels, and in the presence or absence of comorbid conditions such as diabetes mellitus.
• The inclusion of CAC in the MESA risk score (McClelland 2015) was found to significantly
improve the risk prediction of CAD (C-statistics 0.80 vs. 0.75, p < 0.0001).
• There is insufficient published evidence from published RCTs to determine that treatment guided
by CAC scoring levels in addition to the traditional risk factors improves the clinical management
and/or clinical outcomes in asymptomatic adults at intermediate CV risk.

It should be noted that all data were obtained from observational population-based studies, which have
inherent limitations, including relying on data recorded in registries and databases; baseline CAC
measurement and assessment were done using earlier technology; and major developments were seen
over time in lifestyle, statin use, antihypertensive drugs, antiplatelet and other therapies as well as in the
technology and equipment used to measure and assess the CAC.

Key question 2
Does the benefit of using aspirin for the prevention of CVD events in adult patients with diabetes
outweigh its harms?

• Based on recent guidelines and meta-analyses (including Barbarawi 2019, Christiansen 2019,
and Zheng 2019) and randomized controlled trials, aspirin may be used for CVD prevention in
patients who are at high risk for CV events. Diabetic patients with 10-year CVD risk ≥ 10% will
benefit the most from aspirin therapy. For diabetic patients who are at intermediate or low risk for
CVD, aspirin therapy showed a slight benefit, but at a higher risk of bleeding (Seidu 2019, Khan
2019). According to the published guidelines, low-dose aspirin should not be given on a routine
basis to prevent ASCVD among adults once they reach age 70, and it should not be considered
for any adult with increased bleeding risk.
• The ASCEND trial (ASCEND Study Collaborative Group 2018), which examined the efficacy and
safety of enteric coated aspirin in diabetic patients without known CVD, showed that the number
of patients needed to treat to avoid a major CVD event (NNT) was 91 in an average of 7 years,
while the corresponding number of major bleeding incidents (NNH) was 111; i.e., the observed
reduction in CVD events may be offset by the risk of major bleeding.
• It is thus suggested that aspirin should not be used on a routine basis in the primary prevention of
cardiovascular events, especially in individuals with diabetes. and that individual assessment of
diabetic patients for CV risk should be considered before initiation of aspirin therapy.
• Shared decision-making is needed and should consider the patient’s age, bleeding history and
risk, cardiovascular risk factors, quality of life, preferences, and willingness to undergo long‐term
aspirin therapy.
• In cases where aspirin is to be used for primary prevention, it is recommended to be given at the
lowest dose possible (75–100 mg). The ESC guideline recommends uncoated aspirin with co-
administration of a proton-pump inhibitor for patients at high risk for bleeding.

Key question 3
Are the harms and benefits of aspirin use similar among patients with type 1 and type 2 diabetes?

• There is no standardized method for measuring aspirin responsiveness/resistance.

• Rates of aspirin resistance may vary widely based on the method used to assess platelet function
and have been reported to range from 5% to 40%.
• There is weak evidence indicating no significant difference between type 1 and type 2 diabetes in
their responsiveness to aspirin therapy.
• There is insufficient evidence to determine whether there are any differences between type 1and
type 2 diabetes patients as regards the safety and efficacy of aspirin in the primary prevention of
ASVCD or the harms associated with the use of aspirin.
• All national guideline recommendations on the use of aspirin therapy for reducing the risk of
ASCVD in diabetics do not differentiate between patients with type 1 and type 2 diabetes.

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 • The published studies evaluating the efficacy and safety of aspirin use for the primary prevention
of ASCVD in diabetics included patients with diabetes without distinction between types. No sub-
analyses were performed to determine whether there were any differences between type 1 and
type 2 diabetes patients in the observed benefits and harms associated with the use of aspirin.

Key question 4
Is there published evidence to support annual or more frequent lipid monitoring of patients
receiving statin with or without other lipid-lowering therapies (ezetimibe and PSCk9-I)?

• The literature search did not identify any published studies that would provide evidence on the
optimal frequency of monitoring patients receiving any lipid-lowering therapy.

Key question 5
Does the use of SGLT2 drugs reduce cardiovascular risk and/or events in patients without a
history of type 2 diabetes?

• The literature search identified a large number of randomized controlled trials and meta-analyses
of RCTs evaluating the safety and efficacy of SGLT2 inhibitors for reducing HbA1c levels in
patients with diabetes mellitus.
• However, the search did not reveal any published trials to date that examined the use of this
class of medications in individuals without diabetes but with established ASCVD or risk factors for
the disease. While recent trials have shown a benefit in patients with heart failure, guidance and
management have not yet been established for SGLT2 inhibitors, and they should not be used
routinely at this point.
• There is strong evidence from three major cardiovascular outcomes trials with valid
methodology—EMPA-REG OUTCOME with empagliflozin (Zinman 2015), the CANVAS program
with canagliflozin (Neal 2017), and DECLARE-TIMI 58 with dapagliflozin (Wiviott 2018)—as well
as from the CREDENCE renal outcome trial (Perkovic 2019) and meta-analyses pooling their
results (Zelniker 2019, Zou 2019, Arnott 2020) that SGLT2 inhibitors could have an overall
cardioprotective benefit, particularly for heart failure, in patients with DM.
• The moderate benefit observed with SGLT2 inhibitors on atherosclerotic major adverse
cardiovascular events was only significant in patients with established ASCVD, but not among
those with risk factors and no ASCVD at baseline.
• There was a significant reduction in hospitalization for heart failure and progression of renal
disease with the use of SGLT2 versus placebo regardless of existing ASCVD or a history of heart
failure.
• Overall, the analyses of the individual studies and their pooled results suggest that patients with
established CVD may gain greater benefits from SGLT2 inhibitor therapy than those at lower risk.
• SGLT2 is associated with increased rates of diabetic ketoacidosis.
• CANVAS found that canagliflozin was associated with significant increases in the risks of
amputations or fractures compared with controls, but no such findings have been reported in trials
with other SGLT2 inhibitors.
• The major published trials reviewed were at low risk of bias, but there were some differences
between the treatment groups with regard to the concomitant medication used and HbA1c
control.
• All participants in the EMPA-REG OUTCOME trial had an established CVD at enrollment,
compared to two thirds in the CANVAS program, and 40% of those enrolled in the DECLARE-
TIMI 58 study. The latter more closely resemble those seen in routine clinical practice.

Key question 6
What is the incremental benefit of using the triglyceride-lowering drug (icosapent ethyl) on
cardiovascular outcomes beyond the optimal reduction of low-density lipoprotein cholesterol?

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A recently published trial (Reduction of Cardiovascular Events with EPA-Intervention Trial [REDUCE-IT]
[Bhatt 2019]) showed that in patients with established atherosclerotic heart disease, or diabetes and an
additional risk factor, on statin therapy and with residual hypertriglyceridemia (fasting triglyceride level
135–499 mg/dL), icosapent ethyl was associated with an absolute 4.8% reduction in cardiovascular
events (cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable
angina), NNT = 21 (95% CI, 15–23) in 4.9 years (with a 0.9% absolute reduction in cardiovascular death,
NNT = 111 in 4 years).

The results of the trial conflict with other RCTs that examined the effect of omega-3 fatty acids on CV
outcomes and showed negative results. The JELIS trial (reviewed for the previous update of the
guideline, showed a 19% relative risk reduction in cardiovascular events when 1.8 g daily of
eicosapentaenoic acid (EPA) was added to low-intensity statin therapy. JELIS was limited by an open-
label design, lack of placebo control, and geographic limitation to patients in Japan. The REDUCE-IT trial,
on the other hand, used a higher dose of purified EPA formulation in selected patients and was controlled
and double-blinded. However, the mechanism of action responsible for the observed benefit of icosapent
ethyl is not known and is currently being investigated.

The REDUCE-IT trial was a multicenter, double-blinded, large RCT with sufficient power and ITT analysis.
However, it had limitations, including but not limited to the following:
• The placebo used contained mineral oil which, as reported by some investigators, may reduce
the absorption of statins leading to the increase in LDL-C and C-reactive protein levels, which
may potentially magnify the effect of icosapent ethyl.
• The trial was initiated in 2011 when there were insufficient data to recommend ezetimibe and
PCSK9 was not available.
• The protocol was amended twice during the study (changing the lower limit of TG level and
amending the secondary end point).
• The trial was sponsored by Amarin Pharma, which was involved in the development of the
protocol, collection, management and analysis, and interpretation of the data.
• In addition to the unknown mechanism for the benefit observed with icosapent ethyl, the
REDUCE-IT trial leaves other questions unanswered, including:
o Would the benefit of icosapent ethyl be significant in primary prevention individuals, who
constituted only 30% of the study population?
o Would the benefit of icosapent ethyl persist in patients receiving ezetimibe and PCSK9
drugs on top of baseline statin therapy?

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Barbarawi M, Kheiri B, Zayed Y, et al. Aspirin Efficacy in Primary Prevention: A Meta-analysis of Randomized
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Guideline Development Process and Team
Development process
The guideline team developed the ASCVD Primary Prevention Guideline using an evidence-based
process, including systematic literature search, critical appraisal, and evidence synthesis. For details, see
Evidence Summary and References.

This edition of the guideline was approved for publication by the Guideline Oversight Group in
October 2020.

Team
The ASCVD Primary Prevention Guideline team included representatives from the following specialties:
cardiology, clinical laboratory, endocrinology, family medicine, internal medicine, and pharmacy.

Clinician lead: Dave McCulloch, MD, Medical Director, Clinical Improvement

Guideline coordinator: Avra Cohen, MN, RN, Clinical Improvement & Prevention

Peter Barkett, MD, Internal Medicine

Robin Brusen, MD, Cardiology
Sari (Lisa) Davison, MD, Primary Care
Melissa Hull, PharmD, Clinical Pharmacist
Anneliese Johnson, MD, General Internal Medicine
Megan Kavanagh, Patient Engagement Team, Clinical Improvement & Prevention
John Polnak, PharmD, Clinical Pharmacist
Nadia Salama, MD, MPH, PhD, Epidemiologist, Clinical Improvement & Prevention
Tina Shah, MD, Cardiology
Ann Stedronsky, Clinical Publications, Clinical Improvement & Prevention
Brad Volk, MD, Family Medicine
Avantika Waring, MD, Endocrinology

Disclosure of conflict of interest

Kaiser Permanente requires that team members participating on a guideline team disclose and resolve all
potential conflicts of interest that arise from financial relationships between a guideline team member or
guideline team member's spouse or partner and any commercial interests or proprietary entity that
provides or produces health care–related products and/or services relevant to the content of the
guideline.

Team members listed above have disclosed that their participation on the ASCVD Primary Prevention
Guideline team includes no promotion of any commercial products or services, and that they have no
relationships with commercial entities to report.

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