Primary Prevention- No Diabetes and LDL-C <190 mg/dL

Introduction

Based on strong evidence from primary prevention trials in patients that were free of atherosclerotic cardiovascular disease (ASCVD), the 2018 multi-society (including American College of Cardiology and American Heart Association (ACC/AHA)) cholesterol guideline includes a fourth statin benefit group that includes primary prevention individuals without diabetes aged 40-75 years and an low-density lipoprotein cholesterol (LDL-C) level of 70-189 mg/dL. This group is further subdivided based on 10-year ASCVD risk into four sub-groups: “low risk” (10-year ASCVD risk <5%), “borderline risk” (10-year ASCVD risk ≥5% to <7.5%), “intermediate risk” (10-year ASCVD risk ≥7.5% to <20%) and “high risk” (10-year ASCVD risk ≥20%). Either moderate- or high-intensity statin therapy is appropriate for intermediate and high risk patients. Moderate evidence from primary prevention trials also supports the use of statins in individuals with borderline risk.

The current (2018) multi-society and the prior (2013) ACC/AHA cholesterol guidelines better identify high-risk patients for statin therapy than the earlier National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guideline. Even lower-risk patients may also benefit from statin therapy. Although the margin of individual benefit may be smaller in lower-risk persons, lower-risk persons comprise the majority of the population and the majority of ASCVD events occur in low-risk persons. In addition, the relative reduction in cardiovascular (CV) risk from statins is greater in low-risk than in high-risk persons. Thus, an even larger burden of ASCVD events would be prevented if statins were more widely utilized in lower-risk persons.

Risk assessment for initiation of statin therapy for primary prevention when LDL-C is <190 mg/dL should start with risk estimation using the ACC/AHA risk calculator. This tool can estimate 10-year and lifetime ASCVD risk. Several factors may be considered that can indicate ASCVD risk greater than estimated by the traditional risk factors included in the ACC/AHA risk calculator. This information may inform decision-making for statin initiation for the primary prevention of ASCVD. Risk assessment is discussed briefly below and in detail in the next sections, Risk Assessment: Primary Prevention LDL-C <190 mg/dL.

The clinician-patient discussion incorporates shared decision-making, with the decision to initiate statin therapy for primary prevention individualized based on the potential for an ASCVD risk reduction benefit, the potential for adverse events, and patient preferences.

Ideally, healthy lifestyle habits should begin in childhood and be maintained throughout life to minimize the risk of developing cardiovascular disease (CVD).

In adults, risk assessment and control of CV risk factors should begin by age 20 and may include assessment of lifetime risk.

Figure 8-3 provides the 2018 multi-society cholesterol guideline algorithm for risk assessment and initiation of LDL-C-lowering therapy in the primary prevention patient groups.

Clinical Highlight I

• Encourage healthy lifestyle habits and risk factor control for all persons regardless of age.
• Do not estimate risk for persons with clinical ASCVD or LDL-C ≥190 mg/dL for whom statin therapy is mandatory; or in those with advanced heart failure or receiving dialysis for whom there is no recommendation for statin therapy.
• Age 20-39 y: Assess lifetime risk with a focus on improving or maintaining healthy lifestyle habits and consider statin therapy in selected high risk patients.
• Age 40-75 y: Estimate 10-year ASCVD risk every 4-6 y and consider need for statin therapy to reduce ASCVD risk.
• Age 40-75 y, high 10-year ASCVD risk (≥20%): Initiate high-intensity statin therapy to reduce LDL-C by ≥50%.
• Age 40-75 y, intermediate 10-year ASCVD risk (≥7.5% to <20%): Initiate at least a moderate-intensity statin therapy to reduce LDL-C by ≥30%.
• Age 40-75 y, borderline 10-year ASCVD risk (≥5% to <7.5%): Consider moderate-intensity statin therapy, especially if risk enhancers are present.
• Age 40-75 y, low 10-year ASCVD risk (<5%): Prioritize lifestyle-based ASCVD risk management.
• Selected high and intermediate risk primary prevention patients (eg, statin-intolerant patients) may benefit from the addition of nonstatin therapy.

Enlarge 

Risk Assessment

To guide the decision to initiate statin therapy, the 2018 multi-society cholesterol guideline recommends assessment of 10-year ASCVD risk every 4 to 6 years in individuals aged 40-75 years who do not have clinical ASCVD, have an LDL-C <190 mg/dL and are not receiving a statin.

See Risk Assessment: Primary Prevention LDL-C <190 mg/dL for further discussion.

Risk Prediction Equations

The 2018 multi-society cholesterol guideline recommends using the risk prediction equations developed by the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk for estimating 10-year and lifetime ASCVD risk. The Pooled Cohort and lifetime risk equations predict the risk of hard CV events (nonfatal and fatal MI and stroke) in non-Hispanic White and African American men and women. Thus, they represent an advance from earlier Framingham Risk Score equations used in the NCEP ATP III guideline, since these equations were developed from data only in White men and women in the Framingham Study to predict the risk of nonfatal and fatal coronary events.

The calculator can be found at tools.acc.org/ASCVD-Risk-Estimator-Plus/.

Table 13-1 lists the groups of patients in whom 10-year ASCVD risk should be estimated and in whom it should not.

Do not estimate 10-year or lifetime risk in several groups of patients.

• Individuals with clinical ASCVD (secondary prevention): these patients should all be treated with high-intensity or maximally tolerated statin therapy unless contraindications are present.
• LDL-C ≥190 mg/dL: these patients are at high 10-year and lifetime ASCVD risk and should all be treated with high-intensity or maximally tolerated statin therapy unless contraindications are present.
• Advanced heart failure or receiving dialysis: even though these patients are at high risk of CV events and death, statins have failed to reduce ASCVD events in four trials. The 2018 multi-society cholesterol guideline made no recommendations regarding statin therapy in these patient groups. In post hoc analyses of these trials, there may be some patients who could benefit from statin therapy in these groups.
• Individuals ≥80 years of age: risk assessment may be useful for guiding decision-making in individuals 76-79 years of age. However, after age 79, risk prediction equations perform poorly due to high rates of competing non-CV mortality.

Recommendations for risk assessment and management in children are provided in the National Heart, Lung, and Blood Institute (NHLBI) prevention guidelines for children and adolescents.

Enlarge 

Additional Factors That Inform Decision Making

Estimated lifetime ASCVD risk may further inform the decision to initiate primary prevention statin therapy, along with other factors that may indicate increased ASCVD risk, termed “ASCVD risk enhancers” in the 2018 multi-society cholesterol guidelines (examples include persistent LDL-C ≥160 mg/dL, family history of premature ASCVD, chronic kidney disease and others; see Figure 8-3 for a list of risk enhancers and Table 13-2 for a list of risk-increasing conditions from the 2013 ACC/AHA risk assessment guideline). The presence of risk enhancers is a crucial factor in the decision to initiate statin therapy in patients with borderline and intermediate 10-year ASCVD risk.

Enlarge 

Enlarge 

Healthy Lifestyle Habits and Risk Factor Control

All patients should be counseled to adhere to healthy lifestyle habits and control weight. Participants in randomized trials were counseled on healthy lifestyle habits and the ASCVD risk reduction benefit of statins added to this.

ASCVD risk factors should be treated or controlled whenever possible. Identify and control hypertension. Smoking is particularly detrimental. Aggressively work with patients to encourage immediate smoking cessation.

Initiating Statin Therapy: Primary Prevention (No Clinical ASCVD) and No Diabetes and LDL-C < 190 mg/dL

The 2018 multi-society cholesterol guideline based its recommendations for primary prevention on data from three exclusively primary prevention statin trials: JUPITER, AFCAPS/TexCAPS, and MEGA, as well as a consideration of the potential rates of adverse events from statin therapy. The rates of hard ASCVD events in placebo group in each trial were extrapolated to 10 years using standard statistical methods (Table 13-3).

The potential for adverse events includes serious myopathy and rhabdomyolysis, hemorrhagic stroke (both rare events in the Cholesterol Treatment Trialists' (CTT) meta-analyses) and modest excess of type 2 diabetes (T2D), more so for high-intensity than moderate-intensity statin therapy. The potential differential in adverse events for moderate- and high-intensity statins was weighed against the potential for ASCVD risk reduction as can be seen in the comparison of the number-needed-to-treat (NNT) to prevent one ASCVD event versus the number-needed-to-treat to prevent one cardiovascular event (NNT) to cause one adverse event (number needed to harm [NNH]) (Figure 13-1).

These data led to the major recommendations for primary prevention in individuals 40-75 years of age with LDL-C level <190 mg/dL and without diabetes:

• For patients with high 10-year ASCVD risk (≥20%), initiate high-intensity statin therapy to reduce LDL-C level by at least 50% (COR I)
• For patients with intermediate 10-year ASCVD risk (≥7.5% to <20%), initiate moderate-intensity statin therapy to reduce LDL-C level by 30-49% (COR I); the presence of risk enhancers in this group favors intensification of statin therapy (COR IIa)
• For patients with borderline 10-year ASCVD risk (≥5% to <7.5%), moderate-intensity statin therapy may be justified if risk discussion reveals risk enhancers (COR IIb)
• For patients with low 10-year ASCVD risk (<5%), lifestyle should be emphasized to control risk (COR I)

The age range for the recommendations was based on the age range of participants in these trials; for patients 20-39 years of age, the lifetime risk of ASCVD should be estimated and controlled with lifestyle. Statin therapy may be considered in patients 20-39 years of age with family history of premature ASCVD and an LDL-C level ≥160 mg/dL. The trials included patients with a wide range of LDL-C, with the lowest LDL-C of approximately 70 mg/dL included in JUPITER (Figure 13-2) MEGA included some participants with LDL-C ≥190 mg/dL, but this group of patients has already been identified for statin therapy regardless of 10-year ASCVD risk. Individuals with serious comorbidities including heart failure, chronic renal failure, or receiving hemodialysis were excluded from these trials.

Enlarge 

Enlarge 

Enlarge 

Excess Risk of Diabetes With Statins

Subsequent analyses have found that only study participants with diabetes risk factors experienced an excess risk of diabetes on statin therapy. An analysis of JUPITER found that patients treated with rosuvastatin 20 mg who developed diabetes were diagnosed about 6 weeks earlier than those receiving placebo. In the face of a 45% reduction in the relative risk of ASCVD events in the rosuvastatin group, this minimal additional duration of diabetes is of no clinical significance. Therefore, the net benefit of high-intensity statins may be greater than previously appreciated.

Treating Lower-Risk Patients Beneficial

The borderline and intermediate 10-year ASCVD risk groups are defined by risk ranges lower than in the earlier NCEP ATP III guideline, which defined 10-20% 10-year coronary artery disease (CAD) risk as intermediate risk and ≥20% 10-year CAD risk as high risk. However, a 2012 CTT meta-analysis evaluating low-risk participants in the statin trials found that the relative risk reduction was about 2-fold higher in patients with <10% 5-year major CVD risk (which includes coronary revascularization) than in those with ≥10% risk (Figure 13-3). Moreover, a significant 10% reduction in total mortality was observed in patients with <10% risk.

The recommendation to initiate statin therapy for primary prevention rests on the concept of the potential for net benefit. Without inclusion of diabetes, the NNH of 1000 over 10 years (Figure 13-1), suggests that almost all patients will experience a net benefit from statin therapy.

A cost-benefit analysis of statin therapy in specific 10-year ASCVD risk groups found that treating individuals with ≥7.5% 10-year ASCVD risk (48% of US adults) with at least a moderate-intensity generic statin to be very cost effective ($37,000 per quality adjusted life year [QALY]) compared to treating only those with ≥10% risk. A more lenient threshold of ≥4% 10-year ASCVD risk (61% of US adults) would cost $81,000 per QALY and ≥3% 10-year ASCVD risk (67% of US adults) would save an additional 161,560 ASCVD events and cost $140,000 per QALY, still below the current threshold of $150,000 for cost-effective therapy.

Taken together, these findings should largely overcome resistance to treating lower risk patients with generic statin therapy.

Enlarge 

Enlarge 

Clinician-Patient Discussion

Shared decision-making was first incorporated into ASCVD prevention decision-making in the 2013 ACC/AHA cholesterol guideline and this paradigm was retained in the 2018 multi-society guideline. The clinician-patient discussion should include consideration of the potential for a net benefit from statin therapy and elicit the preferences of the informed patient. Shared decision-making may improve long-term adherence to preventive therapies. Decision tools are not yet available to aid estimation of net benefit but hopefully will be developed in the future as data become available for safety based on individual patient characteristics.

• Potential for ASCVD risk reduction: the potential for an ASCVD risk reduction benefit is based on the absolute ASCVD risk of the patient (based on 10-year ASCVD risk and other factors that may increase ASCVD risk) and the relative risk reduction obtained from the intensity of statin therapy selected (moderate intensity about 30%-35% and high intensity about 45%).
• Potential for adverse effects: individualized estimation of the potential for adverse events is not currently available, but in general can probably be confined to the potential for serious myopathy or hemorrhagic stroke for most patients. The excess risk of diabetes does not appear to have the potential for harm. Some patients may be taking drugs that interfere with statin metabolism or increase the risk of myopathy when used with statins. A statin that has minimal or no drug interactions can usually be selected.
• Patient preferences: patient preferences should be elicited after a discussion of the potential for net benefit from statin therapy. About 70% of patients prefer an active role in decision-making. Patients place a range of values on the burden of taking a daily pill for prevention and the risk of experiencing an adverse effect from therapy. Clinicians should provide a supportive environment for patient questions and offer opportunities for participation in decision-making.
• System support: reimbursement frameworks are needed to support shared decision-making. A healthcare team approach and out-of-office support may be helpful as well.

Nonstatin Therapy ≥20% 10-Year ASCVD Risk

Primary prevention patients with >20% 10-year ASCVD risk can be considered equivalent to those with diabetes or lower-risk patients with clinical ASCVD. They should be managed similarly to those patient groups. The 2018 multi-society cholesterol guideline recommends (COR I) initiating statin therapy to reduce LDL-C by at least 50%. The 2022 ACC Expert Consensus Decision Pathway on nonstatin use agrees with this assessment, and adds that ezetimibe may be reasonable in patients who do not achieve ≥50% LDL-C reduction and whose LDL-C levels remain ≥70 mg/dL.

< 20% 10-Year ASCVD Risk

Primary prevention patients with <20% 10-year ASCVD risk are likely to experience substantial ASCVD risk reduction with high-intensity statin therapy and significant risk reductions from moderate-intensity statin therapy. Nonstatin therapy is a low priority for these patients given the potential for statin-based ASCVD risk reduction benefit in lower-risk patients (see NNT discussion in Nonstatins: Evolving Role in ASCVD Prevention), expense/cost, and potential for jeopardizing adherence to statin therapy. Exceptions may include those with a <50% LDL-C reduction on statin therapy or patients with LDL-C ≥130 mg/dL on maximally tolerated statin intensity. The 2018 multi-society cholesterol guidelines state that ezetimibe or a bile acid sequestrant may be reasonable (COR IIb) in intermediate risk patients who would benefit from more aggressive LDL-C lowering but who cannot tolerate or have contraindications to high-intensity statins.