Population Subgroups: Women, Age & >75 Years, Race, and Ethnicity

Introduction

Atherosclerotic cardiovascular disease (ASCVD) risk factors increase the risk of ASCVD for men and women, younger and older adults and across races and ethnicities. However, incidence rates for coronary artery disease (CAD) and stroke vary by race and sex. ASCVD events occur at younger ages in African American men, White men and African American women than in White women. A greater proportion of stroke events occur in African Americans and White women. For this reason, the 2018 multi-society cholesterol guideline recommended using the American College of Cardiology and American Heart Association (ACC/AHA) Pooled Cohort Equations for estimating ASCVD risk. These equations were developed to predict the risk of nonfatal and fatal MI and stroke for White and African American women and men in the United States.

The 2018 multi-society cholesterol guideline derived the primary prevention risk groups for consideration of statin therapy from the ASCVD rates observed in the placebo groups of primary prevention trials. The most accurate estimate of 10-year ASCVD risk should be used to guide initiation of statin therapy for primary prevention in women and non-White patient subgroups.

Women

ASCVD is the leading cause of death in women. Fewer women participated in the secondary and primary prevention statin trials, but it appears women with clinical ASCVD experience similar relative reductions in ASCVD risk as men (Figure 16-1).

Women without clinical ASCVD also experience a substantial reduction in ASCVD risk from statins. Given the smaller number of women enrolled in primary prevention trials, it is difficult to determine whether the magnitude of CV risk reduction is the same as for men. In primary and secondary prevention combined, women and men experience about a 10% reduction in total mortality.

The statin adverse event rate, including the modest excess risk of diabetes in individuals at risk for diabetes, appears to be similar in women as men in randomized trials. While the 2018 multi-society cholesterol guideline did not make sex-specific treatment recommendations, focusing largely on the presence of ASCVD or on the level of ASCVD risk to guide treatment, it did make several specific recommendations for issues specifically related to women (see the subsections below).

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Initiating Statin Therapy

Membership in a statin benefit group should drive the decision to initiate statin therapy in women: clinical ASCVD, low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL, diabetes ages 40-75, or 10-year ASCVD risk ≥7.5%. Lower risk women may also benefit from statin therapy depending on other risk characteristics, such as LDL-C ≥160 mg/ dL, family history of premature ASCVD, or coronary artery calcium (CAC) >75% percentile for age (see Cardiovascular Disease Prevention for further discussion).

Some data suggest women who experience early-onset menopause or pregnancy complications such as gestational diabetes, pre-eclampsia, eclampsia, or small for gestational age infants may be at increased risk of ASCVD later in life. Women with autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis, HIV infection, organ transplantation, or cancer survivors also appear to be at increased ASCVD risk. Whether these factors independently add to risk prediction using the Pooled Cohort Equations has not yet been determined. However, consideration of these factors should inform the clinician-patient discussion when considering initiating statin therapy; the 2018 multi-society cholesterol guideline specifically recommends (Class of Recommendation [COR] I) taking premature menopause and pregnancy-associated disorders into consideration when deciding on lifestyle changes and statin initiation.

Pregnancy and Lactation

Statins are contraindicated during pregnancy and lactation (see Statins). This is an important issue for women with familial hypercholesterolemia (FH), Type 1 diabetes (T1D) or type 2 diabetes (T2D), or with clinical ASCVD who require statin therapy to reduce ASCVD risk during their child-bearing years. If statin therapy is indicated for a woman with child-bearing potential, the 2018 multi-society guideline recommends (COR I) that she be counseled to practice effective forms of contraception; she should also be counseled on the potential for adverse fetal effects should a pregnancy occur. Stopping the statin 1 to 2 months before considering conception, or immediately after a pregnancy is discovered, is recommended (COR I).

Choice of Statin Intensity

High-intensity statin therapy should be used if indicated unless contraindications or other safety considerations are present. In the TNT study, women had slightly higher rates of muscle symptoms than men in both the high- and moderate-intensity treatment groups. Discontinuation rates were slightly higher for women (6.5%) than for men in the atorvastatin 80 mg group (3.7%). Persistent ALT elevations >3 times the upper limit of normal were similar in women and men.

Moderate-intensity statin therapy should be used in women who are unable to tolerate high-intensity statin therapy or who have characteristics that might influence the safety of high-intensity statin therapy. Characteristics that could influence safety include but are not limited to:

• History of previous statin-associated side effects or muscle disorders
• Serious or multiple comorbidities
• Impaired renal or hepatic function
• Unexplained ALT elevations higher than three times ULN
• Patient characteristics or concomitant use of medications affecting statin metabolism
• Age older than 75
• History of hemorrhagic stroke
• Asian ancestry.

In addition, a moderate-intensity statin might be preferred as initial therapy in small or frail women.

Nonstatins

There is little to no data from pregnant women for niacin, fenofibrate, gemfibrozil, ezetimibe, bempedoic acid and inclisiran. PCSK9 monoclonal antibodies cross the placenta. In general and as a precaution, nonstatin therapy is not recommended in pregnant women unless the benefits justify the risks. Fewer data are available for women from the nonstatin CV outcomes trials. Decisions to initiate statin combination therapy in women with childbearing potential must consider carefully the potential benefits and risk to both the mother and the fetus.

The early nonstatin monotherapy trials did not enroll women (Coronary Drug Project [niacin], Helsinki Heart Study [gemfibrozil], VA-HIT [gemfibrozil], and Lipid Research Clinics Primary Prevention Trial [cholestyramine]). ACCORD found evidence of harm in diabetic women with the addition of fenofibrate to simvastatin therapy, although there was no evidence of harm when fenofibrate was used as monotherapy in diabetic women (FIELD). Both treatment strategies had similar effects in women as in men in AIM-HIGH (simvastatin-niacin [±ezetimibe] vs simvastatin [±ezetimibe]). There was no evidence of treatment heterogeneity in women and men in IMPROVE-IT (ezetimibe added to simvastatin vs simvastatin) or HPS-2 THRIVE (niacin added to simvastatin vs simvastatin).No sex-based differences in response or adverse events were noted in the PCSK9 inhibitor trials FOURIER, ODYSSEY OUTCOMES, or ORION-10/11. In CLEAR HARMONY, bempedoic acid treatment had a greater LDL-C-lowering effect in women than in men.

Age >75 Years

The 2018 multi-society cholesterol guidelines offer different recommendations for initiation of statin therapy for secondary and primary prevention in individuals >75 years of age, as discussed later in this section.

Patient preferences are of particular importance in decisions about initiating cholesterol-lowering therapy in individuals of advanced age. At age 75, most men and women in the United States will live another 10 to 12 years on average, a time frame sufficient to experience a benefit from statin therapy to reduce ASCVD risk. On the other hand, the incidence of other chronic diseases and functional limitations become more common around age 75 and may influence the decision to begin or continue preventive therapies.

There are few data to guide the decision to discontinue statin therapy in older patients. Simplification of the medication regimen may be desirable for patients with multiple comorbidities or serious cognitive impairment who may be unlikely to experience an ASCVD risk reduction benefit over the next 2 years. It should be noted that statin or statin/ezetimibe therapy did not reduce ASCVD events in patients with NYHA Class II-IV heart failure (GISSI, CORONA) or in patients receiving maintenance hemodialysis (4D, AURORA, SHARP). Statins do not appear to influence dementia progression. Whether statins would be beneficial in other groups of patients with serious, life-threatening comorbidities is unknown.

Secondary Prevention

Substantial data show that moderate-intensity statins reduce CV risk in individuals >75 years of age with clinical ASCVD. Based on moderate-quality evidence from randomized clinical trials in patients age 75 and older with clinical ASCVD, the 2018 multi-society cholesterol guideline states that high- or moderate-intensity statin therapy is reasonable (COR IIa) for this age group, following a risk-benefit evaluation and discussion around patient preferences. The IDEAL trial did report worse adherence in patients >65-80 years of age with atorvastatin 80 mg than simvastatin 20-40 mg. The current cholesterol guideline also states that if patients >75 years are tolerating high-intensity statin therapy, it is reasonable (COR IIa) to continue with the therapy following a risk-benefit discussion and taking patient preferences into account.

Primary Prevention

Fewer data are available for primary prevention after age 75, and the data that are available are conflicting. In PROSPER, a trial performed in primary and secondary prevention patients aged 70-82 years, pravastatin 40 mg daily did not reduce the risk of cardiovascular events in the primary prevention subgroup. In contrast, in JUPITER, rosuvastatin 20 mg did reduce the risk of cardiovascular (CV) events in those aged 70-92 years.

On the basis of age alone, most patients 75-79 years of age will have >7.5% 10-year ASCVD risk using the Pooled Cohort Equations and will thus also have the potential to experience a substantial reduction in their absolute risk of ASCVD from statin therapy. Initiation of statin therapy for primary prevention after age 75 should be based on the potential for an ASCVD risk reduction benefit, the potential for adverse effects, drug-drug interactions, and patient preferences. Additional considerations may include increasing comorbidities and priorities of care. For patients 75 years and older with diabetes, the 2018 multi-society guideline considers it reasonable (COR IIa) to initiate statin therapy in patients 75 and older with diabetes, following a risk-benefit assessment and discussion, and to continue statin therapy (COR IIa) in patients who are already receiving it. For patients 75 years and older with an LDL-C level of 70-189 mg/dL, it may be reasonable (COR IIb) to initiate moderate-intensity statin therapy. In a subset of these patients (age 76-80), it may be reasonable (COR IIb) to obtain a CAC score and exclude those with a CAC score of 0 from statin therapy. For all primary prevention patients 75 and older, it may be reasonable (COR IIb) to stop statin therapy if functional decline, multimorbidity, frailty, or reduced life expectancy limits its benefits.

Nonstatins

There is limited data available for nonstatin therapy in individuals >75 years of age. In the IMPROVE-IT trial, men and women with a recent acute coronary syndrome and an additional high-risk characteristic who were >75 years experienced a significant reduction in CV events. The anti-PCSK9 monoclonal antibody evolocumab was shown in the FOURIER trial to be as efficacious in adults over age 69 as in other age groups in preventing ASCVD outcomes. Similarly, in the ODYSSEY OUTCOMES trial alirocumab was demonstrated to be equally efficacious in preventing ASCVD outcomes in patients 75 and older and those younger than 75.

Race and Ethnicity

The 2018 multi-society cholesterol guideline considers it reasonable (COR IIa) for physicians to consider their patients’ racial/ethnic features which can influence ASCVD risk when choosing or adjusting the type and intensity of statin therapy. For a list of racial/ethnic considerations in ASCVD risk evaluation and management, see Table 16-1.

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Risk Assessment

The ACC/AHA Pooled Cohort Equations estimate 10-year ASCVD risk in White and African American men and women. Few prospective data were available for other races or ethnicities. The Pooled Cohort Equations for White women and men should be used as the starting point for racial/ethnic groups other than African Americans, with the risk estimate qualitatively adjusted up or down based on race/ethnicity. Individuals of South Asian ancestry (Indian, Pakistani, or Bangladeshi descent) and Asian-Pacific Islander, Alaskan Natives and Native Americans are at higher risk of premature ASCVD than US non-Hispanic White individuals. Individuals of East Asian ancestry (defined as those of Chinese, Japanese, Vietnamese and Korean descent) generally have the lowest ASCVD risk. Hispanic individuals have historically had lower ASCVD risk than non-Hispanic white, but with increasing acculturation and rising obesity prevalence their risk may be approaching that of the non-Hispanic White population.

Cardiovascular Outcomes Trials

Few individuals of non-European ancestry have been enrolled in CV outcomes trials. JUPITER enrolled the largest number of individuals of African ancestry or Hispanic ethnicity.

All racial/ethnic groups experienced similar reductions in the relative risk of CV events and similar rates of adverse events with rosuvastatin 20 mg.

Given that statins reduce the relative risk of CVD across all patient subgroups, it is reasonable to use the four statin benefit groups to guide treatment in non-White patients (clinical ASCVD, LDL-C ≥190 mg/dL, diabetes age 40-75 years and 10-year ASCVD risk ≥7.5%).

Safety in East Asian Populations

High-intensity statins have not been evaluated in East Asian populations. However, there is some indication of an altered pharmacokinetics and safety profile with simvastatin 80 mg and rosuvastatin. Moderate-intensity simvastatin therapy was well-tolerated in those with Asian ancestry in SEARCH and lower intensity pravastatin therapy was well tolerated in the Japanese population enrolled in MEGA. Moderate-intensity statin therapy may be more appropriate on this basis. Refer to manufacturer’s package insert. East Asian patients in HPS-2 THRIVE experienced a higher risk of myopathy with simvastatin-niacin therapy.

Manufacturer’s package insert in the United States recommends a starting dose of rosuvastatin 5 mg in Asian patients; Chinese patients are advised to use caution with simvastatin doses exceeding 20 mg when also taking niacin ≥1 g/day.