（2025）NLA／AGS：大于75岁无动脉粥样硬化性心血管疾病史老年人高胆固醇血症的管理临床共识

ABSTRACT

The risk of atherosclerotic cardiovascular disease increases with advancing age. Elevated LDL-cholesterol and non-HDLcholesterol levels remain predictive of incident atherosclerotic cardiovascular events among individuals older than 75years. Risk prediction among older individuals is less certain because most current risk calculators lack specificity in those older than 75years and do not adjust for co-morbidities, functional status, frailty, and cognition which significantly impact prognosis in this age group. Data on the benefits and risks of lowering LDL-cholesterol with statins in older patients without atherosclerotic cardiovascular disease are also limited since most primary prevention trials have included mostly younger patients. Available data suggest that statin therapy in older primary prevention patients may reduce atherosclerotic cardiovascular events and that benefits from lipid-lowering with statins outweigh potential risks such as statin-associated muscle symptoms and incident Type 2 diabetes mellitus. While some evidence suggests the possibility that statins may be associated with incident cognitive impairment in older adults, a preponderance of literature indicates neutral or even protective statin-related cognitive effects. Shared decision-making which is recommended for all patients when considering statin therapy is particularly important in older patients. Randomized clinical trial data evaluating the use of non-statin lipid-lowering therapy in older patients are sparse. Deprescribing of lipidlowering agents may be appropriate for select patients older than 75years with life-limiting diseases. Finally, a patient-centered approach should be taken when considering primary prevention strategies for older adults.

Since 2014, the National Lipid Association (NLA) has issued several scientific statements on key aspects of the management of lipids and lipoproteins to prevent cardiovascular disease ( https://www.lipid.org/practicetools/documents ). The current Expert Clinical Consensus, focused on the treatment of hypercholesterolemia among individuals older than 75years without clinically manifest atherosclerotic cardio vascular disease (ASCVD), was developed as a collaboration between the NLA and the American Geriatrics Society (AGS). The governing bodies of both organizations appointed members with relevant expertise to the writing group which was jointly chaired by a representative of NLA (V. B.) and AGS (S.A.L.). The Expert Clinical Consensus was developed by a diverse group of clinical lipidologists, cardiologists, geriatricians, and pharmacists with cumulative expertise in clinical medicine, geriatrics, cardiology, endocrinology, pharmacology, clinical trials, epidemiology, health outcomes research, and public health.

Synopsis

The chairs and members of the writing group jointly developed a set of key clinical questions to be addressed by the panel. Once the key clinical questions were agreed upon, writing assignments were jointly determined by the group based on content expertise with a primary and secondary author assigned to each question. The literature was reviewed and recommendations were developed using the 2019 Update of the American Heart Association (AHA) / American College of Cardiology (ACC) rating system for clinical guidelines, assigning a Class of Recommendation (I-III) and a Level of Evidence (A-C with sub categories) for each recommendation (Figure 1 ). 1, 2 Each section and its associated recommendations were discussed in detail by the writing group. Preliminary recommendations were presented at the Annual Scientific Meeting of AGS (AGS23) in May 2023 and feedback from the audience was incorporated as appropriate. Final recommendations based on consensus of at least $60\%$ of the expert panel were then reviewed by external peer reviewers, edited as appropriate and approved by the respective Boards of the NLA and AGS on 9/20/2024.

QUESTION 1 |For the population of adults older than 75years without established ASCVD, what is the association between low-density lipoprotein cholesterol (LDL-C) and incident ASCVD?

|COR|LOE|RECOMMENDATION for QUESTION 1| |---|---|---| ||B-NR| Among adultsolderthan75yearswithout established ASCVD, LDL-C plasma level is associated with incident ASCVD and should | ||| associated with incident ASCVD and should be measured as part of ASCVD risk stratification. |

Cross-sectional and prospective cohort studies show that atherogenic lipoproteins increase with age from early adulthood to the 7th decade, but gradually decrease in subsequent decades. 3, 4 This decrease among the oldest old (8th decade and beyond) is likely multifactorial including survivor bias (i.e., selective mortality at younger ages among those with the highest atherogenic lipoprotein levels) and declines in cholesterol associated with co-morbidities (e.g., heart failure, malignancies, malnutrition). Many studies have shown strong and graded associations between LDL-C level and incident ASCVD in women and men and across ethnicities among young and middle-aged populations. In contrast, early epidemiologic analyses among older individuals suggested an inverse association between total cholesterol and outcomes which is most consistent with reverse causation. 5 More contemporary analyses suggest that the association of LDL-C level to incident ASCVD is maintained in the oldest age groups. 6

## Recommendation-specific supportive text

In 2007, a meta-analysis of 61 prospective studies analyzed ischemic heart disease mortality as a function of total cholesterol or non-high- density lipoprotein cholesterol (non-HDL-C) stratified by sex and age (5th to 9th decade). 7 Relative risk of ischemic heart disease mortality related to the level of total cholesterol or non-HDL-C was highest among 40-49 year-olds. Relative risk decreased in a graded fashion with each advancing decade, but it remained statistically significant to age 80-89years. In contrast, absolute risk was lowest in the youngest age group and increased with advancing age.

The prospective Copenhagen General Study investigated the association of LDL-C with incident myocardial infarction (MI) and ASCVD in 91,131 participants ranging in age from 20-100years old; 10,591 participants were 70-79years old and 3,188 participants were 80-100years old. 6 Higher LDL-C was predictive of incident MI and ASCVD independent of age. As in the Prospective Studies Collaboration, relative risks of MI and ASCVD (expressed as adjusted hazard ratios (HRadj)) were highest in the youngest (20-49 year-old) age group (MI HRadj 1.68 ( $95\%$ CI 1.45-1.87); ASCVD HRadj 1.47 $95\%$ CI 1.32-1.64)) and lowest in the oldest (80-100 year-old) age group (MI HRadj 1.28 ( $95\%$ CI 1.08-1.52); ASCVD HRadj 1.16 $95\%$ CI 1.05-1.29)). By contrast, absolute risk of events was lowest in the youngest age group and highest in the oldest age group. Based on these prospective observational data, the authors estimated the number needed to treat (NNT) to prevent MI or ASCVD for every $1\,\mathrm{mmol/L}$ ( $38.67~\mathrm{mg/dL})$ lowering of LDL-C over 5years. The estimated NNT declined with each decade of age (Figure 2 ). For ASCVD, the estimated NNT for 80-100 year-old participants was 42 compared to 345 for 50-59 year-old participants; for MI, the respective estimated NNTs were 80 and 439. Thus, LDL-C is an important risk factor among patients older than 75years and should be measured for ASCVD risk stratification.

|CLASS(STRENGTH)OFRECOMMENDATION| |---| |CLASS1(STRONG) Benefit>>>Risk| | Suggested phrases for writing recommendations: Isrecommended Isindicated/useful/effective/beneficial Shouldbeperformed/administered/other Comparative-Effectiveness (Phrases): Treatment / strategy A is recommended /indicated in preference to treatment /strategy B Treatment/strategyAshouldbe chosenover treatment/strategyB | |CLASS2a(MODERATE) Benefit>>Risk| | Suggested phrases for writing recommendations: Isreasonable Can beuseful/effective/beneficial Comparative-Effectiveness (Phrases): Treatment / strategy A is probably recommended /indicated in preference to treatment/ strategy B It is reasonable to choose treatment/ strategy A over treatment/ strategyB | |CLASS 2b(WEAK) Benefit=Risk| | Suggested phrases for writing recommendations: May/might bereasonable May/might be considered Usefulness/effectiveness isunknown/unclear/uncertain or notwell-established | | CLASS 3:No Benefit (MODERATE) Benefit=Risk [Generally,LOE A or Buse only] | | Suggested phrases for writing recommendations: Isnot recommended Isnotindicated/useful/effective/beneficial Should not be performed/administered /other | |LASS3:Harm(STRONG) Risk>Benefit| | Suggested phrases for writing recommendations: Potentially harmful Causes harm Associatedwithexcessmorbidity/mortality Should not be performed/administered/other | |LEVEL (QUALITY)OF EVIDENCE| |LEVELA| | High-quality evidence from ≥1 randomized controlled trial Meta-analyses of high-quality randomized controlled trials One or more randomized controlled trials corroborated by high-quality registry studies | |LEVELB-R Randomized| | Moderate-quality evidencefrom≥1 randomized controlled trial Meta-analyses of moderate-quality randomized controlled trials | |LEVELB-NR Non-randomized| | Moderate-quality evidence from ≥1 well-designed,well-executed nonrandomized studiebsevatnalsudieristy Meta-analysesof such studies | |LEVELC-LD Limited data| | Randomized ornonrandomized observational orregistry studies with limitations of design or execution Meta-analyses of such studies Physiological or mechanistic studies in human subjects | |LEVEL C-EO Expert Opinion|

FIGURE 1 |2019 Updated ACC/AHA Clinical Practice Guideline Recommendation Classification System (table modified from the 2019 ACC/

AHA Clinical Practice Guideline Recommendation Classification System). 1,2

 FIGURE 2 |Number needed to treat for primary prevention of MI and ASCVD by age. Data from the Prospective Copenhagen General Study. 6 The graph shows the number needed to treat (NNT) to prevent 1 event over 5years for 1mmol/L (\~39mg/dL) lower LDL-C by age group for the endpoints myocardial infarction and ASCVD. NNT declines with advancing age consistent with greater benefit in the older compared to younger age groups.

QUESTION 2 |For the population of adults older than 75years without established ASCVD, how should ASCVD risk be assessed and stratified?

|COR|LOE|RECOMMENDATIONS for QUESTION 2| |---|---|---| ||B-NR| Inadultsolderthan75years,theutilityof traditional riskequations toassess5or10- year risk of ASCVD is uncertain. | ||B-NR| Inadultsolderthan75years,clinicians mayconsiderusingmodels adjusted formayconsiderusingmodels adjusted for competing risks to estimate ASCVD risk and the potential benefit of primary prevention | ||B-NR|| |a|B-NR|| |a|B-NR| the potential benefit of primary prevention statintherapyforanindividualpatient. In adults aged76-80yearsoldwithLDL-C 70-189mg/dLinwhomthereisclinical uncertaintyaboutstatininitiation,itis reasonabletomeasurecoronary artery calcium (CAC) and to withhold statin therapy if theCACscore is 0. Inadultsaged76-80yearsoldwithLDL-C 70-189 mg/dLwith aCACscore of≥100 or CAC ≥75th percentile compared with age, | |a|B-NR|| |||| ||C-LD|| ||C-LD| 70-189 mg/dLwith aCACscore of≥100 or CAC ≥75th percentile compared with age, sex, and race-matched individuals, it may | ||| be reasonable to engage inshared decision- making regarding initiation of statin therapy. |

Synopsis

Calibrating the use and intensity of preventive therapies to anindividual's absolute ASCVD risk is the foundation of riskassessment. 8, 9 Generally, this includes (a) the use of riskstratification tools to estimate 10-year risk of an ASCVD event, (b) personalizing this risk estimate, and (c) then furtherrefining this risk using imaging in select patients. For older adults, several risk stratification tools are available (Table 1 ). Since chronologic age is one of the most heavily weighted riskfactors in all the currently available risk stratification tools, these tools are limited by a lack of specificity in identifying older adults most likely to benefit from preventive therapies including statin therapy. Most risk stratification tools do not incorporate other considerations that are very important in older adults including co-morbidities, life expectancy, functional status, frailty, and cognition and most do not take into account the competing risk of non-cardiovascular mortality 10 , which may lead to the over-estimation of ASCVD risk and of the potential benefit

from risk factor reduction. Use of models that adjust for competing risk in older adults can help estimate individualized treatment effects and inform clinical decision making. Assessment of vascular age using markers of subclinical atherosclerosis (e.g., CAC scoring [Table 2 ]) can assist clinicians in refining risk assessment and identifying older adults most likely to benefit from preventive therapies including statin therapy. Lifestyle therapy including a heart healthy diet and physical activity remains first line therapy in older adults, regardless of the results of risk assessment, given the independent association with all-cause mortality and favorable impact on physical functioning and mental wellbeing.

Recommendation-specific supportive text

1. Although several ASCVD and global cardiovascular disease risk stratification algorithms are available for clinicians to use in individuals older than 75years (Table 1 ) 8, 10–14 , they have notable limitations including a small number of individuals in this age group in the derivation cohort, limited non-white enrollment, or derivation in countries outside the United States, all limiting generalizability to the overall U.S. population.

The pooled cohort risk equations (PCE) 11 , which are sex and race-specific were derived from five community-based cohorts of Black and White participants in the U.S. aged 40-79years and are generally considered most applicable to the U.S. population. Like other risk stratification algorithms, the PCE are also heavily influenced by age, yielding risk estimates among older individuals with favorable risk profiles that are well above the traditional 10-year ASCVD risk thresholds used to perform risk discussion regarding statin treatment. Despite these limitations, the use of the PCE could be helpful in individual patients. First, clinicians could use the 10-year risk estimation as a medium to communicate risk in a numeric form to the patient and to discuss healthy lifestyle choices with the patient. 15 Second, a higher risk may identify which risk factor(s) might be driving the higher ASCVD risk in an older adult and allow clinicians and patients to focus prevention efforts on those specific risk factors (e.g., uncontrolled hypertension, smoking).

TABLE 1 |Major risk assessment algorithms available to assess ASCVD risk in older adults.

| (Models not adjusted for competing risk) |Population|Outcomes/Comments| |---|---|---| | Pooled Cohort Risk Equationsll https://tools.acc.org/ascvd-risk- estimator-plus/#!/calculate/ estimate/ http://static.heart.org/riskcalc/ | · Derived from 5 community-based cohorts of Black and White participants in the U.S. · Sex and race specific risk calculator for ASCVD risk assessment in 4 groups: white men, white women, black men, black, women. | · Estimates 10-year risk of hard ASCVD events (nonfatal MI, CHD death, fatal or nonfatal stroke). . Variables used to calculate AsCVD risk include age, | || · Derived from 5 community-based cohorts of Black and White participants in the U.S. · Sex and race specific risk calculator for ASCVD risk assessment in 4 groups: white men, white women, black men, black, women. | . Variables used to calculate AsCVD risk include age, sex, race, total cholesterol, HDL-C, SBP, antihypertensive therapy, history of diabetes mellitus, and current smoking. · Reasonably well calibrated in the general U.S. population. · Large numbers of studies available on reclassification by CAC. | ||| therapy, history of diabetes mellitus, and current smoking. · Reasonably well calibrated in the general U.S. population. · Large numbers of studies available on reclassification by CAC. · Available for non-Hispanic White and non-Hispanic African American patients 40-79years of age. · Small number of adults above age 70 (predominantly contributed by the Cardiovascular Health Study). | | Reynolds Risk Scorel2, 13 http://www.reynoldsriskscore. orgy | · Score derived from healthcare professionals (mostly White patients) enrolled in clinical trials. · Input variables include age, sex, total cholestero,HDL-C,P,current smoking, hsCRP, and parental history of MI before | · Outcomes include CHD death, nonfatal MI, fatal or nonfatal stroke, and coronary revascularization. · Uncertain utility in other ethnic groups and reclassification with CAC not weli known. | || · Developed in a predominantly White population of Framingham study participants. · Utility in other ethnic groups is not || | Framingham General CVD Risk Score14 https://reference.medscape.com/ calculator/252/framingham -risk-score-2008# | population of Framingham study participants. · Utility in other ethnic groups is not known. Developed for individuals 30-74years of age. | · Assesses risk of total CVD (CHD death, MI, coronary insufficiency, angina, ischemic stroke, hemorrhagic stroke, transient ischemic attack, intermittent claudication, and heart failure. ° Input variables include age, sex, total cholesterol, HDL-C, SBP, antihypertensive therapy, history of diabetes mellitus, and current smoking. | |https://qrisk.org/three/index.|| · Outcomes include CHD, ischemic stroke, or transient ischemic attack. | || · Risk score developed using a total of 1309 general practices in England: data from 981 practices were used to develop the scores and data from a separate set of 328 practices were used to validate the scores. · 7.89 million patients aged 25-84years were in the derivation cohort and 2.67 million patients were in the validation cohort. | · Several traditional risk factors used, as in PCE, but also includes several additional variables including BMI, SBP includes several additional variables including BMI, SBP variability, corticosteroid use, chronic kidney disease, atrial fibrillation, erectile dysfunction in men, migraine, rheumatoid arthritis, SLE, severe mental illness, HIV, atypical antipsychotic use, Townsend score (measure of material deprivation) etc. | |||| || · Mean age between 42-43years in the derivation and validation cohorts. | · Applicability to broad U.S. population is not known. · Impact of reclassification with CAC is unclear. | | Models Adjusted For Competing Risk||| | SCORE2-OP risk prediction algorithms10 https://www.heartscore.org/ | risk of cardiovascular disease in individuals aged over 70years in four geographical risk regions in Europe. || ||| · Outcomes include non-fatal myocardial infarction, non-fatal stroke, and cardiovascular mortality. Secondary outcomes include hospitalization from heart failure. · The external validation showed C index for discrimination ranging between 0.63 (95% CI 0.61-0.65) and 0.67 (95% CI 0.64-0.69). Although external validation cohorts included U.S. cohorts, the current risk charts are only available for use | ||· Competing risk and sex-adjusted.| in 4 regions in Europe with unclear validation across various ethnic groups in the U.s. Impact of reclassification by CAC | |||| |NORRISK217| · Model adjusted for competing risk for estimating 10-year risk of myocardial infarction or stroke. · Developed using data from the prospective Cohort of Norway (CONOR) | infarction or stroke by serum total cholesterol, systolic blood pressure and smoking status to help clinicians determine | |NORRISK217|| which patients meet recommended thresholds for statin and antihypertensive treatment. | |NORRISK217| study linked to the Cardiovascular Disease in Norway (CVDNOR) project, a database |· Limitations of NORRISK2 are that it may have limited| |NORRISK217| in Norway (CVDNOR) project, a database of all hospital stays with a CVD-related discharge diagnosis in Norway. | generalizability outside Norway, and the population only included men and women up to age 79. | || · Developed in 31,445 men and 35,267 women in 1994-1999. External validationwomen in 1994-1999. External validation population consisted of 19,980 men and 19,309 women in 2000-2003. | . Figure depicting estimated 10-year risk is available here: https://doi.org/10.1177/2047487317693949 |

| Risk Assessment Algorithm (Models not adjusted for competing risk) |Population||| |---|---|---|---| |PROSPER18|||Outcomes/Comments| || ·Derived using competing risk analysis for myocardial infarction, stroke and || · The model was fitted for the prediction of 3.2-year risk (median follow-up), and these estimates were extrapolated to | ||vascular death in patients 70 or older with||derive 5-year and 10-year CVD event risks.| ||(N=2550) and without (N=3253) vascular||· By entering patient characteristics in the model formula,| ||disease from the“PROspective Study of||it is possible to estimate the CVD risk and absolute risk| || Pravastatin in Elderly at Risk"(PROSPER) trial. || reduction (ARR) with and without statin treatment for an individual patient; however, an interactive clinical tool has | ||· Validated in the “Secondary||not been developed. The ARR can be translated into an| ||Manifestations of ARTerial disease'||individual number needed to treat—-the number of patients | ||(SMART) cohort study (N=1442) and the||with the same risk profile who would need to be treated to| ||"Anglo-Scandinavian Cardiac Outcomes|| prevent 1 event in 5 or 10years.| || Trial-Lipid Lowering Arm" (ASCOT-LLA) trial (N=1893). ||·Limitations of this model are that it was derived and| |||results cannot be extrapolated to the very old (>85years) and|validated only in Northern European populations, and| ||· Covariates included glomerular filtration||| ||rate and the number of medications per|| to patients with stage IV or V chronic kidney disease (eGFR |

Table Footnote: The utility of traditional risk equations to assess 5 or 10-year risk of ASCVD in older patients is uncertain and clinicians should consider using the

competing-risk adjusted models.

Clinicians could discuss how the patient's 10-year ASCVD risk would be reduced if all risk factors were optimal. This could motivate patients to improve their adherence to lifestyle therapy and preventive medications. Recently, the AHA published risk equations (Predicting Risk of CVD EVENTs [PREVENT]) 16 which assess the risk of cardiovascular events (ASCVD and heart failure). These equations included adults between the ages of 30-79years of age and adjusted for competing risk of non-cardiovascular deaths. In addition to traditional risk factors included in PCEs, PREVENT also includes statin use and estimated glomerular filtration rate as predictors in the model. PREVENT equations also allow the use of optional predictors such as urine albumin to creatinine ratio, hemoglobin A1C, and social deprivation index. Although PREVENT includes heart failure as an outcome in addition to ASCVD, which is of importance especially for older adults, it remains to be seen if PREVENT performs better than PCE or other risk equations in individuals older than 75years. 16

2. There are 4 competing-risk adjusted models for ASCVD risk estimation in older adults (SCORE2-OP, NORRISK2, PROSPER, and the CHS-Rotterdam model). 10, 17–20

Use of these models can help estimate individualized treatment effects and inform clinical decision making, though it should be noted that they are not yet standard of care. An interactive tool that uses one of these models, SCORE2-OP, is available online ( https://www.heart score.org/en_GB ). Limitations of the models are that they may have limited generalizability outside the Northern European populations in which they were developed, and results of NORRISK2 and PROSPER cannot be extrapolated to the very old $(\geq\!85$ years). Lastly, some important determinants for ASCVD risk in older adults were not included in all the models, such as kidney function or other markers of frailty.

3. Several epidemiologic studies have shown that adults aged 75years and older with ${\mathrm{CAC}}\!=\!0$ have low ASCVD event rates and mortality (Table 2 ). 21–25 In the 10-year follow-up from the MESA study 21 , the 10-year ASCVD rate was $5.6\%$ among those aged 75years or older with ${\mathrm{CAC}}\!=\!0$ . In the CAC consortium 22 , individuals 75years or older with zero CAC had a 5.6-year survival rate of $98\%$ . Clinicians should note that the prevalence of ${\tt C A C}\!=\!0$ among older adults varies in these studies ( $19\%$ in MESA and $16\%$ in CAC

TABLE 2 |Key studies summarizing the role of CAC in risk stratification in older adults.

|Study|Patient Characteristics|Outcomes/Results| |---|---|---| |MESA21|6814 participants|· CAC 0, 1-100, 101-300, >300 was noted among 19%, 30%, 20%,| || · 964 (14%) between 75-85years of age | and 31% of the participants aged ≥75 years.| ||· Follow-up of 11.1years| individuals with CAC 0, 1-100, 101-300, and > 300, respectively. · In multivariable models, each doubling of CAC was associated with HR (95% CI) of 1.12 (1.06-1.17). | |||· Prevalence of CAC 0, 1-100, 101-400, and >400 was 16%, 23%,| |CAC Consortium22| 44,052 individuals referred for CAC · 1663 (3.8%)≥75 years of age | 25%, 36% respectively among those aged ≥75 years.| ||| · Estimated survival at a mean follow-up of 5.6years was 98.1%, 92.3%, 91.3%, and 81.1%, respectively among those with CAC 0, | || 2028 asymptomatic participants ·Aged 69.6±6.2years · Median follow-up was 9.2years | · Median CAC score was 84 Agatston units (AU) (25th to 75th percentile: 8 to 382 AU). ·10.5% with CAC 0 | |Rotterdam Study23| 2028 asymptomatic participants ·Aged 69.6±6.2years · Median follow-up was 9.2years || || 2028 asymptomatic participants ·Aged 69.6±6.2years · Median follow-up was 9.2years |· Individuals were classified into low (|

consortium among those 75years or older versus $10.5\%$ among participants in the Rotterdam Study [mean age 69.6, $\mathrm{SD}\!=\!6.2$ years]). This reflects the population studied (epidemiologic cohort versus a referred population) as well as the characteristics of the studied population (White and South Asian 26 populations and males have higher proportion with $\mathrm{CAC}\!>\!0$ compared with other ethnic groups, and women). Given the very low ASCVD risk and overall mortality associated with ${\mathrm{CAC}}\!=\!0$ in these studies, it is reasonable to withhold statin therapy in older adults for primary ASCVD prevention, especially since ${\mathrm{CAC}}\!=\!0$ is associated with low ASCVD event rates in the short to intermediate term time horizon. 27

4. Older adults with subclinical atherosclerosis, as identified by CAC score $\geq\!100$ have a higher risk of ASCVD events. In the MESA study 21 , CAC scores of 1–100, 101–300, and $>300$ were noted in $30\%$ , $20\%$ , and $31\%$ of individuals aged 75years or older, respectively, with corresponding 10-year ASCVD event rates of 14.3, 18.1, and $24.7\%$ , respectively. Using a cut-off score of 100, approximately $50\%$ of in- dividuals older than 75years will be identified as “high-risk” providing an opportunity for a risk-based discussion regarding statin therapy in such individuals. Prevalence of $\scriptstyle\mathrm{CAC}\geq100$ varies based on sex and ethnicity with lower prevalence in women, Chinese, Black and Hispanic individuals compared with men, Whites, and South Asian individuals. Although absolute CAC scores generally predict ASCVD outcomes over a much shorter time-horizon compared with percentiles which generally predict long-term or lifetime ASCVD outcomes, 28 it is reasonable to use age-, sex-, race-based percentile cut-offs in this age segment given high absolute CAC prevalence. An age, sex, race-based CAC score ≥ 75th percentile may identify patients at high-risk of

TABLE 3 |Statin intensity as defined in the 2018 AHA/ACC/ Multisociety guidelines. 31

||Expected|Expected| |---|---|---| ||Mean LDL-C|Mean LDL-C| ||Lowering*|Daily Dose (mg)| |High-Intensity|≥50%|Atorvastatin 40-80| |Moderate-Intensity||Rosuvastatin 20-40| |Moderate-Intensity|30 to49%|Atorvastatin 10-20| |Moderate-Intensity|30 to49%|Rosuvastatin 5-10| |||Simvastatin 20-40| |||Pravastatin 40-80| |||Lovastatin 40-80| |||Fluvastatin 80| |Low-Intensity||Pitavastatin 1-4| |Low-Intensity|||

\*Based on the total adult population (not exclusively patients older than 75years).

short-term ASCVD events 29 ( https://www.mesa-nhlbi.org/ Calcium/input.aspx ) Therefore, in adults aged 76–80years with LDL-C 70–189mg/dL with a CAC score of ${\geq}100$ or CAC ≥ 75th percentile compared with age, sex, and race matched individuals, it may be reasonable to engage in shared decision making regarding initiation of statin therapy even though randomized controlled trial (RCT) evidence that statin therapy reduces ASCVD risk in individuals identified as high risk using a CAC-based approach is limited. The decision should incorporate patient values and preferences as well as consideration of significant competing health risks, cognitive and functional status, and life expectancy.

Synopsis

Statin intensity refers to the percentage of expected lowering of LDL- C in the general adult population and is detailed in Table 3 which is adapted from the 2018 AHA/ACC Multisociety guidelines. 31 Two nationwide studies from Denmark provide insights on LDL-C lowering with statins

QUESTION 3 |In the population of adults older than 75years without established ASCVD, does statin therapy reduce ASCVD events?

|COR|LOE|RECOMMENDATION for QUESTION3| |---|---|---| ||| Inadultsolderthan75yearswithanLDL- C of 70-189 mg/dL,initiation of a statin for | ||B-NR| C of 70-189 mg/dL,initiation of a statin for the primary prevention of ASCVD events maybereasonable in those without a life | ||B-NR| maybereasonable in those without a life limiting illness. |

and ASCVD event reduction among adults older than 75years. Corn etal. showed that LDL-C response to low to moderateintensity statins was slightly greater ( $2–5\%$ depending on statin and dose) among adults without ASCVD older than 75years compared to individuals age 50 or younger. 32 Differences in response to high-intensity statin therapy were minimal. Andersson et al. compared the incidence of major vascular events (acute coronary syndrome, non-hemorrhagic stroke and coronary revascularization) between individuals aged 50-69years with those aged 70-74, 75-79, 80-84, and 85years or older. Over a median follow-up of 2.5years, there were no differences by age group in major vascular event reduction per 1mmol/L reduction in LDL-C with adjusted HR of 0.76, 0.73, 0.81, 0.81, and 0.77, respectively. 33

Among individuals without ASCVD up to age 75 enrolled in randomized controlled outcomes trials of statin therapy, the average time to benefit was 2.5years for reduction of ASCVD events. 34 Whether this can be extrapolated to individuals older than 75years is unknown. Of 186,854 participants in 28 major statin trials, only $8\%$ were over age 75, and only $2\%$ of those in primary prevention trials were over age 75. 35 When data from these trials were analyzed in aggregate and trials among patients with heart failure or on dialysis were

(Continues)

|Randomized controlled clinical trials in primary prevention among individuals 75years or older. TABLE 4

|(Continued) TABLE 4

excluded, there was no statistical heterogeneity by age in the protective effect of statins for reduction of major cardiovascular events or vascular deaths per 1mmol/L LDL-C reduction over 4.9years of follow-up. 35 In contrast, a trend towards smaller proportional risk reductions with advancing age was apparent among trial participants without a history of vascular disease. 35

Recommendation-specific supportive text

To date, 6 statin trials have enrolled participants older than 75years, with few individuals over 80years. 36 (Table 4 ) Two of these trials were mixed primary and secondary prevention (the Heart Protection Study (HPS) 37 and Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) 38 ), while 3 had an upper age limit of 79-82years (HPS 37 , PROSPER 38 and Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA) 39 ). PROSPER is notable as the only trial specifically conducted in older adults; however, data on the 2,355 participants over age 75 has only been published in aggregate, including those both with and without prior ASCVD. 38

Among the 14,483 participants older than 75years at randomization included in the Cholesterol Treatment Trialist (CTT) meta-analysis 35 who were randomized to a statin versus placebo or more intensive statin therapy vs. placebo or less intensive statin therapy, the absolute event rate was 1051 $(4.5\%)$ vs. 1153 $(5.0\%)$ , RR 0.87 ( $95\%$ CI 0.77-0.99). When individuals enrolled in heart failure or dialysis trials were excluded, the absolute event rates were 4.1 and $4.7\%$ , respectively with a RR of 0.82 $95\%$ CI 0.70-0.95). When the analysis was restricted to the 6,007 participants without prior vascular disease, results were attenuated and no longer statistically significant: 295 $(2.7\%)$ vs. 308 $(2.8\%)$ events, RR 0.92 ( $95\%$ CI 0.73-1.16). This heterogeneity persisted when heart failure and dialysis trials were excluded. A challenge to interpreting these data is the limited sample size and lack of generalizability, including healthy volunteer bias, and trials designed to specifically exclude older adults with complex medical conditions or who do not live independently. 40–42 Leveraging territory-wide public electronic medical records in Hongkong and a target trial emulation study design, Xu et al. compared cardiovascular outcomes and adverse events among older statin users and non-users without prior coronary heart disease. 43 Absolute risk reduction in CVD incidence over 5years was $1.20\%$ ( $95\%$ $\operatorname{CI}0.57\%–1.82\%$ ) among 75 to 84 year old individuals and $4.44\%$ $(95\%\,\mathrm{CI}\,1.40\%{\cdot}7.48\%)$ among those aged 85years or older. There was no increase in myopathies or liver dysfunction in either group. Two ongoing randomized trials, the STAREE trial 44 and the PREVENTABLE Trial 45 are addressing benefits and risks of statin therapy in this age group prospectively (see Future Directions).

Synopsis

Adults older than 75years are intrinsically more susceptible to iatrogenic risks from medications amidst age-related changes in metabolism, body composition, mitochondrial energetics,

QUESTION 4 |For the population of adults older than 75years without established ASCVD, how should we weigh potential safety concerns versus benefits of statin therapy?

|COR|LOE|RECOMMENDATIONSforQUESTION4| |---|---|---| ||C-LD| established AsCVD, it may be reasonable to usestatinsforASCVDriskreduction,despite thepotentialriskofSAMS* | ||B-R| Inadultsolderthan75yearswithout establishedAsCVD,itmaybereasonable to use statins for ASCVD risk reduction, despitethepotentialriskofnewonset | |na|B-R| Inadultsolderthan75yearswithout establishedAsCVD,itisreasonableto proceed with statin initiation despite concerns overdrug-inducedcognitiveimpairment. |

$=$

and cognition. Sarcopenia, frailty, and insulin resistance are common, along with changes in pharmacokinetics and pharmacodynamics. Therefore, many hypothesize that older adults may be more susceptible to statin-associated muscle symptoms (SAMS), new onset type 2 diabetes mellitus (T2DM), and cognitive decline if they use statins.

Meta-analyses of RCTs and recent observational data from patient registries do not indicate any increase in the risk of SAMS among those above age 75 compared to younger individuals. 49, 50 Multiple meta-analyses suggest that statin therapy leads to a small increase in risk of new onset T2DM. It is estimated that statin therapy is associated with one additional case of T2DM per 255 patients taking statins for 4years 51 , largely confined to patients with risk factors for T2DM including advanced age. 51, 52 Risk of new onset T2DM is greater with high-intensity statin regimens than with the moderate-intensity statins typically used in primary prevention among older adults. 53 The increase in risk of new onset T2DM associated with statin therapy is outweighed by robust reductions in major cardiovascular events among individuals with T2DM. 51, 53

Analyses of the impact of statin therapy on cognition have significant methodological limitations. 54 The diagnosis of dementia or cognitive change as an endpoint is rarely measured systematically, and confounders like education level and intelligence are rarely considered. Many studies do not adequately measure longitudinal changes in cognition and types of dementia are generally not distinguished. Few studies use invivo brain imaging, cerebrospinal fluid analysis or serological biomarkers. While there has been some literature suggesting the possibility that statins may be associated with incident cognitive impairment in older adults, a preponderance of literature indicates neutral or even protective statin-related cognitive effects. 55–57

Recommendation-specific supportive text

1. SAMS: The CTT Collaboration 49 meta-analysis of SAMS included 19 double-blind trials of statin versus placebo ( $\scriptstyle{\tilde{n}}=123,940$ ) and 4 double-blind trials of a more intensive

versus a less intensive statin regimen $(n\!=\!30,\!724)$ ). The RR of muscle related events comparing statin and placebo treatment was 1.07 $95\%$ CI 0.95–1.20) among the subset of participants over age 75years, comparable to RR among those age 65years or younger (RR 1.03 $95\%$ CI 0.97–1.10)) and those aged older than 65 up to 75years (RR 1.11 ( $95\%$ CI 1.04–1.19)). Reports of SAMS are higher in clinical practice than in clinical trials, at least in part because patients with adverse effects during the clinical trial run-in phase are excluded from participation in the main trial. The Patient and Provider Assessment of Lipid Management registry 50 enrolled 6717 older individuals $\scriptstyle{N=1704}$ $(25\%)$ were aged older than 75years). Among current statin users, older patients were less likely to report any symptoms $(41.3\%$ versus $46.6\%$ ; $p\!=\!0.003\$ ) or myalgias $(27.3\%$ versus $33.3\%$ ; $p\!<\!0.001\!)$ than younger patients.

The SAMSON (Self-Assessment Method for Statin SideEffects Or Nocebo) trial 58 used a crossover design to assess 60 participants with a history of statin intolerance ( $85\%$ were SAMS). Although age was not specifically studied, $83\%$ of the population was aged 60years and older (mean age $65.5{\pm}8.6$ years). The trial demonstrated that $90\%$ of SAMS were attributable to a nocebo effect, triggered by taking a pill itself, not by the statin in the pill, plausibly because the individual believes that the pill will cause harm. While 26 of 60 participants taking the statin had to stop the medication early due to intolerable side-effects, so did 23 of 60 taking placebo. However, 6 months after completion of the protocol (i.e., after participants understood their results), 30 of 60 $(50\%)$ participants successfully restarted statins, including 10 who had stopped statins during the trial because of side effects. Statin intolerance, and management strategies for SAMS are discussed in other NLA publications. 59, 60

2. New onset T2DM: A post hoc analysis of the JUPITER 52 trial first demonstrated an increase in new onset T2DM among participants with at least one diabetes-risk factor randomized to rosuvastatin (HR 1.28, $95\%$ CI 1.07–1.54), but no risk increase among those without risk factors for T2DM. Risks of T2DM were counterbalanced by a $39\%$ reduction in the primary combined endpoint of myocardial infarction, stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death (HR 0.61, $95\%$ CI 0.47–0.79) and a nonsignificant $17\%$ reduction in total mortality (HR 0.83, $95\%$ CI 0.64–1.07). In participants with at least one major diabetes risk factor, 134 vascular events or deaths were avoided for every 54 cases of newly diagnosed T2DM. This increase in new onset T2DM risk was subsequently confirmed in three meta-analyses. 51,53,61 Pooled data from 13 statin trials showed a $9\%$ increase in new onset T2DM, translating to approximately 1 new case of T2DM for every 255 individuals treated with a statin for 4years. 51 The most recent analysis from the Cholesterol Treatment Trialists' Collaboration confirmed the increase in risk of T2DM with low/moderate intensity and with high intensity statin use, but there was no heterogeneity of this risk by age. 53 In the PROSPER trial of 70–82year-old participants, $6.6\%$ of those randomized to pravastatin developed

T2DM compared to $5.1\%$ of those allocated to placebo. 38 A propensity-matched analysis of Medicare Advantage Prescription Drug claims found a $4.82\%$ cumulative incidence of T2DM over 7years with an adjusted OR of 1.26 $95\%$ CI 1.12–1.41) among statin users. 62 Mean age in those with new onset T2DM was $72.1\pm5.1$ years. In an exploratory analysis of PROSPER, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was a powerful predictor of T2DM comparing top and bottom tertiles in models adjusted for baseline characteristics and treatment (HR 4.8, $95\%$ CI 3.14, 7.33), but was not predictive of subsequent ASCVD events or death during 3.2years of follow-up. These data suggest that incident T2DM in older patients may not be associated with a worse prognosis. 63

3. Cognition: In a retrospective analysis of the Effects of Aspirin on All Cause Mortality in the Healthy Old (ASPREE) trial 55 $(N{=}18,846$ , median age 74years, $56.4\%$ women, $31.3\%$ on statin), statin use was not associated with incident dementia, mild cognitive impairment (MCI), or cognitive change over 4.5years of follow-up. There was a trend toward an increase in Alzheimer's Disease (HR 1.33; $95\%$ CI: 1.00 to 1.77; $p\!=\!0.05)$ ). Patients in the lowest quartile of baseline cognitive function on statins had higher hazards for dementia and change in episodic memory, a component of cognitive testing most associated with Alzheimer's Disease $(\mathrm{P}_{\mathrm{interaction}}<0.0001)$ ). Samaras et al. 57 completed a prospective observational study of 1037 older community-dwelling adults over 6years comparing statin users (age $78.6\pm4.8$ years) and non-users (age $79.3\pm4.8$ years). There were no differences in the rate of decline in memory or global cognition between groups. Statin initiation during the observation period was associated with blunting of the rate of memory decline. There were no differences in brain volume changes on magnetic resonance imaging between statin users and non-users. Adhikari etal. 56 reported on 1,404,459 participants age ≥ 60years in a meta-analysis of 24 studies. In 3 randomized controlled trials (HPS, PROSPER and HOPE-3) the rate of incident cognitive decline was approximately $20\%$ in the placebo group; no significant association between statin use and adverse cognitive effects were detected. 37, 64, 65 Seven out of 10 observational studies showed no association between statins and incident dementia, two showed a similar decline in cognition between statin users and non-users, and one showed a slower decline with statin use. Smith etal. 66 found less cognitive decline among older adults $N\!\!=\!443$ , mean age $73\pm7.4$ years) with MCI who were treated with statins compared to a similar population $\scriptstyle N=325$ , mean age $72.9\pm7.7$ years) who were not treated with statins. Future trials such as PREVENTABLE 45 and STAREE 44 will provide further insights on the cognitive effects of statins.

Synopsis

Comorbidity burden and life expectancy vary widely among older adults of the same age. 67 There is thus considerable variability in the likelihood that an older adult will benefit from preventive and therapeutic interventions. Any benefit from

QUESTION 5 |For the population of adults older than 75years without established ASCVD, how do we assess the expected net benefit of statin therapy?

|COR|LOE|RECOMMENDATIONSforQUESTION5| |---|---|---| |||Inadultsolderthan75yearswithout| |||establishedAsCVD,validatedmortality| ||B-NR| indexesthatincludecomorbid conditions and functional status are recommended to help cliniciansincorporate thepatient'sremaining | ||B-NR|| ||B-NR| statintherapyforASCVDprevention Inadultsolderthan75yearswithout establishedAscVD,integratingscreening for frailty,dementia,and functional impairment into decisions about initiating | |a|| statintherapyforASCVDprevention Inadultsolderthan75yearswithout establishedAscVD,integratingscreening for frailty,dementia,and functional impairment into decisions about initiating | |a|||

preventive measures may be attenuated by competing health risks from multiple chronic conditions, and the risk of adverse outcomes may be magnified. Lifetables and validated mortality indexes which consider co-morbidities are available to allow clinicians to refine their patient's prognosis. Furthermore, as discussed under Question 2 , competing risk-adjusted models can help assess ASCVD risk and potential benefit.

Frailty, a syndrome of biologic aging and vulnerability, ranges in prevalence from $7\%$ in community-dwelling older adults to over $50\%$ in institutionalized patients. 68, 69 The prevalence of functional limitation is $66\%$ in adults aged 65years and older (Centers for Disease Control and Prevention. Health, United States, 2020-2021: Functional Limitation. https://www.cdc. gov/nchs/hus/topics/functional-limitation.htm . Updated January 16, 2024. Accessed February 21, 2024). In the U.S. in 2022, an estimated $37.2\%$ of people aged 75–84years and $35.7\%$ of people aged 85years and older have Alzheimer's dementia and other dementias. 70 Mild cognitive impairment affects 12- $18\%$ of people aged 60 and older in the United States. 70 Frailty, cognition and functional impairment should be considered in person-centered decision making about preventive measures. Numerous tools are available to assess these geriatric conditions at the bedside, and decision aids can be helpful in assessing patient preferences.

Recommendation-specifc supportive text

1. There is substantial variability in life expectancy among older adults of the same age, e.g., a healthy 85-year-old woman is expected to live an additional 10years (and would be likely to benefit from primary prevention) while a frail, multimorbid 85-year-old woman may have less than 2years remaining life expectancy and may not stand to benefit. 71 Clinicians can consider morbidity burden, functional status and frailty to estimate life expectancy. 71

If an individual's life expectancy is greater than the time to benefit for a given preventive intervention, the intervention may help and should generally be recommended. 72 If

the life expectancy is shorter than the time to benefit, the intervention is more likely to harm and generally should not be recommended. If the life expectancy is approximately equal to the time to benefit, patient preferences should be the guiding factor in decision making. An online calculator, ePrognosis ( https://eprognosis.ucsf.edu/ ), can help clinicians incorporate evidence-based information about life expectancy for older adults into decisions about preventive therapies such as statins. For example, for an individual with advanced dementia, the time to benefit of primary prevention statin therapy may exceed life expectancy and the goals of therapy may shift over time from preventing illness and prolonging life to reducing the burden of treatment and maintaining quality of life. 73

2. For patients with frailty, severe functional impairment or dementia, incorporating patient preferences in decisions about statin therapy is essential for patient-centered care. 74 These conditions are associated with physical and functional decline, increased mortality risk, 75, 76 and increased risk of harm from polypharmacy. 77–79 Yet, individuals with frailty, functional impairment and dementia should not automatically be denied statin therapy. Although few studies have included such patients, a retrospective cohort study of 326,981 Veterans aged 75years and older without ASCVD at baseline found that new statin use was significantly associated with a lowerrisk of all-cause and cardiovascular mortality, even at advanced ages (e.g., aged ${\tt>}90$ years) and in those with dementia. 80 This association was evident within 2years and remained significant in those with frailty.

However, for some patients with frailty, severe functional impairment or dementia, goals of therapy may shift from preventing illness and prolonging life to reducing the burden of treatment and maintaining quality of life. 73 Practical tools to assess functional status, frailty and cognition are listed in Table 5 . The presence of any of these syndromes may prompt elicitation of patient values and preferences for prevention and medication use (see Question 6 , Section 2 ).

Synopsis

Safety and efficacy monitoring for statin therapy among older patients follows conventional standards of care. CAC scoring

QUESTION 6 |In adults older than 75years without established ASCVD, what strategies should be utilized for initiation, monitoring, and intensification of statin therapy?

|COR|LOE|RECOMMENDATIONS for QUESTION6| |---|---|---| |||Inadultsolderthan75yearswithout| |||established AsCVD treated with statins,| ||| ongoing monitoring of LDL-C every 3 to 12 monthsasclinicallyindicatedis recommended. | ||C-EO|| ||C-EO| Inadultsolderthan75yearswithout established AsCVD,shared decision making should be used when making patient- centered decisions regarding theuse of statin therapy. | ||C-EO||

can augment ASCVD risk estimation among older patients without ASCVD and can inform the decision to initiate statin therapy and intensity of statin therapy or inform decisions to discontinue statins. CAC scoring among older patients without ASCVD is addressed in Question 2 , Recommendation 3.

Considering the clinical uncertainties described above, incorporating patient priorities and preferences in decisions about statin therapy (including initiation of therapy, continuation of therapy, and monitoring of therapy) is essential to improve patientcentered preventive care. 74 Shared decision making involves seeking the patient's participation in clinical decision making, helping the patient explore and compare potential treatment options, assessing the patient's values and preferences, and reaching a decision with the patient. Shared decision making is important for all patients, but it may be particularly useful among older primary prevention patients when there is limited evidence of improved ASCVD outcomes and other patient preferred outcomes with statin therapy.

Recommendation-specific supportive text

1. An exploratory analysis of the JUPITER trial compared outcomes in 5695 participants age 70–97years to those age 50–69years old. 88 Within this older subgroup, rosuvastatin reduced major ASCVD events by $39\%$ with favorable point estimates for cardiovascular death and total mortality and greater absolute reductions in major ASCVD events compared to the younger group. Assessment for adverse effects, and measurements of lipid values, liver function tests, and hemoglobin A1C occurred every six months.

TABLE 5 |Practical tools to assess geriatric domains of frailty, gait speed, cognition and functional status.

|Tool|Description|Time| Online guidance| |---|---|---|---| |Frailty: Clinical Frailty Scale81| 9 categories based on physical function and medical conditions in the past 2 weeks |3min| https:/www.dal.ca/sites/gmr/our- tools/clinical-frailty-scale.html | |Chair Stand and Gait Speed82-84|Focused mobility assessment||https://www.nejm.org/doi/| |||2min|full/10.1056/NEJMvcm2009406| |Cognition: Mini Cog85| Brief cognitive screen|3min|https://mini-cog.com/downl| ||||oad-the-mini-cog-instrument/| |Frailty: CGA-FI86. 87| Comprehensive Geriatric Assessment that incorporates medical history, functional, and cognitive status to calculate a frailty index |30min| https://efrailty.hsl.harvard.edu/ tools/CGA-FI/index.html |

Serious adverse events were more common in older than younger patients, but similar between rosuvastatin and placebo within each age group. As discussed in Question 4 , new onset T2DM was more common in the rosuvastatin group in older patients, but comparable to the increase seen in younger participants. The U.S. Food and Drug Administration removed the recommendation for routine liver function test measurements with statin therapy in 2012. The 2018 AHA/ACC/Multisociety cholesterol guidelines recommend measurement of liver function tests at baseline and if there are signs or symptoms of hepatotoxicity during therapy. The guidelines further recommend a comprehensive evaluation of musculoskeletal symptoms prior to statin treatment because such symptoms are common in the general adult population and especially in older individuals. Serum creatine kinase testing should be performed for patients with severe SAMS or muscle weakness during treatment. 31 Monitoring of LDL-C is recommended 4 to 12weeks after starting therapy or making statin dose adjustments and every 3 to 12months thereafter as clinically indicated to monitor adherence and safety without distinctions by patient age. Among those with risk factors for the development ofT2DM, monitoring of hemoglobin A1C levels is also recommended. 31 Clinicians should use these results and shared decision making to manage therapy to achieve patient-specific therapeutic objectives.

2. The fundamental competent and practical steps of shared decision-making include: information sharing, patient education, exploring patient preferences, decision support tools, deliberation and discussion, shared decisionmaking agreement, and ongoing communication and review. 89 Given limited evidence of improved ASCVD outcomes with statin therapy in adults age 75years or older, including these patients in decision making about statin initiation, type of statin and statin intensity, and about continuation or discontinuation of therapy is important to reduce decisional conflict and ensure that therapy is consistent with patient priorities and preferences. Prospective randomized trials that utilized shared decision-making with or without validated decision tools in younger patients have demonstrated reductions in decisional conflict and increased patient acceptance of statin therapy. 90–92 as has provision of statistics addressing relative risk reduction in ASCVD events. 93 The Mayo Clinic Statin Choice Decision Aid ( https://statindecisionaid.mayoclinic.org/ ) has been validated in clinical trials 92, 94, 95 and is available to facilitate shared decision-making in clinical practice.

Older adults with multimorbidity may face multiple preferencesensitive decisions, and treatment of one condition may exacerbate another condition, making it impractical to use decision aids for each choice. A better approach to eliciting preferences among older adults with multimorbidity may be to ask patients to rank a set of universal health outcomes such as living as long as possible, preserving function, and alleviating pain and other symptoms. 96–98 The clinician and patient can then consider these factors within the shared decision-making process. Statin therapy could be considered in terms of how likely it is to help the patient achieve their most-desired outcome or avoid their

least-desired outcome. Understanding a patient's priorities can help to inform the overall approach to medications, including statins. 98

QUESTION 7 |In adults older than 75years without established ASCVD, what are the best practices for statin deprescribing?

|COR|LOE|RECOMMENDATIONS for QUESTION7| |---|---|---| ||C-EO| Inselectadultsolderthan75years withoutestablishedAsCVDinwhomwithoutestablishedAsCVDinwhom statindeprescribingisconsidered,sharedstatindeprescribingisconsidered,shared decision-makingbetweenclinician,patient, and/orcaregiverisreasonable. | |ma|C-EO|| ||B-NR| Inadultsolderthan75yearswithout establishedAsCVD,statindiscontinuationestablishedAsCVD,statindiscontinuation mayincrease theriskof ASCVDeventsmayincrease theriskof ASCVDevents compared to treatment continuation. | ||B-NR|| ||C-LD| Inadultsolderthan75yearswithout establishedAsCVDwithlife-limitingestablishedAsCVDwithlife-limiting illness and estimatedsurvival |

Synopsis

Deprescribing medications is an important part of the prescribing continuum and an essential component of high-quality care for older adults with multiple comorbidities, geriatric syndromes and polypharmacy who are more susceptible to medicationrelated harms. Benefits of deprescribing statins (e.g., taking fewer medications, avoiding interactions with other medications such as antibiotics or antifungal agents that are metabolized through the same pathway as the statin, avoiding adverse effects in general) must be balanced against the potential for harm, such as an increase in ASCVD events after statin discontinuation. General principles of deprescribing include viewing deprescribing as a routine part of care designed to improve patient well-being (rather than withdrawal of appropriate care) and shared decision-making with the patient/caregiver. 99 Three large cohort studies provide evidence for clinicians and patients regarding the risks and benefits of statin discontinuation on cardiovascular events in older adults without a history of cardiovascular disease who are taking statins (Table 6 ). 100–102 One small prospective trial found benefits of deprescribing among older adults near the end of life. 103

Recommendation-specific supportive text

1. Clinical decision making and communication for deprescribing statins can be complex regardless of the patient's medical conditions and frailty. It is prudent for clinicians to have thoughtful conversations with their patients and their caregivers regarding the potential benefits and risks of statin continuation and deprescribing in older age. Some clinicians may need to acknowledge and overcome their own uncertainty about stopping statins if their patients are interested in discontinuation. A study of 180 acutely ill Australian older adults found that $95\%$ were willing to

stop their statin, predominantly over concerns for adverse effects. 104 When discussing statin discontinuation through shared decision-making, clinicians may also need to alter their communication about deprescribing based on their patient's preferences. A survey of 90 Danish general practitioners identified that the most important topic clinicians wanted to discuss related to stopping statins was goals of therapy, while adverse effects were considered less important. 105 However, a U.S. study of 835 older adults found that most patients preferred phrasing focused on the risk of adverse effects when discussing deprescribing a statin. 106 Although existing data suggest the risk of statin-related adverse effects is low, older adults with frailty, severe functional or cognitive impairment, or polypharmacy have not been well-represented in studies that assessed adverse effects. Adverse effects, even mild ones, may play a greater role in driving decisions about statin therapy for such patients, and observational data suggest that nonspecific symptoms such as fatigue and dizziness are associated with the total number of medications as well as with individual medications. 107 Another small qualitative study of clinicians, caregivers and older adults with dementia found that patients and caregivers preferred clinicians to explain that aging and comorbid conditions may shift the balance of benefits and risks of medications such as statins. Examples of such phrasing are “Our bodies change over time and certain medicines may no longer be needed” and “These medications take years to have an effect and I think that we should focus on what can help you right now”. 108

2. Three observational cohort studies of older adults taking statins for primary prevention in France, Denmark and Italy (aggregate $N\!>\!200,\!000$ individuals) reported an increased risk of cardiovascular events over a subsequent 2–5year period among patients who stopped their statin, compared to patients who continued (Table 6 ). 100–102 Adjusted HRs suggested an approximately $30\%$ increase in admissions for ASCVD events during follow-up among those who discontinued statins. The reasons for statin discontinuation were unknown. While investigators adjusted for baseline characteristics or performed propensitymatching prior to data analysis, results may in part reflect residual unmeasured or unknown confounding. It is also unknown whether these estimates translate to the U.S. population. Nevertheless, these studies provide risk estimates for statin discontinuation that can be incorporated into shared decision-making conversations.

3. Deprescribing may provide benefits for patients near the end of their life. Kutner etal. evaluated 60-day survival after statin deprescribing in an unblinded randomized, parallel group non-inferiority trial of 381 individuals with life-limiting illness and an estimated survival of $_{<1}$ year; $36\%$ of patients were enrolled in hospice. There were no differences in 60-day survival or cardiovascular events between the 2 groups. Quality of life was improved and medication cost (using 2012 retail pricing) lowered among those who discontinued their statin. 103 These results indicate that it may be reasonable to discontinue statin therapy in patients with limited life expectancy due to co-morbid conditions. Further research would be helpful to guide deprescribing discussions in this population.

QUESTION 8 |For the population of adults older than 75years without established ASCVD, when should non-statin therapies be considered for ASCVD risk reduction?

|COR|LOE|RECOMMENDATIONS for QUESTION 8| |---|---|---| |||| ||C-LD| Foradultsolderthan75yearswithout established ASCVD,butwithLDL-C aboveestablished ASCVD,butwithLDL-C above guideline-recommended thresholdsandguideline-recommended thresholdsand additional risk factors, use of ezetimibe for | ||C-LD| guideline-recommended thresholdsand additional risk factors, use of ezetimibe foradditional risk factors, use of ezetimibe for reduction of LDL-C andASCVD risk may bereduction of LDL-C andASCVD risk may be considered. | ||C-LD|| ||C-LD| Foradultsolderthan75yearswithout establishedAsCVDandwithstatin intolerance,use of bempedoic acid for reductionofLDL-C andASCVDriskmaybe considered. |

Synopsis

Due to a lack of randomized controlled trials, non-statin therapy for adults older than 75years without prevalent ASCVD was not addressed in recent US or ESC guidelines of cholesterol management. 31, 109–111 Ezetimibe as monotherapy has been evaluated since in a single randomized controlled open label trial, EWTOPIA 75 (Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older) which showed a $2.6\%$ absolute and $34\%$ relative reduction in risk of MACE in the ezetimibe group. 112 The combination of statin and ezetimibe has not been evaluated in outcomes trials among adults older than 75years without ASCVD. Among adults older than 75years in whom a decision is made to use LDL-C lowering therapy for the primary prevention of ASCVD, statins are preferred given the available evidence, but ezetimibe therapy may be considered as an alternative if statin therapy is not tolerated, deemed inadvisable, or based on patient preference.

Limited data on bempedoic acid among statin-intolerant high-risk primary prevention patients are available from a subgroup analysis of the CLEAR Trial (Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients). Bempedoic acid reduced the primary endpoint of major adverse cardiovascular events by $30\%$ (absolute risk reduction $2.3\%$ ( $5.3\%$ vs. $7.6\%$ ). The mean age among primary prevention patients was 68years. In the overall trial, $15\%$ of participants were aged 75years or older, but data specific to this subgroup were not provided. There was no interaction of treatment by age. 113 Thus, among statin intolerant individuals older than 75years in whom a decision is made to lower LDL-C to reduce ASCVD risk, bempedoic acid may be considered.

Secondary prevention trials with both evolocumab and alirocumab suggest similar benefits and safety of PCSK9 inhibition in older ( ${\geq}65$ years of age) and younger individuals. 114, 115 To date, there are no large randomized controlled outcomes trials using PCSK9 inhibition for primary prevention of ASCVD. Current data are not sufficient to make a recommendation for the treatment of adults aged 75 or older without ASCVD.

Figure 3 summarizes some key steps in managing hypercholesterolemia among this population.

(Continues)

|Studies of Statin Deprescribing. TABLE 6

|(Continued) TABLE 6

Recommendation specific text

1. The EWTOPIA trial 112 randomized 3796 Japanese patients aged 75years or older without coronary artery disease to ezetimibe or usual care and followed them for a median of 4.1years; $19\%$ of patients were $\geq\!85$ years old, mean age was 80.6years. Patients had an LDL- $\mathrm{C\!\geq\!140\,mg/dL}$ off lipidlowering therapy for at least 4weeks and had at least one of the following: diabetes (present in $25\%$ ), hypertension, smoking, low HDL-C, hypertriglyceridemia, or a history of stroke (present in $7\%$ ) or PAD (present in $3\%$ ). The mean baseline LDL-C level was approximately $162\,\mathrm{mg/DL}$ . Due to loss of follow-up, withdrawn consent, and trial irregularities, only 1716 ezetimibe patients and 1695 usual care patients were analyzed. The level of LDL-C at 1year was $144.1\,\mathrm{mg/DL}$ among usual care and $126.1\,\mathrm{mg/DL}$ in the ezetimibe group, translating to an incremental LDL-C reduction of approximately $18\,\mathrm{mg/dL}$ in the ezetimibe group. The primary outcome, a composite of sudden cardiac death, fatal/nonfatal myocardial infarction, coronary revascularization, or fatal/ non-fatal stroke, was reduced by $34\%$ (133 events in the control group $[7.8\%]$ , 89 events in the ezetimibe group $[5.2\%]$ , HR 0.66, $95\%$ CI 0.50–0.86, $p\!=\!0.002\!,$ ). It is of note that the primary outcome was significantly reduced among patients without a history of stroke or PAD and there was no significant interaction by presence or absence of diabetes, chronic kidney disease or within any other pre-defined subgroup. Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; $95\%$ CI, 0.37–0.98; $p\!=\!0.039$ ) and coronary revascularization (HR, 0.38; $95\%$ CI, 0.18–0.79; $p\!=\!0.007)$ ) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence

of stroke, all-cause mortality, or adverse events between trial groups.

2. In the CLEAR Outcomes trial (Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients) enrolled both secondary prevention patients and high-risk primary prevention patients. 113 In the overall cohort, $15\%$ of participants were 75years or older. Primary prevention patients were on average older than the overall trial population (mean 68years vs. 65.5years) and had a higher prevalence of diabetes, but the proportion who were older than 75years has not been published. 116 Approximately $20\%$ of primary prevention participants were taking very low dose statins at entry to the trial. There was no interaction of treatment by age for the primary endpoint (major adverse cardiovascular events) in the overall trial analysis, but confidence intervals were wide. 113 Risk reduction for the primary endpoint was numerically greater in the primary prevention cohort (HR 0.70 $[95\%$ CI, 0.55–0.89]) than in the secondary prevention cohort (HR 0.91 [0.82 to 1.01]), p for interaction 0.03. 113, 116 Absolute risk reduction among primary prevention patients was $2.3\%$ ( $5.3\%$ vs. $7.6\%$ ). Outcomes and adverse events among the primary prevention cohort have not been reported for those older than 75years.

Future directions

Several ongoing randomized trials will help close the knowledge and evidence gap for statin benefit in older adults without a history of ASCVD and will provide guidance on selection of older patients for deprescribing statins.

 FIGURE 3 |Managing hypercholesterolemia in primary prevention patients older than 75years, with LDL-C 70–189mg/dL. Colors correspond to class of recommendation in Figure 1 . ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; LDL-C, low density lipoprotein cholesterol.

Randomized Controlled Outcomes Trials of Statins in Older Patients Without ASCVD

The Statin Therapy for Reducing Events in the Elderly (STAREE) trial enrolled approximately 10,000 Australians aged 70years and older to evaluate the effects of atorvastatin $40~\mathrm{mg}$ daily compared to placebo in patients free of ASCVD, diabetes, and dementia. 44 Patient-oriented outcomes being assessed over an expected six years of follow-up include: disability-free survival, major cardiovascular events, dementia, stroke, heart failure, cancer, hospitalization/institutionalization, and quality of life. The study is expected to be complete in 12/2025 ( clini caltrials.gov , accessed 8/14/2024). This will be the first randomized controlled trial exclusively in older adults without a history of ASCVD.

A second randomized controlled trial, PRagmatic EValuation of evENTs And Benefits of Lipid-lowering in oldEr Adults (PREVENTABLE), is currently enrolling 20,000 communitydwelling US adults aged at least 75years free of ASCVD, dementia, and disability. 45 Similar to STAREE, PREVENTABLE will evaluate the effects of atorvastatin $40\;\mathrm{mg}$ daily vs. placebo for 5years (estimated median follow-up 3.8years) and for similar patient-oriented outcomes (e.g., prevention of MCI and dementia, disability-free survival, incident ASCVD events, hospitalization). Secondary outcomes include physical performance, frailty, heart failure, and quality of life. Key differences in PREVENTABLE compared to STAREE include older age or participants and potential for enrollment of higher numbers of diverse individuals. 45 PREVENTABLE is expected to complete in 12/2026 ( clinicaltrials.gov , accessed 8/14/2024).

Randomized Controlled Trials of Statin Deprescribing in Older Patients

Two large prospective deprescribing studies will help inform clinicians and patients about the benefits and risks of deprescribing statins in older adults without a history of ASCVD. The SITE study 117 enrolled 1230 French participants aged 75years and older who were taking statins for primary prevention of ASCVD. Patients were randomized to continue or discontinue their statin, with a follow-up of 3years. The study was completed in January 2023 and will report on outcomes of incremental cost per quality-adjusted life year gained, overall mortality, quality of life, cardiovascular events, T2DM, and cognitive disorders. The STREAM study ( https://clinicaltrials.gov/study/NCT05178420 ) in Switzerland is actively enrolling 1800 participants and is expected to be complete in November 2026. The study is a noninferiority clinical trial of adults aged 70years and older who are taking a statin for primary prevention of ASCVD and are randomized to either continue or discontinue their statin with a follow-up of a mean of 24 months. The major outcomes of the study will be all-cause death and major non-fatal cardiovascular events.

Conclusion

The STAREE and PREVENTABLE trials will shed light on the benefits of statin initiation in adults over age 70years. The SITE

and STREAM studies will be the first large prospective trials to inform the benefits and risks of discontinuing statins later in life. Future trials should include more diverse study articipants to better represent the diverse patient populations treated with statins in the US and globally. In addition, better risk stratification methods in older individuals using improved risk equations derived from diverse cohorts, new imaging modalities or new biomarkers may further enhance ASCVD prediction allowing better targeting of those at greatest risk. While we await further evidence, in those who do not have a life limiting illness, primary prevention therapy with a statin can be considered as part of shared decision-making.

Evidence

The content of this manuscript is supported by citations, which are listed in the References section.

Ethics Statement

This submission did not involve human test participants or volunteers.

Peer Review

This Expert Clinical Consensus underwent peer review. Non-author editors of the journal and leadership from the National Lipid Association and American Geriatrics Society managed peer review.

Declaration of Artificial Intelligence and AI-assisted Technologies in the Writing Process

Artificial intelligence was not used in the writing of the text nor creation of its figures.

Disclaimers and Limitations

This Expert Clinical Consensus is intended to be an educational tool that incorporates the current medical science and the clinical experiences of lipid specialists, geriatricians, and pharmacists. The intent is to facilitate and improve the clinical care and management of patients. This Expert Clinical Consensus should not be interpreted as “rules” and/ or directives regarding the medical care of an individual patient. The decision regarding the optimal care of the patient is best facilitated with a patient-centered approach, managed by the clinician tasked with directing an individual treatment plan. In areas regarding inconclusive or insufficient scientific evidence, the authors used their professional judgment. This statement is not a substitute for maintaining awareness of emerging science. Finally, decisions by clinicians and healthcare professionals to apply the principles in this Expert Clinical Consensus are best made by considering local resources, individual patient circumstances, patient agreement, and knowledge of federal, state, and local laws and guidance.

Updating

This Expert Clinical Consensus may require future updates. The timing of such an update will be determined by the National Lipid Association and American Geriatrics Society.

CRediT Authorship Contribution Statement

Vera Bittner: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. Sunny A. Linnebur: Writing – review & editing, Writing – original draft, Methodology, Conceptualization. Dave L. Dixon: Writing – review & editing, Writing – original draft, Methodology. Daniel E. Forman: Writing– review & editing, Writing – original draft, Methodology. Ariel R. Green: Writing – review &

editing, Writing – original draft, Methodology. Terry A. Jacobson: Writing – review & editing, Writing – original draft, Methodology. Ariela R. Orkaby: Writing– review & editing, Writing – original draft, Methodology. Joseph J. Saseen: Writing – review & editing, Writing – original draft, Methodology. Salim S. Virani: Writing – review & editing, Writing – original draft, Methodology.

Declaration of Competing Interest

VB received research support from Amgen, DalCor, Esperion, Novartis, Sanofi and from the National Institute on Aging via subcontract from Atrium Health/Wake Forest University; is a data safety monitoring board member for Eli Lilly and Verve Therapeutics; and attended an advisory board for New Amsterdam Pharma. SAL has no disclosures. DLD received research funding from Boehringer Ingelheim. DEF received research funding from the National Institute on Aging, Veterans Health Administration, and the Patient-Centered Outcomes Research Institute. ARG received research support from the National Institute on Aging and the National Institute on Aging IMbedded Pragmatic Alzheimer’s disease and AD-Related Dementias Clinical Trials Collaboratory. TAJ has no disclosures. ARO received funding from the National Institute on Aging and the Department of Veterans Affairs. JJS was a data safety monitoring board member for Amgen. SSV received research support from National Institutes of Health, United Kingdom National Institutes for Health and Care Research, Department of Veterans Affairs, Tahir and Jooma Family, and Asharia Family.

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