Primary Prevention Statin Therapy in Older Adults

Abstract

Purpose of review:

The purpose of this review is to assess the evidence for primary prevention statin treatment in older adults, within the context of the most recent guideline recommendations, while also highlighting important considerations for shared decision-making.

Recent findings:

As the average lifespan increases and the older adult population grows, the opportunity for prevention of morbidity and mortality from cardiovascular disease is magnified. Randomized trials and meta-analyses have demonstrated a clear benefit for primary prevention statin use through age 75, with uncertainty beyond that age. Despite this data supporting their use, current guidelines conflict in their statin treatment recommendations in those aged 70 to 75. Reflecting the paucity of evidence, the same guidelines are equivocal around primary prevention statins in those beyond age 75. Two large ongoing randomized trials (STAREE & PREVENTABLE) will provide additional insights into the treatment benefits and risks of primary prevention statins in the older adult population. In the meantime, a holistic approach in treatment decisions remains paramount for older patients.

Summary:

The benefits of primary prevention statin treatment are apparent through age 75, which is reflected in the current ACC/AHA and USPSTF recommendations. Ongoing trials will clarify the utility in those beyond age 75.

INTRODUCTION

The older adult population is rapidly expanding.(1) The number of individuals 80 years old or above in the United States (U.S.) alone rose from 1.7 million in 1950 to a projected 33.7 million in 2050 (40%).(2) Globally, the number of persons aged 80 years or over is projected to triple worldwide from 2019 to 2050.(3)

As life expectancy increases, so too does the opportunity for disease prevention. The prevention of atherosclerotic cardiovascular disease (ASCVD) is a particular priority among older adults who are overrepresented among populations presenting with myocardial infarction (MI) and stroke, and have worse long-term mortality.(4, 5) Indeed, individuals who are free of ASCVD at age 65, have a life-time risk for developing cardiovascular disease that exceeds 50%(6) and ASCVD is responsible for 39% of all deaths among individuals 75–84 years of age.(7) ASCVD also causes significant morbidity for older populations including predicting future disability and reducing quality of life by leading to difficulties with mobility and managing activities of daily living.(8, 9) Finally, the burden of ASCVD has major cost implications for both patients and the healthcare system at large. The percentage of patients experiencing financial toxicity related to cardiovascular disease exceeds that seen with cancer.(10–13)

As the population ages, the opportunity for ASCVD prevention in older adults has only increased. Preventing a first ASCVD event, including the need for costly hospitalizations and ongoing chronic vascular disease management, carries major implications in older adults who are most vulnerable to in-hospital complications, post-hospitalization disability, and long-term effects of polypharmacy.(14–23) Statins are considered a cornerstone of both primary and secondary prevention of ASCVD.(24–29) Historically, older adults have been underrepresented in randomized trials investigating statin treatment, with data on primary prevention statin treatment particularly limited. Available evidence suggests that the benefits of lipid lowering treatment likely extend to those at advanced age: for every 1 mmol/L reduction in LDL-C cholesterol in older adults (>75 years old), there is a 26% proportional reduction in major vascular events (30, 31). Given the much higher event rate in older adults, the absolute benefit of lipid-lowering is likely to exceed that in younger patients. While the benefits of statin therapy are well-established in younger (< age 75 years) adults, data are more sparse in older adults. This uncertainty is reflected in recently released guideline recommendations in both the U.S. and Europe, which vary in their treatment recommendations and age cutoffs for statin therapy (24–26). The purpose of this review is to assess the evidence for the use of statins for primary prevention of cardiovascular disease in older adults, while also highlighting the areas of particular complexity for shared decision making regarding statins in older patients.

DISCUSSION

Evidence-base Primary Prevention Statin Treatment in Older Adults

Compared with the evidence base in younger adults, the evidence-base underlying statin therapy in the primary prevention setting for older adults is more modest, especially in those ≥75 years old. Nevertheless, a limited number of studies have examined this issue, including patients in their 70s and above. The first RCT evaluating primary prevention statin use that included individuals above the age of 70 years old was the AFCAPS/TexCAPS trial published in 1998, which demonstrated the benefit of lovastatin 20–40 mg daily mg versus placebo to reduce the risk of a first major coronary event in 6605 individuals up to age 73.(32) This study excluded adults over 73 years of age, and the mean age was 58 years (SD ±7 years). However, 21% of subjects were 65 or older. Subsequently, the Heart Protection Study (HPS) (simvastatin 40 mg vs placebo in 20,536 high-risk adults aged 40–80 years) was a mixed primary and secondary prevention study that found a significant reduction in all-cause mortality with simvastatin treatment versus placebo (12.9% vs. 14.7%, p=0.0003).(33) HPS included 5805 participants at least 70 years of age at study entry and was the first large randomized primary prevention trial of statins that included patients over the age of 75, with 1263 participants between 75 and 80 years of age.(33) Shortly thereafter, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid-Lowering Trial (ALLHAT-LLT) assessed the value of pravastatin 20–40 mg in primary prevention treatment among more than 10,000 ambulatory adults ≥55 years old (mean age 66 years), and found no significant improvement in mortality or cardiovascular outcomes among those treated.(34) The negative results of the trial were attributed to the modest differential achieved in LDL-C (16.7%) and total cholesterol (9.6%) compared with prior statin trials. The lack of benefit on mortality extended to the 5809 patients ages ≥65 years old that were enrolled in the trial.(34) In fact, a non-significant trend toward increased mortality associated with pravastatin use was observed among the 726 patients ≥75 years.(35) However, this post hoc exploratory analysis was limited by excessive crossover between treatment groups and a relatively small sample size.(36)

While the aforementioned RCTs included some older adults, the vast majority of those included were younger than age 65. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was the first and only dedicated evaluation of statin therapy in an older population to date, randomizing 5804 individuals 70–82 years of age including those with and without cardiovascular disease to pravastatin 40 mg versus placebo. Overall, those treated with pravastatin experienced significant reductions in the primary endpoint of coronary heart disease (CHD) death or non-fatal MI or fatal or non-fatal stroke (HR 0.85, 95% CI 0.74–0.97), as well as the secondary endpoint of CHD death or non-fatal MI. While there was a suggestion of attenuated efficacy among the 3239 individuals without vascular disease at baseline (HR 0.94, 95% CI 0.77–1.15) compared with the 2565 with prior vascular disease (HR 0.78, 95% CI 0.66–0.93), the interaction test was not significant (p=0.19).(37)

The contrasting findings of these early trials were followed by multiple RCTs weighing firmly on the side of benefit for statins in primary prevention, especially for patients between age 70 and 75. First, the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA),(38) a randomized trial of 10,305 individuals with hypertension and at least three other cardiovascular risk factors (but not hyperlipidemia), found that the absolute benefits of atorvastatin 10 mg were greatest among older patients, with a 37% relative reduction in the composite of nonfatal MI and fatal CHD among the 4445 patients ≥65 years old (mean age 71 years).(39) The Collaborative Atorvastatin Diabetes Study (CARDS) trial demonstrated a dramatic 37% relative risk reduction with primary prevention atorvastatin 10 mg/day versus placebo in 2838 persons with diabetes aged 40 to 75 years old,(40) with a consistent 38% relative risk reduction in the subset of patients ≥65 years old (N=1129; mean age=69 years).(41) A secondary analysis of the JUPITER (Justification for Use of Statins in Prevention) trial demonstrated that the use of rosuvastatin 20 mg/day in 5695 older individuals (≥70 years old) resulted in a 39% reduction in the hazard of a first cardiovascular event with a trend toward improvement in all-cause mortality (p=0.09).(42) The absolute benefits with rosuvastatin treatment were actually highest among older aged patients in JUPITER. Most recently, the HOPE-3 trial randomized 12,705 patients to rosuvastatin 10 mg/daily versus placebo, including 3086 patients ≥70 years old, finding a 24% risk reduction in cardiovascular events with primary prevention statin treatment.(43) A meta-analysis of the ≥70 year old cohort of patients from JUPITER and HOPE-3 found a 26% relative risk reduction for nonfatal MI, nonfatal stroke, and cardiovascular death.(44)

Pooled data from statin randomized trials have shown that statins do appear to be effective in older adults, especially those up to age 75. The Cholesterol Treatment Trialists performed a meta-analysis of randomized trials assessing the efficacy and safety of statin therapy in older people that included 14,483 individuals >75 years old, including 6449 (45%) without a history of vascular disease.(30) This meta-analysis included an even larger group of 27,314 individuals in the >70 to ≤75 age group, including 10,546 without a history of vascular disease; notably, that age category did not include the likely thousands of 70 year old patients in the meta-analysis who were grouped into the >65 to ≤70 category (36,567 total, 15,896 primary prevention). Among those with and without pre-existing vascular disease there was a 12% proportional reduction in vascular mortality per 1.0 mmol/L reduction in LDL cholesterol. The researchers did find that among adults over 75 years, the relative risk reductions in cardiovascular risk per mmol/L reduction in LDL-C did appear to attenuate with older age (p trend 0.004). Notably, however, this trend was no longer statistically significant after exclusion of trials of heart failure or dialysis patients. Among those patients without vascular disease, the authors observed an attenuated treatment effect among older compared with younger individuals (p trend = 0.05). In those >75 years of age, the observed relative risk on statins was 0.92 per 1 mmol/L reduction in LDL cholesterol for major vascular events (95% Confidence Interval = 0.73–1.16);among those >70 to ≤ 75 years old, the RR was 0.84 (95% CI: 0.70–1.01), with a point estimate similar to the effect seen in those >55 to ≤ 60 years (RR 0.81, 95% CI 0.67–0.99). Interestingly, the greatest benefit in any age group was observed in those >65 to ≤70 years of age with a relative risk reduction of 39% (RR 0.61, 95% CI 0.51–0.73). The authors acknowledged the weak trend towards smaller relative risk reductions with increasing age in patients with a primary prevention indication for statin treatment but also pointed to the limited sample size in that particular cohort which precluded a reliable assessment.(30)

Data from non-statin trials also indirectly supports the benefit of statins in older adults. While ezetimibe is not a statin, the benefits of ezetimibe have been shown to correlate with the degree of LDL-C lowering, similar to that observed in statin clinical trials.(45) Ezetimibe was studied in an exclusively older population in Japan in the Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75) trial, which randomized adults aged 75 and older free of coronary artery disease to ezetimibe 10 mg vs usual care. At a median follow-up of 4.1 years, those on ezetimibe had a statistically significant 34% reduction in the primary endpoint of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke and reduced cardiac events by 40%.(46) When the data from EWTOPIA are combined with clinical trial data examining statins and proprotein convertase subtilisin/kexin type 9 inhibitors, respectively, meta-analyses suggest that LDL-C lowering significantly reduced the risk of major vascular events in older patients by 26% per 1 mmol/L reduction in LDL-C cholesterol.(31) This treatment effect was not statistically different from that observed in younger individuals, nor was there evidence of treatment difference in patients with established ASCVD at baseline vs. those without (p-interaction = 0.89).(31)

Even if the impact of statins on a person’s relative risk of CV disease may be attenuated in older adults, because the absolute risk of cardiovascular disease is so much higher in older patients, the absolute benefits of statin therapy may still be greater in older populations.(47) For example, those ≥70 years of age represented 32% of the JUPITER population but experienced 55% of the cardiovascular events observed; in HOPE-3, those ≥70 years old made up 24% of the trial population but experienced 43% of the events.(44) Given that older populations are at the highest risk for ASCVD events, they also likely glean the most absolute benefit from statin treatment. This is especially true in the 70 to 75 year old age group where there were far more patients included in randomized trials to date and less suggestion of attenuated benefit for primary prevention statin treatment from ASCOT-LLA, JUPITER, HOPE-3, and the Cholesterol Treatment Trialists’ Collaboration.(30, 38, 42–44) Given that the absolute benefit with statin treatment is mostly driven by the absolute underlying ASCVD risk, even if one assumes a strongly attenuated benefit in the ≥75 year old age group, the absolute benefits may still be substantial with a relatively low number needed to treat to prevent one event in that population.(47)

Statin Safety

Statins are generally considered safe and well-tolerated, with a risk of myopathy of approximately one case per 10,000 person years, 2–3 cases of rhabdomyolysis per 100,000 person-years, newly diagnosed diabetes mellitus of 0.2% per year, and serious hepatoxicity of approximately 0.0001%.(48, 49) Concerns about safety are particularly important when considering therapeutic decisions in older adults. While an early case control study suggested a link between older age (>65 years) and the risk of rhabdomyolysis,(50) these findings have not been substantiated in randomized trials: the available randomized trial data and meta-analyses have not documented any heterogeneity in statin-related adverse effects by age.(30, 51, 52) Beyond serious adverse events, muscle symptoms are a common concern among patients when faced with statin treatment decisions. Among 6717 adults enrolled in the Patient and Provider Assessment of Lipid Management (PALM) registry in 2015, older adults on statin therapy (≥75) were actually slightly less likely to report any symptoms (41.3% vs. 46.6%, p = 0.003) or myalgias (27.3% vs. 33.3%, p <0.001) on treatment compared with their younger counterparts.(53) Reassuringly, the majority of older adults who discontinue statin therapy eventually restart treatment.(54, 55) Furthermore, the impact of the so-called “nocebo effect” of statin therapy and associated muscle complaints has been well-documented in recent years,(56–60) with >90% of muscle related symptoms attributable to placebo.(61)

Non-muscle related adverse effects related to statins are also rare. New onset diabetes occurs infrequently but does appear to possibly be age related, occurring in predisposed individuals with metabolic syndrome.(62, 63) Many older adults have worries about the potential for cognitive impacts of statin therapy. The currently available data suggest that there is no increased risk of dementia associated with statin treatment in older populations, and that these medications can be used safely in older adults without significant cognitive concerns.(49, 64) This includes several systematic reviews and meta-analyses investigating this issue, some of which have actually suggested a potential cognitive benefit with statin use.(65–70) The safety of intensive lipid lowering on cognitive function has been further reinforced by the results of the Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk (EBBINGHAUS) trial, a subset of 1,204 patients from the Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects with Elevated Risk (FOURIER) trial, demonstrating that evolocumab added to statin therapy did not affect cognitive performance.(71) There was also no impact on patient-reported cognition in the overall FOURIER trial population with evolocumab treatment, including in those with very low LDL-C levels achieved (<20 mg/dL).(72)

Guideline Recommendations

Figure 1 summarizes the state of the evidence surrounding primary prevention statin treatment in older adults, placing the current guideline recommendations in the context of prior studies and ongoing trials. Guideline recommendations reflect the relative lack of data in older adults and are somewhat variable in how statin recommendations are treated in older populations. The 2018 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Management of Blood Cholesterol reflect the uncertainty in the evidence for treatment in older adults ≥75 years of age, providing a class IIb (LOE B-R) recommendation that moderate-intensity statin therapy may be reasonable in individuals ≥75 years with LDL-C 70 to 189 mg/dL for the primary prevention of ASCVD.(24) In adults up to age 75, the ACC/AHA guideline provides a class I recommendation for statin treatment if they have LDL-C >=190 mg/dL, diabetes mellitus, or a 10-year ASCVD risk ≥7.5% with risk enhancers present. Notably, all statin treatment recommendations from the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease are included or adapted from the 2018 ACC/AHA Cholesterol guideline, but the 2019 document does not provide the specific class Iib recommendation for the ≥75 age group, leaving treatment decisions entirely up to clinical assessment and a risk discussion.(73)

Figure 1.

State of the evidence. Figure 1 displays a summary of the available data on the left of the figure, the most recent guideline recommendations centrally, and emerging data on the right.

The latest 2021 European Society of Cardiology (ESC) Guidelines on cardiovascular disease prevention in clinical practice provide even more conservative recommendations in this population, defining older adults as those ≥ 70 years rather than ≥75 years and providing just a Class Iib treatment recommendation for lipid-lowering drugs to be considered in older patients at ‘very high risk’ with a calculated 10-year cardiovascular disease risk threshold ≥15%.(25) This is compared with a Class Iia recommendation for those ≤69 years at ‘very high risk’, with lower risk thresholds in the younger age groups (≥7.5% in those <50 years old and ≥10% in those 50–69 years).(25) The exclusion of individuals >69 years old from a strong recommendation for primary prevention statin treatment by the European guidelines may represent a key missed prevention opportunity in a relatively high-risk cohort of 70 to 75 year old patients who could benefit from lipid-lowering treatment.

Most recently, the U.S. Preventive Services Task Force (USPSTF) published their Task Force Recommendation Statement on Statin Use for the Primary Prevention of Cardiovascular Disease in Adults, providing a Grade B recommendation to offer statin treatment to adults 40 to 75 years with 1 or more cardiovascular risk factors and an estimated 10-year cardiovascular disease risk of ≥10%.(26) They also provide a Grade C recommendation for selective offering of statin treatment for those with estimated risk of 7.5% to <10%.(26) However, the USPSTF made no recommendations for statins for adults ≥76 years or older due to insufficient current evidence to properly assess the balance of benefits and harms of primary prevention statin treatment in that age group (Grade I).

Emerging Data

Uncertainty around the balance of benefits and harms for primary prevention statin use in older individuals has consistently been highlighted as one of the key evidence gaps for further investigation.(26) Two ongoing randomized controlled trials are directly addressing the existing evidence gaps in the use of statin treatment in older adults without preexisting vascular disease. The Statin Therapy for Reducing Events in the Elderly (STAREE; NCT02099123) trial is randomizing 18,000 community-dwelling adults in Australia ≥70 years old without known ASCVD to either atorvastatin 40 mg/day or placebo. The study co-primary outcomes are time to death or development of dementia or significant disability and time to a major fatal or non-fatal cardiovascular event. STAREE is also examining a variety of secondary endpoints including cognitive decline and incident dementia, frailty or disability, and QOL and is scheduled to complete in December 2023. The ongoing Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE; NCT04262206) trial will randomize 20,000 community-dwelling U.S. older adults (≥75 years old) without preexisting cardiovascular disease to atorvastatin 40 mg/daily versus placebo. PREVENTABLE will determine whether primary prevention statin treatment can reduce the primary composite of death, dementia and persistent disability, with secondary endpoints of mild cognitive impairment and cardiovascular events. Follow-up is planned for up to 5 years across approximately 100 U.S. sites with an estimated study completion date of December 31^st, 2026.

Putting it All Together: Considerations for Shared Decision Making

In the context of patient-provider shared decision making, what should patients and clinicians consider when making statin treatment decisions in older adults?

First, given that an individual’s absolute potential benefit from statin therapy is proportional to their absolute risk of cardiovascular disease, any decision regarding statin therapy should begin with a comprehensive cardiovascular risk assessment. Next, clinicians should assess patient priorities regarding cardiovascular disease prevention, and review each patient’s potential benefit in this context. While mortality benefits are certainly important, avoiding excess morbidity becomes more important as patients age, with evolving priorities and preferences.(74) For example, an older patient may prioritize the value of avoiding a prolonged hospitalization for MI or a debilitating stroke over the excess burden of taking one additional medication. The potential cardiovascular benefit for an individual must also be considered in light of any competing risks of non-cardiovascular mortality. The adverse effects of polypharmacy in older adults must also be considered when initiating additional medications in light of potential drug-drug interactions.(75, 76) Fortunately, statins are available as low-cost generic formulations even for people without prescription drug insurance, so unlike with other new therapies, cost is rarely a barrier for statin adherence. In addition to the significant clinical burden associated with the need for acute treatment of incident ASCVD, hospitalizations for ASCVD events are incredibly costly.(10–13) There is no debate over the fact that preventing fatal and non-fatal ASCVD events in older adults would be beneficial to both the individual and to the healthcare system in terms of cost savings.(47) Fundamentally, clinicians and patients must weigh the net benefit of primary prevention statins in older adults by balancing an individual’s potential benefits, including lower cardiovascular risks and avoiding burdensome hospitalizations, with the potential tradeoffs & harms from treatment that may result from polypharmacy and potential side effects (Figure 2). These decisions occur within the context of that patient’s competing conditions, which become more frequent and complex in the aging population, and through the lens of that patient’s unique priorities

Figure 2:

Considering the net benefit of primary prevention statins in older adults: Balancing benefits, harms, & tradeoffs

The aforementioned discussion focuses on initiation of statins in older adults. Given that age is the primary driver of risk in the pooled cohort equations, more than 97% aged 66–75 would potentially meet eligibility criteria to be considered for statin treatment based on the ACC/AHA guidelines and nearly all patients over age 75 when considering 10-year calculated risk alone.(77) Treatment of individuals ≥75 years old could prevent 105,000 myocardial infarctions and 68,000 CHD deaths over 10 years in the United States alone.(78–80) However, equally important is what to do for patients who reach the age of 70 or 75 and are already taking a statin. Recommendations on statin discontinuation are limited.(81) The ACC/AHA guideline does comment on statin discontinuation in older patients, suggesting that it may be reasonable to stop statin therapy when functional decline, multimorbidity, frailty, or reduced life-expectancy limits the potential benefits of statin treatment (Iib, LOE B-R).(24) This recommendation is based on a single unblinded randomized trial of statin continuation vs. discontinuation in a mixed population of primary and secondary prevention patients that enrolled 381 patients (mean age 74.1 years) with an advanced, life-limiting illness determined to have limited life expectancy between 1 month and 1 year, recent deterioration in functional status and no recent active cardiovascular disease.(82) The trial failed to meet the noninferiority margin for its primary endpoint of the proportion of participants who died within 60 days, which was actually modified midway through the study from the original primary endpoint of survival with an original sample size estimate of 1200 participants. There was a suggestion of modest improvements in quality of life among those patients who had their statin discontinued. A cross-sectional survey of Australian inpatients >=65 years old taking a statin, finding that 95% would be willing to have their statin deprescribed if their doctor said it was possible.(83) However, the guidelines also acknowledge that older patients with frailty and multiple chronic conditions may prefer to remain on treatment because they have the highest baseline risk and are the most likely to benefit from statin treatment. Importantly, none of the large primary prevention randomized trials included stopping individual patient’s statins and there may be harm associated with stopping statins in non-palliative patients. For example, two separate cohort studies of individuals ≥75 years of age in both Denmark and France found that discontinuation of statins was associated with higher rates of cardiovascular events compared with primary prevention statin continuation.(84, 85) Another large population-based cohort study of 29,047 Italians 65 years and older (mean age 76.5 years) found that statin discontinuation in older adults receiving polypharmacy lead to an increase in the long-term risk of fatal and nonfatal cardiovascular outcomes.(86) Thus, clinicians should exercise caution when considering statin discontinuation in older adults, with an emphasis on individualized shared-decision making in this complex population.

CONCLUSION

As average life expectancy increases and the number of individuals surviving old age grows, the opportunity to accrue benefits from intensive preventive efforts is magnified. The available evidence suggests a treatment benefit for primary prevention statin use at least up to age 75, which is reflected in both the ACC/AHA and USPSTF recommendations but not the ESC guidelines. Guideline recommendations are consistently equivocal in their recommendations for primary prevention statins beyond age 75, reflecting the paucity of available data. The most recent guidelines appropriately acknowledge the importance of taking a holistic approach in statin treatment decisions for older patients, with clinicians encouraged to consider these shared decisions within the context of potential multimorbidity and polypharmacy. Ultimately, ongoing randomized trials will shed further light on the potential benefits of primary prevention statin treatment in older adults, including not only the impact on cardiovascular disease but also on cognitive outcomes.

KEY POINTS.

• The available evidence suggests a clear treatment benefit for primary prevention statin treatment up to age 75.

• Current recommendations are equivocal around primary prevention statin use beyond age 75, reflecting the uncertainty around treatment benefits extending to more advanced chronologic ages.

• Ongoing clinical trials will provide insights into the treatment benefits of primary prevention statins in older adults, including in those beyond age 75.