Overview

This chapter will review issues related to the management of lipid disorders for cardiovascular disease (CVD) risk reduction in older patients. Because lipid metabolism and regulation do not vary greatly between younger and older people, age-related influences on cardiovascular risk and lipoprotein-mediated disease processes will be our central focus. Risk assessment and patient selection, as outlined in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, will also be reviewed.[1]

Age and cardiovascular risk

Clinicians typically approach the task of assessing cardiovascular risk by focusing on patients’ age as an obvious “nonmodifiable risk factor.” The Framingham risk score estimates a 10-year absolute risk for CVD events; age contributes enormously to the end result and is the greatest contributor to absolute cardiovascular risk. Multiple observations have concluded that atherosclerosis is a process that begins in early life.[2, 3] Compelling work by Hobbs and others focused on identifying the variant of the PCSK-9 gene has supported the concept that even a moderate reduction of low-density lipoprotein cholesterol (LDL-C) over a lifetime can result in a lowering of coronary events.[4] Their hypothesis that LDL-C might be sufficient and necessary for the cause and progression of atherosclerosis points to a lower threshold of benefit, one that was presaged by Brown and Goldstein.[5] The concept of lifetime exposure was further supported by the analysis by Ferrence et al. in which they speculated that a delay of statin therapy until later in life results in a nearly threefold increase in cardiovascular events.[6] Advanced age reflects an increased duration of exposure to various risk factors and an accumulation of coronary disease burden.[7] The Framingham Risk Score is less robust in elderly people (>70 years of age). A comparison of the risk factor counting method as outlined in the National Cholesterol Education Program Guidelines to a multivariate analysis demonstrated that these guidelines underestimated risk among at least 10% of persons with fewer than two risk factors. Those misclassified as low risk were older and more likely to be male.[8] This issue was addressed in 2013 ACA/AHA Task Force on Practice Guidelines, which derived risk equations from community-based cohorts focusing on first hard atherosclerotic cardiovascular disease (ASCVD) event to predict 10-year risk in non-Hispanic African American and non-Hispanic white men and women aged 40 to 70.[1]

Recognizing that age is such a powerful predictor for risk of heart disease, clinicians should address common modifiable risk factors in older patients such as LDL-C in order to slow the development of subclinical disease. Many elderly people are eligible for secondary prevention, and many others qualify as high-risk primary prevention. Treatment of older people has been summarized as follows:

It is clear from clinical trials that both younger and older patients who are at risk for atherosclerotic events benefit from intensive lipid-lowering therapy for both primary and secondary prevention. Ultimately, treatments should be based on a comprehensive assessment of overall cardiovascular risk, life expectancy, and patient preference, not just chronologic age.

Lessons from observational data

The incidence of coronary disease in individuals over 65 years of age is high. The middle of the 1990s saw the publication of numerous analyses questioning the predictive value of cholesterol in determining cardiovascular risk in older patients. However, in a study including patients from 52 countries (INTERHEART), the two most important predictors of coronary disease mortality were total cholesterol and smoking. In fact, abnormal lipid profiles, as determined by an Apolipoprotein A/Apolioprotein B ratio, were the most important population attributable risk in both younger and older individuals.[10] The 2013 ACC/AHA Cardiovascular Risk Guidelines supported assessment of coronary artery calcium scoring, high sensitivity C-reactive protein, ApoB, creatinine, and micro-albuminuria as the most useful marker in improving risk assessment in the intermediate risk group.[1] The purpose of the Cardiovascular Health Study (CHS) was to address the uncertainty of the risks of smoking and cholesterol in predicting overall cardiovascular risk in older patients. The ankle brachial blood pressure, carotid artery stenosis and wall thickness, electrocardiographic and echocardiographic abnormalities, and positive responses to the Rose angina and claudication questionnaire were found to be significant predictors of CVD in both men and women. At present, these measures are readily accessible to clinicians and can add greatly to the assessment of patients at risk for cardiovascular events.[11] The combination of these assessments with the demonstrated benefit of current preventive therapies is an effective strategy to reduce the incidence of and mortality associated with CVD in older patients. The importance of the CHS was to build a better understanding of the specific risk issues in managing older people and overcome some of the historical bias in the medical community to manage cardiovascular risk, particularly high cholesterol. Current standards have changed to keep up with the generation of additional evidence and risk assessment strategies.

2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults

Recent ACC/AHA guidelines, based upon evidence from 27 randomized clinical trials, outline optimal goals for LDL-C and HDL-C levels in both primary and secondary prevention and evaluate the efficacy of statins (or HMG-CoA reductase inhibitors) as the drug of choice to achieve LDL-C reductions in individuals with clinical ASCVD, LDL-C ≥190 mg/dL, comorbid diabetes or with estimated risk of ASCVD of ≥7.5%.[1] Rather than titrating medications toward a target LDL-C and HDL-C, the guidelines recommend the use of the 10-year risk of ASCVD and LDL-C 70 mg/dL–189 mg/dL levels to determine initiation of low-, moderate-, or high-dose statins. Guidelines support the continuation of moderate dose statins in people over the age of 75 years for secondary prevention, but caution is warranted due to comorbidities and the risk for polypharmacy in older adults. Although the 2013 guideline for cholesterol management has been the subject of debate, it is critically important for clinicians to appreciate the context for which they were written:

Given the potential for a significant absolute risk reduction, statins can also be used for primary prevention in persons aged 70 years with an increased 10-year risk of ASCVD. These new guidelines would increase new statin prescriptions by 12.8 million as compared to Adult Treatment Panel (ATP) III guidelines, and most of this increase in prescriptions would be for primary prevention in adults aged 60–75 years.[12]

Clinical trials and duration of therapy

Numerous clinical trials demonstrate benefits of lowering LDL-C in older persons with established CHD. Increased levels of LDL-C carry predictive power for the development of CHD in older persons as well as younger individuals. Implications from several recent clinical studies with an even broader range of baseline risk of cardiovascular disease influenced the NCEP ATP III panel to revise thinking on the intensity of treatment.[13] As reported in the Cardiovascular Health Study in 2002, the use of statin therapy in study participants at baseline who were 65 years or older and free of cardiovascular disease resulted in a 56% lower risk of CV events and 44% lower all-cause mortality.[14] Although the value of lipid lowering in older patients with known coronary disease is evident, the decision to manage risk has been modified in the current guidelines. Since relatively few individuals older than 75 were included in randomized clinical trials of high- versus moderate-intensity statin therapy, there was not clear evidence of an additional reduction in ASCVD events from utilizing higher doses of statins. Most of the benefit in older patients was seen in moderate-intensity statin trials; thus, moderate-intensity statin therapy should be considered for individuals older than 75 with clinical ASCVD. This should be considered in the context of potential for adverse effects and drug-drug interactions as well as patient choice and access to medicines.[1]

We are often asked, “How long will I be on this medication?” In more medical terms, do the benefits we see with the clinical trials last a lifetime? The answer, of course, is not known, but it would seem to lie in what we know and believe about the role of LDL-C in causing cardiovascular disease and the probability that lowering LDL-C with statins stabilizes or prevents atherosclerosis progression and limits atherosclerosis. We have strong indications that the benefit of long-term statin therapy occurs and persists in older as well as in younger and middle-aged individuals. In the 10-year follow-up of the Simvastatin Survival Study, a reduction in mortality from coronary disease, with no increase in death from cancer or other causes, in the simvastatin-treated group was noted.[15] Follow-up from the Heart Protection Study further supported this observation that ongoing lipid lowering treatment with a statin confers benefits over time without an increased risk of non-cardiovascular mortality.[16]

The Cholesterol Treatment Trialist Collaboration meta-analysis of 27 statin therapy trials demonstrated even a substantial risk reduction among low-risk patients with a five-year risk of a coronary event of less than 10% – a reduction comparable to the event reductions seen in higher-risk groups. Again, there was no compromise in safety related to cancer or other non-cardiovascular mortality over the long term. Although the most common concern for patients is muscle-related side effects, as referenced in this meta-analysis, statin therapy is associated with a small increased risk of myopathy (excess incidence of about 0.05% over 5 years) and, more rarely, of rhabdomyolysis (excess incidence of about 0.01% over 5 years).[38] The risks of myopathy are typically dose-related but, with the exception of simvastatin 80 mg daily (or lower doses in Asian populations), intensive statin regimens have not been shown to result in substantial myopathy risks.[17]

A recent report from Thompson et al. concluded that the long-term adverse events related to statin therapy – including myopathy, central nervous system effects, and the occurrence of diabetes – appear to be low but that the cumulative risk needs further study.[18]

Primary prevention in older patients

Two out of three first major coronary events occur in persons over the age of 65. Many older persons with advanced coronary atherosclerosis are asymptomatic and require further assessment – as well as clinical judgment – to determine a proper risk/benefit estimate. Given that CHD deaths account for one-half of all CHD events in older patients and the assumption that statin therapy reduces risk for all CHD categories by approximately one-third, there is likely mortality benefits of lipid lowering of 50% in older patients.[11] Recent guidelines also strongly support the use of low, moderate, or high dose statins for risk reduction based on their LDL-C levels at initiation of therapy and ten-year ASCVD risk.[1] Based on this construct, the prospects for reducing clinical CHD in the older patients by LDL-C lowering are good.

The first specific prevention trial to evaluate the role of lipid lowering with statins in older patients (aged 70–82) was the Prospective Study of Pravastatin in the Elderly (PROSPER). Older men (n = 2,804) and women (n = 3,000) at high risk of developing cardiovascular disease and stroke were randomized to placebo or 40 mg pravastatin. Patients were evaluated over an average of 3.2 years and assessed based on a composite endpoint of major coronary events, including nonfatal MI and CHD death. Each endpoint was reduced with treatment by 19% and 24%, respectively. Although no reduction in stroke occurred in the treatment group, there was a 25% reduction in transient ischemic events. These results support the notion that the benefits of statin therapy could be safely extended to older persons.[13]

A more contemporary trial in evaluating the possible role of lipid lowering in at-risk patients was completed in a large hypertensive population. The Anglo-Scandinavian Cardiac Outcomes Trial – Lipid-Lowering Arm (ASCOT-LLA) program evaluated more than 10,000 patients aged 40–79 (average 63 years of age) with at least three risk factors in addition to high blood pressure. Patients were randomly assigned to either atorvastatin 10 mg or placebo. The original study design was to provide follow-up for an average of five years, but the trial was stopped at a median follow-up of 3.3 years due to a marked reduction of events in the treatment group. Treatment with atorvastatin resulted in a reduction in the incidence of fatal and nonfatal stroke by 27% (p = 0.024), total cardiovascular events by 21% (p = 0.0005), and total coronary events by 29% (p = 0.0005).[13]

Another recent randomized trial evaluated the role of rosuvastatin as a lipid lowering agent in primary prevention in elderly persons with high C-reactive protein and low LDL-C levels. This double-blinded trial, based on a secondary analysis of the Justification for the Use of statin in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, randomized patients to rousuvastatin 20 mg or placebo. Participant profiles differed from the original JUPITER trial participants in that among more than 17,000 patients, 32% were aged 70 years or older. These patients were predominantly female and more likely to be hypertensive as compared to younger participants enrolled in the JUPITER trial.[19]

The primary endpoint of this study was occurrence of first major cardiovascular event or death from components of primary endpoints. Inclusion criteria included LDL-C level at screening of 130 mg/dL and C-reactive protein level of 2.0 mg/L at the beginning of the study. LDL-C was reduced to half (54 mg/dL) and C-reactive protein was reduced by 36%–37% in the treatment group as compared to placebo at twelve months. An absolute reduction of 48% or more was seen in the primary endpoint in the participant group treated with 20 mg rousuvastatin. Although the trial was stopped early, assessment of cumulative risks in the treatment group continued for up to four years. Statistically, the number needed to treat (NNT) to prevent one cardiovascular event or death in adults over 70 years was 24 (95% CI: 15 to 57) as compared to 36 (95% CI: 23 to 77) in younger individuals, thus indicating the relative benefit in treating older patients based on age.[19]

The results of both PROSPER and ASCOT support the efficacy of statin therapy in older, high-risk persons without established CVD. In addition, there is evidence that the absolute benefit and risk reduction seen in older patients treated with statin therapy for primary prevention of cardiovascular events is greater than that in younger patients.

Secondary prevention in older persons with established CVD

Early landmark trials using both simvastatin (Scandinavian Simvastatin Survival Study [4S]) and pravastatin (Cholesterol and Recurrent Events [CARE] trial) helped to establish the benefit of cholesterol lowering in a wide range of patients with established coronary disease.[20, 21] Both of these studies also demonstrated a treatment benefit in patients greater than 60 years of age. In the LIPID (Long-term Intervention with Pravastatin in Ischemic Disease) Study, an analysis of the comparative effects of pravastatin on CVD outcomes in patients with CHD who are 65 years of age or older compared with those in patients 31–64 years of age was performed. Whereas older patients were at greater risk for death, MI, unstable angina, and stroke than younger patients, pravastatin reduced the risk for all CV events to the same degree. Given that older patients are at greater risk than younger patients for these events, the absolute benefit of treatment is significantly greater in older patients. For every 1,000 people treated over six years, pravastatin prevented 45 deaths and 133 major cardiovascular events in older patients compared with the prevention of 22 deaths and 107 major cardiovascular events in younger patients.[22]

A Bayesian meta-analysis of statin use in elderly patients aged 62–82 was undertaken using data for secondary prevention in elders from nine clinical trials, including the 4S, CARE, and Heart Protection Study. It was shown that statins reduced all-cause mortality by 22% over five years (RR 0.78; 95% CI 0.65 to 0.89), mortality due to CHD by 30% (RR 0.70; 95% CI 0.53 to 0.83), nonfatal MI by 26% (RR 0.75; 95% CI 0.56 to 0.94), and revascularization as consequence of disease progression by 30% (RR 0.70; 95% CI 0.53 to 0.83). To save one life, the NNT with statins was 28 (95% CI 15 to 56).[23]