Statin Treatment for Older Adults: The Impact of the 2013 ACC/AHA Cholesterol Guidelines - new analysis: "the evidence is lacking for older adults without major cardiovascular risk aside from age"
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Significant association between statin-associated myalgia and vitamin D deficiency among treated HIV-infected patients - (04/11/17) ......To conclude, low vitamin D levels seem to be associated with the development of statin-induced myalgia in HIV-infected patients under cART like in the general population, but additional, enlarged, and controlled studies are needed to examine the potential role of vitamin D deficiency in the reduced statin tolerance by HIV-infected people
"the evidence is lacking for older adults without major cardiovascular risk aside from age"
Statin Treatment for Older Adults: The Impact of the 2013
ACC/AHA Cholesterol Guidelines
Drugs Aging (2015)
Yitzchak Weinberger ⋅ Benjamin H. Han
The 2013 American College of Cardiology (ACC) and American Heart Association (AHA) practice guidelines for the treatment of blood cholesterol significantly changed the paradigm of how providers should prescribe statin therapy, especially for older adults. While the evidence supports statin therapy for older adults with cardiovascular disease for secondary prevention and with high cardiovascular risk for primary prevention, the evidence is lacking for older adults without major cardiovascular risk aside from age. The unclear evidence base for older adults must be considered along with the potential harms of statin therapy when incorporating the 2013 ACC/ AHA practice guidelines for considering statin treatment, particularly for primary prevention for older adults.
In the last century, there has been an increase in the population aging. Advanced life-saving procedures, new medications, and our evolving medical knowledge are key factors in increased longevity. The focus on prevention has contributed to the growing numbers of older people. Cardiovascular disease (CVD) remains the number one cause of death, and the application of measures to prevent it has undoubtedly contributed to the increase of the older population.
Age is one of the most recognized non-modifiable risk factors for CVD. Other modifiable risk factors such as hypertension, diabetes mellitus, dyslipidemia, and obesity may be increased with older age . Therefore, primary and secondary prevention for CVD is of importance for
older adults who possess the inherent risk for developing CVD.
Statins are very effective in lowering low-density lipoprotein (LDL) cholesterol  and shown to be cardioprotective through their anti-inflammatory and oxidative properties . This has been associated with a decrease in cardiovascular disease outcomes , but for only for specific patient populations. Unfortunately, many clinical research trials have excluded older adults , and the evidence base for many treatments for older patients is lacking. The 2013 American College of Cardiology/ American Heart Association (ACC/AHA) practice guidelines for cholesterol treatment have the greatest implications for older age groups; however, the evidence especially for primary prevention is unclear.
2 ACC/AHA Blood Cholesterol Guidelines
The new paradigm shift for which populations should be considered for statin treatment comes from new recommendations and prescribing guidelines issued in 2013 by the ACC/AHA . The guidelines identified four groups of patients who should be considered for statin treatment. These groups are adults with: (1) clinical atherosclerotic cardiovascular disease (ASCVD) defined as coronary artery disease, cerebrovascular disease, and peripheral arterial disease, (2) LDL levels[190 mg/dL, (3) patients with diabetes mellitus aged 40-75 years with LDL levels [70 mg/dL, (4) LDL [70mg/dL and a 10-year risk of ASCVD of at least 7.5 %. New pooled cohort equations and a risk-calculator were developed to estimate the 10-year risk of developing ASCVD outcomes for the purposes of primary prevention . The guidelines specify to calculate ASCVD risk using the calculator for adults up to the age of 79 years, and do not mention considerations to stop statin therapy for adults aged over 79 years.
These guidelines were met with much criticism. The majority expressed concern with regard to the great increase in the number of patients subject to statin therapy [7-9]. A recent study concluded that under the new guidelines, an increase in the net number of new statins prescriptions would exceed 10 million . This expansion would be mostly in older adults between the ages of 60 and 75 years. The guidelines themselves indicate that age would be a major deciding factor in initiating statins. Using the 10-year ASCVD risk calculator  with its stated optimal values for total cholesterol of 170 mg/dL, high density lipoprotein (HDL) of 50 mg/dL, systolic blood pressure of 110 mm Hg, not taking medications for hypertension, not having diabetes mellitus, and not a smoker: all white men aged between 63 and 75 years, all white women aged between 71 and 75 years, all African American men aged between 66 and 75 years, and all African American women aged between 70 and 75 years would be determined to be statin candidates for primary prevention. A new condition, ''statinopause'' or ''statin deficiency'', was coined to describe this .
3 Evidence for Primary Prevention for Older Adults
The 2013 ACC/AHA cholesterol guidelines do recommend statin treatment as primary prevention for older adults, and careful review of the evidence used for the guidelines is warranted for the basis of these practice recommendations. A 2009 meta-analysis on the effect of statins in subjects without CVD disease that included more than 70,000 participants, found a decrease in mortality and reduction in coronary and cerebrovascular events .This analysis, however, was not focused on the older population; in a subgroup analysis of those aged older than 65 years the same benefit was found. However, the benefits in the older sub-group did not reach statistical significance. The confidence interval for all-cause mortality and cerebrovascular events in the subgroup of patients aged[65 years crossed the identity line pointing towards no definitive evidence of benefit.
A more recent meta-analysis that focused only on older patients aged >65 years did find statins to significantly reduce the incidence of myocardial infarction (MI) and stroke, but not significantly reduce all-cause death or cardiovascular death . Again, careful examination of the eight studies selected for this meta-analysis shows that all of the studies involved patients with high cardiovascular risk ranging from hypercholesterolemia to diabetes mellitus. Therefore, this meta-analysis only shows benefit for a subpopulation of older adults, and is not generalizable to older adults without high cardiovascular risk.
The first statin trial to include a cohort of older individuals was the AFCAPS/TexCAPS study . This trial included over 6,000 participants of whom roughly 20 % were aged >65 years. The entry lipid parameters were hypercholesterolemia and/or low HDL levels with the benefits of lovastatin vs the placebo being studied. Treatment with lovastatin resulted in a 37 % reduction (p<0.001) in the risk of an acute major coronary event. Thus, this trial demonstrated the efficacy of a statin in primary prevention among specifically older adults with hypercholesterolemia and/or low HDL.
Following the AFCAPS/TexCAPS trial, the ALLHATLLA  trial evaluated pravastatin vs placebo in subjects aged >55 years who were also enrolled in its portion of the blood pressure-lowering trial (ALLHAT). Subjects aged >65 years comprised 55 % of the trial participants. All
participants had hypertension, as it was a lipid study within a hypertensive study. A large number of participants also had diabetes mellitus (35 %), and a smaller yet significant percent had history of cardiovascular heart disease (CHD) (15 %). This trial did not find significant reduction in total mortality, CHD, or stroke in the statin group.
Like the ALLHAT-LLA, the ASCOT-LLA , was a statin trial within a larger hypertensive trial (ASCOT). The entry criterion was high-risk individuals with at least three cardiovascular risk factors. Participants aged >60 years comprised 64 % of the study population. Atorvastatin vs placebo was studied. The treatment group across all ages had a significant reduction in primary endpoints of myocardial infarction and fatal CHD events (36 % reduction). This trial supported the use of statins for primary prevention specifically for high-risk older adults.
The HPS  and PROSPER  were also clinical trials investigating statins in high-risk individuals, but also included a cohort for secondary prevention. HPS studied simvastatin vs placebo in individuals aged 40-80 years. Although the percentage of patients aged older than
65 years were not reported in the primary prevention group, overall, more than half of the trial participants were aged older than 65 years. The treatment group had a significant 25 % reduction in the primary endpoint of first major coronary artery disease event. This reduction was regardless of age.
The PROSPER  trial is the only trial specifically designed to study statins in older adults aged 70 years and older. It enrolled high-risk participants as well as those with established vascular disease to study the effect of pravastatin vs placebo. Of the study population, 55.8 % were considered primary prevention, although with high risk for cardiovascular disease, and the remainder with established vascular disease. The primary outcome included
the composite of CHD death, non-fatal MI, and fatal or non-fatal stroke. The primary endpoint was reduced by 15 % (p = 0.014) and included a 24 % reduction in CHD death and a 19 % reduction in combined CHD death and non-fatal MI. However the study did not reach statistical significance for statin benefit in stroke prevention and reduction of all-cause mortality. The long-term follow-up of the PROSPER trial also did not reach a significant reduction of all-cause mortality in the pravastatin group .
The CARDS  trial examined atorvastatin vs placebo in patients with diabetes mellitus. More than 50 % of the patient population were aged older than 60 years, with 12 %aged older than 70 years. The study was terminated early because of a significant decrease in events in the atorvastatin group, indicating a statin benefit in adults with diabetes mellitus.
In a sub-study analysis of the more recent JUPITER  study, which included 5,695 participants aged over 70 years, a significant reduction in major cardiovascular events was found in the statin group. The number needed to treat to prevent a cardiovascular event in 4 years was in fact smaller in the older cohort compared with the younger cohort studied in the parent trial, JUPITER. In addition, the entry criteria for the JUPITER study required a high-sensitivity C-reactive Protein (hsCRP) level of ≥2 mg/dL. In clinical practice, it is unclear how to interpret older adults with an hsCRP of C2 mg/dL, and whether this population is generalizable to older adults without significant cardiovascular disease risk factors.
from the published report in JAMA Intern Med today:
The other major randomized trial that had a large proportion of older individuals, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER),17 included 5695 individuals 70 years and older with no cardiovascular disease at baseline but with a high-sensitivity C-reactive protein level of 2 mg/L or more (to convert C-reactive protein level to nanomoles per liter, multiply by 9.524). A secondary analysis of participants 70 years and older in the JUPITER study17 found all-cause mortality of 1.63 per 100 person-years in those receiving rosuvastatin and 2.04 per 100 person-years in those receiving placebo, a difference that was not statistically significant (P = .09). The JUPITER study has come under criticism pertaining to the early termination of the trial and strong commercial conflicts of interest.37
There is a lack of data for primary prevention in older patients. Although these individuals may benefit most from statins owing to their age being a significant risk factor, it is difficult to justify initiating statin therapy to all older adults especially those without risk factors aside from age. The few clinical trials done for this age group focused specifically on a subset of older adults with high cardiovascular risk. A review of all the randomized controlled trials of statin therapy for primary prevention that included older individuals can be found in Table 1.
5 Implications for Older Adults
These clinical trials demonstrate the benefit of statins in older adults, and are the evidence base for the 2013 ACC/AHA cholesterol guidelines. However, as critics point out, none of these trials deal with age as a risk factor alone. Older subjects in these trials had additional risk factors besides age. To date, no studies have been conducted to assess statins for primary prevention in the low-risk older population, it also may not be clear if LDL still predicts coronary heart disease and mortality as one ages . A recent study of older participants aged 85 years and older found that higher total cholesterol levels were associated with lower mortality, including cardiovascular and non cardiovascular mortality . This has been explained conceptually as ''reverse epidemiology'', where higher cholesterol may be a reflection of a more ''robust'' aging with better nutritional status, fewer comorbidities, and less frailty. This results in a dilemma for providers caring for older adults who have to weigh the risks and benefits of statin therapy with an incomplete evidence base for patients often with multiple competing health and social concerns.
From a geriatric provider perspective, there are risks and downsides to statin therapy for older adults, particularly for those with multiple chronic conditions and frailty. Statins are known to cause myopathy and have been associated with liver dysfunction and cataracts in observational studies , and exertional fatigue . The most common adverse event of statin therapy is myopathy. The ACC/ AHA in their clinical advisory estimated that severe myopathy occurs at a rate of 0.08 % with lovastatin and simvastatin . The advisory paper concluded that the risk of myopathy is particularly increased in those aged 80 years or older, although comparative rates between and older and younger subjects were not reported. In a retrospective study on statin monotherapy, patients aged 65 years and older were more likely to be hospitalized with rhabdomyolysis compared with those aged younger than 65 years (relative risk, 5.4; 95 % confidence interval 1.3-21.6) . A possible reason for this increase has been suggested to be related to drug-drug interactions. Statin-induced myopathy is dose dependent, and many drugs interact with statins to raise the plasma-statin concentration. As older adults often have multiple chronic conditions that result in having to take several medications, their risk for myopathy is greater.
More recently, concern has been raised that statins may be associated with cognitive impairment. In 2012, the US Food and Drug Administration stated that ''ill-defined memory loss'' and ''confusion'' were noted among statin users . The cognitive impairment was not related to fixed dementias such as Alzheimer's dementia, but rather thought to be reversible with cessation of the statin drug. However, two large meta-analysis studies that included 38 trials did not find an association between statins and cognitive impairment. To the contrary, a possible protective effect of statins on long-term cognition was noted .
The association between statins and diabetes mellitus has been suggested by the JUPITER trial . There is controversy as to whether this risk differs with the different statin drugs. It seems, however, that the higher intensity statins are associated with a higher risk of diabetes mellitus than the moderate intensity statins . Age also seems to be a risk factor for developing diabetes mellitus for those taking statins, as this association is found primarily in trials with older patients . A recent study by Swerdlow et al.  used an updated meta-analysis of 20 randomized controlled studies to show that statin therapy increases the risk of incident type 2 diabetes mellitus, with an odds ratio of 1.12 (95 % confidence interval 1.06—1.18). The study further showed using the technique of ''Mendelian randomization'', that the gene encoding the HMG-coenzyme A (HMGCoA) reductase protein, when suppressed, causes a slight increase in the incidence of type 2 diabetes mellitus, suggesting that the diabetogenic effect of statins is inherent in the inhibition of HMGCoA.
These possible harm scan complicate the care of older adults and may contribute to geriatric conditions  and a decline in function. This underscores the importance of carefully weighing the benefits vs the risks prior to initiating statin treatment. The addition of any new long-term medication to an older adult's drug regimen is never taken lightly given possible drug-drug interactions, adverse drug reactions, and difficulties with medication adherence , particularly those with multiple chronic conditions. Further, there is no guidance, given the lack of data, for adults over the age of 80 years in regard to when to stop statin therapy if it had been indicated for primary prevention.
The 2013 ACC/AHA guidelines will have a profound impact on the way statin drugs will be prescribed for older adults. Many more adults, who previously were not recommended for statins, will now become candidates for starting statin therapy. Older age groups are particularly impacted by the new guidelines, as age appears to be the major determining factor in initiating a statin for primary prevention. The evidence for statins in secondary prevention and primary prevention in higher risk older patients exists and its benefits may outweigh its risks. However, there is currently no evidence to support giving statin therapy to low-risk older adults for primary prevention, which the 2013 ACC/AHA guidelines recommend. More studies are needed to better characterize, estimate, and stratify risk of cardiovascular outcomes for older adults without clinical evidence of ASCVD or with established high-risk factors. The decision to endorse statin treatment for older adults should involve consideration of possible benefits, risks, and competing interests and include a shared provider-patient decision-making discussion.