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Statins for Primary Prevention of Cardiovascular Events and Mortality in Older Men
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"Our data suggest that statins taken for primary prevention in relatively healthy men >70 years are associated with a significant 18% lower risk of mortality but with a non-significant lower risk of major CV events. In exploratory analysis we found no statistically significant difference by age category at baseline, or functional status, while those with elevated total cholesterol may benefit from statins to reduce major CVD events. The finding of benefit in those with elevated cholesterol in subgroup analysis is intriguing and should prompt further study to better understand which individuals in the heterogeneous aging population may benefit from statin therapy for the primary prevention of cardiovascular disease. Given that the prevalence of CVD rises with age, evidence based preventive strategies are needed for the aging population."
Statins effects in Older Adults Risks/Benefits - Primary Prevention / ALLHAT-LLT Study "patients without atherosclerotic cardiovascular disease" - (05/25/17) - "Conclusions and Relevance No benefit was found when pravastatin was given for primary prevention to older adults with moderate hyperlipidemia and hypertension, and a nonsignificant direction toward increased all-cause mortality with pravastatin was observed among adults 75 years and older."....
Study Casts Doubt on Need for Statins in the 'Healthy Old' - But specialists cite research flaws, limitations - (05/25/17)
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" - (05/25/17)
Statins - Analysis of Efficacy and Safety in Patients Aged 65-75 Years at Randomization [from Jules: relatively low risk, with Diabetes] - (05/25/17)
Statin (JUPITER study) in Elderly with Relatively Low Risk Factors - (05/25/17)


Statins for Primary Prevention in Older Adults: An Unresolved Conundrum
Michael W. Rich, MD
Department of Medicine, School of Medicine, Washington
University, St. Louis, MO
Carl F. Pieper, DrPH
Department of Biostatistics and Bioinformatics, Duke
University Medical Center, Durham, NC
This editorial comments on the article by Orkaby et al.
The value of statins for primary prevention of cardiovascular disease (CVD) in older adults is controversial,[1, 2] primarily because individuals aged 75 and older, and especially those aged 80 and older, have been markedly underrepresented in statin clinical trials. This controversy is reflected in the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, which states that "initiation of statins for primary prevention of atherosclerotic CVD in individuals >75 years of age requires consideration of additional factors, including increasing comorbidities, safety considerations, and priorities of care."[3] Similarly, in a recent editorial, Gurwitz and colleagues opined that, "In the absence of clear evidence of net benefit for statins for primary prevention in adults older than 75 years and uncertainty about the risks of therapy, clinicians might reasonably follow a shared decision-making approach in discussing the use of statins for this indication with older patients."[4]
Despite the paucity of data from high-quality clinical trials, the question of whether to prescribe (or de-prescribe) statins in individuals aged 75 and older without known CVD is one that clinicians confront virtually every day. Thus, new evidence to help guide such decisions is needed, and therein lies the importance of the study by Orkaby and colleagues reported in this issue of the Journal of the American Geriatrics Society.[5]
The authors conducted a propensity analysis using a one-to-one greedy-matching protocol to examine the association between statin use and mortality and cardiovascular (CV) events in 1,130 matched pairs of male physicians aged 70 and older (median age 77) without preexisting CVD who participated in the Physicians' Health Study and were followed for a median of 7 years. As shown in the authors' Table 1, statin users and nonusers were well matched on relevant baseline characteristics.
The principal findings of the study were that all-cause mortality was 18% lower in the statin group (hazard ratio (HR) = 0.82, 95% confidence interval (CI) = 0.69-0.98), and although not statistically significantly so, there were fewer major CV events and strokes in those receiving statins. In subgroup analysis, the effect of statins on all-cause mortality was more pronounced in participants aged 70 to 76 (HR = 0.83, 95% CI = 0.61-1.11) than in those aged 77 and older (HR = 1.14, 95% CI = 0.89-1.47) at baseline, but the CIs overlapped. Participants with baseline total cholesterol of 200 mg/dL or greater who were taking statins experienced fewer major CV events than those who were not (HR = 0.68, 95% CI = 0.50-0.94), while those with baseline cholesterol of less than 200 mg/dL who were taking statins had more CVD events than those who were not (HR = 1.43, 95% CI = 0.99-2.07), although there was no evidence of a differential effect of statins on mortality as a function of baseline cholesterol. The effects of statins on mortality and CV events were similar in participants with and without functional limitations.
How should these findings be interpreted? The authors concluded that statins were associated with lower mortality and a nonsignificantly lower risk of CV events in this cohort of male physicians aged 70 and older without known CVD. In our opinion, the findings warrant a more-nuanced interpretation. Although CIs for the effect of statins on mortality in participants aged 70 to 76 versus those aged 77 and older at baseline overlapped, the test for interaction was marginally significant (P = 0.047), suggesting that any benefit of statins may be limited to the younger subgroup. There was also no evidence that statins reduced major CV events in participants aged 77 and older at baseline (HR = 1.05, 95% CI = 0.77-1.45).
The apparent lack of benefit of statins for primary prevention in participants aged 77 and older at baseline in the Physicians' Health Study is consistent with prior reports. As the authors noted, a metaanalysis of eight primary prevention trials in older adults (mean age 73) found fewer CV events but not lower mortality.[6] Similarly, the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin failed to show a survival benefit in 5,695 individuals aged 70 and older followed for a median of 1.9 years.[7] More recently, an analysis from the lipid arm of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that pravastatin 40 mg compared to usual care (no statin) was associated with mortality hazards of 1.08 (95%CI 0.85-1.37; P = 0.55) for adults aged 65 to 74 years and 1.34 (95%CI 0.98-1.84; P = 0.07) for those 75 years and older.[8] Another analysis found that treatment of all U.S. adults aged 75 to 94 with a statin would increase disability-adjusted life-years and would be cost effective, but even a small adverse effect of statins on health-related quality of life would eliminate these benefits.[9, 10]
Apart from these considerations, the study has some limitations, most of which the authors acknowledge. The study cohort comprised relatively healthy male physicians, and the findings may not be applicable to women or older adults with multimorbidity or frailty.
Despite propensity matching, there was potential for residual confounding, including confounding by indication. The lack of information on statin use during follow-up precluded conducting a time-varying analysis that could have provided further insights into the association between statin use and clinical outcomes.
Another limitation relates to the method of conducting the time-to-event analysis. The metric of time that was used was time since enrollment rather than age at event. Age and risk are confounded. Of greatest import is the dichotomization of age at 76. In a study with up to 12 years of follow-up (median 7 years), all surviving participants, including those initially younger than 77, would age into the older subgroup (≥77), and many of the subjects in the younger group at baseline spent the majority of the follow-up period aged 77 and older.
There are two possible solutions to this problem. First, the authors could have used time-varying covariates to define age group as the actual age group at the time of the event (and, similarly, for statin use at the time of the event, had that information been available). Second, the authors could have defined the metric of time as age at event, rather than time to event, with left censoring to address the immortal time. Such an analysis could have easily incorporated age group membership at the time of the event. Thus, the results presented must be interpreted as age cohort effects that fail to consider the effect of increasing age over the course of follow-up.
In the end, the study by Orkaby and colleagues is important because it adds to the ongoing discussion about the role of statins for primary prevention in older adults. The findings support the use of statins for primary prevention in selected individuals up to age 76 at baseline (especially those with high total cholesterol), but their value in individuals aged 77 and older is uncertain. There is a compelling need for prospective randomized trials to provide more definitive data on the utility of statins for primary and secondary prevention of CVD in individuals aged 75 and older. The ongoing Australian Statin Therapy for Reducing Events in the Elderly Trial is randomizing subjects aged 70 and older without CVD, diabetes mellitus, advanced kidney disease, or dementia to atorvastatin 40 mg or placebo.[11] The primary outcome is disability-free survival outside long-term residential care. Target enrollment is 18,000 participants, and the trial is projected to conclude in December 2020. At the time of this writing, the National Institutes of Health is also contemplating a statin trial in older adults; the authors of this editorial strongly support such an initiative.
Statins for Primary Prevention of Cardiovascular Events and Mortality in Older Men
Jnl of Am Geriatric Soc - Sept 2017- Ariela R. Orkaby, MD, MPH,* J. Michael Gaziano, MD, MPH,* Luc Djousse, MD, ScD,* and
Jane A. Driver, MD, MPH* - From the *Geriatric Research, Education, and Clinical Center (GRECC) and Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA; Division of Aging, Brigham and Women's Hospital; and Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

We sought to determine whether statin use for primary prevention is associated with a lower risk of cardiovascular events or mortality in older men.
Prospective cohort study.
Physicians' Health Study participants.
7,213 male physicians ≥70 years without a history of cardiovascular disease (CVD).
Multivariable propensity score for statin use with greedy matching (1:1) to minimize confounding by indication.
Median baseline age was 77 (70-102), median follow-up was 7 years. Non-users were matched to 1,130 statin users. Statin use was associated with an 18% lower risk of all-cause mortality, HR 0.82 (95% CI 0.69-0.98) and non-significant lower risk of CVD events, HR 0.86 (95% CI 0.70-1.06) and stroke, HR 0.70 (95% CI 0.45-1.09). In subgroup analyses, results did not change according to age group at baseline (70-76 or >76 years) or functional status. There was a suggestion that those >76 at baseline did not benefit from statins for mortality, HR 1.14 (95% CI 0.89-1.47), compared to those 70-76 at baseline, HR 0.83 (95% CI 0.61-1.11); however the CIs overlap between the two groups, suggesting no difference. Statin users with elevated total cholesterol had fewer major CVD events than non-users, HR 0.68 (95% CI 0.50-0.94) and HR 1.43 (95% CI 0.99-2.07)), respectively.
Statin use was associated with a significant lower risk of mortality in older male physicians ≥70 and a nonsignificant lower risk of CVD events. Results did not change in those who were >76 years at baseline or according to functional status. There was a suggestion that those with elevated total cholesterol may benefit. Further work is needed to determine which older individuals will benefit from statins as primary prevention. Guidelines suggest there is limited evidence to recommend statins for primary prevention of cardiovascular disease (CVD) in adults >75 years.[1, 2] This may be a direct result of excluding older individuals, particularly those with multimorbidity, from randomized trials.[3] However, prescriptions for statins for individuals >70 has increased significantly in the last two decades.[4] In 2008, 40% of the Medicare population was prescribed a statin.[5] In 2011, 12.5 million Medicare beneficiaries were >80,[6] amounting to a significant investment of resources for a drug for which there is as yet no clear evidence of benefit in the oldest and fastest growing segment of the population.[7] Multiple primary and secondary prevention trials[8-13] demonstrated that statins reduce mortality and cardiovascular (CV) events in those <75 years. A meta-analysis of primary prevention statin trials in older adults (mean age 73) revealed a reduction in CV events, but not mortality.[14] Limited, conflicting evidence has generated significant debate,[15-17] and calls for additional trials.[18]
One challenge involves identifying older adults at increased CVD risk who might benefit from statins for primary prevention. Using the Pooled Cohort Risk Assessment Equation,[1] as recommended by cholesterol guidelines, white men >70 with optimal risk factors have a predicted 10-year risk of CVD of 15.7%. The guidelines suggest that those with an estimated risk >7.5% should be offered a statin. No specific recommendations are made for patients >75. Existing risk assessments, such as the Framingham risk score and the European SCORE were not developed in older cohorts and do not account for multimorbidity, function, frailty, or life limiting illnesses.[19]
Additionally, the older adult population has long had inconsistent prescription patterns for many medications, including under-prescription of statins.[20] This may reflect clinicians' hesitancy to use a drug with side effects and drug-drug interactions that has not been studied in the very old.[21] Thus, we sought to examine the relationship between statin use for primary prevention of major CV events and mortality in men >70, with particular attention to those >75 years in subgroup analysis.
Study Population

This study used data from Physicians' Health Study (PHS) participants. PHS methods have been described in detail.[22] Briefly, PHS I began in 1982 as a randomized, double-blind, placebo-controlled trial of aspirin and beta-carotene in 22,071 US male physicians aged 40 to 84 years, with no history of myocardial infarction (MI), stroke, transient ischemic attack, or cancer at randomization. PHS II[23] began in 1997 and was a randomized trial of efficacy of beta-carotene, vitamin C, vitamin E, and a multivitamin on CVD and cancer risk in 7,641 PHS I physicians who agreed to participate in the second trial and 7,000 newly recruited male physicians. All PHS subjects have been followed prospectively, using annual mailed health questionnaires to collect self-reported data, including new CVD diagnoses. Each participant signed an informed consent and the institutional review board at Brigham & Women's Hospital approved the study.
This analysis focused on all physicians ≥70 in the PHS cohort who completed annual questionnaires from 1999, the year a specific question regarding statin use was added. Of the 9,988 PHS participants (≥70 years in 1999), 2,670 participants were excluded because of prevalent CVD (MI, stroke, or peripheral vascular disease) and an additional 105 were excluded due to missing information on statin use at baseline.
The primary outcome is a composite of self-reported and subsequently validated major CV events, MI, stroke, and coronary revascularization (PTCA or CABG). Outcomes were assessed annually by questionnaires; ascertainment of events has been described previously.[24] All-cause mortality was the co-primary outcome, confirmed by an endpoints committee after review of medical records, death certificates, and family report. Details on mortality validation in PHS have been published.[25] Secondary outcomes were coronary heart disease (CHD) alone, and stroke alone. All outcomes were updated through 2012.
Other Variables
Data on demographics, including age and race (white or other); anthropometrics, including age and body mass index (BMI); comorbidities, such as congestive heart failure (CHF), hyperlipidemia (HL), hypertension (HTN), diabetes, kidney disease, and dementia; and lifestyle factors, including smoking, alcohol consumption, and activities of daily living; and concurrent medications, such as aspirin and anti-hypertensive use were assessed by annual questionnaires. Alcohol consumption was classified as none, 1-3 drinks per month, 1-6 drinks per week, and ≥7 drinks per week. Smoking was classified as never, past, or current. Diagnosis of diabetes was self-reported and validated in a subsample.[26] HL was defined by self-report, elevated measured or self-reported cholesterol value, or history of anti-lipemic medication use. HTN was defined by self-report, report of blood pressure >140/90 mm Hg, or use of antihypertensive medications. Functional status was assessed with questions regarding difficulty with activities of daily living, such as bathing, grocery shopping, walking several blocks, or climbing stairs.
Statin use
Beginning in 1999, statin use was assessed by an annual questionnaire with the following question: "Over the past twelve months, on approximately how many DAYS did you take the following [medication]? Statins: (e.g., atorvastatin, cerivastatin, lovastatin, pravastatin, simvastatin, Zocor, etc.)." Respondents could choose varying amounts of use over a 12-month period: 0 (none), 1-13 days, 14-30 days, 31-60 days, 61-90 days, 91-120 days, 121-180 days, 181+ days. Because <4% of participants reported using statins for >0 and <180 days, statin exposure was dichotomized as users for those participants reporting ≥181 days and non-users for <180 days.
Statistical Analyses
Participant characteristics were summarized using descriptive statistics-the t-test for continuous variables and chi-square for binary and categorical variables. Cox proportional hazard models were run to estimate the hazard ratio (HR) and 95% confidence interval (CI) of having a major CV event. Proportional hazards assumptions were tested using product terms of variables and log-transformed person-time, and assumptions were met (all P > .05).
Due to significant differences between statin users and non-users, presumably due to the fact that statins are prescription drugs most often used for hypercholesterolemia and for those at increased risk of CV events due to co-morbidities, such as diabetes, we used propensity score (PS) analysis to attempt to reduce confounding by indication.[27, 28] We developed a multivariable logistic regression model to create a PS to assess the probability of being a statin user verses a statin non-user. The majority of variables were missing <5% of responses and <10% of participants were missing >10% of the variables for the PS. We therefore used indicator variables to account for the small amount of missing covariates.
Elevated cholesterol is the most important driver of statin prescription; therefore we excluded those without information on cholesterol. Additionally, questions on functional status were only sent to physicians from the original PHS cohort; therefore only physicians from the original cohort were included in the PS analysis. The final PS model included 27 predictors of statin use, including comorbidities, markers of functional status, quadratic equation for age, and an interaction term for cholesterol and age. The propensity score is typically used in one of four ways: stratifying, matching, inverse probability of treatment weighting, or as a covariate.[28, 29] Due to a considerable lack of overlap of the propensity scores amongst statin users and non-users (see Supplementary Appendix S1) we used the matching method.[29] Statin users and non-users were matched 1:1 using the ("greedy") nearest neighbor with caliper matching algorithm.[30] The paired-matches were maintained in all analyses. Person-time of follow up was calculated from 1999-2012 until the primary event occurred (MI, stroke, revascularization, or death). Using Cox proportional hazards, we estimated the time to event HR and 95% CI of the risk of major CV events in the matched cohort. In a sensitivity analysis, we used age-at-event as the time scale. Subgroup analyses examined age, functional status, and total cholesterol. To ensure matched pairs were not broken, the PS was rerun within each subgroup. To examine function we created a dichotomous variable reflecting functional status as a proxy for frailty. Participants who reported any difficulty with either moderate activity, walking one block, climbing one flight of stairs, grocery shopping, bathing, or bending were considered to be functionally impaired.
Analysis was done using SAS® 9.3 and 9.4 (SAS Institute Inc.).
Seven thousand two hundred and thirteen participants were eligible for analysis. At baseline statin questionnaire, 1,531 (21.2%) reported using statins >180 days in the prior year. Median age was 76.9 ± 5.2 years (min 70, max 102). Statin users were more likely to be younger, have hyperlipidemia, hypertension, and diabetes. Users were also more likely to be taking aspirin. There was no significant difference in smoking, alcohol use, or weekly exercise. Non-users were more likely to have dementia and have limitations in physical activity, such as walking, bathing, or dressing. Median time of follow up was 7.1 years (inter-quartile range 4.8-8.4), during which a total of 1,137 CV events occurred.
A total of 5,758 individuals were available for propensity score analysis, of which 1,322 reported taking a statin at baseline. The C-statistic for the PS model was 0.86. Using the ("greedy") matching method there were 1,130 matched pairs, with excellent overlap in propensity score distribution between users and non-users, and with a mean score in both groups of 0.44 (SD 0.13, P = .97). A total of 362 major CV events occurred in the PS matched cohort. Baseline characteristics are shown in Table 1. In the PS matched group, statin use was associated with an 18% lower risk of mortality, HR 0.82 (95% CI 0.69-0.98), P = .03, and a non-significant lower risk of major CV events, HR 0.86 (95% CI 0.70-1.06), P = 0.17. (Table 2 and Supplementary Appendix S2).
In secondary analyses, we separated CHD events from stroke and found no significant relationship between statin use and stroke, HR 0.70 (95% CI 0.45-1.09), P = .12; or CHD events, HR 0.95 (95% CI 0.74-1.21), P = .66. We also considered the competing risk of mortality[31] and found no evidence in our study. As age is the most important predictor of CVD, to account for a possible cohort effect we repeated our main analysis using "age with left censoring" rather than "days from baseline" as the time scale. The results were similar for major CV events, HR 0.87 (95% CI 0.71-1.07), all-cause mortality HR 0.84 (95% CI 0.85-1.01), CHD events, HR 0.92 (95% CI 0.72-1.17), and stroke, HR 0.69 (95% CI 0.44-1.08).
In subgroup analyses, we examined the cohort effect of "age at baseline," dichotomizing at median age (76), functional status, and cholesterol. Results did not change according to age category at baseline or functional status, although there was a suggestion that those who were >76 years at baseline did not benefit from statins, HR 1.14 (95% CI 0.89-1.47), compared to those who were 70-76 at baseline, HR 0.83 (95% CI 0.61-1.11), however as the confidence intervals overlap between the two groups of age, this suggests no difference between the groups. Amongst those who had elevated measured total cholesterol (>200 mg/dL) at baseline there was a statistically significant association between statin use and reduced risk of CVD events, HR 0.68 (95% CI 0.50-0.94) while those with a low total cholesterol who took statins had an increased risk of major CV events, HR 1.43 (95% CI 0.99-2.07), with overall P-interaction .003. This was not seen when we restricted the outcome to all-cause mortality (Table 3).
Our study found a significant inverse association between all-cause mortality amongst relatively healthy older male physicians who used statins compared to non-users, and a modest, though non-statistically significant, lower risk of major CV events in men ≥70 years that took statins for primary prevention for an average of 7 years. This is in contrast to findings from a subgroup analysis of 5,695 participants >70 years in the JUPITER (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin) trial, which found a benefit in stroke and MI reduction, but not all-cause mortality in statin users;[32] and a meta-analysis of eight primary prevention trials of 24,674 adults >65 years (mean 73) which also reported no mortality benefit over 3.5 years of follow-up (relative risk (RR) 0.94 (95% CI 0.86-1.04, P = 0.21)), although there was a significant reduction in MI risk (RR 0.61 (95% CI 0.43-0.85, P = .003)) and risk of stroke (RR 0.76 (95% CI 0.63-0.93, P = .006)).[14]
Our observational findings for major CV events are similar to the effect size reported in the pravastatin in elderly individuals at risk of vascular disease (PROSPER) randomized controlled trial (n = 5,804, age range 70-82), which reported a significant 19% reduction in major CV events, HR 0.81 (95% CI 0.69-0.94, P = .006). However, in our study we specifically restricted to primary prevention and included individuals >82 years at baseline. In PROSPER, 44% of participants had a history of CVD, and in subgroup analysis examining primary prevention there was no significant reduction of CV events in those randomized to pravastatin verses placebo, HR 0.94 (95% CI 0.77-1.15), although P = .19 for interaction was not significant.[33] Additionally, PROSPER did not find a significant reduction in all-cause mortality, (HR 0.97 (95% CI 0.83-1.14, P = .74)), although results were not reported amongst those who did not have a history of CVD. Participants included in trials for primary prevention required at least one cardiovascular risk factor, as in the PROSPER trial, or an elevated C-reactive protein in JUPITER.[12] We did not have such restrictions in our cohort as current risk calculators assign a high risk of CV events to all men >70, even without risk factors.
An ongoing prospective cohort study in France has followed 7,484 men and women, mean age 74 years, for an average of 9 years.[34] Individuals taking lipid-lowering medications (including statins and fibrates) had a significant lower risk of stroke, HR 0.66 (95% CI 0.49-0.90), but no significant association with CHD. In our study we did not achieve a similar statistically significant association in reduction of strokes. This may be due to the small number of events in this relatively healthy cohort of older male physicians. In an exploratory subgroup analysis we examined the impact of age cohort at baseline. This is important to consider in studies such as ours where a cohort effect of age can lead to a survival bias, as those who were >76 at baseline are more likely to experience mortality than those who are younger at baseline. We did not find a significant difference between those who were <76 at baseline or older on the outcome of major CVD events. For the outcome of all-cause mortality, although there was a difference between the two age categories (with possible benefit in those between the age of 70-76 at baseline and possible harm in those over 76 years), the confidence intervals for each group overlapped, suggesting no statistically significant difference between the two groups.
We also found a statistically significant lower risk of major CV events in those with elevated total cholesterol at baseline, while low cholesterol was associated with an increased risk of CV events. Although exploratory, this may reflect underlying illnesses such as malignancy or advanced frailty, which are associated with low cholesterol and mortality. Furthermore, those with higher cholesterol at baseline may have been prescribed a more potent statin, contributing to a lower risk. This result may also be reflective of residual confounding by indication. There was suggestion of benefit in those with no functional limitation, although this did not reach statistical significance, in part due to a relatively small sample size. Perhaps incorporating functional status into the CV risk assessment will better identify individuals who may benefit from preventive therapy, such as statins. For example, in a French cohort of 3,208 men and women ≥65 years, followed for 5 years, slow walking speed was associated with an increased risk of death from cardiovascular disease (HR 2.92 (95% CI 1.46, 5.84)).[35]
It is worth noting that one concern for providers and patients is that side effects of statins, such as myalgias, may lead to decreased functional status. A longitudinal study of 2,005 individuals aged 70-79, taking statins, were followed for 5 years for evidence of functional decline over time.[36] The authors reported no evidence of worsening functional status measured by gait speed in statin users, OR = 0.90 (95% CI 0.77-1.06). The results of this study may be biased, as the authors did not employ statistical methods to address confounding by indication, such as the propensity score. A cost-effectiveness analysis of statins in the prevention of CVD, using data from the PROSPER trial, showed that while there may be a small (albeit statistically significant) lower risk of CV events for those over 75, this may be outweighed by the small (but significant) increased relative risk of mild cognitive impairment (1.10-1.24) and functional decline (1.12-1.29).[37]
The fact that the reduction in CV events in our study did not reach statistical significance may be due to low rates of outcomes in this relatively healthy cohort. When we performed sensitivity analysis, using age as the time scale, rather than the classic time-to-event analysis, in order to address the possibility of cohort effect and to acknowledge the increasing risk of CVD due to advanced age (e.g., an 85 year old at baseline has a higher risk of CVD than a 70 year old due to age alone), we found very similar results (absolute percent change when comparing hazard ratios obtained from time-to-event analysis with those derived from age at event ranging from 1.2% to 3.7%). These results did not reach statistical significance due to lack of power; however, the analysis should be repeated in a larger cohort.
The aging population is heterogeneous, and to date, evidence is lacking as to which older adults will benefit the most from statin therapy. There is increasing evidence that statins can, and perhaps should, be stopped in nursing home patients, particularly those with dementia[38] or those with a life-limiting illness.[39] Including dementia in the models or stratifying by frailty did not change our results, although this may be limited by sample size. It remains unknown whether older individuals with multi-morbidity, who have a life expectancy of at least 2 years, may benefit from CVD prevention with statins. A patient centered approach in the decision to start or continue a statin in an elderly patient is of the utmost importance,[40] with attention to function, multi-morbidity, cognition, and polypharmacy.[41]
STAREE (statins therapy for reducing events in the elderly) is an ongoing randomized clinical trial that has randomized individuals >70 without prior CVD, dementia, diabetes, or a life-limiting illness to atorvastatin or placebo.[42] The main outcome is mortality and functional status assessed by the need for institutionalization; results are expected in 2019. However, as with many trials before, this study excludes many patients routinely seen in primary care (e.g., the older adult with frailty and multi-morbidity, with or without cognitive impairment).[43]
Limitations of our study include the observational nature; only men participated, statin type and dose were not available, and covariates were not updated annually. As with any non-randomized trial of drug effects, there may be remaining confounding by indication, even with the propensity score matching approach. Our results may underestimate the effect of statins due to sample size or misclassification of statin use, which could not be updated over time in the propensity score model. This very healthy group of physicians may not represent the average community-dwelling older individual, but suggests that there may be a group of older individuals who might derive benefit from statin therapy.
Our data suggest that statins taken for primary prevention in relatively healthy men >70 years are associated with a significant 18% lower risk of mortality but with a non-significant lower risk of major CV events. In exploratory analysis we found no statistically significant difference by age category at baseline, or functional status, while those with elevated total cholesterol may benefit from statins to reduce major CVD events. The finding of benefit in those with elevated cholesterol in subgroup analysis is intriguing and should prompt further study to better understand which individuals in the heterogeneous aging population may benefit from statin therapy for the primary prevention of cardiovascular disease. Given that the prevalence of CVD rises with age, evidence based preventive strategies are needed for the aging population.

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