Statins for Primary Prevention of Cardiovascular Events and Mortality in Older Men

Ariela R. Orkaby, MD, MPH; J. Michael Gaziano, MD, MPH; Luc Djousse, MD, ScD; Jane A. Driver, MD, MPH

Disclosures

J Am Geriatr Soc. 2017;65(11):2362-2368. 

In This Article

Discussion

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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