Statins: Risk assessment and treatment decisions

Mildred is a generally healthy 85-year-old female. She has a history of osteoporosis and when she developed hypertension in her 60s she was placed on a statin.

Issue

Mildred has heard that statin use may lead to development of Alzheimer’s disease so asks if she needs to continue taking it.

Background

The 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidaemia for the Prevention of Cardiovascular Disease in the Adult (updated from 2012)¹ continue to recognize a variable quantity of data related to statin use in the elderly. This is due to inclusion limitations of older adults in clinical trials. It is acknowledged that the guidelines are not absolute, but rather are intended “…to launch one-on-one discussion between practitioner and patient.”²

Treatment decisions are based on risk regardless of age. The most widely used risk assessment scale, the Framingham Heart Study Risk Score (FRS)³ has not been validated for individuals older than age 75. An alternative approach is to consider cardiovascular (CV) age, a calculation that includes a number of risk factors but is based on the concept of age adjusted for remaining life expectancy.⁴ The 2016 guidelines suggest that consideration be given to discussion of cardiovascular age as a mechanism to better target therapy.

Primary prevention

Evidence for primary prevention is limited in the older population. A systematic review published in 2013⁵ looked at eight trials enrolling 24,674 subjects identified as being at high CV risk, but without known CV disease, with a mean age of 73 (range 65-82) and 3.5 years of follow-up. Key outcomes included benefit on risk of myocardial infarction (MI) (RR 0.606 [0.434 – 0.847]) and risk of stroke (RR 0.762 [0.626 – 0.926]). In contrast, no statistically significant benefit was seen for all-cause mortality (RR 0.941 [0.856 – 1.035]) or for cardiovascular death (RR 0.907 [0.686 – 1.199]). A limitation is that these data were primarily from subgroups of individuals > age 65 from larger trials. The 2016 guidelines continue to recommend providing treatment for individuals at high risk for CV events. This is with the caveat that for adults older than age 75 who are otherwise robust, a discussion should take place regarding the risks and benefits in the context of their individual situation. For individuals at intermediate risk, the 2016 guidelines recommend therapy for men > 50 or women > 60 with > 1 CV risk factor. No recommendation is identified specifically for those > age 75.

Secondary prevention

Evidence for secondary prevention comes primarily from one systematic review published in 2008⁶ looking at nine trials enrolling 19,569 subjects with coronary heart disease. The age range was 65-82 and the mean follow-up was 4.9 years. Key outcomes included a benefit for all-cause mortality (RR 0.78 [0.65 – 0.89]); coronary heart disease mortality (RR 0.70 [0.53 – 0.83]); non-fatal MI (RR 0.74 [0.60 – 0.89]); need for revascularization (RR 0.70 [0.53 – 0.83]); and Stroke (RR 0.75 [0.56 – 0.94]). The 2016 guidelines identify that a mortality outcome has not been shown when used for secondary prevention. This is largely based on the results of the PROSPER trial (Pravastatin in elderly individuals at risk for vascular disease) which enrolled subjects between the ages of 65 and 82 and included both primary and secondary prevention cohorts.⁷ The published results of the trial did not identify an effect on all-cause mortality; however the 2008 systematic review was able to obtain data that allowed separation of the cohorts. These data were included in the meta-analysis.

Adverse events

The most common adverse events identified include musculoskeletal events and elevations in CK or hepatic transaminases. Roberts et al⁸ in a meta-analysis published in 2007 identified an absolute difference in musculoskeletal adverse events of 1.3% in those treated with a statin versus placebo. Differences between other adverse events were not statistically significant. A safety signal for new-onset diabetes has been identified in several publications.^9,10 More recently, the association between statins and cataract formation has re-emerged with the HOPE3 trial showing an excess of cataract surgery (3.8% versus 3.1% in the placebo group, p=0.02).¹¹

Effects on cognition

Cognitive impairment in association with statin use was initially identified on the basis of case reports and led to an FDA warning in 2012. Subsequent to this warning, a number of meta-analyses concluded looking at the potential for cognitive impairment associated with statin use. These analyses did not demonstrate an association.¹² A Cochrane Review¹³ looking at the impact of statins on the treatment of dementia identified four randomized controlled trials including 1,154 subjects established on cholinesterase inhibitor therapy. Trials did not show increases on mini-mental state examination scores.

Another question that arises relates to continuation of statins in those started prior to age 65. While the 2016 guidelines do not provide specific direction, taking a risk-based approach continues to be advised, and age alone is not generally considered to be an indication to stop treatment for those tolerating it.

What should Mildred do

As it appears she is tolerating the statin, and there is no good evidence to support her fear of a role in Alzheimer’s Disease, there is no indication for discontinuation based on her age alone. She could be reassessed for risk based on cardiovascular age and engage in conversation to learn the risks and benefits of continued use. American guidelines suggest moderate dosage as being appropriate.¹⁴

References:

1. Anderson TJ, Gregoire J et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidaemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardio (2016) 32(11):1263-1282.
2. Anderson TJ, Gregoire J et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidaemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardio (2016) 32(11):1263-1282.
3. www.ccs.ca/images/Guidelines/Tools_and_Calculators_En/Lipids_Gui_2012_FRS_BW_EN.pdf (accessed December 2016)
4. chiprehab.com/ (accessed December 2016)
5. Savarese G, Gotto AM et al. Benefits of Statins in Elderly Subjects Without Established Cardiovascular Disease: A Meta-Analysis. JACC (2013) 62(22):2090-99.
6. Afilalo J, Duque G et al. Statins for Secondary Prevention in Elderly Patients: A Hierarchical Bayesian Meta-Analysis. JACC (2008) 51(1):37-45.
7. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-3.
8. Roberts C, Guallar E, Rodriguez A. Efficacy and Safety of Statin Monotherapy in Older Adults: A Meta-Analysis. J Geront Med Sci (2007) 62A(8):879-87.
9. Rajpathak SN, Kumbhani DJ et al. Statin Therapy and Risk of Developing Type II Diabetes: A Meta-Analysis. Diabetes Care (2009) 32(10):1924-29.
10. Goldfine AB. Statins: Is it Really Time to Reassess Benefits and Risks. NEJM 2012 366(19): 1752-55.
11. Yusuf S, Bosch J et al. Cholesterol Lowering in Intermediate Risk Persons Without Cardiovascular Disease. NEJM 2016 374(21):2021-31.
12. Ott BR, Daiello LA et al. Do Statins Impair Cognition? A Systematic review and Meta-Analysis of Randomized Controlled Trials. JGIM (2015) 30(3):348-58.
13. McGuinness B, Craig D et al. Statins for the Treatment of Dementia. Cochrane Database of Systematic Reviews 2014, Issue 7.
14. Stone NJ, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. http://circ.ahajournals.org/content/129/25_suppl_2/S1.full