statin efficacy in older people

A recent meta-analysis done by the Cholesterol Treatment Trialists’ Collaboration assessed the efficacy and safety of statin therapy in older people, confirming protection in those with cardiovascular disease, though questioning the benefit in those >75 yo without (see statin elderly metaanal lancet2019 in dropbox, or doi.org/10.1016/S0140-6736(18)31942-1).

Details:

-- 22 trials (n= 134,537) and detailed summary from another (n= 12,705) of statins vs control and 5 trials of more intensive vs less intensive statin therapy (n= 39,612), all with individual participant data

-- 6 age groups were assessed: <55 yo, 56-60 yo, 61-65 yo, 66-70 yo, 71-75 yo, and >75 yo

-- for patients <75 yo: mean age 62, 73% male, 56% history of vascular disease, diabetes 19%, current smoker 21%, treated hypertension 48%, systolic blood pressure 138/81, BMI 27, total cholesterol 209/LDL 127/HDL 46

-- for patients >75 yo: mean age 79, 59% male, 55% history of vascular disease, diabetes 17%, current smoker 10%, treated hypertension 60%, blood pressure 143/79, BMI 26, total cholesterol 197/LDL 124/HDL 50

-- primary endpoint: effects on major vascular events (major coronary events, strokes, coronary revascularizations), cause-specific mortality, and cancer incidence

-- 14,483 (8%) of the 186,854 participants were >75 yo

-- mean duration of follow-up: 4.9 years

Results:

-- major vascular events: 21% proportional reduction per 1.0 mmol/L (38.67 mg/dL) reduction in LDL, independent of whether the statin therapy was a lower or more intensive regimen and independent of age group; RR 0.79 (0.77-0.81)

    -- nonsignificant trend to slight diminishment of these proportional reductions with aging

    -- major coronary events: decreased 24% per 1.0 mmol/L reduction in LDL, RR 0.76 (0.73-0.79). significant trend toward smaller proportional risk reductions with increasing age

    -- coronary revascularization: decreased 25% per 1.0 mmol/L reduction in LDL, RR 0.75 (0.73-0.78); no significant difference across age groups or by statin intensity

    -- stroke: 16% reduction per 1.0 mmol/L reduction in LDL, RR 0.84 (0.80-0.89); no difference with age

    -- not much difference if exclude trials limited to patients with heart failure or undergoing dialysis (where statin therapy does not seem to be that effective): instead of 21% RR, it is 23%

--major vascular events, excluding those with heart failure or on dialysis, by age (all per 1.0 mmol/L reduction in LDL), all statistically significant:

    -- <55yo: 25% risk reduction, RR 0.75 (0.69-0.81)

    -- 56-60: 22% risk reduction, RR 0.78 (0.72-0.85)

    -- 61-65: 21% risk reduction, RR 0.79 (0.74-0.86)

    -- 66-70: 26% risk reduction, RR 0.74 (0.69-0.80)

    -- 71-75: 20% risk reduction, RR 0.80 (0.77-0.99)

    -- >75: 18% risk reduction, RR 0.82 (0.70-0.95)

-- nonvascular mortality, cancer death, or cancer incidence: no effect of statin therapy at any age

-- combining all of this, there was a 9% decrease in all-cause mortality with statins; RR 0.91 (0.88-0.93)

Commentary:

-- one concern is that in older patients, there are studies finding that the overall rate of initiation of statins is substantially lower in those >75 yo; and the rate of statin prescriptions in the elderly without known cardiovascular disease is much lower than that

-- the conclusion in the above study that “there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease” is formally correct but I am concerned it is misleading and might lead to even less statin use in primary prevention in those >75yo:

    -- this study had an important bias: the older age group in this study was healthier. They have made it to age 75, and some important demographics were better (10% current smokers vs 21% in those younger). So, it is not surprising that the apparent benefit of statins might decrease some in this older population

    -- this was only a 4.9 year study, and patients in good health have the following life expectancies (see https://eprognosis.ucsf.edu/ ):

        -- females: 14-year mortality risk: 19-24%

        -- males: 14-year mortality risk: 42-52%

    --but, people in this age group still largely ultimately do die from cardiovascular disease: those >65 yo are still most likely to die from heart disease (#1 cause, 31% combining heart and cerebrovascular in 2016, see https://www.cdc.gov/nchs/data/hus/2017/020.pdf ). 

    -- and, overall the actual number of events (reflecting their absolute risk) in those without pre-existing cardiovascular disease is much lower, even though there is a very similar relative risk reduction with statins (ie, these people in primary prevention would need a longer study to show significant absolute benefit)

--there is an ongoing trial (STAREE) assessing the effect of atorvastatin 40 mg per day in 18,000 primary prevention patients >70 yo, which might give a more definitive answer for statin use in primary prevention (if the study is long enough…).

--other studies have assessed age as a basis for several potential adverse outcomes, including risk of myopathy (no difference), diabetes (slightly higher in older people in some studies), cognitive decline (mixed results). See http://gmodestmedblogs.blogspot.com/2016/06/statins-adverse-effects-again.html  . So, not a huge concern

-- limitations of study: as a meta-analysis, the usual suspects: combining different studies with different populations, comorbidities, numbers of patients (they did require studies to have a minimum of 1000 patients and last at least 2 years, but the largest studies may still overwhelm the smaller ones in terms of numbers, giving disproportionate advantage to the larger ones even if there were less generalizable exclusion criteria etc; and this all gets lost further when people from different studies are then subdivided into their age categories). but this is a huge meta-analysis and the results are pretty impressive and seemingly internally consistent

so, for people who are >75 yo

    --it is clear that those with underlying cardiovascular disease are very likely to benefit from statins

    --in those who do not have underlying cardiovascular disease and are baseline pretty healthy at that age are also likely to benefit from statins if indicated, since their ultimate mortality is still pretty likely to be cardiovascular

    --and, of course, we should be reinforcing a healthy lifestyle (weight loss if indicated, exercise, healthy diet, etc) as the foundation for good cardiovascular (and general) health

My bottom line: I am concerned that older people, and especially healthy older people with a significant likelihood of a long future, are being undertreated, though their risk of atherosclerotic disease is still quite high. And that this short-term analysis with their inherent biases may inadvertently lead to decreased statin use.

geoff

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