Statins in the elderly?

​A post-hoc secondary analysis of data from the ALLHAT-LLT trial assessed the value of pravastatin, 40 mg per day, versus placebo in older patients, finding no benefit (see statin elderly prav not help ALLHAT jamaintmed2017 in dropbox, or doi:10.1001/jamainternmed.2017.1442)

Details:

-- the ALLHAT-LLT study, a community-based study which included 10,355 patients who had a fasting LDL level of 120 to 189 mg/dL and fasting triglycerides level < 350 mg/dL. 4546 were excluded for being younger than 65 and an additional 2942 because of baseline atherosclerotic disease, resulting in 1467 people in the pravastatin group and 1400 in usual care (UC)

-- The intervention was open label pravastatin 40 mg per day versus UC. Mean follow-up 4.6 years

-- mean age 71, 51% female, 40% white/31% Latino, 25% on aspirin/90% on anti-hypertensives/10% of women on estrogens, 22% current smokers, 51% diabetics, BMI 30, mean blood pressure 147/83

-- baseline LDL was 148 mg/dL, decreasing to 109 mg/dL in those on pravastatin and 129 mg/dL in UC. The proportion taking statins was 78% versus 29%, respectively, by year 6 [ie, pretty large cross-over of patients]; this was more pronounced for participants 65 to 74 years old, where 32% of the UC group were taking a statin, though in those >75 yo, 15% were.

Results:

-- all-cause mortality in pravastatin vs UC was non-significantly different for all adults 65 and older (HR 1.18, p=0.09), including nonsignificant HR of 1.08 those age 65 to 74, and 1.34 for those 75 years old or greater [ie nonsignificant trend to worse prognosis in group on pravastatin]

-- coronary heart disease event rates were also not significantly different among the groups. No change with multivariable regression. No significant interaction between the treatment group and age.

Commentary:

-- it is true that there are not rigorous data on older people and statin use, especially for adults greater than 75 years old, with much of the existing data being post-hoc analyses.

-- One concern with the ALLHAT trial is that it was not a truly randomized controlled trial, with the control group being usual care. As a result, the 29% taking statins in the UC group might have been a very high risk group and thereby dilute the difference with the pravastatin group; and conversely 22% of those assigned to pravastatin did not take it (were they self-selected as healthier and less likely to have an atherosclerotic event??).  So ultimately, there was only a 20 mg/dL difference between the groups (and, pravastatin is one of the weaker statins). Another issue which may have disadvantaged the pravastatin group: among people 75 years and older, the mean systolic blood pressure was 150.6 mmHg in the pravastatin group and 147.5 mmHg in the UC group (p=0.01). Their finding of nonsignificant increases in overall mortality as well as in cardiovascular and stroke mortality, and heart failure event rates (all of which are strikingly contrary to the statin studies in younger people which show marked benefit of statins) suggest to me that intrinsic biases of the current ALLHAT study may have played an important role (though coronary heart disease rates were nonsignificantly lower in the pravastatin group)

--other issues: this was an open label study (with its attendant potential biases), did not include nonpharmacologic therapies of diet/exercise (and did those on statins stop doing these healthful behaviors because perhaps they found out from their clinicians that their lipids were better and they thought they didn't need to continue the lifestyle changes, as was found in another statin study??), and those already on a statin were excluded from the study (those likely at higher cardiovascular risk, leaving the actual cohort at lower risk).

-- There is reasonable theoretical benefit for using statins in the elderly: in people older than 65, about one half of all deaths are from atherosclerotic disease. And, statins reveal their effectiveness pretty quickly, within 6 months to a year.

-- In general, although the relative risk of hyperlipidemia causing atherosclerotic disease in the elderly is lower than in younger people, the absolute risk in fact increases a lot with age.

-- See http://blogs.bmj.com/ebm/2015/07/28/primary-care-corner-with-geoffrey-modest-md-lipid-lowering-in-elderly/ , which reviews some of the data showing benefit of statins in the elderly, including a relatively recent meta-analysis of 8 trials, finding for example a 39% relative risk reduction for MI in those on statins, with number needed to treat of 24 for one year to prevent one MI. Relatively similar numbers for stroke prevention. Though these are mostly post-hoc subgroup analyses of bigger studies.

So, there really should be high quality randomized controlled studies of statin use in the elderly. The pathophysiology of atherosclerosis and the mechanics of statin use would suggest significant benefit for the elderly, even within 6 months of initiating statin therapy, and with minimal likely adverse effects. However, the current information is basically from post-hoc secondary analyses. Given our aging population and their high mortality rates from atherosclerotic disease, it really makes sense to have large rigorous studies. In the meantime, I will continue to treat the elderly with statins on an individual basis, having had (I think) good success: several elderly patients with severe CAD who have lived for decades on statins, dying in their mid 90s, and only one patient with an adverse effect/intolerance.

Also, as I mentioned in a recent blog, I am really concerned that the wrong message is getting out to clinicians: Physician's First Watch and NEJM Journal Watch stated "Pravastatin Doesn't Improve Clinical Outcomes in Seniors" . I think these sound-bite type analyses do in fact dumb-down the process of critical analysis of potentially important clinical articles, reinforcing (by omission) that the results of this study sound pretty definitive and thereby perhaps convincing some clinicians to stop prescribing statins. This approach is ahistorical (ie, omits the wealth of prior data suggesting benefit), and tends to reinforce the conception that the newest study trumps (perhaps bad term) all of the older studies (ironically, in this case, this study was based on a post-hoc analysis of a really old study, though I do think that in general newer studies tend to be accepted by us disproportionately, and inappropriately in some cases)

geoff​

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