Severely frail elderly patients do not need lipid-lowering drugs

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After performing a systematic review, members of the Palliative and Therapeutic Harmonization (PATH) program and the Dalhousie Academic Detailing Service found that evidence does not support lipid-lowering therapy for severely frail elderly patients.


  • There is no reason to prescribe or continue statins for primary prevention in severely frail elderly patients, as these drugs are unlikely to provide benefit in terms of outcomes relevant to this population.
  • Statins are probably not necessary for secondary prevention in patients who are severely frail, although there may be extenuating circumstances for their use.
  • There is no reason to start or continue statins for heart failure, as there is insufficient evidence that they are effective for this indication in any population.
  • There is no reason to start or continue other lipid-lowering drugs in conjunction with statins.
  • As the frail elderly may be more vulnerable to the side effects of statins, lower doses may be more appropriate if these drugs are prescribed.
  • If there is concern regarding myopathy, a drug interaction, or other adverse effects, consider a trial of statin discontinuation.



Frail elderly patients are at high risk of adverse clinical outcomes, including those due to polypharmacy. Several groups tackle “deprescribing” by developing lists of medications that are potentially inappropriate for the elderly, such as the Beers or STOPP/START criteria.1–4

See related editorial

In contrast, our group (the Palliative and Therapeutic Harmonization [PATH] program and the Dalhousie Academic Detailing Service) has developed evidence-based, frailty-specific guidelines for treating hypertension5 and diabetes,6 in which we advocate less-stringent treatment targets and tapering or discontinuing medications, as needed.

The PATH program7 is a clinical approach that prioritizes the consideration of frailty when making treatment decisions. The Dalhousie Academic Detailing Service collaborates with the Nova Scotia Health Authority to research and develop evidence-informed educational messages about the treatment of common medical conditions.

Here, we address lipid-lowering therapy in this population.


Frailty is defined in several ways. The Fried model8,9 identifies frailty when 3 of the following characteristics are present: unintentional weight loss, exhaustion, muscle weakness, slow walking speed, or low levels of activity. The Clinical Frailty Scale10,11 and the Frailty Assessment for Care-planning Tool (FACT)5 use deficits in cognition, function, and mobility to define frailty. According to these scales, people are considered severely frail when they require assistance with basic activities of daily living (such as bathing or dressing), owing to cognitive or physical deficits from any cause.

In reviewing the evidence, we consider five questions:

  • What is the quality of the evidence? (Up to 48% of clinical practice guideline recommendations may be based on low-level evidence or expert opinion.12)
  • How did the study population compare with the frail?
  • Are study outcomes and potential benefits clinically relevant to those who are frail?
  • How long did it take for the clinical benefit of a treatment to become apparent, and are the frail elderly likely to live that long?
  • Have the harms of treatment been sufficiently considered?


We found no studies that specifically evaluated the benefit of lipid-lowering for severely frail older adults. Therefore, we examined randomized controlled trials that enrolled non-frail older adults,13–28 subgroup analyses of randomized controlled trials,29,30 meta-analyses that analyzed subgroups of elderly populations,31,32 and publications describing the study designs of randomized controlled trials.33–37

Studies of lipid-lowering therapy discussed in this paper

Most of the evidence comes from post hoc subgroup analyses of elderly populations. Although meta-analysis is commonly used to compare subgroups, the Cochrane handbook and others consider subgroup comparisons observational by nature.38,39 (See Table 1 for lipid-lowering studies discussed in this article.)

Studies of statins for primary prevention of cardiovascular disease

For evidence of benefit from lipid-lowering for primary prevention (ie, to reduce the risk of cardiovascular events in patients with no known cardiovascular disease at baseline but at increased risk), we reviewed the meta-analysis conducted by the Cholesterol Treatment Trialists’ (CTT) Collaborators.32 Since this meta-analysis included the major trials that enrolled elderly patients, individual publications of post hoc, elderly subgroups were, for the most part, not examined individually. The exception to this approach was a decision to report on the PROSPER13 and JUPITER28 trials separately, because PROSPER is the most representative of the elderly population and JUPITER reached the lowest LDL-C of primary prevention trials published to date and included a large elderly subgroup (n = 5,695).

Savarese et al40 evaluated the benefits of statins for older adults who did not have established cardiovascular disease. We did not report on this meta-analysis, as not all of the subjects that populated the meta-analysis were representative of a typical prevention population. For instance, in the Anglo-Scandinavian Cardiac Outcomes Trial lipid-lowering arm,41 14% of the subjects had had a previous stroke or transient ischemic attack. In the Antihypertensive and Lipid-Lowering Treatment Trial,42 16% of the population had a family history of premature coronary heart disease.

In addition, all the trials in the Savarese meta-analysis were also included in the CTT meta-analysis.32 The CTT reports on baseline risk using patient-level data stratified by age and risk, which may be more relevant to the question of primary prevention for older adults, as highlighted in our review.

PROSPER (Prospective Study of Pravastatin in the Elderly at Risk),13 a well-conducted, double-blind, randomized controlled trial with low probability of bias, compared pravastatin 40 mg and placebo. It was the only study that specifically enrolled older adults, with prespecified analysis of primary and secondary prevention subgroups. The primary prevention subgroup accounted for 56% of the 5,084 participants.

JUPITER (Justification for the Use of Statins in Prevention)28 compared rosuvastatin 20 mg and placebo in 17,802 participants. All had low-density lipoprotein cholesterol (LDL-C) levels below 3.4 mmol/L (130 mg/dL) and elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP), ie, 2 mg/L or higher. Subsequently, Glynn et al performed a post hoc, exploratory subgroup analysis of elderly participants (N = 5,695).29

The JUPITER trial had several limitations.43,44 The planned follow-up period was 5 years, but the trial was stopped early at 1.9 years, after a statistically significant difference was detected in the primary composite outcome of reduction in all vascular events. Studies that are stopped early may exaggerate positive findings.45

Further, JUPITER’s patients were a select group, with normal LDL-C levels, elevated hsCRP values, and without diabetes. Of 90,000 patients screened, 72,000 (80%) did not meet the inclusion criteria and were not enrolled. This high rate of exclusion limits the generalizability of study findings beyond the shortcomings of post hoc subgroup analysis.

The meta-analysis performed by the CTT Collaborators32 used individual participant data from large-scale randomized trials of lipid-modifying treatment. This analysis was specific to people at low risk of vascular disease. In a supplementary appendix, the authors described the reduction in major vascular events for each 1.0 mmol/L decrease in LDL-C in three age categories: under age 60, ages 61 to 70, and over age 70.

The authors also stratified the results by risk category and provided information about those with a risk of major vascular events of less than 20%, which would be more representative of a purer primary prevention population.

For the elderly subgroup at low risk, the CTT Collaborators32 only reported a composite of major vascular events (coronary death, nonfatal myocardial infarction [MI], ischemic stroke, or revascularization) and did not describe individual outcomes, such as prevention of coronary heart disease.

Study results are based on postrandomization findings and therefore may be observational, not experimental.46

Studies of statins for secondary prevention of cardiovascular disease

The aim of secondary prevention is to reduce the risk of recurrent cardiovascular events in patients who already have cardiovascular disease.

To address the question of whether statins reduce cardiovascular risk, we reviewed:

PROSPER,13 which included a preplanned analysis of the secondary prevention population.

Afilalo et al,31,47 who performed a meta-analysis of the elderly subgroups of nine major secondary prevention studies (19,569 patients) using published and unpublished data.

To address the question of whether statins benefit individuals with heart failure, we found two relevant studies:

GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca Heart Failure)25 and CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure),26 which were large, international, well-conducted randomized controlled trials that examined statin use in heart failure.

To answer the question of whether statins benefit individuals after a stroke or transient ischemic attack, we found one relevant study:

SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels),27 which evaluated the benefit of statins in older adults with a history of stroke or transient ischemic attack. It was a prospective, double-blind, placebo-controlled, international trial conducted at 205 centers. One to 6 months after their cerebrovascular event, patients were randomized to receive either atorvastatin 80 mg or placebo. Given the young age of patients in this trial (mean age 63), we also reviewed a post hoc subgroup analysis of the elderly patients in SPARCL (age > 65).30

Next Article:

Statin therapy in the frail elderly: A nuanced decision

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