Age is Just a Number: Discontinue Statins with Care

Author(s)
Maricar Conson, PharmD
W. Cheng Yuet, PharmD, BCACP

Reviewed By
Chase Board, PharmD
Dawn Fuke, PharmD, BCPS

Citation
Giral P, Neuman A, Weill A, Coste J. Cardiovascular effect of discontinuing statins for primary prevention at the age of 75 years: a nationwide population-based cohort study in France. Eur Heart J. 2019; 40 :3516-3525.

The Problem

 

Older adults — more than 14 million Americans age 75 years and older¹ —face a dilemma. They are at high risk for atherosclerotic cardiovascular disease (ASCVD) due to endothelial dysfunction, inflammation, and vascular stiffness associated with aging and frequently have several cardiovascular risk factors.² On the other hand, older adults are more susceptible to adverse effects associated with statins.³ Current guidelines weigh the risks versus benefits of initiating statins for primary prevention.^3,4 And many adults, often in their 60s or early 70s, decide to initiate statin therapy for the primary prevention of ASCVD. However, at some point in a patient’s life, the potential benefits may no longer be so clear … or the risks and costs increase. Unfortunately, there is little information on the potential consequences of statin discontinuation in patients who are tolerating statins.

 

What’s Known

 

The benefit of statin therapy is well-established for secondary prevention of ASCVD among all age groups⁴; however, the role of statins for primary ASCVD prevention remains less clear especially among adults older than 75 years of age. There is no recommendation for or against statin use in the 2018 American College of Cardiology-American Heart Association (ACC-AHA) guidelines for this patient population, with most evidence limited to post-hoc and subgroup analyses.^4-9 Instead, ACC-AHA recommends a shared decision-making process between clinicians and patients. Likewise, there is no definitive recommendation to discontinue statins for primary ASCVD prevention in relatively healthy patients after 75 years of age.

 

Several studies have evaluated patient adherence or non-adherence to statin therapy. However, these studies have typically included somewhat younger patient populations and did not evaluate outcomes, like cardiovascular events or hospitalizations, following statin discontinuation. One cohort study did analyze 2-year adherence rates to statin therapy in patients at least 66 years of age with and without acute coronary syndromes. Although the rates of subsequent cardiovascular events were not assessed, investigators inferred that the study patients likely received limited or no benefit from statin therapy due to premature discontinuation which was more common among the secondary prevention group.¹⁰ A randomized controlled trial by Kutner and colleagues found that statin discontinuation was associated with improved quality of life, decreased medication burden, and decreased overall medication costs in a small cohort of palliative care patients (n = 381) with limited life expectancy.¹¹ After 60 days of follow-up, there was no significant difference in cardiovascular event rates in those who discontinued and those who continued statin therapy.

 

In a meta-analysis of 28 randomized controlled trials, the Cholesterol Treatment Trialists’ Collaboration evaluated the efficacy and safety of statins among six age groups ranging from 55 years to older than 75 years.¹²  While fewer than 8% of the patients included in this meta-analysis were aged 75 years or older, the population size was still large enough (n=14483) to draw some conclusions. The proportional risk reduction in major vascular events was smaller among older adults without vascular disease when compared to their younger counterparts (p_trend=0.004). However, the difference in proportional risk reduction was no longer present when heart failure and dialysis trials were excluded (p_trend=0.1) – suggesting that “healthy” older adults might benefit as much as younger adults. Retrospective studies have noted associations between statin therapy and adverse effects that may contribute to the frailty, disability, and polypharmacy; however, these studies were observational and the findings have not been observed in randomized clinical trials.^13,14 Lastly, the ALLHAT-LLT randomized controlled trial found no benefit of statin therapy for primary prevention in older adults.¹⁵ The totality of evidence to date suggests that older patients may benefit less from statins when used for primary prevention and the initiation of therapy requires shared decision making with patients. However, once statin therapy is started, what harm, if any, exists if we discontinue it?

 

What’s New

 

A recent retrospective, population-based cohort study evaluated the effect of statin discontinuation (defined as three consecutive months without exposure) on cardiovascular outcomes in a cohort of patients who turned 75 years old between 2012 and 2014. The study was conducted in France. To be included in the analysis, participants had a statin medication possession ratio > 80% in each of the two years prior to the index date. Patients with a cardiovascular disease diagnosis or related in-hospital procedure within the previous two years were excluded. Additional exclusion criteria include patients taking at least one of the following treatments during the study period: (i) combined use of aspirin and another antiplatelet agent, (ii) combined use of antiplatelet agent, -blocker, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker or aliskiren, and (iii) long-term treatment with an antiplatelet agent other than aspirin (defined as > 3 prescriptions filled over 1 year period). The primary outcome was a hospital admission for a cardiovascular event classified as coronary, cerebrovascular, and other vascular events.

 

A total of 120,173 patients were included in the analysis with a mean duration of follow-up of 2.4 years. Included patients were predominantly female (59.2%). Patients in this cohort most commonly received antihypertensive agents (79.0%) followed by antidiabetic agents (26.6%), antiplatelet agents (24.6%), and anticoagulants (13.8%). Only 2.3% of patients were receiving non-statin lipid-lowering agents. The most common comorbidity was diabetes (24.4%). Among patients with frailty indicators, 2.4% had bed confinement status, a home hospital bed, or anti-bedsore equipment.

 

Among the included patients in the analysis, a total of 17204 (14.3%) discontinued statins and 5396 (4.5%) were admitted for a cardiovascular event (incidence rate = 2.1 per 100 patient years).

 

Table 1: Cardiovascular events after statin discontinuation

	Adjusted HR [95% CI]
Any cardiovascular event	1.33 [1.18-1.50]
Coronary event	1.46 [1.21-1.75]
Cerebrovascular event	1.26 [1.05-1.51]
Any other vascular event	1.02 [0.74-1.40]

HR = hazard ratio; CI = confidence interval

 

Among 75-year-old patients who were previously adherent to statin therapy for at least two years, the discontinuation of statins was associated with a 33% increased risk of admission for a cardiovascular event. See Table 1.  Four years after the subject’s 75^th birthday, the adjusted cumulative incidence rate of a cardiovascular event was 10.1% [95% CI 8.8-11.3%] among those who discontinued statin therapy versus 7.6% [95% CI 7.3-7.9%] among those who continued statins.

 

Our Critical Appraisal

 

Historically, studies evaluated the proportional cardiovascular risk reduction among older adults compared to younger adults which may justify the benefit of initiating statin therapy. However, until now, there is has been little evidence on the cardiovascular effects associated with discontinuing statins in older adults. The investigators reported that discontinuing statins in patients more than 75 years of age was associated with a 33% increased risk of admission for a cardiovascular event. This finding is possibly explained by a change in LDL—elevations in LDL cholesterol are associated with cardiovascular events and are independent of age. Epidemiological data show that concentrations of total plasma cholesterol decline in the last decades of life, which may be due to a decrease LDL-C synthesis or it might be due to a survival bias in older adults with lower LDL-C levels.¹³ To their credit, the investigators attempt to correct for time-varying confounders and report the use and continuation of other cardiovascular medications that may affect the outcomes of interest.

 

None-the-less, it is important to note the limitations of this (and any) retrospective cohort study. The investigators are not able to control for unidentified confounders. For example, the study did not collect or report relevant cardiovascular risk factors including baseline LDL-C levels, tobacco use, or body mass index.  The investigators were not able to determine if cardiovascular mortality increased in those who discontinued statin therapy.  Furthermore, a small percentage of subjects requiring statins for secondary prevention may have been misclassified based on the exclusion criteria.

 

Bottom Line

 

This study suggests that adults age 75 years or older without vascular disease who are currently taking statins may benefit from continuing statin therapy to prevent cardiovascular events. Additional studies are needed to determine whether statin discontinuation affects cardiovascular mortality in this population. Despite the limitations of this retrospective study, this evidence contributes to the risk versus benefit analysis and should be considered in addition to patient preferences, life expectancy, and potential for drug-drug interactions.⁴ Based on the existing literature, it is reasonable to continue statins for primary prevention in older adults unless, of course, intolerance develops or there is a change in life expectancy (e.g., end-stage disease). It is prudent for clinicians to evaluate all patient-specific factors for both ASCVD risk and statin-associated adverse effects since age is “just a number.”

 

Key Points

• Statin discontinuation was associated with an increased risk of admission for cardiovascular events in adults older than 75 years of age who did not have established ASCVD.
• It is unknown if statin discontinuation would contribute to cardiovascular mortality.
• Retrospective cohort studies have several limitations and these findings need to be confirmed in prospective clinical trials.
• Older adults (75 years and older) may benefit from continued statin use for the primary prevention of ASCVD events but statins should be stopped in those who are unable to tolerate therapy or who have a limited life expectancy.

FINAL NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.