Practical Pearls: When Is It Reasonable to Consider Withholding Lipid Lowering Therapy?

Lipid lowering therapy is a cornerstone of cardiovascular risk reduction. However, withholding or stopping lipid lowering therapy may be worth consideration in some individuals. These include elderly patients with comorbidities limiting life expectancy, individuals with a coronary artery calcium score of 0 (CAC =0), patients with end stage renal disease (ESRD), and pregnant and lactating women. This review will discuss these scenarios.

Primary Prevention in Elderly Patients with Significant Comorbidities and Limited Life Expectancy

Recommendations for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in adults > 75 years are limited. The 2018 multi-society cholesterol guidelines excluded patients in this age group.¹ Decisions in these patients are complicated by factors such as frailty, polypharmacy, and cognitive impairment, as well as a paucity of data in this population.^2,3

The Copenhagen general population study enrolled 90,000 individuals aged 20-100 years. Adults aged 80-100 years had the highest absolute risk of a myocardial infarction (MI), the risk increasing with higher LDL levels. This group also had the lowest calculated number needed to treat (NNT, 80) to prevent an MI in 5 years.⁴ In contrast, the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial found no major adverse cardiac events (MACE) benefit with pravastatin use for primary prevention in adults ages 70-82 years.⁵

The PRagmatic EValuation of evENTs and Benefits of Lipid lowering in oldEr adults (PREVENTABLE, NCT04262206) will assess the effects of statins on dementia, disability, cardiovascular death, and cognitive disability in adults >75 years. The Statins in Reducing Events in the Elderly (STAREE, NCT04536870) trial will compare the effects of atorvastatin vs placebo on disability, frailty, and major CV events. Statins In The Elderly (SITE, NCT02547883) is evaluating the effect of withdrawing statins on all-cause mortality and incremental cost per quality-of-life years gained in adults ≥ 75 years.⁶ While these findings are awaited, shared decision making of risks versus benefits evaluating competing comorbidities, atherosclerotic disease burden, and considering the impact of a cardiovascular event on quality of life may aid decision-making in this population.

The Power of Zero

Many studies have demonstrated a lower risk of cardiovascular outcomes and all-cause mortality among individuals with CAC = 0 as compared with CAC > 0, even after adjusting for traditional risk factors.^7,8 Patients with a CAC = 0 had a 10-year risk below the threshold for statin initiation (4.5%) even with a calculated 10-year ASCVD risk in the 7.5-20% range, and with risk enhancers^9,10 like hsCRP > 2 mg/dL.
 
Withholding statin therapy in individuals with CAC = 0 has been evaluated in two retrospective studies. Out of 950 subjects from the Multiethnic Study of Atherosclerosis (MESA) with a high sensitivity CRP of > 2 mg/dL, the 5-year NNT for statin use was 124 in these subjects⁹ versus 19 in those with CAC > 0. In a Walter Reed study¹¹ with 10-year follow up, statin use was not associated with a lower risk of MACE in individuals with CAC = 0. The 2018 Multisociety guideline on the Management of Blood Cholesterol¹ suggests that adults 40-75 years without diabetes, cigarette smoking, or strong family history of premature ASCVD can delay or withhold statin initiation with a CAC =0 (de-risking).
 
Certain considerations, however, should refine the choice to withhold statins in patients having a CAC=0. The data on the long-term prognostic significance of CAC = 0 in young adults are emerging.¹² In a cohort study, 25% of patients with CAC = 0 developed CAC in 5 years.¹³ This duration was shorter in patients with a high burden of risk factors like diabetes suggesting serial testing at 3-5 years may be needed in these individuals.^14–16 Lastly, patients with heterozygous FH, even with a CAC = 0, are conventionally treated with at least a statin.¹⁷ For many patients with uncertainty in individual risk, a CAC = 0 may help with shared decision making around statin initiation. The approach for these patients could include a focus on lifestyle management with periodic re-estimation of risk.
 
End Stage Renal Disease (ESRD)

Four randomized controlled trials (RCT) evaluated the effect of statins in patients with ESRD undergoing hemodialysis (HD). The 4D study found no statistically significant effects on cardiovascular death, non-fatal MI, and non-fatal stroke with atorvastatin 20 mg/day in diabetic patients with and without ASCVD, on HD.¹⁸ Similar results were noted in the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) with rosuvastatin 10 mg/day.¹⁹ SHARP (Study of Heart and Renal Protection) evaluated a combination of simvastatin and ezetimibe in a primary prevention cohort with CKD, with and without HD, finding a 27% benefit in major vascular events compared with placebo. In subgroup analysis, the benefit was seen in the non – HD cohort but not the HD cohort. However, the trial was not powered for this analysis.²⁰
 
Whether the lack of benefit in these trials was due to a lower dose of statins being used or competing risks of death in this population is not fully understood. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend against the routine initiation of a statin in all comers with ESRD but recommend continuation if already receiving a statin.²¹

Pregnancy and Lactation

Statins have traditionally been contraindicated when pregnancy is planned and during pregnancy due to concerns of teratogenicity and unfavorable effects on metabolic pathways that regulate morphogenesis demonstrated in pre-clinical animal models.^22,23 Women are advised against statin therapy until the cessation of lactation due to the potential detrimental effects on cholesterol biosynthesis in the neonate. Most statins can be found in breast milk, however, specific information on the type of statin and how much can cross into breast milk is limited.

 More recent systematic reviews and meta-analyses did not demonstrate clear associations between statin use and teratogenicity and seem to suggest that statins are, “probably not teratogenic”.^24–26 In 2021 the Food and Drug Administration removed the strongest warnings against statin use during pregnancy.²⁷ However, barring certain high-risk patients like homozygous FH or prior ASCVD events, current guidelines still recommend holding statins during pregnancy and lactation.^1,28 Table 1 describes the common considerations for lipid lowering medications in pregnancy and lactation.

Conclusion

The benefits of lipid lowering therapy in ASCVD prevention have been well described and widely adopted. However, the benefits from therapy are not uniform across patient subgroups. This review aims to empower clinicians to have a nuanced risk-benefit discussion based on each individual patient’s clinical profile.

Dr. Satish has no financial relationships to disclose. Dr. D’Souza has no financial relationships to disclose. Dr. Agarwala has no financial relationships to disclose.

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