Benefits and Risks Associated With Statin Therapy for Primary Prevention in Old and Very Old Adults: Real-World Evidence From a Target Trial Emulation Study

We read with interest the article on statin therapy by Xu et al. (1). We believe that such a large study showing that statin therapy may prevent cardiovascular disease (CVD) in the elderly and very elderly adults is useful information for clinicians. However, we are submitting this letter because we had the following concerns as we read the article. In the current study, the frequency of specialist outpatient visits for both groups of patients was nearly equal when compared up to one year prior to baseline. What about the frequency of specialist outpatient and general practitioner visits after baseline? At baseline, lipid data, comorbidities, and the Charlson Comorbidity Index were similar in both groups, suggesting that the patient backgrounds were similar. Nevertheless, despite similar lipid data, the attending physicians did not administer statins to the non-treated patients for various reasons. As a result, patients in the statin group were bound to have improved lipid data compared to those in the non-treated group. Therefore, the possibility of a “detection bias” that may have led to differences in the detectability of CVD should be considered. Was more detailed confirmation of the presence of symptoms by the attending physician and more frequent testing because of poor lipid data done? (2) If CVD was fatal enough to lead to all-cause mortality, both groups would certainly be less likely to miss its occurrence. However, if the symptoms of CVD were minor, and associated with “subclinical endpoints,” they may be detected only when the physician interviews the patient in detail at the time of medical examination, or when the patient undergoes a thorough and aggressive examination (3, 4). Especially in an elderly population, comprising more than 60% of individuals with diabetes, as in this study, asymptomatic myocardial infarction may be present in a certain proportion of the population (4, 5). We would like to know if there was a difference in the frequency of visits and examinations after the intervention in the two groups. Furthermore, we would also like some clarity on the ratio of critical and non-critical CVDs in the two groups, and whether non-critical CVDs are also reduced by statins.

Reference

1. Xu W, Lee AL, Lam CLK, et al. Benefits and Risks Associated With Statin Therapy for Primary Prevention in Old and Very Old Adults: Real-World Evidence From a Target Trial Emulation Study. Ann Intern Med. 2024;177(6):701-710.

2. Cholesterol Treatment Trialists’ (CTT) Collaboration, Fulcher J, O’Connell R, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385(9976):1397-1405.

3. Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720-3826.

4. Dai X, Busby-Whitehead J, Forman DE, et al. Stable ischemic heart disease in the older adults. J Geriatr Cardiol. 2016;13(2):109-114. 5, Scheidt-Nave C, Barrett-Connor E, Wingard DL. Resting electrocardiographic abnormalities suggestive of asymptomatic ischemic heart disease associated with non-insulin-dependent diabetes mellitus in a defined population. Circulation. 1990;81(3):899-906.

The study by Xu et al confirmed the benefit of statin administration for primary atherosclerotic cardiovascular disease (ASCVD) prevention in old individuals (1). These findings are interesting in the light of the new data published regarding the updated Predicting Risk of Cardiovascular Disease Events (PREVENT) equations leading to lower estimated ASCVD risk compared to the 2013 Pooled Cohort Equations (PCE), which in turn results in lower statin treatment eligibility (2). Specifically, the discrepancy in ASCVD risk estimation by PCE and PREVENT equations is increasing across age, and shifts in statin recommendations seem to be largest among adults aged 60 to 69 years (~50% no longer recommended statins) (2). These findings might enhance physician inertia and reduce patient adherence, contributing further to the already inadequate dyslipidemia control in high ASCVD risk patients (3). A challenging point is that the majority of adults eligible for statin therapy based on the less strict PREVENT equations did not report statin use (2). The study by Xu et al included a Hong Kong population where PCE equations seem to perform adequately in female individuals at ASCVD risk of ≥7.5% (4). For a white female nonsmoker nondiabetic individual with the average characteristics of the 60-74 years age group in the study by Xu et al (67 years old, systolic blood pressure 148 mmHg under treatment, total cholesterol 235 mg/dl, high-density lipoprotein cholesterol 52 mg/dl, low-density lipoprotein cholesterol 153 mg/dl, body mass index 28 kg/m^2, estimated glomerular filtration rate 98 mL/min/1.73 m^2) the calculated 10-year ASCVD would be 13.2% with the PCE and 7.4% with the PREVENT equation, translated to statin eligibility only with the first one (threshold 7.5%). Yet, in this age group the estimated hazard ratio for ASCVD was 0.94 (0.89-0.98) for female statin initiators versus noninitiators (1). The scientific debate on ASCVD risk estimates should not discourage statin therapy in the majority of the individuals at high ASCVD risk. All individuals aged ≥70 years, are at high risk for ASCVD and above the statin treatment threshold, irrespective of the equation applied. Thus, statin eligibility should be individualized based on the performance status/life expectancy. In individuals aged 40-69 years the differences in the ASCVD risk estimates are lower, but close to the thresholds for statin therapy recommendation. In these cases, we strongly support the routine implementation of carotid ultrasonography or coronary calcium score to detect asymptomatic atherosclerosis, which would reclassify some of them to high-risk necessitating statin therapy (5).

References

1. Xu W, Lee AL, Lam CLK, et al. Benefits and Risks Associated With Statin Therapy for Primary Prevention in Old and Very Old Adults: Real-World Evidence From a Target Trial Emulation Study. Ann Intern Med. 2024;177:701-10. [PMID: 38801776] doi: 10.7326/M24-0004

2. Anderson TS, Wilson LM, Sussman JB. Atherosclerotic Cardiovascular Disease Risk Estimates Using the Predicting Risk of Cardiovascular Disease Events Equations. JAMA Intern Med. 2024:e241302. [PMID: 38856978] doi: 10.1001/jamainternmed.2024.1302

3. Ray KK, Haq I, Bilitou A, et al. Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study. Lancet Reg Health Eur. 2023;29:100624. [PMID: 37090089] doi: 10.1016/j.lanepe.2023.100624

4. Lee CH, Woo YC, Lam JK, et al. Validation of the Pooled Cohort equations in a long-term cohort study of Hong Kong Chinese. J Clin Lipidol. 2015;9:640-6 e2. [PMID: 26350809] doi: 10.1016/j.jacl.2015.06.005

5. Pursnani A, Massaro JM, D'Agostino RB, et al. Guideline-Based Statin Eligibility, Coronary Artery Calcification, and Cardiovascular Events. JAMA. 2015;314:134-41. [PMID: 26172893] doi: 10.1001/jama.2015.7515

In fig. 2 to the right, "PP analysis", the outcome incidence is shown to be higher in initiators than in noninitiators of statin therapy, in contrast to the HRs which are all below 1 lower than in the ITT analysis. Therefore I think that in PP analysis the columns "Initiators" and "Noninitiators" are mixed up. Please check that and correct it as appropriate.