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American Journal of Kidney Diseases

Effect of Aspirin on CKD Progression in Older Adults: Secondary Analysis From the ASPREE Randomized Clinical Trial

Published:April 13, 2022DOI:https://doi.org/10.1053/j.ajkd.2022.02.019
      To the Editor:
      Aspirin is a commonly prescribed and “over-the-counter” therapy in older persons. While its use in the secondary prevention of cardiovascular disease (CVD) events is well established,
      • Smith S.C.
      • Benjamin E.J.
      • Bonow R.O.
      • et al.
      AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association.
      aspirin is not recommended for primary CVD prevention in adults aged 60 years or older.
      • Davidson K.W.
      • Barry M.J.
      • et al.
      US PSTF
      Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement.
      Low-dose aspirin increases the risk of bleeding in older persons,
      • McNeil J.J.
      • Wolfe R.
      • Woods R.L.
      • et al.
      Effect of aspirin on cardiovascular events and bleeding in the healthy elderly.
      but whether it has any effect on kidney function is not clear.
      • Harris R.C.
      Physiologic and pathophysiologic roles of cyclooxygenase-2 in the kidney.
      ,
      • Violi F.
      • Targher G.
      • Vestri A.
      • et al.
      Effect of aspirin on renal disease progression in patients with type 2 diabetes: a multicenter, double-blind, placebo-controlled, randomized trial. The renaL disEase progression by aspirin in diabetic pAtients (LEDA) trial. Rationale and study design.
      We sought to investigate the effect of low-dose aspirin on kidney function in healthy older persons enrolled in the Aspirin in Reducing Events in the Elderly (ASPREE) trial (Clinicaltrials.gov identifier, NCT01038583).
      • McNeil J.J.
      • Woods R.L.
      • Nelson M.R.
      • et al.
      Effect of aspirin on disability-free survival in the healthy elderly.
      ASPREE was a large double-blind, randomized, placebo-controlled trial designed to assess whether daily treatment with 100 mg of enteric-coated aspirin could extend the duration of life free of dementia and persistent physical disability.
      The aim of the present study was to compare the trajectory of kidney measures, namely estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR), in participants randomized to aspirin treatment or placebo from the trial’s commencement until its cessation.
      In brief, 19,114 healthy community-dwelling individuals aged ≥70 years (aged ≥65 years for African American and Hispanic participants in the United States) were recruited in Australia and in the United States. Recruitment took place from March 2010 through December 2014, with annual assessments conducted from randomization until the intervention period ended in June 2017 (median follow-up, 4.7 years). Participants were randomly assigned to receive a 100 mg tablet of enteric-coated aspirin or matching placebo daily in double-blind fashion. For this analysis, 7 participants with stage G5 chronic kidney disease
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
      were omitted, as were 1,349 participants missing baseline kidney measures. Full details, including the ASPREE trial protocol and main results, are reported in detail elsewhere and in Item S1.
      • McNeil J.J.
      • Woods R.L.
      • Nelson M.R.
      • et al.
      Effect of aspirin on disability-free survival in the healthy elderly.
      ,
      ASPREE Investigator Group
      Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial.
      ,
      • Wolfe R.
      • Murray A.M.
      • Woods R.L.
      • et al.
      The aspirin in reducing events in the elderly trial: Statistical analysis plan.
      Exposure was randomization to aspirin or placebo. Outcome measures were change in kidney function, assessed as annual eGFR decline and, separately, annual increase in UACR. No participant was documented as commencing dialysis or receiving a kidney transplant during the intervention period, and participants reaching sustained eGFR <15 mL/min/1.73 m2 during the trial period were not removed from the analysis.
      Linear mixed models were used, which included the group (randomized aspirin vs placebo, ie, intention to treat), annual visit number (0 [baseline], 1, 2, 3, 4, 5, and 6 years; referred to as “time”), a participant-specific intercept (baseline eGFR or UACR), and a participant-specific slope describing change in eGFR or UACR over time (per annual visit). A treatment-by-time interaction was included to examine whether the trajectory of eGFR or UACR for an average participant differed between the treatment groups. As the UACR distribution was skewed, it was log2-transformed in all models. To account for dropout owing to death, a sensitivity analysis was performed using a shared random effect joint model for longitudinal eGFR or UACR and the overall survival outcome.
      • Henderson R.
      • Diggle P.
      • Dobson A.
      Joint modelling of longitudinal measurements and event time data.
      The survival component was modeled using a Cox proportional hazards model, adjusted for baseline age, sex, aspirin, diabetes, and time-dependent value of eGFR or UACR.
      The primary analysis comprised 17,758 participants (Fig S1). Baseline characteristics were well matched across treatment arms (Table 1). The mean age of the cohort was 75.1 ± 4.5 (SD) years and 56.4% were female. The median number of eGFR and UACR values per patient were 5 (range, 1-7) and 4 (range, 1-7), respectively. Among participants included in the primary analysis, 983 deaths occurred (523 in the aspirin group, 460 in the placebo group).
      Table 1Baseline Characteristics of the Participants Randomized to Aspirin Versus Placebo
      Placebo (n = 8,938)Aspirin (n = 8,820)
      Age at randomization, y75.1 ± 4.575.2 ± 4.6
      Female sex5,035 (56.3%)4,987 (56.5%)
      Ethnicity
       White/Australia7,600 (85.0%)7,514 (85.2%)
       White/United States531 (5.9%)525 (6.0%)
       Black435 (4.9%)438 (5.0%)
       Hispanic236 (2.6%)227 (2.6%)
       Other/unknown136 (1.5%)116 (1.3%)
      Location: Australia (vs United States)7,770 (86.9%)7,653 (86.8%)
      Smoking history
       Never smoked4,923 (55.1%)4,869 (55.2%)
       Former smoker3,655 (40.9%)3,619 (41.0%)
       Current smoker360 (4.0%)332 (3.8%)
      Alcohol intake
       Current6,840 (76.5%)6,758 (76.6%)
       Never1,563 (17.5%)1,528 (17.3%)
       Former535 (6.0%)534 (6.1%)
      Diabetes mellitus950 (10.6)964 (10.9%)
      Hypertension
       No2,278 (25.5%)2,286 (25.9%)
       Yes; on medication, normal BP2,208 (24.7%)2,170 (24.6%)
       Yes; on medication, high BP2,466 (27.6%)2,488 (28.2%)
       Yes; not on medication, high BP1,986 (22.2%)1,876 (21.3%)
      Systolic BP, mm Hg139 ± 17139 ± 16
      Diastolic BP, mm Hg77 ± 1077 ± 10
      Frailty
       Not frail5,246 (58.7%)5189 (58.8%)
       Pre-frail3,509 (39.3%)3425 (38.8%)
       Frail183 (2.0%)206 (2.3%)
      BMI category
      Baseline BMI missing in n = 78.
       Underweight: <20 kg/m2162 (1.8%)171 (1.9%)
       Normal: 20-<25 kg/m22,143 (24.1%)2,164 (24.6%)
       Overweight: 25-<30 kg/m23,970 (44.6%)3,864 (44.0%)
       Obese: ≥30 kg/m22,619 (29.4%)2,587 (29.4%)
      BMI, kg/m2
      Baseline BMI missing in n = 78.
      28.1 ± 4.728.1 ± 4.8
      eGFR, mL/min/1.73 m273.0 ± 13.972.9 ± 14.0
      UACR, mg/mmol0.8 [0.5-1.5]0.8 [0.5-1.5]
      Baseline eGFR < 60 mL/min/1.73 m21,615 (18.1%)1,637 (18.6%)
      Baseline albuminuria1,035 (11.6%)1,010 (11.5%)
      Continuous variables given as mean ± SD or median [interquartile range]. eGFR calculated with Chronic Kidney Disease Epidemiology Collaboration equation. Abbreviations: BMI, body mass index; BP, blood pressure.
      a Baseline BMI missing in n = 78.
      Summary measures over time for eGFR and UACR, by treatment assignment, are shown in Fig 1. Results of the mixed models are in Table S1. Mean annual eGFR decline was not different in participants randomized to aspirin (−0.97 [95% CI, −1.02 to −0.92] mL/min/1.73 m2) compared with those randomized to placebo (−0.99 [95% CI, −1.04 to −0.94] mL/min/1.73 m2; P for interaction = 0.6). Likewise, annual increase in UACR was similar in participants randomized to aspirin (mean log2(UACR), 0.055 [95% CI, 0.050-0.059]) compared with placebo (0.051 [95% CI, 0.046-0.056]; P for interaction = 0.3). Results of the joint longitudinal and survival models for both outcomes are in Table S2. Results were all consistent with the results of the main analysis models, with no evidence of an effect of aspirin treatment on either eGFR decline or UACR increase over time, allowing for loss to follow-up owing to mortality.
      Figure thumbnail gr1
      Figure 1Mean eGFR and UACR by treatment allocation and study visit. Error bars represent 1 SD either side of the mean (eGFR) and above the mean (UACR). UACR y-axis has log scale.
      In summary, we found no evidence of an effect of aspirin on kidney measure trajectories, as assessed separately by eGFR and UACR, in healthy community-dwelling older persons, over an average of nearly 5 years of follow-up. The results of our study, the largest-available trial of older individuals receiving aspirin compared with placebo, suggests that fears over decline in kidney function associated with low-dose aspirin among older individuals may not be justified.

      Article Information

      Authors’ Contributions

      Conceived the research questions and designed the study: KRP, RW, JBW, LTPT, RLW, JJM, AMM; involved in acquisition and interpretation of data: KRP, RW, JBW, LTPT, RLW, MEE, MRN, CMR, RCS, JJM, AMM; analyzed the data: KRP, LTPT, RW. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

      Support

      ASPREE was supported by the National Institutes of Health National Institute on Aging (NIH NIA) and the National Cancer Institute (U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (334047, 1127060); and Monash University and the Victorian Cancer Agency. This work was supported by the aforementioned funders, plus NIH NIA grant U19AG062682. CMR is supported through an NHMRC Principal Research Fellowship (APP136372). The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.

      Financial Disclosure

      The authors declare that they have no other relevant financial interests.

      Acknowledgements

      We thank the trial staff in Australia and the United States, the participants who volunteered for this trial, and the general practitioners and staff of the medical clinics who cared for the participants.

      Peer Review

      Received October 1, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form February 10, 2022.

      Supplementary Material

      References

        • Smith S.C.
        • Benjamin E.J.
        • Bonow R.O.
        • et al.
        AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association.
        J Am Coll Cardiol. 2011; 58: 2432-2446
        • Davidson K.W.
        • Barry M.J.
        • et al.
        • US PSTF
        Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement.
        JAMA. 2022; 327: 1577-1584
        • McNeil J.J.
        • Wolfe R.
        • Woods R.L.
        • et al.
        Effect of aspirin on cardiovascular events and bleeding in the healthy elderly.
        N Engl J Med. 2018; 379: 1509-1518
        • Harris R.C.
        Physiologic and pathophysiologic roles of cyclooxygenase-2 in the kidney.
        Trans Am Clin Climatol Assoc. 2013; 124: 139-151
        • Violi F.
        • Targher G.
        • Vestri A.
        • et al.
        Effect of aspirin on renal disease progression in patients with type 2 diabetes: a multicenter, double-blind, placebo-controlled, randomized trial. The renaL disEase progression by aspirin in diabetic pAtients (LEDA) trial. Rationale and study design.
        Am Heart J. 2017; 189: 120-127
        • McNeil J.J.
        • Woods R.L.
        • Nelson M.R.
        • et al.
        Effect of aspirin on disability-free survival in the healthy elderly.
        N Engl J Med. 2018; 379: 1499-1508
        • Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
        KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
        Kidney Int Suppl. 2013; 3: 1-150
        • ASPREE Investigator Group
        Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial.
        Contemp Clin Trials. 2013; 36: 555-564
        • Wolfe R.
        • Murray A.M.
        • Woods R.L.
        • et al.
        The aspirin in reducing events in the elderly trial: Statistical analysis plan.
        Int J Stroke. 2018; 13: 335-338
        • Henderson R.
        • Diggle P.
        • Dobson A.
        Joint modelling of longitudinal measurements and event time data.
        Biostatistics. 2000; 1: 465-480