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Canadian Journal of Cardiology

Controversy Over the Surrogacy of Proteinuria or Albuminuria for Cardiovascular Outcomes

      To the Editor:
      We were pleased to read the excellent review by Harrison et al.,
      • Harrison T.G.
      • Tam-Tham H.
      • Hemmelgarn B.R.
      • et al.
      Change in proteinuria or albuminuria as a surrogate for cardiovascular and other major clinical outcomes: a systematic review and meta-analysis.
      recently published in the Canadian Journal of Cardiology, entitled “Change in Proteinuria or Albuminuria as a Surrogate for Cardiovascular and Other Major Clinical Outcomes: A Systematic Review and Meta-analysis”. The authors declared that “There is ongoing controversy around the surrogacy of proteinuria or albuminuria, particularly for cardiovascular (CV) outcomes”; therefore, the aim of their review article was to assess the surrogacy of changing proteinuria or albuminuria for CV events, end-stage renal disease (ESRD), and all-cause mortality. Results of the study showed inconsistent treatment effects for proteinuria and CV events (20 trials; TER 1.11 [95% confidence interval (CI), 1.01-1.22]). Treatment effects on proteinuria or albuminuria were also inconsistent with the effects on all-cause mortality (21 trials; TER 1.17 [95% CI, 1.07-1.28]), and they concluded that “Change in proteinuria or albuminuria might be a suitable surrogate outcome for ESRD. However, overall treatment effects on these potential surrogates are inconsistent and overestimate the treatment effects on CV events and all-cause mortality.” Although the results were interesting, the obtained statistically significant level would be a matter of controversy. Borderline lower limits of 95% CIs made their significance level doubtable, whereas the 95% prediction interval (PI) suggested that the intervention effect could be null or even be in the opposite direction,
      • IntHout J.
      • Ioannidis J.P.A.
      • Rovers M.M.
      • Goeman J.J.
      Plea for routinely presenting prediction intervals in meta-analysis.
      as PI presents a wider range of interval than CI. Therefore, to evaluate clinical significance, PI was proposed in contrast to statistical significance. To explain further, CI quantifies the accuracy of the mean, whereas PI addresses the actual dispersion of effect sizes, and the 2 measures are not interchangeable. We suggest that the authors calculate the prediction interval for evaluating clinical significances to reach more reliable results.
      • Borenstein M.
      • Hedges L.V.
      • Higgins J.P.
      • Rothstein H.R.
      Introduction to Meta-Analysis.
      We would like to mention another statistical issue as well. Meta-analysis uses normal distribution to estimate pooled CI (z-value), whereas relative risk (RR) follows a skewed distribution, which affects the results significantly. To tackle this issue, it would better to log-transform RR and pooled them and then inverse log by an exponential function and report RR instead of log-RR. The review authors did not mention, in the statistical part in the case, whether the process of analysis followed this point. We also assessed the methodological quality of this review using the 16-item A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 appraisal tool.
      • Shea B.J.
      • Reeves B.C.
      • Wells G.
      • et al.
      AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.
      According to AMSTAR 2, this study scored 16 items out of 16 (Table 1), so this systematic review provided an accurate and comprehensive summary of the results of the available studies that address the question of interest and is classified as high-quality, although the surrogacy of proteinuria or albuminuria for CV outcomes is still a matter of controversy.
      Table 1Methodological quality of the included meta-analyses and systematic reviews through AMSTAR 2
      ItemsN (%)
      1Did the research questions and inclusion criteria for the review include the components of PICO (population, intervention, control group, and outcome)?Yes
      2Did the report of the review contain an explicit statement that the review methods were established prior to conduct of the review, and did the report justify any significant deviations from the protocol?Yes
      3Did the review authors explain their selection of the study designs for inclusion in the review?Yes
      4Did the review authors use a comprehensive literature search strategy?Yes
      5Did the review authors perform study selection in duplicate?Yes
      6Did the review authors perform data extraction in duplicate?Yes
      7Did the review authors provide a list of excluded studies and justify the exclusions?Yes
      8Did the review authors describe the included studies in adequate detail?Yes
      9Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?Yes
      10Did the review authors report on the sources of funding for the studies included in the review?Yes
      11If meta-analysis was justified, did the review authors use appropriate methods for statistical combination of results?Yes
      12If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?Yes
      13Did the review authors account for RoB in individual studies when interpreting/discussing the results of the review?Yes
      14Did the review authors provide a satisfactory explanation for—and discussion of—any heterogeneity observed in the results of the review?Yes
      15If they performed quantitative synthesis, did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?Yes
      16Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?Yes
      AMSTAR 2 ClassificationHigh
      AMSTAR, A Measurement Tool to Assess Systematic Reviews.

      Disclosures

      The authors have no conflicts of interest to disclose.

      References

        • Harrison T.G.
        • Tam-Tham H.
        • Hemmelgarn B.R.
        • et al.
        Change in proteinuria or albuminuria as a surrogate for cardiovascular and other major clinical outcomes: a systematic review and meta-analysis.
        Can J Cardiol. 2019; 35: 77-91
        • IntHout J.
        • Ioannidis J.P.A.
        • Rovers M.M.
        • Goeman J.J.
        Plea for routinely presenting prediction intervals in meta-analysis.
        BMJ Open. 2016; 6: e010247
        • Borenstein M.
        • Hedges L.V.
        • Higgins J.P.
        • Rothstein H.R.
        Introduction to Meta-Analysis.
        John Wiley & Sons, Hoboken, NJ2011
        • Shea B.J.
        • Reeves B.C.
        • Wells G.
        • et al.
        AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both.
        BMJ. 2017; 358: j4008

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