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Background <p>To demonstrate nuances of emulating placebo-controlled trials in the target trial emulation framework using claims, we aimed to expand evidence from the TOPCAT trial on spironolactone effectiveness in heart failure with preserved ejection fraction (HFpEF) to the U.S. HFpEF population.</p> Methods <p>We compared spironolactone initiation and continued use versus non-initiation in 2012-2020 Medicare claims with the clone-censor-weight approach for five effectiveness endpoints. Anticipating threats to validity, we pre-specified 1) benchmarking against TOPCAT Americas results, and 2) a negative control outcome (non-cardiovascular mortality). To demonstrate frequent investigator-induced biases outside the target trial emulation framework, we additionally implemented a ‘naïve’ ever- vs never-user comparison.</p> Results <p>Here we show results based on 320,881 patients with heart failure and preserved ejection fraction (mean age 80.6 years (standard deviation 8.37); female 62%) from the overall Medicare cohort, of which 49,729 qualify for benchmarking against TOPCAT. In the benchmarking cohort, relative risks with spironolactone use compared to non-use for effectiveness outcomes range from 0.97 (95% confidence interval: [0.94; 1.01]) for the composite of heart failure hospitalization, cardiac arrest and cardiovascular death to 1.14 (95% confidence interval: [1.11; 1.18]) for all-cause mortality. Non-cardiovascular mortality results suggest presence of residual confounding. Bias correction improves agreement with the TOPCAT estimates, while the naïve analysis produces substantially biased results.</p> Conclusions <p>In emulations of placebo-controlled trials, residual confounding remains a persistent threat. It is critical to pre-specify built-in guardrails to detect and address this bias.</p>

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Empirical assessment of constraints and credibility when emulating a placebo-controlled trial with the clone-censor-weight approach

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Anna-Janina Stephan,
  • Gerard Portela,
  • Raisa Levin,
  • Nils Krüger,
  • Sebastian Schneeweiss,
  • Rishi J. Desai

摘要

Background

To demonstrate nuances of emulating placebo-controlled trials in the target trial emulation framework using claims, we aimed to expand evidence from the TOPCAT trial on spironolactone effectiveness in heart failure with preserved ejection fraction (HFpEF) to the U.S. HFpEF population.

Methods

We compared spironolactone initiation and continued use versus non-initiation in 2012-2020 Medicare claims with the clone-censor-weight approach for five effectiveness endpoints. Anticipating threats to validity, we pre-specified 1) benchmarking against TOPCAT Americas results, and 2) a negative control outcome (non-cardiovascular mortality). To demonstrate frequent investigator-induced biases outside the target trial emulation framework, we additionally implemented a ‘naïve’ ever- vs never-user comparison.

Results

Here we show results based on 320,881 patients with heart failure and preserved ejection fraction (mean age 80.6 years (standard deviation 8.37); female 62%) from the overall Medicare cohort, of which 49,729 qualify for benchmarking against TOPCAT. In the benchmarking cohort, relative risks with spironolactone use compared to non-use for effectiveness outcomes range from 0.97 (95% confidence interval: [0.94; 1.01]) for the composite of heart failure hospitalization, cardiac arrest and cardiovascular death to 1.14 (95% confidence interval: [1.11; 1.18]) for all-cause mortality. Non-cardiovascular mortality results suggest presence of residual confounding. Bias correction improves agreement with the TOPCAT estimates, while the naïve analysis produces substantially biased results.

Conclusions

In emulations of placebo-controlled trials, residual confounding remains a persistent threat. It is critical to pre-specify built-in guardrails to detect and address this bias.