# Causal Inference for Better Understanding Clinical Trials Results: Reconciling Discrepant Comparative Evidence from Two Major Cardiovascular Safety Trials of Urate-Lowering Therapy

> **NIH NIH R03** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $89,500

## Abstract

Project Summary / Abstract
Clinical trials are the gold standard of causal inference. However, analyses typically employed in clinical trials
cannot answer nuanced questions involving mediating mechanisms. As a result, debate continues regarding the
cardiovascular implications of gout medications, such as urate-lowering therapy and, increasingly, colchicine,
despite the two major cardiovascular trials among gout patients: Cardiovascular Safety of Febuxostat and
Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) and Febuxostat versus Allopurinol
Streamlined Trial (FAST). CARES showed an increase in deaths among febuxostat users. However, it had a high
loss to follow-up rate. On the other hand, some of the effect estimates in FAST favored febuxostat. However, there
were differential discontinuation of urate-lowering therapy and differential use of colchicine in FAST. These
idiosyncrasies have led to lingering questions.
 1. Did the increased use of colchicine (cardio-protective in non-gout trials) among the febuxostat group affect
 FAST results in favor of febuxostat?
 2. Did higher drug discontinuation in the febuxostat group in FAST and higher loss to follow-up in the allopurinol
 group in CARES bias their results?
In this proposed study, we will use advanced causal inference methods to address these questions via parallel
analyses of FAST and CARES. In Aim 1, we will first conduct a comparative effectiveness study of colchicine
prophylaxis compared to no prophylaxis or non-steroidal anti-inflammatory drug prophylaxis in FAST and CARES.
We will then conduct causal mediation analysis to quantify the extent to which colchicine use explains the protective
point estimates favoring febuxostat in FAST. In Aim 2, We will estimate the "per-protocol effect" of febuxostat
compared to allopurinol on cardiovascular outcomes. This approach estimates the effect of these medications
under a causal scenario of full adherence and follow-up, reducing this significant interpretability difficulty of these
trials. Our methodologically innovative project is expected to help to reconcile the discrepant results from FAST
and CARES. PI will also develop a valuable collaboration network and preliminary data demonstrating the
usefulness of causal inference methods in clinical trial analysis. We will further disseminate these advanced
methods via online and offline methodology tutorials.

## Key facts

- **NIH application ID:** 10507247
- **Project number:** 1R03AR081309-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Sara K. Tedeschi
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $89,500
- **Award type:** 1
- **Project period:** 2022-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10507247

## Citation

> US National Institutes of Health, RePORTER application 10507247, Causal Inference for Better Understanding Clinical Trials Results: Reconciling Discrepant Comparative Evidence from Two Major Cardiovascular Safety Trials of Urate-Lowering Therapy (1R03AR081309-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10507247. Licensed CC0.

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