Economic Evaluation of Factorial Trials: Cost-Utility Analysis of the Atorvastatin in Factorial With Omega EE90 Risk Reduction in Diabetes 2 × 2 × 2 Factorial Trial of Atorvastatin, Omega-3 Fish Oil, and Action Planning

Helen A Dakin,Alastair M Gray,Andrew Farmer,Rury R Holman

doi:10.1016/j.jval.2020.05.018

Abstract

ObjectivesWe applied principles for conducting economic evaluations of factorial trials to a trial-based economic evaluation of a cluster-randomized 2 × 2 × 2 factorial trial. We assessed the cost-effectiveness of atorvastatin, omega-3 fish oil, and an action-planning leaflet, alone and in combination, from a UK National Health Service perspective.MethodsThe Atorvastatin in Factorial With Omega EE90 Risk Reduction in Diabetes (AFORRD) Trial randomized 800 patients with type 2 diabetes to atorvastatin, omega-3, or their respective placebos and randomized general practices to receive a leaflet-based action-planning intervention designed to improve compliance or standard care. The trial was conducted at 59 UK general practices. Sixteen-week outcomes for each trial participant were extrapolated for 70 years using the United Kingdom Prospective Diabetes Study Outcomes Model v2.01. We analyzed the trial as a 2 × 2 factorial trial (ignoring interactions between action-planning leaflet and medication), as a 2 × 2 × 2 factorial trial (considering all interactions), and ignoring all interactions.ResultsWe observed several qualitative interactions for costs and quality-adjusted life-years (QALYs) that changed treatment rankings. However, different approaches to analyzing the factorial design did not change the conclusions. There was a ≥99% chance that atorvastatin is cost-effective and omega-3 is not, at a £20 000/QALY threshold.ConclusionsAtorvastatin monotherapy was the most cost-effective combination of the 3 trial interventions at a £20 000/QALY threshold. Omega-3 fish oil was not cost-effective, while there was insufficient evidence to draw firm conclusions about action planning. Recently-developed methods for analyzing factorial trials and combining parameter and sampling uncertainty were extended to estimate cost-effectiveness acceptability curves within a 2x2x2 factorial design with model-based extrapolation.

Highlights

Factorial randomized controlled trials (RCTs) compare different combinations of $2 treatments.[1,2] These enable $2 independent treatments to be evaluated efficiently and allow estimation of interactions between treatments
There is extensive evidence demonstrating that statins are highly effective and cost-effective at reducing low-density lipoprotein cholesterol (LDL-C) levels and preventing cardiovascular events,[5,6,7,8] there was limited evidence in diabetic patients typical of those managed in primary care at the time the trial was funded
AFORRD (ISRCTN 76737502) comprised a double-blind RCT conducted in adults with type 2 diabetes and no known cardiovascular events who were managed in UK primary care and were not thought to require immediate lipid-lowering treatment.[14,15]

Summary

Introduction

Factorial randomized controlled trials (RCTs) compare different combinations of $2 treatments.[1,2] These enable $2 independent treatments to be evaluated efficiently and allow estimation of interactions between treatments (ie, how much the effect of 1 treatment changes when another treatment is given). There is extensive evidence demonstrating that statins are highly effective and cost-effective at reducing low-density lipoprotein cholesterol (LDL-C) levels and preventing cardiovascular events,[5,6,7,8] there was limited evidence in diabetic patients typical of those managed in primary care at the time the trial was funded

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