Emulation of the EMPEROR-Reduced Trial Using Healthcare Claims Data

This is a non-randomized, non-interventional study that is part of the RCT DUPLICATE initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School. It is intended to emulate, as closely as is possible in healthcare insurance claims data, the EMPEROR-Reduced trial described below. Although many features of the trial cannot be directly replicated in healthcare claims, key design features, including outcomes, exposures, and inclusion/exclusion criteria, were selected to proxy those features from the trial. Randomization cannot be achieved in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice. Investigators assume that the RCT provides the reference standard treatment effect estimate and that failure to replicate RCT findings is indicative of the inadequacy of the healthcare claims data for emulation for a range of possible reasons and does not provide information on the validity of the original RCT finding.

The EMPEROR-Reduced trial, was a superiority trial to evaluate the effect of Empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), versus placebo on the risk of cardiovascular death and hospitalisation for heart failure among individuals with chronic heart failure with reduced ejection fraction.

The database study is designed to emulate EMPEROR-Reduced. It will be a new-user comparative cohort study, conducted using 3 national United States claims databases comparing the effect of empagliflozin versus sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP4i), on all-cause mortality and hospitalisation for heart failure. While the EMPEROR-Reduced trial compared empagliflozin to placebo, use sitagliptin was chosen as an active comparator proxy for placebo to minimize confounding by indication sitagliptin was specifically chosen because a major randomized controlled trial on cardiovascular outcomes demonstrated that it does not affect the cardiovascular outcomes under investigation. Furthermore, clinical guidelines during the study period recommended both SGLT2 inhibitors and DPP4 inhibitors as second- or third-line options for glucose lowering, and the therapies are similarly costly, reducing concerns about channelling of patients based on socioeconomic status.

Optum: Study period between 1st August 2014 - 31st December 2024. Marketscan: Study period between 1st August 2014 - 30th September 2022. Medicare: Study period between 1st August 2014 - 30th September 2022.

Inclusion criteria

• At least 18 years of age
• Heart failure with reduced ejection fraction
• Type 2 diabetes mellitus
• Use of oral diuretics
• Use of appropriate medical therapy for HF

Exclusion criteria

• Concurrent use of both study drugs on cohort entry date
• MI, CABG or other major cardiovascular surgery, GI surgery or disorder, stroke or TIA
• Implantable cardiac defibrillator
• Hypotension
• Major surgery
• GI surgery or disorder
• Cancer
• Heart transplant
• LVAD
• Liver disease
• Atrial fibrillation
• Hypertension
• Impaired renal function
• Anemia
• Ketoacidosis
• Pregnancy
• Ventricular arrhythmia
• Heart block
• Cardiomyopathy
• Valvular heart disease
• Chronic pulmonary disease
• Combined comorbidity score
• Chronic alcohol and or drug abuse
• Noncompliance
• Acute decompensated HF
• Use of SGLT2i or DPP4i