Investigators are building an empirical evidence base for real world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.

This is a non-randomized, non-interventional study that is part of the Randomized Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology (RCT-DUPLICATE) initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School.

This study is part of a series that applies the Benchmark, Expand, and Calibration (BenchExCal) approach, in which an initial trial emulation is benchmarked against a completed randomized controlled trial (RCT) to inform a subsequent database study for related clinical questions or expanded indications. In this empirical example, the related clinical question has also been evaluated in a completed randomized trial, allowing comparison of the expanded database emulation with the corresponding RCT findings.

It is intended to emulate, as closely as is possible in healthcare insurance claims data the EMPEROR-Preserved 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-Preserved trial is a superiority trial to evaluate the effect of empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), vs placebo on cardiovascular death and hospitalisation for heart failure among individuals with chronic heart failure with preserved ejection fraction.

The database study is designed to emulate the EMPEROR-Preserved trial. It will be a new-user active-comparator cohort study, conducted using 3 national United States claims databases, where the effect of empagliflozin vs sitagliptin was compared, a dipeptidyl peptidase-4 inhibitor (DPP4i), on all-cause mortality and hospitalisation for heart failure. While the EMPEROR-Preserved trial was conducted in participants with and without T2DM, both subgroups showed similar effect estimates in their results. Furthermore, while the trial compared empagliflozin to placebo, sitagliptin was used 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.

Study period:

Optum: Eligible cohort entry period from August 1, 2014 to August 31, 2024. Marketscan: Eligible cohort entry period from August 1, 2014 to September 31, 2023.

Medicare: Eligible cohort entry period from August 1, 2014 to September 31, 2020.

Inclusion Criteria:

• At least 18 years of age
• Heart failure with preserved ejection fraction
• Structural heart disease
• Previous HHF
• BMI < 45 kg/m2
• Type 2 diabetes mellitus
• Use of oral diuretics

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
• Pacemaker
• Liver disease
• Atrial fibrillation
• Hypertension
• Impaired renal function
• Anemia
• History of ketoacidosis
• Pregnancy
• 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

Individuals aged 18 years or older with heart failure and preserved ejection fraction and type 2 diabetes