Prospective Monitoring of Angiotensin Receptor Neprilysin Inhibitor in Older Adults With Heart Failure and Frailty

The objective of this study is to establish a near-real-time prospective monitoring program in Medicare, Optum and MarketScan Research data to evaluate the benefit of new cardiovascular disease (CVD) drugs for older adults with frailty. Prospective monitoring program seeks to find early effectiveness and safety signals of new drugs by updating the analysis at regular intervals as new Medicare data become available. This study specifically aims to emulate a prospective surveillance of the effectiveness and safety of Angiotensin Receptor Neprilysin Inhibitor(ARNI) vs. a comparator, Angiotensin II Receptor Blockers (ARBs), in older adults with Heart Failure with Reduced Ejection Fraction (HFrEF) and different frailty status. This program will be enhanced by incorporating a novel claims-based frailty index, which has been shown useful in assessing how the benefits and harms of drug therapy vary by frailty.

Study Overview

• Status: Active, not recruiting
• Conditions: Frailty; Heart Failure, Systolic
• Intervention / Treatment: Drug: sacubitril/valsartan; Drug: Angiotensin II Receptor Blockers

Detailed Description

Data sources of use for this study are: Medicare Database, Optum Database, and MarketScan Research Database. All data from years 2014-2020 will be included in the study.

This study follows a sequential cohort monitoring design. The monitoring analysis will include 1) retrospective analysis of available data (2015-2017) at the time of first analysis (January 2021) and 2) prospective analysis of new data (2018-2020) as they become available to the researchers. Within each database, we will emulate biannual updating of data by creating a propensity score (PS)-matched cohort of new users every 6-month interval, beginning on the first marketing of ARNI (July 7, 2015-December 31, 2015, and 6-month intervals afterwards). Each sequential cohort will be followed for development of the outcomes of interest. Outcome analysis will be performed at a pre-specified 6-month interval (prospective analysis). The surveillance will be performed by frailty status (frail vs non-frail) at the time of drug initiation. The results from each database will be pooled using fixed-effects meta-analysis (assuming low heterogeneity across the databases).

• Study Type: Observational
• Enrollment (Anticipated): 40000

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02120
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Study population includes older patients with heart failure with reduced ejection fraction who initiates an angiotensin receptor neprilysin inhibitor or an angiotensin II receptor blocker.

Description

Inclusion Criteria:

• Continuous enrollment for medical and drug insurance (e.g., Medicare Part A, B, and D) in [-365, 0] days
• Diagnosis of Heart Failure either two outpatient diagnosis or one inpatient diagnosis in [-365, 0] days

• Reduced Ejection Fraction < 45% identified using a validated claims-based algorithm in [-365, 0] days

  • Day 0 is the initiation date of the study drug.

Exclusion Criteria:

• No prior use of Angiotensin receptor neprilysin inhibitor or angiotensin II receptor blocker in [-365, -1] days
• No recent HF hospitalization, defined as HF diagnosis (defined in attached protocol) in the primary position in the inpatient dataset in [-60, 0] days
• No recent nursing facility stay (defined in attached protocol) for [-60, 0] days
• Age < 65 years
• Exposure to both drugs on day 0
• Contraindication to either drug (exclusion assessment window: [-60, 0] days, unless specified otherwise; algorithms specified in attached protocol)

Note: If a patient meets the above-mentioned eligibility criteria more than once, only the first record will be included.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
New users of angiotensin receptor neprilysin inhibitor	Drug: sacubitril/valsartan; Initiation of sacubitril/valsartan, identified using prescription fill in pharmacy claims
New users of angiotensin II receptor blockers	Drug: Angiotensin II Receptor Blockers; Initiation of ARBs, identified using prescription fill in pharmacy claims; Other Names: losartan; Irbesartan; Olmesartan; azilsartan; candesartan; eprosartan; telmisartan; valsartan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with composite events of death or heart failure hospitalization	All-cause mortality OR heart failure hospitalization	July 2015 - December 2020
Number of patients with composite serious adverse events	Hypotension OR acute kidney injury/acute kidney failure OR hyperkalemia OR angioedema	July 2015 - December 2020

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with all-cause mortality	All-cause mortality is defined by the National Death Index file or vital status information in the claims dataset.	July 2015 - December 2020
Number of patients with heart failure hospitalization	Heart failure hospitalization is defined as any hospitalization with relevant diagnosis codes in the primary position.	July 2015 - December 2020
Number of patients with hypotension	Hypotension is defined as any hospitalization or Emergency Department visit with relevant diagnosis codes in the primary position.	July 2015 - December 2020
Number of patients with hyperkalemia	Hyperkalemia is defined as any hospitalization or Emergency Department visit with relevant diagnosis codes in the primary position.	July 2015 - December 2020
Number of patients with acute kidney injury/acute kidney failure	Acute kidney injury/Acute kidney failure is defined as any hospitalization or Emergency Department visit with relevant diagnosis codes in the primary position.	July 2015 - December 2020
Number of patients with angioedema	Angioedema is defined as any hospitalization or Emergency Department visit with relevant diagnosis codes in the primary position.	July 2015 - December 2020

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Dae Hyun Kim, MD, MPH, ScD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2021
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: February 3, 2021
• First Submitted That Met QC Criteria: February 3, 2021
• First Posted (Actual): February 8, 2021

Study Record Updates

• Last Update Posted (Actual): February 15, 2021
• Last Update Submitted That Met QC Criteria: February 11, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Heart Failure; Frailty; Heart Failure, Systolic; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Angiotensin II Type 1 Receptor Blockers; Vasoconstrictor Agents; Angiotensin II Type 2 Receptor Blockers; Valsartan; Losartan; Olmesartan; Sacubitril and valsartan sodium hydrate drug combination; Candesartan; Telmisartan; Irbesartan; Angiotensin II; Giapreza; Angiotensinogen; Angiotensin Receptor Antagonists; Eprosartan
• Other Study ID Numbers: 2019P000110-ARNI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No