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

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).

• sacubitril/valsartan (Drug): Initiation of sacubitril/valsartan, identified using prescription fill in pharmacy claims
• Angiotensin II Receptor Blockers (Drug), also known as azilsartan, candesartan, eprosartan, Irbesartan, losartan, Olmesartan, telmisartan, valsartan: Initiation of ARBs, identified using prescription fill in pharmacy claims

Primary outcomes

• Number of patients with composite events of death or heart failure hospitalization [July 2015 - December 2020]: All-cause mortality OR heart failure hospitalization
• Number of patients with composite serious adverse events [July 2015 - December 2020]: Hypotension OR acute kidney injury/acute kidney failure OR hyperkalemia OR angioedema

Secondary outcomes

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

Sex: All, ages: 65 Years to any

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 Protocol (PDF, 2021-02-11)

• Dae Hyun Kim, MD, MPH, ScD, Principal investigator, Brigham and Women's Hospital