Replication of the PARADIGM-HF Heart Failure Trial in Healthcare Claims Data.
Conditions: Heart Failure
Sponsor: Brigham and Women's Hospital

Replication of the PARADIGM-HF Heart Failure Trial in 
Healthcare Claims Data  
DUPLICATE PARADIGM-HF January 25, 2021 
 
NCT04736433 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭ
1. RCT DeƚailƐ
This section provides a high-level overview of an RCT that the described real-world evidence study is trying to replicate as closely
as possible given the remaining limitations inherent in the healthcare databases.
1.1 Title
AngioƚenƐinͲNeƉƌilǇƐin Inhibiƚion ǀeƌƐƵƐ EnalaƉƌil in Heaƌƚ FailƵƌe ;PARADIGM-HF ƚƌialͿ 
1.2 Intended aim(s) 
The primary objective of the study is to determine LCZϲϵϲ ϮϬϬ mg twice daily, a combination of sacubitril/valsartan, is 
superior to enalapril ϭϬ mg twice daily in reducing the composite endpoint in place of Angiotensin Converting Enzyme 
inhibitors (ACEi) and Angiotensin II receptor blockers (ARBs) 
1.3 Primary endpoint for replication and RCT finding 
Composite endpoint of death from cardiovascular (CV) causes or hospitalization for heart failure (HF) 
1.4 Required power for primary endpoint and noninferiority margin (if applicable) 
After following ϴϬϬϬ patients for ϯϰ months, at an overall two-sided alpha level of Ϭ.Ϭϱ, the primary end point would occur 
in ϮϰϭϬ patients, which would provide a power of ϵϳй to detect a ϭϱй reduction in the risk of this outcome. 
1.5 Trial estimate 
HR с Ϭ.ϴϬ (ϵϱй CI Ϭ.ϳϯ–Ϭ.ϴϳ) comparing LCZϲϵϲ to enalapril (McMurry et al., ϮϬϭϰ, NEJM) 
2. PeƌƐon ƌeƐƉonƐible foƌ imƉlemenƚaƚion of ƌeƉlicaƚion in Aeƚion
Helen Tesfaye, Pharm.D, ScM implemented the study design in the Aetion Evidence Platform. She is not responsible for the validity
of design and analytic choices. All implementation steps are recorded, and implementation history is archived in the platform.
3. Daƚa SoƵƌce;ƐͿ
Optum Cliniformatics Data Mart, IBM MarketScan, Medicare
4. SƚƵdǇ DeƐign Diagƌam

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
Ϯ
The study design diagram visualizes key aspects of the longitudinal study design for expediated review 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϯ
5. Cohoƌƚ Idenƚificaƚion
5.1 Cohort Summary 
This study will involve a new user, parallel group retrospective cohort study design comparing sacubitril/valsartan to ACE 
inhibitors. Although the trial compared sacubitril/valsartan to enalapril, we expanded the definition of the comparator group to 
include all ACEi therapies to improve power, since all medications within this class of medication are indicated and guideline 
recommended for use in heart failure with reduced ejection fraction patients and would be expected to have similar effects on 
the primary outcome of CV death and HF hospitalization. 
The patients will be required to have continuous enrollment during the baseline period of ϭϴϬ days before initiation of 
sacubitril/valsartan or a ACEi (cohort entry).  
5.2 Important steps for cohort formation 
New users (defined as no use of sacubitril/valsartan in ϭϴϬ days prior to index date) of the exposure will be identified. New users 
of a comparator drug were identified as patients with no ACEi fills during the ϲϬ days prior to the index date to allow for patients 
who are switching among ACEi drugs or restarting ACEi after a brief lapse.  
ϱ.Ϯ.ϭ   Eligible cohort entry date 
Sacubitril/valsartan was approved by FDA for market availability on July ϳ, ϮϬϭϱ. 
Optum: July ϳ, ϮϬϭϱ – March ϯϭ, ϮϬϮϬ (end of data availability) 
Marketscan: July ϳ, ϮϬϭϱ – December ϯϭ, ϮϬϭϴ (end of data availability) 
Medicare: July ϳ, ϮϬϭϱ – December ϯϭ, ϮϬϭϳ (end of data availability) 
5.2.2 Specify inclusion/exclusion criteria for cohort entry and define the index date 
Inclusion and exclusion criteria were adapted from the trial as closely as possible. Definitions for all inclusion/exclusion are 
provided in AƉƉendiǆ A and are summarized in the flowcharts below. 
5.3 Flowchart of the study cohort assembly 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϰ
OƉƚƵm 
MaƌkeƚƐcan 
MedicaƌeΎ 
LeƐƐ EǆclƵded 
PaƚienƚƐ 
Remaining 
PaƚienƚƐ 
LeƐƐ EǆclƵded 
PaƚienƚƐ 
Remaining 
PaƚienƚƐ 
LeƐƐ EǆclƵded 
PaƚienƚƐ 
Remaining 
PaƚienƚƐ 
All ƉaƚienƚƐ 
ϳϳ,ϲϳϯ,ϲϯϵ 
ϮϬϬ,ϮϬϯ,ϵϬϴ 
Ϯϯ,ϰϲϲ,ϭϳϱ 
Did not meet cohort entry criteria 
-ϳϯ,ϰϰϱ,ϴϰϲ
ϰ,ϮϮϳ,ϳϵϯ 
-ϭϵϲ,ϱϯϯ,ϳϲϬ
ϯ,ϲϳϬ,ϭϰϴ 
-ϭϴ,ϯϰϴ,ϳϭϯ
ϱ,ϭϭϳ,ϰϲϮ 
Excluded due to insufficient enrollment 
-ϲϮϯ,ϵϱϰ
ϯ,ϲϬϯ,ϴϯϵ 
-ϯϰϬ,Ϭϱϭ
ϯ,ϯϯϬ,Ϭϵϳ 
-ϭ,Ϯϴϴ,ϴϲϳ
ϯ,ϴϮϴ,ϱϵϱ 
Excluded due to prior use of referent 
-ϯ,ϭϲϴ,ϵϮϭ
ϰϯϰ,ϵϭϴ 
-Ϯ,ϵϲϳ,ϴϴϲ
ϯϲϮ,Ϯϭϭ 
-ϯ,ϰϵϱ,ϳϴϵ
ϯϯϮ,ϴϬϲ 
Excluded due to prior use of exposure 
-Ϯϵ,ϳϳϴ
ϰϬϱ,ϭϰϬ 
-ϭϮ,ϱϭϭ
ϯϰϵ,ϳϬϬ 
-ϯϯ,Ϭϭϯ
Ϯϵϵ,ϳϵϯ 
Excluded because patient qualified in хϭ exposure category 
-ϴ
ϰϬϱ,ϭϯϮ 
-ϯ
ϯϰϵ,ϲϵϳ 
-ϵ
Ϯϵϵ,ϳϴϰ 
Excluded based on Age 
Ϭ 
ϰϬϱ,ϭϯϮ 
-ϭ
ϯϰϵ,ϲϵϲ 
Ϭ 
Ϯϵϵ,ϳϴϰ 
Excluded based on Gender 
-ϯϵ
ϰϬϱ,Ϭϵϯ 
Ϭ 
ϯϰϵ,ϲϵϲ 
Ϭ 
Ϯϵϵ,ϳϴϰ 
Excluded based on Inclusion #ϭ - Age хсϭϴ years old 
-ϲϮϰ
ϰϬϰ,ϰϲϵ 
-ϭ,ϯϱϰ
ϯϰϴ,ϯϰϮ 
-ϳϮϭ
Ϯϵϵ,Ϭϲϯ 
Inclusion #ϯ - HFrEF prediction algorithm applied to 
reference group† 
-ϯϴϭ,ϱϯϭ
ϮϮ,ϵϯϴ 
-ϯϯϳ,ϮϰϮ
ϭϭ,ϭϬϬ 
-Ϯϱϵ,ϴϭϲ
ϯϵ,Ϯϰϳ 
Excluded based on Inclusion #ϰb - Hospitalization for HF 
within the last ϭϮ months 
-ϵ,ϯϮϭ
ϭϯ,ϲϭϳ 
-ϰ,ϲϭϴ
ϲ,ϰϴϮ 
-ϭϬ,ϲϴϱ
Ϯϴ,ϱϲϮ 
Excluded based on Inclusion #ϱa - ACEis or ARBs 
-ϭ,ϮϮϰ
ϭϮ,ϯϵϯ 
-ϯϴϱ
ϲ,Ϭϵϳ 
-ϭ,ϱϯϰ
Ϯϳ,ϬϮϴ 
Excluded based on Inclusion #ϱb - Beta-blockers 
-ϲϳϯ
ϭϭ,ϳϮϬ 
-Ϯϰϴ
ϱ,ϴϰϵ 
-Ϯ,ϭϮϴ
Ϯϰ,ϵϬϬ 
Excluded based on Exclusion #ϯ - Known history of 
angioedema 
-ϱϲ
ϭϭ,ϲϲϰ 
-Ϯϵ
ϱ,ϴϮϬ 
-ϮϬϬ
Ϯϰ,ϳϬϬ 
Excluded based on Exclusion #ϰ - Treatment with both ACEis 
AND ARBs 
-ϭϱ
ϭϭ,ϲϰϵ 
-ϵ
ϱ,ϴϭϭ 
-ϯϰ
Ϯϰ,ϲϲϲ 
Excluded based on Exclusion #ϱ - Acute decompensated HF 
-ϭ,ϬϲϬ
ϭϬ,ϱϴϵ 
-ϰϯϱ
ϱ,ϯϳϲ 
-ϱ,ϰϱϳ
ϭϵ,ϮϬϵ 
Excluded based on Exclusion #ϲ - Symptomatic hypotension 
-ϳϯϰ
ϵ,ϴϱϱ 
-ϮϰϬ
ϱ,ϭϯϲ 
-ϭ,ϵϲϰ
ϭϳ,Ϯϰϱ 
Excluded based on Exclusion #ϳ - Low eGFR / renal 
dysfunction 
-ϭ,Ϭϲϰ
ϴ,ϳϵϭ 
-ϰϬϯ
ϰ,ϳϯϯ 
-Ϯ,ϴϯϯ
ϭϰ,ϰϭϮ 
Excluded based on Exclusion #ϴ - Hyperkalemia 
-ϱϳ
ϴ,ϳϯϰ 
-ϭϰ
ϰ,ϳϭϵ 
-ϭϭϲ
ϭϰ,Ϯϵϲ 
Excluded based on Exclusion #ϵ - ACS, Stroke, TIA, CABG, PCI, 
Other CV Procedures, Carotid Angioplasty 
-ϳϲϱ
ϳ,ϵϲϵ 
-ϱϰϲ
ϰ,ϭϳϯ 
-Ϯ,ϵϭϮ
ϭϭ,ϯϴϰ 
Excluded based on Exclusion #ϭϭ - Implantation of CRT device 
-ϰϭ
ϳ,ϵϮϴ 
-ϭϵ
ϰ,ϭϱϰ 
-ϭ,ϱϱϬ
ϵ,ϴϯϰ 
Excluded based on Exclusion #ϭϮ - History of heart transplant 
or LVAD 
-ϱϲ
ϳ,ϴϳϮ 
-ϯϯ
ϰ,ϭϮϭ 
-ϯϱ
ϵ,ϳϵϵ 
Excluded based on Exclusion #ϭϯ - History of severe 
pulmonary disease 
-ϰϲϯ
ϳ,ϰϬϵ 
-ϮϬϱ
ϯ,ϵϭϲ 
-ϭ,ϬϮϵ
ϴ,ϳϳϬ 
Excluded based on Exclusion #ϭϰ - Diagnosis of peripartum- 
or chemotherapy-induced cardiomyopathy 
-ϯϴ
ϳ,ϯϳϭ 
-ϯϰ
ϯ,ϴϴϮ 
-ϲϬ
ϴ,ϳϭϬ 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϱ
Excluded based on Exclusion #ϭϱ - Documented untreated 
ventricular arrhythmia with syncopal episodes 
-ϭϴ
ϳ,ϯϱϯ 
-ϲ
ϯ,ϴϳϲ 
-Ϯϱ
ϴ,ϲϴϱ 
Excluded based on Exclusion #ϭϲ - Second- and third-degree 
AV block 
-ϳϯ
ϳ,ϮϴϬ 
-Ϯϵ
ϯ,ϴϰϳ 
-ϳϯ
ϴ,ϲϭϮ 
Excluded based on Exclusion #ϭϳ - Presence of 
haemodynamically significant mitral and/or aortic valve 
disease 
-ϭϮϰ
ϳ,ϭϱϲ 
-ϰϯ
ϯ,ϴϬϰ 
-Ϯϰϲ
ϴ,ϯϲϲ 
Excluded based on Exclusion #ϭϵa - History of active 
inflammatory bowel disease (IBD) 
-ϭϴ
ϳ,ϭϯϴ 
-ϭϮ
ϯ,ϳϵϮ 
-ϯϳ
ϴ,ϯϮϵ 
Excluded based on Exclusion #ϭϵb - Active duodenal/gastric 
ulcers 
-ϭϯ
ϳ,ϭϮϱ 
-ϴ
ϯ,ϳϴϰ 
-Ϯϱ
ϴ,ϯϬϰ 
Excluded based on Exclusion #ϭϵc - Evidence of hepatic 
disease 
-ϭϳϯ
ϲ,ϵϱϮ 
-ϴϬ
ϯ,ϳϬϰ 
-Ϯϲϱ
ϴ,Ϭϯϵ 
Excluded based on Exclusion #ϭϵd - Current treatment with 
cholestyramine or colestipol resins 
Ϭ 
ϲ,ϵϱϮ 
Ϭ 
ϯ,ϳϬϰ 
-ϰ
ϴ,Ϭϯϱ 
Excluded based on Exclusion #Ϯϭ - Ivabradine use 
-ϲ
ϲ,ϵϰϲ 
-ϭϬ
ϯ,ϲϵϰ 
-ϰ
ϴ,Ϭϯϭ 
Final cohoƌƚ 
ϲ͕ϵϰϲ 
ϯ͕ϲϵϰ 
ϴ͕Ϭϯϭ 
* The Medicare data cut included all patients with a diagnosis for HF, stroke, or diabetes.
† Algorithm provided in Desai et al. (ϮϬϭϴ).
6 
VaƌiableƐ 
6.1 Exposure-related variables: 
Study drug: 
The study exposure of interest is initiation of sacubitril/valsartan (ARNi) at any dose and frequency. Initiation will be 
defined by no use of sacubitril/valsartan during the prior ϭϴϬ days before treatment initiation (washout period). Patients 
are required to be incident users with respect to their exposure group only, since one of the RCT inclusion criteria was prior 
treatment with ACEi or ARB.  
Comparator agents: 
Initiators of ACEi, any dose and frequency. 
6.2 Preliminary Covariates: 
Age 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϲ
Sex 
Combined Comorbidity Index (CCI), measured over the default baseline covariate assessment period of ϭϴϬ days 
prior to and including the index prescription date 
Covariates listed above are a small subset of covariates that will ultimately be controlled in the design and analysis phase 
of the study. They are included in the preliminary assessment to determine the presence of adequate overlap between 
the two population of patients to proceed to the next phase of the study. Remaining covariates are defined only after 
the study has passed the initial feasibility analysis and initial power assessment and are listed in Table ϭ (AƉƉendiǆ B).  
6.3 Outcome variables and study follow-up: 
6.3.1 
Outcome variables 
Effectiveness outcome variables of interest (definitions provided in AƉƉendiǆ A): 
PƌimaƌǇ oƵƚcome͗ Composite of hospitalization for heart failure and all-cause mortality 
Secondary outcomes:  
o
Heart failure hospitalization
o
All-cause death
Control outcomes of interest (control outcomes only serve to assess aspects of study validity but are not further 
interpreted, definitions provided in Appendix A):  
1. Bleeding (we expect to see a null association, as renin angiotensin aldosterone inhibitors are not expected to
have any impact on this outcome)
6.3.2 
Study follow-up 
Both as-treated (AT) and intention-to-treat (ITT) analysis will be conducted with treatment defined as the index drug 
on the day of cohort entry. Because adherence in the real-world databases is expected to be much worse than in 
the trial, the AT analysis is the ƉƌimaƌǇ analysis, as it targets the relative hazard of outcomes on treatment.  
For the AT analysis, the follow-up will start the day after the initiation of sacubitril/valsartan or ACEi and will continue 
until the earliest date of the following events: 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϳ
The first occurrence of the outcome of interest, 
The date of end of continue registration in the database, 
End of the study period, 
Nursing home admission 
o
Nursing home admissions are considered a censoring event because the data sources utilized typically
provide little to no data on a patient, particularly on drug utilization, after admission. We will utilize this
as an exclusion reason for cohorts for the same reason.
The date of drug discontinuation, defined as the date of the last continuous treatment episode of the index 
drug (sacubitril/valsartan or ACEi) н a ϯϬ-day grace period, 
The date of switching from an exposure to comparator and vice versa, 
The date of switching to or initiation of any angiotensin II receptor blockers (ARBs), including combination 
medications containing ARBs, 
The date of switching to or initiation of aliskiren, including combination therapies. 
For the ITT analyses, the censoring based on the switching and treatment discontinuation will be replaced with a 
maximum allowed follow-up time of ϯϲϱ days. 
7 Iniƚial FeaƐibiliƚǇ AnalǇƐiƐ 
Aetion report name: 
Optum- https://bwh-dope.aetion.com/projects/details/ϭϬϲϵ/results/ϲϭϴϲϯ/result/Ϭ 
Marketscan- https://bwh-dope.aetion.com/projects/details/ϭϬϳϮ/results/ϲϭϴϱϮ/result/Ϭ 
Medicare - https://bwh-dope.aetion.com/projects/details/ϭϬϳϯ/results/ϲϭϴϱϰ/result/Ϭ  
Date conducted: ϭϭ/Ϯϰ/ϮϬϮϬ 
Complete Aetion feasibility analysis using age, sex, and CCI as the only covariates and the primary endpoint (Section ϲ.ϯ.ϭ) as the 
outcome.  
Complete study flowchart from Section ϱ.ϯ 
Report patient characteristics by treatment group 
Optum 
Marketscan 
Medicare 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϴ
Variable 
Reference - 
ACE inhibitors 
Exposure - 
Sacubitril/valsa
rtan 
Difference 
Reference - 
ACE inhibitors 
Exposure - 
Sacubitril/valsa
rtan 
Difference 
Reference - 
ACE Inhibitors 
Exposure - 
Sacubitril/valsa
rtan Copy 
Differ
Number of 
patients 
4,217 
2,729 
- 
2,218 
1,476 
- 
6,293 
1,738 
-
Age 
...mean (sd) 
66.94 (13.39) 
68.39 (12.07) 
-1.45 (-2.06, -
0.84) 
60.86 (14.92) 
61.21 (13.50) 
-0.36 (-1.29,
0.57) 
77.16 (8.29) 
76.04 (7.56) 
1.12 (
1.5
...median 
[IQR] 
68.00 [58.00, 
77.00] 
70.00 [61.00, 
77.00] 
- 
60.00 [52.00, 
71.00] 
60.00 [53.00, 
70.00] 
- 
76.00 [70.00, 
84.00] 
75.00 [70.00, 
81.00] 
-
Gender 
..Males; n (%) 
2,829 (67.1%) 
1,773 (65.0%) 
2.1% (-0.2%, 
4.4%) 
1,606 (72.4%) 
1,018 (69.0%) 
3.4% (0.4%, 
6.5%) 
3,433 (54.6%) 
1,003 (57.7%) 
-3.2% (-
0.5
...Females; n 
(%) 
1,388 (32.9%) 
956 (35.0%) 
-2.1% (-4.4%,
0.2%) 
612 (27.6%) 
458 (31.0%) 
-3.4% (-6.5%, -
0.4%) 
2,860 (45.4%) 
735 (42.3%) 
3.2% (
5.8
CCI (180 days)- 
ICD9 and 
ICD10 v2 
...mean (sd) 
6.52 (2.50) 
6.70 (2.24) 
-0.18 (-0.29, -
0.06) 
5.51 (2.22) 
5.70 (2.04) 
-0.19 (-0.33, -
0.05) 
7.53 (2.91) 
7.00 (2.51) 
0.53 (
0.6
...median 
[IQR] 
6.00 [5.00, 
8.00] 
6.00 [5.00, 
8.00] 
- 
5.00 [4.00, 
7.00] 
5.00 [4.00, 
7.00] 
- 
7.00 [5.00, 
9.00] 
7.00 [5.00, 
9.00] 
-
Report summary parameters of study population 
Optum 
Marketscan 
Medicare 
Variable 
Value 
Value 
Value 
Number of patients in full cohort 
6,946 
3,694 
8,031 
Number of patients dropped as incomplete cases 
0 
0 
2 
Number of patients that did not begin follow-up 
16 
5 
7 
Number of patients in analytic cohort 
6,930 
3,689 
8,022 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϵ
Number of events 
1435 
592 
1992 
Number of person-years 
3,277.04 
1,877.04 
3,093.20 
Number of patients in group: ACE Inhibitors - Reference 
4,208 
2,216 
6,286 
Number of patients in group: Sacubitril/Valsartan - Exposure 
2,722 
1,473 
1,736 
Risk per 1,000 patients 
207.07 
160.48 
248.32 
Rate per 1,000 person-years 
437.9 
315.39 
643.99 
Report median follow-up time by treatment group 
Patient Group 
Optum 
Median Follow-Up 
Time (Days) [IQR] 
Marketscan 
Median Follow-Up 
Time (Days) [IQR] 
Medicare 
Median Follow-Up 
Time (Days) [IQR] 
Overall Patient Population 
95 [43, 213] 
117 [58, 242] 
82 [39, 173] 
Referent - ACE Inhibitors 
99 [42, 209] 
118 [58, 240] 
81 [38, 170] 
Exposure - Sacubitril/Valsartan 
92 [44, 217] 
111 [57, 246] 
86 [45, 183] 
Report reasons for censoring in the overall study population 
Optum 
Marketscan 
Medicare 
Overall 
6930 
3689 
8022 
Outcome 
1,361 (19.6%) 
558 (15.1%) 
1,933 (24.1%) 
Start of an additional exposure 
252 (3.6%) 
155 (4.2%) 
156 (1.9%) 
End of Index Exposure 
2,445 (35.3%) 
1,264 (34.3%) 
2,078 (25.9%) 
Specified date reached 
1,101 (15.9%) 
721 (19.5%) 
1,964 (24.5%) 
End of patient data 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
End of patient enrollment 
645 (9.3%) 
713 (19.3%) 
691 (8.6%) 
Switch to ARBs or Aliskiren + Nursing Home admission Occurred 
1,126 (16.2%) 
278 (7.5%) 
1,200 (15.0%) 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
ϭϬ
 
8 Iniƚial Poǁeƌ AƐƐeƐƐmenƚ 
 
Aetion report name: 
Optum- https://bwh-dope.aetion.com/projects/details/ϭϬϲϵ/results/ϲϭϴϲϮ/result/Ϭ 
Marketscan- https://bwh-dope.aetion.com/projects/details/ϭϬϳϮ/results/ϲϭϴϱϯ/result/Ϭ 
Medicare- https://bwh-dope.aetion.com/projects/details/ϭϬϳϯ/results/ϲϭϴϱϱ/result/Ϭ  
 
Date conducted: ϭϭ/Ϯϰ/ϮϬϮϬ 
 
In order to complete the initial power analysis, the dummy outcome of a ϵϬ-day gap in database enrollment will be used. Complete a 
ϭ:ϭ PS-matched comparative analysis using this outcome. PS should include only ϯ covariates: age, sex, and combined comorbidity 
index. 
 
x In the appropriate excel sheet below, report number of patients matched in each treatment group. Input the overall risk of 
outcome from Section ϳ. Input the desired or assumed HR, alpha level, and non-inferiority margin (if applicable) from the RCT 
(Section ϭ.ϯ.ϭ). The number of expected events and corresponding power are then calculated automatically. If the study is to be 
implemented in more than one database, copy and paste excel sheet to report power for each database separately and for the 
pooled analysis that uses data from all databases together. 
  
Optum 
Marketscan 
Medicare 
Pooled 
Number of people matched 
  
  
  
  
Reference 
2722.0 
1468.0 
1736.0 
5926.0 
Exposure 
2722.0 
1468.0 
1736.0 
5926.0 
  
  
  
  
  
Risk per 1,000 patients 
207.1 
160.5 
248.3 
 -- 
Rate per 1,000 person-years 
437.9 
315.4 
644.0 
  
  
  
  
  
  
N of events 
1,435 
592 
1,992 
4,019 
N of patients (both groups) at Step 1 
6,946 
3,694 
8,031 
18,671 
Risk per 1,000 patients 
206.6 
160.3 
248.0 
215.3 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϭ
Superiority Analysis (Pooled)
Number of patients matched
Reference
5,926
Exposed
5,926
Risk per 1,000 patients
215.25
Desired HR from RCT
0.8
Alpha (2-sided)
0.05
Number of events expected
2551.143
Power
0.99988126

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϮ
Superiority Analysis (Optum)
Number of patients matched
Reference
2,722
Exposed
2,722
Risk per 1,000 patients
207.10
Desired HR from RCT
0.8
Alpha (2-sided)
0.05
Number of events expected
1127.4524
Power
0.9629782
Superiority Analysis (Marketscan)
Number of patients matched
Reference
1,468
Exposed
1,468
Risk per 1,000 patients
160.50
Desired HR from RCT
0.8
Alpha (2-sided)
0.05
Number of events expected
471.228
Power
0.677969637

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϯ
Superiority Analysis (Medicare)
Number of patients matched
Reference
1,736
Exposed
1,736
Risk per 1,000 patients
248.30
Desired HR from RCT
0.8
Alpha (2-sided)
0.05
Number of events expected
862.0976
Power
0.905904762
x Stop analyses until feasibility and power are reviewed by primary investigators, FDA, and assigned members of advisory board. 
Reviewed by PI: 
Jessica Franklin 
Date reviewed: 
ϭϮ/Ϯ/ϮϬ 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
ϭϮ/ϴ/ϮϬ 
Reasons for stopping 
analysis (if required): 
9. Balance AƐƐeƐƐmenƚ
Optum- https://bwh-dope.aetion.com/projects/details/ϭϬϲϵ/results/ϲϯϭϯϭ/result/Ϭ
Marketscan- https://bwh-dope.aetion.com/projects/details/ϭϬϳϮ/results/ϲϯϭϮϵ/result/Ϭ
Medicare- https://bwh-dope.aetion.com/projects/details/ϭϬϳϯ/results/ϲϯϭϮϴ/result/Ϭ
Date conducted: ϭϮ/ϮϮ/ϮϬϮϬ 
After review of initial feasibility and power analyses, complete creation of the remaining covariates from Section ϲ.Ϯ. Again, using the 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϰ
dummy outcome of a ϵϬ-day gap in database enrollment, complete a ϭ:ϭ PS-matched analysis. The PS should include the complete 
list of covariates. 
x Provide plot of PS distributions stratified by treatment group. 
Note- Please refer to AƉƉendiǆ B. 
x Report covariate balance after matching. 
Note- For Table ϭ, please refer to AƉƉendiǆ B. 
x Report reasons for censoring by treatment group. 
Overall 
Referent 
Exposure 
Dummy outcome 
0 (0%) 
0 (0%) 
0 (0%) 
Death 
150 (2.47%) 
64 (2.11%) 
86 (2.84%) 
Start of an additional 
exposure 
309 (5.09%) 
106 (3.49%) 
203 (6.69%) 
End of Index Exposure 
2285 
(37.67%) 
1206 
(39.76%) 
1079 
(35.58%) 
Specified date reached 
1868 (30.79) 
879 
(28.98%) 
989 
(32.61%) 
End of patient 
enrollment 
696 
(11.47%) 
366 
(12.07%) 
330 
(10.88%) 
Switch to ARBs or 
Aliskiren + Nursing 
Home admission 
Occurred 
758 
(12.50%) 
412 
(13.58%) 
346 
(11.41%) 
x Report follow-up time by treatment group. 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϱ
Patient Group 
Optum 
Median 
Follow-Up Time 
(Days) [IQR] 
Marketscan 
Median 
Follow-Up Time 
(Days) [IQR] 
Medicare 
Median 
Follow-Up Time 
(Days) [IQR] 
Overall Patient Population 
118 [58, 286] 
139 [59, 296] 
102 [46, 189] 
Referent - ACE Inhibitors 
126 [60, 309] 
142 [77, 295] 
102 [42, 170] 
Exposure - Sacubitril/Valsartan 
108 [56, 266] 
136 [58, 300] 
106 [58, 218] 
x Report overall risk of the primary outcome. 
Optum 
MarketScan 
Medicare 
Pooled 
Risk per 1,000 patients 
206.6 
160.3 
248.0 
215.3 
6. Final Poǁeƌ AƐƐeƐƐmenƚ
Date conducted: ϭϮ/ϮϮ/ϮϬϮϬ 
x Re-calculate power in the appropriate excel table, using the revised number of matched patients from the PS-match in Section ϵ. 
All other parameters in the table should be the same as in Section ϴ. 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϲ
Superiority Analysis (Pooled)
Number of patients matched
Reference
3,033
Exposed
3,033
Risk per 1,000 patients
215.25
Desired HR from RCT
0.8
Alpha (2-sided)
0.05
Number of events expected
1305.7065
Power
0.980850168
Superiority Analysis (Optum)
Number of patients matched
Reference
1,279
Exposed
1,279
Risk per 1,000 patients
206.60
Desired HR from RCT
0.8
Alpha (2-sided)
0.05
Number of events expected
528.4828
Power
0.727390963

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϳ
Superiority Analysis (Marketscan)
Number of patients matched
Reference
748
Exposed
748
Risk per 1,000 patients
160.30
Desired HR from RCT
0.8
Alpha (2-sided)
0.05
Number of events expected
239.8088
Power
0.408308308

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϴ
Superiority Analysis (Medicare)
Number of patients matched
Reference
1,006
Exposed
1,006
Risk per 1,000 patients
248.30
Desired HR from RCT
0.8
Alpha (2-sided)
0.05
Number of events expected
499.5796
Power
0.703266933
x Stop analyses until balance and final power assessment are reviewed by primary investigators, FDA, and assigned members of 
advisory board. 
Reviewed by PI: 
Jessica Franklin 
Date reviewed: 
ϭϮ/Ϯϲ/ϮϬ 
Reviewed by FDA: 
Date reviewed: 
Reasons for stopping 
analysis (if required): 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
ϭϵ
RefeƌenceƐ 
Desai RJ, Lin KJ, Patorno E, et al. Development and Preliminary Validation of a Medicare Claims–Based Model to Predict Left 
Ventricular Ejection Fraction Class in Patients With Heart Failure. Circ: Cardiovascular Quality and Outcomes. ϮϬϭϴ;ϭϭ(ϭϮ). 
doi:ϭϬ.ϭϭϲϭ/CIRCOUTCOMES.ϭϭϴ.ϬϬϰϳϬϬ 
McMurray JJV, Packer M, Desai AS, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. New England Journal of 
Medicine. ϮϬϭϰ;ϯϳϭ(ϭϭ):ϵϵϯ-ϭϬϬϰ. doi:ϭϬ.ϭϬϱϲ/NEJMoaϭϰϬϵϬϳϳ 

#
PARADIGM-HF trial definitions
Implementation in routine care
References/Rationale
Color coding
LCZ696 (sacubitril/valsartan) 200 mg twice daily vs. enalapril 10 mg twice daily
Aim: To determine if LCZ696 is superior to enalapril in reducing the risk of death and of hospitalization for HF
Sacubitril/valsartan vs. enalapril 
Exposure: new-use of sacubitril/valsartan   Reference: enalapril
Criteria
Adequate mapping in claims
The primary outcome is a composite of death from cardiovasclar causes or hositalization for heart failure
Measured 14 days after drug initiation in diagnosis position specified below and inpatient care 
setting: 
Hospital admission for CHF (Inpatient only, any position)
ICD-9 diagnosis: 428.x, 398.91, 402.01, 402.11, 402.91, 404.01, 404.11, 404.91, 404.03, 404.13, 
404.93
ICD-10 diagnosis: I50.1, I50.2x, I50.4, I50.814, I09.81, I11.0 (hypertensive heart disease with HF), 
I13.0 (hypertensive heart and chronic kidney disease with HF and stage 1 through stage 4 CKD), I13.2 
(hypertensive heart and CKD with HF and with stage 5 CKD or ESRD)   
CV death 
Inpatient mortality - heart failure --
Mortality- Dependent on data source. 
1. CV mortality
Information on CV mortality through data linkage with the National Death Index (NDI) will be
available for Medicare and Optum Clinformatics.
2. All-cause inpatient mortality
Identified using the discharge status codes-
Optum-
• 20 = EXPIRED
• 21 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 22 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 23 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 24 = EXPIRED TO BE DEFINED AT STATE LEVEL
Intermediate mapping in claims
Poor mapping or cannot be measured 
in claims 
1
Age ≥ 18 years
Age 18 years or older at drug initiation
Can't be measured in claims but not 
important for the analysis
2
NYHA functional class II–IV
Measured 45 days prior to and including the day of oral drug initiation in generic prescription claims 
requiring 28 days supply of Loop or Thiazide diuretics 
Loop Diuretics: 
Bumetanide, Furosemide, Torsemide, Ethacrynic acid
-OR-
Thiazide and Thiazide-like Diuretics:
Hydrochlorothiazide, Chlorothiazide, Chlorthalidone, Indapamine, Metolazone, Cyclothiazide, 
Hydroflumethiazide, Bendroflumethiazide, Benzthiazide, Methyclothiazide, Polythiazide
3
LVEF ≤ 35%
Measured 180 days prior to and including the day of index drug initiation in any diagnosis position 
and inpatient or outpatient care setting
Systolic Heart Failure 
ICD-9 diagnosis: 428.2x
ICD-10 diagnosis: I50.2x
Combined Systolic/Diastolic Heart Failure
ICD-9 diagnosis: 428.4x 
ICD-10 diagnosis: I50.4x
4
Plasma BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL at the screening visit and a hospitalization for HF within the last 12 
months
4a Plasma BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL at the screening visit
AND the following:
Please see the following Google Drive for further details or any missing information : 
https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV
ICD-10 codes are not listed in this document because of excel cell size limitations and excessive number of ICD- 
10 codes. Full ICD-10 code lists will be available in the above Google Drive Folder (link above). ICD-9 to ICD-10 
code conversions were completed using a SAS macro that implements forward/ backward mapping based on the 
CMS ICD-9 to ICD-10 mapping: https://www.nber.org/data/icd9-icd-10-cm-and-pcs-crosswalk-general-
equivalence-mapping.html
Trial details - active comparision - 2 weeks run-in
EXPOSURE vs. COMPARISON
PRIMARY OUTCOME
INCLUSION CRITERIA
Appendix A

4b Hospitalization for heart failure within the last 12 months
Meaured 365 days prior to drug initiation in any diagnosis position and inpatient care setting 
Hospital Admission for CHF 
ICD-9 diagnosis: 428.x, 398.91, 402.01, 402.11, 402.91, 404.01, 404.11, 404.91, 404.03, 404.13, 
404.93
ICD-10 diagnosis: I50.1, I50.2x, I50.4, I50.814, I09.81, I11.0, I13.0, I13.2 
5
Treatment with a stable dose of an ACE inhibitor or an ARB equivalent to enalapril 10 mg/day for at least 4 weeks before the 
screening visit; and treatment with a stable dose of a beta-blocker for at least 4 weeks prior to the screening visit, unless 
contraindicted or not tolerated
5a Treatment with a  stable dose  of an ACE inhibitor or an ARB equivalent to enalapril 10 mg/day  for at least 4 weeks before 
the screening visit
Measured 47 days to 2 days prior to drug initiation in prescription claims requiring 28 days supply of 
oral ACEi or ARB  - 
ACE inibitors' generic names for prescription claims: 
Enalapril, Captopril, Cilazapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, 
Trandolapril, Zofenopril, Benazepril  
-OR-
ARBs generic names for prescription claims:
Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan, Azilsartan 
AND the following:
5b Treatment with a stable dose of a beta-blocker for at least 4 weeks  prior to the screening visit, unless contraindicated or not 
tolerated
Measured 45 days prior to index drug initiation in prescription claims (generic names) of an oral 
beta-blocker for at least 4 weeks (28 days)
Beta-blocker generic names for prescription claims:
Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Esmolol, Labetalol, Metoprolol, 
Metiranolol, Nebivolol, Nadolol, Propranolol, Pindolol, Sotalol, Penbutolol, Oxprenolol
6
Although not required, the protocol specified that an aldosterone antagonist should also be considered in all patients, taking 
account of renal function, serum potassium, and tolerability. If given, the dose of aldosterone antagonist should be stable for 
at least 4 weeks prior to the screening visit
1
History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACE inhibitors (ACEIs), ARBs, 
or neprilysin inhibitors, as well as known or suspected contraindications to the study drugs
2
Previous history of intolerance to recommended target doses of ACEIs or ARBs
3
Known history of angioedema
Measured from the start of all available data to index drug initiation in any diagnosis position and 
inpatient or outpatient care setting
ICD-9 diagnosis: 995.1
ICD-10 diagnosis: T78.3x
4
Requirement for treatment with both ACEIs and ARBs
Measured 180 days prior to and including day of drug initiation in prescription claims (generic 
names) for any of oral ACEi and ARB for two subsequent dispensings
ACE inibitors' generic names for prescription claims: 
Enalapril, Captopril, Cilazapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril, 
Trandolapril, Zofenopril, Benazepril 
-AND-
ARBs generic names for prescription claims:
Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan, Azilsartan 
5
Current acute decompensated heart failure (exacerbation of chronic heart failure manifested by signs and symptoms that may 
require intravenous therapy)
Measured 7 days prior to and including day of drug initiation in any diagnosis position and inpatient 
and emergency care setting
ICD-9 diagnosis: 428.41, 428.43
ICD-10 diagnosis: I50.23, I50.41, I50.43
6
Symptomatic hypotension and/or a systolic blood pressure <100 mmHg at Visit 1 (screening) or <95 mmHg at Visit 3 or at 
Visit 5 (randomization)
Measured 30 days prior to and including day of drug initiation in any diagnosis position and inpatient 
or outpatient care setting
Hypotension:
ICD-9 diagnosis: 458.xx, 785.5x 
ICD-10 diagnosis: I95.xx, R57.xx
EXCLUSION CRITERIA
Appendix A

7
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at Visit 1 (screening), Visit 3 (end of enalapril run-in), or 
Visit 5 (end of LCZ696 run-in and randomization) or >35% decline in eGFR between Visit 1 and Visit 3 or between Visit 1 and 
Visit 5
Measured 30 days prior to and including day of drug initiation in any diagnosis position and inpatient 
or outpatient care setting
Acute kidney injury (AKI) 
ICD-9 diagnosis: 584.xx, 586
ICD-10 diagnosis: N17.x, N19
Acute glomerulnephritis 
ICD-9 diagnosis: 580.xx
ICD-10 diagnosis: N00.3, N00.8, N00.9, N01.3
Chronic Kidney Disease (CKD) - Stage IV and V
ICD-9 diagnosis: 585.4, 585.5 
ICD-10 diagnosis: N18.4, N18.5
ESRD 
ICD-9 diagnosis: 403.01, 403.11, 403.91, 404.03, 404.13, 585.6
ICD-10 diagnosis: I12.0,  N18.6
Hemodialysis/Peritoneal Dialysis
ICD-9 diagnosis: V45.1x, V56.xx, 996.56, 996.68, 996.73
ICD-10 diagnosis: Z49.xx, Z91.15, Z99.2, T85.611x, T85.621x, T85.631x, T85.691x, T85.71x
ICD-9 procedure: 39.95, 54.98
ICD-10 procedure: 5A1D70Z, 5A1D80Z, 5A1D90Z, 3E1M39Z
CPT-4 code: 90935, 90937, 90939
8
Serum potassium >5.2 mmol/L at Visit 1 (screening) or >5.4 mmol/L at Visit 3 or Visit 5 (randomization)
Measured 30 days prior to and including day of drug initiation in any diagnosis position and inpatient 
or outpatient care setting
Hyperkalemia
ICD-9 diagnosis: 276.7
ICD-10 diagnosis: E87.5
9
Acute coronary syndrome, stroke, transient ischaemic attack, cardiac, carotid, or other major cardiovascular surgery, PCI, or 
carotid angioplasty within the 3 months prior to Visit 1.
Measured 90 days prior to and including day of drug initiation in any diagnosis position and inpatient 
or outpatient care setting
Acute Coronary Syndrome: STEMI & NSTEMI 
ICD-9 diagnosis: 410.xx (exclude 410.x2), 411.0
ICD-10 diagnosis: I21.xx, I22.xx, I23.xx
Acute Coronary Syndrome: Unstable Angina 
ICD-9 diagnosis: 413.xx (exclude 413.1), 411.1, 411.8, 411.81, 411.89
ICD-10 diagnosis: I20.xx (exclude I20.1), I24.xx (exclude 124.1)
Stroke 
ICD-9 diagnosis: 430.xx, 431.xx, 433.x1, 434.xx (excluding  434.x0), 436.x, 997.02 
ICD-10 diagnosis: G97.3x, I60.xx, I61.xx I62.xx, I63.xx, I67.89, I97.81x, I97.82x
TIA 
ICD-9 diagnosis: 435.xx
ICD-10 diagnosis: G45.xx
CABG/ Transmyocardial Revascularization
ICD-9 diagnosis: V45.81, 996.03
ICD-10 diagnosis: Z95.1
ICD-9 procedure: 36.1x, 36.2, 36.3x
ICD-10 procedure: Refer to "CABG & Revascularization" tab within this spreadsheet for complete list 
of procedure codes
CPT 4
d
33140 33141 33510
33548 33572 92937 92938
10
Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months after Visit 1
Included above 
11
Implantation of a cardiac resynchronization therapy (CRT) device within 3 months prior Visit 1 or intent to implant a CRT
Measured 90 days prior to and including day of drug initiation in any diagnosis position and inpatient 
or outpatient care setting 
Pacemaker and Implantable cardiac Defibillators: 
ICD-9 diagnosis: V45.01, V45.02, V45.09, V53.31, V53.32, 996.01, 996.04, 996.61
ICD-10 diagnosis: Z95.0, Z95.810, Z45.010, Z45.018, Z45.02, T82.110A, T82.111A, T82.120A, 
T82.121A, T82.190A, T82.191A, T82.6XXA, T82.7XXA
ICD-9 procedure: 00.50, 00.51, 00.53, 00.54, 37.7x, 37.8x, 37.94 - 37.98
ICD-10 procedure: Refer to "CRT_Implant" tab
CPT-4 code: 33200 - 33208, 33220 - 33229, 33230 - 33238, 33240 - 33249, 33262 - 33264, 33270, 
33271, 93640 - 93642, 93280 - 93289, 93290 - 93299 
Appendix A

12
History of heart transplant or on a transplant list or with LV assistance device
Measured from all available data to and including the day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting
Heart Transplantation
ICD-9 diagnosis: V42.1, V49.83, 996.83 
ICD-10 diagnosis: Z94.1, Z76.82, T86.20, T86.21, T86.22
ICD-9 procedure: 33.6, 37.51
ICD-10 procedure: 02YA0Z0, 02YA0Z1, 02YA0Z2
CPT-4 code: 33935, 33945
LVAD/Implantable Heart
ICD-9 diagnosis: V43.2x 
ICD-10 diagnosis: Z95.811, Z95.812
ICD-9 procedure: 37.60, 37.66 
ICD-10 procedure: 02HA0RS, 02HA3RS, 02HA4RS, 5A02116, 5A02216, 02HA0QZ, 02HA3QZ, 02HA4QZ
CPT-4 code: 33975, 33976, 33979, 33981 - 33983, 33977, 33978, 33980
13
History of severe pulmonary disease
Measured from all available data to and including day of drug initiation in any diagnosis position and 
in inpatient or outpatient care setting
Worsening Asthma/Status Asthmaticus
ICD-9 diagnosis: 493.01, 493.02, 493.11, 493.12, 493.2x, 493.91, 493.22 
ICD-10 diagnosis: J45.21, J45.22, J45.901, J45.902
COPD/Chronic Tuberclosis
ICD-9 diagnosis: 491.xx, 492.xx, 494.x, 496, 506.4, 748.61, 011.5x
ICD-10 diagnosis: J41.x, J43.x, J47.x, J44.x, J68.4, Q33.4, A15.0
Pulmonary Firbrosis or Interstitial Lung Disease (ILD) 
ICD-9 diagnosis:  515, 516.3x, 516.8, 516.9
ICD-10 diagnosis: J84.10, J84.111, J84.112, J84.113, J84.114, J84.115, J84.116, J84.117, J84.09, J84.2, 
J84.89, J84.9
Cystic Fibrosis
ICD-9 diagnosis: 277.0x
ICD-10 diagnosis: E84.xx
Pulmonary Hypertension/Other Pulmonary Heart Disease
ICD-9 diagnosis: 416.xx
ICD-10 diagnosis: I27.xx
Sarcoidosis
ICD 9 di
i
135
Pulmonary firbrosis/Interstitial lung disease:
Jones N, Schneider G, Kachroo S, et al. A systematic review of validated 
methods for identifying pulmonary fibrosis and interstitial lung disease 
using administrative and claims data. Pharmacoepidemiol Drug Saf. 
2012;21(1):256-60. Available at: 
http://www.ncbi.nlm.nih.gov/pubmed/22262614.
14
Diagnosis of peripartum- or chemotherapy-induced cardiomyopathy within the 12 months prior to Visit 1
Measured from 365 days prior to and including day of drug initiation in any diagnosis position and 
inpatient or outpatient care setting
Peripartum Cardiomyopathy
ICD-9 diagnosis: 674.5x 
ICD-10 diagnosis: O90.3
Chemotherapy-Induced Cardiomyopathy
ICD-9 diagnosis: 425.9 
ICD-10 diagnosis: I42.7
15
Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1
15a Documented ventricular arrhythmia within the 3 months prior to Visit 1
Measured 90 days prior to and including day of drug initiation in any diagnosis position and inpatient 
and outpatient care setting
ICD-9 diagnosis: 427.1, 427.4x, 427.5
ICD-10 diagnosis: I47.2, I49.01, I49.02, I46.9
AND the following:
15b Syncopal episodes within the 3 months prior to Visit 1
Measured 90 days prior to and including day of drug initiation in any diagnosis position and inpatient 
and outpatient care setting
Syncopal Episodes
ICD-9 diagnosis: 780.2
ICD-10 diagnosis: R55
AND the following:
Appendix A

15c Untreated ventricular arrhythmia within the 3 months prior to visit 1
Measured 90 days prior to and including day of drug initiation WITHOUT any of these non-drug 
treatments for ventricular tachycardia in any diagnosis position and inpatient and outpatient care 
setting
Implantable Cardioverter-Defbrillator
ICD-9 diagnosis: V45.00, V45.02, V45.09, V53.32, 996.04, 996.61 
ICD-10 diagnosis: Z95.9, Z95.810, Z95.818, Z45.02, T82.110A, T82.111A, T82.120A, T82.121A, 
T82.190A, T82.191A
ICD-9 procedure: 00.51, 00.54, 37.94 - 37.98
ICD-10 procedure: 02HK0KZ, 02HK3KZ, 02HK4KZ, 02HL0KZ, 02HL3KZ, 02HL4KZ, 0JH609Z, 0JH639Z, 
0JH809Z, 0JH839Z
CPT-4 code:  33220, 33223, 33230, 33231, 33240 - 33249, 33262 - 33264, 33270, 93640 - 93642, 
93280 - 93285, 93287, 93289, 93292, 93295
               OR the following:
15d Untreated ventricular arrhythmia within the 3 months prior to visit 1
Measured 90 days prior to and including day of drug initiation WITHOUT any of these oral drug 
treatments for ventricular arrythmia in prescription claims
Beta-blockers: Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Labetalol, 
Metoprolol, Metiranolol, Nebivolol, Nadolol, Propranolol, Pindolol, Sotalol, Penbutolol, Oxprenolol
Non-DHP CCB: Diltiazem, Verapamil
Antiarrhythmic drugs: Amiodarone, Procainamide, Mexiletine, Flecainide, Moricizine
16
Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker
Measured 180 days prior to and including day of drug initiation in any diagnosis position and 
inpatient and outpatient care setting
Second- and Third-degree AV block
ICD-9 diagnosis: 426.0, 426.1x (except 426.11)
ICD-10 diagnosis: I44.2, I44.30, I44.1
17
Presence of haemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV 
dilatation
Measured 180 days prior to and including day of drug initiation in any diagnosis position and in 
inpatient and outpatient care setting
ICD-9 diagnosis: 394.0, 395.0, 395.2, 396.0, 396.2, V42.2, V43.3
ICD-10 diagnosis: I05.0, I06.0, I06.2, I08.0, Z95.3, Z95.2
ICD-9 procedure: 35.01, 35.02, 35.05, 35.06, 35.11, 35.12, 35.21, 35.22, 35.23, 35.24, 35.97
ICD-10 procedure: 02NF3ZZ, 02NF4ZZ, 02NG3ZZ, 02NG4ZZ, 02RF372, 02RF38Z, 02RF3JZ, 02RF3KZ, 
X2RF332, 02RF37H, 02RF38H, 02RF3JH, 02RF3KH, 027F04Z, 027F0DZ, 027F0ZZ, 02NF0ZZ, 02QF0ZZ, 
027G04Z, 027G0DZ, 027G0ZZ, 02NG0ZZ, 02QG0ZZ, 02VG0ZZ, 02RF07Z, 02RF08Z, 02RF0KZ, 
02RF47Z, 02RF48Z, 02RF4KZ, X2RF032, X2RF432, 02RF0JZ, 02RF4JZ, 02RG07Z, 02RG08Z, 02RG0KZ, 
02RG37Z, 02RG38Z, 02RG3KZ, 02RG47Z, 02RG48Z, 02RG4KZ, 02RG0JZ, 02RG3JZ, 02RG4JZ 02UG3JZ
CPT-4 codes: 33400 - 33403, 33405, 33406, 33420 - 33430, 0257T, 0258T, 0259T
18
Presence of other haemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic 
stenosis
Included in the definition of exclusion criterion # 17
19
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study 
drugs, including, but not limited to, any of the following:
19a History of active inflammatory bowel disease during the 12 months before Visit 1
Measured 365 days prior to and including day of drug initiation in any diagnosis position in inpatient 
and outpaient care setting 
Ulcerative Colitis 
ICD-9 diagnosis: 556.xx
ICD-10 diagnosis: K51.xx
Crohn's Disease 
ICD-9 diagnosis: 555.x 
ICD-10 diagnosis: K50.xx
Thirumurthi S, Chowdhury R, Richardson P, Abraham NS. Validation of ICD-
9-CM diagnostic codes for inflammatory bowel disease among veterans. 
Dig Dis Sci. 2010 Sep;55(9):2592-8. doi: 10.1007/s10620-009-1074-z. Epub 
2009 Dec 24. PubMed PMID: 20033847
OR the following: 
19b Active duodenal or gastric ulcers during the 3 months prior to Visit 1
Measured 90 days prior to and including day of drug initiation in any diagnosis position in inpatient 
and outpaient care setting
Duodenal Ulcers 
ICD-9 diagnosis: 532.0x, 532.1x, 532.2x, 532.3x, 532.9x 
ICD-10 diagnosis: K25.0 - K25.3, K25.9
Gastric Ulcers 
ICD-9 diagnosis: 531.0x, 531.1x, 531.2x, 531.3x, 531.9x 
ICD-10 diagnosis: K26.0 - K26.3, K26.9
OR the following: 
Appendix A

19c
Evidence of hepatic disease as determined by any one of the following: aspartate aminotransferase or alanine 
aminotransferase values exceeding 2× upper limit of normal at Visit 1, history of hepatic encephalopathy, history of 
oesophageal varices, or history of porto-caval shunt
Measured from the start of all available data of drug initiation in any diagnosis position in inpatient 
and outpaient care setting
Hepatic Encephalopathy/Coma 
ICD-9 diagnosis: 070.0, 070.2x, 070.4x, 070.6, 070.71, 572.2
ICD-10 diagnosis: B15.0, B16.0, B16.2, B17.11, B19.0, B19.11, B19.21, K72.90, K72.91
Esophageal Varicies 
ICD-9 diagnosis: 456.0, 456.1, 456.2x, 572.3 
ICD-10 diagnosis: I85.xx, K76.6
Porto-Caval Shunt 
ICD-9 procedure: 39.1, 42.91
ICD-10 procedure: Codes are in the sheet 'PCShunt' 
CPT-4 code: 37182, 37183, 37241 
Cirrohosis/Chronic Hepatic Diseases
ICD-9 diagnosis: 571.0, 571.2, 571.3, 571.4, 571.5, 571.6
ICD-10 diagnosis: K70.0, K70.30, K70.9, K73.0, K73.2, K73.8, K73.9, K75.4, K74.0, K74.60, K74.69, 
K74.3, K74.4, K74.5, K74.1
NASH 
ICD-9 diagnosis: 571.8,  
ICD-10 diagnosis: K76.0
H
ti C
OR the following: 
19d Current treatment with cholestyramine or colestipol resins
Measured 30 days prior to and including the day of index drug initiation for oral generic prescription 
claims of
Cholestyramine, Colestipol, Colesevelam
20
Presence of any other disease with a life expectancy of 5 years
Charlson Comborbidity Index > 10
21
Any Ivabradine use -- Approved in April 2015 (same year as Entresto) 
Measure since  2015/all available data in drug prescription claims for any dispensings of
Generic name: Ivabradine
Brand name: Corlanor
Appendix A

Variable
Codes and Medications (all medical claims, inpatient and outpatient should be used to 
define the coniditions unless otherwise specified)
Coefficients 
("Score")
When Measured for replicating
When Measured 
(Rishi's algorithm)
1
Intercept
N/A
-1.37219
2
Cardiomyopathy
ICD-9 diagnosis: 425.x
ICD-10 diagnosis: I42.x, I43.x
1.415113
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
3
Diastolic heart failure
ICD-9 diagnosis: 428.3x (not co-occuring with 428.2x )
ICD-10 diagnosis: I50.3x (not co-occuring with I50.2x )
-0.950856
Measured between 180 days 
prior to and including the date 
of drug  initiation and pick claim 
closest to the index initiation
on index date
4
Left heart failure
ICD-9 diagnosis: 428.1x (not co-occuring with more specific systolic or diastolic HF codes 
of 428.2x or 428.3x )
ICD-10 diagnosis: I50.1 (not co-occuring with more specific systolic or diastolic HF codes 
of I50.2x or I50.3x )
0.766415
Measured between 180 days 
prior to and including the date 
of drug  initiation and pick claim 
closest to the index initiation
on index date
5
Systolic heart failure
ICD-9 diagnosis: 428.2x (not co-occuring with 428.3x )
ICD-10 diagnosis: I50.2x (not co-occuring with I50.3x)
0.754954
Measured between 180 days 
prior to and including the date 
of drug  initiation and pick claim 
closest to the index initiation
on index date
6
Myocardial infarction
ICD-9 diagnosis: 410.xx
ICD-10 diagnosis: I21.01, I21.02, I21.09, I21.11, I21.19, I21.21, I21.29, I21.3, I21.4, I22.0, 
I22.1, I22.2, I22.8, I22.9
0.651778
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
7
Unspecified heart failure 
ICD-9 diagnosis: 428.0x, 428.4x, 428.9x, 428.2x PLUS 428.3x
ICD-10 diagnosis: I50.4x, I50.8x, I50.9, I50.2x PLUS I50.3x
-0.577221
Measured between 180 days 
prior to and including the date 
of drug  initiation and pick claim 
closest to the index initiation
on index date
8
Number of hospitalizations for CHF
ICD-9 diagnosis: 428.x, 398.91, 402.01, 402.11, 402.91, 404.01, 404.11, 404.91, 404.03, 
404.13, 404.93
ICD-10 diagnosis: I50.1, I50.2x, I50.4, I50.814, I09.81, I11.0, I13.0, I13.2 
0.346289
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date 
(including index 
date)
9
Male gender
Male
0.323651
Measured on the date of index 
drug initiation
on index date
10
Implantable cardioverter defibrillator
ICD-9 diagnosis: V45.02
ICD-10 diagnosis: Z95.810
ICD-9 procedure: 37.94 - 37.98
ICD-10 procedure:  Please  copy from ICD-10 codes tabs for implantable cardioverter 
defibrillator
0.275032
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
Appendix A

11
ACE inhibitor
Prescription claims for: Benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, 
perindopril, quinapril, ramipril, trandolapril 
0.221748
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
12
Index diagnosis recorded during an outpatient visit
Any diagnosis position in an outpatient care setting
ICD-9 diagnosis: 428.x, 398.91, 402.01, 402.11, 402.91, 404.01, 404.11, 404.91, 404.03, 
404.13, 404.93
ICD-10 diagnosis: I50.1, I50.2x, I50.4x, I50.814, I09.81, I11.0, I13.0, I13.2 
-0.187191
Measured between 180 days 
prior to and including the date 
of drug  initiation and pick claim 
closest to the index initiation
on index date
13
Mineralocorticoid receptor antagonist
Prescription claims for: Eplerenone, spironolactone
0.166008
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
14
Anemia
ICD-9 diagnosis: 280.xx - 285.xx
ICD-10 diagnosis: Please  copy from ICD-10 codes tabs for anemia
-0.165353
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
15
Valve disorder
ICD-9 diagnosis: 394.x - 397.x, 398.9x, V42.2, V43.3
ICD-10 diagnosis: Please  copy from ICD-10 codes tabs for valve disorder
ICD-9 procedure: 35.1x, 35.2x
ICD-10 procedure: Please  copy from ICD-10 codes tabs for valve disorder
CPT code: 33660-33665, 33400-33403, 33420-33430, 33460, 33463-33468, 33475, 
33496, 0257T, 0258T, 0259T, 0262T
-0.163684
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
16
Digoxin
Prescription claims for: Digoxin
0.163224
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
17
Thiazide diuretic
Prescription claims for: Bendroflumethiazide, Benzthiazide, Chlorothiazide, 
Chlorthalidone, Hydrochlorothiazide, Indapamide, Methyclothiazide, Metolazone, 
Polythiazide, Quinethazone, Trichlormethiazide
-0.160819
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
18
Obesity
ICD-9 diagnosis: 278.00, 278.01, V85.3x, V85.4x
ICD-10 diagnosis: E65.x, E66.x, E67.x, E68.x
CPT codes: 43842, 43843, 43846, 43847, 43848, G0447
Prescriptions claims for: orlistat, sibutramine, phentermine, benzphetamine,
phendimetrazine, diethylpropion
-0.141956
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
19
Nitrate
Prescription claims for: Nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, 
ranolazine
0.129225
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
20
Other dysrythmias
ICD-9 diagnosis: 427.0x, 427.1x, 427.2x, 427.4x, 427.6x, 427.8x, 427.9x, 785.0x
ICD-10 diagnosis: Please copy from ICD-10 tab for other dysrythmias
0.116652
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
21
Hypertension
ICD-9 diagnosis: 401.xx, 402.xx, 405.xx
ICD-10 diagnosis: I10, I11.0, I11.9, I12.0, I12.9, I13.0, I13.10, I13.11, I13.2, I15.0, I15.1, 
I15.2, I15.8, I15.9
-0.098539
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
Appendix A

22
Beta blocker
Prescription claims for oral: Acebutolol, atenolol, betaxolol, bisoprolol, carteolol, 
carvedilol, labetalol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, propranolol
0.087257
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
23
Loop diuretic
Prescription claims for oral: Bumetanide, furosemide, torsemide, ethacrynic acid
0.084251
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
24
Rheumatic heart disease
ICD-9 diagnosis: 393 - 398.x
ICD-10 diagnosis: I05.xx - I09.xx
-0.073889
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
25
Psychosis
ICD-9 diagnosis: 290.8x, 290.9x, 295.xx, 297.xx, 298.xx, 299.xx, 780.0x - 780.5x
ICD-10 diagnosis: Please copy from ICD-10 tab for Psychosis
-0.068198
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
26
Coronary artery bypass graft
ICD-9 procedure: 36.1x, 36.2x
ICD-10 procedure: Please copy from ICD-10 tab for CABG
CPT code: 33510 – 33536, 33545, 33572
-0.040175
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
27
COPD
ICD-9 diagnosis: 491.xx, 492.xx, 496.xx, 493.2x
ICD-10 diagnosis: J41.x, J42.x, J43.x, J44.x
-0.037023
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
28
Sleep apnea
ICD-9 diagnosis: 327.2x, 780.51, 780.53, 780.57
ICD-10 diagnosis: G47.3x
-0.03556
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
29
Hypertensive nephropathy
ICD-9 diagnosis: 403.xx, 404.xx 
ICD-10 diagnosis: I12.x, I13.xx
-0.03383
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
30
Depression
ICD-9 diagnosis: 293.83, 296.2x, 296.3x, 296.9x, 298.0x, 300.4x, 309.1x, 309.28, 311.xx
ICD-10 diagnosis: F06.3x, F32.x, F33.x, F34.x, F39.x, F43.21, F43.23
-0.033829
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
31
Hypotension
ICD-9 diagnosis: 458.xx
ICD-10 diagnosis: I95.x
-0.017282
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
32
Stable angina
ICD-9 diagnosis: 413.xx
ICD-10 diagnosis: Please copy from ICD-10 tab for stable angina
-0.015657
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
33
Age
Continous
-0.005747
Measured on the date of index 
drug initiation
on index date
Appendix A

34
Atrial fibrillation
ICD-9 diagnosis: 427.3x
ICD-10 diagnosis: I48.x
-0.002267
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
35
Hyperlipidemia
ICD-9 diagnosis: 272.xx
ICD-10 diagnosis: E78.xx
-0.001805
Measured 180 days prior to and 
including the date of index drug 
initiation 
6 months prior to 
index date + index 
date + 30days post-
index
Appendix A

Mortality- Dependent on data source. 
1. All-cause mortality / inpatient mortality
Identified using the vital status file-
Medicare
Identified using the discharge status codes-
Optum-
• 20 = EXPIRED
• 21 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 22 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 23 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 24 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 25 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 26 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 27 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 28 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 29 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 40 = EXPIRED AT HOME (HOSPICE)
• 41 = EXPIRED IN A MEDICAL FACILITY (HOSPICE)
• 42 = EXPIRED - PLACE UNKNOWN (HOSPICE)
Truven-
• 20 - Died
• 22 - Died
• 23 - Died
• 24 - Died
• 25 - Died
• 26 - Died
• 27 - Died
• 28 - Died
• 29 - Died
• 40 - Other died status or Expired at home (Hospice claims only) (depends on year)
• 41 - Other died status or Expired in medical facility (Hospice claims only) (depends on year)
• 42 - Other died status or Expired - place unknown (Hospice claims only) (depends on year)
• 21 - Died or Disch./Transf. to court/law enforcement (depends on year)
Appendix A

CPT-4 Code Range
33010 - 33050
33120 - 33130
33140 - 33141
33200 - 33249
33250 - 33275
33300 - 33340
33361 - 33478
33496
 33500 - 33507
33600 - 33622
33641 - 33697
33702 - 33722
33724 - 33732
33735 - 33768
33770 - 33783
33786 - 33788
33800 - 33853
33860 - 33877
33880 - 33891
33910 - 33926
33962 - 33993
33999
ICD-9 Procedure Codes
ICD-10 Procedure Codes
36.91, 36.99
02Q00ZZ, 02Q03ZZ, 02Q04ZZ, 02Q40ZZ, 02Q43ZZ, 
02Q44ZZ, 02H40YZ, 02H43YZ, 02H44YZ, 02N00ZZ, 
02N03ZZ, 02N04ZZ, 02N10ZZ, 02N13ZZ, 02N14ZZ, 
02N20ZZ, 02N23ZZ, 02N24ZZ, 02N30ZZ, 02N33ZZ, 
02N34ZZ, 02Q00ZZ, 02Q03ZZ, 02Q04ZZ, 02Q40ZZ, 
02Q43ZZ, 02Q44ZZ
37.0, 37.1x, 37.3x, 37.4x, 37.5x 
(exclude 37.51), 37.6x
0W9D30Z, 0W9D30Z, 0W9D3ZX, 0W9D3ZX, 
0W9D3ZZ, 0W9D3ZZ, 0W9D40Z, 0W9D40Z, 
0W9D4ZX, 0W9D4ZX, 0W9D4ZZ, 0W9D4ZZ, 
02N60ZZ, 02N60ZZ, 02N63ZZ, 02N63ZZ, 02N64ZZ, 
02N64ZZ, 02N70ZZ, 02N70ZZ, 02N73ZZ, 02N73ZZ, 
Appendix A

Trial ID 
pNDA32
Trial Name (with web links)
PARADIGM-HF
Trial Name (with pdf links)
PARADIGM-HF
NCT
NCT01035255 
Trial category
Primary indication
Therapeutic Area
Cardiology/Vascular Diseases
Study batch
Heart failure medications
RCT Category 
1a- Intended S with label change
Brand Name
Entresto
Generic Name
Sacubitril/valsartan
Sponsor
Novartis
Year
2015
Measurable endpoint
Composite endpoint including death from 
cardiovascular causes or and hospitalization for 
heart failure
Exposure
LCZ696 200 mg
Comparator
Enalapril 10 mg
Population
80% Diuretic, 29% Digitalis, 93% β blocker, 54% 
Mineralocorticoid antagonists, 15% ICD & 7% 
CRT users
Trial finding
HR = 0.80 (95% CI 0.73– 0.87)
Notes
No. of Patients
8442
Non-inferiority margin
-
Assay Sens. Outcome
Assay Sens. Endpoint (from trial)
Finding for potential Assay Sens. Outcome from 
trial- 
Power
Blinding
Double-blinded
Statistical Method
Approval indication
To reduce the risk of CV death and 
hospitalization for heart failure in patient swith 
chronic heart failure (NYHA class II-IV) and 
reduced rejection fraction
Appendix A

Optum
MarketScan
Medicare
BEFORE PS MATCHING
AFTER PS MATCHING
Appendix B: Sacubitril/Valsartan vs. ACE Inhibitors

Variable
Reference - ACE inhibitors
Exposure - 
Sacubitril/valsartan
St. Diff
Reference - ACE inhibitors
Exposure - 
Sacubitril/valsartan
St. Diff
Reference - ACE Inhibitors
Exposure - 
Sacubitril/valsartan Copy
St. Diff
Reference - ACE Inhibitors
Exposure - 
Sacubitril/valsartan Copy
St. Diff
Number of patients
17,244
2,424
10,721
1,289
18,303
1,658
46,268
5,371
Age - Continuous
...mean (sd)
69.53 (11.82)
68.49 (12.18)
0.0867
63.95 (14.26)
60.92 (13.48)
0.2184
77.09 (8.22)
76.02 (7.61)
0.1351
71.23 (11.22)
69.00 (11.33)
0.1978
...median [IQR]
71.00 [63.00, 78.00]
70.00 [61.00, 78.00]
0.0833
63.00 [55.00, 75.00]
60.00 [52.00, 69.00]
0.2162
76.00 [70.00, 83.00]
75.00 [70.00, 81.00]
0.1262
71.12 (11.22)
69.14 (11.33)
0.1756
Age Categories
...18 - 54; n (%)
1,882 (10.9%)
332 (13.7%)
-0.0853
2,583 (24.1%)
377 (29.2%)
-0.1155
0 (0.0%)
0 (0.0%)
#DIV/0!
4,465 (9.7%)
709 (13.2%)
-0.1101
...55 - 64; n (%)
3,133 (18.2%)
468 (19.3%)
-0.0282
3,626 (33.8%)
504 (39.1%)
-0.1103
0 (0.0%)
0 (0.0%)
#DIV/0!
6,759 (14.6%)
972 (18.1%)
-0.0947
...65 - 74; n (%)
5,925 (34.4%)
807 (33.3%)
0.0232
1,785 (16.6%)
169 (13.1%)
0.0985
7,965 (43.5%)
777 (46.9%)
-0.0684
13,890 (30.0%)
1,584 (29.5%)
0.0109
...>= 75; n (%)
6,304 (36.6%)
817 (33.7%)
0.0608
2,727 (25.4%)
239 (18.5%)
0.1673
10,338 (56.5%)
881 (53.1%)
0.0684
16,642 (36.0%)
1,698 (31.6%)
0.0931
Gender
...Male; n (%)
11,865 (68.8%)
1,549 (63.9%)
0.1038
7,721 (72.0%)
882 (68.4%)
0.0788
10,308 (56.3%)
951 (57.4%)
-0.0222
22,173 (47.9%)
2,500 (46.5%)
0.0280
...Female; n (%)
5,379 (31.2%)
875 (36.1%)
-0.1038
3,000 (28.0%)
407 (31.6%)
-0.0788
7,995 (43.7%)
707 (42.6%)
0.0222
13,374 (28.9%)
1,582 (29.5%)
-0.0132
Region without zero category Copy
...Northeast; n (%)
2,101 (12.2%)
273 (11.3%)
0.0280
2,048 (19.1%)
244 (18.9%)
0.0051
3,372 (18.4%)
321 (19.4%)
-0.0255
5,473 (11.8%)
594 (11.1%)
0.0220
…Midwest; n (%)
8,056 (46.7%)
1,390 (57.3%)
-0.2134
3,548 (33.1%)
302 (23.4%)
0.2167
7,376 (40.3%)
771 (46.5%)
-0.1253
15,432 (33.4%)
2,161 (40.2%)
-0.1414
...South; n (%)
3,985 (23.1%)
416 (17.2%)
0.1475
4,096 (38.2%)
636 (49.3%)
-0.2252
4,795 (26.2%)
357 (21.5%)
0.1105
8,780 (19.0%)
773 (14.4%)
0.1236
...West; n (%)
3,086 (17.9%)
342 (14.1%)
0.1038
1,015 (9.5%)
106 (8.2%)
0.0458
2,760 (15.1%)
209 (12.6%)
0.0724
5,846 (12.6%)
551 (10.3%)
0.0723
...Unknown+missing; n (%)
16 (0.1%)
3 (0.1%)
0.0000
14 (0.1%)
1 (0.1%)
0.0000
Calendar Time - Year of Initiation (2015/16 - 2020)
...2015-2016; n (%)
4,935 (28.6%)
253 (10.4%)
0.4720
6,045 (56.4%)
380 (29.5%)
0.5647
11,756 (64.2%)
607 (36.6%)
0.5743
16,691 (36.1%)
860 (16.0%)
0.4705
...2017; n (%)
3,881 (22.5%)
500 (20.6%)
0.0462
2,610 (24.3%)
438 (34.0%)
-0.2147
6,547 (35.8%)
1,051 (63.4%)
-0.5743
10,428 (22.5%)
1,551 (28.9%)
-0.1469
...2018; n (%)
3,960 (23.0%)
622 (25.7%)
-0.0629
2,066 (19.3%)
471 (36.5%)
-0.3907
0 (0.0%)
0 (0.0%)
#DIV/0!
3,960 (8.6%)
622 (11.6%)
-0.0997
...2019 - 2020; n (%)
4,468 (25.9%)
1,049 (43.3%)
-0.3721
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
4,468 (9.7%)
1,049 (19.5%)
-0.2802
Combined comorbidity score, 180 days 
...mean (sd)
5.30 (2.55)
5.29 (2.40)
0.0040
4.21 (2.23)
4.21 (2.12)
0.0000
5.30 (2.72)
4.75 (2.39)
0.2148
5.05 (2.55)
4.86 (2.33)
0.0778
...median [IQR]
5.00 [3.00, 7.00]
5.00 [3.00, 7.00]
0.0000
4.00 [3.00, 5.00]
4.00 [3.00, 5.00]
0.0000
5.00 [3.00, 7.00]
4.00 [3.00, 6.00]
0.3906
4.77 (2.55)
4.45 (2.33)
0.1310
CV Comorbidity - Pulmonary hypertension/Other pulmonary heart disease ; n (%)
2,893 (16.8%)
506 (20.9%)
-0.1050
1,274 (11.9%)
218 (16.9%)
-0.1428
3,611 (19.7%)
369 (22.3%)
-0.0639
6,504 (14.1%)
875 (16.3%)
-0.0613
CV Comorbidity - Other dysrythmias ; n (%)
9,611 (55.7%)
1,383 (57.1%)
-0.0282
5,648 (52.7%)
685 (53.1%)
-0.0080
9,911 (54.1%)
854 (51.5%)
0.0521
19,522 (42.2%)
2,237 (41.6%)
0.0122
CV Comorbidity - Valve disorder ; n (%)
2,246 (13.0%)
442 (18.2%)
-0.1437
657 (6.1%)
80 (6.2%)
-0.0042
2,921 (16.0%)
323 (19.5%)
-0.0917
5,167 (11.2%)
765 (14.2%)
-0.0902
CV Comorbidity - Hospitalization for heart failure; n (%)
13,310 (77.2%)
1,891 (78.0%)
-0.0192
8,185 (76.3%)
971 (75.3%)
0.0234
15,029 (82.1%)
1,198 (72.3%)
0.2352
28,339 (61.2%)
3,089 (57.5%)
0.0754
CV Comorbidity - Implantable cardioverter defibrillator ; n (%)
4,746 (27.5%)
641 (26.4%)
0.0248
2,170 (20.2%)
319 (24.7%)
-0.1080
2,292 (12.5%)
249 (15.0%)
-0.0726
7,038 (15.2%)
890 (16.6%)
-0.0383
CV Comorbidity - Hypotension; n (%)
2,300 (13.3%)
294 (12.1%)
0.0360
1,109 (10.3%)
112 (8.7%)
0.0546
3,148 (17.2%)
235 (14.2%)
0.0825
5,448 (11.8%)
529 (9.8%)
0.0645
CV Comorbidity - Hypertension; n (%)
15,907 (92.2%)
2,298 (94.8%)
-0.1056
9,139 (85.2%)
1,140 (88.4%)
-0.0946
17,177 (93.8%)
1,591 (96.0%)
-0.1001
33,084 (71.5%)
3,889 (72.4%)
-0.0200
CV Comorbidity - Coronary atherosclerosis and other forms of chronic ischemic heart disease ; n (%)
11,601 (67.3%)
1,788 (73.8%)
-0.1430
6,342 (59.2%)
753 (58.4%)
0.0163
12,704 (69.4%)
1,286 (77.6%)
-0.1866
24,305 (52.5%)
3,074 (57.2%)
-0.0946
CV Comorbidity - Hyperlipidemia ; n (%)
12,847 (74.5%)
1,968 (81.2%)
-0.1619
6,470 (60.3%)
782 (60.7%)
-0.0082
13,795 (75.4%)
1,390 (83.8%)
-0.2096
26,642 (57.6%)
3,358 (62.5%)
-0.1002
CV Comorbidity - Unstable Angina (Inpatient or Outpatient) ; n (%)
2,054 (11.9%)
312 (12.9%)
-0.0303
1,149 (10.7%)
126 (9.8%)
0.0297
1,978 (10.8%)
209 (12.6%)
-0.0560
4,032 (8.7%)
521 (9.7%)
-0.0346
CV Comorbidity - Implantation of CRT device; n (%)
6,249 (36.2%)
845 (34.9%)
0.0272
3,356 (31.3%)
457 (35.5%)
-0.0891
3,595 (19.6%)
357 (21.5%)
-0.0470
9,844 (21.3%)
1,202 (22.4%)
-0.0266
CV Comorbidity - Stable Angina ; n (%)
2,435 (14.1%)
452 (18.6%)
-0.1219
1,114 (10.4%)
143 (11.1%)
-0.0226
2,085 (11.4%)
293 (17.7%)
-0.1794
4,520 (9.8%)
745 (13.9%)
-0.1271
CV Comorbidity - Stroke/TIA; n (%)
1,680 (9.7%)
179 (7.4%)
0.0823
848 (7.9%)
67 (5.2%)
0.1093
2,531 (13.8%)
151 (9.1%)
0.1480
4,211 (9.1%)
330 (6.1%)
0.1134
CV Comorbidity - Peripheral Vascular Disease (PVD) or PVD Surgery; n (%)
2,927 (17.0%)
376 (15.5%)
0.0407
1,096 (10.2%)
119 (9.2%)
0.0338
4,607 (25.2%)
378 (22.8%)
0.0562
7,534 (16.3%)
754 (14.0%)
0.0642
CV Comorbidity - Myocardial Infarction; n (%)
5,921 (34.3%)
817 (33.7%)
0.0127
2,982 (27.8%)
298 (23.1%)
0.1081
6,043 (33.0%)
543 (32.8%)
0.0043
11,964 (25.9%)
1,360 (25.3%)
0.0137
CV Comorbidity - Atrial fibrillation; n (%)
8,728 (50.6%)
1,103 (45.5%)
0.1022
4,718 (44.0%)
476 (36.9%)
0.1450
10,418 (56.9%)
870 (52.5%)
0.0885
19,146 (41.4%)
1,973 (36.7%)
0.0965
CV Comorbidity - CABG/PCI; n (%)
5,216 (30.2%)
865 (35.7%)
-0.1172
1,948 (18.2%)
181 (14.0%)
0.1145
5,049 (27.6%)
586 (35.3%)
-0.1664
10,265 (22.2%)
1,451 (27.0%)
-0.1116
CV Medication - ACE inhibitors; n (%)
17,244 (100.0%)
1,288 (53.1%)
1.3291
10,721 (100.0%)
764 (59.3%)
1.1716
18,303 (100.0%)
1,018 (61.4%)
1.1213
35,547 (76.8%)
2,306 (42.9%)
0.7370
CV Medication - Use of ARBs ; n (%)
570 (3.3%)
1,271 (52.4%)
-1.3091
340 (3.2%)
629 (48.8%)
-1.2169
804 (4.4%)
727 (43.8%)
-1.0379
1,374 (3.0%)
1,998 (37.2%)
-0.9436
CV Medication - Beta blocker ; n (%)
17,106 (99.2%)
2,414 (99.6%)
-0.0518
10,629 (99.1%)
1,284 (99.6%)
-0.0623
18,163 (99.2%)
1,645 (99.2%)
0.0000
35,269 (76.2%)
4,059 (75.6%)
0.0140
CV Medication - Digoxin ; n (%)
2,468 (14.3%)
299 (12.3%)
0.0589
1,512 (14.1%)
187 (14.5%)
-0.0114
3,069 (16.8%)
268 (16.2%)
0.0162
5,537 (12.0%)
567 (10.6%)
0.0442
CV Medication - SGLT-2 Inhibitors ; n (%)
215 (1.2%)
82 (3.4%)
-0.1472
176 (1.6%)
40 (3.1%)
-0.0991
91 (0.5%)
13 (0.8%)
-0.0373
306 (0.7%)
095 (1.8%)
-0.0991
CV Medication - Loop diuretic ; n (%)
13,101 (76.0%)
2,053 (84.7%)
-0.2203
7,601 (70.9%)
1,099 (85.3%)
-0.3536
14,036 (76.7%)
1,424 (85.9%)
-0.2376
27,137 (58.7%)
3,477 (64.7%)
-0.1237
CV Medication - Thiazide diuretics ; n (%)
1,358 (7.9%)
301 (12.4%)
-0.1494
957 (8.9%)
158 (12.3%)
-0.1106
1,716 (9.4%)
204 (12.3%)
-0.0933
3,074 (6.6%)
505 (9.4%)
-0.1033
CV Medication - Mineralocorticoid receptor antagonist ; n (%)
5,642 (32.7%)
1,112 (45.9%)
-0.2728
3,722 (34.7%)
678 (52.6%)
-0.3669
4,839 (26.4%)
707 (42.6%)
-0.3458
10,481 (22.7%)
1,819 (33.9%)
-0.2506
CV Medication - Nitrate; n (%)
3,470 (20.1%)
542 (22.4%)
-0.0562
2,113 (19.7%)
292 (22.7%)
-0.0734
3,868 (21.1%)
405 (24.4%)
-0.0788
7,338 (15.9%)
947 (17.6%)
-0.0455
CV Medication - PCSK9 Inhibitors; n (%)
22 (0.1%)
7 (0.3%)
-0.0448
12 (0.1%)
5 (0.4%)
-0.0601
7 (0.0%)
1 (0.1%)
-0.0447
029 (0.1%)
008 (0.1%)
0.0000
CV Medication - Use of Statins ; n (%)
12,062 (69.9%)
1,780 (73.4%)
-0.0777
6,996 (65.3%)
837 (64.9%)
0.0084
12,124 (66.2%)
1,209 (72.9%)
-0.1460
24,186 (52.3%)
2,989 (55.7%)
-0.0683
CV Medication - Use of other lipid-lowering drugs ; n (%)
904 (5.2%)
141 (5.8%)
-0.0263
600 (5.6%)
90 (7.0%)
-0.0576
946 (5.2%)
117 (7.1%)
-0.0791
1,850 (4.0%)
258 (4.8%)
-0.0390
CV Medication - CCB (non-dihydropyridine) - Non-combo with ACEi; n (%)
962 (5.6%)
116 (4.8%)
0.0360
573 (5.3%)
44 (3.4%)
0.0932
1,397 (7.6%)
92 (5.5%)
0.0850
2,359 (5.1%)
208 (3.9%)
0.0579
CV Medication - CCB (dihydropyridine) - Non-combo with ACEi, ARB; n (%)
2,589 (15.0%)
418 (17.2%)
-0.0599
1,401 (13.1%)
178 (13.8%)
-0.0205
3,085 (16.9%)
263 (15.9%)
0.0270
5,674 (12.3%)
681 (12.7%)
-0.0121
Other Comorbidity - Osteoporosis ; n (%)
919 (5.3%)
135 (5.6%)
-0.0132
283 (2.6%)
33 (2.6%)
0.0000
1,865 (10.2%)
132 (8.0%)
0.0765
2,784 (6.0%)
267 (5.0%)
0.0439
Other Comorbidity - Dementia ; n (%)
1,767 (10.2%)
151 (6.2%)
0.1462
672 (6.3%)
51 (4.0%)
0.1042
4,311 (23.6%)
170 (10.3%)
0.3602
6,078 (13.1%)
321 (6.0%)
0.2434
Other Comorbidity - Hypothyroidism ; n (%)
721 (4.2%)
87 (3.6%)
0.0310
571 (5.3%)
62 (4.8%)
0.0228
1,863 (10.2%)
97 (5.9%)
0.1585
2,584 (5.6%)
184 (3.4%)
0.1063
Other Comorbidity - Hyperthyroidism ; n (%)
229 (1.3%)
40 (1.7%)
-0.0329
148 (1.4%)
18 (1.4%)
0.0000
321 (1.8%)
33 (2.0%)
-0.0146
550 (1.2%)
073 (1.4%)
-0.0177
Other Comorbidity - Hyperkalemia ; n (%)
1,116 (6.5%)
150 (6.2%)
0.0123
445 (4.2%)
48 (3.7%)
0.0257
1,341 (7.3%)
97 (5.9%)
0.0564
2,457 (5.3%)
247 (4.6%)
0.0323
Other Comorbidity - Depression; n (%)
2,995 (17.4%)
418 (17.2%)
0.0053
1,184 (11.0%)
130 (10.1%)
0.0293
4,488 (24.5%)
305 (18.4%)
0.1490
7,483 (16.2%)
723 (13.5%)
0.0760
Other Comorbidity - COPD ; n (%)
4,922 (28.5%)
719 (29.7%)
-0.0264
1,829 (17.1%)
179 (13.9%)
0.0885
5,826 (31.8%)
463 (27.9%)
0.0853
10,748 (23.2%)
1,182 (22.0%)
0.0287
Other Comorbidity - Pneumonia; n (%)
3,145 (18.2%)
488 (20.1%)
-0.0483
1,642 (15.3%)
215 (16.7%)
-0.0382
4,653 (25.4%)
324 (19.5%)
0.1418
7,798 (16.9%)
812 (15.1%)
0.0491
Other Comorbidity - Acute kidney injury (AKI) ; n (%)
4,102 (23.8%)
541 (22.3%)
0.0356
1,922 (17.9%)
247 (19.2%)
-0.0334
5,227 (28.6%)
375 (22.6%)
0.1378
9,329 (20.2%)
916 (17.1%)
0.0797
Other Comorbidity - CKD Stage 1-2; n (%)
1,021 (5.9%)
155 (6.4%)
-0.0208
325 (3.0%)
29 (2.2%)
0.0503
1,072 (5.9%)
125 (7.5%)
-0.0640
2,093 (4.5%)
280 (5.2%)
-0.0326
Other Comorbidity - CKD Stage 3-4; n (%)
4,224 (24.5%)
588 (24.3%)
0.0047
1,389 (13.0%)
159 (12.3%)
0.0211
4,649 (25.4%)
464 (28.0%)
-0.0588
8,873 (19.2%)
1,052 (19.6%)
-0.0101
Other Comorbidity - Any Chronic Kidney Disease; n (%)
5,817 (33.7%)
830 (34.2%)
-0.0106
1,983 (18.5%)
228 (17.7%)
0.0208
6,713 (36.7%)
639 (38.5%)
-0.0372
12,530 (27.1%)
1,469 (27.4%)
-0.0067
Other Comorbidity - Hemodialysis/Peritoneal dialysis ; n (%)
63 (0.4%)
6 (0.2%)
0.0366
39 (0.4%)
1 (0.1%)
0.0601
88 (0.5%)
0 (0.0%)
0.1003
151 (0.3%)
006 (0.1%)
0.0448
Other Comorbidity - DM Related Complications; n (%)
3,822 (22.2%)
592 (24.4%)
-0.0521
1,701 (15.9%)
237 (18.4%)
-0.0664
4,556 (24.9%)
409 (24.7%)
0.0046
8,378 (18.1%)
1,001 (18.6%)
-0.0129
Other Comorbidity - Diabetic/Hypertensive Nephropathy; n (%)
5,349 (31.0%)
792 (32.7%)
-0.0365
1,996 (18.6%)
266 (20.6%)
-0.0504
4,918 (26.9%)
552 (33.3%)
-0.1399
10,267 (22.2%)
1,344 (25.0%)
-0.0660
Other Comorbidity - Sleep apnea; n (%)
3,567 (20.7%)
628 (25.9%)
-0.1232
2,211 (20.6%)
303 (23.5%)
-0.0700
2,859 (15.6%)
332 (20.0%)
-0.1152
6,426 (13.9%)
960 (17.9%)
-0.1096
Other Comorbidity - Cancer ; n (%)
2,002 (11.6%)
281 (11.6%)
0.0000
1,162 (10.8%)
108 (8.4%)
0.0815
2,905 (15.9%)
228 (13.8%)
0.0591
4,907 (10.6%)
509 (9.5%)
0.0366
Other Comorbidity - Type 1 DM ; n (%)
648 (3.8%)
97 (4.0%)
-0.0103
542 (5.1%)
50 (3.9%)
0.0579
991 (5.4%)
72 (4.3%)
0.0512
1,639 (3.5%)
169 (3.1%)
0.0224
Other Comorbidity - Type 2 DM ; n (%)
8,156 (47.3%)
1,313 (54.2%)
-0.1383
4,297 (40.1%)
581 (45.1%)
-0.1012
8,959 (48.9%)
852 (51.4%)
-0.0500
17,115 (37.0%)
2,165 (40.3%)
-0.0678
Other Comorbidity - Anemia ; n (%)
4,612 (26.7%)
663 (27.4%)
-0.0158
2,276 (21.2%)
250 (19.4%)
0.0448
7,712 (42.1%)
578 (34.9%)
0.1484
12,324 (26.6%)
1,241 (23.1%)
0.0811
Lifestyle - Obesity ; n (%)
4,592 (26.6%)
829 (34.2%)
-0.1658
2,387 (22.3%)
387 (30.0%)
-0.1759
3,922 (21.4%)
399 (24.1%)
-0.0644
8,514 (18.4%)
1,228 (22.9%)
-0.1113
Lifestyle - Alcohol/Drug Abuse or Dependence; n (%)
1,823 (10.6%)
202 (8.3%)
0.0787
821 (7.7%)
87 (6.7%)
0.0387
1,365 (7.5%)
83 (5.0%)
0.1034
3,188 (6.9%)
285 (5.3%)
0.0669
Lifestyle - Smoking; n (%)
7,970 (46.2%)
1,118 (46.1%)
0.0020
2,185 (20.4%)
251 (19.5%)
0.0225
8,146 (44.5%)
681 (41.1%)
0.0688
16,116 (34.8%)
1,799 (33.5%)
0.0274
Other Medication - AGI & Meglitinides ; n (%)
77 (0.4%)
13 (0.5%)
-0.0149
57 (0.5%)
3 (0.2%)
0.0508
132 (0.7%)
10 (0.6%)
0.0124
209 (0.5%)
023 (0.4%)
0.0149
Other Medication - Insulin; n (%)
2,459 (14.3%)
402 (16.6%)
-0.0637
1,444 (13.5%)
195 (15.1%)
-0.0457
2,865 (15.7%)
244 (14.7%)
0.0279
5,324 (11.5%)
646 (12.0%)
-0.0155
Other Medication - Glitazones; n (%)
183 (1.1%)
34 (1.4%)
-0.0270
95 (0.9%)
16 (1.2%)
-0.0294
213 (1.2%)
30 (1.8%)
-0.0494
396 (0.9%)
064 (1.2%)
-0.0294
Other Medication - 1st and 2nd Generation SUs; n (%)
2,076 (12.0%)
335 (13.8%)
-0.0537
1,133 (10.6%)
154 (11.9%)
-0.0412
2,165 (11.8%)
242 (14.6%)
-0.0828
4,241 (9.2%)
577 (10.7%)
-0.0501
Other Medication - DPP-4 Inhibitors ; n (%)
761 (4.4%)
158 (6.5%)
-0.0926
598 (5.6%)
97 (7.5%)
-0.0769
935 (5.1%)
147 (8.9%)
-0.1493
1,696 (3.7%)
305 (5.7%)
-0.0946
Other Medication - GLP-1 RA ; n (%)
326 (1.9%)
101 (4.2%)
-0.1341
210 (2.0%)
47 (3.6%)
-0.0971
151 (0.8%)
24 (1.4%)
-0.0575
477 (1.0%)
125 (2.3%)
-0.1022
Other Medication - Metformin ; n (%)
3,558 (20.6%)
643 (26.5%)
-0.1394
2,040 (19.0%)
292 (22.7%)
-0.0912
3,361 (18.4%)
363 (21.9%)
-0.0873
6,919 (15.0%)
1,006 (18.7%)
-0.0990
Other Medication - NSAIDS (COX-2 Selective) ; n (%)
724 (4.2%)
126 (5.2%)
-0.0473
414 (3.9%)
55 (4.3%)
-0.0202
904 (4.9%)
97 (5.9%)
-0.0443
1,628 (3.5%)
223 (4.2%)
-0.0364
Other Medication - NSAIDS (Non-Selective) ; n (%)
1,212 (7.0%)
221 (9.1%)
-0.0772
1,554 (14.5%)
225 (17.5%)
-0.0819
731 (4.0%)
51 (3.1%)
0.0487
1,943 (4.2%)
272 (5.1%)
-0.0428
BEFORE MATCHING
OPTUM
MARKETSCAN
MEDICARE
POOLED
Appendix B: Sacubitril/Valsartan vs. ACE Inhibitors

Other Medication - Use of antiplatelet agents ; n (%)
4,412 (25.6%)
695 (28.7%)
-0.0697
3,239 (30.2%)
404 (31.3%)
-0.0238
4,061 (22.2%)
466 (28.1%)
-0.1363
8,473 (18.3%)
1,161 (21.6%)
-0.0826
Other Medication - Use of heparin and other low-molecular weight heparins ; n (%)
370 (2.1%)
42 (1.7%)
0.0293
6 (0.1%)
0 (0.0%)
0.0447
472 (2.6%)
18 (1.1%)
0.1115
842 (1.8%)
060 (1.1%)
0.0586
Other Medication - Use of oral anticoagulants ; n (%)
6,844 (39.7%)
935 (38.6%)
0.0225
4,175 (38.9%)
471 (36.5%)
0.0495
7,403 (40.4%)
690 (41.6%)
-0.0244
14,247 (30.8%)
1,625 (30.3%)
0.0109
Other Medication - Use of other hypertension drugs; n (%)
1,923 (11.2%)
300 (12.4%)
-0.0372
1,199 (11.2%)
179 (13.9%)
-0.0816
2,063 (11.3%)
202 (12.2%)
-0.0280
3,986 (8.6%)
502 (9.3%)
-0.0245
Other Medication - Use of antipsychotics ; n (%)
541 (3.1%)
60 (2.5%)
0.0364
233 (2.2%)
22 (1.7%)
0.0362
1,073 (5.9%)
46 (2.8%)
0.1524
1,614 (3.5%)
106 (2.0%)
0.0918
Other Medication - Use of dementia meds ; n (%)
518 (3.0%)
50 (2.1%)
0.0571
216 (2.0%)
21 (1.6%)
0.0301
1,295 (7.1%)
66 (4.0%)
0.1357
1,813 (3.9%)
116 (2.2%)
0.0990
Other Medication - Use of antiparkinsonian meds ; n (%)
435 (2.5%)
74 (3.1%)
-0.0364
189 (1.8%)
28 (2.2%)
-0.0286
741 (4.0%)
45 (2.7%)
0.0723
1,176 (2.5%)
119 (2.2%)
0.0198
Other Medication - Use of anxiolytics/hypnotics ; n (%)
1,014 (5.9%)
159 (6.6%)
-0.0289
671 (6.3%)
85 (6.6%)
-0.0122
1,137 (6.2%)
123 (7.4%)
-0.0477
2,151 (4.6%)
282 (5.3%)
-0.0323
Other Medication - Use of anticonvulsants ; n (%)
3,043 (17.6%)
403 (16.6%)
0.0266
1,319 (12.3%)
137 (10.6%)
0.0534
3,713 (20.3%)
267 (16.1%)
0.1090
6,756 (14.6%)
670 (12.5%)
0.0614
Other Medication - Use of antidepressants ; n (%)
4,418 (25.6%)
618 (25.5%)
0.0023
2,297 (21.4%)
266 (20.6%)
0.0196
5,702 (31.2%)
454 (27.4%)
0.0836
10,120 (21.9%)
1,072 (20.0%)
0.0467
Other Medication - Use of lithium ; n (%)
14 (0.1%)
2 (0.1%)
0.0000
16 (0.1%)
0 (0.0%)
0.0447
16 (0.1%)
0 (0.0%)
0.0447
030 (0.1%)
002 (0.0%)
0.0447
Other Medication - Use of Benzodiazepine; n (%)
2,208 (12.8%)
328 (13.5%)
-0.0207
1,321 (12.3%)
184 (14.3%)
-0.0589
2,763 (15.1%)
257 (15.5%)
-0.0111
4,971 (10.7%)
585 (10.9%)
-0.0064
Other Medication - Use of opioids ; n (%)
5,405 (31.3%)
712 (29.4%)
0.0413
3,310 (30.9%)
336 (26.1%)
0.1065
6,255 (34.2%)
447 (27.0%)
0.1567
11,660 (25.2%)
1,159 (21.6%)
0.0851
Other Medication - Use of COPD/asthma meds ; n (%)
3,139 (18.2%)
549 (22.6%)
-0.1094
1,703 (15.9%)
265 (20.6%)
-0.1219
3,142 (17.2%)
358 (21.6%)
-0.1114
6,281 (13.6%)
907 (16.9%)
-0.0919
HU - Bone mineral density; n (%)
348 (2.0%)
56 (2.3%)
-0.0207
99 (0.9%)
17 (1.3%)
-0.0384
364 (2.0%)
31 (1.9%)
0.0072
712 (1.5%)
087 (1.6%)
-0.0081
HU - Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy; n (%)
646 (3.7%)
86 (3.5%)
0.0107
440 (4.1%)
54 (4.2%)
-0.0050
789 (4.3%)
63 (3.8%)
0.0254
1,435 (3.1%)
149 (2.8%)
0.0177
HU - Flu vaccine; n (%)
2,851 (16.5%)
446 (18.4%)
-0.0501
1,106 (10.3%)
142 (11.0%)
-0.0227
4,410 (24.1%)
491 (29.6%)
-0.1243
7,261 (15.7%)
937 (17.4%)
-0.0458
HU - Mammogram; n (%)
775 (4.5%)
135 (5.6%)
-0.0503
404 (3.8%)
62 (4.8%)
-0.0493
830 (4.5%)
88 (5.3%)
-0.0371
1,605 (3.5%)
223 (4.2%)
-0.0364
HU - Frailty Score: Empirical Version 365 days 
...mean (sd)
0.23 (0.07)
0.22 (0.06)
0.1534
0.20 (0.06)
0.20 (0.05)
0.0000
0.27 (0.09)
0.24 (0.07)
0.3721
0.24 (0.08)
0.22 (0.06)
0.2828
...median [IQR]
0.21 [0.18, 0.26]
0.21 [0.18, 0.25]
0.0000
0.19 [0.16, 0.23]
0.19 [0.16, 0.21]
0.0000
0.25 [0.20, 0.32]
0.23 [0.19, 0.27]
0.2481
0.22 (0.08)
0.21 (0.06)
0.1414
HU - Number of hospitalizations during CAP
...mean (sd)
1.06 (0.84)
1.03 (0.76)
0.0375
0.96 (0.74)
0.90 (0.68)
0.0844
1.39 (1.10)
1.04 (0.89)
0.3498
1.17 (0.93)
1.00 (0.78)
0.1981
...median [IQR]
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
0.0000
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
0.0000
1.00 [1.00, 2.00]
1.00 [0.00, 1.00]
0.0000
1.00 (0.93)
1.00 (0.78)
0.0000
HU - Number of Emergency Department (ED) visits 
...mean (sd)
1.71 (2.73)
1.79 (2.36)
-0.0314
2.23 (4.68)
2.17 (3.64)
0.0143
2.07 (2.66)
1.59 (2.55)
0.1842
1.97 (3.26)
1.82 (2.77)
0.0496
...median [IQR]
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
0.0000
0.00 [0.00, 3.00]
0.00 [0.00, 3.00]
0.0000
1.00 [0.00, 3.00]
1.00 [0.00, 2.00]
0.0000
0.77 (3.26)
0.76 (2.77)
0.0033
HU - Number of Internal Medicine/Family Medicine Visits 
...mean (sd)
14.57 (17.87)
14.29 (17.89)
0.0157
9.73 (14.69)
9.03 (13.38)
0.0498
12.75 (15.11)
8.88 (11.78)
0.2857
12.73 (16.10)
11.36 (15.17)
0.0876
...median [IQR]
9.00 [4.00, 19.00]
9.00 [4.00, 19.00]
0.0000
5.00 [2.00, 12.00]
5.00 [2.00, 11.00]
0.0000
8.00 [4.00, 16.00]
6.00 [3.00, 11.00]
0.1476
7.68 (16.10)
7.11 (15.17)
0.0364
HU - Number of Distinct Medication Prescriptions (not generalized to generics) 
...mean (sd)
30.67 (20.95)
34.27 (21.45)
-0.1698
25.34 (13.88)
30.86 (15.63)
-0.3735
27.59 (17.12)
33.01 (17.68)
-0.3115
28.22 (18.00)
33.06 (19.05)
-0.2612
...median [IQR]
26.00 [17.00, 38.00]
30.00 [20.00, 42.00]
-0.1887
23.00 [16.00, 32.00]
28.00 [20.00, 38.00]
-0.3383
24.00 [16.00, 35.00]
29.00 [21.00, 40.00]
-0.2873
24.51 (18.00)
29.21 (19.05)
-0.2536
HU - Number of Cardiologist visits 
...mean (sd)
10.80 (10.03)
13.40 (10.60)
-0.2520
5.27 (7.42)
7.15 (7.98)
-0.2440
8.94 (9.61)
11.44 (11.32)
-0.2381
8.78 (9.32)
11.30 (10.27)
-0.2570
...median [IQR]
8.00 [4.00, 15.00]
11.00 [6.00, 18.00]
-0.2907
3.00 [0.00, 8.00]
5.00 [2.00, 10.00]
-0.2596
6.00 [2.00, 12.00]
9.00 [4.00, 15.00]
-0.2857
6.05 (9.32)
8.94 (10.27)
-0.2947
HU - Number of Electrocardiogram
...mean (sd)
3.68 (3.91)
4.18 (4.12)
-0.1245
2.90 (2.79)
3.12 (2.87)
-0.0777
3.42 (3.25)
3.63 (3.59)
-0.0613
3.40 (3.42)
3.76 (3.69)
-0.1012
...median [IQR]
3.00 [1.00, 5.00]
3.00 [2.00, 6.00]
0.0000
2.00 [1.00, 4.00]
2.00 [1.00, 4.00]
0.0000
3.00 [1.00, 5.00]
3.00 [1.00, 5.00]
0.0000
2.77 (3.42)
2.76 (3.69)
0.0028
HU - Number of Echocardiogram
...mean (sd)
2.28 (5.02)
2.58 (4.76)
-0.0613
1.52 (1.70)
1.66 (1.59)
-0.0851
1.33 (1.25)
1.60 (1.40)
-0.2034
1.73 (3.27)
2.06 (3.38)
-0.0992
...median [IQR]
1.00 [0.00, 2.00]
1.00 [1.00, 3.00]
0.0000
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
0.0000
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
0.0000
1.00 (3.27)
1.00 (3.38)
0.0000
SES Proxy - Copay for pharmacy cost (charges in U.S. $)
...mean (sd)
24.10 (34.04)
26.12 (30.50)
-0.0625
14.67 (18.89)
15.10 (17.86)
-0.0234
22.05 (33.42)
26.07 (29.82)
-0.1269
21.10 (30.93)
23.46 (27.77)
-0.0803
...median [IQR]
14.62 [5.79, 30.27]
18.66 [6.73, 34.59]
-0.1250
10.46 [3.57, 19.54]
12.42 [4.76, 20.28]
-0.1066
12.90 [4.04, 28.02]
18.49 [5.40, 34.97]
-0.1765
12.98 (30.93)
17.11 (27.77)
-0.1405
SES Proxy - Low income indicator; n (%)
3,942 (22.9%)
541 (22.3%)
0.0143
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
3,942 (8.5%)
541 (10.1%)
-0.0551
SES Proxy - Business type
...Commercial; n (%)
3,171 (18.4%)
610 (25.2%)
-0.1653
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
3,171 (6.9%)
610 (11.4%)
-0.1566
...Medicare; n (%)
14,073 (81.6%)
1,814 (74.8%)
0.1653
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
14,073 (30.4%)
1,814 (33.8%)
-0.0729
SES Proxy - Insurance Plan type
...Comprehensive; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
2,527 (23.6%)
175 (13.6%)
0.2591
0 (0.0%)
0 (0.0%)
#DIV/0!
2,527 (5.5%)
175 (3.3%)
0.1074
...HMO; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
1,060 (9.9%)
112 (8.7%)
0.0413
0 (0.0%)
0 (0.0%)
#DIV/0!
1,060 (2.3%)
112 (2.1%)
0.0136
...PPO; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
4,951 (46.2%)
686 (53.2%)
-0.1403
0 (0.0%)
0 (0.0%)
#DIV/0!
4,951 (10.7%)
686 (12.8%)
-0.0652
...Others; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
2,183 (20.4%)
316 (24.5%)
-0.0984
0 (0.0%)
0 (0.0%)
#DIV/0!
2,183 (4.7%)
316 (5.9%)
-0.0536
SES Proxy - Dual status code (with Medicaid); n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
4,785 (26.1%)
343 (20.7%)
0.1278
4,785 (10.3%)
343 (6.4%)
0.1413
Appendix B: Sacubitril/Valsartan vs. ACE Inhibitors

Variable
Reference - ACE 
inhibitors
Exposure - 
Sacubitril/valsartan
St. Diff
Reference - ACE 
inhibitors
Exposure - 
Sacubitril/valsartan
St. Diff
Reference - ACE 
Inhibitors
Exposure - 
Sacubitril/valsartan 
St. Diff
Reference - ACE 
Inhibitors
Exposure - 
Sacubitril/valsartan 
St. Diff
Number of patients
1,279
1,279
748
748
1,006
1,006
3,033
3,033
Age - Continuous
...mean (sd)
68.68 (11.85)
67.91 (12.31)
0.0637
59.59 (13.80)
60.00 (13.63)
-0.0299
75.41 (7.47)
75.61 (7.51)
-0.0267
68.67 (11.17)
68.51 (11.33)
0.0142
...median [IQR]
69.00 [61.00, 77.00]
69.00 [60.00, 77.00]
0.0000
58.50 [51.00, 68.00]
60.00 [52.00, 68.00]
-0.1094
74.00 [69.00, 81.00]
75.00 [69.00, 81.00]
-0.1335
68.07 (11.17)
68.77 (11.33)
-0.0622
Age Categories*
...18 - 54; n (%)
137 (10.7%)
196 (15.3%)
-0.1371
263 (35.2%)
236 (31.6%)
0.0764
0 (0.0%)
0 (0.0%)
#DIV/0!
400 (13.2%)
432 (14.2%)
-0.0291
...55 - 64; n (%)
285 (22.3%)
256 (20.0%)
0.0563
265 (35.4%)
284 (38.0%)
-0.0540
0 (0.0%)
0 (0.0%)
#DIV/0!
550 (18.1%)
540 (17.8%)
0.0078
...65 - 74; n (%)
427 (33.4%)
411 (32.1%)
0.0277
111 (14.8%)
103 (13.8%)
0.0286
514 (51.1%)
492 (48.9%)
0.0440
941 (31.0%)
903 (29.8%)
0.0261
...>= 75; n (%)
430 (33.6%)
416 (32.5%)
0.0234
109 (14.6%)
125 (16.7%)
-0.0578
492 (48.9%)
514 (51.1%)
-0.0440
Gender
...Male; n (%)
880 (68.8%)
855 (66.8%)
0.0428
541 (72.3%)
535 (71.5%)
0.0178
589 (58.5%)
604 (60.0%)
-0.0305
1,469 (48.4%)
1,459 (48.1%)
0.0060
...Female; n (%)
399 (31.2%)
424 (33.2%)
-0.0428
207 (27.7%)
213 (28.5%)
-0.0178
417 (41.5%)
402 (40.0%)
0.0305
816 (26.9%)
826 (27.2%)
-0.0068
Region without zero category 
...Northeast; n (%)
142 (11.1%)
140 (10.9%)
0.0064
137 (18.3%)
142 (19.0%)
-0.0180
159 (15.8%)
195 (19.4%)
-0.0946
301 (9.9%)
335 (11.0%)
-0.0360
…Midwest; n (%)
722 (56.5%)
715 (55.9%)
0.0121
202 (27.0%)
180 (24.1%)
0.0665
482 (47.9%)
469 (46.6%)
0.0260
1,204 (39.7%)
1,184 (39.0%)
0.0143
...South; n (%)
227 (17.7%)
247 (19.3%)
-0.0412
370 (49.5%)
366 (48.9%)
0.0120
232 (23.1%)
221 (22.0%)
0.0263
459 (15.1%)
468 (15.4%)
-0.0083
...West; n (%)
188 (14.7%)
177 (13.8%)
0.0257
39 (5.2%)
60 (8.0%)
-0.1130
133 (13.2%)
121 (12.0%)
0.0362
321 (10.6%)
298 (9.8%)
0.0264
...Unknown+missing; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
Calendar Time - Year of Initiation (2015/16 - 2020)
...2015-2016; n (%)
146 (11.4%)
153 (12.0%)
-0.0187
229 (30.6%)
233 (31.1%)
-0.0108
355 (35.3%)
374 (37.2%)
-0.0395
797 (26.3%)
785 (25.9%)
0.0091
...2017; n (%)
293 (22.9%)
280 (21.9%)
0.0240
264 (35.3%)
256 (34.2%)
0.0231
651 (64.7%)
632 (62.8%)
0.0395
293 (9.7%)
280 (9.2%)
0.0171
...2018; n (%)
321 (25.1%)
319 (24.9%)
0.0046
255 (34.1%)
259 (34.6%)
-0.0105
0 (0.0%)
0 (0.0%)
#DIV/0!
321 (10.6%)
319 (10.5%)
0.0033
...2019 - 2020; n (%)
519 (40.6%)
527 (41.2%)
-0.0122
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
519 (40.6%)
527 (41.2%)
-0.0122
Combined comorbidity score, 180 days 
...mean (sd)
5.30 (2.47)
5.27 (2.43)
0.0122
4.24 (2.12)
4.19 (2.06)
0.0239
4.77 (2.49)
4.76 (2.40)
0.0041
4.86 (2.40)
4.83 (2.33)
0.0127
...median [IQR]
5.00 [4.00, 7.00]
5.00 [3.00, 7.00]
0.0000
4.00 [3.00, 6.00]
4.00 [3.00, 5.00]
0.0000
4.00 [3.00, 6.00]
4.00 [3.00, 6.00]
0.0000
4.42 (2.40)
4.42 (2.33)
0.0000
CV Comorbidity - Pulmonary hypertension/Other pulmonary heart disease ; n (%)
250 (19.5%)
257 (20.1%)
-0.0151
132 (17.6%)
126 (16.8%)
0.0212
209 (20.8%)
223 (22.2%)
-0.0341
459 (15.1%)
480 (15.8%)
-0.0194
CV Comorbidity - Other dysrythmias ; n (%)
735 (57.5%)
736 (57.5%)
0.0000
424 (56.7%)
409 (54.7%)
0.0403
506 (50.3%)
519 (51.6%)
-0.0260
1,241 (40.9%)
1,255 (41.4%)
-0.0102
CV Comorbidity - Valve disorder ; n (%)
254 (19.9%)
237 (18.5%)
0.0356
46 (6.1%)
49 (6.6%)
-0.0205
202 (20.1%)
203 (20.2%)
-0.0025
456 (15.0%)
440 (14.5%)
0.0141
CV Comorbidity - Hospitalization for heart failure; n (%)
1,041 (81.4%)
1,051 (82.2%)
-0.0207
602 (80.5%)
593 (79.3%)
0.0299
743 (73.9%)
740 (73.6%)
0.0068
1,784 (58.8%)
1,791 (59.1%)
-0.0061
CV Comorbidity - Implantable cardioverter defibrillator ; n (%)
328 (25.6%)
303 (23.7%)
0.0441
170 (22.7%)
170 (22.7%)
0.0000
137 (13.6%)
145 (14.4%)
-0.0231
465 (15.3%)
448 (14.8%)
0.0140
CV Comorbidity - Hypotension; n (%)
167 (13.1%)
169 (13.2%)
-0.0030
67 (9.0%)
73 (9.8%)
-0.0274
160 (15.9%)
150 (14.9%)
0.0277
327 (10.8%)
319 (10.5%)
0.0097
CV Comorbidity - Hypertension; n (%)
1,206 (94.3%)
1,208 (94.4%)
-0.0043
666 (89.0%)
658 (88.0%)
0.0313
972 (96.6%)
960 (95.4%)
0.0613
2,178 (71.8%)
2,168 (71.5%)
0.0067
CV Comorbidity - Coronary atherosclerosis and other forms of chronic ischemic heart disease ; n (%)
959 (75.0%)
946 (74.0%)
0.0229
436 (58.3%)
427 (57.1%)
0.0243
780 (77.5%)
788 (78.3%)
-0.0193
1,739 (57.3%)
1,734 (57.2%)
0.0020
CV Comorbidity - Hyperlipidemia ; n (%)
1,026 (80.2%)
1,020 (79.7%)
0.0125
446 (59.6%)
446 (59.6%)
0.0000
830 (82.5%)
835 (83.0%)
-0.0132
1,856 (61.2%)
1,855 (61.2%)
0.0000
CV Comorbidity - Unstable Angina (Inpatient or Outpatient) ; n (%)
161 (12.6%)
173 (13.5%)
-0.0267
78 (10.4%)
81 (10.8%)
-0.0130
146 (14.5%)
139 (13.8%)
0.0201
307 (10.1%)
312 (10.3%)
-0.0066
CV Comorbidity - Implantation of CRT device; n (%)
428 (33.5%)
409 (32.0%)
0.0320
239 (32.0%)
239 (32.0%)
0.0000
193 (19.2%)
205 (20.4%)
-0.0301
621 (20.5%)
614 (20.2%)
0.0075
CV Comorbidity - Stable Angina ; n (%)
232 (18.1%)
241 (18.8%)
-0.0180
94 (12.6%)
79 (10.6%)
0.0625
203 (20.2%)
184 (18.3%)
0.0482
435 (14.3%)
425 (14.0%)
0.0086
CV Comorbidity - Stroke/TIA; n (%)
81 (6.3%)
101 (7.9%)
-0.0623
44 (5.9%)
45 (6.0%)
-0.0042
83 (8.3%)
90 (8.9%)
-0.0214
164 (5.4%)
191 (6.3%)
-0.0384
CV Comorbidity - Peripheral Vascular Disease (PVD) or PVD Surgery; n (%)
192 (15.0%)
189 (14.8%)
0.0056
69 (9.2%)
68 (9.1%)
0.0035
230 (22.9%)
238 (23.7%)
-0.0189
422 (13.9%)
427 (14.1%)
-0.0058
CV Comorbidity - Myocardial Infarction; n (%)
450 (35.2%)
447 (34.9%)
0.0063
190 (25.4%)
182 (24.3%)
0.0255
363 (36.1%)
362 (36.0%)
0.0021
813 (26.8%)
809 (26.7%)
0.0023
CV Comorbidity - Atrial fibrillation; n (%)
576 (45.0%)
562 (43.9%)
0.0221
258 (34.5%)
275 (36.8%)
-0.0480
537 (53.4%)
524 (52.1%)
0.0260
1,113 (36.7%)
1,086 (35.8%)
0.0187
CV Comorbidity - CABG/PCI; n (%)
478 (37.4%)
478 (37.4%)
0.0000
142 (19.0%)
120 (16.0%)
0.0790
369 (36.7%)
374 (37.2%)
-0.0104
847 (27.9%)
852 (28.1%)
-0.0045
CV Medication - ACE inhibitors; n (%)
1,279 (100.0%)
1,279 (100.0%)
#DIV/0!
748 (100.0%)
748 (100.0%)
#DIV/0!
1,006 (100.0%)
1,006 (100.0%)
#DIV/0!
2,285 (75.3%)
2,285 (75.3%)
0.0000
CV Medication - Use of ARBs ; n (%)
118 (9.2%)
127 (9.9%)
-0.0238
92 (12.3%)
89 (11.9%)
0.0123
75 (7.5%)
81 (8.1%)
-0.0224
193 (6.4%)
208 (6.9%)
-0.0201
CV Medication - Beta blocker ; n (%)
1,273 (99.5%)
1,273 (99.5%)
0.0000
747 (99.9%)
746 (99.7%)
0.0448
998 (99.2%)
999 (99.3%)
-0.0116
2,271 (74.9%)
2,272 (74.9%)
0.0000
CV Medication - Digoxin ; n (%)
162 (12.7%)
158 (12.4%)
0.0091
104 (13.9%)
106 (14.2%)
-0.0086
172 (17.1%)
160 (15.9%)
0.0323
334 (11.0%)
318 (10.5%)
0.0161
CV Medication - SGLT-2 Inhibitors ; n (%)
48 (3.8%)
42 (3.3%)
0.0270
18 (2.4%)
22 (2.9%)
-0.0311
2 (0.2%)
5 (0.5%)
-0.0508
050 (1.6%)
047 (1.5%)
0.0081
CV Medication - Loop diuretic ; n (%)
1,078 (84.3%)
1,081 (84.5%)
-0.0055
645 (86.2%)
637 (85.2%)
0.0286
880 (87.5%)
859 (85.4%)
0.0614
1,958 (64.6%)
1,940 (64.0%)
0.0125
CV Medication - Thiazide diuretics ; n (%)
147 (11.5%)
155 (12.1%)
-0.0186
82 (11.0%)
88 (11.8%)
-0.0252
97 (9.6%)
119 (11.8%)
-0.0712
244 (8.0%)
274 (9.0%)
-0.0359
CV Medication - Mineralocorticoid receptor antagonist ; n (%)
573 (44.8%)
578 (45.2%)
-0.0080
393 (52.5%)
386 (51.6%)
0.0180
443 (44.0%)
427 (42.4%)
0.0323
1,016 (33.5%)
1,005 (33.1%)
0.0085
CV Medication - Nitrate; n (%)
289 (22.6%)
277 (21.7%)
0.0217
172 (23.0%)
160 (21.4%)
0.0385
245 (24.4%)
230 (22.9%)
0.0353
534 (17.6%)
507 (16.7%)
0.0239
CV Medication - PCSK9 Inhibitors; n (%)*
0 (0.0%)
3 (0.2%)
-0.0633
2 (0.3%)
1 (0.1%)
0.0448
3 (0.3%)
0 (0.0%)
0.0776
003 (0.1%)
003 (0.1%)
0.0000
CV Medication - Use of Statins ; n (%)
907 (70.9%)
926 (72.4%)
-0.0333
495 (66.2%)
475 (63.5%)
0.0566
728 (72.4%)
743 (73.9%)
-0.0339
1,635 (53.9%)
1,669 (55.0%)
-0.0221
CV Medication - Use of other lipid-lowering drugs ; n (%)
67 (5.2%)
68 (5.3%)
-0.0045
44 (5.9%)
48 (6.4%)
-0.0208
81 (8.1%)
71 (7.1%)
0.0377
148 (4.9%)
139 (4.6%)
0.0141
CV Medication - CCB (non-dihydropyridine) - Non-combo with ACEi; n (%)
50 (3.9%)
58 (4.5%)
-0.0299
22 (2.9%)
27 (3.6%)
-0.0395
58 (5.8%)
59 (5.9%)
-0.0043
108 (3.6%)
117 (3.9%)
-0.0158
CV Medication - CCB (dihydropyridine) - Non-combo with ACEi, ARB; n (%)
205 (16.0%)
208 (16.3%)
-0.0082
113 (15.1%)
110 (14.7%)
0.0112
133 (13.2%)
143 (14.2%)
-0.0291
338 (11.1%)
351 (11.6%)
-0.0158
Other Comorbidity - Osteoporosis ; n (%)
60 (4.7%)
57 (4.5%)
0.0095
21 (2.8%)
16 (2.1%)
0.0453
74 (7.4%)
74 (7.4%)
0.0000
134 (4.4%)
131 (4.3%)
0.0049
Other Comorbidity - Dementia ; n (%)
102 (8.0%)
91 (7.1%)
0.0341
36 (4.8%)
36 (4.8%)
0.0000
94 (9.3%)
94 (9.3%)
0.0000
196 (6.5%)
185 (6.1%)
0.0165
Other Comorbidity - Hypothyroidism ; n (%)
40 (3.1%)
48 (3.8%)
-0.0384
28 (3.7%)
34 (4.5%)
-0.0404
76 (7.6%)
63 (6.3%)
0.0511
116 (3.8%)
111 (3.7%)
0.0053
Other Comorbidity - Hyperthyroidism ; n (%)
27 (2.1%)
22 (1.7%)
0.0293
9 (1.2%)
10 (1.3%)
-0.0090
25 (2.5%)
21 (2.1%)
0.0267
052 (1.7%)
043 (1.4%)
0.0243
Other Comorbidity - Hyperkalemia ; n (%)
78 (6.1%)
79 (6.2%)
-0.0042
45 (6.0%)
35 (4.7%)
0.0578
70 (7.0%)
68 (6.8%)
0.0079
148 (4.9%)
147 (4.8%)
0.0047
Other Comorbidity - Depression; n (%)
207 (16.2%)
216 (16.9%)
-0.0188
76 (10.2%)
75 (10.0%)
0.0066
187 (18.6%)
182 (18.1%)
0.0129
394 (13.0%)
398 (13.1%)
-0.0030
Other Comorbidity - COPD ; n (%)
378 (29.6%)
380 (29.7%)
-0.0022
108 (14.4%)
104 (13.9%)
0.0143
290 (28.8%)
297 (29.5%)
-0.0154
668 (22.0%)
677 (22.3%)
-0.0072
Other Comorbidity - Pneumonia; n (%)
263 (20.6%)
270 (21.1%)
-0.0123
147 (19.7%)
139 (18.6%)
0.0280
185 (18.4%)
203 (20.2%)
-0.0456
448 (14.8%)
473 (15.6%)
-0.0223
Other Comorbidity - Acute kidney injury (AKI) ; n (%)
284 (22.2%)
321 (25.1%)
-0.0683
158 (21.1%)
150 (20.1%)
0.0247
259 (25.7%)
253 (25.1%)
0.0138
543 (17.9%)
574 (18.9%)
-0.0258
Other Comorbidity - CKD Stage 1-2; n (%)
68 (5.3%)
79 (6.2%)
-0.0387
18 (2.4%)
18 (2.4%)
0.0000
81 (8.1%)
75 (7.5%)
0.0224
149 (4.9%)
154 (5.1%)
-0.0092
Other Comorbidity - CKD Stage 3-4; n (%)
310 (24.2%)
289 (22.6%)
0.0378
90 (12.0%)
84 (11.2%)
0.0250
267 (26.5%)
273 (27.1%)
-0.0135
577 (19.0%)
562 (18.5%)
0.0128
Other Comorbidity - Any Chronic Kidney Disease; n (%)
421 (32.9%)
408 (31.9%)
0.0214
133 (17.8%)
125 (16.7%)
0.0291
381 (37.9%)
371 (36.9%)
0.0207
802 (26.4%)
779 (25.7%)
0.0159
Other Comorbidity - Hemodialysis/Peritoneal dialysis ; n (%)*
7 (0.5%)
4 (0.3%)
0.0317
1 (0.1%)
1 (0.1%)
0.0000
4 (0.4%)
0 (0.0%)
0.0896
011 (0.4%)
004 (0.1%)
0.0601
Other Comorbidity - DM Related Complications; n (%)
289 (22.6%)
304 (23.8%)
-0.0284
118 (15.8%)
115 (15.4%)
0.0110
235 (23.4%)
224 (22.3%)
0.0262
524 (17.3%)
528 (17.4%)
-0.0026
Other Comorbidity - Diabetic/Hypertensive Nephropathy; n (%)
419 (32.8%)
402 (31.4%)
0.0300
143 (19.1%)
141 (18.9%)
0.0051
329 (32.7%)
319 (31.7%)
0.0214
748 (24.7%)
721 (23.8%)
0.0210
Other Comorbidity - Sleep apnea; n (%)
298 (23.3%)
307 (24.0%)
-0.0165
171 (22.9%)
177 (23.7%)
-0.0189
177 (17.6%)
189 (18.8%)
-0.0311
475 (15.7%)
496 (16.4%)
-0.0191
Other Comorbidity - Cancer ; n (%)
150 (11.7%)
150 (11.7%)
0.0000
58 (7.8%)
56 (7.5%)
0.0113
126 (12.5%)
131 (13.0%)
-0.0150
276 (9.1%)
281 (9.3%)
-0.0069
Other Comorbidity - Type 1 DM ; n (%)
40 (3.1%)
47 (3.7%)
-0.0331
24 (3.2%)
22 (2.9%)
0.0174
36 (3.6%)
40 (4.0%)
-0.0209
076 (2.5%)
087 (2.9%)
-0.0247
Other Comorbidity - Type 2 DM ; n (%)
662 (51.8%)
673 (52.6%)
-0.0160
348 (46.5%)
322 (43.0%)
0.0704
531 (52.8%)
504 (50.1%)
0.0540
1,193 (39.3%)
1,177 (38.8%)
0.0102
Other Comorbidity - Anemia ; n (%)
380 (29.7%)
356 (27.8%)
0.0420
155 (20.7%)
144 (19.3%)
0.0350
340 (33.8%)
348 (34.6%)
-0.0169
720 (23.7%)
704 (23.2%)
0.0118
Lifestyle - Obesity ; n (%)
407 (31.8%)
437 (34.2%)
-0.0511
222 (29.7%)
222 (29.7%)
0.0000
236 (23.5%)
239 (23.8%)
-0.0071
643 (21.2%)
676 (22.3%)
-0.0267
Lifestyle - Alcohol/Drug Abuse or Dependence; n (%)
113 (8.8%)
122 (9.5%)
-0.0243
66 (8.8%)
64 (8.6%)
0.0071
60 (6.0%)
56 (5.6%)
0.0171
173 (5.7%)
178 (5.9%)
-0.0086
Lifestyle - Smoking; n (%)
613 (47.9%)
628 (49.1%)
-0.0240
181 (24.2%)
163 (21.8%)
0.0571
440 (43.7%)
436 (43.3%)
0.0081
1,053 (34.7%)
1,064 (35.1%)
-0.0084
Other Medication - AGI & Meglitinides ; n (%)*
5 (0.4%)
4 (0.3%)
0.0169
5 (0.7%)
2 (0.3%)
0.0567
11 (1.1%)
7 (0.7%)
0.0424
016 (0.5%)
011 (0.4%)
0.0149
Other Medication - Insulin; n (%)
192 (15.0%)
210 (16.4%)
-0.0385
129 (17.2%)
108 (14.4%)
0.0768
162 (16.1%)
150 (14.9%)
0.0332
354 (11.7%)
360 (11.9%)
-0.0062
Other Medication - Glitazones; n (%)
17 (1.3%)
20 (1.6%)
-0.0251
15 (2.0%)
11 (1.5%)
0.0381
17 (1.7%)
18 (1.8%)
-0.0076
034 (1.1%)
038 (1.3%)
-0.0184
Other Medication - 1st and 2nd Generation SUs; n (%)
187 (14.6%)
184 (14.4%)
0.0057
87 (11.6%)
84 (11.2%)
0.0126
131 (13.0%)
137 (13.6%)
-0.0177
318 (10.5%)
321 (10.6%)
-0.0033
AFTER MATCHING
OPTUM
MARKETSCAN
MEDICARE
POOLED
Appendix B: Sacubitril/Valsartan vs. ACE Inhibitors

Other Medication - DPP-4 Inhibitors ; n (%)
90 (7.0%)
85 (6.6%)
0.0159
56 (7.5%)
46 (6.1%)
0.0556
90 (8.9%)
85 (8.4%)
0.0178
180 (5.9%)
170 (5.6%)
0.0129
Other Medication - GLP-1 RA ; n (%)
51 (4.0%)
51 (4.0%)
0.0000
21 (2.8%)
23 (3.1%)
-0.0177
17 (1.7%)
13 (1.3%)
0.0329
068 (2.2%)
064 (2.1%)
0.0069
Other Medication - Metformin ; n (%)
337 (26.3%)
341 (26.7%)
-0.0091
179 (23.9%)
172 (23.0%)
0.0212
218 (21.7%)
217 (21.6%)
0.0024
555 (18.3%)
558 (18.4%)
-0.0026
Other Medication - NSAIDS (COX-2 Selective) ; n (%)
72 (5.6%)
64 (5.0%)
0.0268
36 (4.8%)
31 (4.1%)
0.0340
43 (4.3%)
43 (4.3%)
0.0000
115 (3.8%)
107 (3.5%)
0.0160
Other Medication - NSAIDS (Non-Selective) ; n (%)
126 (9.9%)
129 (10.1%)
-0.0067
136 (18.2%)
137 (18.3%)
-0.0026
35 (3.5%)
34 (3.4%)
0.0055
161 (5.3%)
163 (5.4%)
-0.0044
Other Medication - Use of antiplatelet agents ; n (%)
355 (27.8%)
377 (29.5%)
-0.0376
249 (33.3%)
237 (31.7%)
0.0342
282 (28.0%)
292 (29.0%)
-0.0222
637 (21.0%)
669 (22.1%)
-0.0268
Other Medication - Use of heparin and other low-molecular weight heparins ; n (%)*
29 (2.3%)
27 (2.1%)
0.0136
1 (0.1%)
0 (0.0%)
0.0447
27 (2.7%)
9 (0.9%)
0.1357
056 (1.8%)
036 (1.2%)
0.0494
Other Medication - Use of oral anticoagulants ; n (%)
478 (37.4%)
470 (36.7%)
0.0145
255 (34.1%)
270 (36.1%)
-0.0419
429 (42.6%)
419 (41.7%)
0.0182
907 (29.9%)
889 (29.3%)
0.0131
Other Medication - Use of other hypertension drugs; n (%)
149 (11.6%)
140 (10.9%)
0.0222
105 (14.0%)
97 (13.0%)
0.0293
105 (10.4%)
108 (10.7%)
-0.0098
254 (8.4%)
248 (8.2%)
0.0072
Other Medication - Use of antipsychotics ; n (%)
33 (2.6%)
36 (2.8%)
-0.0123
10 (1.3%)
11 (1.5%)
-0.0170
32 (3.2%)
27 (2.7%)
0.0296
065 (2.1%)
063 (2.1%)
0.0000
Other Medication - Use of dementia meds ; n (%)
35 (2.7%)
25 (2.0%)
0.0462
15 (2.0%)
14 (1.9%)
0.0072
33 (3.3%)
34 (3.4%)
-0.0056
068 (2.2%)
059 (1.9%)
0.0212
Other Medication - Use of antiparkinsonian meds ; n (%)
34 (2.7%)
38 (3.0%)
-0.0180
13 (1.7%)
13 (1.7%)
0.0000
26 (2.6%)
29 (2.9%)
-0.0183
060 (2.0%)
067 (2.2%)
-0.0139
Other Medication - Use of anxiolytics/hypnotics ; n (%)
78 (6.1%)
81 (6.3%)
-0.0083
39 (5.2%)
54 (7.2%)
-0.0830
54 (5.4%)
62 (6.2%)
-0.0342
132 (4.4%)
143 (4.7%)
-0.0144
Other Medication - Use of anticonvulsants ; n (%)
181 (14.2%)
194 (15.2%)
-0.0282
76 (10.2%)
68 (9.1%)
0.0373
166 (16.5%)
165 (16.4%)
0.0027
347 (11.4%)
359 (11.8%)
-0.0125
Other Medication - Use of antidepressants ; n (%)
306 (23.9%)
317 (24.8%)
-0.0210
159 (21.3%)
159 (21.3%)
0.0000
284 (28.2%)
280 (27.8%)
0.0089
590 (19.5%)
597 (19.7%)
-0.0050
Other Medication - Use of lithium ; n (%)*
0 (0.0%)
0 (0.0%)
#DIV/0!
3 (0.4%)
0 (0.0%)
0.0896
2 (0.2%)
0 (0.0%)
0.0633
002 (0.1%)
000 (0.0%)
0.0447
Other Medication - Use of Benzodiazepine; n (%)
197 (15.4%)
187 (14.6%)
0.0224
92 (12.3%)
104 (13.9%)
-0.0474
131 (13.0%)
141 (14.0%)
-0.0293
328 (10.8%)
328 (10.8%)
0.0000
Other Medication - Use of opioids ; n (%)
385 (30.1%)
386 (30.2%)
-0.0022
213 (28.5%)
206 (27.5%)
0.0223
267 (26.5%)
281 (27.9%)
-0.0315
652 (21.5%)
667 (22.0%)
-0.0121
Other Medication - Use of COPD/asthma meds ; n (%)
296 (23.1%)
269 (21.0%)
0.0507
139 (18.6%)
152 (20.3%)
-0.0430
195 (19.4%)
218 (21.7%)
-0.0569
491 (16.2%)
487 (16.1%)
0.0027
HU - Bone mineral density; n (%)
28 (2.2%)
28 (2.2%)
0.0000
8 (1.1%)
9 (1.2%)
-0.0094
16 (1.6%)
14 (1.4%)
0.0165
044 (1.5%)
042 (1.4%)
0.0084
HU - Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy; n (%)
61 (4.8%)
55 (4.3%)
0.0240
30 (4.0%)
27 (3.6%)
0.0209
36 (3.6%)
41 (4.1%)
-0.0260
097 (3.2%)
096 (3.2%)
0.0000
HU - Flu vaccine; n (%)
235 (18.4%)
238 (18.6%)
-0.0052
76 (10.2%)
83 (11.1%)
-0.0292
306 (30.4%)
304 (30.2%)
0.0044
541 (17.8%)
542 (17.9%)
-0.0026
HU - Mammogram; n (%)
63 (4.9%)
62 (4.8%)
0.0047
36 (4.8%)
30 (4.0%)
0.0390
51 (5.1%)
46 (4.6%)
0.0233
114 (3.8%)
108 (3.6%)
0.0106
HU - Frailty Score: Empirical Version 365 days 
...mean (sd)
0.22 (0.06)
0.22 (0.06)
0.0000
0.20 (0.05)
0.19 (0.05)
0.2000
0.24 (0.07)
0.24 (0.07)
0.0000
0.22 (0.06)
0.22 (0.06)
0.0000
...median [IQR]
0.21 [0.18, 0.25]
0.21 [0.18, 0.25]
0.0000
0.18 [0.16, 0.22]
0.18 [0.16, 0.21]
0.0000
0.22 [0.19, 0.27]
0.22 [0.19, 0.27]
0.0000
0.21 (0.06)
0.21 (0.06)
0.0000
HU - Number of hospitalizations during CAP
...mean (sd)
1.06 (0.77)
1.08 (0.76)
-0.0261
0.98 (0.65)
0.95 (0.66)
0.0458
1.07 (0.91)
1.07 (0.90)
0.0000
1.04 (0.79)
1.04 (0.79)
0.0000
...median [IQR]
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
0.0000
1.00 [1.00, 1.00]
1.00 [1.00, 1.00]
0.0000
1.00 [1.00, 1.00]
1.00 [0.75, 1.00]
0.0000
1.00 (0.79)
1.00 (0.79)
0.0000
HU - Number of Emergency Department (ED) visits 
...mean (sd)
1.81 (2.51)
1.84 (2.32)
-0.0124
2.56 (5.33)
2.40 (3.90)
0.0343
1.73 (2.19)
1.65 (2.78)
0.0320
1.97 (3.35)
1.92 (2.93)
0.0159
...median [IQR]
1.00 [0.00, 3.00]
1.00 [0.00, 3.00]
0.0000
2.00 [0.00, 3.00]
2.00 [0.00, 3.00]
0.0000
1.00 [0.00, 3.00]
1.00 [0.00, 2.00]
0.0000
1.25 (3.35)
1.25 (2.93)
0.0000
HU - Number of Internal Medicine/Family Medicine Visits 
...mean (sd)
14.51 (18.56)
14.34 (19.30)
0.0090
9.77 (15.50)
8.91 (12.31)
0.0614
8.50 (9.54)
8.89 (10.84)
-0.0382
11.35 (15.32)
11.19 (15.28)
0.0105
...median [IQR]
9.00 [4.00, 18.00]
9.00 [4.00, 19.00]
0.0000
5.00 [2.00, 11.75]
5.00 [2.00, 11.00]
0.0000
6.00 [3.00, 11.00]
6.00 [3.00, 11.00]
0.0000
7.02 (15.32)
7.02 (15.28)
0.0000
HU - Number of Distinct Medication Prescriptions (not generalized to generics) 
...mean (sd)
33.63 (25.85)
33.96 (20.50)
-0.0141
30.49 (17.53)
30.50 (15.10)
-0.0006
31.27 (19.20)
32.09 (16.13)
-0.0462
32.07 (21.91)
32.49 (17.88)
-0.0210
...median [IQR]
28.00 [19.00, 41.00]
30.00 [20.00, 43.00]
-0.0857
28.00 [19.00, 38.00]
28.00 [20.00, 38.00]
0.0000
27.00 [19.00, 38.00]
29.00 [21.00, 40.00]
-0.1128
27.67 (21.91)
29.18 (17.88)
-0.0755
HU - Number of Cardiologist visits 
...mean (sd)
13.79 (13.06)
13.37 (10.66)
0.0352
6.17 (8.33)
6.95 (7.55)
-0.0981
11.33 (12.78)
11.70 (11.61)
-0.0303
11.09 (11.97)
11.23 (10.33)
-0.0125
...median [IQR]
11.00 [5.00, 18.00]
11.00 [6.00, 18.00]
0.0000
4.00 [0.00, 9.00]
5.00 [2.00, 10.00]
-0.1258
8.00 [3.00, 15.00]
9.00 [4.00, 15.00]
-0.0819
8.28 (11.97)
8.86 (10.33)
-0.0519
HU - Number of Electrocardiogram
...mean (sd)
4.47 (4.88)
4.32 (4.33)
0.0325
3.27 (3.08)
3.22 (2.91)
0.0167
3.88 (3.82)
3.73 (3.96)
0.0386
3.98 (4.15)
3.85 (3.90)
0.0323
...median [IQR]
3.00 [1.00, 6.00]
3.00 [2.00, 6.00]
0.0000
2.00 [1.00, 4.00]
2.00 [1.00, 4.00]
0.0000
3.00 [1.00, 5.00]
3.00 [1.00, 5.00]
0.0000
2.75 (4.15)
2.75 (3.90)
0.0000
HU - Number of Echocardiogram
...mean (sd)
2.86 (5.89)
2.82 (5.27)
0.0072
1.78 (2.00)
1.76 (1.58)
0.0111
1.66 (1.50)
1.62 (1.34)
0.0281
2.20 (4.05)
2.16 (3.60)
0.0104
...median [IQR]
1.00 [1.00, 3.00]
1.00 [1.00, 3.00]
0.0000
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
0.0000
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
0.0000
1.00 (4.05)
1.00 (3.60)
0.0000
SES Proxy - Copay for pharmacy cost (charges in U.S. $)
...mean (sd)
27.20 (42.97)
25.88 (29.41)
0.0359
14.87 (18.19)
14.75 (14.06)
0.0074
25.85 (36.56)
26.03 (30.53)
-0.0053
23.71 (36.11)
23.18 (26.88)
0.0167
...median [IQR]
15.93 [5.74, 32.88]
18.14 [6.52, 33.73]
-0.0600
10.53 [3.58, 20.38]
12.40 [5.11, 19.94]
-0.1150
16.10 [5.26, 32.03]
18.78 [5.57, 34.95]
-0.0796
14.65 (36.11)
16.94 (26.88)
-0.0719
SES Proxy - Low income indicator; n (%)
275 (21.5%)
299 (23.4%)
-0.0455
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
275 (9.1%)
299 (9.9%)
-0.0273
SES Proxy - Business type
...Commercial; n (%)
325 (25.4%)
340 (26.6%)
-0.0274
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
325 (10.7%)
340 (11.2%)
-0.0160
...Medicare; n (%)
954 (74.6%)
939 (73.4%)
0.0274
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
954 (31.5%)
939 (31.0%)
0.0108
SES Proxy - Insurance Plan type
...Comprehensive; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
105 (14.0%)
94 (12.6%)
0.0412
0 (0.0%)
0 (0.0%)
#DIV/0!
105 (3.5%)
094 (3.1%)
0.0224
...HMO; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
62 (8.3%)
71 (9.5%)
-0.0422
0 (0.0%)
0 (0.0%)
#DIV/0!
062 (2.0%)
071 (2.3%)
-0.0207
...PPO; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
403 (53.9%)
400 (53.5%)
0.0080
0 (0.0%)
0 (0.0%)
#DIV/0!
403 (13.3%)
400 (13.2%)
0.0029
...Others; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
178 (23.8%)
183 (24.5%)
-0.0164
0 (0.0%)
0 (0.0%)
#DIV/0!
178 (5.9%)
183 (6.0%)
-0.0042
SES Proxy - Dual status code (with Medicaid); n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
202 (20.1%)
203 (20.2%)
-0.0025
202 (6.7%)
203 (6.7%)
0.0000
_______________________________________________________________________
*Excluded from PS model: Age Cateogries, Use of Lithium, Use of AGI & Meglinitides, PCSK9 Inhibitors, Use of heparin or LMWH, Hemodialysis/Peritoneal dialysis
Appendix B: Sacubitril/Valsartan vs. ACE Inhibitors