Abstract
Previous evidence suggests modest improvements in antihypertensive medication adherence occurred from 2007 to 2012 among US adults ≥65 years of age. Whether adherence improved over time among adults <65 years of age is unknown. We assessed trends in antihypertensive medication nonpersistence and low adherence among 379,658 commercially-insured adults <65 years of age initiating treatment in 2007-2014 using MarketScan® claims. Nonpersistence was defined as having no days of medication available to take during the final 90 days of the 365 days following initiation. Among beneficiaries who were persistent to treatment, low adherence was defined by having antihypertensive medication available to take for <80% of the days in the 365 days following initiation (i.e., proportion of days covered <80%). In 2007 and 2014, 23.3% and 23.5% of patients were nonpersistent to treatment, respectively, and 42.3% and 40.2% had low adherence, respectively. The relative risks for nonpersistence and low adherence were lower among beneficiaries initiating treatment with an angiotensin converting enzyme inhibitor (0.95, 95%CI 0.94-0.97 and 0.97, 95%CI 0.96-0.98, respectively), angiotensin receptor blocker (0.86, 95%CI 0.85-0.88 and 0.99, 95%CI 0.97-1.00, respectively), or multiclass regimen (0.82, 95%CI 0.80-0.84 and 0.88, 95%CI 0.86-0.89, respectively), prescribed 90-day versus 30-day prescriptions (0.67, 95%CI 0.66-0.68 and 0.70, 95%CI 0.69-0.71, respectively), or who received medications by mail versus at the pharmacy (0.93, 95%CI 0.90-0.95 and 0.90, 95%CI 0.88-0.92, respectively). In conclusion, several modifiable factors were associated with lower rates of both antihypertensive medication nonpersistence and low adherence among adults <65 years of age initiating treatment in 2007-2014.
Keywords: medication adherence, nonpersistence, low adherence, nonadherence, MarketScan, hypertension, cardiovascular disease, epidemiology, risk factors, claims data, trends
Graphical Abstract
Antihypertensive medication is effective at lowering systolic and diastolic blood pressure.1 Meta-analyses of randomized controlled trials show that lowering blood pressure (BP) with antihypertensive medication reduces the risk for cardiovascular disease (CVD) events and all-cause mortality.2,3 Despite these data, 53.4% of US adults taking antihypertensive medication have uncontrolled BP as defined by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults.4
Low adherence to antihypertensive medication is a well-recognized factor contributing to the high prevalence of uncontrolled BP.5,6 Additionally, low adherence is associated with increased risk for CVD events and excess healthcare costs among adults with hypertension.5,6 A number of organizations including the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the World Health Organization have advocated for programs directed at improving antihypertensive medication adherence.5–9 Results from an analysis of Medicare claims data indicate that antihypertensive medication adherence improved modestly from 2007 to 2012 among US adults ≥ 65 years of age.10 However, Medicare provides health insurance primarily for older adults, and data were not presented for adults < 65 years of age. Adherence in younger adults may be especially important because the cumulative exposure to high BP over the life course has been associated with increased CVD risk, and better control of BP at younger ages may decrease this risk.11 Therefore, the purpose of this study was to assess trends in antihypertensive medication nonpersistence and low adherence among adults < 65 years of age who initiated antihypertensive medication treatment between 2007 and 2014. An additional aim of the current study was to identify demographic characteristics and comorbid conditions associated with antihypertensive medication nonpersistence and low adherence among adults < 65 years of age.
Methods
We conducted a retrospective cohort study of US adults < 65 years of age who initiated antihypertensive medication between 2007 and 2014 using de-identified Truven Health MarketScan® Commercial Claims Data. MarketScan includes claims data from over 150 health insurance payers, representing all states in the US, and is fully compliant with the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Inpatient and outpatient medical service and outpatient prescription claims are available through the MarketScan database. Use of these data were approved by the University of Alabama at Birmingham Institutional Review Board. Data used in the current study can be obtained from Truven Health Analytics through a licensing agreement. Other study information is available from the corresponding author.
For each beneficiary, we identified the first claim for an outpatient antihypertensive medication fill (index fill) between 2007 and 2014. We restricted the analyses to beneficiaries with continuous insurance coverage for the 365 days prior to (i.e., the look-back period) and the 365 days following (i.e., the follow-up period) their index fill. We excluded beneficiaries who were ≥ 65 years of age at the end of the follow-up period to focus on the population of adults who would not be eligible for Medicare coverage due to age during the follow-up period. To increase the probability that we studied beneficiaries initiating treatment, we excluded beneficiaries with any claims for antihypertensive medication fills during the look-back period. Also, to increase the probability that we were studying beneficiaries initiating treatment to lower their BP, we restricted the analysis to beneficiaries with ≥ 2 outpatient claims linked to physician evaluation and management codes with International Classification of Diseases, 9th Revision (ICD-9) diagnoses of 401.x (malignant, benign or unspecified essential hypertension), ≥ 7 days apart, during the look-back period.
Antihypertensive medication fills
All antihypertensive medication fills were identified using outpatient prescription claims. Data extracted from claims included date of the fill, drug class, days of supply obtained, and copay-per-day of supply. Medication classes included angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), beta blockers, calcium channel blockers (CCB), diuretics (thiazide and loop, separately), and “other” (aldosterone receptor antagonists, alpha blockers, central acting agents, direct vasodilators, potassium-sparing diuretics, renin inhibitors). For each beneficiary, the initial antihypertensive medication treatment regimen was defined using all classes filled within seven days of the index fill. The initial treatment regimen was categorized as being with a single class, multiclass/multiple pill, or multiclass/combination therapy. We defined combination therapy as initiating treatment with a single pill containing two or more antihypertensive classes.
Outcomes
Nonpersistence was defined as not having antihypertensive medication available to take in the last 90 days of the follow-up period.12 Among beneficiaries who were persistent to treatment, antihypertensive medication adherence was calculated using the interval-based proportion of days covered (PDC) method.13 We calculated the PDC using the number of days for which antihypertensive medication was available to take during the follow-up period as the numerator and 365 days as the denominator (Figure 1, Top Panel).13,14 For beneficiaries who filled more than one class of antihypertensive medication during the 365 days following initiation, the PDC was calculated by counting days with any antihypertensive medication available to take as the numerator and 365 days as the denominator (Figure 1, Bottom Panel). Low adherence was defined with the commonly used threshold of PDC < 80%.5,13–15 A PDC for antihypertensive medication < 80% has been associated with an increased risk for CVD events.16
Figure 1.
Interval-based proportion of days covered (PDC) calculation method for defining low antihypertensive medication adherence. Calculation method for PDC among MarketScan beneficiaries filling one class of antihypertensive medication (Top Panel) and two or more classes of antihypertensive medication (Bottom Panel).
Covariates
Covariates were selected a priori and included age, sex, antihypertensive drug class initiated, initiation with a single, multiclass, or combination antihypertensive regimen, initiation with a 90-day fill, copay-per-day of supply, use of mail order for prescription refills, insurance type, and comorbidities including diabetes, coronary heart disease (CHD), stroke, chronic kidney disease (CKD), heart failure (HF), history of depression, a serious fall injury, and polypharmacy. Information on race/ethnicity is not available in the MarketScan® database. Previously published algorithms were used to define comorbidities in claims data (Table S1). Copay-per-day of supply for each beneficiary’s complete antihypertensive medication regimen was categorized into quartiles (<$0.06, ≥$0.06 to <$0.19, ≥$0.19 to <$0.46, ≥$0.46).17 Insurance type was categorized as managed care, fee for service, high deductible, and unknown. Polypharmacy was defined as having claims for ≥ 10 different medication classes during the look-back period. We also included covariates that indicated change in insurance type or the development of comorbidities (new diagnosis code for diabetes, CHD, stroke, CKD, depression), or experiencing a serious fall injury during the 182 days following antihypertensive treatment initiation, since these factors may influence medication-taking behavior.
Statistical analyses
Characteristics of beneficiaries initiating antihypertensive medication were calculated for each calendar year from 2007 through 2014. We assessed linear trends in characteristics across calendar year using Poisson regression for dichotomous variables and analysis of variance for continuous variables. For each calendar year, the percentage of beneficiaries who were nonpersistent to antihypertensive medication and with low adherence, separately, in the 365 days following initiation was calculated for the overall population and in subgroups defined by age (18 to 24, 25 to 34, 35 to 44, 45 to 54, 55 to <64 years), sex, antihypertensive medication classes initiated, initiating treatment with multiple drug classes or a 90-day prescription (versus 30-day) or by mail order or pharmacy, and insurance type. Trends in nonpersistence and low adherence across calendar year were calculated using Poisson regression.
We calculated risk ratios (RR) for antihypertensive medication nonpersistence and low adherence, separately, associated with calendar year of initiation and study covariates. After an initial unadjusted model, a second model included multivariable adjustment for calendar year of initiation, age, sex, and all variables in the look-back period simultaneously. A third model included adjustment for calendar year of initiation, age, sex, all variables from the look-back period and variables from the 182 days following antihypertensive medication initiation as described above. To avoid co-linearity, we examined the association of each antihypertensive medication class with nonpersistence and low adherence in separate regression models, setting the reference category to beneficiaries initiating treatment without the class being examined.
We conducted several sensitivity analyses. First, rather than requiring beneficiaries have ≥ 2 claims for hypertension in the look-back period, we required ≥ 1 claim to be included in the analysis. Second, we defined nonpersistence as having no antihypertensive medication available to take during the final 60 days of the follow-up period. Third, beneficiaries with a history of CHD, HF, diabetes or CKD were excluded because they may be prescribed antihypertensive medication due to these conditions rather than for hypertension. Fourth, we defined low adherence using the prescription-based PDC method.13 To calculate the prescription-based PDC, the numerator was defined as the number of days with medication available to take between the dates of the first and last fills for antihypertensive medication within 365 days of initiation with the denominator defined as the number of days between these fills.13
Three secondary analyses were conducted. First, we calculated the mean PDC, using the interval-based approach, for each calendar year. Second, we calculated the percentage of beneficiaries who had nonpersistence to treatment or low adherence, pooled together, for each calendar year. The RR for this pooled outcome across calendar year was calculated in three models with progressive adjustment as described above. Third, among beneficiaries who initiated treatment with ≥ 2 antihypertensive medications, we calculated the percentage with low adherence, partial adherence, and full adherence (Figure S1). Specifically, low adherence was defined as not having at least one class of antihypertensive medication to take for ≥ 80% of the 365 days following treatment initiation. Full adherence was defined as having the same number or more classes of antihypertensive medication as filled in the initial prescription regimen available to take for ≥ 80% of the 365 days following initiation. Among beneficiaries without full adherence, beneficiaries were considered to have partial adherence if they had one or more class of any antihypertensive medication available to take for ≥ 80% of the 365 days following initiation. All analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, NC).
Results
Overall, 379,658 beneficiaries initiating antihypertensive medication met the inclusion criteria for the current analysis. The mean age of beneficiaries increased from 2007 to 2014 (Table 1). The proportion of beneficiaries who initiated antihypertensive medication with a thiazide diuretic and ARB decreased from 38.4% to 30.4% and 35.6% to 17.9%, respectively, while initiating a combination regimen declined from 35.5% to 23.1% between 2007 to 2014. Initiation with an ACE-I increased from 30.9% to 45.0% over this time period. The proportion of beneficiaries who initiated antihypertensive medication with a single drug class, a 90-day fill, were enrolled in a high deductible insurance plan, and had polypharmacy during the look-back period increased between 2007 and 2014. The diagnosis of comorbid conditions including diabetes, CHD, stroke, CKD, heart failure, or depression in the year prior to initiation increased during the study period. The mean copay-per-day of supply decreased over the study period.
Table 1.
Characteristics of MarketScan beneficiaries initiating antihypertensive medication, by calendar year (n=379,658).
Calendar Year | P trend |
||||||||
---|---|---|---|---|---|---|---|---|---|
Characteristic | 2007 (n=32,877) |
2008 (n=38,544) |
2009 (n=49,288) |
2010 (n=62,196) |
2011 (n=60,991) |
2012 (n=49,376) |
2013 (n=45,529) |
2014 (n=40,857) |
|
Age, years, mean (SD) | 49.4 (9.5) | 49.8 (9.4) | 49.7 (9.5) | 50.4 (9.4) | 50.5 (9.4) | 50.6 (9.5) | 50.7 (9.5) | 50.9 (9.4) | <0.001 |
18-24 | 1.3% | 1.2% | 1.2% | 1.1% | 1.2% | 1.6% | 1.6% | 1.5% | <0.001 |
25-34 | 6.4% | 6.0% | 6.5% | 5.6% | 5.4% | 5.1% | 5.0% | 4.9% | <0.001 |
35-44 | 20.1% | 18.9% | 19.0% | 17.6% | 17.5% | 17.2% | 16.7% | 16.5% | <0.001 |
45-54 | 37.1% | 37.1% | 36.7% | 36.2% | 35.6% | 34.9% | 34.8% | 33.9% | <0.001 |
55-63 | 35.1% | 36.8% | 36.7% | 39.6% | 40.3% | 41.2% | 42.0% | 43.3% | <0.001 |
Male | 51.5% | 49.0% | 50.4% | 50.8% | 50.7% | 51.4% | 51.3% | 50.8% | <0.001 |
Antihypertensive class initiated | |||||||||
Thiazide-type diuretic | 38.4% | 38.4% | 35.7% | 35.1% | 34.3% | 33.3% | 32.1% | 30.4% | <0.001 |
ACE-I | 30.9% | 31.5% | 37.0% | 39.2% | 40.3% | 39.5% | 40.5% | 45.0% | <0.001 |
Calcium channel blocker | 17.1% | 17.4% | 16.0% | 14.9% | 15.0% | 16.2% | 16.3% | 16.3% | <0.001 |
Angiotensin receptor blocker | 35.6% | 33.9% | 26.2% | 21.7% | 20.6% | 21.5% | 19.9% | 17.9% | <0.001 |
Loop diuretic | 2.1% | 2.1% | 2.3% | 2.6% | 2.6% | 2.6% | 2.7% | 2.7% | <0.001 |
Beta blocker | 15.6% | 16.7% | 18.2% | 19.4% | 20.2% | 20.4% | 20.4% | 19.2% | <0.001 |
Other | 6.7% | 7.1% | 7.0% | 6.9% | 6.7% | 6.0% | 5.9% | 5.3% | <0.001 |
Treatment regimen | |||||||||
Single Class | 59.0% | 59.2% | 62.8% | 65.5% | 65.8% | 66.5% | 67.9% | 68.6% | <0.001 |
Multiclass | 5.5% | 6.1% | 6.2% | 6.7% | 7.3% | 7.7% | 7.9% | 8.3% | <0.001 |
Combination | 35.5% | 34.7% | 31.0% | 27.8% | 26.8% | 25.9% | 24.2% | 23.1% | <0.001 |
Initiated with a 90-day fill | 18.3% | 20.7% | 17.8% | 21.5% | 22.0% | 23.3% | 21.1% | 24.5% | <0.001 |
Mail Oder | 11.7% | 8.7% | 8.9% | 7.5% | 7.9% | 9.7% | 7.7% | 7.5% | <0.001 |
Copay-per-day of supply, $, mean (SD) | 0.54 (0.49) | 0.43 (0.50) | 0.41 (0.48) | 0.36 (0.49) | 0.32 (0.43) | 0.30 (0.41) | 0.24 (0.37) | 0.16 (0.31) | <0.001 |
Year before initiation | |||||||||
Insurance type in index month | |||||||||
Managed Care | 93.0% | 93.1% | 90.7% | 78.6% | 79.5% | 86.5% | 83.7% | 72.6% | <0.001 |
Fee for service | 3.7% | 2.7% | 2.1% | 2.7% | 2.4% | 3.9% | 4.8% | 5.0% | <0.001 |
High deductible | 1.7% | 1.9% | 4.4% | 5.3% | 6.4% | 8.2% | 10.4% | 20.9% | <0.001 |
Unknown | 1.6% | 2.3% | 2.8% | 13.4% | 11.7% | 1.4% | 1.0% | 1.5% | <0.001 |
Diabetes | 9.3% | 10.9% | 14.1% | 17.9% | 18.5% | 18.5% | 20.2% | 22.0% | <0.001 |
Coronary heart disease | 2.9% | 3.4% | 4.0% | 5.1% | 4.9% | 4.6% | 4.7% | 4.9% | <0.001 |
Stroke | 1.0% | 1.1% | 1.1% | 1.2% | 1.2% | 1.3% | 1.5% | 1.5% | <0.001 |
Chronic kidney disease | 2.7% | 3.0% | 3.7% | 4.3% | 4.6% | 4.9% | 5.1% | 5.7% | <0.001 |
Heart failure | 0.6% | 0.8% | 1.0% | 1.1% | 1.0% | 1.2% | 1.2% | 1.3% | <0.001 |
History of depression | 6.3% | 7.0% | 8.4% | 10.1% | 10.0% | 9.8% | 10.5% | 10.8% | <0.001 |
Serious fall injury | 0.7% | 0.8% | 0.8% | 0.8% | 0.8% | 0.8% | 0.8% | 0.9% | <0.001 |
Polypharmacy | 12.3% | 11.7% | 13.4% | 14.7% | 15.0% | 15.0% | 16.5% | 17.1% | <0.001 |
Six months after initiation | |||||||||
Insurance change | 2.5% | 3.1% | 4.0% | 3.1% | 2.2% | 2.0% | 4.6% | 3.3% | <0.001 |
Newly diagnosed diabetes | 2.5% | 2.5% | 2.7% | 2.4% | 2.4% | 2.4% | 2.3% | 2.5% | 0.269 |
Newly diagnosed coronary heart disease | 1.4% | 1.4% | 1.5% | 1.6% | 1.5% | 1.4% | 1.4% | 1.5% | 0.328 |
Newly diagnosed stroke | 0.3% | 0.4% | 0.4% | 0.4% | 0.5% | 0.4% | 0.4% | 0.5% | <0.001 |
Newly diagnosed chronic kidney disease | 1.2% | 1.4% | 1.5% | 1.6% | 1.7% | 1.8% | 1.9% | 1.9% | <0.001 |
Newly diagnosed depression | 1.8% | 2.1% | 2.4% | 2.5% | 2.7% | 2.6% | 2.9% | 3.1% | <0.001 |
Serious fall injury | 0.3% | 0.3% | 0.3% | 0.4% | 0.3% | 0.4% | 0.3% | 0.4% | 0.089 |
Numbers in table are mean (standard deviation) for age and number (percent) for other characteristics.
SD=standard deviation; ACE-inhibitor=angiotensin converting enzyme inhibitor.
Multiclass=incident prescription fill for ≥ 2 medications within 7 days.
Insurance type definitions provided in Table S1.
Unadjusted nonpersistence and low adherence trends over time
In 2007, 23.3% of beneficiaries who initiated antihypertensive medication were nonpersistent to treatment compared with 23.5% in 2014 (Figure 2). Among beneficiaries who were persistent to antihypertensive medication, 42.3% had low adherence in 2007 compared with 40.2% in 2014. The proportion of beneficiaries who either had nonpersistence or low adherence to antihypertensive medication in 2007 was 55.7% and 54.2% in 2014.
Figure 2.
Percentage of MarketScan beneficiaries who had nonpersistence, low adherence, or either nonpersistence or low adherence to antihypertensive medication within one year of initiation in 2007 through 2014. Nonpersistence was defined as not having antihypertensive medication available to take in the last 90 days of the 365-day period following treatment initiation. Among beneficiaries who did not have nonpersistence, low adherence was defined as a proportion of days covered < 80% for antihypertensive medication during the 365 days following treatment initiation.
Between 2007 and 2014, the proportion that was nonpersistent to antihypertensive medication increased from 15.7% to 18.0% among beneficiaries who initiated with a 90-day fill and from 14.7% to 19.0% among those receiving medications through mail order (Table S2). Between 2007 and 2014, the proportion with nonpersistence decreased from 21.0% to 18.3% among beneficiaries initiating treatment with a multiclass/multiple pill regimen. Between 2007 and 2014, the proportion with low adherence decreased from 58.0% to 52.5% among beneficiaries 25-34 years of age, from 43.5% to 39.4% among beneficiaries initiating treatment with ARBs, from 55.3% to 46.3% among beneficiaries initiating treatment with a loop diuretic, and from 47.7% to 38.3% among beneficiaries with high deductible insurance plans (Table S3). Low adherence increased from 32.3% to 38.8% among beneficiaries enrolled in a fee-for-service insurance plan.
Multivariable-adjusted antihypertensive medication nonpersistence
After multivariable adjustment for demographic, clinical, and health services factors, the RR for nonpersistence in 2014 compared with 2007 was 0.90 (95% CI 0.87-0.92) (Table 2). Over the entire study period, treatment nonpersistence was less common among older beneficiaries (25 to 34, 35 to 44, 45 to 54, 55 to <64 years of age compared with those <25 years of age), beneficiaries initiating treatment with a CCB, ACE-I, ARB, multiclass or combination regimen, and receiving 90-day fills or medications through mail order. Also, copay-per-day of supply of $0.19 to <$0.46 and ≥$0.46 versus <$0.06 were associated with lower risk of nonpersistence, and beneficiaries with a high deductible insurance plan versus managed care insurance plans were less likely to have nonpersistence. Nonpersistence was more common among women and beneficiaries who initiated treatment with a thiazide or loop diuretic, or “other” antihypertensive medication class, had fee-for-service insurance versus being in a managed care plan, had diabetes or history of depression, experienced a serious fall injury, or had polypharmacy during the look-back period. The risk for nonpersistence was lower among beneficiaries who were newly diagnosed with diabetes, CHD, or CKD and higher among those who had newly diagnosed depression or experienced a serious fall injury in the six months following treatment initiation.
Table 2.
Unadjusted and multivariable adjusted relative risks and 95% confidence intervals for nonpersistence of antihypertensive medication among MarketScan beneficiaries in 2007-2014 (n=379,658)
Characteristic | Unadjusted RR (95% CI) |
p-value | Multivariable Adjusted 1 RR (95% CI) |
p-value | Multivariable Adjusted 2 RR (95% CI) |
p-value |
---|---|---|---|---|---|---|
Calendar year | ||||||
2007 | 1(ref) | 1(ref) | 1(ref) | |||
2008 | 1.05 (1.02-1.08) | 0.8306 | 1.01 (0.99-1.04) | 0.3606 | 1.01 (0.99-1.04) | <0.001 |
2009 | 1.18 (1.15-1.20) | 1.11 (1.08-1.14) | 1.11 (1.08-1.14) | |||
2010 | 1.18 (1.15-1.20) | 1.11 (1.09-1.14) | 1.11 (1.09-1.14) | |||
2011 | 1.17 (1.15-1.20) | 1.10 (1.07-1.12) | 1.10 (1.07-1.12) | |||
2012 | 1.12 (1.10-1.15) | 1.04 (1.01-1.06) | 1.04 (1.01-1.07) | |||
2013 | 1.11 (1.08-1.14) | 1.00 (0.97-1.02) | 1.00 (0.97-1.02) | |||
2014 | 1.01 (0.98-1.03) | 0.90 (0.87-0.92) | 0.90 (0.87-0.92) | |||
Age, years | ||||||
<25 | 1(ref) | 1(ref) | 1(ref) | |||
25-34 | 0.85 (0.81-0.88) | <0.001 |
0.87 (0.84-0.91) | <0.001 |
0.87 (0.84-0.91) | <0.001 |
35-44 | 0.71 (0.68-0.73) | 0.74 (0.72-0.77) | 0.74 (0.72-0.77) | |||
45-54 | 0.61 (0.59-0.63) | 0.65 (0.63-0.67) | 0.65 (0.63-0.67) | |||
55-63 | 0.57 (0.55-0.59) | 0.62 (0.60-0.64) | 0.62 (0.60-0.64) | |||
Female versus male sex | 1.03 (1.02-1.04) | <0.001 | 1.03 (1.02-1.04) | <0.001 | 1.03 (1.02-1.04) | <0.001 |
Antihypertensive drug class initiated | ||||||
Thiazide-type diuretic | 0.97 (0.96-0.98) | <0.001 | 1.05 (1.04-1.07) | <0.001 | 1.05 (1.04-1.07) | <0.001 |
Calcium channel blocker | 0.90 (0.89-0.92) | <0.001 | 0.98 (0.96-0.99) | 0.003 | 0.98 (0.96-0.99) | 0.004 |
ACE-inhibitor | 1.00 (0.99-1.01) | 0.949 | 0.95 (0.94-0.97) | <0.001 | 0.95 (0.94-0.97) | <0.001 |
Angiotensin receptor blocker | 0.76 (0.75-0.77) | <0.001 | 0.86 (0.85-0.88) | <0.001 | 0.86 (0.85-0.88) | <0.001 |
Loop diuretic | 1.42 (1.38-1.46) | <0.001 | 1.41 (1.37-1.45) | <0.001 | 1.41 (1.37-1.45) | <0.001 |
Beta blocker | 0.96 (0.95-0.97) | <0.001 | 0.99 (0.97-1.00) | 0.075 | 0.99 (0.97-1.00) | 0.118 |
Other | 1.18 (1.16-1.20) | <0.001 | 1.22 (1.20-1.25) | <0.001 | 1.22 (1.20-1.25) | <0.001 |
Treatment regimen | ||||||
Single Class | 1(ref) | 1(ref) | 1(ref) | |||
Multiclass | 0.74 (0.72-0.76) | <0.001 | 0.82 (0.80-0.84) | <0.001 | 0.82 (0.80-0.84) | <0.001 |
Combination | 0.87 (0.86-0.88) | <0.001 | 0.93 (0.92-0.94) | <0.001 | 0.93 (0.92-0.94) | <0.001 |
Initiated with a 90-day fill | 0.65 (0.64-0.66) | <0.001 | 0.67 (0.66-0.68) | <0.001 | 0.67 (0.66-0.68) | <0.001 |
Mail order | 0.65 (0.64-0.67) | <0.001 | 0.93 (0.90-0.96) | <0.001 | 0.93 (0.90-0.95) | <0.001 |
Copay-per-day of supply | ||||||
Quartile 1 (<$0.06) | 1(ref) | 1(ref) | 1(ref) | |||
Quartile 2 (≥$0.06 to <$0.19) | 1.08 (1.06-1.09) | <0.001 | 1.03 (1.01-1.04) | <0.001 | 1.03 (1.01-1.04) | <0.001 |
Quartile 3 (≥$0.19 to <$0.46) | 0.85 (0.84-0.87) | <0.001 | 0.80 (0.79-0.81) | <0.001 | 0.80 (0.79-0.81) | <0.001 |
Quartile 4 (≥$0.46) | 0.75 (0.74-0.77) | <0.001 | 0.71 (0.70-0.72) | <0.001 | 0.71 (0.70-0.72) | <0.001 |
Insurance type | ||||||
Managed Care | 1(ref) | 1(ref) | 1(ref) | |||
Fee for service | 0.95 (0.92-0.98) | 0.002 | 1.04 (1.01-1.08) | 0.006 | 1.05 (1.01-1.08) | 0.005 |
High deductible | 0.92 (0.90-0.94) | <0.001 | 0.88 (0.86-0.90) | <0.001 | 0.88 (0.86-0.90) | <0.001 |
Unknown | 0.95 (0.93-0.97) | <0.001 | 0.93 (0.91-0.96) | <0.001 | 0.93 (0.91-0.96) | <0.001 |
Year before initiation | ||||||
Diabetes | 1.05 (1.04-1.07) | <0.001 | 1.08 (1.07-1.10) | <0.001 | 1.08 (1.07-1.10) | <0.001 |
CHD | 0.98 (0.95-1.00) | 0.096 | 1.02 (0.99-1.05) | 0.117 | 1.02 (0.99-1.05) | 0.176 |
Stroke | 0.93 (0.89-0.98) | 0.007 | 0.95 (0.90-1.00) | 0.057 | 0.95 (0.91-1.00) | 0.068 |
CKD | 1.02 (0.99-1.04) | 0.216 | 1.02 (0.99-1.05) | 0.135 | 1.02 (0.99-1.05) | 0.146 |
Heart failure | 0.95 (0.90-1.00) | 0.065 | 1.00 (0.94-1.05) | 0.883 | 1.00 (0.95-1.06) | 0.987 |
History of depression | 1.10 (1.08-1.11) | <0.001 | 1.05 (1.03-1.07) | <0.001 | 1.05 (1.03-1.07) | <0.001 |
Serious fall injury | 1.08 (1.02-1.15) | 0.005 | 1.07 (1.01-1.13) | 0.014 | 1.07 (1.01-1.14) | 0.013 |
Polypharmacy | 1.07 (1.06-1.09) | <0.001 | 1.04 (1.02-1.05) | <0.001 | 1.04 (1.02-1.05) | <0.001 |
Six months after initiation | ||||||
Insurance type changed | 1.02 (0.99-1.05) | 0.163 | 1.01 (0.98-1.04) | 0.532 | ||
Newly diagnosed diabetes | 0.90 (0.87-0.94) | <0.001 | 0.94 (0.90-0.97) | <0.001 | ||
Newly diagnosed CHD | 0.84 (0.80-0.88) | <0.001 | 0.88 (0.83-0.92) | <0.001 | ||
Newly diagnosed stroke | 0.92 (0.85-1.01) | 0.072 | 0.96 (0.88-1.05) | 0.339 | ||
Newly diagnosed CKD | 0.91 (0.87-0.95) | <0.001 | 0.92 (0.88-0.96) | <0.001 | ||
Newly diagnosed depression | 1.07 (1.04-1.11) | <0.001 | 1.04 (1.01-1.08) | 0.010 | ||
Serious fall injury | 1.12 (1.03-1.22) | 0.008 | 1.12 (1.03-1.22) | 0.006 | ||
RR=relative risk; CI=confidence interval; ACE-inhibitor=angiotensin converting enzyme inhibitor; CHD=coronary heart disease; CKD=chronic kidney disease.
Multiclass=incident prescription fill for ≥ 2 medications within 7 days.
Insurance type definitions provided in Table S1.
Multivariable Adjusted 1—includes calendar year, age, sex, antihypertensive drug class initiated, single/multiclass/combination initiation, 90-day fill (yes/no), mail order (yes/no), copay-per-day of supply, insurance type in index month, diabetes, coronary heart disease, stroke, chronic kidney disease, heart failure, history of depression, serious fall injury, and polypharmacy, in the year prior to antihypertensive medication initiation.
Multivariable Adjusted 2—includes variables in Multivariable Adjusted 1 and variables from the six months after antihypertensive medication initiation.
To avoid co-linearity, each antihypertensive medication class was evaluated in separate regression models with beneficiaries initiating an antihypertensive medication class being compared to beneficiaries initiating treatment without that class.
Multivariable adjusted low adherence to antihypertensive medication
The risk of low adherence among patients initiating antihypertensive medication in 2014 was not different compared with their counterparts initiating treatment in 2007 (RR 1.00, 95% CI 0.98-1.02) after multivariable adjustment (Table 3). Low adherence was less common among older beneficiaries (25 to 34, 35 to 44, 45 to 54, 55 to <64 years of age compared with those <25 years of age), beneficiaries initiating treatment with an ACE-I, ARB, beta blocker, or multiclass regimen, initiating treatment with a 90-day prescription, or medications by mail order. Beneficiaries who had a history of stroke during the look-back period were less likely to have low adherence. Low adherence was more common among women and beneficiaries who initiated treatment with a thiazide diuretic, loop diuretic, “other” antihypertensive medication, or combination regimen. Diabetes, history of depression, and polypharmacy during the look-back period and higher copay-per-day of supply of antihypertensive medication were also associated with increased risk of low adherence. Low adherence was less common among beneficiaries who were newly diagnosed with CHD and more common among beneficiaries who changed insurance type, had a newly diagnosed stroke, had newly diagnosed depression, and experienced a serious fall injury in the six months following antihypertensive medication treatment initiation.
Table 3.
Unadjusted and multivariable adjusted relative risks and 95% confidence intervals for low adherence to antihypertensive medication among MarketScan beneficiaries in 2007-2014, among beneficiaries who were persistent to treatment (n=280,913)
Low adherence | ||||||
---|---|---|---|---|---|---|
Characteristic | Unadjusted RR (95% CI) |
p-value | Multivariable Adjusted 1 RR (95% CI) |
p-value | Multivariable Adjusted 2 RR (95% CI) |
p-value |
Calendar year | ||||||
2007 | 1(ref) | 1(ref) | 1(ref) | |||
2008 | 1.00 (0.98-1.02) | <0.001 | 1.02 (1.00-1.04) | 0.0168 | 1.02 (1.00-1.04) | 0.5652 |
2009 | 1.04 (1.02-1.06) | 1.05 (1.03-1.07) | 1.05 (1.03-1.07) | |||
2010 | 1.00 (0.98-1.02) | 1.03 (1.01-1.05) | 1.03 (1.01-1.05) | |||
2011 | 1.00 (0.98-1.01) | 1.03 (1.02-1.05) | 1.03 (1.02-1.05) | |||
2012 | 0.96 (0.94-0.98) | 1.00 (0.98-1.02) | 1.00 (0.98-1.02) | |||
2013 | 0.99 (0.98-1.01) | 1.03 (1.01-1.05) | 1.03 (1.01-1.05) | |||
2014 | 0.95 (0.93-0.97) | 1.00 (0.98-1.02) | 1.00 (0.98-1.02) | |||
Age, years | ||||||
<25 | 1(ref) | 1(ref) | 1(ref) | |||
25-34 | 1.01 (0.98-1.05) | <0.001 | 1.00 (0.96-1.03) | <0.001 | 0.99 (0.96-1.03) | <0.001 |
35-44 | 0.93 (0.90-0.97) | 0.92 (0.89-0.95) | 0.92 (0.89-0.95) | |||
45-54 | 0.78 (0.76-0.81) | 0.78 (0.76-0.81) | 0.78 (0.76-0.81) | |||
55-63 | 0.66 (0.64-0.68) | 0.68 (0.66-0.71) | 0.68 (0.66-0.71) | |||
Female versus male sex | 1.08 (1.07-1.08) | <0.001 | 1.08 (1.07-1.08) | <0.001 | 1.07 (1.06-1.08) | <0.001 |
Antihypertensive drug class initiated | ||||||
Thiazide-type diuretic | 1.07 (1.06-1.08) | <0.001 | 1.05 (1.03-1.06) | <0.001 | 1.05 (1.03-1.06) | <0.001 |
Calcium channel blocker | 0.98 (0.97-0.99) | 0.003 | 0.99 (0.98-1.00) | 0.109 | 0.99 (0.98-1.00) | 0.104 |
ACE-inhibitor | 0.95 (0.94-0.96) | <0.001 | 0.97 (0.96-0.98) | <0.001 | 0.97 (0.96-0.98) | <0.001 |
Angiotensin receptor blocker | 1.03 (1.02-1.04) | <0.001 | 0.99 (0.98-1.00) | 0.016 | 0.99 (0.97-1.00) | 0.011 |
Loop diuretic | 1.23 (1.20-1.26) | <0.001 | 1.30 (1.27-1.33) | <0.001 | 1.30 (1.27-1.34) | <0.001 |
Beta blocker | 0.92 (0.90-0.93) | <0.001 | 0.95 (0.94-0.96) | <0.001 | 0.95 (0.94-0.96) | <0.001 |
Other | 1.06 (1.04-1.08) | <0.001 | 1.04 (1.02-1.06) | <0.001 | 1.04 (1.02-1.06) | <0.001 |
Treatment regimen | ||||||
Single Class | 1(ref) | 1(ref) | 1(ref) | |||
Multiclass | 0.84 (0.83-0.86) | <0.001 | 0.87 (0.86-0.89) | <0.001 | 0.88 (0.86-0.89) | <0.001 |
Combination | 1.07 (1.06-1.08) | <0.001 | 1.07 (1.06-1.08) | <0.001 | 1.07 (1.06-1.08) | <0.001 |
Initiated with a 90-day fill | 0.64 (0.64-0.65) | <0.001 | 0.70 (0.69-0.71) | <0.001 | 0.70 (0.69-0.71) | <0.001 |
Mail order | 0.65 (0.64-0.66) | <0.001 | 0.90 (0.88-0.92) | <0.001 | 0.90 (0.88-0.92) | <0.001 |
Copay-per-day of supply | ||||||
Quartile 1 (<$0.06) | 1(ref) | 1(ref) | 1(ref) | |||
Quartile 2 (≥$0.06 to <$0.19) | 1.05 (1.04-1.07) | <0.001 | 1.04 (1.03-1.06) | <0.001 | 1.04 (1.03-1.06) | <0.001 |
Quartile 3 (≥$0.19 to <$0.46) | 1.05 (1.04-1.07) | <0.001 | 1.02 (1.01-1.04) | <0.001 | 1.02 (1.01-1.04) | <0.001 |
Quartile 4 (≥$0.46) | 1.12 (1.10-1.13) | <0.001 | 1.06 (1.05-1.07) | <0.001 | 1.06 (1.05-1.07) | <0.001 |
Insurance in index month | ||||||
Managed Care | 1(ref) | 1(ref) | 1(ref) | |||
Fee for service | 0.86 (0.84-0.88) | <0.001 | 0.99 (0.96-1.02) | 0.425 | 0.99 (0.96-1.02) | 0.452 |
High deductible | 0.96 (0.94-0.98) | <0.001 | 0.98 (0.97-1.00) | 0.072 | 0.98 (0.97-1.00) | 0.057 |
Unknown | 0.90 (0.88-0.92) | <0.001 | 0.93 (0.91-0.95) | <0.001 | 0.93 (0.91-0.95) | <0.001 |
Year before initiation | ||||||
Diabetes | 1.07 (1.06-1.08) | <0.001 | 1.13 (1.12-1.15) | <0.001 | 1.13 (1.12-1.15) | <0.001 |
CHD | 0.91 (0.89-0.93) | <0.001 | 0.99 (0.97-1.01) | 0.356 | 0.99 (0.96-1.01) | 0.204 |
Stroke | 0.89 (0.86-0.93) | <0.001 | 0.93 (0.89-0.97) | 0.001 | 0.93 (0.90-0.97) | 0.002 |
CKD | 0.98 (0.96-1.00) | 0.076 | 1.00 (0.98-1.02) | 0.984 | 1.00 (0.98-1.02) | 0.947 |
Heart failure | 0.94 (0.90-0.98) | 0.007 | 0.99 (0.95-1.04) | 0.701 | 0.99 (0.95-1.04) | 0.811 |
History of depression | 1.06 (1.04-1.07) | <0.001 | 1.03 (1.02-1.05) | <0.001 | 1.04 (1.02-1.05) | <0.001 |
Serious fall injury | 1.00 (0.95-1.05) | 0.990 | 1.02 (0.98-1.07) | 0.332 | 1.02 (0.98-1.07) | 0.335 |
Polypharmacy | 1.06 (1.05-1.07) | <0.001 | 1.03 (1.02-1.04) | <0.001 | 1.03 (1.02-1.04) | <0.001 |
Six months after initiation | ||||||
Insurance type changed | 1.06 (1.03-1.08) | <0.001 | 1.05 (1.02-1.07) | <0.001 | ||
Newly diagnosed diabetes | 0.95 (0.93-0.98) | <0.001 | 0.98 (0.95-1.01) | 0.168 | ||
Newly diagnosed CHD | 0.85 (0.82-0.89) | <0.001 | 0.89 (0.85-0.92) | <0.001 | ||
Newly diagnosed stroke | 1.04 (0.97-1.11) | 0.254 | 1.07 (1.01-1.14) | 0.027 | ||
Newly diagnosed CKD | 0.99 (0.95-1.02) | 0.462 | 0.99 (0.96-1.03) | 0.613 | ||
Newly diagnosed depression | 1.07 (1.05-1.10) | <0.001 | 1.05 (1.02-1.07) | <0.001 | ||
Serious fall injury | 1.06 (0.99-1.14) | 0.112 | 1.09 (1.02-1.17) | 0.015 |
RR=relative risk; CI=confidence interval; ACE-inhibitor=angiotensin converting enzyme inhibitor; CHD=coronary heart disease; CKD=chronic kidney disease.
Multiclass=incident prescription fill for ≥ 2 medications within 7 days.
Insurance type definitions provided in Table S1.
Multivariable Adjusted 1—includes calendar year, age, sex, antihypertensive drug class initiated, single/multiclass/combination initiation, 90-day fill (yes/no), mail order (yes/no), copay-per-day of supply, insurance type in index month, diabetes, coronary heart disease, stroke, chronic kidney disease, heart failure, history of depression, serious fall injury, and polypharmacy, in the year prior to antihypertensive medication initiation.
Multivariable Adjusted 2—includes variables in Multivariable Adjusted 1 and variables from the six months after antihypertensive medication initiation.
To avoid co-linearity, each antihypertensive medication class was evaluated in separate regression models with beneficiaries initiating an antihypertensive medication class being compared to beneficiaries initiating treatment without that class.
Sensitivity analysis
After multivariable adjustment, antihypertensive medication nonpersistence was less common in 2014 compared with 2007 in each of the sensitivity analyses (Table S4) The multivariable-adjusted RR of low adherence in 2014 compared with 2007 was 0.97 (95% CI 0.96-0.99) when hypertension was defined as having ≥ 1 diagnosis during the look-back period (Table S5). There was no evidence for a difference in low adherence between 2007 and 2014 after multivariable adjustment in any of the other sensitivity analyses.
Secondary analyses
The mean PDC increased from 2007 to 2014 from 0.65 to 0.66 (Table S6). The multivariable adjusted RR of either nonpersistence or low adherence to antihypertensive medication, pooled together, in 2014 compared with 2007 was 0.97 (95% CI 0.96-0.99) (Table S7). Among beneficiaries initiating antihypertensive medication with ≥ 2 classes, 43.8%, 17.2%, and 39.0% had low, partial, and full adherence, respectively, in 2007 compared with 40.7%, 20.8% and 38.6% with low, partial, and full adherence, respectively, in 2014 (Table S8).
Discussion
Among US adults < 65 years of age, antihypertensive medication nonpersistence in the year following treatment initiation was slightly less common in 2014 compared with 2007 after multivariable adjustment. The risk for low adherence remained unchanged over this time after multivariable adjustment period. Both nonpersistence and low adherence were less common among older beneficiaries and those initiating treatment with an ACE-I, ARB, multiclass regimens, filling 90-day prescriptions or medications by mail order, and more common among women, those who initiated treatment with a thiazide or loop diuretic, had diabetes or history of depression, or were taking ≥ 10 classes of medication (i.e., polypharmacy) prior to initiating antihypertensive medication.
Nonpersistence and low adherence result from both intentional (i.e., not taking medication because of fear of side effects) and unintentional (i.e., forgetfulness) reasons.18,19 While both of these aspects may be difficult to address, a prior systematic review and meta-analysis reported that multicomponent interventions focused on motivational interviewing and medication taking prompts can improve medication adherence.20 While BP control has improved over time in the US, this change has occurred concurrently with an increase in the use of antihypertensive medication from 1999-2000 to 2011-2012.21 Addressing the high risk of nonpersistence and low adherence, as reported in the current study, represents an opportunity to further improve BP control in the US population.
The proportion of beneficiaries in the current study of adults < 65 years of age who had nonpersistence or low adherence to antihypertensive medication in 2014 was 54.2%. This is higher than the proportion of Medicare beneficiaries ≥ 65 years of age in a prior study who had nonpersistence or low adherence (46.2%).10 Prior studies have also reported higher rates of nonadherence among younger adults and the authors of those studies hypothesized this may be due to a reluctance to accept the diagnosis of a lifelong chronic disease and difficulty maintaining a medication regimen due to work and other competing demands.22,23 Although improving adherence for all age groups is necessary, directing interventions towards younger adults may be particularly beneficial given the high prevalence of nonadherence and potential benefits of reducing their cumulative exposure to high BP levels on lifetime CVD risk.11,24 Additionally, the 2017 ACC/AHA guideline on the prevention, detection, evaluation and management of high BP in adults lowered the threshold for diagnosis of hypertension to systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.25 This change has been estimated to recommend pharmacological antihypertensive medication for an additional 1.9 million US adults < 65 years of age.26
Initiating treatment with an ACE-I, ARB, or receiving 90-day fills or medications by mail order were associated with a lower risk of antihypertensive medication nonpersistence and low adherence. A previous meta-analysis reported that ARBs and ACE-Is were associated with the highest rates of adherence compared with other antihypertensive medication classes,15 potentially due to lower rates of side effects.27 Although rates of nonadherence in the current study were lower for ARBs compared with other antihypertensive drug classes, ARB use declined over the study time frame. Future studies should examine the underlying reasons for this decline as a prior meta-analysis of randomized trials reported that ARBs were associated with a 50% lower participant withdrawal rate due to adverse events compared with ACE-I.28 Increasing the use of 90-day prescriptions and mail-order service may improve adherence rates by lowering barriers to maintaining supplies of medications.29,30
Antihypertensive medication nonpersistence and low treatment adherence were more common among women than men in contrast to previous findings among adults ≥ 65 years of age.10 However, many women in the current study were of child bearing age, and caring for dependents has been reported to be associated with nonadherence.31 Risk of nonpersistence and low adherence was also higher among those who initiated treatment with a thiazide or loop diuretic, or had diabetes, history of depression or polypharmacy in the 365 days prior to initiation of antihypertensive medication. Loop diuretics are often taken twice daily, and higher pill-taking frequency has previously been associated with lower rates of adherence.32,33 For individuals with diabetes, more intensive control of BP was recommended during the time frame of the current study.34 This may have required higher doses or antihypertensive medication pill burden and increased side effects.35 Depression has been consistently identified as a predictor of nonadherence.36 Screening and treatment for depression among adults taking antihypertensive medication should be considered to improve rates of adherence. The association of polypharmacy in the year prior to initiation with increased risk for nonadherence has been reported in some, but not all, prior studies.22
Beneficiaries with higher copay-per-day of supply for their antihypertensive medication were less likely to have nonpersistence although previous studies have identified higher copays as a barrier to adherence.37 In most cases, more expensive antihypertensive medication classes have fewer side effects, and the benefit of fewer side effects may outweigh the risk of nonpersistence due to cost.38 Higher copay-per-day of supply was associated with increased risk for low adherence similar to prior studies.37 Although copay-per-day of supply was less than $0.46 for three fourths of beneficiaries, reductions in copayments may still result in improvements in both nonpersistence and low adherence.37,39
The risk for nonpersistence and low adherence was lower among beneficiaries who were newly diagnosed with CHD in the six months following initiation. Higher levels of adherence following CHD have been previously reported.40 The risk of nonpersistence and low adherence was higher among those who experienced a serious fall injury following initiation of antihypertensive medication, similar to some, but not all, previous studies.41 Side effects such as dizziness, that may cause concern about additional falls and contribute to increased nonadherence, may be avoided by using combinations of lower dose antihypertensive medications versus a single, higher dose medication.41–43 Low adherence was also more common among beneficiaries who changed insurance type. Insurance type changes may result in the need to find a new primary care physician and delay chronic disease care.44
Strengths of the current study included a large sample size that allowed investigation of antihypertensive medication nonpersistence and low adherence, overall and among subgroups of US adults, and eight years of data to assess trends over time. However, there were several limitations to the current study. Potentially important confounders including obesity and BP levels were not available. We were only able to determine that beneficiaries filled prescriptions for antihypertensive medication. Confirmation that beneficiaries took the medication was not possible as biochemical analysis of blood and urine was not performed. Finally, the results may not be generalizable to US adults without commercial insurance.
Perspectives
In the current study, adherence to antihypertensive medication did not substantially improve over time among commercially-insured adults < 65 years of age initiating treatment, and more than half of beneficiaries either had nonpersistence to treatment or low adherence in 2014. Also, many previously identified demographic and clinical correlates of nonadherence including younger age, female sex, diabetes, and polypharmacy remained associated with nonadherence in the current study of a contemporary cohort. The current analyses suggest some possible approaches to improving adherence. Specifically, health systems should consider promoting the use of antihypertensive medications associated with a low rate of nonpersistence or low adherence (e.g., ACE-I or ARB). In addition, given their association with lower rates of nonpersistence and low adherence, 90-day and mail order prescriptions should be promoted, and randomized controlled trials should be conducted to determine the impact of these scalable interventions on antihypertensive medication adherence.
Supplementary Material
Novelty and Significance.
What is New
Rates of nonpersistence to antihypertensive medication among adults <65 years of age decreased modestly from 2007 to 2014, but low adherence did not decrease.
Over 50% of adults <65 either had nonpersistence or low adherence in 2014.
What is Relevant
Nonpersistence and low adherence to antihypertensive medication is associated with increased cardiovascular disease risk.
We identified demographic, clinical, and health services related factors associated with nonpersistence and low adherence among adults <65, some of which are modifiable.
Summary
Rates of adherence to antihypertensive medication among adults <65 are suboptimal and have not improved substantially over time. Research and interventions to improve adherence among this population is needed.
Acknowledgements
Sources of Funding
Gabriel S. Tajeu: NIH/NHLBI 5T32 HL00745733; NIH/NIDDK 3R01DK108628-05S1
Ian Kronish: R01-HL123368; R01 HS024262
Marie Krousel-Wood: 5K12HD043451-14; 1 U54 GM104940; UL1TR001417, 1 R01 HL130500-01A1; R01 HL133790; 1 R21 LM012448-2; 1P20GM109036-01A1
Daichi Shimbo: NHLBI K24-HL125704
Adam Bress: NHLBI 1K01HL133468-01
Matthew Mefford: AHRQ 5T32 HS013852-15
Disclosures
Daichi Shimbo is a consultant for Abbott Vascular and Novartis Pharmaceuticals Corporation.
Paul Muntner receives grant support from Amgen Inc. unrelated to the current manuscript.
Adam Bress receives grant support to his institution from Novartis, Amgen, and Amarin Corporation unrelated to the current manuscript.
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