Trends and Treatment Patterns Among US Adults with Resistant Hypertension

Abstract

Background:

Resistant hypertension is associated with adverse cardiovascular outcomes and mortality. In the past decade, management guidelines have shifted to target lower blood pressures (BP). Current prevalence and prescribing patterns among adults with resistant hypertension are not well characterized.

Methods:

We used data from the National Health and Nutrition Examination Survey (NHANES) from 2003–2020. Apparent treatment resistant hypertension (aTRH) was defined as patients on a diuretic, either with a systolic blood pressure (BP) ≥130 or diastolic BP ≥80 mmHg while on 3 medications or those on ≥ 4 medications regardless of BP. Medications were identified through pill bottle review.

Results:

Of 24,579 adults with HTN, 1,939 had aTRH (42.4% male, 19.9% Black), corresponding to a weighted total of 6,989,821 US patients. Among hypertensive adults, the prevalence of aTRH was 6.41% (95% CI 5.97-6.88%) and remained stable over time. Over the study duration, aTRH prevalence among adults on treatment decreased from 17.7% to 12.6%. The overall prevalence of hypertension rose from 50.1% to 54.0%, while the prevalence of uncontrolled BP decreased from 75.0% to 68.7%. Over time, use of 3 drug regimens for aTRH decreased (57.8% to 42.9%), while 4 drug regimens increased (34.0% to 51.8%). aTRH was most strongly associated with older patients, those of Black race, higher BMI, and more advanced cardiovascular comorbidities.

Conclusion:

The prevalence of aTRH has remained stable over the past two decades despite the rising incidence of HTN. Use of multidrug treatment regimens has increased, aligning with national guidelines. However, uncontrolled HTN remains high.

Graphical Abstract

INTRODUCTION

Hypertension is one of the most important modifiable factors to reduce the risk of cardiovascular disease and associated mortality.¹ Nearly half of adults in the United States (US) have hypertension and of these, nearly three-quarters remain uncontrolled.^2,3 Among patients diagnosed with hypertension, a substantial proportion develop treatment resistant hypertension,^4–6 a condition characterized by uncontrolled blood pressure (BP) despite maximally tolerated doses of three antihypertensive medications (including a diuretic) or four antihypertensive medications (including a diuretic) regardless of BP control.^4,7 Importantly, it has been demonstrated that patients with resistant hypertension are at a higher risk of end-organ damage and have a nearly 50% greater risk for cardiovascular events and mortality as compared to those with non-resistant disease.^8,9 When medication dosing or adherence is unknown, the term apparent treatment resistant hypertension (aTRH) is often used in place of resistant hypertension.

The publication of the Systolic Blood Pressure Intervention Trial (SPRINT) introduced a paradigm shift of targeting lower BP thresholds among those with elevated cardiovascular risk and hypertension, and the results are often generalized to the broader hypertensive population.¹⁰ In 2017, the American College of Cardiology (ACC)/American Heart Association (AHA) published an update to the clinical practices guidelines for the detection and management of hypertension, and in 2018 the AHA published an updated scientific statement on resistant hypertension which lowered the BP threshold necessary for diagnosis.^11,12 The guidelines also emphasized the use of combination medical therapy and optimally dosed diuretics to improve BP control within the resistant population. The impact of these recent changes on those with resistant hypertension and antihypertensive medication prescribing trends remains unclear.

In this study, we utilize data from the National Health and Nutrition Examination Survey (NHANES) to characterize trends in the prevalence and treatment of aTRH, as well as anti-hypertensive prescribing patterns in the US over the past two decades.

METHODS

Data Source

NHANES is a cross-sectional survey of the US population collected by the National Center for Health Statistics (NCHS) at the Center for Disease Control and Prevention (CDC). As described previously, participants are surveyed in two-year cycles and a stratified, multistage, probability sampling method is used to generate a nationally representative estimate of the noninstitutionalized US population.⁶ Data from NHANES are collected utilizing a combination of in-person interviews and examinations performed by trained staff. All data and materials for this analysis are publicly available through the NCHS website and can be accessed at https://wwwn.cdc.gov/nchs/nhanes/default.aspx.

For the current analysis, data from eight survey cycles spanning the years 2003–2020 were merged to generate the primary cohort. The appropriate survey weighting was applied to each individual cycle prior to aggregation. Due to limitations in data collection during the COVID-19 pandemic, data collected between 2019–2020 was combined with the previous cycle (2017–2018) to ensure a nationally representative cohort was formed during those years. For each survey year, baseline demographic data, comorbidities, medication information, and examination information including BP data and relevant laboratory studies were extracted for analysis. All participants provided written informed consent approved by the NCHS Institutional/Ethics Review Board.¹³

Participant Characteristics

Demographics and baseline comorbidities were ascertained via trained staff utilizing a standardized questionnaire. Age, sex, and race were self-reported. Race was stratified into three groups: non-Hispanic White, non-Hispanic Black, and Other (a composite variable which included Mexican American, Other Hispanic, Non-Hispanic Asian and other races including multi-racial). Comorbidities, including angina, asthma, cancer, congestive heart failure (CHF), coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), diabetes, hyperlipidemia, liver disease, myocardial infarction, smoking history and stroke, were collected by self-report on the standardized NHANES questionnaires.

Physical exam and laboratory data were collected in a mobile examination center to allow for standardized conditions in a controlled environment. Glomerular filtration rate was estimated via the 2021 race-free CKD-EPI equation using serum creatinine, age and sex extracted from the NHANES data set. Body mass index (BMI) was calculated based on height and weight measurements obtained during the physical exam portion of the NHANES questionnaire.

BP Measurement and Antihypertensive Medication Utilization

BP measurements were obtained during a single examination visit for each participant by a trained professional. From 2003 to 2004 through the 2017 to 2018 cohorts, BP was measured using a mercury sphygmomanometer (Baum true gravity mercury wall model) with standard Baum cuffs.¹⁴ For the 2017 to 2020 cohort, BP was measured using a validated oscillometric device (Omron 907 XL).¹⁵ Prior analysis has identified a slight discrepancy in blood pressure measurements when comparing results from mercury sphygmomanometer and oscillometric devices.¹⁶ These differences were not found to translate into a statistically significant difference in the prevalence of hypertension, so we did not apply an adjustment to the relevant cohort. Within the NHANES examination files, a maximum of four systolic and diastolic BP measurements were recorded per visit. The mean of all available measurements was calculated and contributed to the classification of hypertension status. Participants <18 years of age, without at least 2 BP readings or not meeting one of the 3 conditions for hypertension, as outlined below, were excluded from the analysis.

Antihypertensive medications were identified via pill bottle review by survey staff. These were extracted from the NHANES data set using Multum Lexicon codes and subsequently organized into medication classes (Table S1). These codes were used to identify medication therapeutic class and cross-referenced to each participant’s complete medication list to compute the number of antihypertensive medications prescribed at the time of survey collection. For those on fixed dose combination medications, each constituent medication was counted individually. For example a two drug combination pill would be counted as two separate medications. As data within NHANES is limited in its ability to assess medication dosing or adherence, which are important factors for differentiating pseudo-resistant hypertension from resistant hypertension, the term apparent treatment resistant hypertension (aTRH) will be used in place of resistant hypertension.

Primary Outcome and Exposure

Hypertension was defined broadly and included all patients with treated and untreated hypertension. This was defined as one of the following: (1) a positive response to the question, “Have you ever been told you have high blood pressure?”, (2) if the participant was on an antihypertensive medication (as defined in Table S1) or (3) if the participant had uncontrolled BP. In the primary analysis uncontrolled BP was defined using the ACC/AHA 2017 hypertension guidelines of systolic BP ≥130 mm Hg or diastolic BP ≥ 80 mm Hg for the full study duration 2003–2020. We performed several sensitivity analyses modifying both the definition of hypertension and the threshold utilized to define uncontrolled hypertension. Namely, we applied the older Joint National Committee (JNC) 7 guidelines which defined uncontrolled hypertension as systolic BP ≥140 mm Hg or diastolic ≥ 90 mm Hg. Given the release of the 2017 ACC/AHA hypertension guidelines part way through the study period, this additional analysis was conducted to provide consistency over time and to assess how the retrospective application of this definition to pre-2017 subjects would effect outcomes.

The primary outcome was the prevalence of aTRH among US adults with hypertension. We defined aTRH more narrowly as patients with a systolic blood pressure (BP) ≥130 or diastolic BP ≥80 mmHg while on 3 medications (including a diuretic) or those on ≥ 4 medications (including a diuretic) regardless of BP. Prevalence was assessed for each NHANES survey cycle from 2003–2020 to assess for trends over time. Secondary outcomes included the prevalence of medication and combination therapy utilization among adults with aTRH, predictors of aTRH, and prevalence of uncontrolled hypertension overall.

Statistical analysis

All analyses were conducted utilizing the NHANES multistage probability survey design with the associated participant weights, strata, and primary sampling unit variables to obtain national estimates. A nationally representative cohort which approximated the entire US population with hypertension was generated. The total number of adults with hypertension and aTRH were reported before and after weighting. Baseline characteristics, including participant demographics, comorbidities, and medication information, were characterized by aTRH.

We evaluated factors associated with aTRH, using survey-weighted multivariable logistic regression models with adjustment for participant demographics (including age, sex, race, and BMI) and comorbidities (including CHF, CAD, angina, myocardial infarction, stroke, hyperlipidemia, diabetes mellitus, and CKD).

Continuous variables were presented as means (standard deviation [SD]) and categorical variables as percentages. Prevalence was reported as a percentage for relevant outcomes. A 95% confidence interval (CI) was generated utilizing logistic regression models to calculate a Wald-type interval for each outcome. As overall rates of missing data were low, complete case analysis was performed to address missing data within each statistical model. Two-sided P-values were calculated, with P <0.05 considered significant. Analyses were performed utilizing STATA (v18.0, Statacorp) and R (v4.3.2, R Foundation for Statistical Computing). Figures were created with Python (v3.10, Python Software Foundation).

RESULTS

Study Population and Participant Characteristics

In total, 86,618 participants were identified in NHANES spanning the years 2003–2020. Of these, 24,579 adults with hypertension were identified and included within the primary analytical cohort (Figure S1). After applying survey weights, the final cohort represented a total 108,982,485 adults with hypertension (50.8%, 95% CI, 49.9–51.8%), including 6,989,821 with aTRH (6.41%, 95% CI, 5.98-6.88% of the hypertension population) (Figure S2).

Table 1 depicts the baseline characteristics, stratified by aTRH status. Among all adults with hypertension, the mean age was 54.5 years, 52.1% were male, and 70.0% were of White race. As compared to participants with non-resistant hypertension, those with aTRH were older (mean age 65.8 years vs 53.7 years), had higher rates of obesity (58.8% vs 45.2%), had more advanced renal dysfunction, and higher rates of cardiopulmonary comorbidities. Cardiovascular disease and risk factors were more common among participants with aTRH, including 17.2% with comorbid CHF, 17.5% with CAD, 15.4% with a prior myocardial infarction, 12.6% with a prior stroke, 64.4% with hyperlipidemia, and 39.0% with diabetes mellitus (Table 1).

Table 1:

Baseline patient characteristics, stratified by aTRH status.

Characteristic	Overall	Non-aTRH Hypertension	aTRH Hypertension
Number of Patients	24,579	22,640	1,939
Weighted Number of Patients	108,982,485	101,992,664	6,989,821
Age (mean (SD))	54.49 (16.04)	53.71 (15.98)	65.84 (12.10)
Male Sex (%)	52.09	52.75	42.39
Race (%)
White	69.98	70.07	68.69
Black	12.73	12.24	19.87
Other	17.29	17.69	11.43
Body Mass Index (%)
<18.5	0.93	0.99	0.12
18.5–25	20.1	20.67	11.69
25–30	32.9	33.14	29.31
>30	46.07	45.2	58.88
Comorbidities (%)
Asthma	15.01	15.04	14.59
Arthritis	36.27	34.85	56.85
Congestive Heart Failure	4.3	3.42	17.19
Coronary Artery Disease	6.25	5.48	17.52
Angina	3.98	3.48	11.28
Myocardial Infarction	6	5.35	15.41
Stroke	4.89	4.36	12.6
COPD	9.26	8.91	14.24
Liver Disease	4.89	4.81	6.18
Hyperlipidemia	47.96	46.74	64.43
Smoking History	39.09	40.15	23.84
Cancer	13.72	13.23	20.67
Diabetes	16	14.46	39.02
Renal Function
eGFR > 90	52.65	54.66	23.23
eGFR 60–89	37.37	36.85	45.01
eGFR 30–60	9.04	7.78	27.52
eGFR < 30	0.94	0.72	4.24

Abbreviations: aTRH, apparent treatment resistant hypertension; SD, standard deviation; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate.

Temporal Trends in Hypertension, aTRH, and BP Control

Over the study duration of 2003–2020, the prevalence of hypertension increased from 50.1% (95% CI, 46.8-53.3%) in 2003–2004 to 54.0% (95% CI 51.2-56.7%) of the total US population in 2017–2020 (Figure 1A). In sensitivity analyses of alternative hypertension definitions, estimates of overall hypertension prevalence ranged from 21.4% to 50.8%. Among those identified with hypertension, a total of 6,989,821 had aTRH, corresponding to an overall prevalence of 6.41% (95% CI 5.98-6.88%). Over the study period, aTRH prevalence remained constant ranging from 6.43% (95% CI, 5.06-8.15%) between 2003–2004 and 5.77% (95% CI, 4.75-6.99%) between 2017–2020 (Figure 1B). The estimate of overall aTRH prevalence ranged from 6.41% to 14.6% across varying sensitivity analyses when the definition of hypertension was modified by different criteria (Table S2). Among patients on antihypertensive therapy, the prevalence of aTRH decreased from approximately 17.7% (95% CI, 14.1-22.1%) between 2003–2004 to 12.6% (95% CI, 10.4-15.2%) between 2017–2020 (Figure 1C). Among those with aTRH and CHF, 30.9% (95% CI, 24.5–38.2%) had controlled BP. Over the study duration, rates of uncontrolled BP decreased from 75.0% (95% CI, 72.4-77.4%) in 2003–2004 to 68.7% (95% CI, 66.9-70.5%) in 2017–2020 (Figure 1D) (Table S3).

Figure 1:

National temporal trends in hypertension, aTRH, and uncontrolled blood pressure. (A) Prevalence of hypertension among all U.S. adults, (B) prevalence of aTRH among patients with hypertension, (C) prevalence of aTRH among patients with hypertension on antihypertensive medications and (D) prevalence of patients with uncontrolled blood pressure among patients with hypertension.

Medication Utilization Among Participants with aTRH

Table 2 demonstrates the current medication regimens utilized among US hypertensive adults at the time of data collection. The mean (SD) systolic BP among all adults with hypertension was 131.5 (17.7) mm Hg, compared to 139.4 (19.8) mm Hg among adults with aTRH. Among non-aTRH adults, 68.7% had uncontrolled BP, compared with 79.7% among adults with aTRH.

Table 2:

Hypertension status and current medication regimen, stratified by aTRH status

Characteristics	Overall	Non-aTRH Hypertension	aTRH Hypertension	P-Value
Systolic BP (mean (SD))	131.52 (17.72)	131.01 (17.45)	139.02 (19.83)	<0.001
Diastolic BP (mean (SD))	74.56 (13.67)	74.91 (13.46)	69.49 (15.59)	<0.001
Systolic BP (median (IQR))	130.3 (120–140.7)	130 (119.3–140)	137.3 (128–150)	<0.001
Diastolic BP (median (IQR))	76 (66.7–83.3)	76.7 (67.3–83.3)	70 (60–80)	<0.001
Uncontrolled BP1 (%)	69.41	68.7	79.69	<0.001
Anti-Hypertensive Medication Count (%)
0	48.86	52.2	0
1	23.08	24.66	0
2	17.01	18.17	0
3	7.75	4.75	51.47
4	2.74	0.18	40.05
5	0.44	0.02	6.59
6+	0.12	0	1.9
Medication Class (%)
MRA	1.44	0.97	8.26	<0.001
Beta Blockers	20.18	16.81	69.36	<0.001
ACE Inhibitor/ ARB	32.99	29.47	84.31	<0.001
Calcium Channel Blocker	12.99	10.08	55.42	<0.001
Loop Diuretic	5.03	3.16	32.31	<0.001
Thiazide Diuretic	16.28	12.45	72.13	<0.001
ENaC Inhibitor	2.21	1.34	15.0	<0.001
Minoxidil	0.06	0.04	0.38	<0.001
Clonidine	1.23	0.81	7.36	<0.001
Combination Therapy (%)
ACE-Inhibitor/ARB + CCB + Diuretic2	1.42	0.58	13.56	<0.001
ACE-Inhibitor/ARB + CCB + Diuretic2 + MRA	0.05	0	0.76	<0.001
ACE-Inhibitor/ARB + CCB + Diuretic2 + MRA + BB	0.02	0	0.31	<0.001
ACE-Inhibitor/ARB + CCB + Diuretic2 + BB	1.13	0	17.54	<0.001

Abbreviations: aTRH, apparent treatment resistant hypertension; SD, standard deviation; BP, blood pressure; MRA, mineralocorticoid receptor antagonist; ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; BB, beta blocker; ENaC, epithelial sodium channel.

¹Uncontrolled BP defined as either systolic BP ≥ 130 or diastolic BP ≥ 80.

²Diuretic consists of either a thiazide diuretic or loop diuretic.

In both adults with resistant and non-resistant hypertension, the most frequently prescribed antihypertensive medications were angiotensin-converting enzyme (ACE) inhibitors/ angiotensin receptor blockers (ARB) (33.0%), beta blockers (20.2%), and thiazide diuretics (16.3%). Among those with aTRH, 84.3% were on ACE inhibitors/ARBs, 72.1% on thiazide diuretics, 55.4% on calcium channel blockers, 32.3% on a loop diuretic and 8.3% on mineralocorticoid receptor antagonists (MRA). Moreover, in the aTRH population, clonidine and minoxidil were utilized in 7.36% and 0.38% of adults, respectively (Table 2). Over the study duration, utilization of both ACE inhibitors/ARBs and beta blockers increased among the general hypertensive population (ACE/ARB: 25.5% to 35.3%; beta blocker: 17.2-22.3%) and the aTRH populations (ACE/ARB: 79.0% to 89.2%; beta blocker: 62.9% to 74.8%) (Figure 2A). Among adults with aTRH, utilization of MRAs increased over time from 6.3% in 2003–2004 to 13.3% in 2017–2020. Rates of other medication utilization, including calcium channel blockers, loop diuretics, and thiazide diuretics, remained relatively stable (Figure 2B).

Figure 2:

National temporal trends in antihypertensive medication utilization. Medication class utilization among (A) all patients with hypertension and (B) patients with aTRH.

Among all US adults with hypertension, 48.9% were not on any antihypertensive medications, while 23.1% were on just one. Among those with aTRH, 51.5% were on three antihypertensive medications, 40.1% on four, and 8.49% were on five or more (Table 2). Among the general hypertensive population, the percentage of those on a single agent increased from 18.6% (95% CI, 17.1-20.3%) between 2003–2004 to 26.6% (95% CI, 24.6-28.8%) between 2017–2020, while the percentage of those on combination therapy remained stable over time (Figure S2A). Conversely, over the study duration, the utilization of three drug regimens for aTRH decreased from 57.8% (95% CI, 46.8-68.0%) in 2003–2004 to 42.9% (95% CI, 35.0-51.2%) in 2017–2020, while the utilization of four drug regimens increased from 34.0% (95% CI, 23.9-45.8%) to 51.8% (95% CI, 43.4-60.1%) over the same period (Figure S2B).

Patient Characteristics Associated with aTRH

In adjusted analyses, aTRH was most strongly associated with older age (adjusted OR 1.04; 95% CI, 1.03–1.05), Black race (versus White race) (adjusted OR 1.90; 95% CI, 1.61–2.25), higher BMI (BMI>30 vs BMI<18.5; adjusted OR 11.4; 95% CI, 4.29–30.4), comorbid CHF (adjusted OR 2.26; 95% CI, 1.84–2.78), diabetes mellitus (adjusted OR 1.88; 95% CI, 1.61–2.18), and advanced renal failure (eGFR < 30 vs eGFR > 90; adjusted OR 3.95; 95% CI, 2.72–5.73) (Table 3).

Table 3:

Characteristics associated with aTRH among patients with hypertension

Characteristic	Odds Ratio (95% CI)	P-Value
Age (per year)	1.04 (1.03–1.05)	<0.001
Male Sex vs Female Sex	0.84 (0.72–0.99)	0.033
Black Race vs White Race	1.90 (1.61–2.25)	<0.001
Other Race vs White Race	0.96 (0.77–1.19)	0.708
BMI 18.2–25 vs BMI <18.5	4.88 (1.87–12.8)	0.001
BMI 25–30 vs BMI <18.5	7.81 (2.90–21.1)	<0.001
BMI >30 vs BMI <18.5	11.4 (4.29–30.4)	<0.001
CHF	2.26 (1.84–2.78)	<0.001
CAD	1.26 (0.95–1.68)	0.111
Angina	1.38 (1.04–1.84)	0.03
Myocardial Infarction	1.05 (0.81–1.37)	0.708
Stroke	1.39 (1.12–1.73)	0.003
Hyperlipidemia	1.27 (1.06–1.52)	0.01
Diabetes Mellitus	1.88 (1.61–2.18)	<0.001
eGFR 60–89 vs eGFR > 90	1.59 (1.26–2.01)	<0.001
eGFR 30–59 vs eGFR > 90	2.65 (2.06–3.41)	<0.001
eGFR < 30 vs eGFR > 90	3.95 (2.72–5.73)	<0.001

Survey-weighted multivariable logistic regression model was adjusted for participant demographics (including age, sex, race, and BMI) and comorbidities (including CHF, CAD, angina, myocardial infarction, stroke, hyperlipidemia, diabetes mellitus, and eGFR status).

Abbreviations: aTRH, apparent treatment resistant hypertension; BMI, body mass index; CHF, congestive heart failure, CAD, coronary artery disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.

DISCUSSION

In this nationally representative cross-sectional study, we examined the prevalence and treatment trends among adults with aTRH in the US. We found that the prevalence of hypertension increased over time, while the number of adults with uncontrolled hypertension declined. Nonetheless, the rate of aTRH in the general hypertensive population remained stable. Among patients with aTRH, there was an overall trend towards increased utilization of antihypertensive combination therapy, including increased use of 4 drug regimens and decreased use of 3 drug regimens. We did not observe significant changes in the utilization of individual classes of medications and the use of adjuvant therapies, such as minoxidil and clonidine, remained low. While further efforts are needed to prevent uncontrolled hypertension and aTRH, our findings suggest improvements in BP control and medication therapy intensification, aligning with national guidelines.

In our contemporary data set we found a relative plateau in the prevalence of hypertension in the early 2000s, followed by a gradual increase in prevalence from 49.0% in 2010–2011 to 53.0% in 2017–2020, aligning with prior work.^2,17 Over this period there have been significant changes to the hypertension management guidelines. Following publication of SPRINT in 2015, which found that targeting a lower systolic BP of 120 mmHg reduced the rate of cardiovascular events and mortality compared with a traditional BP goal of 140 mmHg.¹⁰ In 2017, the ACC/AHA hypertension guidelines applied these findings to redefine hypertension to encompass patients with a systolic BP ≥130 mmHg or diastolic BP ≥ 80 mmHg,¹¹ and in 2018, the AHA released a new scientific statement on resistant hypertension management to align with this definition.¹²

In the present analysis, our findings expand upon several prior publications on resistant hypertension. As compared to prior work, we applied the contemporary 2017 definition of hypertension for the full study duration 2003–2020 and consequently identified a broader population of patients with both hypertension and aTRH. Importantly, in this cohort, we found that despite the increasing prevalence of hypertension, the rate of aTRH among the general hypertensive population has remained stable, ranging from 6.4% between 2003–2004 to 5.8% between 2017–2020. Among patients with hypertension on medical therapy, the prevalence of aTRH decreased from approximately 17.7% in 2003–2004 to 12.6% in 2017–2020. These findings are largely consistent with prior published works, which have described a prevalence ranging from 5.5% to as high as 28% across different cohorts.^6,9,17,18 One more recent study reported a rate of aTRH of 8.5% within a community based population of hypertensive adults.¹⁹

Our aTRH estimates are lower than other analyses¹⁸ due to application of a more rigorous definition of aTRH, requiring patients to be on ≥3 antihypertensive medications with uncontrolled BP including a diuretic or on 4 medications (also including a diuretic) regardless of BP.¹² It is worth noting that after applying these more contemporary definitions, the observed prevalence of resistant hypertension did not increase over the past decade and in fact, decreased among patients taking antihypertensives. Previous work has identified several factors within a study design that impact prevalence estimates of aTRH including medication reconciliation, dosing and qualifying regimen; BP goal and baseline demographics.²⁰ The sensitivity analysis included in the supplement demonstrates how changing the definition for aTRH alters the size of our cohort of interest.

We did find that the number of hypertensive adults with uncontrolled hypertension declined during the study period, from 75.0% in 2003–2004 to 68.7% in 2017–2020, suggesting that BP control is improving nationwide. Nevertheless, those with uncontrolled hypertension still constitute a large portion of the US hypertensive population. Almost 50% of hypertensive adults reported not currently taking any antihypertensive therapy. This finding could be a result of underdiagnosis in the general population, limited access to care or non-compliance among other reasons. Additionally among those on therapy, adherence to guideline recommended medication regimens was poor, likely further contributing to the prevalence of uncontrolled BP. For example, although there was a trend towards increased utilization, less than 1 in 5 adults with aTRH were prescribed an MRA despite high quality evidence supporting its use.¹² Limited adaption could be related to the above issues or concerns specific to MRA use such as hyperkalemia, the need for routine monitoring of labs or concerns about renal dysfunction. The rate of uncontrolled hypertension was similar to prior studies which have assessed hypertension control at specific time points during the duration of our study; however, few have evaluated trends over time.^17,21 Prior work has suggested that intensification of BP therapy has been insufficient in the past, with minimal improvement over time, yet the more contemporary intensification of antihypertensive therapy observed in our study appears to correlate with improved BP control.²²

Although our findings have emphasized the significance of resistant hypertension, to date, the subgroups at the highest risk for this condition have remained incompletely understood. We did find that obesity and more advanced renal disease were strongly associated with the presence of aTRH. While these conditions have been implicated as risks factors in previous studies, our findings emphasize that these associations persist despite the increasing availability of obesity related pharmacotherapy.^23–26

This study has several limitations. NHANES does not collect information on medication adherence or dosage, which limits our ability to draw conclusions regarding medication efficacy and effects on BP. The cross-sectional study design provides only a single office based-visit assessment of BP. Guidelines recommend that a diagnosis of hypertension be based on more than 1 visit. Additionally it’s estimated that 15–30% of adults are effected by whitecoat hypertension,²⁷ so inclusion of only office based BP readings may have increased the size of the hypertension cohort or introduced error which could influence our prevalence estimates. Nevertheless, the standardized BP protocol which was utilized in NHANES has been well-described.²⁸ Additionally, we applied the ACC/AHA 2017 hypertension guidelines to a cohort of patients from 2003–2020 in an effort to describe BP trends over time with greater veracity and to allow for a single modern definition of aTRH. This means that some adults in the early 2000s were categorized as having uncontrolled BP in our analysis when they would have been considered to have had appropriate BP control at that time (Table S6). As discussed above we conducted several sensitivity analyses to better understand how these changes in definition affected our primary analysis and determined that the effect was limited (supplement figure 3). Our hypertension definition was more inclusive compared with previous analyses. By including those who reported a prior diagnosis of hypertension regardless of whether they were on medication or had controlled BP, we may have overestimated the hypertensive population. We believe, however, that this broader definition reflects clinical practice and may also better capture those with masked hypertension, which is estimated to be present in 14–38% of adults.²⁹ Conversely, our definition of resistant hypertension was more rigorous than that of prior work. By requiring that patients be on a diuretic, we may have underestimated the population with aTRH. The results of our regression analysis should be interpreted with caution. Given the observational nature of our data, additional confounders could be present.³⁰ Finally we reported data through March 2020 which included a 4 year cohort from 2017–2020 due to the COVID-19 pandemic. It is unclear whether these trends would have continued given the disruptions of care associated with the pandemic.^31,32

CONCLUSION

In conclusion, this contemporary analysis of resistant hypertension investigated the prevalence and practice patterns across two decades of nationally representative data. We found that rates of hypertension increased over the last two decades, while the overall prevalence of aTRH has remained stable among adults with hypertension. Optimal medication regimens remain underutilized in the US, but there have been gains in therapy intensification and BP control, aligning with national guidelines.

PERSPECTIVES

Hypertension is highly prevalent among US adults, many of whom have uncontrolled blood pressure and may go on to develop treatment resistant hypertension. In the past decade, management guidelines have shifted to target lower blood pressures (BP) and encourage combination drug therapy. We found that over the past 20 years the prevalence of apparent treatment resistant hypertension (aTRH) among US adults has remained stable despite the rising incidence of hypertension. Use of multidrug treatment regimens has increased, aligning with national guidelines, however most US adults with hypertension and apparent treatment resistant hypertension have uncontrolled blood pressure, which has not improved over the past 2 decades. Further interventions are needed, likely at a population level to educate patients about the risks of hypertension and importance of adherence to medical therapy.

Supplementary Material

Supplemental_Publication_Material

Figure S1: Study flow diagram for patient selection.

Figure S2: Flow diagram of aTRH cohort selection

Figure S3: National temporal trends in combination antihypertensive therapy utilization.

Figure S4: Prevalence of aTRH among US adults by JNC7 definition, ACC/AHA 2017 definition and hybrid definition

Figure S5: Prevalence of aTRH among US adults stratified by Race

Table S1: Antihypertensive medications identified in analysis and associated internal NHANES survey code.

Table S2: Sensitivity analysis for estimates of aTRH, hypertension, and uncontrolled BP prevalence performed based on changes to variables definitions for the analysis

Table S3: Trends in prevalence of hypertension, aTRH, and uncontrolled BP. Raw data from Figure 1 in main text.

Table S4: Baseline characteristics among those with non-aTRH hypertension, stratified by survey cycle

Table S5: Baseline characteristics among those with aTRH, stratified by survey cycle

Table S6: Prevalence of hypertension by definition stratified by survey cycle

Pathophysiological Novelty and Relevance.

What is new?

We report contemporary trends in the prevalence of hypertension and apparent treatment resistant hypertension (aTRH) over the past 2 decades among US adults. We found that the prevalence of hypertension has continued to rise, while the prevalence of aTRH has remained static. Almost half of adults with hypertension are untreated and among those on treatment, most have uncontrolled blood pressure.

What is Relevant?

Uncontrolled hypertension is highly prevalent among US adults. As a major modifiable risk factor to reduce the risk of cardiovascular disease, our study provides insights about how the prevalence of hypertension and aTRH has changed over the past 20 years and characteristics of adults with aTRH. Concerningly almost half of adults with hypertension are not currently on treatment.

Clinical/Pathophysiological Implications

Hypertension and treatment resistant hypertension are risk factors for adverse cardiovascular events. A better understanding of current national trends in hypertension management may be useful to providers to aid in their management of patients with uncontrolled hypertension.

Abbreviations:

ACE

Angiotensin-Converting Enzyme Inhibitor

ARB

Angiotensin Receptor Blocker

aTRH

Apparent treatment resistant hypertension

BMI

Body mass index

BP

Blood pressure

CAD

Coronary artery disease

CI

Confidence interval

CHF

congestive heart failure

COPD

Chronic obstructive pulmonary disease

MRA

Mineralocorticoid receptor antagonist