Abstract
Resistant hypertension, defined as blood pressure (BP) levels above goal while taking ≥3 classes of antihypertensive medication or ≥4 classes regardless of BP level, is associated with increased cardiovascular disease (CVD) risk. The 2018 American Heart Association Scientific Statement on Resistant Hypertension recommends healthy lifestyle habits and thiazide-like diuretics and mineralocorticoid receptor antagonists for adults with resistant hypertension. The term apparent treatment-resistant hypertension (aTRH) is used when pseudoresistance cannot be excluded. We estimated the use of healthy lifestyle factors and recommended antihypertensive medication classes among US black adults with aTRH. Data were pooled for black participants in the Jackson Heart Study in 2009–2013 (n=2,496) and the REasons for Geographic and Racial Differences in Stroke study in 2013–2016 (n=3,786). Outcomes included lifestyle factors (not smoking, not consuming alcohol, ≥75 minutes of vigorous intensity or ≥150 minutes of moderate or vigorous physical activity per week, body mass index <25 kg/m2) and recommended antihypertensive medications (thiazide-like diuretics and mineralocorticoid receptor antagonists). Overall, 28.3% of participants who reported taking antihypertensive medication had aTRH. Among participants with aTRH, 14.5% and 1.2% had ideal levels of 3 and 4 of the lifestyle factors, respectively. Also, 5.9% of participants with aTRH reported taking a thiazide-like diuretic and 9.8% reported taking a mineralocorticoid receptor antagonist. In conclusion, evidence-based lifestyle factors and recommended pharmacological treatment are under-utilized in black adults with aTRH. Increased use of lifestyle recommendations and antihypertensive medication classes specifically recommended for aTRH may improve BP control and reduce CVD-related morbidity and mortality among US black adults.
Keywords: Hypertension, Resistant hypertension, Antihypertensive agents, Blacks, Health Behaviors
Graphical Abstract
In 2018, the American Heart Association (AHA) published an update to its 2008 Scientific Statement on resistant hypertension (1, 2). The 2018 Scientific Statement defined resistant hypertension by the need for four or more classes of antihypertensive medication to achieve blood pressure (BP) control, systolic blood pressure (SBP) < 130 mmHg and diastolic blood pressure (DBP) < 80 mmHg (2). The term apparent treatment-resistant hypertension (aTRH) is used when pseudoresistance (e.g., white coat effect, medication non-adherence) cannot be excluded (3). aTRH has been associated with an increased risk for target organ damage, cardiovascular disease (CVD), and all-cause mortality (2, 4, 5).
It has been known for decades that black compared with white adults in the United States (US) with hypertension are less likely to have controlled BP (6–8). Additionally, several studies have reported that aTRH is more common among black than white adults with hypertension (9, 10). In the 2009–2014 National Health and Nutrition Examination Survey (NHANES), 27.3% of non-Hispanic black adults had aTRH compared with 18.9% of non-Hispanic white adults (9). It is unclear whether black adults with aTRH receive evidence-based approaches to lower BP as recommended in the 2018 AHA Scientific Statement on resistant hypertension (2, 11, 12). Non-pharmacologic interventions including weight loss among those who are overweight or obese, reduction in alcohol consumption, and physical activity have been shown to lower BP, and their use among black adults with aTRH may assist in achieving controlled BP with fewer classes of antihypertensive medication (2, 13). Additionally, thiazide-like diuretics (i.e., chlorthalidone and indapamide) and mineralocorticoid receptor antagonists (i.e., spironolactone and eplerenone) have been shown to improve BP control among adults with resistant hypertension in randomized trials (2, 11, 12, 14).
The purpose of this study was to quantify lifestyle factors and antihypertensive medication use among black adults with aTRH, with the goal of identifying potential targets for intervention. To do so, we analyzed data from self-identified black adults enrolled in the Jackson Heart Study (JHS) and REasons for Geographic And Racial Differences in Stroke (REGARDS) study.
METHODS
Requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be submitted to the REGARDS and JHS executive committees at https://www.jacksonheartstudy.org and http://regardsstudy.org, respectively. The JHS was designed to identify reasons for the high risk for CVD among black adults and to identify potential interventions to lower this risk. Between 2000 and 2004, 5,306 non-institutionalized self-identified black men and women ≥ 21 years of age from the three counties that make up the Jackson, MS metropolitan area were enrolled in the JHS (15, 16). The JHS was approved by the institutional review boards of the University of Mississippi Medical Center, Jackson State University, and Tougaloo College and all participants provided written informed consent. The REGARDS study was designed to identify reasons for the higher stroke mortality in the Southeast US compared to other geographic regions of the US and among black compared with white adults (17). Between 2003 and 2007, 30,239 US adults ≥ 45 years of age from across the contiguous US were enrolled in the REGARDS study. The REGARDS study was approved by the institutional review board at UAB and other participating centers and all participants provided written informed consent.
We restricted the current analysis to data collected from JHS and REGARDS study participants at the most recent exams, JHS Exam 3 in 2009–2013 (n=3,819) and REGARDS study exam 2 in 2013–2016 (n=14,448). We excluded JHS participants who reported not taking antihypertensive medication (n=1,319) and those who were missing data on systolic or diastolic BP (n=4). We excluded white REGARDS study participants (n=9,111), participants who reported not taking antihypertensive medication (n=1,547) and those missing data on systolic or diastolic BP (n=4). The final sample size included 2,496 participants from the JHS and 3,786 participants from the REGARDS study (pooled sample n=6,282; Figure S1).
Data Collection
Information on age, sex, education, cigarette smoking, alcohol intake, physical activity, antihypertensive and glucose-lowering medication use, and history of coronary heart disease (CHD) and stroke was assessed by self-report. Height and weight were measured during a study visit and used to calculate body mass index (BMI). Blood and urine specimens were collected in both studies and used to measure serum creatinine, serum glucose and urinary albumin and urinary creatinine. Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (18). In both studies, diabetes was defined as a fasting serum glucose ≥ 126 mg/dL, non-fasting serum glucose ≥ 200 mg/dL, or self-report of a prior diagnosis of diabetes with glucose-lowering medication use. Additionally, JHS participants with hemoglobin A1c (HbA1c) HbA1c ≥ 48 mmol/mol (≥ 6.5%) were considered to have diabetes. Urinary albumin and urinary creatinine were used to calculate the albumin-to-creatinine ratio (ACR). History of CHD was defined by a self-reported myocardial infarction or evidence of a myocardial infarction on the study electrocardiogram. Additionally, REGARDS study participants who self-reported a history of coronary revascularization were considered to have a history of CHD. A history of stroke was defined by self-report of a physician diagnosis of a stroke at Exam 3 in JHS and at baseline in the REGARDS study. Additionally, a history of stroke included adjudicated strokes between baseline and the follow-up visit in the REGARDS study. Participants with a history of CHD or stroke were categorized as having a history of CVD.
BP Measurement
In both the JHS and the REGARDS study, each participant had their SBP and DBP measured twice on their upper arm using an appropriately sized cuff after a 5-minute seated rest. BP was measured attended using an oscillometric device (Omron HEM-907XL) in the JHS and an aneroid sphygmomanometer (American Diagnostic Corporation, Hauppauge, NY) in the REGARDS study. The two measurements were averaged for all analyses. The full BP measurement protocol for JHS can be found on the study’s website (19). In JHS, BP measurement using the right arm was the preferred location unless there was a reason that the right arm could not be used (e.g., if a participant had a mastectomy). The cuff was fitted to the bare skin with the cubital fossa positioned at heart level. JHS study participants were seated with their legs uncrossed in a quiet room before the BP measurement was taken. REGARDS study participants were seated with their feet on the floor and rested before their first BP measurement. BP quality control in the REGARDS study included monitoring of readings by digit preference and retraining of technicians as needed.
Antihypertensive medication
For the JHS, participants were asked to bring the containers for all of the medications they had taken in the previous two weeks to their exam visit. In the REGARDS study, participants were asked to show the containers of medications taken in the past two weeks to study staff during their in-home visit. For each study, the names of the medications were recorded onto study forms and subsequently classified into generic names. Antihypertensive medications were grouped into the following classes: angiotensin-converting enzyme (ACE) inhibitors, alpha-blockers, angiotensin II receptor blockers (ARB), beta blockers, dihydropyridine and non-dihydropyridine calcium channel blockers (CCB), central acting alpha 2-agonists, mineralocorticoid receptor antagonists, thiazide-type or thiazide-like diuretics, potassium-sparing diuretics, loop diuretics, and direct acting vasodilators. Mineralocorticoid receptor antagonists included spironolactone or eplerenone and thiazide-like diuretics included chlorthalidone, indapamide or metolazone.
Apparent Treatment Resistant Hypertension
Participants with uncontrolled BP while taking three classes of antihypertensive medication and those taking four or more classes of antihypertensive medication, regardless of their BP level, were considered to have aTRH. Uncontrolled BP, SBP ≥ 130 mm Hg or DBP ≥ 80 mm Hg, was defined according to the 2017 ACC/AHA BP guideline (13) and the 2018 AHA Scientific Statement on resistant hypertension (2). As many JHS and REGARDS study participants were not taking a diuretic and to allow for the broader investigation of aTRH, we did not restrict the sample to participants taking a diuretic.
Healthy lifestyle factors
We studied four lifestyle factors: smoking, alcohol intake, physical activity, and BMI. Each lifestyle factor was categorized as being ideal, intermediate or poor as follows:
Smoking status: never or quit >1 year ago (ideal), quit within the past year (intermediate), and current (poor);
Alcohol intake: none (ideal), >0 to ≤14 drinks for men and >0 to ≤7 drinks per week for women (intermediate), and >14 drinks for men and >7 drinks per week for women, (poor);
Physical activity: ≥150 minutes per week moderate intensity or ≥75 minutes per week vigorous intensity or ≥150 minutes per week moderate and vigorous intensity exercise (ideal), 1 to 149 minutes per week moderate intensity or 1 to 74 minutes per week vigorous intensity or 1 to 149 minutes per week moderate and vigorous intensity exercise (intermediate), and none (poor); and
BMI: <25 kg/m2 (ideal), 25 to <30 kg/m2 (intermediate), and ≥ 30 (poor) kg/m2.
These lifestyle factors were selected as they are associated with BP or CVD risk (13, 20–22) and data on these factors were available in both the JHS and the REGARDS study. Ideal, intermediate and poor levels for physical activity, BMI, and smoking are consistent with those used in the AHA’s Life’s Simple 7 ideal cardiovascular health metric (20).
Statistical Analysis
We pooled data for black participants taking antihypertensive medication from the JHS and REGARDS study for all analyses. Descriptive statistics were calculated for all participants taking antihypertensive medication and those with aTRH, separately. Among participants with aTRH, descriptive statistics were also calculated for those with controlled and uncontrolled BP, separately. We calculated the distribution of each lifestyle factor (ideal, intermediate, or poor) among participants with aTRH, overall and with controlled and uncontrolled BP, separately. Next, we calculated the percentage of participants with aTRH taking each class of antihypertensive medication and combinations of antihypertensive medication. We also calculated the proportion of participants with aTRH, overall and with controlled and uncontrolled BP, separately, taking a thiazide-like diuretic and mineralocorticoid receptor antagonist. Three secondary analyses were conducted. First, descriptive statistics, distributions of lifestyle factors and use of antihypertensive medication classes based on the pill bottle review were calculated for participants with aTRH and their counterparts with controlled BP on ≤ 2 classes of antihypertensive medication. Second, the distribution of lifestyle factors and proportion of participants taking a thiazide-like diuretic or mineralocorticoid receptor antagonist were calculated for participants with aTRH who had a thiazide diuretic (i.e., thiazide like or thiazide type) identified during their pill bottle review. Third, descriptive statistics, distributions of lifestyle factors, and antihypertensive medication use were calculated for JHS and REGARDS study participants, separately, with aTRH overall and with controlled and uncontrolled BP. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and verified by an independent analyst using R version ≥3.5.3. (Vienna, Austria).
RESULTS
Of the 6,282 black participants in the JHS and REGARDS study taking antihypertensive medication, 28.3% had aTRH including 21.3% with uncontrolled BP and 7.0% with controlled BP. The mean age of participants with aTRH was 70.6 (SD=9.2) years, 34.1% were male, and 17.9% had less than a high school education (Table 1). The mean SBP was 135.1 mm Hg (SD=18.4) and mean DBP was 76.2 mm Hg (SD=10.7) among participants with aTRH.
Table 1.
Characteristics of black adults taking antihypertensive medication and with apparent treatment resistant hypertension overall, and with uncontrolled and controlled blood pressure, separately.
| Characteristic | All adults taking antihypertensive medication | Adults with apparent treatment resistant hypertension | ||
|---|---|---|---|---|
| Overall | Uncontrolled blood pressure† | Controlled blood pressure‡ | ||
| (n=6,282) | (n=1,776) | (n=1,336) | (n=440) | |
| Age, years | 69.2 (10.0) | 70.6 (9.2) | 70.5 (9.3) | 70.7 (8.9) |
| Male | 33.0% | 34.1% | 33.4% | 36.1% |
| Education less than high school | 15.3% | 17.9% | 17.7% | 18.6% |
| Income less than $25,000 | 39.6% | 45.0% | 46.2% | 41.5% |
| Diabetes | 41.4% | 51.7% | 49.8% | 57.6% |
| CKD†† | 37.8% | 50.9% | 51.4% | 49.6% |
| Albuminuria‡‡ | 20.6% | 30.1% | 32.7% | 22.0% |
| Reduced eGFR††† | 24.8% | 34.7% | 33.6% | 38.1% |
| SBP, mmHg | 128.3 (16.9) | 135.1 (18.4) | 141.5 (15.9) | 115.7 (9.5) |
| DBP, mmHg | 74.5 (10.0) | 76.2 (10.7) | 79.3 (9.8) | 66.9 (7.6) |
| History of CVD | 21.3% | 29.8% | 29.1% | 31.9% |
Numbers in the table are mean (standard deviation) or percentages.
Uncontrolled apparent treatment resistant hypertension: systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 80 mm Hg while taking ≥3 classes of antihypertensive medication.
Controlled apparent treatment resistant hypertension: systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg while taking ≥4 classes of antihypertensive medication.
Chronic kidney disease is defined by the presence of albuminuria or reduced estimated glomerular filtration rate.
Albumin-to-creatinine ratio > 30 mg/g.
Estimated glomerular filtration rate < 60 ml/min/1.73 m2
aTRH: apparent treatment resistant hypertension.
CKD: chronic kidney disease.
eGFR: estimated glomerular filtration rate.
SBP: systolic blood pressure.
DBP: diastolic blood pressure.
CVD: cardiovascular disease.
Among participants with aTRH, 3.3%, 24.3%, 56.6%, 14.5%, and 1.2% had ideal levels of 0, 1, 2, 3 and 4 lifestyle factors, respectively (Table 2). The majority of participants with aTRH were non-smokers (88.9%) and did not consume alcohol (71.0%). In contrast, 18.0% and 9.6% of participants with aTRH had ideal levels of physical activity and BMI, respectively. The proportion of participants with ideal levels of each lifestyle factor was within 5 percentage points when comparing those with aTRH and controlled and uncontrolled BP.
Table 2.
Distribution of lifestyle factors among participants with apparent treatment resistant hypertension.
| Lifestyle factors | Percentage participants with aTRH | ||
|---|---|---|---|
| Overall | Uncontrolled blood pressure† | Controlled blood pressure‡ | |
| (n=1776) | (n=1336) | (n=440) | |
| Number of ideal lifestyle factors | |||
| 0 | 3.3% | 3.5% | 2.7% |
| 1 | 24.3% | 24.9% | 22.7% |
| 2 | 56.6% | 55.2% | 60.9% |
| 3 | 14.5% | 15.1% | 12.7% |
| 4 | 1.2% | 1.4% | 0.9% |
| Smoking status | |||
| Poor | 8.6% | 8.9% | 7.7% |
| Intermediate | 2.5% | 2.3% | 3.2% |
| Ideal | 88.9% | 88.8% | 89.1% |
| Alcohol intake | |||
| Poor | 1.8% | 1.8% | 1.6% |
| Intermediate | 27.2% | 28.2% | 24.1% |
| Ideal | 71.0% | 70.0% | 74.3% |
| Physical activity* | |||
| Poor | 50.4% | 48.8% | 55.4% |
| Intermediate | 31.6% | 32.2% | 29.8% |
| Ideal | 18.0% | 19.0% | 14.8% |
| Body mass index | |||
| Poor | 63.3% | 62.8% | 64.7% |
| Intermediate | 27.1% | 27.5% | 25.9% |
| Ideal | 9.6% | 9.7% | 9.4% |
aTRH: apparent treatment resistant hypertension.
Uncontrolled apparent treatment resistant hypertension: systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 80 mm Hg while taking ≥3 classes of antihypertensive medication.
Controlled apparent treatment resistant hypertension: systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg while taking ≥4 classes of antihypertensive medication.
Smoking (ideal: never or quit >1 year ago, intermediate: quit ≤1 year ago, poor: current).
Alcohol intake (ideal: none, intermediate: >0 to ≤7 alcoholic drinks per week for women and >0 to ≤14 drinks per week for men, poor: >7 alcoholic drinks per week for women and >14 drinks per week for men).
Physical activity (ideal: ≥150 minutes per week moderate intensity or ≥75 minutes per week vigorous intensity or ≥150 minutes per week moderate and vigorous intensity exercise, intermediate: 1 to 149 minutes per week moderate intensity or 1 to 74 minutes per week vigorous intensity or 1 to 149 minutes per week moderate and vigorous intensity exercise, poor: 0 minutes of moderate/vigorous intensity exercise).
Modified for the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants. Participants in the REGARDS study were asked: How many times per week do you engage in physical activity enough to work up a sweat? We defined ideal: 4 or more times per week, intermediate: 1 to 3 times per week, poor: none.
Body mass index (ideal: <25 kg/m2, intermediate: 25 to <30 kg/m2, poor: ≥30kg/m2).
Among participants with aTRH, 63.6% reported taking a thiazide-like or type diuretic, 62.4% a dihydropyridine CCB, and 43.5% reported taking a cardioselective or nonselective beta blocker (Table 3). Also, 45.6% and 43.3% of participants reported taking ACE inhibitors and ARBs, respectively. The two most common antihypertensive medication class combinations reported by participants with aTRH were an ACE, dihydropyridine CCB, and thiazide diuretic followed by an ARB, dihydropyridine CCB, and thiazide diuretic at 4.9% and 4.4%, respectively. The 1,776 participants with aTRH reported a total of 472 unique combinations of antihypertensive medication.
Table 3.
Percentage of participants with apparent treatment resistant hypertension taking each class of antihypertensive medication (top panel) and the most common antihypertensive medication class combinations (bottom panel).
| Antihypertensive medication | %, among those with aTRH |
|---|---|
| (n=1776) | |
| Class of antihypertensive medication | |
| Angiotensin converting enzyme inhibitors | 45.6% |
| Alpha blockers | 9.2% |
| Alpha and beta blocker combination | 18.2% |
| Angiotensin II receptor blockers | 43.3% |
| Beta blockers | |
| Cardioselective and nonselective | 43.5% |
| Cardioselective and vasodilatory | 3.8% |
| Intrinsic sympathomimetic activity | 0.4% |
| Calcium channel blockers | |
| Dihydropyridines | 62.4% |
| Non-dihydropyridines | 11.5% |
| Central acting agents | 4.3% |
| Diuretics | |
| Loop | 30.9% |
| Potassium-sparing | 12.1% |
| Thiazide-like or thiazide-type | 63.6% |
| Mineralocorticoid receptor antagonist | 9.8% |
| Renin inhibitors | 0.5% |
| Vasodilators | 11.0% |
| Antihypertensive medication class combinations | |
| ACE, CCB (dihydropyridine), Diuretic (Thiazide-like or type) | 4.9% |
| ARB, CCB (dihydropyridine), Diuretic (thiazide-like or type) | 4.4% |
| ACE, Beta blocker (cardioselective + nonselective), CCB (dihydropyridine), Diuretic (thiazide-like or type) | 4.1% |
| ARB, Beta blocker (cardioselective + nonselective), CCB (dihydropyridine), Diuretic (thiazide-like or type) | 3.1% |
| ARB, Beta blocker (cardioselective + nonselective), Diuretic (thiazide-like or type) | 2.7% |
| ACE, Beta blocker (cardioselective + nonselective), Diuretic (thiazide-like or type) | 2.6% |
| ARB, Beta blocker (cardioselective + nonselective), CCB (dihydropyridine) | 2.0% |
| ACE, Beta blocker (cardioselective + nonselective), CCB (dihydropyridine) | 1.9% |
| ACE, Beta blocker (cardioselective + nonselective), CCB (dihydropyridine), Diuretic (loop) | 1.6% |
| ARB, Beta blocker (cardioselectitve + nonselective), CCB (dihydropyridine), Diuretic (loop) | 1.5% |
aTRH: apparent treatment resistant hypertension.
ACE: angiotensin converting enzyme inhibitor.
CCB: Calcium channel blocker.
ARB: Angiotensin II receptor blocker.
Among all participants with aTRH, 5.9% reported taking chlorthalidone, indapamide or metolazone and 9.8% reported taking spironolactone or eplerenone (Figure 1). Reported use of chlorthalidone, indapamide or metolazone was 5.5% and 7.1% of participants with aTRH and uncontrolled and controlled BP, respectively (p=0.245). Taking spironolactone or eplerenone was reported by 7.3% and 17.3% of participants with aTRH and uncontrolled and controlled BP, respectively (p<0.001).
Figure 1.
Proportion of participants with apparent treatment resistant hypertension taking a thiazide-like diuretic or mineralocorticoid receptor antagonist.
aTRH: apparent treatment resistant hypertension; AHA: American Heart Association
* Thiazide-like diuretic includes chlorthalidone, indapamide or metolazone.
† Mineralocorticoid receptor antagonist includes spironolactone or eplerenone.
p-value = 0.245 comparing the proportion taking a thiazide-like diuretic among those with uncontrolled and controlled blood pressure.
p-value <0.001 comparing the proportion taking a mineralocorticoid receptor antagonist among those with uncontrolled and controlled blood pressure.
Uncontrolled apparent treatment resistant hypertension: systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 80 mm Hg while taking ≥3 classes of antihypertensive medication.
Controlled apparent treatment resistant hypertension: systolic blood pressure < 130 mm Hg and diastolic blood pressure < 80 mm Hg while taking ≥4 classes of antihypertensive medication.
Participants with controlled BP on 1 or 2 classes of antihypertensive medication were less likely to have ideal alcohol intake but were more likely to have intermediate and ideal levels of physical activity and BMI than their counterparts with aTRH (Table S1). A thiazide-like or thiazide-type diuretic was the most common antihypertensive medication reported to be taken by participants with controlled BP on ≤ 2 classes of antihypertensive medication (Table S2). Compared to participants with controlled BP on ≤ 2 classes of antihypertensive medication, participants with aTRH were older, more likely to be male, and have diabetes (Table S3). When the sample was restricted to participants with aTRH taking a thiazide diuretic, 15.4% and 1.3% had ideal levels of 3 and 4 lifestyle factors, respectively (Table S4). Also, 9.3% of participants with aTRH taking a thiazide diuretic reported taking chlorthalidone, indapamide or metolazone and 5.4% reported taking spironolactone or eplerenone (Figure S2.)
Stratified analyses
Demographic characteristics are presented for JHS and REGARDS study participants, separately, in Table S5. The proportion of JHS and REGARDS study participants with 3 or 4 lifestyle factors in the ideal range was within 1% (Table S6). Taking a thiazide-like diuretic and mineralacorticoid receptor antagonist was reported by 2.8% and 11.1% of participants with aTRH in the JHS, respectively, and by 7.7% and 9.1% of participants with aTRH in the REGARDS study, respectively (Figure S3).
DISCUSSION
The present study documents the low use of recommended antihypertensive medications and ideal lifestyle factors in black adults with aTRH. Prior studies show that controlling BP according to the 2017 ACC/AHA BP guideline could prevent approximately 400,000 CVD events in US black adults (23) and that the population-attributable risk of hypertension is higher in blacks compared with white adults (24). Achieving higher rates of BP control among black adults may have an important role in reducing disparities in hypertension-related morbidity and mortality.
The majority of black adults with aTRH in the present study were non-smokers and did not consume alcohol. However, a low proportion of participants had ideal levels of physical activity and BMI. In a prior analysis that used the REGARDS study data, Diaz et. al. examined the impact of six lifestyle factors on future risk of CVD and all-cause mortality among REGARDS study participants with aTRH at baseline and found that nonsmoking and physical activity were associated with lower risk for cardiovascular events and mortality (25).
In the present study, the use of ARBs, ACE inhibitors, CCBs, and thiazide-type diuretics among black adults with aTRH was relatively high, ranging from 43.3% to 63.6%. However, use of thiazide-like diuretics and mineralocorticoid receptor antagonists were low. These findings are consistent with findings from a study by Fontil et. al., that evaluated the underutilization of the most effective medications for resistant hypertension using 2006–2010 data from the National Ambulatory Medical Care Survey (N=1567; n=313 blacks) (26). Among patients with aTRH, chlorthalidone and a mineralocorticoid receptor antagonist were reported to be taken by <3% and <4% of patient visits, respectively.
The under-utilization of thiazide-like diuretics and mineralocorticoid receptor antagonists for patients with aTRH represents a missed opportunity to efficiently achieve BP control (9, 26, 27). Randomized trials have demonstrated the efficacy of these drug classes for achieving BP control among individuals with resistant hypertension (28–30). The PATHWAY-2 trial demonstrated that spironolactone was a more effective add-on therapy to the rAS blocker, calcium antagonist, diuretic regimen for lowering SBP in patients with resistant hypertension compared with placebo, doxazosin, and bisoprolol in predominantly white patients in the United Kingdom (30). In other studies, chlorthalidone and indapamide have been shown to be more effective than hydrochlorothiazide for lowering BP without differences in the adverse events profile, thereby making them the favored choice when thiazide treatment is being considered for treating resistant hypertension (29, 31, 32). Although compared to thiazide-type diuretics, thiazide-like diuretics have a longer half-life and more potent BP-lowering effect, direct randomized trials comparing these two subclasses on CVD events are lacking (33–35).
There are many potential reasons for their under-utilization in the present study. First, study visits were conducted between 2009 and 2016 and many clinicians may not have been aware of the role of chlorthalidone or indapamide and spironolactone or eplerenone for managing resistant hypertension. Second, clinicians may not have been familiar with the AHA scientific statements on resistant hypertension (2). It should be noted that the 2008 AHA Statement on resistant hypertension recommend chlorthalidone and spironolactone for treatment of resistant hypertension. Third, the BP goals were lower in the 2017 ACC/AHA BP guideline compared with previous recommendations in the US (36). Fourth, clinicians have to address a wide range of medical issues during office visits, which may limit the time available to focus on antihypertensive medication changes. Other factors including medication costs, risk of side effects, and pill burden may also contribute to the under-utilization of recommended treatments for managing resistant hypertension.
Strengths of the present study include the large sample of black participants with aTRH in JHS and the REGARDS study. This is an under-studied population given their high prevalence of aTRH (9). Also, the detailed data collection allowed us to investigate both lifestyle factors and antihypertensive medications use. Data from an upcoming study visit that is planned for the JHS will provide important information about whether the new BP guideline and recommendations for aTRH management are being adopted. Despite these strengths, the results should be interpreted in the context of potential and known limitations. Although antihypertensive medication classes were identified by a pill bottle review, data on whether they were actually being taken could not be confirmed. The time periods for the REGARDS study and JHS data collection did not overlap. We evaluated aTRH and, do not know the true prevalence of resistant hypertension in this population after excluding pseudoresistance. Due to the small number of people with refractory hypertension (n=143), resistant and refractory hypertension were reported solely under the umbrella of resistant hypertension. In a prior study, 6.2% of US adults with resistant hypertension had refractory hypertension (37). While the REGARDS study enrolled participants from across the US, black adults from the southeast US were oversampled. The generalizability to blacks in the US is unknown. Data on dietary patterns and 24-hour urine sodium assessment, two factors with strong associations with BP control, were not available. We did not have information on whether participants with aTRH had seen a hypertension specialist.
Perspectives
In the current study, thiazide-like diuretics and mineralocorticoid receptor antagonists were under-utilized and the prevalence of ideal levels of lifestyle factors was low among black adults with aTRH. These findings identified pharmacological and non-pharmacological gaps in care that can be addressed to improve BP control in black adults with aTRH. By addressing these lifestyle and pharmacological factors, it may be possible to reduce the prevalence of aTRH in blacks taking antihypertensive medication.
Supplementary Material
Novelty and Significance.
What is New?
The 2017 American College of Cardiology/American Heart Association blood pressure guidelines and a 2018 American Heart Association Scientific Statement provide an updated definition of resistant hypertension. The present study provides contemporary data on the use of recommended lifestyle and antihypertensive medications for blacks with aTRH.
What is Relevant?
Compared with white adults, BP is more difficult to control in black adults. Also, aTRH is associated with an increased risk for cardiovascular disease. The present study suggests that lifestyle factors and thiazide-like diuretics and mineralocorticoid receptor antagonists are under-utilized among black adults with aTRH.
Summary
The present study documents the need to increase the use of evidence-based lifestyle factors and recommended pharmacological antihypertensive medication classes among US black adults with aTRH.
Acknowledgments
All listed authors have made substantial contributions to the conceptualization, data collection/analysis and/or writing of this manuscript. The authors wish to thank the staffs and participants of the JHS. The authors also thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at: https://www.uab.edu/soph/regardsstudy/.
Sources of Funding
The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.
REGARDS is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Service. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIA. Representatives of the NINDS were involved in the review of the manuscript but were not directly involved in the collection, management, analysis or interpretation of the data.
This work was supported by a R13HL144012-01 and R01HL117323 from the NIH/NHLBI. Drs. Langford and Bress are supported by a K01HL135467 and K01HL133468 from the NIH/NHLBI, respectively. Dr. Tajeu was supported by a 3R01DK108628-05S1 from the NIH/NIDDK.
The funders did not play a role in conceptualizing the present study, conducting analyses, or developing the manuscript.
Disclosures
Dr. Bress receives research support to his institution from Novartis, Amarin Corporation, and Amgen unrelated to the current manuscript. Dr. Muntner receives research support to his institution from Amgen unrelated to the current manuscript.
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