Abstract
Background and Purpose
Blood pressure control is a paramount goal in secondary stroke prevention; however, high prevalence of uncontrolled blood pressure and use of multiple antihypertensive medication classes in stroke patients suggest this goal is not being met. We determined the prevalence and factors associated with apparent treatment-resistant hypertension in persons with/without stroke or transient ischemic attack..
Methods
Data came from REGARDS, a national, population-based cohort of 30,239 black and white adults ≥ 45 years, enrolled 2003–2007, restricted to 11,719 participants with treated hypertension. Apparent treatment-resistant hypertension was defined as: 1) uncontrolled blood pressure (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg) with ≥ 3 antihypertensive medication classes, or 2) use of ≥ 4 antihypertensive medication classes, regardless of blood pressure level. Poisson regression was used to calculate characteristics associated with apparent treatment-resistant hypertension.
Results
Among hypertensive participants, prevalence of apparent treatment-resistant hypertension was 24.9% (422/1,694) and 17.0% (1,708/10,025) in individuals with and without history of stroke or transient ischemic attack, respectively. After adjustment for cardiovascular risk factors, the prevalence ratio for apparent treatment-resistant hypertension for those with versus without stroke or transient ischemic attack was 1.14 (95% CI: 1.03–1.27). Among hypertensive participants with stroke or transient attack, male sex, black race, larger waist circumference, longer duration of hypertension, and reduced kidney function were associated with apparent treatment-resistant hypertension.
Conclusions
The high prevalence of apparent treatment-resistant hypertension among hypertensive persons with history of stroke or transient ischemic attack suggests the need for more individualized blood pressure monitoring and management.
Keywords: resistant hypertension, prevalence, predictors, stroke, transient ischemic attack, secondary prevention
Introduction
Hypertension is considered to be the most important risk factor for primary and secondary stroke prevention. 1,2 In persons with history of stroke, the prevalence of hypertension is high, with estimates ranging from 70% to 82%. 3–7 Although there have been few clinical trials examining blood pressure treatment in secondary prevention, meta-analyses of such trials show that risk of recurrent stroke is reduced with antihypertensive medications. 8–10 American Heart Association/American Stroke Association guidelines recommend blood pressure reduction for prevention of recurrent stroke as well as prevention of other vascular events in persons who have had an ischemic stroke or transient ischemic attack.1,2
Control of BP following stroke is a substantial challenge. Reports of risk factor management in stroke survivors have described low prevalence of BP control. 5,7,11–16 Among 2,830 black and white participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who reported a physician-diagnosis of stroke or TIA, 2,200 (78%) were being treated for hypertension but 732 (33.3%) had uncontrolled BP (i.e., systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg).12 Uncontrolled hypertension among black stroke survivors is a particular challenge. 12,15,16 Reasons for this are multifactorial and include medication non-adherence/non-persistence/non-fulfillment due to costs, side effects, etc., complexity of treatment regimen, not receiving regular medical care, treatment resistant hypertension, and lack of healthy behaviors such as physical activity, etc. 17–19 As stroke is considered a cardiac risk equivalent, such a co-morbid condition increases the complexity of treating hypertension.20,21
Apparent treatment resistant hypertension is defined as uncontrolled blood pressure on three or more antihypertensive medication classes or, regardless of blood pressure, being on four or more antihypertensive medication classes.19 There are few studies on the burden of apparent treatment resistant hypertension in secondary stroke prevention. The objective of this study was to determine the prevalence and factors associated with apparent treatment-resistant hypertension among those with a history of stroke or transient ischemic attack in the REGARDS cohort.
Methods
REGARDS is a national, population-based cohort study of 30,239 community-dwelling individuals, aged 45 or older at enrollment in 2003–2007. Details of methods have been previously described.22,23 REGARDS was designed to investigate causes of regional and black-white disparities in stroke mortality with oversampling of blacks and residents of the “buckle” of the Stroke Belt16 [coastal plain region of North Carolina (NC), South Carolina (SC), and Georgia (GA)], and the rest of the Stroke Belt17 (remainder of NC, SC, GA, plus Alabama, Mississippi, Tennessee, Arkansas, and Louisiana. Individuals were randomly selected from a commercially available list and contacted by mail followed by telephone for recruitment and verbal consent. Exclusion criteria included self-reported medical conditions (such as cancer) that would prevent long-term participation, or being on a waiting list for nursing home. The final sample comprised 21% from the stroke buckle, 35% from rest of stroke belt area, 44% from the other 40 contiguous states, and 42% black, 55% women. Using a computer-assisted telephone interview, trained interviewers obtained demographics, medical history and risk factors. A brief physical exam including blood pressure measurements, blood and urine samples, and an electrocardiogram was conducted during an in-home visit 3–4 weeks after the telephone interview. Participants were asked to provide all prescription and nonprescription medications they had taken in the past two weeks and medication names (but not dosages) were recorded during the in-home visit. Written consent was obtained during the in-person evaluation. Biological samples were stored and analyzed at the central laboratory at the University of Vermont, and electrocardiograms were centrally read by electrocardiographers at Wake Forest University who were blinded to clinical data. The institutional review boards of participating institutions approved the study methods. The primary analysis for this report was limited to participants who reported history of hypertension with concurrent use of antihypertensive medication determined from medication inventory (n=15,004.) We excluded participants missing data on systolic blood pressure or diastolic blood pressure (n=87), history of stroke or transient ischemic attack (n=221), or self-reported antihypertensive medication use (n=23), reducing the number to 14,673. The primary analysis cohort consisted of 11,719, excluding participants with uncontrolled hypertension who were taking one or two antihypertensive medications (n=2,954) because they did not met criteria for apparent treatment-resistant hypertension; however, these individuals were included in secondary analysis described below.
During the in-person exam, two blood pressure measurements were taken by a trained technician using a standard protocol and regularly tested aneroid sphygmomanometer (American Diagnostic Corporation), after the participant was seated for 5 minutes. When possible, measurements were taken in the left arm; a large size cuff was used if the arm circumference was greater than 13 inches. The cuff was inflated to 20 mmHg above the pulse obliteration level, and slowly deflated. This process was repeated after a 30-second rest period to obtain the second blood pressure on the same arm. Quality control was monitored by central examination of digit preference and retraining of technicians took place as necessary.24 Systolic blood pressure and diastolic blood pressure were defined as the average of two measurements. Uncontrolled blood pressure was defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg; apparent treatment-resistant hypertension was defined as uncontrolled blood pressure on three or more antihypertensive medication classes or, regardless of blood pressure level, being on four or more antihypertensive medication classes.19 Antihypertensive medication classes were coded from the in-home medication inventory and defined using classes in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).25–27 The classes included angiotensin-converting enzyme inhibitors, aldosterone receptor blockers, α-blockers, angiotensin receptor blockers, β-blockers, calcium channel blockers, central-acting agents, diuretics, and direct vasodilators. One-pill combinations were coded into multiple medication classes.26 Medication adherence was assessed using the 4-item Morisky Medication Adherence Scale, with a score of 0 indicating perfect adherence.28
Assessment of Stroke/Transient Ischemic Attack Status
History of stroke or transient ischemic attack was characterized using the question, “Were you ever told by a physician that you had a mini-stroke or TIA, also known as a transient ischemic attack?” and same question asking about stroke. Participants were categorized as no history of stroke or transient ischemic attack, transient ischemic attack only, stroke (with or without transient ischemic attack), and the combined category of stroke or transient ischemic attack.
Covariates
Age, race, sex, education, annual household income, smoking, alcohol use, physical activity, and duration of hypertension (calculated in years, based on response to question: how old were you when you were first told that you have high blood pressure?) were defined by self-report. Physical activity level was defined by response to the question “How many times per week do you engage in intense physical activity, enough to work up a sweat?” categorized as 4 or more times per week, 1–3 times a week or none. History of myocardial infarction was defined by self-report or evidence from study electrocardiogram. Diabetes was defined as fasting glucose level ≥ 126 ml/dL (or ≥ 200 ml/dL if participant was non-fasting), or self-reported medication use for glucose control. Statin use was obtained from medication inventory. High sensitivity C-reactive protein (CRP), total cholesterol, and high density lipoprotein (HDL) cholesterol were measured centrally. CRP was analyzed in batches by particle- enhanced immunonephelometry using the BNII nephelometer (N High Sensitivity CRP; Dade Behring, Deerfield, IL) with interassay coefficients of variation of 2.1–5.7%. Total cholesterol, HDL and glucose were measured by colorimetric reflectance spectrophotometry using the Ortho Vitros Clinical Chemistry System 950IRC instrument (Johnson & Johnson Clinical Diagnostics, Rochester, NY). 23 The isotope-dilution mass spectrometry-traceable serum creatinine method was used to estimate glomerular filtration rate (eGFR) with the Chronic Kidney Disease Epidemiology Collaboration equation.29 Urinary albumin was measured with the BN ProSpec Nephelometer from Dade Behring (Marburg, Germany) and urinary creatinine was measured with a rate-blanked Jaffé procedure, using the Modular-P analyzer (Roche/Hitachi; Indianapolis, IN). Albumin-to-creatinine ratio (ACR) was categorized as < 30 or ≥ 30 mg/g.
Statistical Analyses
Characteristics of participants and prevalence of apparent treatment-resistant hypertension were calculated for participants with no history of stroke or transient ischemic attack, history of transient ischemic attack alone, history of stroke (with or without transient ischemic attack), and history of stroke or transient ischemic attack. Poisson regression was used to calculate the crude and multivariable-adjusted prevalence ratios (PR) of apparent treatment-resistant hypertension by stroke/transient ischemic attack status. The initial model adjusted for age, race, and sex. A second model additionally adjusted for geographic region (stroke belt, buckle, or other), education, income, physical activity, smoking, alcohol use, waist circumference, diabetes, total cholesterol, HDL-cholesterol, statin use, CRP, history of myocardial infarction, and duration of hypertension. The final model added eGFR and ACR (log transformed). Four sensitivity analyses were conducted: (1) restricted to participants with perfect medication adherence, (2) including participants with uncontrolled blood pressure on 1–2 antihypertensive medication classes, (3) using an alternative definition of apparent treatment-resistant hypertension that excluded individuals that met the definition of apparent treatment-resistant hypertension that were not on a diuretic, and (4) because blacks may have low-renin hypertension and be more responsive to treatment with a diuretic, analysis was repeated only for those on a diuretic.
Results
Among participants who were treated for hypertension, 18.2% (2,130/11,719) had apparent treatment-resistant hypertension. There was a monotonic increase in prevalence of apparent treatment-resistant hypertension across the stroke/transient ischemic attack spectrum: 17.0% among persons with negative history, 22.8% in those with transient ischemic attack only, and 26.0% in those with stroke (Table 1.) As expected, participants with history of stroke or transient ischemic attack had a poorer cardiovascular risk profile (i.e., lower household income, more likely to be smokers, less physically active, have diabetes, and history of myocardial infarction than those without such a history (Table 1.)
Table 1.
Characteristics of REGARDS hypertensiveparticipants by history of stroke or transient ischemic attack, N=11,719
| Characteristic | No history of stroke or transient ischemic attack (n=10,025) | History of transient ischemic attack only (n=596) | History of stroke, with or without transient ischemic attack (n=1,098) | p-value |
|---|---|---|---|---|
|
| ||||
| Age, years | 65.7 (8.9) | 69.4 (9.0) | 68.1 (8.8) | <0.001 |
|
| ||||
| Men, n (%) | 4,195 (41.8) | 233 (39.1) | 534 (48.6) | <0.001 |
|
| ||||
| Black race, n (%) | 4,957 (49.5) | 256 (43.0) | 607 (55.3) | <0.001 |
|
| ||||
| Region, n (%) | ||||
| Non-belt | 4,276 (42.7) | 275 (46.1) | 498 (45.4) | 0.225 |
| Belt | 3,532 (35.2) | 197 (33.1) | 376 (34.2) | |
| Buckle | 2,217 (22.1) | 124 (20.8) | 224 (20.4) | |
|
| ||||
| Income <$20,000, n (%) | 1,961 (19.6) | 137 (23.0) | 330 (30.1) | <0.001 |
|
| ||||
| Less than high school education, n (%) | 1,399 (14.0) | 107 (18.0) | 253 (23.1) | <0.001 |
|
| ||||
| Waist circumference, cm | 99.2 (15.6) | 98.8 (15.4) | 99.8 (16.0) | 0.340 |
|
| ||||
| Current smoking, n (%) | 1,261 (12.6) | 78 (13.1) | 185 (16.9) | <0.001 |
|
| ||||
| Current alcohol use, n (%) | 3,358 (34.2) | 167 (28.5) | 279 (25.8) | <0.001 |
|
| ||||
| Physical activity, n (%) | ||||
| None | 3,666 (37.0) | 264 (45.0) | 529 (49.2) | <0.001 |
| 1–3 times per week | 3,551 (35.9) | 198 (33.7) | 301 (28.0) | |
| 4+ times per week | 2,678 (27.1) | 125 (21.3) | 245 (22.8) | |
|
| ||||
| Duration of hypertension, years | 11.0 (5.0, 22.0) | 15.0 (7.0, 25.0) | 15.0 (7.0, 26.0) | <0.001 |
|
| ||||
| Diabetes, n (%) | 2,875 (29.7) | 217 (37.8) | 425 (40.4) | <0.001 |
|
| ||||
| History of myocardial infarction, n (%) | 1,484 (15.1) | 149 (25.7) | 315 (29.4) | <0.001 |
|
| ||||
| Statin use, n (%) | 4,222 (42.1) | 289 (48.5) | 625 (56.9) | <0.001 |
|
| ||||
| Total cholesterol, mg/dL | 186.1 (39.0) | 182.2 (40.3) | 180.4 (41.9) | <0.001 |
|
| ||||
| HDL-cholesterol, mg/dL | 50.6 (15.7) | 49.3 (14.4) | 48.4 (14.9) | <0.001 |
|
| ||||
| C-reactive protein, mg/L | 2.6 (1.2, 6.0) | 2.5 (1.1, 6.2) | 2.8 (1.2, 6.3) | 0.241 |
|
| ||||
| eGFR, mL/min/1.73m2 | 81.7 (21.8) | 75.7 (23.2) | 74.7 (23.6) | <0.001 |
|
| ||||
| Albumin-to-creatinine ratio, mg/g | 8.0 (4.9, 17.9) | 10.2 (5.5, 26.6) | 12.8 (6.0, 39.4) | <0.001 |
|
| ||||
| Systolic blood pressure, mmHg | 126.4 (13.7) | 127.9 (14.8) | 128.5 (15.6) | <0.001 |
|
| ||||
| Diastolic blood pressure, mmHg | 75.8 (8.7) | 74.6 (9.0) | 75.4 (9.6) | 0.032 |
|
| ||||
| 2 or more prior strokes*, n (%) | --- | --- | 275 (25.6) | --- |
|
| ||||
| Apparent treatment-resistant hypertension, n (%) | 1,708 (17.0) | 136 (22.8) | 286 (26.0) | <0.001 |
|
| ||||
| Diuretic use, n (%) | 5,785 (57.7) | 370 (62.1) | 643 (58.6) | 0.102 |
|
| ||||
| Beta blocker use, n (%) | 3,786 (37.8) | 282 (47.3) | 529 (48.2) | <0.001 |
|
| ||||
| Calcium channel blocker use, n (%) | 3,907 (39.0) | 265 (44.5) | 520 (47.4) | <0.001 |
|
| ||||
| ACE inhibitor use, n (%) | 4,291 (42.8) | 255 (42.8) | 539 (49.1) | <0.001 |
|
| ||||
| ARB use, n (%) | 2,758 (27.5) | 163 (27.4) | 290 (26.4) | 0.740 |
|
| ||||
| Alpha blocker use, n (%) | 627 (6.3) | 33 (5.5) | 102 (9.3) | <0.001 |
|
| ||||
| Aldosterone antagonist use, n (%) | 231 (2.3) | 16 (2.7) | 37 (3.4) | 0.085 |
|
| ||||
| Vasodilator use, n (%) | 69 (0.7) | 5 (0.8) | 22 (2.0) | <0.001 |
|
| ||||
| Central acting agent use, n (%) | 38 (0.4) | 4 (0.7) | 5 (0.5) | 0.524 |
|
| ||||
| Number of antihypertensive medication classes being taken, n (%) | ||||
| 0 | 0 (0) | 0 (0) | 0 (0) | --- |
| 1 | 3,044 (30.4) | 144 (24.2) | 246 (22.4) | <0.001 |
| 2 | 3,563 (35.5) | 192 (32.2) | 323 (29.4) | <0.001 |
| 3 | 2,502 (25.0) | 183 (30.7) | 362 (33.0) | <0.001 |
| 4 | 775 (7.7) | 69 (11.6) | 130 (11.8) | <0.001 |
| 5+ | 141 (1.4) | 8 (1.3) | 37 (3.4) | <0.001 |
HDL: high density lipoprotein; eGFR: estimated glomerular filtration rate; ACE: angiotensin converting enzyme; ARB: angiotensin receptor blocker
Numbers are mean (standard deviation) or number (percent), except for duration of hypertension, c-reactive protein, and albumin-to-creatinine ratio, which are presented as median (25th percentile, 75th percentile).
limited to individuals with a history of stroke
After adjustment for age, race, and sex, compared to those with no history of stroke or transient ischemic attack, participants with history of transient ischemic attack were 31% (PR=1.31; 95% CI: 1.12–1.52) more likely to have apparent treatment-resistant hypertension, and those with a history of stroke were 36% (PR=1.36; 95% CI: 1.22–1.52) more likely to have apparent treatment-resistant hypertension (Table 2). Adjustment for risk factors attenuated this increased risk to 15% (PR = 1.15; 95% CI: 0.97–1.36) for those with transient ischemic attack alone, and to 18% (PR = 1.18; 95% CI: 1.05 – 1.33) for those with history of stroke. Further adjustment for measures of kidney function (eGFR and ACR) attenuated the excess to 13% (PR=1.13; 95% CI: 0.96 – 1.34 for history of transient ischemic attack only and PR=1.13; 95% CI 1.00 – 1.27 for history of stroke). In the fully adjusted model, participants in the combined group of stroke or transient ischemic attack were 14% (PR=1.14; 95% CI: 1.03 – 1.27) more likely to have apparent treatment-resistant hypertension than those with no history of stroke or transient ischemic attack.
Table 2.
Prevalence ratios (and 95% confidence intervals) for apparent treatment-resistant hypertension associated with history of TIA, history of stroke, and history of combined stroke or TIA among REGARDS study participants.
| n | Crude prevalence ratio (95% CI) | Age, race, sex-adjusted prevalence ratio (95% CI) | + adjustment for stroke risk factors† prevalence ratio (95% CI) | + adjustment for measures of kidney function‡ prevalence ratio (95% CI) | ||
|---|---|---|---|---|---|---|
| Mutually exclusive symptomatic strata | No History of Stroke or transient ischemic attack | 10,025 | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) | 1.00 (ref) |
| History of transient ischemic attack only | 596 | 1.34 (1.15, 1.56) | 1.31 (1.12, 1.52) | 1.15 (0.97, 1.36) | 1.13 (0.96, 1.34) | |
| History of stroke (with or without transient ischemic attack) | 1,098 | 1.50 (1.35, 1.67) | 1.36 (1.22, 1.52) | 1.18 (1.05, 1.33) | 1.13 (1.00, 1.27) | |
| History of stroke or transient ischemic attack combined (relative to no history of stroke/transient ischemic attack) | 1,694 | 1.46 (1.33, 1.61) | 1.37 (1.24, 1.50) | 1.18 (1.07, 1.31) | 1.14 (1.03, 1.27) | |
CI: confidence interval
Adjusted for age, race, sex, geographic region of residence, education, income, physical activity, current smoking, alcohol use, waist circumference, diabetes, total cholesterol, high-density lipoprotein cholesterol, statin use, c-reactive protein, history of myocardial infarction, and duration of hypertension.
Adjusted for model above, plus estimated glomerular filtration rate, and albumin-to-creatinine ratio (log transformed).
Among the 1,694 participants with history of stroke or transient ischemic attack treated for hypertension, after age and race adjustment, being a man was associated with higher PR for apparent treatment-resistant hypertension (PR = 1.29; 95% CI: 1.09 – 1.52; Table 3.) Additionally, after age and sex adjustment, black race was associated with a higher PR for apparent treatment-resistant hypertension (PR = 1.62; 95% CI: 1.36 – 1.93). After adjustment for age, race, and sex, larger waist circumference, longer duration of hypertension, diabetes, history of myocardial infarction, statin use, eGFR < 60 mL/min/1.73m2, and ACR ≥ 30 mg/g were each associated with a higher PR for apparent treatment-resistant hypertension. The prevalence of apparent treatment-resistant hypertension decreased monotonically with increasing levels of physical activity. After multivariable adjustment, being a man remained associated with a higher PR for apparent treatment-resistant hypertension, as well as black race, larger waist circumference, longer duration of hypertension, and eGFR < 60 mL/min/1.73m2, and ACR ≥ 30 mg/g.
Table 3.
Prevalence ratios for apparent treatment-resistant hypertension associated with study covariates among REGARDS study participants with history of stroke or transient ischemic attack
| Age, race, sex-adjusted prevalence ratio (95% CI) | Multivariable-adjusted‡ prevalence ratio (95% CI) | |
|---|---|---|
|
| ||
| Age, per 10 years | 1.07 (0.97, 1.18) | 0.97 (0.86, 1.09) |
|
| ||
| Men | 1.29 (1.09, 1.52) | 1.23 (1.01, 1.49) |
|
| ||
| Black race | 1.62 (1.36, 1.93) | 1.34 (1.10, 1.63) |
|
| ||
| Region | ||
| Nonbelt | 1 (ref) | 1 (ref) |
| Belt | 1.05 (0.87, 1.26) | 1.07 (0.88, 1.32) |
| Buckle | 1.10 (0.88, 1.37) | 1.05 (0.84, 1.32) |
|
| ||
| Income <$20,000 | 1.03 (0.86, 1.24) | 0.98 (0.81, 1.19) |
|
| ||
| Less than high school education | 1.09 (0.90, 1.32) | 1.13 (0.92, 1.38) |
|
| ||
| Waist circumference, per 15 cm | 1.28 (1.18, 1.38) | 1.21 (1.11, 1.33) |
|
| ||
| Duration of hypertension, per 10 years | 1.19 (1.13, 1.26) | 1.18 (1.11, 1.26) |
|
| ||
| Diabetes | 1.59 (1.34, 1.88) | 1.18 (0.97, 1.43) |
|
| ||
| Current smoking | 0.80 (0.62, 1.02) | 0.86 (0.65, 1.13) |
|
| ||
| Alcohol use | 0.94 (0.77, 1.14) | 1.00 (0.80, 1.24) |
|
| ||
| Physical activity | ||
| None | 1 (ref) | 1 (ref) |
| 1–3 times per week | 0.82 (0.67, 0.99) | 0.88 (0.72, 1.09) |
| 4+ times per week | 0.74 (0.59, 0.94) | 0.86 (0.67, 1.09) |
|
| ||
| History of myocardial infarction | 1.27 (1.06, 1.51) | 1.10 (0.91, 1.33) |
|
| ||
| Statin use | 1.31 (1.11, 1.55) | 1.19 (0.97, 1.45) |
|
| ||
| Total cholesterol, per 40 mg/dL | 0.98 (0.91, 1.07) | 1.06 (0.96, 1.15) |
|
| ||
| HDL-cholesterol, per 15 mg/dL | 0.93 (0.84, 1.02) | 1.01 (0.91, 1.13) |
|
| ||
| C-reactive protein > 3 mg/L | 1.09 (0.91, 1.29) | 0.93 (0.78, 1.12) |
|
| ||
| eGFR < 60 mL/min/1.73m2 | 1.47 (1.24, 1.75) | 1.39 (1.15, 1.68) |
|
| ||
| Albumin-to-creatinine ratio ≥ 30 mg/g | 1.78 (1.51, 2.09) | 1.48 (1.23, 1.79) |
CI: confidence interval
Adjusted for age, race, sex, geographic region of residence, income, education, physical activity, current smoking, alcohol use, waist circumference, diabetes, total cholesterol, high-density lipoprotein cholesterol, statin use, c-reactive protein, history of myocardial infarction, duration of hypertension, estimated glomerular filtration rate, and albumin-to-creatinine ratio (log transformed).
Sensitivity Analyses
The results were markedly similar when restricted to 9,912 participants reporting perfect medication adherence (Table e-1). After multivariable adjustment, participants with history of stroke or transient ischemic attack were 14% (PR=1.14; 95% CI: 0.99 – 1.30) more likely to have apparent treatment-resistant hypertension than those with no history of stroke/transient ischemic attack. Including participants with uncontrolled blood pressure on one or two classes of antihypertensive medications (n=14,673) did not change the results substantially (Table e-2). Using the alternative definition of apparent treatment-resistant hypertension (excluding individuals that met the definition of apparent treatment-resistant hypertension who were not on a diuretic), the results remained statistically significant; participants with history of stroke/transient ischemic attack were 18% (PR=1.18; 95% CI: 1.05 – 1.32) more likely to have apparent treatment-resistant hypertension than those with no history of stroke/transient ischemic attack (Table e-3). Finally, restriction of analysis to those with treatment including a diuretic reduced the likelihood of black participants having apparent treatment resistant hypertension, with the age-race-sex adjusted PR decreasing from 1.62 (CI: 1.09 – 1.52) to 1.30 (CI 1.10 – 1.54), and the multivariable adjusted PR decreasing from 1.34 (CI: 1.10 – 1.63) to 1.15 (0.94 – 1.39) (Table e-4).
Discussion
Treatment and control of hypertension has long been recognized as among the most important goals in secondary stroke prevention.8,30–32 Our results suggest that the prevalence of apparent treatment-resistant hypertension is higher among those with TIA than their counterparts without a history of TIA/stroke and higher still among those with a history of stroke. While the goal of BP control among those with cerebrovascular symptoms is important, achieving that goal in individuals following stroke has been shown to be particularly challenging.5,11–15,33 In addition, among those with stroke or TIA, there are groups of individuals with particularly high prevalence of apparent treatment-resistant hypertension including blacks (with 34% increased prevalence ratio), men (with a 23% increase), and those with evidence of kidney disease (a 48% increase among those with ACR ≥ 30 mg/g, and a 39% increase among those with an eGFR < 60). Smaller (but still statistically significant) increases in the prevalence of apparent treatment-resistant hypertension were observed among those with less regular physical activity, those with larger waist size, and those with longer duration of hypertension. These findings suggest that a diagnosis of apparent treatment-resistant hypertension may be particularly appropriate for further diagnostic evaluations and more intensive monitoring to meet blood pressure targets.
Because of the cross-sectional nature of these data, the direction of causation between the apparent treatment-resistant hypertension and the stroke event cannot be determined (i.e., whether the higher prevalence of apparent treatment-resistant hypertension is a product of the stroke, or the stroke was a product of previously existing apparent treatment-resistant hypertension). However, because hypertension is such a powerful risk factor for stroke, one could presume that the difficult- to-control hypertension existed prior to the stroke event. If this is the case, then the difficult-to-control hypertension contributed to the stroke event and the higher prevalence of resistant hypertension likely places the stroke survivor at continued higher risk for subsequent stroke and other vascular events. Whether apparent treatment-resistant hypertension plays a differential role in recurrent stroke risk separate from hypertension that is easier to control is currently being investigated using data from the REGARDS cohort.
Our results are similar to those from the large Kaiser Permanente Southern California health system. They show a 21.0% prevalence of apparent treatment-resistant hypertension in 49,081 individuals with confirmed cerebrovascular disease (by ICD-9 codes), and after multivariable adjustment for risk factors, a 17% (95% CI: 1.13, 1.22) increased risk of having resistant hypertension. 34 Within all persons with resistant hypertension, after multivariable adjustment, they found increased risk for age (per 5-years), men, blacks, and persons with BMI ≥ 30 kg/m2, eGFR < 60 mL/min/1.73 m2, diabetes, ischemic heart disease, and congestive heart failure,34 very similar to the factors we found within our cohort of individuals with stroke/TIA history. They reported that, in general, all individuals with resistant hypertension had better adherence to antihypertensive medications than those without resistant hypertension. Our study extends this report by the use of a national, population-based study and identifying factors associated with apparent treatment-resistant hypertension specific to persons with a history of stroke and TIA.
Hypertension control rates in secondary stroke prevention studies have ranged from 30% to 67% over time periods ranging from six months to five years post-stroke.4,5,11–15,33 Reasons for uncontrolled hypertension are multifaceted and involve the individual patient, the health-care providers, and the health-care system. Individual reasons for lack of control in persons being treated for hypertension include patient noncompliance, inadequate therapy, and inappropriate therapy, with the latter two linked to potential for apparent treatment-resistant hypertension. Failure to diagnosis and manage apparent treatment-resistant hypertension may be contributing to stroke recurrence rates as well as rates of incident stroke. That persons of African ancestry are more likely to have apparent treatment-resistant hypertension and specific associated pathophysiology of hypertension, i.e., low-renin hypertension, etc. has been suggested as a major contributor to the black-white stroke disparity.35 Therefore, especially in blacks, it is recommended that physicians take an individualized approach to assess and manage BP levels, including additional diagnostic evaluations including measurement of plasma renin, aldosterone changing medications and incorporating advice related to lifestyle changes. 19,36 The supplemental analysis restricted to those on diuretic medication showed a substantial mediation of the risk in blacks, suggesting that treatment with diuretics may be a key to this individualized approach.
There are several strengths and limitations to our study. REGARDS is a geographically and socioeconomically diverse study of blacks and whites including a large number of participants with a history of physician-diagnosed stroke or transient ischemic attack, and a standardized protocol with stringent quality control for blood pressure and other measurements. Strengths also include that the person conducting the in-home visit did not know the participant’s cerebrovascular history and medications were obtained from inspection of the medication bottles in the participant’s home. The high prevalence of apparent treatment-resistant hypertension may be attributable to nonadherence with treatment but we did not have adherence specific to antihypertensive medications. In REGARDS, however, the majority of all apparent treatment-resistant hypertension individuals indicated being adherent with medication use in general.26 The cross-sectional design of this analysis provides only a one-time assessment of blood pressure but misclassification was minimized because the definition of apparent treatment-resistant hypertension included a combination of measurements, medication inventory, and self-report. We did not rule out pseudoresistant hypertension defined by poor adherence or inadequate BP measurements. Covariates such as eGFR, ACR, and diabetes were also only measured once and others were based on self-report. Important covariates such as heart failure may have been missed. Residual confounding remains a possibility similar to other epidemiological studies. Although history of stroke and transient ischemic attack was self-reported and subject to recall bias, previous work in REGARDS has shown strong associations with these history questions and subsequent stroke risk. 37 Also, another report showed self-report of stroke to have a positive predictive value of 79%, sensitivity of 80%, and specificity of 99%. 38 We do not have information on stroke type, but we would expect that the majority were ischemic and blood pressure recommendations do not vary by stroke subtype.2
In summary, we report that one in four persons with a history of stroke or transient ischemic attack has apparent treatment-resistant hypertension, and we identified subgroups with an even higher prevalence of apparent treatment-resistant hypertension. This suggests the need for more individual blood pressure monitoring and management.
Supplementary Material
Clinical Significance.
Among hypertensive participants with stroke/transient ischemic attack, after multivariable adjustment, male sex, black race, larger waist circumference, longer duration of hypertension, and reduced kidney function were associated with higher prevalence of apparent treatment-resistant hypertension.
Sensitivity analysis of only those participants with a stroke or transient attack whose medications included a diuretic resulted in attenuation of the increased risk of apparent treatment-resistant hypertension for blacks but not whites.
Acknowledgments
Sources of Funding
The REGARDS research project is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, 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 National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis or interpretation of the data. The authors 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 http://www.regardsstudy.org
Footnotes
All co-authors report no disclosures.
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