Abstract
Refractory hypertension is a recently described phenotype of antihypertensive treatment failure defined as uncontrolled blood pressure (BP) despite the use of 5 or more different antihypertensive agents, including chlorthalidone and spironolactone. Recent studies indicate that refractory hypertension is uncommon, with a prevalence of approximately 5-10% of patients referred to a hypertension specialty clinic for uncontrolled hypertension. The prevalence of white coat effect i.e. uncontrolled automated office BP (AOBP) ≥135/85 mmHg and controlled out-of-office BP <135/85 mmHg by awake ambulatory BP monitor (ABPM) in hypertensive patients overall is approximately 30-40%. The prevalence of white coat effect among patients with refractory hypertension has not been previously reported.
In this prospective evaluation, consecutive patients referred to University of Alabama at Birmingham (UAB) Hypertension Clinic for uncontrolled hypertension were enrolled. Refractory hypertension was defined as uncontrolled AOBP ≥135/85 mmHg with use of 5 or more antihypertensive agents, including chlorthalidone and spironolactone. AOBP measurements were based on 6 serial readings, done automatically with use of a BpTRU device unobserved in clinic. Out-of-office BP measurements were done by 24-hr ABPM.
Thirty-four patients were diagnosed with refractory hypertension, of whom 31 had adequate ABPM readings. White coat effect was present in only two patients, or 6.5% of the 31 patients with refractory hypertension, suggesting that white coat effect is largely absent from patients with refractory hypertension. These findings suggest that white coat effect is not a common cause of apparent lack of BP control in patients failing maximal antihypertensive treatment.
Keywords: refractory hypertension, white coat effect, ambulatory blood pressure monitoring
Introduction
Resistant hypertension (RHTN) is defined as uncontrolled BP despite use of effective doses of 3 or more different classes of antihypertensive medications, including a diuretic. Controlled RHTN refers to patients whose BP is controlled with use of 4 or more antihypertensive agents 1.
Recently, the term refractory hypertension has been applied to an extreme phenotype of antihypertensive treatment failure defined as lack of BP control in spite of use of 5 or more antihypertensive medications. Typically, these patients are treated with maximal recommended doses of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, a calcium channel blocker (typically amlodipine), a thiazide-type diuretic (typically chlorthalidone) and an aldosterone antagonist (spironolactone or eplerenone). Other medications that may be used include combined α– and β-antagonists (e.g., labetalol), centrally acting α2-adrenergic agonists (e.g., clonidine or guanfacine) and direct vasodilators (e.g., minoxidil or hydralazine). Loop diuretics are usually reserved for patients with clinical evidence of fluid retention, advanced chronic kidney disease or heart failure 2-4.
Recent cross-sectional analyses have found that refractory hypertension is rare, with a prevalence of 5-10% of patients referred to hypertension specialty clinics for uncontrolled hypertension 2-4. Patients with refractory hypertension are more likely to be of African descent and female, compared to patients with controlled RHTN or controlled non-resistant hypertension 2,4. Patients with refractory hypertension have higher rates of cardiovascular complications, including stroke, left ventricular hypertrophy, and congestive heart failure compared to patients with controlled RHTN 3.
White coat effect is defined as uncontrolled office BP, but controlled out-of-office BP, preferably ascertained by awake readings on ABPM. Multiple studies indicate that white coat effect is common (30-60% prevalence) in patients with RHTN 5-7. The white coat effect is one of the most common causes of pseudo-resistance to antihypertensive treatment, in addition to medication non-adherence, poor BP measurement technique, and under-treatment 5-7.
The prevalence of white coat effect has not been previously reported in patients with refractory hypertension, i.e., patients failing maximum antihypertensive treatment based on office BP measurement. Given the high prevalence of white coat effect in RHTN, it was hypothesized that white coat effect in refractory hypertension would also be common.
Methods
Study Population
Consecutive patients were prospectively recruited between April 2014 and March 2017 from those referred to the UAB Hypertension Clinic for uncontrolled RHTN. The patients were evaluated for secondary causes of hypertension, including hyperaldosteronism, pheochromocytoma, and renal artery stenosis as clinically indicated. Patients were eligible for enrollment if their automated office BP (AOBP) remained elevated ≥135/85 mm Hg after having been seen by a hypertension specialist for a minimum of 3 follow-up visits and after having been prescribed at least 5 antihypertensive agents from different classes, including chlorthalidone and spironolactone. Exclusions included patients with suspected non-adherence based on self-report or low medication refill rates, chronic kidney disease (CKD) stage 4 or 5 (eGFR <30 ml/min/1.73m2) or pregnancy. The study was approved by the UAB Institutional Review Board, and written informed consent was obtained from all participants.
Automated Office BP Measurement
AOBP was measured after at least 5 minutes of quiet rest in a sitting position with the back supported and the arm supported at heart level 8. The office BP was measured using the BpTRU device, which automatically obtains 6 serial BP readings, one minute apart, before displaying the average of the last 5 readings. All BpTRU assessments were unattended, i.e., unobserved in clinic 9-13. An appropriate sized cuff was used with a cuff bladder encircling at least 80% of the arm 13,14. A BP cutoff of ≥ 135/85 mmHg for elevated BP was used based on recent literature validating automated BP devices 15,16. Serial, automated, unattended BP measurements, as with the BpTRU device, have been shown to minimize white coat effects 15-17.
Attended Office BP Measurement
Office BP measurements were also done for all study subjects as part of the research protocol. These assessments were done as a single, attended reading, using an automated device, with the patient seated.
24-hr Ambulatory Blood Pressure Monitoring (ABPM)
An automated, noninvasive, oscillometric device (Oscar 2; Suntech Medical Inc, Morrisville, NC) was used to perform ABPM 18,19. Recordings were made every 20 minutes during the daytime (awake) and every 30 minutes during the nighttime (asleep) phases of the 24-hr period. Awake and asleep times were determined by patient self-report. All patients were counselled to take all antihypertensive medications during ABPM period. ABPM was determined to be valid if >80% of measurements were successful. Controlled ABPM was defined as mean daytime (awake) BP <135/80 mmHg, mean 24-hr BP <130/80 mmHg, and mean nighttime (asleep) BP of 120/70 mmHg 18,19.
Statistical Analysis
Descriptive data are expressed as mean ± SD for normally distributed variables and median (interquartile range) for non-normal data. Categorical variables are expressed as number (percent). Data analysis was carried out using SAS version 9.3 (SAS Institute Inc; Cary, NC).
Results
Thirty-four subjects were enrolled. Of these, 31 subjects had valid ABPM readings and were included in the final analysis (Figure 1).
Figure 1. Schematic of enrolled study participants.
Baseline Characteristics
The mean age of the evaluated subjects was 53.7±9.5 years; 70.6% were female and 79.4% were African American. Patients were generally obese with a median BMI of 35.3±7.3 kg/m2. Overall, 47.1% had been diagnosed with diabetes and 41.2% had known obstructive sleep apnea (Table 1).
Table 1. Baseline characteristics of patients with refractory hypertension (n=31).
| Mean ± SD | |
|---|---|
|
|
|
| Demographics | |
| Age (years) | 53.7 ± 9.5 |
| Female | 24 (70.6%) |
| African American | 27 (79.4%) |
| Number of BP Medications | 6 (5-6)* |
| Comorbidities | |
| Current smoker | 6 (17.6%) |
| Dyslipidemia | 18 (52.9%) |
| Congestive heart failure | 9 (26.5%) |
| Coronary artery disease | 8 (23.5%) |
| Peripheral vascular disease | 5 (14.7%) |
| Diabetes | 16 (47.1%) |
| Prior stroke/transient ischemic attack | 7 (20.6%) |
| Obstructive sleep apnea | 19 (55.9%) |
| Chronic obstructive pulmonary disease | 8 (24.2%) |
| Hypertension History | |
| Age at hypertension diagnosed (years) | 36.1±13.3 |
| Parents with hypertension (%) | 63.6±38.1 |
| Siblings with hypertension (%) | 42.5±42.2 |
| Clinic Measurements | |
| Body mass index (kg/m2) | 35.3±7.3 |
| Automated Office BP* (AOBP) | |
| Systolic BP (mmHg) | 159.0±23.3 |
| Diastolic BP (mmHg) | 94.0±13.8 |
| Heart rate (bpm†) | 75.1±13.3 |
| Office BP* | |
| Systolic BP (mmHg) | 166.4±26.6 |
| Diastolic BP (mmHg) | 99.5±16.5 |
| Heart rate (bpm) | 74.9±15.1 |
| Biochemical | |
| Sodium (mMol/L) | 137.8±2.8 |
| Potassium (mMol/L) | 4.0±0.5 |
| Bicarbonate (mMol/L) | 27.3±3.1 |
| Blood urea nitrogen (mg/dL) | 15.6±7.9 |
| Serum creatinine (mg/dL) | 1.1±0.4 |
| eGFR by MDRD‡ (ml/min/1.73 m2) | 56.7±6.4 |
| Serum aldosterone (ng/dL) | 8.9±6.6 |
| Plasma renin activity (ng/mL/hr) | 2.1±3.0 |
median (interquartile range);
bpm, beats per minute;
MDRD, modification of diet in renal disease
Biochemical Evaluation
Serum electrolytes, creatinine, aldosterone and plasma renin activity were generally within normal range. (Table1).
Automated Office BP Measurement
The mean office BP reading obtained with the BpTRU device after 5-minutes rest was 159.0±23.3 / 94.0±13.8 mmHg. The mean office heart rate during BpTRU measurement was 75.1±13.3 beats/min (Table 1).
Attended Office BP Measurement
The mean attended BP was 166.4±26.6 / 99.5±16.5 mmHg. The mean attended office heart rate was 74.9±15.1 beats/min (Table 1).
White Coat Effect
Of the 31 evaluated subjects with refractory hypertension, a significant white coat effect was present in two subjects (6.5%) based on an uncontrolled AOBP ≥135/85 mmHg or office BP measurement ≥140/90 mmHg and a controlled, awake (daytime) ambulatory BP <135/85 mmHg. The same prevalence of 2 out of 31 subjects was observed if an overall 24-hr ABPM <130/80 mmHg or asleep (nighttime) ambulatory BP <120/70 mmHg was applied to define out-of-office BP control (Figure 1).
24-hr ABPM Profiles
The mean awake (daytime) ABP for all participants was 166.6±22.6 / 95.7±16.5 mmHg; the mean 24-hr ABP was 162.0±23.3 / 91.9±15.0 mmHg, and the mean asleep (nighttime) ABP was 154.3±24.5 / 85.3±15.1 mmHg (Table 2). Of the 31 evaluated patients with refractory hypertension, 29 (93.5%) had nocturnal hypertension, i.e. asleep (nighttime) ABP ≥120/70 mmHg. Patients were also analyzed for dipping patterns. Dipping was defined as a decrease in BP exceeding 10% of mean daytime values during sleep 20. There are four dipping categories for calculating SBP dipping, i.e., 1 - night-time SBP/ (day-time SBP) × 100. The categories are: reverse dippers <0%, non-dippers 0% - 10%, dippers 10%-20%, and extreme dippers >20% 21. In the current study, nine patients (29%) had nocturnal dipping >10%. Of these, seven patients or 22.5% were dippers and two or 6.5% had extreme dipping. Twenty-two patients or 71% had a non-dipping pattern. Of these, eighteen patients or 58.1% were non-dippers; four patients or 12.9% had a higher nocturnal BP than daytime BP (i.e., reverse dipping) (Table 2).
Table 2. ABPM values of patients with refractory hypertension (n=31).
| Mean ± SD | |
|---|---|
|
|
|
| ABPM* summary | |
| 24-hr systolic BP (mmHg) | 162.0 ± 23.3 |
| 24-hr diastolic BP (mmHg) | 91.9 ± 15.0 |
| 24-hr heart rate (beats/minute) | 73.5 ± 10.8 |
| 24-hr mean arterial pressure (mmHg) | 115.7 ± 16.4 |
| Awake (Daytime) systolic BP (mmHg) | 166.6 ± 22.6 |
| Awake (Daytime) diastolic BP (mmHg) | 95.7 ± 16.5 |
| Awake (Daytime) heart rate (beats/minute) | 75.0 ± 11.1 |
| Awake mean arterial pressure (mmHg) | 119.8 ± 17.1 |
| Asleep (Nighttime) systolic BP (mmHg) | 154.3 ± 24.5 |
| Asleep (Nighttime) diastolic BP (mmHg) | 85.3 ± 15.1 |
| Asleep (Nighttime) heart rate (beats/minute) | 70.4 ± 12.3 |
| Asleep mean arterial pressure (mmHg) | 108.8 ± 16.5 |
| Dipping n (%) | |
| Reverse dipper (<0%) | 4 (12.9%) |
| Non-dipper (0-10%) | 18 (58.1%) |
| Dipper (10-20%) | 7 (22.6%) |
| Extreme dipper (>20%) | 2 (6.5%) |
| BP† Surge | |
| Evening systolic BP (mmHg) | 167.6 ± 27.7 |
| Lowest asleep systolic BP (mmHg) | 142.4 ± 24.5 |
| Preawake systolic BP (mmHg) | 162.1 ± 31.9 |
| Pre rising supine BP (mmHg) | 149.1 ± 31.6 |
| Morning systolic BP on rising (mmHg) | 163.2 ± 29.9 |
| Morning systolic BP (mmHg) | 164.3 ± 26.6 |
| Nocturnal hypertension† n (%) | 29 (93.5%) |
| Sleep trough systolic BP surge‡ (mmHg) | 21.6 ± 19.7 |
| Pre waking systolic BP surge§ (mmHg) | 4.3 ± 16.5 |
| Rising systolic BP surge‖ (mmHg) | 7.9 ± 16.5 |
| Morning evening systolic BP difference¶ (mmHg) | -2.8 ± 21.7 |
ABPM, ambulatory blood pressure monitoring;
Nocturnal hypertension defined as an average nighttime BP ≥ 120/≥70 mm Hg
Sleep trough systolic BP surge = morning systolic BP – lowest asleep systolic BP
Pre-waking systolic BP surge = morning systolic BP on rising – pre-awake systolic BP
Rising systolic BP surge = morning systolic BP – evening systolic BP
Morning evening systolic BP difference = morning systolic BP – evening systolic BP
Ambulatory BP measurements were further characterized by specific times in order to evaluate surges of BP. The mean SBP for the evening period (e.g., 2-hour average of four 30-minute BP readings before going to sleep) was 167.6±27.7 mmHg. The lowest asleep SBP (e.g., 1-hour average of the 3 BP readings centered on the lowest nighttime reading) averaged 142.4±24.5 mmHg. Preawake BP (e.g., 2-hour average of 4 BP readings just before wake-up) was 162.1±31.9 mmHg, and pre-rising supine BP (BP in a supine position <30 minutes before rising) was 149.1±31.6 mmHg and the morning systolic BP upon rising was 163.2±29.9 mmHg. Systolic BP for the 2 hours (average of four 30-minute BP readings) just after waking (e.g., morning BP) was 164.3±26.6 mmHg.
Surges of BP are summarized in Table 2. The sleep-trough surge defined as the morning BP minus the lowest asleep BP 22-25 was 21.6±19.7 mmHg. The pre-waking surge defined as the morning BP minus pre-wake BP 22-24 was 4.3±16.5 mmHg. Rising BP surge defined as the morning BP on rising minus pre-rising supine BP was 7.9±16.5 mmHg 26. The evening SBP was higher than the morning SBP with a difference of 2.8±21.7 mmHg (Table 2, Figure 2).
Figure 2. Box plots for ambulatory systolic BP at different times of day.
Boxplot whiskers represent the BP range for the defined time. Median BP denoted by a line, and mean BP denoted by an “◆”.
Evening: 2-hour average of four 30-minute systolic BP readings before going to sleep, Lowest asleep: 1-hour average of the 3 systolic BP readings centered on the lowest nighttime reading
Preawake: 2-hour average of 4 systolic BP readings just before wake-up Rising morning - systolic BP upon rising
Morning: 2 hours average of four 30-minute systolic BP readings just after waking
Discussion
This is the first study to report the prevalence of white coat effect in patients with refractory hypertension, that is, patients failing maximum antihypertensive treatment. The results are unexpected in that a significant white coat effect is largely absent from this group of patients in contrast to the high prevalence of a white coat effect in patients with RHTN and in the general hypertensive population. We also report a higher prevalence of non-dipping nocturnal BP in patients with refractory hypertension than patients with RHTN (71% vs. 65%, respectively) 27. The current findings demonstrate that refractory hypertension, as a phenotype, is distinct from RHTN by ABPM measurement. Patients with refractory hypertension have consistently high office and out-of-office BP levels, including nocturnal hypertension (93.5%).
A prominent white coat effect is common among patients with RHTN, with a prevalence of 20-40%. In a cross-sectional study Muxfeldt et al. reported the prevalence of white coat effect in RHTN as 37% 28. Similarly, de la Sierra et al. reported a prevalence rate of white coat effect of 37.5% in patients with apparent RHTN. 5. Grigoryan et al. determined the prevalence of causes of apparent treatment resistance, including white coat effect, in participants in a study relating BP control to medication adherence 29. Of the 140 patients with RHTN included the analysis, 31 (22%) had controlled BP levels during 24-hr ABPM, i.e. white coat effect. In contrast, the white coat effect was only 6.5% in our study population of patients with refractory hypertension.
Other causes of apparent antihypertensive treatment resistance are non-adherence to prescribed medication, under-treatment, and inaccurate BP measurement. In the Grigoryan study, 20 patients (29%) of the 140 with RHTN were non-adherent with the prescribed medications; 69 patients (49%) were undertreated (receiving less than the maximum doses of prescribed medications), and none were receiving chlorthalidone and/or spironolactone, the recommended diuretic combination for treating uncontrolled RHTN 29,30. Further Jung et al. determined medication adherence among 108 patients referred to a hypertension specialty clinic for RHTN by measuring levels of antihypertensive drugs or their metabolites by liquid chromatography-mass spectrometry 31. After screening out patients with suspected non-adherence, 17 (15%) patients with white coat effect and 15 (14%) with secondary causes of hypertension, 76 patients were tested. Of those, 40 (53%) were determined to be non-adherent, including 23 patients (30%) who were taking none of their prescribed medications. Azizi et al., in a similar fashion, determined medication adherence in 85 persons with RHTN participating in the Renal Denervation for Hypertension trial (DENERHTN) 32. Based on measurement of urinary drug or drug metabolite levels, only 50% of participants were adherent with the provided medicines at 6 months of follow-up.
Under-treatment is also widespread among patients with apparent RHTN. Egan et al. assessed antihypertensive regimens in a large network of primary care clinics in the Southeastern United States 33. Of the over 44,000 patients with RHTN, only 15% were determined to have been prescribed optimal antihypertensive regimens including a diuretic and 2 other medications at 50% or more of the maximum recommended dose. By requiring maximum tolerated doses of 5 different medication classes, which specifically includes chlorthalidone and spironolactone, our study design excluded patients who may have been undertreated. While physician-related treatment inertia can expand the RHTN group, it would not have contributed to the occurrence of refractory hypertension.
Inaccurate BP measurement can contribute to mislabeling blood pressure control in the office. However, the current study limits this effect by performing rigorous office BP assessments. Blood pressure measurements were made according to guidelines and with collection of unattended, serial BP readings using the BpTRU device 15,16. Taken together with the ABPM measurements, nearly all refractory patients had true uncontrolled hypertension, both in and outside of clinic.
Unattended AOBP measurements without a rest period and daytime ambulatory BP values have generally been reported to be similar or, with the former being slightly lower. 34,35. In contrast, unattended systolic AOBP measurements obtained after a rest period, as done in the current study, have been reported to be 7-9 mmHg below daytime ambulatory values 12,36,37. This is consistent with the current findings, in that unattended, automated systolic BP values were, on average, 7.6 mmHg lower than the daytime ambulatory systolic BP values. However, when office BP values (single, attended measurements) were used as the reference BP levels, the prevalence of a prominent white coat effect was the same as with the unattended readings. Therefore, the current findings indicate that patients with refractory hypertension generally have sustained BP levels in and outside of clinic, regardless of whether the clinic BP measurements were done attended or unattended.
One important unknown is the degree of medication adherence in our study population. Poor adherence is a common cause of pseudo-resistance, and could account for the high prevalence of uncontrolled BP by ABPM in our population. In the current study, adherence was monitored by patient self-report and medication refill rates, but clearly, true determination of adherence will require detection of urinary or plasma drug or drug metabolite levels, as has been done in patients with RHTN.
In addition to high awake BPs by ABPM, this cohort of patients with refractory hypertension had high nighttime BP levels, with 93.5% meeting criteria for nocturnal hypertension. Nighttime dipping was seen in only 29% of patients with refractory hypertension, which is substantially lower than the 50-60% prevalence of nocturnal dipping typically observed in patients with RHTN 38,39. Non-dipping has been attributed to failure to suppress nighttime sympathetic output 40. Such an effect in patients with refractory hypertension would be consistent with the findings of Dudenbostel et al. which recently provided evidence of heightened sympathetic activity in patients with refractory hypertension, including at night 4. As refractory patients have higher non-dipping pattern and nocturnal hypertension, they tend to manifest a lower morning BP surge. In addition to the sustained out-of-office BP levels typifying refractory hypertension, i.e., absence of white-coat effects, lack of normal nocturnal BP dipping would further increase cardiovascular risk in this group of patients.
As been observed previously, patients with refractory hypertension were predominantly African American and female. Although speculative, antihypertensive treatment failure may be related, in at least in part, to socioeconomic issues, including socioeconomic stressors, unique to these subgroups that increase sympathetic output and worsen treatment resistance. Prospective studies are needed to evaluate this possibility.
Strengths of the current study include careful evaluation of all patients to rule out secondary causes of hypertension; treatment of patients by hypertension specialists with 5 or more antihypertensive medications at maximal tolerated doses; rigorous assessment of AOBP levels based on serial, unobserved BP measurements; and use of 24-hr APBM for determination of out-of-clinic BP levels. Study weaknesses include the relatively small cohort size and lack of determination of medication adherence by measurement urinary or plasma drug or drug metabolites.
Perspectives
A significant white coat effect is largely absent from patients with refractory hypertension based on careful AOBP measurements. The higher prevalence of nocturnal hypertension confirms that refractory hypertension is a phenotype of sustained antihypertensive treatment failure, both in and out of the office and during day and night time. Such continuous lack of BP control portends increased cardiovascular risk and may reflect mechanisms of antihypertensive treatment failure different from patients presenting with RHTN, but whose BP can be controlled.
Novelty and Significance.
What is new: The prevalance of white coat effect is reported for the first time patients with refractory hypertension, a antihypertensvie treatment failure phenotype.
What is relevant: A low prevalence of white coat effect and a high prevalance of nocturnal hypertension confirm that refractory hypertension is a phenotype of sustained antihypertensive treatment failure, both in and out of the office and also during wakefulness and during sleep. Such continuous lack of BP control portends increased cardiovascular, renal, and cerebrovascular risk.
Summary: A significant white coat effect is largely absent from patients with refractory hypertension which is a novel phenotype of antihypertensive treatment failure.
Acknowledgments
Sources of funding: The research was supported by the National Institutes of Health (NIH R01 HL113004) and the American Heart Association (SFRN 15SFRN2390002).
Footnotes
Conflict of Interest / Disclosures: None
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