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Masked Uncontrolled Hypertension Is Not Attributable to Medication Nonadherence

Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.119.13258Hypertension. 2019;74:652–659

Abstract

Masked uncontrolled hypertension (MUCH) in treated hypertensive patients is defined as controlled automated office blood pressure (BP; <135/85 mm Hg) in-clinic but uncontrolled out-of-clinic BP by ambulatory BP monitoring (awake [daytime] readings ≥135/85 mm Hg or 24-hour readings ≥130/80 mm Hg). To determine whether MUCH is attributable to antihypertensive medication nonadherence. One hundred eighty-four enrolled patients were confirmed to have controlled office BP; of these, 167 patients were with adequate 24-hour ambulatory BP recordings. Of 167 patients, 86 were controlled by in-clinic BP assessment but had uncontrolled ambulatory awake BP, indicative of MUCH. The remaining 81 had controlled in-clinic and ambulatory awake BP, consistent with true controlled hypertension. After exclusion of 9 patients with missing 24-hour urine collections, antihypertensive medication adherence was determined based on the detection of urinary drugs or drug metabolites by high-performance liquid chromatography–tandem mass spectrometry. Of the 81 patients with MUCH, 69 (85.2%) were fully adherent and 12 (14.8%) were partially adherent (fewer medications detected than prescribed). Of the 77 patients with true controlled hypertension, 69 (89.6%) were fully adherent with prescribed antihypertensive medications and 8 (10.4%) were partially adherent. None of the patients in either group were fully nonadherent. There was no statistically significant difference in complete or partial adherence between the MUCH and true controlled groups (P=0.403). Measurement of urinary drug and drug metabolite levels demonstrates a similarly high level of antihypertensive medication adherence in both MUCH and truly controlled hypertensive patients. These findings indicate that MUCH is not attributable to antihypertensive medication nonadherence.

Introduction

See Editorial, pp 497–498

Masked uncontrolled hypertension (MUCH) in treated hypertensive patients is defined as controlled automated office blood pressure (AOBP; <135/85 mm Hg) in-clinic but uncontrolled out-of-clinic blood pressure (BP) by 24-hour ambulatory BP monitoring (ABPM; awake [daytime], ≥135/85 mm Hg or 24 hours, ≥130/80).1 The prevalence of MUCH among treated hypertensive patients has been reported as 30% to 50%,2–5 which is higher than the prevalence estimates of masked hypertension (MH) among untreated hypertensive individuals (8%–20%).2,3,6 According to definitions proposed in the 2017 Hypertension Clinical Practice Guidelines, de la Sierra et al7 estimated the prevalence of MUCH from the Spanish ABPM registry to be ≈66%.1,8 The severity of clinic BP predicts the prevalence of MUCH, as higher clinic systolic BP levels are associated with higher rates of MUCH.9 Prehypertension is also associated with higher prevalence rates of MUCH than in the normotensive population.10 The prevalence of MUCH is also increased in blacks,11,12 the elderly,13 people with diabetes mellitus,3,4,14 chronic kidney disease,4,9,15–18 and kidney transplant recipients.19–21 MUCH has been shown to be a precursor of sustained hypertension.22 In addition, a high prevalence of nocturnal hypertension and nondipping BP is seen in patients with MH.3,23 Patients with obstructive sleep apnea have also been reported to have an increased prevalence of MH.24,25

Patients with MH/MUCH have evidence of higher sympathetic tone compared with those with true controlled hypertension (hypertension controlled in clinic and out of clinic).15,26 In a recent study, we reported that MUCH patients have increased out-of-clinic sympathetic tone compared with true controlled hypertensive patients.27 MUCH patients have also been shown to have higher anxiety based on Spielberger Strait Trait Anxiety Inventory and Beck Depression Inventory.28

In the Spanish ABPM registry, MUCH has recently been shown to have greater all-cause and cardiovascular mortality compared with true controlled hypertension and treated but uncontrolled hypertension.29 A meta-analysis of 6 studies has also reported that MUCH was associated with increased risk of cardiovascular events and all-cause mortality compared with true controlled hypertension.30

Antihypertensive medication nonadherence is common in patients with resistant hypertension (RHTN), contributing importantly to poor BP control.31 Unknown is to what extent MUCH may simply be a consequence of poor medication adherence. The current study tested the hypothesis that MUCH is attributable to low adherence to prescribed antihypertensive agents. To test this hypothesis, we prospectively determined antihypertensive medication adherence in MUCH patients by measurement of 24-hour urinary drug or drug metabolite levels by high-performance liquid chromatography–tandem mass spectrometry (LC-MS/MS). Patients with true controlled hypertension served as controls.

Methods

Study data will be available on request 1 year after completion of the funding grant (April 2021).

Study Population

Patients with AOBP controlled (<135/85 mm Hg) on antihypertensive medications were prospectively recruited from the University of Alabama at Birmingham Hypertension Clinic after having been seen by a hypertension specialist for a minimum of 3 follow-up visits between April 2014 and March 2019. All study patients had been evaluated for secondary causes of hypertension, including hyperaldosteronism, pheochromocytoma, and renal artery stenosis, as medically indicated. Patients with chronic kidney disease stage 4 or 5 (estimated glomerular filtration rate <30 mL/min per 1.73 m2) and pregnancy were excluded. The study was approved by the University of Alabama at Birmingham Institutional Review Board, and written informed consent was obtained from all participants.

BP Measurement

Unattended Clinic AOBP

AOBP in clinic 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.32 The AOBP was measured using the BpTRU device, which automatically obtains 6 serial BP readings, 1 minute apart, before displaying the average of the last 5 readings. All BpTRU assessments were unattended, that is, unobserved in clinic.33–37 An appropriate sized cuff was used with a cuff bladder encircling at least 80% of the arm.37,38 A BP cutoff of <135/85 mm Hg for controlled BP was used validating automated BP devices.6,39

Out-of-Clinic 24-Hour ABPM

An automated, noninvasive, oscillometric device (Oscar 2; Suntech Medical, Inc, Morrisville, NC) was used to perform 24-hour ABPM. Recordings were made every 20 minutes during the awake (daytime) and every 30 minutes during the asleep (nighttime) phases of the 24-hour period. Awake and asleep times were determined by patient self-report. Patients were counseled to take all antihypertensive medications during the ABPM period. ABPM was determined to be valid if >80% of measurements were successful40 including at least 20 awake (daytime) and 7 asleep (nighttime) valid BP measurements.41 Uncontrolled ABPM was defined as mean awake (daytime) BP ≥135/85 mm Hg or as mean 24-hour BP ≥130/80 mm Hg.1,42

Biochemical Analysis

Renal Function Panel

Serum electrolytes, blood urea nitrogen, and creatinine were measured in a hospital laboratory using standard methods.

24-Hour Urine High-Performance LC-MS/MS to Detect Antihypertensive Medication Adherence

In all study patients, 24-hour urine samples were collected. Study patients were advised to be adherent with antihypertensive medications but were not informed that medication adherence was being tested in the collected urine samples to avoid a Hawthorne effect (eg, change in behavior when it is being observed).43 The urine samples were stored, and an aliquot was shipped at a temperature of −80°C to the National Centre for Adherence Testing, Department of Chemical Pathology and Metabolic Medicine, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom, where they were analyzed by high-performance LC-MS/MS to detect antihypertensive medication adherence as described previously.44 Briefly, the samples were analyzed in batches of 20. Each sample was run in dilution and after extraction. Separation was performed using Agilent Technologies Zorbax Elipse column C18 2.1×50 mm and then the samples were introduced by electrospray ionization to an Agilent technologies 6140 tandem mass spectrometer. The analyte of interest was confirmed by its unique mass to charge ratios.

The assay provides a binary qualitative result for the presence or absence of medications in urine. Patients whose urine analysis confirmed the presence of all medications prescribed were classified as totally adherent and those with fewer medications detected than prescribed were classified as partially adherent. Patients with no detectable drug or metabolite levels were classified as totally nonadherent.

Statistical Analysis

Descriptive analyses were performed to summarize the demographic and biochemical characteristics, as well as the comorbidities of study participants and antihypertensive medication adherence by classes of agents in patients with true controlled hypertension and MUCH. Two-sample t test was used to compare the continuous variables between true controlled hypertensive and MUCH patients. χ2 test or Fisher exact test was used to compare the categorical variables between 2 study groups. Medication adherence was compared using 1-way ANOVA for continuous variables and using χ2 or Fisher exact test for categorical variables between true controlled hypertensive and MUCH patients. according to total and partial antihypertensive medication adherence, that is, true controlled hypertension with total medication adherence, true control hypertension with partial medication adherence, MUCH with total medication adherence, and MUCH with partial medication adherence. All analyses were performed using SPSS, version 25. A 2-sided P<0.05 was considered statistically significant.

Results

After ≥3 consecutive clinic visits, 184 hypertensive patients were prospectively recruited, were prescribed antihypertensive medications, and had controlled clinic BP in clinic (Figure). Of the 184 treated and controlled hypertensive patients, 167 had adequate ABPM recordings. Eighty-six patients (51.5%) were identified as having MUCH, that is, controlled in-clinic (AOBP<135/85 mm Hg) but uncontrolled awake ambulatory BP (ABPM≥135/85 mm Hg). The remaining 81 patients (48.5%) had controlled BP in-clinic (AOBP<135/85 mm Hg) and controlled ambulatory awake BP (ABPM<135/85 mm Hg), indicative of true controlled hypertension (Figure). Of the 86 MUCH patients and 81 true controlled hypertensives, 9 had missing medication adherence data such that 81 MUCH patients and 77 true controlled hypertensives were included in the final analysis (Figure).

Figure.

Figure. Schematic of enrolled study participants. ABPM indicates ambulatory blood pressure monitoring; and AOBP, automated office blood pressure.

Patient Characteristics

The mean age was 58.6±10.6 years for the MUCH patients and 60.6±10.8 years for the true controlled hypertensives (Table 1). Of the MUCH patients, 44.4% were women and 49.4% were black compared with 45.5% women and 49.4% black among the true controlled hypertensive patients (Table 1). The mean body mass index was not statistically different in both the groups, 34.2±6.2 kg/m2 for the MUCH patients and 32.3±6.8 kg/m2 for the true controlled hypertensives (Table 1). MUCH patients had a higher prevalence of diabetes mellitus compared with the true controlled hypertensive patients (42.0% versus 23.4%, respectively; P=0.013). All other comorbidities had similar prevalence in both groups (Table 1). There were no significant differences in serum electrolytes, blood urea nitrogen, and creatinine in MUCH versus true controlled hypertensive patients (Table 1).

Table 1. Demographics, Comorbidities, Vitals, and Biochemistry in Patients With Masked Uncontrolled and True Controlled Hypertension

VariablesMUCH (n=81)True Controlled Hypertension (n=77)P Value
Demographics
 Age, y58.6±10.660.6±10.80.247
 Women36 (44.4%)35 (45.5%)0.899
 Black40 (49.4%)38 (49.4%)0.997
Comorbidities
 Current smoker10 (12.3%)6 (7.8%)0.343
 Dyslipidemia53 (65.4%)52 (67.5%)0.780
 Congestive heart failure5 (6.2%)4 (5.2%)1.000
 Coronary artery disease9 (11.1%)14 (18.2%)0.208
 Peripheral vascular disease6 (7.4%)4 (5.2%)0.568
 Diabetes mellitus34 (42.0%)18 (23.4%)0.013
 Prior stroke/transient ischemic attack13 (16.0%)10 (13.0%)0.585
Body mass index, kg/m234.2±6.232.3±6.80.070
Clinic measurements
 AOBP systolic, mm Hg121.1±8.2114.1±10.4<0.001
 AOBP diastolic, mm Hg73.3±7.770.6±7.60.026
 AOBP heart rate, bpm73.9±11.671.7±12.20.252
ABPM measurements
 24-h (overall) systolic BP, mm Hg145.5±11.6121.5±7.3<0.001
 24-h (overall) diastolic BP, mm Hg79.9±8.368.8±6.5<0.001
 24-h (overall) mean arterial pressure, mm Hg101.9±7.986.3±5.6<0.001
 24-h (overall) pulse pressure, mm Hg65.7±11.452.8±8.2<0.001
 24-h (overall) heart rate, bpm74.2±11.371.1±10.80.085
 Awake (daytime) systolic BP, mm Hg148.1±11.2123.8±7.3<0.001
 Awake (daytime) diastolic BP, mm Hg82.1±8.170.9±6.9<0.001
 Awake (daytime) mean arterial pressure, mm Hg104.1±7.588.0±8.0<0.001
 Awake (daytime) pulse pressure, mm Hg66.0±11.553.5±9.3<0.001
 Awake (daytime) heart rate, bpm75.6±11.472.6±11.30.091
 Asleep (nighttime) systolic BP, mm Hg138.1±19.2114.4±12.2<0.001
 Asleep (nighttime) diastolic BP, mm Hg72.9±11.362.2±7.9<0.001
 Asleep (nighttime) mean arterial pressure, mm Hg94.6±12.779.2±9.1<0.001
 Asleep (nighttime) pulse pressure, mm Hg65.2±14.552.8±10.7<0.001
 Asleep (nighttime) heart rate, bpm69.6±11.766.7±10.30.099
Biochemistry
 Sodium, mMol/L137.9±3.3138.6±2.80.213
 Potassium, mMol/L4.0±0.44.0±0.40.701
 Bicarbonate, mMol/L28.3±2.827.7±3.10.226
 Blood urea nitrogen, mg/dL17.7±7.118.9±7.70.370
 Creatinine, mg/dL1.0±0.31.1±0.50.227

ABPM indicates ambulatory blood pressure monitoring; AOBP, automated office blood pressure; BP, blood pressure; and MUCH, masked uncontrolled hypertension.

BP Measurements in and Out of Clinic

The in-clinic mean AOBP readings were 121.1±8.2/73.3±7.7 mm Hg in MUCH patients versus 114.1±10.4/70.6±7.6 mm Hg in patients with true controlled hypertension (P<0.001 and P=0.026, respectively; Table 1). The out-of-clinic awake (daytime) mean ABPM was 148.1±11.2/82.1±8.1 mm Hg in the MUCH patients compared with 123.8±7.3/70.9±6.9 in true controlled hypertensive patients (both P<0.001; Table 1).

Antihypertensive Medication Adherence

Of the 81 MUCH patients, 69 (85.2%) were fully adherent and 12 (14.8%) patients were partially adherent (Table 2). Of the 77 true controlled hypertensive patients, 69 (89.6%) were fully adherent with all of the prescribed antihypertensive medications and 8 (10.4%) were partially adherent (Table 2). The number of antihypertensive medications prescribed was 3.5±1.3 in MUCH patients and 3.2±1.2 in true controlled hypertension; the number of antihypertensive medications detected by 24-hour urine LC-MS/MS was 3.3±1.2 in MUCH patients and 3.1±1.2 in true controlled hypertension. There were no significant differences in medication adherence with the different antihypertensive medication classes for the MUCH versus true controlled hypertensive groups (Table 2).

Table 2. Antihypertensive Medication Adherence in Patients With Masked Uncontrolled and True Controlled Hypertension

VariablesMUCH (n=81)True Controlled Hypertension (n=77)P Value
Total medication adherence69 (85.2%)69 (89.6%)0.403
Partial medication adherence12 (14.8%)8 (10.4%)0.403
Total antihypertensive medications prescribed3.5±1.33.2±1.20.072
Total antihypertensive medications detected3.3±1.23.1±1.20.184
Antihypertensive medication classes
 Angiotensin-converting enzyme inhibitors (benazepril, fosinopril, lisinopril, quinapril, ramipril)30 (90.9%)34 (97.1%)0.349
 Angiotensin II receptor blockers (azilsartan, candesartan, irbesartan, losartan, olmesartan, valsartan)31 (93.9%)32 (100.0%)0.492
 Calcium channel blockers (amlodipine, diltiazem, felodipine, nifedipine, verapamil)59 (95.2%)48 (98.0%)0.629
 Thiazide diuretics (chlorthalidone, hydrochlorothiazide)61 (95.3%)54 (98.2%)0.623
 Loop diuretics (furosemide, torsemide)4 (100.0%)1 (50.0%)0.333
 Epithelial sodium channel blockers (triamterene)2 (100.0%)2 (100.0%)
 Mineralocorticoid receptor antagonists (eplerenone, spironolactone)27 (93.1%)29 (96.7%)0.612
 α-Blockers (doxazosin)5 (100.0%)2 (100.0%)
 β-Blockers (acebutalol, atenolol, bisoprolol, metoprolol, nebivolol)16 (94.1%)17 (85.0%)0.609
 αβ-Blockers (carvedilol, labetalol)18 (90.0%)9 (100%)1.000
 α2 agonists (clonidine, guanfacine)11 (91.7%)7 (100.0%)1.000
 NO vasodilators (hydralazine)3 (100.0%)1 (100.0%)
 Potassium channel openers (minoxidil)2 (100.0%)

MUCH indicates masked uncontrolled hypertension.

The number of antihypertensive medications prescribed was 3.4±1.2 in MUCH patients with total adherence and 4.5±1.4 in MUCH patients with partial adherence versus 3.1±1.2 in true controlled hypertension with total adherence and 3.9±1.0 in true controlled hypertension with partial adherence. Patients with partial adherence missed on average one prescribed medication in both the MUCH and true controlled groups. The number of antihypertensive medications detected by 24-hour urine high-performance LC-MS/MS was 3.4±1.3 in MUCH patients with total adherence and 3.1±1.2 in MUCH patients with partial adherence versus 3.1±1.2 in true controlled hypertension with total adherence and 2.8±1.0 in true controlled hypertension with partial adherence (Table 3). Patients with full medication adherence were significantly more adherent to angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, thiazide diuretics, mineralocorticoid receptor antagonists, and β-blockers than were patients with partial medication adherence, both in the MUCH and true controlled hypertensive groups.

Table 3. Antihypertensive Medication Adherence in Patients With Masked Uncontrolled and True Controlled Hypertension Subdivided by Total and Partial Antihypertensive Medication Adherence

VariablesMUCHTrue Controlled HypertensionP Value
Total Medication Adherence (n=69)Partial Medication Adherence (n=12)Total Medication Adherence (n=69)Partial Medication Adherence (n=8)
Total antihypertensive medications prescribed3.4±1.24.5±1.43.1±1.23.9±1.00.002
Total antihypertensive medications detected3.4±1.33.1±1.23.1±1.22.8±1.00.406
Antihypertensive medication classes
 Angiotensin-converting enzyme inhibitors (benazepril, fosinopril, lisinopril, quinapril, ramipril)29 (100.0%)1 (25.0%)30 (100.0%)4 (80.0%)<0.001
 Angiotensin II receptor blockers (azilsartan, candesartan, irbesartan, losartan, olmesartan, valsartan)26 (100%)5 (71.4%)30 (100%)2 (100.0%)0.017
 Calcium channel blockers (amlodipine, diltiazem, felodipine, nifedipine, verapamil)52 (100.0%)7 (70.0%)43 (100.0%)5 (83.3%)<0.001
 Thiazide diuretics (chlorthalidone, hydrochlorothiazide)52 (100.0%)9 (75.0%)49 (100.0%)5 (83.3%)<0.001
 Loop diuretics (furosemide, torsemide)4 (100.0%)1 (100.0%)00.333
 Epithelial sodium channel blockers (triamterene)1 (100.0%)1 (100.0%)2 (100%)
 Mineralocorticoid receptor antagonists (eplerenone, spironolactone)23 (100.0%)4 (66.7%)25 (100.0%)4 (80.0%)0.005
 α-Blockers (doxazosin)5 (100%)2 (100%)
 β-Blockers (acebutalol, atenolol, bisoprolol, metoprolol, nebivolol)15 (100.0%)1 (50.0%)17 (100.0%)0<0.001
 αβ-Blockers (carvedilol, labetalol)13 (100.0%)5 (71.4%)8 (100%)1 (100.0%)0.121
 α2 agonists (clonidine, guanfacine)8 (100%)3 (75.0%)6 (100%)1 (100.0%)0.263
 NO vasodilators (hydralazine)3 (100.0%)1 (100%)
 Potassium channel openers (minoxidil)1 (100%)1 (100%)

MUCH indicates masked uncontrolled hypertension.

In addition, analyzing MUCH and true controlled hypertensive patients based on 24-hour ABPM cutoff of 130/80 mm Hg showed similar antihypertensive medication adherence in MUCH patients, with 86.7% of total adherence and 13.3% of partial adherence. In true controlled hypertensive patients, 88.2% were fully adherent with all of the prescribed antihypertensive medications and 11.8% were partially adherent (P=0.483). In addition, based on an ABPM asleep (nighttime) cutoff value of 120/70 mm Hg, the medication adherence rates were not different between MUCH and true controlled patients, with 89.4% of the former being fully and 10.6% being partially versus 84.4% of the latter being fully and 15.6% being partially adherent (P=0.246).

Duration Between BP Measurements and 24-Hour Urine Collection

All the patients completed in-clinic AOBP measurements, out-of-clinic 24-hour ABPM, and 24-hour urine collection for antihypertensive medication adherence during a 1-week period without any change in any antihypertensive medications. The mean duration between the BP measurements and 24-hour urine collection was 1.5±2.9 days (range, 2–7).

Post Hoc Power Analysis

Sample sizes of 81 in the MUCH group and 77 in the true controlled hypertension group resulted in a 78% power to detect equivalence. The margin of equivalence, given in terms of the difference, extended from −20% to 10.4% with an actual difference of −4.4% (85.2% versus 89.6%) using Z test with a significance level of 0.05.

Discussion

This prospective study identified equal antihypertensive medication adherence between patients with MUCH and true controlled hypertension. Precision measurement of drug metabolites in the urine using 24-hour urine LC-MS/MS provided an unbiased assessment of medication adherence. Based on these data, we conclude that MUCH is not attributable to nonadherence.

Multiple assessments of medication adherence in general hypertensive cohorts with use of LC-MS/MS have demonstrated nonadherence (ie, absence of ≥1 antihypertensive medications) rates of 25% to 65% among patients with uncontrolled hypertension.44,45 For example, Gupta et al found that 30% to 40% of a cohort of 1348 hypertensive patients were nonadherent with their prescribed antihypertensive medications. Female sex, younger age, higher number of antihypertensive medications, and the use of certain antihypertensive medication classes, that is, diuretics, were associated with greater degrees of nonadherence.46 In another study of 238 hypertensive patients, serial determinations of medication adherence and subsequent discussion of poor adherence with appropriate patients improved adherence rates from 33% to 100% and lowered systolic and diastolic BP by ≈19.5 and 7.5 mm Hg.47

Medication adherence rates have also been determined in patients with RHTN by LC-MS/MS analysis. Jung et al,48 Strauch et al,49 and Lawson et al50 have reported antihypertensive medication nonadherence rates of 47% to 53% in cohorts of patients with RHTN. Schmieder et al also reported high rates of nonadherence to antihypertensive medications among 79 patients with RHTN undergoing renal denervation. Medication nonadherence was 44% at baseline and 34% 6 months after renal denervation.51 Brinker et al52 reported that informing patients with RHTN of documented low medication adherence improved systolic and diastolic BP by 46±10/26±14 mm Hg in nonadherent group, 12±17/7±7 mm Hg in adherent group, and 11±4/4±2 mm Hg in the untested group (P<0.01) without treatment intensification, while no differences in the number of antihypertensive medications were found (5.3±0.7 versus 4.2±0.4 versus 3.7±0.2 drugs, respectively; P>0.05).

In the current study, antihypertensive medication adherence was measured by detecting urinary drug and drug metabolite levels using LC-MS/MS in MUCH patients versus patients with confirmed controlled hypertension. We found that medication adherence was high in both MUCH and true controlled hypertensive groups (85.2% versus 89.6%) with no statistically significant difference between the 2 groups. These findings allow us to exclude reduced medication adherence as a cause of MUCH. Further, there was no significant difference in the total number or classes of antihypertensive agents detected in the MUCH versus true controlled hypertensive groups, suggesting that undertreatment was also not contributing to the development of MUCH. Patients in both groups, that is, MUCH and true controlled hypertension, who were partially adherent were being treated with a higher number of prescribed antihypertensive medications (4.5±1.4 in MUCH, 3.9±1.0 in true controlled) compared with those who were totally adherent (3.4±1.2 in MUCH, 3.1±1.2 in true controlled).

Because this prospective study was started before release of the updated 2017 Hypertension Clinical Practice Guidelines, we reanalyzed the data with application of the lower BP cutoff value of 130/80 mm Hg.8 Based on an out-of-clinic ABPM awake (daytime) cutoff value of 130/80 mm Hg,8 we found similar antihypertensive medication adherence levels in MUCH and true controlled patients, with 88.9% of the MUCH patients being totally and 11.1% being partially adherent compared with 88.4% of the true controlled patients being totally and 11.6% partially adherent (P=0.579). In addition, based on newer guideline out-of-clinic 24-hour ABPM cutoff of 125/75 mm Hg,8 MUCH patients had similar antihypertensive medication adherence levels compared with true controlled patients (90.1% of MUCH patients were totally and 9.9% partially adherent, whereas 85.3% of true controlled patients were totally and 14.7% partially adherent; P=0.326).

Emerging evidence suggests that increased sympathetic tone may play a role in the pathogenesis of MUCH. We have recently observed that MUCH patients have evidence of higher out-of-clinic sympathetic tone assessed by plasma and urinary catecholamine and metanephrine levels and BP and heart rate variability in and out of clinic compared with true controlled hypertensive patients.27 Other investigators have also reported that MUCH patients have higher anxiety levels as indexed by the Spielberger Strait Trait Anxiety Inventory compared with RHTN after renal denervation.28 Further, risk of MH has been shown to be increased in patients with obstructive sleep apnea who are not receiving antihypertensive medications, suggesting that obstructive sleep apnea–related oxygen desaturation, heightened sympathetic tone, nocturnal hypertension, and nondipping BP may contribute to the development of MH.24,25

Strengths of the current study include the prospective design, inclusion of a diverse cohort of well-characterized patients, rigorous confirmation of MUCH and true controlled hypertension, comparison of MUCH patients to a comparator group of true controlled hypertension, medication adherence tested on uninformed patients to avoid change in behavior (ie, Hawthorne effect), and detection of antihypertensive medications by 24-hour urine LC-MS/MS, the current recommended method for determination of medication adherence.

Study weaknesses include binary determination of drug and drug metabolite levels as opposed to a quantitative assessment. In addition, the time duration between ABPM and drug metabolite testing could have introduced some variation in the detection of the urinary drug metabolites by qualitative analysis. These limitations preclude a more nuanced interpretation of drug exposure, such as potential variation in drug levels related to once versus multiple daily dosing in individual patients.

Patients with MUCH have similar levels of antihypertensive medication adherence compared with patients with hypertension controlled both in the office and in the clinic. These findings suggest that poor adherence to antihypertensive medication is not a cause of MUCH.

Perspectives

Patients with MUCH have similar levels of antihypertensive medication adherence compared with patients with true controlled hypertension. These findings suggest that poor adherence to antihypertensive medication is not a cause of MUCH.

Footnotes

Correspondence to Mohammed Siddiqui, University of Alabama at Birmingham, 933 19th St S, 115 Community Health Services Bldg, Birmingham, AL 35294. Email

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Novelty and Significance

What Is New?

  • This is the first study to evaluate whether masked uncontrolled hypertension (MUCH) attributed to antihypertensive medication nonadherence.

What Is Relevant?

  • This study shows there is similar antihypertensive medication adherence in MUCH patients compared with true controlled hypertension. In a large diverse cohort of hypertensive patients subdivided into MUCH and true controlled hypertension as controls, around 85+% of the patients were adherent to antihypertensive medication in both the groups. This eliminates medication nonadherence as one of the possible causes of MUCH.

Summary

Patients with MUCH have similar antihypertensive medication adherence in MUCH patients compared with true controlled hypertension.