Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment)

ABSTRACT: The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5-50 mg QD) or clonidine (0.1-0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55-1.88]; P=1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy.

Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment).

The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5-50 mg QD) or clonidine (0.1-0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55-1.88]; P=1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01643434.

The white coat effect is not associated with additional increase of target organ damage in true resistant hypertension

Background and objective: White coat effect (WCE) (i.e., the difference between office blood pressure [OBP] and awake ambulatory blood pressure monitoring [ABPM]) may be present in hypertensive individuals. The relationship between occurrence of WCE and target organ damage (TOD) has not yet been assessed in true resistant hypertension (RHTN). Patients and methods: RHTN patients were divided into two groups: RHTN with WCE (WCE, n=66) and RHTN without WCE (non-WCE, n=61). All patients were submitted to OBP measurement, ABPM, echocardiography and renal function evaluation in three visits. Results: No differences were observed between the WCE and non-WCE groups regarding age, body mass index or gender. OBP were 169.8±15.8/95.1±14.0 (WCE) and 161.9±9.0/90.1±10.4mmHg (non-WCE), ABPM=143.0±12.8/86.1±9.9 (WCE) and 146.1±13.6/85.1±14.9mmHg (non-WCE). No statistical differences were observed between WCE and non-WCE subgroups with respect to left ventricular mass index (LVMI) (WCE=131±4.7; non-WCE=125±2.9g/m2), creatinine clearance (WCE=78±4.7; non-WCE=80±3.6ml/min/m2) and microalbuminuria (MA) (WCE=44±8.4; non-WCE=49±6.8mg/g Cr). Conclusions: This finding may suggest that WCE is not associated with additional increase of TOD in true RHTN subjects (AU)

Fundamento y objetivo: El efecto de bata blanca (EBB), es considerado cuando la diferencia entre la PAS/PAD medida en consulta médica y aquella obtenida por monitorización ambulatoria de la presión arterial (MAPA) y puede estar presente durante la consulta médica en pacientes con hipertensión arterial resistente (HTA-R). La relación entre la presencia del efecto bata blanca y daños en órganos diana aún no ha sido evaluada en individuos con HTA-R verdadera. Pacientes y método: En este estudio, sesenta y seis pacientes con HTA-R verdadera presentaron EBB y otros 61 no lo hicieron. A todos los sujetos se les practicó una monitorización ambulatoria de la presión arterial durante 24 horas (MAPA). La afectación de órganos diana se determinó mediante la realización de ecocardiograma y evaluación de la función renal. Resultados: Los valores de PAS y PAD en consulta médica fueron: 169,8±15,8/95,1±14,0 (pacientes con EBB) y 161,9±9,0/90,1±10,4mmHg (pacientes sin EBB), respectivamente y mediante MAPA los valores promedios de PAS y PAD de 24 horas fueron: 143,0±12,8/86,1±9,9 (pacientes con EBB) y 146,1±13,6/85,1±14,9 mmHg (pacientes sin EBB), respectivamente. No se observaron diferencias significativas entre los pacientes con o sin EBB con respecto al índice de masa ventricular izquierda (con EBB=131±4,7; sin EBB=125±2,9g/m2), aclaramiento de creatinina (con EBB=78±4,7; sin EBB=80±3,6ml/min/m2) y microalbuminuria (con EBB=44±8,4; sin EBB=49±6,8mg/g Cr). Conclusiones: Este hallazgo sugiere que el EBB no se asocia a incremento adicional de daños en órganos diana en pacientes con HTA-R verdadera (AU)

The white coat effect is not associated with additional increase of target organ damage in true resistant hypertension.

BACKGROUND AND OBJECTIVE: White coat effect (WCE) (i.e., the difference between office blood pressure [OBP] and awake ambulatory blood pressure monitoring [ABPM]) may be present in hypertensive individuals. The relationship between occurrence of WCE and target organ damage (TOD) has not yet been assessed in true resistant hypertension (RHTN). PATIENTS AND METHODS: RHTN patients were divided into two groups: RHTN with WCE (WCE, n=66) and RHTN without WCE (non-WCE, n=61). All patients were submitted to OBP measurement, ABPM, echocardiography and renal function evaluation in three visits. RESULTS: No differences were observed between the WCE and non-WCE groups regarding age, body mass index or gender. OBP were 169.8±15.8/95.1±14.0 (WCE) and 161.9±9.0/90.1±10.4mmHg (non-WCE), ABPM=143.0±12.8/86.1±9.9 (WCE) and 146.1±13.6/85.1±14.9mmHg (non-WCE). No statistical differences were observed between WCE and non-WCE subgroups with respect to left ventricular mass index (LVMI) (WCE=131±4.7; non-WCE=125±2.9g/m(2)), creatinine clearance (WCE=78±4.7; non-WCE=80±3.6ml/min/m(2)) and microalbuminuria (MA) (WCE=44±8.4; non-WCE=49±6.8mg/g Cr). CONCLUSIONS: This finding may suggest that WCE is not associated with additional increase of TOD in true RHTN subjects.

[Prevalence of anti-hypertensive treatment adherence in patients with resistant hypertension and validation of three indirect methods for assessing treatment adherence]. / Prevalência da adesão ao tratamento anti-hipertensivo em hipertensos resistentes e validação de três métodos indiretos de avaliação da adesão.

This study estimated adherence to anti-hypertensive medication using three indirect methods and their combinations in a cohort of patients with resistant hypertension in Rio de Janeiro, Brazil, 2005. The methods used were: self-reported adherence; physicians' adherence evaluation; and the Morisky-Green test (MGT) translated into Portuguese. The predictive validation was performed comparing office blood pressure and ambulatory blood pressure monitoring, measured on two different occasions, from patients classified as adherent or not. The means were compared using non-parametric tests. Two hundred patients were interviewed. Mean age was 63 years (SD = 10.3), and 73.5% were female. Adherence prevalence was 51% using MGT, 52% according to the physician, and 80.5% according to the patient. Adherent patients showed a reduction in both office blood pressure and ambulatory blood pressure, while non-adherent patients did not. The use of more than one method to evaluate adherence showed that non-adherent individuals according to the three methods (11.9%) had the worst evolution in blood pressure levels. This finding suggests that resistant hypertension cannot be attributed exclusively to low adherence.

Prevalência da adesão ao tratamento anti-hipertensivo em hipertensos resistentes e validação de três métodos indiretos de avaliação da adesão / Prevalence of anti-hypertensive treatment adherence in patients with resistant hypertension and validation of three indirect methods for assessing treatment adherence

O estudo estimou a adesão ao tratamento anti-hipertensivo farmacológico utilizando-se três métodos indiretos em uma coorte de hipertensos resistentes no Rio de Janeiro, Brasil, 2005. Os métodos foram: avaliação pelo paciente; avaliação do médico; teste de Morisky-Green (TMG) adaptado para a língua portuguesa. Foi realizada validação preditiva comparando-se a diferença tanto de pressões de consultório como de monitorização de 24 horas (MAPA), em duas ocasiões, de pacientes com e sem adesão. As médias de pressões entre os grupos foram comparadas usando-se testes não-paramétricos. Foram entrevistados 200 pacientes com idade média de 63 anos (DP = 10,3), 73,5 por cento do sexo feminino. A prevalência de adesão foi de 51 por cento pelo TMG, 52 por cento pelo médico e 80,5 por cento pelo paciente. Ocorreram reduções das pressões arteriais de consultório e na MAPA dos pacientes com adesão por todos os métodos, mas não para os não-aderentes. O emprego de mais de um método para avaliação da adesão mostrou que indivíduos não-aderentes pelos três métodos (11,9 por cento) tiveram pior evolução dos níveis tensionais. Esse achado sugere que a hipertensão resistente não pode ser atribuída unicamente à baixa adesão.

This study estimated adherence to anti-hypertensive medication using three indirect methods and their combinations in a cohort of patients with resistant hypertension in Rio de Janeiro, Brazil, 2005. The methods used were: self-reported adherence; physicians' adherence evaluation; and the Morisky-Green test (MGT) translated into Portuguese. The predictive validation was performed comparing office blood pressure and ambulatory blood pressure monitoring, measured on two different occasions, from patients classified as adherent or not. The means were compared using non-parametric tests. Two hundred patients were interviewed. Mean age was 63 years (SD = 10.3), and 73.5 percent were female. Adherence prevalence was 51 percent using MGT, 52 percent according to the physician, and 80.5 percent according to the patient. Adherent patients showed a reduction in both office blood pressure and ambulatory blood pressure, while non-adherent patients did not. The use of more than one method to evaluate adherence showed that non-adherent individuals according to the three methods (11.9 percent) had the worst evolution in blood pressure levels. This finding suggests that resistant hypertension cannot be attributed exclusively to low adherence.

Screening for primary aldosteronism in a cohort of Brazilian patients with resistant hypertension.

The objective was to estimate the prevalence of plasma aldosterone concentration:plasma renin activity ratio >30 ng/dL:ng/mL/h in patients with resistant hypertension and to describe the computed tomography findings of adrenal glands in those with elevated ratios. In a cross-sectional design, 492 patients were enrolled. All patients with plasma aldosterone concentration:plasma renin activity ratio >or=30 ng/dL:ng/mL/h (n=77) underwent abdominal computed tomography. Patients with an adrenal image of possible aldosterone-producing adenoma underwent a saline-loading test. The prevalence of elevated plasma aldosterone concentration:plasma renin activity ratio was 15.7% (95% confidence interval, 12.6-19.2). Twelve patients showed adrenal abnormalities on computed tomography. The level of renin was low in 50% of the sample. Results indicate a low prevalence of aldosterone-producing adenoma. Our evidence points out the importance of confirming the hypothesis that essential hypertension, low-renin hypertension, and idiopathic hyperaldosteronism could be the same disease, but at different neurohormonal stages, and aldosterone-producing adenoma may be yet another disease.

Importance of the electrocardiographic strain pattern in patients with resistant hypertension.

The electrocardiographic strain pattern is a marker of left ventricular hypertrophy and adverse cardiovascular prognosis. The objective of this study was to assess the factors associated with the presence of ECG strain in patients with resistant hypertension and, specifically, to evaluate the relationships between strain and left ventricular mass (LVM) and structure. In a cross-sectional design, 440 resistant hypertensive subjects were evaluated. Clinical, laboratory, electrocardiographic, 24-hour ambulatory blood pressures, and echocardiographic variables were obtained. Statistical analysis involved bivariate tests, analysis of covariance, and multivariate logistic regression. An ECG strain pattern was present in 101 patients (23%). Patients with strain were more frequently men with lower body mass index, had more target-organ damage, higher 24-hour blood pressure, higher serum creatinine and 24-hour microalbuminuria, and more prolonged QT interval duration than those without strain. After controlling for all covariates, the presence of strain remained associated with increased LVM and wall thicknesses, both in all patients and also in those with echocardiographic left ventricular hypertrophy. Furthermore, the presence of ECG strain was associated with increased LVM (P<0.001), higher 24-hour systolic blood pressure (P<0.001), prolonged maximum QTc-interval duration (P<0.001), lower waist circumference (P=0.009), male gender (P=0.011), physical inactivity (P=0.020), higher serum creatinine (P=0.031) and fasting glycemia (P=0.027), and the presence of coronary heart disease (P=0.001) and peripheral arterial disease (P=0.045). Thus, in resistant hypertension patients, the presence of ECG strain is independently associated with increased left ventricular wall thicknesses and mass and also with other potentially adverse factors. These relationships offer insight into the known association between strain and unfavorable cardiovascular prognosis.

Combined QT interval and voltage criteria improve left ventricular hypertrophy detection in resistant hypertension.

QT interval parameters have been associated with left ventricular hypertrophy (LVH) in hypertensive patients. The aim of this study is to assess this relationship in resistant hypertension and, in particular, to evaluate whether any QT interval parameter could provide additive information for LVH beyond that obtained from the best electrocardiographic voltage criterion. In a cross-sectional study, 471 resistant hypertensives were submitted to standard 12-lead ECGs, 24-hour ambulatory blood pressure monitoring, and 2D echocardiographic examinations. QT interval durations and QRS voltages were measured, and maximum rate-corrected QT interval duration (QTcmax) and dispersion (QTd), and Sokolow's and Cornell's voltage product were calculated. Statistical analyses involved bivariate tests and multivariate logistic regression, with LVH as the dependent variable. A total of 383 patients (81%) had echocardiographic LVH. In bivariate comparisons, both QT interval parameters showed a predictive performance for LVH similar to Cornell's product, the best ECG voltage criterion. In multivariate analysis, QT parameters and Cornell's product were independently associated with LVH, after adjustment for other LVH determinants. QTc interval >440 ms(1/2) and dispersion >60 ms were associated with a 2-fold (95% confidence interval [CI], 1.1 to 3.8) greater chance of having LVH, whereas Cornell's product >240 mV.ms implied a 2.6-fold (95% CI, 1.2 to 6.1) increased chance of LVH. The combination of prolonged QT interval and increased Cornell's product was associated with a 5.3- to 9.3-fold higher chance of having LVH. Hence, although in isolation, no QT interval parameter performs better for LVH detection than simpler Cornell's product, it provides additive information and can be used in combination with voltage criteria to refine LVH risk stratification in resistant hypertension.

Twenty-four hour ambulatory blood pressure monitoring pattern of resistant hypertension.

OBJECTIVE: Ambulatory blood pressure monitoring (ABPM) is a tool to diagnose resistant hypertension (RH). The objective of this study is to describe the pattern of 24-h ABPM in patients using at least three anti hypertensive drugs without blood pressure (BP) control, classifying them as true RH or white-coat RH. METHODS: A cross-sectional study involving resistant hypertensives that were submitted to clinical, laboratory and 2D-echocardiographic evaluation. Ambulatory blood pressure monitoring was used to diagnose true or white-coat RH. The chi-squared test was used for comparisons among categorical variables and Kruskall-Wallis test for continuous ones. RESULTS: Of the 286 patients, 161 (56.3%) were classified as true RH and 125 (43.7%) as white-coat RH. Sex, age, office BP and the cardiovascular risk factors for both groups were similar. True resistant hypertensives had more target organ damage then white-coat resistant hypertensives; nephropathy (40.1 versus 23.9%, P=0.007) and left ventricular hypertrophy (83.3 versus 76.3%, P=0.05). In ABPM, the true RH group had a smaller nocturnal systolic and diastolic BP reduction (6.4+/-8.8 versus 9.8+/-7.5 mmHg, P=0.0004; 10.4+/-9.6 versus 13.6+/-9.2 mmHg, P=0.001) and 68.7% of them were non-dippers versus 49.6% in the white-coat RH group (P=0.001). True RH also had a larger 24 h pulse pressure (65.8+/-13.7 versus 51.5+/-10.0 mmHg, P < 0.0001). CONCLUSIONS: Ambulatory blood pressure monitoring is a fundamental tool to diagnose RH, and to check treatment efficacy. The presence of a greater pulse pressure and a lower nocturnal blood pressure reduction in true RH patients may be responsible for this increased cardiovascular risk profile.