Reduction of Left Ventricular Hypertrophy After Eplerenone Therapy
Condition: Hypertension,Essential; Obstructive Sleep Apnea; Left Ventricular Hypertrophy
MeSH terms: Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Hypertension; Hypertrophy, Left Ventricular; Essential Hypertension; Hypertrophy
Study type: Interventional
Phase: Phase 4

Summary: 
      Obstructive sleep apnea syndrome (OSA) is the most frequent sleep disorder characterized by
      excessive decrease in muscle tone of the soft palate, the tongue and the posterior pharyngeal
      wall. It leads to airway collapse. In cases of decreased airway passage hypoventilation
      (hypopnea) occurs while periodic lack of airflow is called apnea. An obstructive sleep apnea
      syndrome is recognized as an independent cardiovascular risk factor. OSA is very common in
      patients with resistant hypertension. RAH is diagnosed when blood pressure remains elevated
      despite simultaneous use of 3 antihypertensive agents from different groups of drugs at
      optimal to maximum doses, including a diuretic.

      In patients with OSA frequent episodes of hypoxemia during sleep result in the repeated
      activation of the sympathetic nervous system. What is more, the episodes of respiratory
      disorders increases in levels of aldosterone serum concentration with following sodium and
      water retention and elevation of blood pressure finally. An increased aldosterone level also
      stimulates synthesis of collagen, promotes stiffening of the arterial wall, myocardial
      fibrosis with heart muscle remodeling and takes part in development of left ventricular
      hypertrophy (LVH) - common complication of hypertensive patients with OSA. Several studies,
      including the Sleep Heart Health Study have confirmed that severe OSA is associated with high
      prevalence of concentric hypertrophy through sympathetic activation and vasoconstriction.

      Eplerenone is a selective mineralocorticoid receptor inhibitor. It has no affinity for
      glucocorticoid, progesterone and androgen receptors and therefore has lower risk of side
      effects. Eplerenone lowers blood pressure and inhibits heart muscle fibrosis. The hypotensive
      effect is caused by reduction of fluid retention. Probably, in patients with OSA, a reduction
      of fluid accumulation especially at the level of the neck may contribute to lowering the
      resistance in the upper respiratory tract and in that way it may help to decrease the
      severity of OSA.

      As LVH remains a strong and independent predictor of total mortality and death from
      cardiovascular causes, in this study we want to assess whether the addition of Eplerenone to
      a standard antihypertensive therapy will favorably change left ventricular geometry. We also
      want to check if the addition the Eplerenone to a standard antihypertensive therapy could be
      an effective therapeutic option for patients with OSA and RAH.
    

Detailed description: 
      125 patients (78 men and 47 women) aged 18 - 65 years, with diagnosed resistant hypertension
      and moderate or severe OSA were included in the study, which was conducted in years 2014-2017
      in the Department of Hypertension, Angiology and Internal Medicine and the Department of
      Pulmonology, Allergology and Respiratory Oncology at the University of Medical Sciences in
      Poznan, Poland. 23 patients did not complete the study because they did not meet the
      inclusion criteria (10 patients) and did not follow the recommendations (13 patients). 102
      patients were randomized to two groups. In Group A, 50mg Eplerenone was administered orally
      once a day additionally for standard antihypertensive therapy. In Group B, standard
      antihypertensive therapy was not changed for 6 months of follow-up. RAH was recognized when
      in spite of the use of at least 3 antihypertensive agents (including a diuretic) in maximum
      doses, it was impossible to achieve the target values of BP (< 140/90 mmHg). The patients
      were taking on average 3,93 antihypertensive medications including diuretics (100% of
      patients), angiotensin-converting enzyme inhibitors (54% of patients), angiotensin II
      receptor antagonists (45.2% of patients), calcium antagonists (83.9% of patients), β-blockers
      (77.4% of patients), and α-blockers (22.6% of patients). The permission no. 565/14 to conduct
      the study was granted by the Ethics Committee of the University of Medical Sciences in
      Poznan. All patients gave an informed and written consent to participation in the study.
      Blood pressure measurements In all patients, during each visit, BP measurements were
      performed three times at rest in supine position, in standard conditions, using an upper arm
      blood pressure monitor BP monitor (Omron 705IT, Omron Healthcare, Kyoto, Japan). Ambulatory
      24-hours BP automated monitoring (ABPM) was performed using a 24-hour ambulatory peripheral
      BP monitor TM2430 (A&D Medical, San Jose, California, United States). The frequency of
      measurements was every 15 minutes between 7:00 and 22:00 and every 30 minutes between 22:00
      and 7:00.

      Neck circumference measurement The neck circumference was measured in the midway of the neck,
      between the mid-cervical spine and mid-anterior neck, in standing position, with a flexible
      no-stretchable plastic tape, and approximated to the nearest 0.1 cm.

      Echocardiographic examination

      All patients underwent complete transthoracic echocardiographic study with Vivid S6 (GE
      Medical System, Tirat Carmel, Israel) with a 1,5 - 3,6 megahertz cardiac sector probe. A
      standard M-mode, two-dimensional and Doppler echocardiographic examination was performed
      according to the guidelines of American Society of Echocardiography. Three consecutive cycles
      were averaged for every parameter. The same experienced cardiologist who was blinded to the
      presence or absence of OSA performed all echocardiographic examinations. Left ventricular
      end-diastolic diameter (LVED), thickness of intraventricular septum at end diastole (IVS),
      left ventricular posterior wall at end diastole (LVPW) and left ventricular mass (LVM) were
      measured according to American Society of Echocardiography recommendations. The LVH was
      defined as the IVS or the LVPW>12 mm. The left ventricular mass was calculated using a simple
      and anatomically validated formula:

      LVM = 0.8 × 1.04 [(IVS + LVED + LVPW) 3 - LVED 3] + 0.6 LVM was calculated as corrected for
      height and LVM index (LVMI). The relative wall thickness (RWT) was calculated as (2×
      LVPW)/LVEDD, for which the normal limit is <0.42. Based on LVMI and RWT, the LV geometry was
      classified as normal (LVMI <115 g/m2 in men, <95 g/m2 in women and RWT <0.42), concentric
      remodeling (normal LVMI <115 g/m2 in men, <95 g/m2 in women and increased RWT >0.42),
      concentric hypertrophy (LVMI >115 g/m2 in men, >95 g/m2 in women and increased RWT >0.42) or
      eccentric hypertrophy (LVMI >115 g/m2 in men, >95g/m2 in women and normal RWT <0.42).

      Polysomnography (PSG) The probability of OSA was established at first on the base of Epworth
      Sleepiness Scale score. The evaluation of patients was performed in the Sleep Laboratory of
      the Department of Pulmonology, Allergology and Respiratory Oncology at the University of
      Medical Sciences in Poznan, Poland using a full-night polysomnographic monitoring system
      (EMBLA S4000, Remlogic, Denver, Colorado) with Somnologica studio 3.3.2 software (EMBLA,
      Broomfield, Colorado, United States). Standard electroencephalography monitoring, including
      frontal leads (F1, F2), central leads (C3, C4), occipital leads (O1, O2) and reference leads
      at the mastoids (M1, M2); electromyography and electrooculography methodology were performed
      according to The American Academy of Sleep Medicine (AASM) guidelines.

      Airflow was measured using nasal thermistors, and a nasal pressure transducer. Abdominal and
      thoracic movements were assessed by respiratory inductive plethysmography. Oximetry was
      measured using a disposable finger probe (oximeter flex sensor 8000 J, NONIN, Plymouth,
      Massachusetts, United States) placed on the index finger. Snoring sounds, heart rate also
      were recorded. Body position was monitored using body position sensor. Apnea was defined as a
      cessation of airflow lasting for more than 10 sec., and hypopnea as a discrete reduction (two
      thirds) of airflow and/or abdominal ribcage movements lasting for more than 10 sec. and
      associated with a decrease of more than 4% in oxygen saturation. Trained PSG technicians and
      sleep physicians using the criteria of Rechtschaffen and Kales, and in close concordance with
      scoring updates given by the American Academy of Sleep Medicine analyzed all studies. The
      apnea-hypopnea index (AHI) was defined by the total number of apneas and hypopneas per hour
      of sleep. The severity of OSA was determined as: mild (AHI 5-15), moderate (AHI 15 - 30) and
      severe (AHI ≥ 30) (21) on the basis of AHI Design of the study First visit Patients with
      previously diagnosed RAH and with suspected OSA (medical history, the Epworth scale
      assessment) were referred from an outpatient clinic to the hospital ward. After admission
      numerous laboratory tests and imaging, such as aldosterone and Plasma renin activity levels
      (ARO), both before and after tilting, creatinine, urea, GFR, sodium and potassium levels, pro
      B-type natriuretic peptide (BNP), thyrotrophin (TSH), free triiodothyronine (FT3), free
      thyroxine(fT4), 24-hour urine collection for electrolytes, as well as abdominal ultrasound
      examinations, computed tomography of the abdomen and Doppler ultrasound of the renal
      arteries, were performed to exclude secondary causes of arterial hypertension (other than
      primary hyperaldosteronism). What is more, office BP was measured three times at admission
      and afterwards 24-hours ABPM examination was conducted. All participants underwent also
      transthoracic echocardiography. After aforementioned diagnostics and after confirming RAH
      based on 24-hour ABPM, patients were referred to the Department of Pulmonology to perform
      polysomnography.

      In those patients in who moderate or severe OSA (AHI>15/h), had been confirmed, Eplerenone at
      the dose of 50 mg/day was randomly added to the previously used treatment regimen.

      Second visit After six months, office BP (measured three times in standard conditions as
      initially performed), 24-hour ABPM, echocardiography and polysomnography were repeated.

      Statistical analysis The normality of distribution of the analyzed variables was evaluated
      with the Shapiro-Wilk test and Kolmogorov-Smirnov test with the Lilliefors correction. The
      results of the tests showed that distributions of almost all parameters significantly
      differed from the normal distribution. Therefore, nonparametric methods were used in
      statistical analysis. The Wilcoxon signed-rank test was applied for the evaluation of the
      differences between the baseline values and those obtained after treatment. The t test was
      used for variables with normal distribution. Correlations between the values of the
      parameters were evaluated using the Spearman's rank correlation coefficient. P value of less
      than 0.05 was considered significant. The Statistica software, version 10, was used for the
      analysis (www. statsoft. com; license JGNP410B316631AR-J, Stat- Soft, Inc., 2011, Tulsa,
      Oklahoma, United States).
    

Intervention name(s): Eplerenone 50 mg Tab
Intervention type(s): Drug
Intervention description(s): Eplerenone 50 mg Tab once a day
Intervention MeSH terms: Eplerenone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Eplerenone; Concentric hypertrophy