Sleep, Hypertension, and Nocturia: a Multicomponent Approach for Comorbid Illnesses

Study Overview
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Brief Summary
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In this study the investigators target three common and comorbid illnesses among older adults namely nocturia or waking at night to void, poor sleep and hypertension. The aim of this proposal is to test behavioral sleep intervention to improve sleep and nocturia vs switching the time of antihypertensive administration to improve nighttime and in turn daytime blood pressure control.

Detailed Description
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The investigators posit that a vicious cycle operates between nocturia, poor sleep, and nighttime HTN. HTN act through the pressure-natriuresis mechanism that links sodium (Na) and BP homeostasis: periodic increases in BP drive compensatory renal excretion of Na (natriuresis) and water (diuresis) to reduce blood volume and BP. Normally, BP and natriuresis declines during sleep, decreasing nighttime urine volume (NUV). Elevated nighttime BP increases nocturnal natriuresis causing an increase in nighttime urine volume and hence, NP: the major etiologic factor for nocturia in the elderly. In a recently completed study (AG050892, PI:Tyagi), it was found that poor sleep blunts the normal nighttime rise in antidiuretic hormone-a potent Na conserving hormone, which leads to nocturnal natriuresis and, as a result, NP. Hence, our model incorporates the effects of poor sleep and nighttime HTN on natriuresis, NP, and nocturia. The investigators postulate that treatments targeted towards these etiologies will help break this vicious cycle. Traditionally, antihypertensive medications are dosed in the morning targeting daytime BP. However, some research suggests that nighttime BP best predicts risk for major cardiovascular events. Several clinical trials of bedtime dosing of BP medication-chronotherapy- show better nighttime BP control. However, no clinical studies have considered or tested chronotherapy as a treatment for nocturia. With respect to poor sleep, the investigators have shown that brief behavioral treatment of insomnia (BBTI) significantly improves not only sleep but also self-reported nocturia among the elderly. Therefore, the investigators envision a multicomponent approach with chronotherapy (bedtime dosing of certain antihypertensives) and behavioral sleep intervention (BBTI) to concurrently address the prevalent and chronic, mutually exacerbating conditions: nocturia, poor sleep, and HTN. The current proposal aims to collect pilot data for a definitive randomized clinical trial. In the proposed pilot study 30 community-dwelling older adults (aged >65) who take at ≥1 daily non-diuretic antihypertensive medication, have a mean SBP >135 mm Hg, and awaken ≥2 times nightly to void will be randomly assigned to one of the 3 groups of 10 participants each to 1) morning (am) HTN medication dosing, 2) BBTI with am HTN medication dosing, 3) nighttime non-diuretic HTN medication dosing (chronotherapy) for 6 weeks. At baseline and 6 weeks, participants will undergo 48-hour ambulatory BP monitoring, in-home sleep study, complete a 3-day bladder diary. This protocol will allow the investigators to accomplish following Aims: Aim1: To assess the feasibility and effect of chronotherapy and BBTI in older adults with multiple comorbidities: HTN and nocturia Hypothesis 1: Chronotherapy and BBTI will be (a) feasible treatment options among comorbid older adults, and (b) nocturia and nighttime urine volume, and (c) nighttime SBP will have a greater decrease in BBTI and chronotherapy groups than usual care. Aim 2: Assess safety and treatment compliance with chronotherapy. Hypothesis 2: The investigators will assess treatment compliance and also collect data on nocturnal lightheadedness and falls to begin to address the safety of HTN chronotherapy.

Official Title
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Sleep, Hypertension, and Nocturia: a Multicomponent Approach for Comorbid Illnesses

Conditions
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Nocturia, Hypertension, Sleep Disturbance

Intervention / Treatment
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* Behavioral: BBTI
* Other: PM antihypertensive dosing or Chronotherapy
* Other: AM antihypertensive dosing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The study shall include: ambulatory and functionally-independent community-dwelling men and women aged 65+ years, with nocturia ≥2/night, and history of high blood pressure and receives one or more non-diuretic, once daily antihypertensive- angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), calcium channel blocker (CCB), beta blocker Exclusion Criteria: Unstable or acute medical or central nervous system conditions Untreated, current, severe psychiatric condition Untreated, current, severe overactive bladder syndrome Post void residual > 30ml MOCA <26 Currently diagnosed and/or treated Obstructive Sleep Apnea, Restless Legs Syndrome, parasomnia CHF, by exam or NT-proB natriuretic peptide (NT-proBNP)> 30 pmol/L56 Chronic kidney disease, stage III-V (eGFR<60) >14 alcohol drinks per week >3 caffeinated drinks ( 300mg) per day

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In the proposed pilot study 30 community-dwelling older adults (aged >65) who take at ≥1 daily non-diuretic antihypertensive medication, have a mean SBP >135 mm Hg, and awaken ≥2 times nightly to void will be randomly assigned to one of the 3 groups of 10 participants each to 1) morning (am) HTN medication dosing, 2) BBTI with am HTN medication dosing, 3) nighttime non-diuretic HTN medication dosing (chronotherapy) for 6 weeks.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AM antihypertensive dosing arm<br>participants will be asked to continue taking their antihypertensive medication within an hour of awakening | Other: AM antihypertensive dosing<br>* participants will be asked to continue taking their antihypertensive medication within an hour of awakening<br>|
| Experimental: BBTI arm<br>participants will receive the behavioral treatment for insomnia BBTI by the study RN. Participants will also be asked to take their antihypertensive medication within an hour of awakening | Behavioral: BBTI<br>* Participants randomized to BBTI will receive 45- to 60-minute individual intervention session followed by a 30-minute follow-up session 2 weeks later, and 20-minute telephone calls after 1 and 3 weeks. BBTI will focus on four behaviors that promote sleep and discussion of homeostatic and circadian mechanisms of human sleep regulation. These four interventions are simple to conceptualize and implement, and constitute the core of efficacious multi-modal behavioral treatments for insomnia.<br>|
| Experimental: PM antihypertensive dosing or Chronotherapy arm<br>participants will be asked to switch their conventional once daily non-diuretic antihypertensive to bedtime | Other: PM antihypertensive dosing or Chronotherapy<br>* participants will be asked to switch their conventional once daily non-diuretic antihypertensive to bedtime<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean sleep time systolic blood pressure dip | The mean sleep time systolic blood pressure dip will be quantified by calculating the difference between daytime mean systolic pressure and nighttime mean systolic pressure expressed as a percentage of the day value for each participant across the 48-hour recording period comparing baseline and post-intervention | Baseline and at 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nocturia | nocturia frequency per 3-day bladder diary completed by participants comparing baseline and post-intervention | Baseline and at 6 weeks | 
| Pittsburgh Sleep Quality Index (PSQI) score | PSQI is a self-rated questionnaire for evaluating subjective sleep quality. PSQI global scores range from 0-21, with higher scores indicating worse sleep quality. | Baseline and at 6 weeks | 
| Sleep efficiency | Sleep efficiency will be calculated as (total sleep time/time in bed)*100 with time in bed and total sleep times obtained from Zmachine worn by participants pre- and post-intervention | Baseline and at 6 weeks |