Effect of Chronotherapy on Blood Pressure - Time of Intake of Blood Pressure Lowering Drugs

Study Overview
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Brief Summary
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A randomized clinical trials with cross-over design to evaluate changes in blood pressure, renal function (creatinine, estimated glomerular filtration), LDL and HDL-cholesterol after taking antihypertensive drugs in the morning or at bedtime. Blood pressure will be estimated by ambulatory blood pressure measurements. There will be a shift in time of drug intake after 8 weeks for each participant. Approximately 100 individuals aged 40-75 years and on stable anti-hypertensive treatment and blood pressure <150/95 mm Hg will be recruited. No new drugs will be introduced during the study.

Detailed Description
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High blood pressure (hypertension, HT) is very common and can lead to serious cardiovascular complications and premature death. Despite effective drug treatment many patients do not reach the blood pressure goal. No new antihypertensive drugs have been developed lately, so there is a need for other strategies to increase attainment of goals and diminish the rate of complications. The circadian rhythm can affect sleep, body temperature, hormone levels, metabolism and the effect of drugs. The impact of antihypertensive treatment in the short and long run was described in a large randomized study in primary health care where individuals with hypertension were randomly assigned to take the drugs in the morning or at bedtime. Intake at bedtime resulted in lower blood pressure, better kidney function and lower LDL-cholesterol. Further, after a mean time follow-up of 6 years a 50% reduction of cardiovascular death was seen. There was by time running a difference in antihypertensive drugs and also co-morbidity between the groups. Despite this, there is a need to investigate if chronotherapy might play a role in antihypertensive care. The aim of the study is to investigate the effect of intake of drugs in the morning compared to at bed-time. Methods: Patients 40-75 years, will be recruited from two primary health care centers and one clinic of internal medicine. Medical history, current medication will be recorded. Office blood pressure, body height and weight, ECG and ambulatory blood pressure measurement (ABPM) will be performed. Blood will be analyzed for fasting blood glucose, LDL and HDL-cholesterol and creatinine. After inclusion in the study the patients are randomly, by clinic, allocated to take their antihypertensive drugs in the morning or at bed-time during 8 week. The ordinary medication is used during the study period. The patients are instructed to keep a diary on wake-up and bed-times, side effects, sleep quality and other experiences during therapy. After 8 weeks the investigations at base-line are repeated and a visual analogue scale on sleep, daytime tiredness and urine voiding is recorded. The patients shift to intake of medication on the opposite time of day for 8 weeks. The study is completed with a repeated investigation as above. The analyses of data is performed by researchers of the team that are not aware of the patients' allocation. The diaries will be a base for later in-depth-interviews with a part of the patients. The analyses will be intention-to-treat using appropriate methods for the data. Office blood pressure, blood lipids and kidney function at baseline, 8 and 16 weeks, as well as sleep duration, urine voiding at night will be analyzed. ABPM will be analyzed using mean blood pressure around-the-clock, daytime and nighttime blood pressure, dipping and morning surge.

Official Title
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Chronotherapy in Hypertension - a Study of Blood Pressure Levels Following Intake of Antihypertensive Medication in the Morning or at Bedtime

Conditions
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Hypertension, Drug Therapy, Primary Health Care

Intervention / Treatment
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* Other: Time of ordinary antihypertensive medication intake


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of hypertension Stable antihypertensive treatment at least 8 weeks prior to inclusion One to four antihypertensive drugs Exclusion Criteria: Atrial fibrillation/flutter Diabetes Previous stroke or TIA Heart failure Ischemic heart disease Peripheral artery disease Malignant disease with less than one year expected survival Inability to follow study protocol (for instance shift work)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants are randomized in the initial phase to take their ordinary anti-hypertensive medication in the morning or at bedtime for 8 weeks. Then the participants are switching to the alternative intervention during 8 weeks in the second phase of the study.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Morning intake<br>Intake of antihypertensive medication in the morning | Other: Time of ordinary antihypertensive medication intake<br>* Time of ordinary antihypertensive medication intake<br>|
| Active Comparator: Bedtime intake<br>Intake of antihypertensive medication at bedtime | Other: Time of ordinary antihypertensive medication intake<br>* Time of ordinary antihypertensive medication intake<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24 hours blood pressure changes between 8 and 16 weeks. | Ambulatory blood pressure changes between 8 and 16 weeks. Systolic and diastolic mean blood pressure level. | 8 and 16 weeks | 
| Change of dipping of blood pressure between 8 and 16 weeks. | Ratio between daytime and nighttime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level. | 8 and 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daytime blood pressure changes between 8 and 16 weeks. | Ambulatory daytime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level. | 8 and 16 weeks | 
| Nighttime blood pressure changes between 8 and 16 weeks. | Ambulatory nighttime blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level. | 8 and 16 weeks | 
| Office blood pressure changes between 8 and 16 weeks. | Office blood pressure registered after 8 and 16 weeks. Systolic and diastolic mean blood pressure level. | 8 and 16 weeks | 
| Difference in morning surge of blood pressure between 8 and 16 weeks. | Occurrence of morning (yes/no) | 8 and 16 weeks | 
| Difference in LDL cholesterol levels between 8 and 16 weeks. | LDL cholesterol changes according to time of intake of antihypertensive drugs | 8 and 16 weeks | 
| Difference in HDL cholesterol levels between 8 and 16 weeks. | HDL cholesterol changes according to time of intake of antihypertensive drugs | 8 and 16 weeks | 
| Difference in total cholesterol levels between 8 and 16 weeks. | Total cholesterol changes according to time of intake of antihypertensive drugs | 8 and 16 weeks | 
| Difference in p-creatinine levels between 8 and 16 weeks. | P-creatinine changes according to time of intake of antihypertensive drugs | 8 and 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cross-over study