Treatment of HYpertension: Morning Versus Evening (THYME)

Rationale: The nocturnal blood pressure mean is an independent and stronger predictor of cardiovascular disease (CVD) risk than either daytime office, awake or 24hour mean blood pressure. In general, when nocturnal blood pressure does not decline CVD risk is higher, usually referred to as "dippers" versus "non-dippers". Evening administration of treatment might lower nocturnal blood pressure more effectively than morning administration, which is most commonly advised. The main hypothesis of this study is that evening administration of antihypertensive medication might resume the dipping pattern in non-dippers and as a consequence might reduce CVD risk more than morning administration. Primary objective (in short): -to prove that evening administration of enalapril/hydrochlorothiazide in non-dippers can resume a dipping blood pressure pattern in non-dippers Study design: A double-blind placebo-controlled cross-over study Each person will use for one period of six weeks enalapril/hydrochlorothiazide in the morning and placebo in the evening, and one period of six weeks the other way around

This arm will start with six weeks of administration of enalapril/hydrochlorothiazide in the evening and placebo in the morning, followed by six weeks of active treatment in the morning and placebo in the evening

This arm will start with six weeks of morning administration of enalapril/hydrochlorothiazide in the morning and placebo in the evening, followed by six weeks of placebo in the morning and active treatment in the evening

The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared

At the end of each treatment period of six weeks, a 24 hour ambulatory blood pressure measurement will be performed

One safety issue on evening administration of antihypertensive treatment is that blood pressure might get too low. We will assess this especially in the dippers.

Excretion of sodium, potassium, protein and melatonin depend on the circadian clock. Therefore, differences between morning and evening administration of antihypertensive medication are tested

Moring of 24 hour blood pressure measurement after six weeks of treatment according to a certain regime

Inclusion Criteria: Essential hypertension Stable blood pressure on treatment with Angiotensin Converting Enzyme Inhibitor (ACEI) or Angiotensin II Receptor Blocker (ARB) and hydrochlorothiazide Age between 18 and 85 years WHO performance status 0-1 Available for a time period of 15 weeks Written informed consent Dippers: Nocturnal blood pressure fall of 10-20% of daytime values.20 Non-dippers: -Nocturnal blood pressure fall of <10% of daytime values Exclusion Criteria: secondary cause of hypertension use of ARB because of intolerability (e.g. dry cough) of ACEI nocturnal blood pressure fall of >20% or rise renal insufficiency (GFR<60 ml/min) shift work pregnancy or wish to get pregnant use of other antihypertensive medication than ACEI, ARB, hydrochlorothiazide or a calcium channel blocker use of sleeping medication