Morning Versus Evening Dosing of Antihypertensive Medications: A Pilot Study to Assess Feasibility and Efficacy
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional

Summary: 
      Hypertension is a major risk factor for cardiovascular and renal disease, and a leading cause
      of premature mortality worldwide. Ambulatory blood pressure (BP) monitoring (ABPM) allows for
      assessment of BP throughout the day and night. Of all the BP measurements, nighttime systolic
      BP appears to be the best predictor of cardiovascular disease and all-cause mortality.
      Importantly, elevated nighttime BP is a modifiable risk factor; evening dosing of
      antihypertensive medications lower nighttime BP and reduces proteinuria. In a large,
      randomized controlled trial, evening dosing of antihypertensive medications reduced the
      hazard rate for major cardiovascular events by 67%. Findings were similar in the subgroup of
      participants with chronic kidney disease (CKD). However, this single-center study was
      designed to evaluate cardiovascular outcomes, not progression of CKD. The long-term effect of
      nighttime dosing of antihypertensive medications on progression of CKD is unknown.

      To address this important gap in knowledge, the investigators plan to conduct a pragmatic,
      randomized controlled trial. 3600 participants at risk for progression of CKD who are taking
      ≥1 antihypertensive medication once daily will be randomized to morning versus evening dosing
      of at least one antihypertensive medication. The purpose of the current study is to obtain
      pilot data demonstrating the feasibility of the trial and the efficacy of the intervention.
    

Detailed description: 
      Background Hypertension is a major risk factor for cardiovascular and renal disease, and a
      leading cause of premature mortality worldwide. Early hypertension studies showed that
      treating elevated blood pressure (BP) reduces patients' risk of cardiovascular disease and
      all-cause mortality. In subsequent research, patients achieved greater improvement in
      cardiovascular outcomes when their treatment was aimed at a moderate systolic BP target
      (<150mmHg) than at higher targets. Although observational data suggest that even lower BP
      targets may be beneficial, this has not been seen in randomized trials; instead, "intense"
      treatment of hypertension (i.e., to a target systolic BP <120mmHg) was found to have no
      effect on participants' risk for renal disease, cardiovascular disease, or all-cause
      mortality. Similarly negative findings were reported in studies that enrolled participants
      with chronic kidney disease (CKD) and diabetes; all failed to demonstrate a benefit to
      intensive lowering of clinic BP.

      One potential explanation for this apparent lack of benefit of intense BP targets is that the
      study protocols targeted reductions in clinic BP rather than ambulatory BP. Ambulatory BP
      monitoring (ABPM) allows for assessment of BP throughout the day and night. Of all the BP
      measurements, nighttime systolic BP appears to be the best predictor of cardiovascular
      disease and all-cause mortality. In fact, in most observational studies, clinic BP is no
      longer a predictor of adverse events after adjusting for nighttime BP. Importantly, elevated
      nighttime BP is a modifiable risk factor; evening dosing of antihypertensive medications
      lower nighttime BP and reduces proteinuria. In a large, randomized controlled trial, evening
      dosing of antihypertensive medications reduced the hazard rate for major cardiovascular
      events by 67%. Findings were similar in the subgroup of participants with CKD. However, this
      single-center study was designed to evaluate cardiovascular outcomes, not progression of CKD.
      The long-term effect of nighttime dosing of antihypertensive medications on progression of
      CKD is unknown.

      To address this important gap in knowledge, the investigators plan to conduct a pragmatic,
      randomized controlled trial. 3600 participants at risk for progression of CKD who are taking
      ≥1 antihypertensive medication once daily will be randomized to morning versus evening dosing
      of at least one antihypertensive medication. The purpose of the proposed study is to obtain
      pilot data demonstrating the feasibility of the trial and the efficacy of the intervention.

      Overview of Trial Design The study will be conducted in the renal clinic at University of
      Minnesota Medical Center (UMMC). Eligible patients will have chronic kidney disease and be
      taking a once daily antihypertensive medication. Participants will be randomized to receive
      their once daily antihypertensive medication in the morning or the evening. Medication
      therapy management with a focus on antihypertensive medications will take place at the time
      of a clinic visit or via phone after the clinic visit. Adherence to medications will be
      assessed 3-6 weeks after the clinic visit.

      Objective The primary objective of this pilot study is to demonstrate 1) the feasibility of a
      simple randomized trial and 2) the efficacy of medication therapy management for assigning
      participants to take a once daily antihypertensive medication either in the morning or in the
      evening.
    

Intervention name(s): Medication therapy management
Intervention type(s): Behavioral
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other