Antihypertensive Drugs More Effective When Taken At Night

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According to the current study by Hermida and colleagues, taking antihypertensive medications at bedtime rather than in the morning has been shown to be associated with an increase in bedtime blood pressure (BP) decline toward a dipping pattern and better BP control and reduction in urinary protein excretion. Nocturnal hypertension is more common among patients with chronic kidney disease (CKD) who may thus experience greater effects of time medications for hypertension.

This randomized controlled, open-label trial compares the effect of bedtime vs morning administration of BP medications on a composite of cardiovascular disease (CVD) outcomes and BP control.

Clinical Context

According to the current study by Hermida and colleagues, taking antihypertensive medications at bedtime rather than in the morning has been shown to be associated with an increase in bedtime blood pressure (BP) decline toward a dipping pattern and better BP control and reduction in urinary protein excretion. Nocturnal hypertension is more common among patients with chronic kidney disease (CKD) who may thus experience greater effects of time medications for hypertension.

This randomized controlled, open-label trial compares the effect of bedtime vs morning administration of BP medications on a composite of cardiovascular disease (CVD) outcomes and BP control.

Study Synopsis and Perspective

Among patients with CKD and hypertension, taking at least 1 antihypertensive medication at bedtime significantly improves BP control, with an associated decrease in risk for CVD events, according to new research.

Ramón C. Hermida, PhD, and colleagues from the Bioengineering and Chronobiology Laboratories at the University of Vigo, Campus Universitario, Spain, published their findings online October 24 in the Journal of the American Society of Nephrology.

According to the researchers, the beneficial effect of taking BP medication at night has been previously documented, but "the potential reduction in [CVD] risk associated with specifically reducing sleep-time BP is still a matter of debate."

The current prospective study sought to investigate in hypertensive patients with CKD whether bedtime treatment with hypertension medications better controls BP and reduces CVD risk compared with treatment on waking.

The study included 661 patients with CKD who were randomly assigned either to take all prescribed hypertension medications on awakening or to take at least 1 of them at bedtime. Ambulatory BP at 48 hours was measured at least once a year and/or at 3 months after any adjustment in treatment.

The composite measure of cardiovascular events used included death, myocardial infarction, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke. The investigators controlled their results for sex, age, and diabetes.

Patients were followed for a median of 5.4 years; during that time, patients who took at least 1 BP-lowering medication at bedtime had approximately one third of the CVD risk compared with those who took all medications on awakening (adjusted hazard ratio

---

, 0.31; 95% confidence interval [CI], 0.21 - 0.46; P < .001).

A similar significant reduction in risk with bedtime dosing was noted when the composite CVD outcome included only cardiovascular death, myocardial infarction, and stroke (adjusted HR, 0.28; 95% CI, 0.13 - 0.61; P < .001).

Patients taking their medications at bedtime also had a significantly lower mean BP while sleeping, and a greater proportion of these patients had ambulatory BP control (56% vs 45%; P = .003).

The researchers estimate that for each 5-mm-Hg decrease in mean sleep-time systolic BP, there was a 14% reduction in the risk for cardiovascular events during follow-up (P < .001).

According to Dr. Hermida and colleagues, "treatment at bedtime is the most cost-effective and simplest strategy of successfully achieving the therapeutic goals of adequate asleep BP reduction and preserving or re-establishing the normal 24-hour BP dipping pattern."

The authors suggest that a potential explanation for the benefit of nighttime treatment may be associated with the effect of nighttime treatment on urinary albumin excretion levels. "We previously demonstrated that urinary albumin excretion was significantly reduced after bedtime, but not morning, treatment with valsartan," they note. In addition, this reduction was independent of 24-hour changes of BP, but correlated with a decline in BP during sleep.

The study was not commercially supported. The authors and editorialists have disclosed no relevant financial relationships.

J Am Soc Nephrol. Published online October 24, 2011. Abstract

Related Link

Medscape Reference provides a comprehensive article on the pathophysiology, etiology, and prognosis of hypertension along with effective patient education information.

Study Highlights

• The participants were patients older than 18 years with CKD (estimated glomerular filtration rate < 60 mL/minute/1.73 m³, albuminuria, or both on at least 2 occasions at 3 months apart) and hypertension and were receiving antihypertensive medications.
  
• Excluded were pregnant women; patients with type 1 diabetes, AIDS, secondary hypertension, or CV disorders; those who worked a night shift; or those who were intolerant of ambulatory BP measurement (ABPM).
  
• 661 patients (396 men) participated; mean age was 59.2 years.
  
• The diagnosis of hypertension was based on an ABPM of 135/85 mm Hg or higher during awake time or a sleep BP mean of 120/70 mm Hg or higher.
  
• 332 patients were randomly assigned to ingest all antihypertensive medications on awakening and 329 to ingest 1 or more of these medications at bedtime.
  
• The protocol did not permit for divided doses of any medications, and randomization was by each medication.
  
• Blood samples were obtained between 0800 and 0900 hours after overnight fasting, during the same week as ABPM and 24-hour urine collection for albumin excretion.
  
• At inclusion into the study, participants' BP was measured every 20 minutes for systolic BP and diastolic BP between 0700 and 2300 hours and every 30 minutes during the night for 48 consecutive hours, with an ABPM monitor.
  
• Actigraphy was performed on the wrist to document all physical activity associated with the BP measurements.
  
• The procedures for ABPM and actigraphy were repeated annually or after any scheduled change in medications.
  
• Outcomes were all deaths, myocardial infarction, angina pectoris, coronary revascularization, heart failure, acute arterial occlusion, thrombotic occlusion of the retinal artery, stroke, and transient ischemic attack constituting a composite outcome.
  
• At baseline, the treatment groups were similar.
  
• One third had type 2 diabetes, more than 70% had metabolic syndrome, 13% had obstructive sleep apnea, 15% smoked, and more than half were obese.
  
• The median follow-up period was 5.4 years.
  
• There were 139 events during the follow-up period.
  
• There was a significant difference between the 2 groups in event-free survival (log-rank 39.1 and 11.0 for total and major events, respectively).
  
• Patients ingesting 1 or more BP-lowering medications at bedtime had approximately one third of the CVD risk vs those ingesting all medications on awakening (adjusted HR, 0.31; P < .001).
  
• A similar significant reduction in risk with bedtime dosing was noted when the composite CVD outcome included only cardiovascular death, myocardial infarction, and stroke (adjusted HR, 0.28; P < .001).
  
• There were significant reductions in the individual outcomes of myocardial infarction, angina pectoris, coronary revascularization, and heart failure with bedtime treatment.
  
• Patients who ingested bedtime medications also had better nighttime BP control.
  
• Only 14.4% of those with a CVD event had good nighttime BP control.
  
• Event-free survival was significantly associated with the progressive decrease in asleep systolic BP mean during follow-up.
  
• The HR for event-free survival was 0.86 for every 5-mm Hg decrease in asleep systolic BP mean.
  
• The awake systolic BP decline was not associated with event-free survival.
  
• Reduction in urinary albumin excretion was not associated with survival either.
  
• There was a progressive reduction from 60% to 32% in the percentage of patients treated at bedtime across the quintiles of asleep systolic BP mean.
  
• This finding demonstrated a relationship between bedtime medication, sleep time BP reduction, and decreased CV risk.
  
• The authors concluded that taking BP-lowering medications at bedtime vs taking them on awakening reduced the risk for CV events and that sleep time systolic BP was the best predictor of event-free survival.