Vigo, Spain—Pharmacists may want to add some advice when they dispense antihypertensive medications. A new study suggests that high blood pressure (BP) patients who take their pills at bedtime post lower numbers and have a significantly decreased risk of morbidity and mortality from their condition.

The Hygia Chronotherapy Trial, which is published in the European Heart Journal, is touted as the largest to investigate how cardiovascular risk is affected by the time of day patients take their medications.

University of Vigo–led researchers randomized 19,084 patients to either taking their pills upon waking or at bedtime. Participants were followed for an average of more than 6 years, with ambulatory blood pressure checked over 48 hours at least once a year.

Participants in the multicenter, controlled, prospective, randomized, blinded-endpoint trial, with a median age of 60.5 years, were instructed to ingest the entire daily dose of one or more hypertension medications at bedtime or upon awakening. During median patient follow-up, 1,752 participants experienced at least one of the primary cardiovascular disease (CVD) outcomes, including death, myocardial infarction, coronary revascularization, heart failure, or stroke.

Results indicated that patients taking their BP medications at bedtime, compared with the upon-waking treatment-time regimen, showed significantly lower hazard ratio of the primary CVD outcome (0.55 [95% CI, 0.50-0.61], P <.001) and each of its single components (P <.001 in all cases):
• CVD death (0.44 [0.34-0.56])
• Myocardial infarction (0.66 [0.52-0.84])
• Coronary revascularization (0.60 [0.47-0.75])
• Heart failure (0.58 [0.49-0.70])
• Stroke (0.51 [0.41-0.63])

Results were adjusted for significant characteristics, such as age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol levels, asleep systolic BP mean, sleep-time relative systolic BP decline, and previous CVD events.

“Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events,” the authors concluded.

“Current guidelines on the treatment of hypertension do not mention or recommend any preferred treatment time,” added lead author Ramón C. Hermida, PhD, director of the Bioengineering and Chronobiology Labs at the University of Vigo. “Morning ingestion has been the most common recommendation by physicians based on the misleading goal of reducing morning blood pressure levels. However, the Hygia Project has reported previously that average systolic blood pressure when a person is asleep is the most significant and independent indication of cardiovascular disease risk, regardless of blood pressure measurements taken while awake or when visiting a doctor. Furthermore, there are no studies showing that treating hypertension in the morning improves the reduction in the risk of cardiovascular disease.”

The Hygia Project is composed of a network of 40 primary-care centers within the Galician Social Security Health Service in northern Spain and involves 292 physicians.

Researchers suggest that administration-time differences in the effects of BP-lowering medications “arise from circadian rhythm-dependent influences both on their pharmacokinetics and pharmacodynamics as well as on the mechanisms of BP regulation. For example, peak activity of the renin–angiotensin–aldosterone system (RAAS) occurs during sleep.

Accordingly, bedtime in comparison to upon-waking ingestion of once-a-day formulations of angiotensin-II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)—as well as their tested combinations with calcium channel blockers (CCBs) and diuretics—results in considerably enhanced reduction in asleep BP mean without compromised therapeutic effect on awake BP.”

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