Evidence supporting nocturnal dosing of antihypertensives for individual drugs from small trials has existed for many years. Now the Hygia trial provides more convincing data from multiple primary care practices and backed up by scheduled ambulatory blood pressure monitoring (ABPM) from over 19,000 hypertensive patients followed for a median of 6.3 years.

9,532 patients with ABPM-confirmed hypertension were randomized to take their daily medications in the morning and 9,552 to take their meds at bedtime. Although the study controlled the timing of antihypertensive medications, drug type and dosing was at the discretion of primary care physicians. Matching, adherence, and follow-up were good in this study, and a modified intention-to-treat analysis was conducted. The protocol required baseline and annual 48-hour ABPM measurement, with the belief that 48 hours would give more accurate information than 24-hour measurements.

In follow-up, the researchers recorded primary outcomes of stroke, cardiac death, new-onset heart failure, myocardial infarction, or revascularization in 1,752 patients. Nighttime dosing of antihypertensive drugs was associated with decreased all-cause mortality (adjusted hazard ratio [HR] 0.55, 95% CI 0.48-0.63) and cardiovascular death (adjusted HR 0.44, 95% CI 0.34-0.56). The Kaplan-Meier cumulative hazard also demonstrated a significant reduction in total cardiovascular events. Data on individual components of the cardiovascular events were not reported. Interestingly, the ABPM data did not demonstrate that either lower nocturnal systolic blood pressure or a 10% reduction in nocturnal blood pressure from daytime levels were predictive of different outcomes.

These striking results are not without limitations. This study was conducted in a Caucasian Spanish population and only examined primary prevention. The authors reported only composite risks for coronary outcomes, which could be misleading if most events were revascularization rather than myocardial infarction or death. Additionally, the primary care clinicians selected significantly more diuretics and beta blockers for the daytime group, and more calcium channel blockers but fewer prescriptions overall for the nocturnally-dosed group. Nevertheless, these data are a wake-up call for clinicians to consider evening dosing for antihypertensive medications.

For more information, see the topic Hypertension Medication Selection and Management in DynaMed

EBM Focus articles provide concise summaries of clinical trials most likely to inform clinical practice curated by the DynaMed® editorial team.