20,000 Patient Randomized Trial Shows Ingestion of Anti-hypertensive Medication at Night Associated with Better Blood Pressure Control and Improved Cardiovascular Outcomes

A randomized trial, led by Dr. Ramon Hermida, revealed that the routine ingestion of at least one prescribed anti-hypertensive medication in patients with hypertension led to improved control of ambulatory blood pressure and reduced cardiovascular risk. This study, published in the European Heart Journal, compared ingesting anti-hypertensive medication during two potential time points: upon waking and at bedtime.

Multiple trials have previously shown a better control of ambulatory blood pressure with no increase in adverse events when antihypertensive medication is ingested at nighttime as opposed to upon waking. While there is evidence to suggest that hypertension treatment time does influence overall blood pressure control, this not entirely consistent. Additionally, there are not enough long-term studies to document whether this influences outcomes. The MAPEC study is the first study to prospectively randomize patients to compare outcomes in patients randomized to either ingestion of antihypertensive medication at bedtime or upon waking.

In this prospective randomized study, 19,084 patients with hypertension were randomized to either receive their entire daily dose of antihypertensive medication at bedtime (9,552 patients) or upon awakening (9,553 patients). Hypertension was confirmed at the time of inclusion using the 48 hour ambulatory monitoring period and was defined as having an awake systolic blood (SBP) pressure mean ≥ 135 mmHg, awake diastolic blood pressure (DBP) mean ≥ 85 mmHg, asleep SBP mean ≥ 120 mmHg, asleep DBP mean ≥ 70 mmHg, and prescription of BP-lowering treatment. At the time of enrollment and at every follow-up appointment, ambulatory blood pressure was measured for 48 hours. Follow up was done at least annually, and sooner if the patient had uncontrolled blood pressure. The primary outcome of the study was designated to be a composite of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke.

Over a median of 6.3 years of follow-up, a total of 1,752 patients experienced the primary outcome (9.2%). Even after adjusting for age, sex, diabetic status, and other relevant risk factors, patients who took their anti-hypertensive medication at night had a lower incidence of cardiovascular events (HR 0.55, 95% CI 0.50-0.61, p < 0.001). The reduction in event rate applied to all events in the composite outcome (cardiovascular death HR 0.44 (95% CI 0.34–0.56), myocardial infarction HR 0.66 (95% CI 0.52–0.84), coronary revascularization HR 0.60 (95% CI 0.47–0.75), heart failure HR 0.58 (95% CI 0.49–0.70), and stroke HR 0.51 (95% CI 0.41–0.63), p < 0.001 for all). There was no significant difference in adherence rates between the two groups. Additionally, 0.3% of all patients reported sleep-time hypotension (this was not statistically different between the two groups, p = 0.114).

The findings of this study demonstrate that compared to ingesting the antihypertensive medication upon waking, ingesting the medication at night is associated with overall better control of ambulatory blood pressure and a reduced risk of cardiovascular events. Patients who received their treatment at bedtime had significantly lower asleep-blood pressure readings without the loss of awake-blood pressure-lowering efficacy. Additionally, the nighttime group had a greater sleep-time relative blood pressure decline resulting in a significantly lower prevalence of non-dipping. However, the findings of this study will need to be validated by other studies and whether the findings here apply to all ethnic groups will need to be evaluated. Additionally, it is important to note that the study did not assign treatments but rather, the specific treatment, including the class of drugs, was chosen by the clinician. Regardless, the study does demonstrate that nighttime treatment is associated with significantly better blood pressure control and improved cardiovascular outcomes.