The primary outcome—a composite of cardiovascular death, myocardial infarction, coronary revascularization, heart failure, or stroke—occurred in 1752 patients, favoring the bedtime group (HR = 0.55; 95% CI, 0.50-0.61; P < .001). The calculated number of events was 1130 in the morning administration group and 622 in the evening administration group; the authors did not explicitly report the event numbers in each group. Each component of the composite outcome also favored evening administration (P < .001 for all): 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).
The complicated, layered study design and randomization methods limit the ability to critically appraise the study.
Smaller Spanish study also supported evening administration
A prior, smaller, prospective randomized trial conducted by the same researchers as the Hygia Project found even greater benefits to evening BP medication administration.4 The 2156 Spanish patients (52% men; average age, 55 years) from multiple primary care offices were randomized 1:1 to BP medication administration either upon awakening or at bedtime. Dozens of baseline characteristics were evenly distributed except for age (55.0 vs 56.3; P = .021) and creatinine (0.96 vs 0.98; P = .028), both of which were lower in the evening group.
After a median follow-up of 5.6 years, the bedtime group had significantly lower total events (187 events in the morning group vs 68 in the evening group; relative risk [RR] = 0.39; 95% CI, 0.29-0.51; P < .001). Individual cardiovascular outcomes also dramatically favored the evening group: total deaths (12 vs 28; P = .008), cardiovascular deaths (3 vs 14; P = .006), cardiovascular disease events (30 vs 74; P < .001), stroke (7 vs 24; P = .001), and heart failure (8 vs 33; P < .001).
Limits of both the UK trial and the Hygia Project trial included single countries of study with a lack of racial and ethnic diversity, and greater nonadherence to the evening administration of the medications.
Recommendations from others
A 2022 consensus statement from the International Society of Hypertension, published before the UK trial, recommended against bedtime dosing until more high-quality data became available. They pointed to evidence showing higher medication adherence with morning dosing, risk for asleep BP dropping, and worsening daytime BP control as reasons to continue morning administration.5 Other reviewers have questioned the Hygia Project results due to their reported implausibly large effects on cardiovascular outcomes, noting that independent attempts to verify the methods and the data have proven challenging and are not completed.6
Editor’s takeaway
I confess that I was swayed by the results of the Hygia Project; for a year or so, I advised my patients to take at least 1 BP pill at night. But after the UK study came out, I needed to reconsider. I began to worry that the great outcomes of nocturnal therapy may have been a mirage. I have returned to counseling patients to take their BP medications in whichever way fosters consistency while minimizing adverse effects for them.