Greater Cardiovascular Risk Reduction With Antihypertensives at Bedtime Than in Morning

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One simple, no-cost change appears to lower cardiovascular (CV) risk among patients with resistant hypertension. By taking their antihypertensive medications at bedtime instead of in the morning, patients in a Spanish trial significantly reduced their cardiovascular risk.

Researchers have known that sleep-time blood pressure (BP) better predicts CV risk than does either the awake or 24-hour BP means. However, all previous studies relied on a single baseline ambulatory blood pressure monitoring (ABPM) profile on each participant at the beginning of the study. Thus, they could not detect changes in the pattern or level of BP if they occurred.

Reporting at the 48th Congress of the European Renal Association—European Dialysis and Transplant Association in Prague, lead investigator Ramón Hermida, PhD, director of the laboratory of bioengineering and chronobiology at the University of Vigo in Vigo, Spain, told ASN Kidney News that his study tested the hypothesis that bedtime dosing of at least one blood pressure medication would more effectively reduce CV disease (CVD) risk than would conventional morning dosing of all of a patient’s antihypertensive medications. He pointed out that bedtime dosing is a cost-effective and simple strategy to achieve adequate asleep BP reductions and to re-establish a normal 24-hour pattern of BP reduction at night (“dipping pattern”) if it is missing.

Hermida reported the results of a substudy of a larger study of people with hypertension, which was prospective, randomized, and open-label. In the substudy, 776 participants with resistant hypertension had a mean age of 61.6 years, an approximately equal number of men and women, and were randomly assigned to take all their prescribed BP medications upon awakening or at least one of them at bedtime. At the physician’s discretion, additional antihypertensive medication could be added as required, but no nighttime medication was allowed in the morning, meaning that any one drug could not be taken at both times. For controls, who took all BP medication in the morning, any additional BP medications also had to be taken in the morning.

At baseline, BP was measured at 20 min intervals during waking hours and at 30 min intervals at night. A wrist actigraph recorded periods of daytime activity and noctural sleep. These measurements were performed annually, or quarterly if treatment adjustments were necessary. Patients were followed for a median of 5.4 years.

Lower risk of CV events with bedtime dosing

The group of patients assigned to take at least one medication at bedtime had significantly better BP control during sleep, with a greater reduction in the asleep BP mean and the asleep BP declines constituting a more normal dipping pattern when compared to patients taking all their BP drugs in the morning.

When several characteristics of the ABPM were applied in a Cox regression model, only the decrease in sleeping BP was an independent predictor significantly associated with survival. Neither the daytime BP mean nor the morning surge in BP were predictors of survival. The nighttime dosing group had a 62 percent lower relative risk of total CV events compared to the morning group (relative risk 0.38, p<0.001). Their relative risk of major CV events, consisting of CVD death, myocardial infarction, or ischemic or hemorrhagic stroke, was 0.35 (p=0.002).

Referring to the BP study as a whole and not just the results in resistant hypertension, Hermida said that bedtime dosing was associated with greater reductions than morning dosing in the risk of all the individual endpoints of CV mortality, myocardial infarction, development of heart failure, or stroke. These results were true for the study population as a whole as well as when patients with diabetes or CKD were analyzed separately. “These two groups are relevant because they are characterized with a significantly higher cardiovascular risk as compared to the general population,” he said.

Survival advantage with nighttime dosing

At 8 years of follow-up, the group taking at least one BP medication at bedtime had an event-free survival of about 81 percent compared to approximately 64 percent for the group taking all medications in the morning (p<0.001). For every 5 mm Hg decrease in sleep time systolic or diastolic mean BP, there was an 11 percent decrease in the relative risk of a CVD event.

Antihypertensive drugs are normally recommended once a day without specifying a time of day. Surveys in Spain have shown that more than 80 percent of all patients with hypertension take all their BP drugs in a single morning dose. Hermida said there is no clinical rationale for this practice, and in fact, his results argue against it. “From the point of view of cardiovascular risk reduction and renal protection what we found is that most if not all of the hypertensive medications perform much better when ingested in the evening,” he concluded.

“Blood pressure level is not the only significant cardiovascular risk factor. However, it has been basically the only therapeutic goal from the point of view of hypertension treatment so far,” he said. “Controlling nighttime blood pressure needs to be considered as a therapeutic target for cardiovascular risk reduction.”

The main study results were published last year in Chronobiology International (2010; 27(8):1629–1651). A substudy of patients with type 2 diabetes was recently published in Diabetes Care (2011; 34:1270–1276).