Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD

Abstract

Time of ingestion of hypertension medications can affect circadian patterns of BP, but whether this translates into an effect on clinical outcomes is unknown. Here, in an open-label trial, we randomly assigned 661 patients with CKD either to take all prescribed hypertension medications upon awakening or to take at least one of them at bedtime. We measured 48-hour ambulatory BP at baseline and 3 months after any adjustment in treatment or, at the least, annually. After a median follow-up of 5.4 years, patients who took at least one BP-lowering medication at bedtime had an adjusted risk for total cardiovascular events (a composite of death, myocardial infarction, angina pectoris, revascularization, heart failure, arterial occlusion of lower extremities, occlusion of the retinal artery, and stroke) that was approximately one-third that of patients who took all medications upon awakening (adjusted HR 0.31; 95% CI 0.21 to 0.46; P < 0.001). Bedtime dosing demonstrated a similar significant reduction in risk for a composite outcome of cardiovascular death, myocardial infarction, and stroke (adjusted HR 0.28; 95% CI 0.13 to 0.61; P < 0.001). Furthermore, patients on bedtime treatment had a significantly lower mean sleep-time BP and a greater proportion demonstrated control of their ambulatory BP (56% versus 45%, P = 0.003). Each 5-mmHg decrease in mean sleep-time systolic BP was associated with a 14% reduction in the risk for cardiovascular events during follow-up (P < 0.001). In conclusion, among patients with CKD and hypertension, taking at least one antihypertensive medication at bedtime improves control of BP and reduces the risk for cardiovascular events.

Figure 1.

Kaplan-Meier survival curves as a function of time-of-day of hypertension treatment, i.e., for patients with CKD ingesting either all their BP-lowering medications upon awakening or ≥1 medication at bedtime, for total CVD events (top) and major CVD events (cardiovascular deaths, myocardial infarction, ischemic stroke, and hemorrhagic stroke; bottom).

Figure 2.

Hazard ratios (with 95% confidence intervals) of CVD events (adjusted by age, sex, and diabetes) as a function of time-of-day of hypertension treatment, i.e., for patients with CKD ingesting either all their BP-lowering medication upon awakening or ≥1 medication at bedtime. Total events include the following: death (from all causes), cardiovascular events (myocardial infarction, angina pectoris, and coronary revascularization), cerebrovascular events (stroke and transient ischemic attack), heart failure, acute arterial occlusion of lower extremities, and thrombotic occlusion of the retinal artery. Major events include: cardiovascular deaths, myocardial infarction, ischemic stroke, and hemorrhagic stroke.

Figure 3.

Hazard ratio of CVD events (adjusted by age, sex, diabetes, and number of hypertension medications used for treatment) as a function of achieved asleep SBP mean (top) and achieved daytime-determined clinic SBP (bottom) at the time of the last ABPM evaluation. The studied population was divided into five classes of equal size (quintiles).