Advise patients with uncontrolled hypertension to take at least one of their blood pressure (BP) medications at bedtime instead of in the morning. Nighttime dosing leads to better control and lowers the risk for major cardiovascular events.1,2
A man, 60, has struggled to control his BP despite the use of three antihypertensives. What can you recommend to improve his BP control and lower his cardiovascular risk?
You prescribe hydrochlorothiazide for a woman, 55, with newly diagnosed hypertension. What can you tell her about how to take the medication to maximize its beneficial effects?
Management of hypertension often focuses on BP measurements taken in a clinic during the day, although both BP and metabolism fluctuate with circadian rhythms. Most people experience an increase in pressure during the day, with peaks in the morning and evening, followed by a decline in BP at night, during sleep.3
Focus on Nighttime BP
Sleeping BP is gaining attention, particularly the phenomenon of nondipping. Commonly defined as a < 10% decline in systolic pressure during sleep, nondipping is associated with an increased risk for cardiovascular events, such as heart attack and stroke.4 What’s more, mean BP during the night is a better predictor of cardiovascular disease (CVD) risk than BP while the patient is awake.5,6
Evidence suggests that taking an antihypertensive medication at night increases its therapeutic effect,7 yet most patients take it in the morning.8 The study discussed here was designed to investigate whether bedtime dosing significantly affects BP control and CVD risk.
Bedtime dosing benefits patients, and there’s no downside
The MAPEC study was an open-label randomized clinical trial conducted at a single center in Spain.1 Patients were enrolled if they had a diagnosis of either untreated hypertension (based on ambulatory BP monitoring [ABPM] criteria) or resistant hypertension (uncontrolled on ≥ 3 optimally dosed antihypertensive medications). Exclusion criteria included pregnancy, a history of drug/alcohol abuse, night shift work, AIDS, type 1 diabetes, secondary hypertension, and a previous CVD diagnosis.
Patients were randomly assigned to one of two time-of-day dosing groups: morning dosing of all their BP medications (n = 1,109) or dosing of ≥ 1 BP medications at bedtime (n = 1,092). ABPM—in which patients wore a monitor that recorded their BP every 20 minutes during the day and every 30 minutes at night for 48 hours—was conducted once a year, or more frequently when medication adjustments occurred. The use of a specific drug was not required, but physicians were instructed to adjust medications according to a study-specific ABPM protocol.
Patients were followed for a mean of 5.6 years for the endpoints of CVD events and mortality. These endpoints were assessed by researchers blinded to patients’ treatment assignment.
At baseline, the two groups were similar in age (mean, 55), percentage of men (48%), presence of comorbidities, and baseline clinic and ambulatory BP. Throughout the study, patients in the bedtime dosing group had lower mean asleep systolic and diastolic BP, a lower prevalence of a nondipping pattern, and a higher prevalence of controlled ambulatory BP. The bedtime group also had a lower risk for total CVD events (relative risk [RR] = 0.39) and major CVD events (RR = 0.33), and fewer overall deaths (4.16/1,000 vs 2.11/1,000 patient-years). To prevent one CVD event, 63 patients would need to take their BP medication at bedtime instead of in the morning for one year. To prevent one death, 488 patients would need to adhere to the nighttime schedule for
A subgroup analysis of patients with type 2 diabetes (n = 448)2 had similar results: Bedtime dosing led to lower asleep BP, a lower prevalence of a nondipping pattern, and a higher prevalence of controlled ambulatory BP, as well as a lower risk for total CVD events, major CVD events, and CVD-related death. The differences persisted after correction for the use of statins and aspirin. Among those in this subgroup analysis, 29 patients would need to take their BP medications at bedtime for one year to prevent one CVD event, and 263 patients would need to be treated for one year to prevent one death.
Clear advantages of preventing nondipping
We’ve known that a nondipping pattern is associated with higher cardiovascular risks and that taking antihypertensives at bedtime decreases the prevalence of nondipping patterns. The MAPEC study, however, is the first prospective trial to show that bedtime dosing of BP medications lowers the risk for CVD events and death.
Questions about methodology, non-US guidelines
Since MAPEC was an open-label study, the physicians adjusting BP medications were aware of the treatment groups to which patients were allocated. Guidelines for medication titration were provided, but it is unclear whether patients in both groups were treated identically. Patients were also aware of their allocation, creating the potential for bias if one group adhered to their medications more closely than the other.
The study was conducted in a single center in Spain, which may limit its generalizability to the US. Notably, Spain’s medication guidelines recommend ACE inhibitors, angiotensin receptor blockers, β-blockers, and calcium channel blockers as first-line medications; hydrochlorothiazide is a second-line option.
While ABPM appears to be a better indicator of CVD risk compared with clinic BP monitoring, most US physicians still rely on readings taken in their office for diagnosing and managing hypertension. How ambulatory BP translates to clinic BP is somewhat unclear.
Challenges to Implementation
Patient, provider resistance
We see few challenges to implementing bedtime dosing of BP medications for patients with uncontrolled hypertension. It is possible, however, that patients who have a longstanding routine of taking their medications in the morning may be resistant to change. Also, pharmacists and nurses, as well as some physicians, may continue recommending morning dosing, which could be confusing for patients.
1. Hermida RC, Ayala DE, Mojón A, et al. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010;27:1629-1651.
2. Hermida RC, Ayala DE, Mojón A, et al. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care. 2011;34:1270-1276.
3. Hermida RC, Ayala DE, Portaluppi F. Circadian variation of blood pressure: the basis for the chronotherapy of hypertension. Adv Drug Deliv Rev. 2007;59:904-922.
4. Verdecchia P, Porcellati C, Schillaci G, et al. Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension. 1994;24:793-801.
5. Dolan E, Stanton A, Thijs L, et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin study outcome. Hypertension. 2005;46:156-161.
6. Hermida RC, Ayala DE, Mojón A, et al. Decreasing sleep-time blood pressure determined by ambulatory monitoring reduces cardiovascular risk. J Am Coll Cardiol. 2011;58:1165-1173.
7. De la Sierra A, Redon J, Banegas JR, et al. Prevalence and factors associated with circadian blood pressure patterns in hypertensive patients. Hypertension. 2009;53:466-472.
8. Hermida RC, Ayala DE, Calvo C, et al. Chronotherapy of hypertension: administration-time-dependent effects of treatment on the circadian pattern of blood pressure. Adv Drug Deliv Rev. 2007;59:923-939.
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2012;61(3):153-155.
Drs. Kirley, Sharma, and Rowland are in the Department of Family Medicine at the University of Chicago.