Dosing BP Meds At Bedtime: Does It Improve Outcomes?

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Written By

Joshua W. Fleming, Pharm.D.
Patricia A. Ross, Pharm.D., BCPS

Reviewed By

Dawn Fuke, Pharm.D., BCPS
Michael Ernst, Pharm.D., BCPS

Citation

Hermida RC, Ayala DE, Mojon A, and Fernandez JR. Influence of Time of Day of Blood Pressure- Lowering Treatment on Cardiovascular Risk in Hypertensive Patients with Type 2 Diabetes. Diabetes Care. 2011; 34: 1270-76.

Blood pressure is known to follow a circadian rhythm in which the blood pressure falls by approximately 10% overnight. In many patients with hypertension (HTN) this drop in nocturnal blood pressure is blunted.  These patients are affectionately called “non-dippers.”  The non-dipping blood pressure pattern has been associated with a higher risk of cardiovascular events.  Several studies have evaluated the utility of changing blood pressure medication dosing times to bedtime.  Indeed, this has been an area of active investigation by Hermida and colleagues for several years.2  In previous studies they have demonstrated that moving the dose of at least one blood pressure medication to bedtime resulted in improved blood pressure control, reduced the prevalence of non-dipping, and lowered cardiovascular morbidity and mortality.

This prospective, single-center, randomized, open-label, blinded end point study enrolled 448 subjects with high blood pressure and diabetes.3  It was designed to evaluate cardiovascular outcomes after moving the dosing time of at least one blood pressure medication to bedtime.  The primary outcomes of this study were the composite of CVD morbidity and all cause mortality (death, myocardial infarction, angina, revascularization, heart failure, peripheral vascular disease, retinal artery occlusion, stroke, and transient ischemic attack) and major CVD events (CVD deaths, myocardial infarction, and stroke).  Subjects were included if they were at least 18 years of age with type 2 diabetes (DM).  Exclusion criteria included:  pregnancy; history of drug or alcohol abuse; night shift employment; diagnosis of AIDS, type 1 diabetes, secondary hypertension, pre-existing CVD; and intolerance to ambulatory blood pressure monitoring (ABPM).  Subjects were required to wear an ABPM for 48 hours annually or more frequently if changes in blood pressure medications were made.  Subjects were randomized to ingest all prescribed blood pressure medications in the morning upon awakening (n=232) or at least one of their blood pressure medications at bedtime (n=216).  The mean age was 62.5 years, approximately 57% were male, and the mean duration of DM and HTN was 9 and 7.5 years, respectively.  Baseline clinic-measured blood pressure (160/86 mmHg) was higher than the awake ABPM (135/77 mmHg) and asleep ABPM (128/68 mmHg). On average, subjects were followed and evaluated for 5.4 years.

Table 1:3  Primary and Secondary Outcomes – Rate per 1000 patient-years (# of events)

 

Awakening

Bedtime

P

NNT

(n=232)

(n=216)

Primary End Points

Composite CVD + mortality

54.2 (68)

19.8 (23)

<0.001

29

Major CVD events

17.6 (22)

5.2 (6)

<0.001

81

Secondary End Points

Total death

6.4 (8)

2.6 (3)

0.097

NA

Cardiovascular death

4.8 (6)

0.9 (1)

0.038

255

Other cause of death

1.6 (2)

1.7 (2)

0.968

NA

Cardiovascular events

16.0 (20)

6.9 (8)

0.008

111

Cerebrovascular events

6.4 (8)

0.9 (1)

0.01

182

Heart failure

13.6 (17)

6.0 (7)

0.02

128

Other events

12.0 (15)

3.4 (4)

0.005

118

While the results are impressive, the study suffers from significant limitations and omissions.   The study’s generalizability is hampered by the lack of racial diversity as patients were recruited from a single center in Spain.  The randomization procedures were not clearly stated in the manuscript.  Nor do they explicitly state which blood pressure medications (classes and number) were moved to bedtime or how decisions regarding dose adjustments were made.  Baseline blood pressure medication use is not reported.  Thus, it is possible that differences in treatment regimens – not the timing of dose administration – may explain the differences observed in patient outcomes.  Moreover, the lack of detail regarding the process of moving and dosing BP medications makes it difficult to replicate this study in practice.  And the study raises a number of other questions to ponder:

* Do blood pressure medications really need to be taken at bedtime?  Could a patient take blood pressure medications with the evening meal and derive the same benefits? 

* Should we routinely use ABPM in clinical practice … and then dose blood pressure medications at bedtime only in those who are known to be non-dippers?

Unfortunately the details in this manuscript are frustratingly sparse.   The data does suggest that switching at least one blood pressure medication to bedtime will have a positive impact on CVD outcomes.  At face value this intervention seems simple enough, but adherence rates may decline when medications must be taken multiple times per day.  This might inadvertently increase the risk of CVD events.  Is the data compelling enough to change practice?  What do you think?

Comments

1

I think that the data is quite compelling and have made changes based on these findings. When comparing the study from Diabetes Care (2011) with two others by Hermida et al (Chronobiology International 2010 and J Am Soc Nephrol 2011) the NNT was much higher. The NNT for the morbidity/mortality for the other studies is estimated to be 9 and 5, respectively (crude calculations assuming only one event/person). The questions to ponder are trivial (in my opinion) and should not be used by providers as justification to NOT try this intervention. The available evidence points to benefit and has not yet shown to be harmful. If adherence is affected by changing to a nighttime dose, providers (physicians, mid-levels, pharmacists, etc.) should be cognizant of the potential and readily assess adherence after making the change.