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What Time of Day Should I Take My Antihypertensive Medications?
What Time of Day Should I Take My Antihypertensive Medications? -- Posted by Gumbo on 11-20-04 17:28
What Time of Day Should I Take My Antihypertensive Medications?
Posted 10/19/2004
Ari Mosenkis, MD; Raymond R. Townsend, MD
Physicians have long noted that cardiovascular events more commonly occur in
the morning. Indeed, analysis of the Framingham data[1] has demonstrated
that the incidence of sudden cardiac death is 70% higher between 7 a.m. and
9 a.m. than during the rest of the day. Additionally, a meta-analysis of 30
studies including over 60,000 patients has shown that the incidence of
myocardial infarction is 40% greater between the hours of 6 a.m. and 12 p.
m. than during the rest of the day.[2] Similarly, stroke and ventricular
arrhythmias occur with greater frequency in the morning hours. Such cyclic
variations in cardiovascular events have been attributed to the circadian
nature of our biologic clocks, known as "chronobiology." Specifically,
plasma catecholamines and cortisol, as well as vascular tone and effective
circulating volume, are highest in the morning, accounting for the morning
blood pressure (BP) increase (approximately 3/2 mm Hg), and with it a higher
incidence of cardiac events.
One obvious question that arises is: Should we dose antihypertensive agents
in such a fashion (i.e., at bedtime for standard daily drugs and nighttime
for extended-release preparations) so that their peak activity coincides
with, and perhaps blunts the morning increase in BP? Such a treatment
strategy is referred to as "chronotherapeutics." It is important to note
that impressive reductions in cardiovascular end points have been
demonstrated in numerous clinical trials in which BP lowering agents have
not been given at night but have routinely been administered in the morning.
Nevertheless, the issue at hand is whether we might further reduce the
incidence of these end points by dosing antihypertensive agents at night.
Several small studies have looked specifically at BP responses with
nocturnal compared with morning dosing of various agents. These studies were
previously reviewed in this journal.[3] One small study demonstrated better
nocturnal BP control with nightly compared with morning dosing of the
angiotensin-converting enzyme inhibitor quinapril, though the daytime BPs
were similar. Other small studies were unable to show a differential effect
in BP of nightly compared with morning dosing of atenolol, nifedipine
gastrointestinal therapeutic system, or amlodipine. Notably, none of these
small studies looked at long-term cardiovascular end points, such as
cardiovascular death, myocardial infarction, or stroke.
In the last few years, two large prospective studies were published that
assessed cardiovascular end points using nocturnal dosing of
antihypertensive agents. The first such study was the Heart Outcomes
Prevention Evaluation (HOPE) trial,[4] which showed that nightly dosed
ramipril (in addition to other medication), compared with a regimen that did
not include an angiotensin-con-verting enzyme inhibitor, significantly
decreased all cardiovascular outcomes. One notable observation of the HOPE
trial is that only half of the subjects enrolled had hypertension, and only
a small part of the benefit was attributed to a reduction in BP. Though some
attribute these results to possible cardioprotective properties of
angiotensin-con-verting enzyme inhibitors above and beyond their BP lowering
properties, others have argued that, in fact, the nightly dosed ramipril
blunted the early morning BP rise. This effect was undetected because the
BPs recorded in the trial were measured hours later. This theory is
supported by a HOPE substudy[5] of ambulatory BP monitoring in 38 HOPE
participants in which 20 subjects received ramipril at bedtime and 18
subjects received placebo. Though the midday BPs were the same in the two
groups, overnight BPs were significantly lower in the ramipril group (by
17/8 mm Hg) as was 24 hour ambulatory BP (by 10/4 mm Hg).
The Controlled Onset Verapamil Investigation of Cardiovascular End Points
(CONVINCE) trial[6] is the only large prospective trial that compares p. m.
dosing of an antihypertensive agent (controlled onset extended-release
verapamil) with a.m. dosing of an antihypertensive agent
(hydrochlorothiazide or atenolol) (These medications were given in addition
to other drugs). CONVINCE was unable to demonstrate superiority of the
nocturnally dosed drug and thus did not support the concept of
chronotherapeutics.
In conclusion, there are sparse data to support the theory that nocturnal
dosing of antihypertensive drugs further decreases cardiovascular risk. So
for now, the schedule of antihypertensive drug administration can be
determined by other factors such as convenience, concurrence with the
administration of other medications to foster adherence, and timing to
minimize untoward effects of these medications (i.e., nocturnal dosing for
medications that may cause orthostatic hypotension and may result in falls).
If there are no other compelling timing considerations, one may choose
nocturnal dosing (i.e., at bedtime for standard daily drugs and nighttime
for extended-release preparations) so that their peak activities coincide
with, and perhaps helps to blunt, the early morning BP increase.
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