What Time of Day Should I Take My Antihypertensive Medications?

Ari Mosenkis, MD; Raymond R. Townsend, MD

Disclosures

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 24hour 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 (controlledonset 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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