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Is it Time for Chronotherapy?
Compliance with Antihypertensive Therapy


Janice G. Douglas, MD, Chief, Division of Hypertension, Case Western University School of Medicine, Cleveland introduced the symposium, which examined the evidence for and against a link between circadian rhythm and certain cardiovascular events and elucidated the role of chronotherapy in hypertension management.

“Blood pressure and heart rate follow a daily rhythm,” she explained. For most people, heart rate and blood pressure peak between 6 a.m. and 12 noon, hit another peak at 5 p.m., and dive to lows in the very early morning around 3 a.m. and again in the afternoon at 3 p.m. “Both people without hypertension and those with uncomplicated hypertension show this circadian rhythm in blood pressure and heart rate,” she said.

Most people are nocturnal “dippers,” meaning their systolic and diastolic pressures drop by about 10% to 20% at night compared with average daytime readings, Dr. Douglas said. People who don’t show this dip, or “non-dippers,” appear to be at higher risk for cardiovascular events and end-stage
renal disease, she noted.

The daily morning surge in blood pressure and heart rate brings on a well-known increased risk of myocardial infarction, sudden cardiac death, and stroke in the early hours of the day. A study by Elliot linked this surge to a 49% higher risk of stroke, a 40% higher risk of heart attack, and a 29% higher risk of cardiac death (Am J Hypertens 2001;14:291S-295S). There is also a trough effect in the likelihood of a stroke, heart attack, or other event that occurs between midnight and 6 a.m., Dr. Douglas pointed out.

There are many potential contributors to the increased incidence of cardiovascular events in the morning, Dr. Douglas noted, including an increase in catecholamines, more physical activity, higher pulse rate and stiffer arteries.

“The epidemiologic data, when taken together, have mounted a compelling argument that the time of day is extremely important and it might be
important to consider timing of antihypertensive medications such that we can prevent this morning surge in blood pressure,” Dr. Douglas said.

She added that management of hypertensive patients could clearly be improved, and chronotherapy could have a role in this improvement. While National Health and Nutrition Exam-ination Survey (NHANES) data show that awareness of hypertension has risen since the late 1970s and about half of patients get treated, control has slipped from 29% during the 1980s to about 27% in the early 1990s. Figures are probably worse for diabetic patients, Dr. Douglas pointed out, who require even tighter blood pressure control.

But, she added, the development of new formulations of antihypertensive drugs, from short-acting to long-acting to once-daily products, has raised the possibility of controlling the release of these drugs and timing it for when it is most effective.

Awareness of the possibility of using circadian rhythms to help treat hypertension is low among both patients and doctors, Dr. Douglas noted. A 2002 poll of 200 primary care physicians treating hypertensive patients found that while 90% of the doctors knew that circadian factors could boost patients’ risk of stroke or heart attack at certain times of the day only slightly more than half considered the body’s natural rhythms when prescribing treatment for hypertension. And while 80% knew of the increased early-morning risk of heart attack and stroke, only two-thirds told their patients to take their medication in the morning or when they woke up.

“There was a major disconnect between their knowledge of the circadian rhythm and how that influenced administering their hypertensive medication,” said Dr. Douglas.


Does the Epidemiologic Data Stack Up in Support of Chronotherapy?

Thomas G. Pickering, MD, D.Phil., Director, Integrative and Behavioral Cardiovascular Health Program, Mount Sinai Medical Center, New York City, provided an overview of epidemiologic evidence for the links between circadian rhythm and cardiovascular events, as well as the potential of chronotherapy for treating hypertension.

He described a study in which about 200 patients with mild hypertension wore 24-hour blood pressure monitors. The researchers controlled blood pressure for a patient’s position—such as whether or not he or she was lying down—and activity, for example, if he or she was at work or at home. This adjustment eliminated most of the difference in blood pressure seen around the clock, Dr. Pickering noted, which suggests the major factors in the daily pattern of heart rate and blood pressure are due to cycles of activity and arousal.

“Several cardiovascular changes occur when a person wakes up,” Dr. Pickering pointed out. Catecholamines and renin/angiotensin rise, blood pressure and heart rate increase, the heart’s contractility rises, and platelet aggregability increases. “These factors tend to increase the shear stress on our fragile endotheliums and increase myocardial oxygen demand, and together these can increase the prevalence of both thrombotic and hemorrhagic cardiovascular morbid events,” he said. Meanwhile, he noted, fibrinolytic activity shows a morning trough.

“Just about any cardiovascular event you look at shows this same pattern of morbid events, and three hours after awakening, the prevalence of sudden cardiac death increases nearly threefold over what it is during the night,” he said. “So, waking up is a very dangerous thing to do.”

Dr. Pickering noted that there is some evidence that staying in bed after waking up can delay the peak in cardiovascular events. “But most of us living in this modern age, we get up, we pour in the caffeine and then everything starts firing off,” he said.

Physicians tend to give little attention to when antihypertensive medication is given, he noted. But he pointed to a study by White et al. that found that giving a new formulation of delayed-release verapamil to patients at 10 p.m. was able to hold off the early-morning blood pressure surge (Am J Cardiol 1998;81:424-431).

A new study of another delayed-released drug, graded-release diltiazem (GRD), found that the drug when given at night was also able to prevent this surge. GRD is designed to be taken at night and have its peak effect in the morning, which is synchronized with the body’s natural fluctuations in blood pressure. At a dose of 360 mg taken at night there was a statistically significantly greater effect on blood pressure between 6 a.m. and noon than when the same drug was taken in the morning. “With the evening dose, the surge of blood pressure in the morning is more suppressed than with the morning dose,” said Dr. Pickering.


Challenges with Chronotherapy

William C. Cushman, MD, Professor of Preventive Medicine and Medicine, University of Tennessee Health Science Center, Memphis, discussed the challenges of using chronotherapy in treating patients with hypertension.

About three-quarters of untreated people with essential hypertension are dippers, Dr. Cushman noted, while about 20% are non-dippers. There is another group among elderly patients with hypertension, he added, the extreme dippers, whose systolic blood pressure drops more than 20% below its daytime level. While some studies have linked this extreme dipping to end-organ damage, including white matter changes and silent cerebral infarcts, as well as deterioration of vision, Dr. Cushman pointed out, it is not yet clear if these conditions are the result or the cause of major drops in blood pressure.
But both silent cerebrovascular damage and anterior ischemic optic neuropathy are potential risks of excessively low overnight blood pressure. Also, extra-low nighttime blood pressure dips mean an even steeper early morning blood pressure surge.

Non-dippers, on the other hand, show a higher risk of target organ damage and worse cardiovascular outcomes than normal dippers, which suggests there could be a benefit to bringing down the nighttime blood pressure of non-dippers to a pattern more closely resembling normal dipping.

“I think we should be aware that many patients take their blood pressure medications at night, even though most formulations have been studied to be taken in the morning,” he said. This could be particularly concerning for patients who have “excessive dipping at night,” as their risk of excessively dropping blood pressure overnight could increase. Chronotherapeutic antihypertensives, which are designed to have their peak effect after the overnight risk period, may be an optimal therapeutic option in these patients who prefer to take their medications at night.

Therapeutic Perspectives on Chronotherapy

Drs. Pickering and Cushman continued by taking turns discussing therapeutic perspectives on chronotherapy. “The therapeutic implications of the various types of circadian rhythm variation in blood pressure and heart rate are just beginning to be explored,” said Dr. Pickering.

For example, a Japanese study by Kario and colleagues that compared the probability of stroke-free survival among people with different types of blood pressure patterns found that dippers and non-dippers had roughly similar survival, while stroke-free survival was worse for extreme dippers and even worse for “risers” (Hypertens 2001;38:852). Risers, a small subset of patients who have increased blood pressure during the night, are also at greater risk for both fatal and nonfatal strokes and cardiac events.

A trial of CO-ER verapamil found that the drug didn’t have much effect on dippers but did bring down the blood pressure of non-dippers at night, tending to normalize the dipping pattern, which is probably beneficial, Dr. Pickering said (Am J Cardiol 1997:80; 469). Also, he noted, the nighttime blood pressure drop that the drug brought on in non-dippers was not excessive.

Antihypertensive Options
Dr. Cushman addressed whether current formulations of antihypertension drugs address risks adequately. He noted that even though heart attack and stroke are clearly more common in the morning hours, a drug has to work throughout the entire day.

The recent trend has been toward the development of long-acting formulations of drugs that can be given once daily. “With the current drugs, we like to have not only smooth plasma drug concentrations but also smooth blood pressure control over the 24-hour period and, theoretically, a reduced chance of dropping overnight blood pressure too low,” he said. Also, patients on longer-acting drugs are less likely to suffer ill effects from missing a dose, he noted.

The goal, he added, is to find a drug with effects that parallel the diurnal pattern of blood pressure rise and fall. But evidence is lacking on when is the best time to give various medications. In the “overwhelming majority” of hypertension trials, Dr. Cushman noted, the drug was given in the morning if it was a once-a-day formulation.

The CONVINCE Trial is the first long-term study to examine a drug specifically designed to prevent the morning blood-pressure surge. The researchers compared CO-ER verapamil to hydrochlorothiazide or atenolol. While the results are still being evaluated, Dr. Cushman noted that it still isn’t clear whether the goals of controlling blood pressure around the clock, while also optimizing control in the morning hours, are mutually achievable.

Challenges with Current Antihypertensives
Attempts to oversimplify chronotherapy for hypertension could have dangerous results, Dr. Pickering warned. A drug’s specific formulation must be taken into account—as well as a patient’s individual blood pressure pattern—when designing this type of therapy.

“You may be getting the idea that all you need to do is give patients once-a-day drugs at night rather than early in the morning on the grounds that they’ll have a nice drug level when they wake up in the morning for the dangerous morning hours, but that’s not necessarily the case,” Dr. Pickering said.

While this is appropriate for drugs designed specifically for this purpose, just giving a conventional drug at night may bring blood pressure down too low at night and end up having little effect for the rest of the day. “You have to know about the properties of the individual drug when giving it in the morning or the evening, and just simply giving all drugs in the evening is not desirable,” he concluded.

Dr. Cushman noted that all three groups—dippers, non-dippers, and excessive dippers—seem to get some benefit from chronotherapeutic dosing.
Chronotherapeutic agents “offer further advancement towards optimizing blood pressure control, particularly in high risk patients, such those who are elderly, have renal disease, have salt-sensitive hypertension, and others,” he said.


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