During the meeting of the American Society of Hypertension in New York City in May 2003, a discussion of chronotherapy and its importance in the management of hypertension was undertaken. Moderating the roundtable discussion was Dr. Marvin Moser of the Yale University School of Medicine, New Haven, CT. Panel members included Dr. Thomas Pickering, professor of medicine at the Mount Sinai School of Medicine in New York City, and Dr. Henry Black, chairman and professor of preventive medicine at Rush‐Presbyterian‐St. Luke's Medical School in Chicago, IL.
DR. MOSER: There has been a great deal of discussion regarding the time of day when cardiovascular events occur. The data seem to indicate that more events occur during the early morning, 6 a.m. to noon, than at other times. Is it the hour or is it the time of awakening?
DR. PICKERING: There are a lot of data showing that almost any type of cardiovascular morbid event, ranging from the discharge of an implantable defibrillator to having a stroke or myocardial infarction, does occur most commonly between the hours of 6 a.m. and noon, and there is some evidence that this may be related to the changes that occur on arousal and activity as opposed to simply being a function of time of day. The acid test would be to look at what happens to people working night shifts but as far as I'm aware, there are not much data on this.
DR. MOSER: What happens on arousal? Are there changes in catecholamine release or other neurohormonal activity?
DR. PICKERING: A whole lot of things happen. There is sympathetic nervous system arousal so there is an increase in heart rate and blood pressure as well as platelet stickiness, which is partly controlled by sympathetic factors. In addition, the renin angiotensin system gets activated. It is certainly not just blood pressure that goes up but also a lot of other hemostatic and hemodynamic factors that change on awakening.
DR. MOSER: So it is a combination of vasoconstriction, sympathetic overactivity, and an increased tendency to clotting. Would you see these changes at 6 a.m. if you woke up at 5 a.m., or at 4 a.m. if you woke up at 3 a.m.? Is it the time you awaken?
DR. PICKERING: There has been at least one study where people either woke up and got out of bed or woke up and stayed in bed for a few hours and then got up. This study showed that the increase in heart rate and blood pressure was largely delayed until the people actually got up. It's not just the waking up; it's the increase in physical activity as well.
DR. MOSER: So getting up in the middle of the night to go to the bathroom isn't going to trigger anything unusual.
DR. PICKERING: We don't know. That's a good question. There is at least one study in Greece where they have an afternoon siesta. In these people there is a dip in blood pressure in the afternoon and there is actually an evening peak in the incidence of strokes as well as the morning peak that we see in countries without this siesta tradition.
DR. MOSER: Given these data—and they appear to be reasonably good—what do we do about it? Most of the antihypertensive drugs we use have a fairly good trough effect 20 or 22 hours after dosing. But is there anything that might be done to keep blood pressures and the arousal changes under better control in the morning hours?
DR. BLACK: It's a bit complicated. There is clearly an increase in risk within an hour or so after getting out of bed. Even in shift workers this is true. It is well known that we have a circadian pattern to our blood pressure. In the middle of the night when we're sleeping and before the arousal phenomenon starts, our blood pressure tends to be lowest. We have drugs that are equally effective throughout the 24‐hour period and have very little peak‐to‐trough difference. A problem with that, at least theoretically, is that pressures might be too low during the night when pressures are already usually low. Getting up in the middle of the night to go to the bathroom might be risky if your blood pressure is low physiologically. It would be nice to tailor therapy so that it matched the circadian pattern; therapy was minimally active or inactive when you didn't need it; and then became active on awakening.
DR. MOSER: Are there any data with standard blood pressure medications that are taken in the morning to indicate that patients who get their usual dip in blood pressure in the middle of the night are at greater risk?
DR. BLACK: Not necessarily, except for excessive dippers. Excessive dippers and nondippers have more cardiovascular events than dippers. Controlling blood pressure during the day as well as smoothing out both excessive and nondipping would be an excellent approach.
DR. MOSER: Tom, you're the expert. How much difference in risk is there between a normal dipper, a nondipper with less than a 10% decrease in blood pressure during the night, and an excessive dipper?
DR. PICKERING: The data with extreme dippers showing increased risk of stroke actually comes from one Japanese cohort with which I've been involved, but not all investigators agree. Our conclusion from those data were that it wasn't so much the low blood pressure during the night but rather the surge of blood pressure during the morning hours that seemed to be related to whether or not individuals suffered a stroke. As Henry mentioned, there are other data, for instance with anterior ischemic optic neuropathy, that suggest a low blood pressure at night may be harmful. I personally haven't found these data terribly convincing.
DR. MOSER: So it may not be the level of pressure that you achieve during sleep that makes the difference, it's the amount that it surges when you awaken?
DR. PICKERING: That was our conclusion. I don't think we can rule out low blood pressures during sleep. I believe there are some people with ischemic heart disease who have been shown to have silent ischemia during the night when blood pressures are very low (<100/70 mm Hg). So I suspect it's not a simple relationship. There may be some people in whom a very low blood pressure during the night is harmful.
DR. BLACK: I agree, I don't think we should focus too much on that because that is relatively unusual. You should decrease your blood pressure about 10%–15% when you go to sleep. That's what we call “a normal dipper” (i.e., 120/80 mm Hg to about 105–110/70 or 75 mm Hg). Anybody who has less than a 10% drop in blood pressure we have arbitrarily defined as a “nondipper.” Anybody whose pressure decreases more than 20% we consider an “excessive dipper.” If blood pressure rises during sleep, this is a “reverse dipper.”
DR. MOSER: Are there any clinical parameters that you could use short of doing ambulatory blood pressure monitoring that might predict who would have these big swings in blood pressure?
DR. PICKERING: There are people we know tend to have the nondipping pattern. Large numbers of people with certain clinical conditions—metabolic syndrome, diabetes, Cushing's disease, and renal disease—tend to be nondippers.
DR. MOSER: And African Americans.
DR. PICKERING: Yes, they tend to show less dipping during the night.
DR. BLACK: People with heart transplants and peripheral or central neuropathies are also nondippers.
DR. MOSER: Would you worry as much about surges in the nondipper group because blood pressures hadn't decreased to lower levels during the night?
DR. BLACK: Well that's one of the ironies. If it is the surge in blood pressure that is dangerous, then it should be okay to be a nondipper but it has to be more than that. It could well be the number of millimeter‐hours of an increase in blood pressure that you experience that could account for events.
DR. MOSER: In your study, Tom, the people who ended up with maximum surges were a little bit older, they had higher initial blood pressures, and they had a tremendous surge in systolic blood pressure of about 50–55 mm Hg.
DR. PICKERING: Right.
DR. MOSER: So is that enough to say clinically that people with higher pressures who are uncontrolled might be the big surgers, or can't we say that yet?
DR. PICKERING: I don't think we can really put that into clinical practice yet. It was a single study and whether it applies to Americans equally, well I don't think we know yet. It's an area that's worthy of more attention. We should also look at drug studies that examined agents aimed at suppressing the morning surge.
DR. MOSER: Are there any drugs that are particularly designed to address that?
DR. BLACK: Yes there are. One agent designed to be a chronotherapy agent was Covera‐HS, which has to be taken at night. (Pharmacia Corp., Chicago, IL) The active ingredient, verapamil, is released about 4–6 hours after dosing. Small studies indicate the rise in blood pressure in the morning can be diminished.
DR. MOSER: So this was taken at night.
DR. BLACK: Yes. We don't really know whether it's more convenient to take pills at night or in the morning. I guess it depends on what each individual prefers.
DR. MOSER: If you took the medication at 10 p.m., the effect would take hold about 3 a.m. or 4 a.m.
DR. BLACK: Yes, at the time of sympathetic activation and the arousal phenomenon. In the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) study Covera‐HS proved to be equivalent in blood‐pressure lowering to a regimen that began with a diuretic or β blocker and had the other added, if needed, to get to goal blood pressures.
DR. MOSER: Blood pressure changes were almost identical with the hydrochlorothiazide β blockers and Covera‐HS.
DR. BLACK: Average blood pressures were. Blood pressure was always taken as you would in a clinic; mostly in the morning. We had about a 25% increase in events during the 6‐hour period when we expected it.
DR. MOSER: 6 a.m. to noon.
DR. BLACK: Yes. There was no difference between the chronotherapeutic drug (Covera‐HS) or the other comparators with respect to preventing these early morning events. The study was stopped early and may not have been powered to answer that question.
DR. MOSER: So you really didn't get an answer to the question. Theoretically, Tom, do you think this is an area that should be pursued?
DR. PICKERING: I certainly think it's worth testing and it's unfortunate that CONVINCE was stopped early. Had it gone on longer, perhaps we would have had an answer. It would also be nice to have 24‐hour recordings. Most of the large studies now are getting 24‐hour recordings in subsets of patients. These should be helpful.
DR. MOSER: Are there any outcome studies with any of the newer agents that can be given at night or in the morning to indicate effective 24‐hour blood pressure control or specific early morning effects?
DR. BLACK: With respect to events trials, there aren't any that I know of but agents like Cardizem LA (Biovail Corp., Mississauga, Ontario, Canada), a long‐acting formulation of a nondihydropyridine calcium channel blocker, have the advantage of being just as good on 24‐hour monitoring whether you take them in the morning or in the evening.
DR. MOSER: There is a new long‐acting propranolol, InnoPran XL (Reliant Pharmaceuticals, Liberty Corner, NJ), that is also designed to be most effective during the morning hours and that is effective for 24 or more hours. It is supposed to be given at bedtime.
DR. PICKERING: When short‐acting propranolol was given two or three times a day in the Beta Blocker Heart Attack Trial (BHAT) study, there was a marked decrease in coronary events and the morning surge of events in patients with coronary disease was reduced. Whether that was blood pressure reduction or something else I don't really know. A longer‐acting formulation will allow once‐a‐day dosing.
DR. MOSER: It could be blood pressure or it could be a reduction in heart rate increases.
DR. BLACK: In the CONVINCE study there were 99 events in the verapamil group and 88 in the standard of care group in the 6 a.m. to noon time period. Though these differences were not statistically significant, the trend was in the wrong direction. This was somewhat disappointing.
DR. MOSER: So, theoretically the morning surge in blood pressures is something we ought to be concerned about. There are people who have these surges in the morning, whether it's because their pressures are too low and then surge or because they just increase from a normal nondipper status. We do not have an answer about whether or not a specific therapy will reduce events. There are several medications designed to prevent these surges, but we need further proof that they decrease cardiovascular events.
DR. BLACK: I believe patients really like the idea of taking medication that matches a biorhythm. There's something appealing about that and there is logic to it. Why take an antihypertensive medication that's going to lower blood pressure when it was going to be low anyway?
DR. PICKERING: Where there is a choice of different medications in the same class, it's worth taking the one that has the longest duration of action so you have a better expectation of coverage in the early morning.
DR. MOSER: Why not take this longer‐acting medication in the morning?
DR. PICKERING: Even if you take it in the morning, it takes a couple of hours to have its effect, so you miss the morning surge.
DR. BLACK: It may be that the benefits of chlorthalidone relate to the fact that it has a longer than 24‐hour duration of action.
DR. MOSER: From a clinician's point of view, chlorthalidone is an intriguing area to investigate. To summarize, we have some data to strongly suggest that the morning surge is important in terms of cardiovascular events. Further, we have data to show that there are medications available that address this issue but at present we have no data to demonstrate that this approach will definitely reduce cardiovascular events.