Managing the Non-Dippers: Possible? Worth It?
Managing the Non-Dippers: Possible? Worth It?
George Bakris, MD: Hello. I'm Dr. George Bakris, Professor of Medicine and Director of the Hypertensive Diseases Center at the University of Chicago Pritzker School of Medicine. I am joined today by Dr. Mahboob Rahman, Associate Professor at Case Western Reserve University in the Division of Nephrology and Hypertension. Today we are going to be talking about nocturnal blood pressure -- its importance, its relevance, and whether we can convert people who are non-dippers to dipping status. If we can, what does that mean for prognosis? Mahboob, good morning.
Mahboob Rahman, MD: Good morning.
Dr. Bakris: Let's start off by defining a non-dipper.
Dr. Rahman: "Non-dipper" is a term that is used to describe a change in blood pressure that happens during the daytime compared with the nighttime. This is a concept that has been around for quite a long time, ever since the advent of ambulatory blood pressure monitoring. It has been known for years that blood pressure at night is typically lower than blood pressure during the day. There is a somewhat arbitrary cut-off of about 10%. If your blood pressure declines less than 10% during the night compared with what it was during the day, you are defined as a non-dipper.
Dr. Bakris: In other words, the only way you can make that determination is by doing 24-hour ambulatory monitoring.
Dr. Rahman: That is correct. Although there are some home blood pressure monitors now that may have the capacity to do that, for practical purposes it is ambulatory blood pressure -- 24-hour blood pressure monitoring -- that makes that determination.
Dr. Bakris: Let's say that I do a 24-hour monitor on you and I find you to be a non-dipper. What does that mean in terms of my cardiovascular risks, my renal risks, and my chances of having problems? Can you fix that?
Dr. Rahman: If you look back over the last couple of decades, there is a fair amount of data that have shown that if you are a non-dipper or if your blood pressure at night remains elevated, the risks for subsequent cardiovascular disease and renal disease are higher. This has been shown in a number of different studies and in a number of different patient populations.
Dr. Bakris: What if a patient came to you and said, "I have been told by my doctor that I am a non-dipper, and he doesn't know what to do about it. I also have a creatinine of 1.8 mg/dL. Is there any way that I can take care of this? I don't want to have higher cardiovascular risks. Can I change the dosing of my medication? Can I change my medication?"
Dr. Rahman: The short answer to that at this time is that we don't know. Based on the data that we have, for patients who have kidney disease, it doesn't look like we are going to be able to change the profile of their blood pressure to significantly drop the nocturnal blood pressure. In patients without kidney disease, there are some data that show that you can lower nocturnal blood pressure (eg, by using doxazosin at night), but it doesn't seem to be the case in patients with kidney disease or the patient you just described.
Dr. Bakris: That is an important distinction. There definitely are data that show that in the general population with normal kidney function, alpha-blockers, calcium antagonists (if they are given at night), and angiotensin-converting enzyme inhibitors can convert people to dipping status, which is presumably a good thing. However, in people with kidney disease, there is no good evidence that you can do this. What do we do with that? What are the factors besides kidney disease that play a role? There are some data that sleep behavior -- the amount of deep sleep that somebody gets -- can actually affect this. Experts on sleep apnea have data showing that if you fix the sleep apnea, you can restore dipping status in many cases, although not all of them. What about that?
Dr. Rahman: Clearly, there are many factors that contribute to blood pressure remaining elevated at night. You talked about sleep. I think there is a fair amount of evidence in regard to that. People have worked on the sympathetic nervous system and alterations in volume balance in regard to salt sensitivity and insulin resistance. Those are some of the broad categories that people have worked in in trying to understand what contributes to persistent elevation in blood pressure at night. The data in regard to sleep apnea are clearly there. I think the initial studies with continuous positive airway pressure (CPAP) for the treatment of sleep apnea were promising, but some of the more recent studies have shown a little less efficacy. Perhaps it relates to compliance with CPAP more than anything else.
Dr. Bakris: I think you hit the nail on the head. It really has to do with the adherence of the mask -- wearing it -- and people doing what they are supposed to do.
Dr. Rahman: Right.
Dr. Bakris: The last thing I want to talk about is a trial called Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE). CONVINCE was a very large, simple trial published almost a decade ago. It tested medications that had a release mechanism, optimally released at night. The bad news was that it did not look at dipping or non-dipping. It simply looked at mortality, so we don't know whether dipping status was improved or not. But do you think that, if we could give medications with a timed release so that they are maximally released at night, there would be some utility in that? The answer is that we don't know, but do you think it is feasible at least in the general population?
Dr. Rahman: I think so, George. As you know, part of the problem with CONVINCE was that the trial was ended early, earlier than expected, so they could not definitively answer that question. If you look at the body of evidence in the general population (the prevalence of elevated nocturnal blood pressure and the association with cardiovascular risks), I think it is certainly feasible, but we don't know what the long-term outcomes of benefit are in a trial like CONVINCE.
Dr. Bakris: Let's finish up and talk about a study that you and I were both a part of, the African American Study of Kidney Disease (AASK). We did a pilot study to see if we could convert patients to dipping status by dosing at night. Tell us a little bit about that.
Dr. Rahman: This was a pilot study that compared 2 dosing strategies. Administration of once-daily blood pressure medications in the morning was our standard. Then there were 2 strategies that we tested. One was administering the once-daily medications at night. The other strategy was administering once-daily medications in the morning and adding a small dose of medication at night, which is what we called our add-on strategy. The data showed that the reduction in nocturnal blood pressure was not significantly better in the 2 strategies that we compared with our standard strategy. Therefore, although we have good evidence that nocturnal blood pressure is often elevated in patients with kidney disease, we need better strategies to see if we can reduce the nocturnal blood pressure. Perhaps in future trials, we can investigate whether a reduction in nocturnal blood pressure translates to reduced risks for cardiovascular and kidney disease. As you know, patients with kidney disease are at very high risk for cardiovascular disease. Therefore, any strategy that will help us reduce cardiovascular risks in this population is going to be an important one.
Dr. Bakris: I want the audience to appreciate that this is a very important point. It is a very important observation. Patients in AASK had glomerular filtration rates (GFRs) that were in the 40s. These were not people with GFRs of 60 or 70 mL/min/1.73m. They clearly had advanced kidney disease from hypertension, and 100% of the patients were black. It's important to understand this, because there is a paper in the literature suggesting that you can convert people to dipping status. Unfortunately, if you look at that paper carefully, the data don't seem to quite fit and the GFRs are actually higher than what you would expect. We don't know if this can be done or not, and certainly in advanced kidney disease, it doesn't look like we can do this for whatever reason. Mahboob, any final words?
Dr. Rahman: I think that this is an important area of both clinical research and interest, and I think we will be hearing more about it in the future.
Dr. Bakris: Thank you very much for taking the time to talk with us today. It is very much appreciated. On behalf of Dr. Rahman and myself, we wish you all a good day. Thank you for joining us.
George Bakris, MD: Hello. I'm Dr. George Bakris, Professor of Medicine and Director of the Hypertensive Diseases Center at the University of Chicago Pritzker School of Medicine. I am joined today by Dr. Mahboob Rahman, Associate Professor at Case Western Reserve University in the Division of Nephrology and Hypertension. Today we are going to be talking about nocturnal blood pressure -- its importance, its relevance, and whether we can convert people who are non-dippers to dipping status. If we can, what does that mean for prognosis? Mahboob, good morning.
Mahboob Rahman, MD: Good morning.
Dr. Bakris: Let's start off by defining a non-dipper.
Dr. Rahman: "Non-dipper" is a term that is used to describe a change in blood pressure that happens during the daytime compared with the nighttime. This is a concept that has been around for quite a long time, ever since the advent of ambulatory blood pressure monitoring. It has been known for years that blood pressure at night is typically lower than blood pressure during the day. There is a somewhat arbitrary cut-off of about 10%. If your blood pressure declines less than 10% during the night compared with what it was during the day, you are defined as a non-dipper.
Dr. Bakris: In other words, the only way you can make that determination is by doing 24-hour ambulatory monitoring.
Dr. Rahman: That is correct. Although there are some home blood pressure monitors now that may have the capacity to do that, for practical purposes it is ambulatory blood pressure -- 24-hour blood pressure monitoring -- that makes that determination.
Dr. Bakris: Let's say that I do a 24-hour monitor on you and I find you to be a non-dipper. What does that mean in terms of my cardiovascular risks, my renal risks, and my chances of having problems? Can you fix that?
Dr. Rahman: If you look back over the last couple of decades, there is a fair amount of data that have shown that if you are a non-dipper or if your blood pressure at night remains elevated, the risks for subsequent cardiovascular disease and renal disease are higher. This has been shown in a number of different studies and in a number of different patient populations.
Dr. Bakris: What if a patient came to you and said, "I have been told by my doctor that I am a non-dipper, and he doesn't know what to do about it. I also have a creatinine of 1.8 mg/dL. Is there any way that I can take care of this? I don't want to have higher cardiovascular risks. Can I change the dosing of my medication? Can I change my medication?"
Dr. Rahman: The short answer to that at this time is that we don't know. Based on the data that we have, for patients who have kidney disease, it doesn't look like we are going to be able to change the profile of their blood pressure to significantly drop the nocturnal blood pressure. In patients without kidney disease, there are some data that show that you can lower nocturnal blood pressure (eg, by using doxazosin at night), but it doesn't seem to be the case in patients with kidney disease or the patient you just described.
Dr. Bakris: That is an important distinction. There definitely are data that show that in the general population with normal kidney function, alpha-blockers, calcium antagonists (if they are given at night), and angiotensin-converting enzyme inhibitors can convert people to dipping status, which is presumably a good thing. However, in people with kidney disease, there is no good evidence that you can do this. What do we do with that? What are the factors besides kidney disease that play a role? There are some data that sleep behavior -- the amount of deep sleep that somebody gets -- can actually affect this. Experts on sleep apnea have data showing that if you fix the sleep apnea, you can restore dipping status in many cases, although not all of them. What about that?
Dr. Rahman: Clearly, there are many factors that contribute to blood pressure remaining elevated at night. You talked about sleep. I think there is a fair amount of evidence in regard to that. People have worked on the sympathetic nervous system and alterations in volume balance in regard to salt sensitivity and insulin resistance. Those are some of the broad categories that people have worked in in trying to understand what contributes to persistent elevation in blood pressure at night. The data in regard to sleep apnea are clearly there. I think the initial studies with continuous positive airway pressure (CPAP) for the treatment of sleep apnea were promising, but some of the more recent studies have shown a little less efficacy. Perhaps it relates to compliance with CPAP more than anything else.
Dr. Bakris: I think you hit the nail on the head. It really has to do with the adherence of the mask -- wearing it -- and people doing what they are supposed to do.
Dr. Rahman: Right.
Dr. Bakris: The last thing I want to talk about is a trial called Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE). CONVINCE was a very large, simple trial published almost a decade ago. It tested medications that had a release mechanism, optimally released at night. The bad news was that it did not look at dipping or non-dipping. It simply looked at mortality, so we don't know whether dipping status was improved or not. But do you think that, if we could give medications with a timed release so that they are maximally released at night, there would be some utility in that? The answer is that we don't know, but do you think it is feasible at least in the general population?
Dr. Rahman: I think so, George. As you know, part of the problem with CONVINCE was that the trial was ended early, earlier than expected, so they could not definitively answer that question. If you look at the body of evidence in the general population (the prevalence of elevated nocturnal blood pressure and the association with cardiovascular risks), I think it is certainly feasible, but we don't know what the long-term outcomes of benefit are in a trial like CONVINCE.
Dr. Bakris: Let's finish up and talk about a study that you and I were both a part of, the African American Study of Kidney Disease (AASK). We did a pilot study to see if we could convert patients to dipping status by dosing at night. Tell us a little bit about that.
Dr. Rahman: This was a pilot study that compared 2 dosing strategies. Administration of once-daily blood pressure medications in the morning was our standard. Then there were 2 strategies that we tested. One was administering the once-daily medications at night. The other strategy was administering once-daily medications in the morning and adding a small dose of medication at night, which is what we called our add-on strategy. The data showed that the reduction in nocturnal blood pressure was not significantly better in the 2 strategies that we compared with our standard strategy. Therefore, although we have good evidence that nocturnal blood pressure is often elevated in patients with kidney disease, we need better strategies to see if we can reduce the nocturnal blood pressure. Perhaps in future trials, we can investigate whether a reduction in nocturnal blood pressure translates to reduced risks for cardiovascular and kidney disease. As you know, patients with kidney disease are at very high risk for cardiovascular disease. Therefore, any strategy that will help us reduce cardiovascular risks in this population is going to be an important one.
Dr. Bakris: I want the audience to appreciate that this is a very important point. It is a very important observation. Patients in AASK had glomerular filtration rates (GFRs) that were in the 40s. These were not people with GFRs of 60 or 70 mL/min/1.73m. They clearly had advanced kidney disease from hypertension, and 100% of the patients were black. It's important to understand this, because there is a paper in the literature suggesting that you can convert people to dipping status. Unfortunately, if you look at that paper carefully, the data don't seem to quite fit and the GFRs are actually higher than what you would expect. We don't know if this can be done or not, and certainly in advanced kidney disease, it doesn't look like we can do this for whatever reason. Mahboob, any final words?
Dr. Rahman: I think that this is an important area of both clinical research and interest, and I think we will be hearing more about it in the future.
Dr. Bakris: Thank you very much for taking the time to talk with us today. It is very much appreciated. On behalf of Dr. Rahman and myself, we wish you all a good day. Thank you for joining us.
