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Panel discussion and questions—Session I
Panel discussion Norman
M. Kaplan,
and questions-Session
I
M.D.--Moclerator
Dr. Kaplan: I did not see any effect of nadolol on diuretic-induced hypokalemia. Could it have been the very high doses of diuretic that these patients were given that prevented that effect from being observed? Dr. Fkeis: That could be the case. We know that the greater the degree of diuresis, the greater the degree of hypokalemia. Dr. KapZan: Others have observed what Dr. Wood pointed out-that the protection against diuretic-induced hypokalemia can be seen with certain beta blockers. Dr. DiBianco: Can the interaction of cimetidine and propranolol be extended to all beta blockers that are metabolized in the liver? Have there been studies with other beta blockers, such as metoprolol? Dr. Dkhin: Studies with metoprolol gave very similar results to those found with propranolol. Since atenolol is handled very much like nadolol, the results look very similar. In short, there is no interaction of atenolol with cimetidine, but there is an interaction of cimetidine with metoprolol. Dr. Kaplan: Would you assume, then, that those drugs that are lipid soluble would tend to have a similar effect to a drug such as cimetidine? How about ranitidine? Are there similar effects with the other H, antagonists that are now being introduced? Dr. Wood: Since ranitidine does not have the imidazole group, it does not inhibit drug-metabolizing ability; at least, it appears not to do so. It may lower hepatic blood flow, however. Dr. Kaplan: What about alcohol effects? Alcohol is obviously metabolized in the liver. What happens as far as the interactions between alcohol and beta blockers in general are concerned? Are there such interactions? Dr. ivood: We did a study in which we looked at the effect of cimetidine on alcohol and showed essentially no effect. In terms of alcohol’s effect on beta-blocker metabolism, I am unaware of any study. Dr. Kaplan: Here is a question about epinephrine and serum potassium. The whole question of adrenergic stimulation and potassium changes and the effects of beta blockers is very important. A series of studies has now been published showing that stress levels of epinephrine cause an immediate shift of potassium out of blood into cells, lowering plasma potassium levels by as much as 1 mmol/Liter, and this effect can be blocked by beta-2 blockers. This may be a very important reason that beta blockers may be effective in preventing sudden death. Many of the factors that we are relating to beta-blockers therapy may reflect the effect that it has on these shifts in potassium that occur with adrenergic stimulation.
Dr. Stein: Is the reason that starting a diuretic or use of a diuretic in black patients may be more effective concerned with their greater problem with salt and volume in their hypertension? Dr. Freis: We do not know the reason, but that is the explanation that is usually given. It is true that black patients have a low-renin, high-volume, salt-sensitive type of hypertension more often than do white patients. It could well be the reason that they are so responsive to diuretics. Dr. Kaplan: This observation has been fairly well documented by half a dozen or more studies about the difference in racial responses to diuretics and beta blockers. Some people believe it has something to do with renin: black patients tend to have lower renin and therefore to have more response to diuretics. Did Dr. Freis actually measure renin, and does he believe in that explanation? Dr. Freis: We measured renin in another study, which was the propranolol versus hydrochlorothiazide trial. Briefly, there was a crude correlation in that the patients who had low-renin hypertension tended to respond better to diuretics, but the correlation was not close enough to be a reliable guide for selecting a particular type of drug for a particular patient. In addition, black patients had lower average renin levels than white patients in this study, which would support the explanation you have given. Dr. Kaplan: I think, clinically speaking, that elderly and black people do tend to have lower renin, which may be partly why they will respond to diuretics. In the real world of clinical medicine, however, I am not so sure it is worth the trouble to look at renin. Dr. Venkata Ram: Did nadolol decrease the maximum blood pressure recorded in the 24-hour observations compared with what was seen with placebo-that is, the highest levels? Dr. Zanchetti: The answer is yes. Dr. Kaplan: Thus there was a sustained effect, on the highest levels as well as average levels, throughout the day. Dr. Zanchetti: Yes. Dr. Kaplan: I might point out that the technique Dr. Zanchetti was using, which was introduced by some English investigators, is also being used in the United States. More investigators in the United States are using other ambulatory recording techniques that are noninvasive. Would Dr. Zanchetti care to comment on their practical usefulness? Dr. Zanchetti: All techniques have their limitations 1095
October,
1096
Kaplan
and their values. I am now collating some data on ambulatory noninvasive techniques. The invasive technique, such as the Oxford one we have shown, of course gives a more precise measurement of all spontaneous fluctuations in blood pressure without the disturbing influence of either the investigator or the inflating of the cuff. In a recent study published in the Lancet we have shown that the effect of the physician or the investigator on blood pressure is substantial. Of course, with invasive methods there is much more detail because there is a beat-to-beat study, with no influence during sleep, when periodic inflation of the cuff can be disturbing. However, the limitation is that with this invasive method a maximum of only two or three recording sessions can be made in the same patient on different occasions. Thus we obtain perhaps the best possible assessment of variability in 24 hours but do not obtain an assessment of variability in a longitudinal way where several recordings are needed from different days or at different periods of the disease. From this point of view, the noninvasive methods are promising. We need, however, to have validation of most of these methods, because there is a considerable risk of error-through movement of the transducer and so on. Some of these techniques have not yet been entirely validated. Dr. Kaplan: These ambulatory monitors hold great promise for understanding better what our patients are like both as far as their full range of daytime and nighttime blood pressures is concerned and their responses to various medications. The kinds of research that are being done with these monitors, as Dr. Zanchetti showed, are very important. It is amazing, when we look at the literature, to see what we were told about using these various drugs based on very inadequate pharmacokinetic data. Finally, we have begun to measure the blood pressure, which is the obvious point of what we are doing, and to find all kinds of strange and wonderful things about the duration of action of these drugs. Relating specifically to that: with nadolol once a day, was Dr. Freis able to obtain a sustained inhibition of the hydralazine sympathetic stimulation in the patients in his study? Dr. Freis: Yes, we did. Heart rate was not elevated. Dr. Kaplan: Concerning the effects of long-acting propranolol: will it continue to work? I assume that it has been studied and that it does provide a 24-hour effect. Dr. Wood: Yes, it does provide a 24-hour effect, but the actual concentrations are lower than after regular propranolol because long-acting propranolol is less well absorbed. The peak concentrations are much lower than with regular propranolol. Dr. Levenson: Did Dr. Zanchetti analyze the variability of pulse pressure before and after nadolol? The variability of pulsatile pressure and flow could play an important role in the behavior of the large arteries, as far as their buffering effects are concerned. Dr. Zanchetti: Since our program was not set up to analyze pulse pressure itself, we have no measurement of
American
Mart
1984 Journal
that. However, we can make an extrapolation. Systolic and diastolic blood pressures were affected much to the same degree and percentage, about 17 5%for both, and thus I do not expect that the pulse pressure was reduced. We have not measured it specifically, however. Dr. Elton: What are the advantages of using nadolol over another once-daily drug that is also cardioselective and less central nervous sytem penetrating-such as atenolol? Dr. Kaplan: I shall respond simply by saying that I think there is very little difference. I think nadolol is another long-lasting, effective beta blocker, and I think that is its major advantage. We shall hear more about the use of this drug. In keeping with the comments that Dr. Wood made that there are beta-l and beta-2 receptors in most places, this selectivity that we have talked about in the past may not hold. There still may be some effects. The evidence concerning migraine, for instance, which we shall be hearing about, suggests that a drug such as nadolol, with greater beta-2 blocking effects, may have some clinical relevance. As far as I know, in hypertension these drugs are all similar, and I think that is the conclusion that Dr. Wood and others have presented here. There is very little difference between them. The duration of effect may have some particular relevance in angina, for instance, and some of the discussions that shall be presented later relate to that as well. One last question. How does one assess the treatment with beta blockers, diuretics, and combinations when the patients exhibit such great variations in the measurement of blood pressure at office visits? Dr. Wood; I wish to comment on that and on something that someone said earlier. One thing we have to remember as physicians is that all the risk data that relate to blood pressure came from office visits. It is fine to measure blood pressure throughout the day, but what of the patient who measures his blood pressure at home and tells me that it is terrific at home but that every time he comes to see me, he has a diastolic pressure of >lOO mm Hg? What does one do with that kind of patient? I think that, within reason, we have to view the blood pressure that patients have at the clinic as the pressure we shall treat-provided they are not having side effects from the blood pressure medicine at home. Presumably other stresses, such as seeing a physician or doing their job, are also associated with similar rises in blood pressure. Dr. Zanchetti: I certainly agree with that reasonable position. I would not take it to the point of saying that we should be satisfied with the crude evidence we have so far. Now that we have the means of measuring blood pressure in a more selective way, we should try to learn more. We still do not know whether the blood pressure measurement made in this emotional way-that is, the physician’s blood pressure measurement-is the best predictor. There might be better predictors, such as the measurements taken by the patients at home. Thus we need prospective
Volume Number
108 4, Part 2
studies, not only methodologies.Now that we have methodologies, we should verify them, but we should study them in a prospective way to discover more. Dr. Freis: Ambulatory blood pressures taken by nursesand physicians are a mixed bag.They include those of patients who are truly hypertensive in the long term and alsothose of patients whoseblood pressureswill drift down to normal over time without any treatment. Of course,we find in that mixed bag a higher morbidity and mortality risk than we would in completely normal people, probably because,and only because,of the presence of true hypertensive patients. It is our job, however, to try to separatethose people whosepressuresremain high from thosewhosepressuresdo not. It seemsthat the risk should be different in these two groups, and the need for treatment would also be different.
Discussion--Session
I
1097
Dr. Kaplan: It is obvious, from studies suchasthe one that Dr. Freis has reported, that the long-term washout and placebo periods used are an attempt to eliminate those labile patients from studies in which we are looking for sustained hypertension. The samething is clinically important: that patients should not be diagnosed and treated for hypertension unless thay have some fairly persistently elevated pressures-despite the fact, as Dr. Wood correctly points out, that the risk data from that first blood pressuremay be very important. I do think, however, that we would not start treating them with active medications unlessthere are sustained elevations.
M. Kaplan,
and questions-Session
I
M.D.--Moclerator
Dr. Kaplan: I did not see any effect of nadolol on diuretic-induced hypokalemia. Could it have been the very high doses of diuretic that these patients were given that prevented that effect from being observed? Dr. Fkeis: That could be the case. We know that the greater the degree of diuresis, the greater the degree of hypokalemia. Dr. KapZan: Others have observed what Dr. Wood pointed out-that the protection against diuretic-induced hypokalemia can be seen with certain beta blockers. Dr. DiBianco: Can the interaction of cimetidine and propranolol be extended to all beta blockers that are metabolized in the liver? Have there been studies with other beta blockers, such as metoprolol? Dr. Dkhin: Studies with metoprolol gave very similar results to those found with propranolol. Since atenolol is handled very much like nadolol, the results look very similar. In short, there is no interaction of atenolol with cimetidine, but there is an interaction of cimetidine with metoprolol. Dr. Kaplan: Would you assume, then, that those drugs that are lipid soluble would tend to have a similar effect to a drug such as cimetidine? How about ranitidine? Are there similar effects with the other H, antagonists that are now being introduced? Dr. Wood: Since ranitidine does not have the imidazole group, it does not inhibit drug-metabolizing ability; at least, it appears not to do so. It may lower hepatic blood flow, however. Dr. Kaplan: What about alcohol effects? Alcohol is obviously metabolized in the liver. What happens as far as the interactions between alcohol and beta blockers in general are concerned? Are there such interactions? Dr. ivood: We did a study in which we looked at the effect of cimetidine on alcohol and showed essentially no effect. In terms of alcohol’s effect on beta-blocker metabolism, I am unaware of any study. Dr. Kaplan: Here is a question about epinephrine and serum potassium. The whole question of adrenergic stimulation and potassium changes and the effects of beta blockers is very important. A series of studies has now been published showing that stress levels of epinephrine cause an immediate shift of potassium out of blood into cells, lowering plasma potassium levels by as much as 1 mmol/Liter, and this effect can be blocked by beta-2 blockers. This may be a very important reason that beta blockers may be effective in preventing sudden death. Many of the factors that we are relating to beta-blockers therapy may reflect the effect that it has on these shifts in potassium that occur with adrenergic stimulation.
Dr. Stein: Is the reason that starting a diuretic or use of a diuretic in black patients may be more effective concerned with their greater problem with salt and volume in their hypertension? Dr. Freis: We do not know the reason, but that is the explanation that is usually given. It is true that black patients have a low-renin, high-volume, salt-sensitive type of hypertension more often than do white patients. It could well be the reason that they are so responsive to diuretics. Dr. Kaplan: This observation has been fairly well documented by half a dozen or more studies about the difference in racial responses to diuretics and beta blockers. Some people believe it has something to do with renin: black patients tend to have lower renin and therefore to have more response to diuretics. Did Dr. Freis actually measure renin, and does he believe in that explanation? Dr. Freis: We measured renin in another study, which was the propranolol versus hydrochlorothiazide trial. Briefly, there was a crude correlation in that the patients who had low-renin hypertension tended to respond better to diuretics, but the correlation was not close enough to be a reliable guide for selecting a particular type of drug for a particular patient. In addition, black patients had lower average renin levels than white patients in this study, which would support the explanation you have given. Dr. Kaplan: I think, clinically speaking, that elderly and black people do tend to have lower renin, which may be partly why they will respond to diuretics. In the real world of clinical medicine, however, I am not so sure it is worth the trouble to look at renin. Dr. Venkata Ram: Did nadolol decrease the maximum blood pressure recorded in the 24-hour observations compared with what was seen with placebo-that is, the highest levels? Dr. Zanchetti: The answer is yes. Dr. Kaplan: Thus there was a sustained effect, on the highest levels as well as average levels, throughout the day. Dr. Zanchetti: Yes. Dr. Kaplan: I might point out that the technique Dr. Zanchetti was using, which was introduced by some English investigators, is also being used in the United States. More investigators in the United States are using other ambulatory recording techniques that are noninvasive. Would Dr. Zanchetti care to comment on their practical usefulness? Dr. Zanchetti: All techniques have their limitations 1095
October,
1096
Kaplan
and their values. I am now collating some data on ambulatory noninvasive techniques. The invasive technique, such as the Oxford one we have shown, of course gives a more precise measurement of all spontaneous fluctuations in blood pressure without the disturbing influence of either the investigator or the inflating of the cuff. In a recent study published in the Lancet we have shown that the effect of the physician or the investigator on blood pressure is substantial. Of course, with invasive methods there is much more detail because there is a beat-to-beat study, with no influence during sleep, when periodic inflation of the cuff can be disturbing. However, the limitation is that with this invasive method a maximum of only two or three recording sessions can be made in the same patient on different occasions. Thus we obtain perhaps the best possible assessment of variability in 24 hours but do not obtain an assessment of variability in a longitudinal way where several recordings are needed from different days or at different periods of the disease. From this point of view, the noninvasive methods are promising. We need, however, to have validation of most of these methods, because there is a considerable risk of error-through movement of the transducer and so on. Some of these techniques have not yet been entirely validated. Dr. Kaplan: These ambulatory monitors hold great promise for understanding better what our patients are like both as far as their full range of daytime and nighttime blood pressures is concerned and their responses to various medications. The kinds of research that are being done with these monitors, as Dr. Zanchetti showed, are very important. It is amazing, when we look at the literature, to see what we were told about using these various drugs based on very inadequate pharmacokinetic data. Finally, we have begun to measure the blood pressure, which is the obvious point of what we are doing, and to find all kinds of strange and wonderful things about the duration of action of these drugs. Relating specifically to that: with nadolol once a day, was Dr. Freis able to obtain a sustained inhibition of the hydralazine sympathetic stimulation in the patients in his study? Dr. Freis: Yes, we did. Heart rate was not elevated. Dr. Kaplan: Concerning the effects of long-acting propranolol: will it continue to work? I assume that it has been studied and that it does provide a 24-hour effect. Dr. Wood: Yes, it does provide a 24-hour effect, but the actual concentrations are lower than after regular propranolol because long-acting propranolol is less well absorbed. The peak concentrations are much lower than with regular propranolol. Dr. Levenson: Did Dr. Zanchetti analyze the variability of pulse pressure before and after nadolol? The variability of pulsatile pressure and flow could play an important role in the behavior of the large arteries, as far as their buffering effects are concerned. Dr. Zanchetti: Since our program was not set up to analyze pulse pressure itself, we have no measurement of
American
Mart
1984 Journal
that. However, we can make an extrapolation. Systolic and diastolic blood pressures were affected much to the same degree and percentage, about 17 5%for both, and thus I do not expect that the pulse pressure was reduced. We have not measured it specifically, however. Dr. Elton: What are the advantages of using nadolol over another once-daily drug that is also cardioselective and less central nervous sytem penetrating-such as atenolol? Dr. Kaplan: I shall respond simply by saying that I think there is very little difference. I think nadolol is another long-lasting, effective beta blocker, and I think that is its major advantage. We shall hear more about the use of this drug. In keeping with the comments that Dr. Wood made that there are beta-l and beta-2 receptors in most places, this selectivity that we have talked about in the past may not hold. There still may be some effects. The evidence concerning migraine, for instance, which we shall be hearing about, suggests that a drug such as nadolol, with greater beta-2 blocking effects, may have some clinical relevance. As far as I know, in hypertension these drugs are all similar, and I think that is the conclusion that Dr. Wood and others have presented here. There is very little difference between them. The duration of effect may have some particular relevance in angina, for instance, and some of the discussions that shall be presented later relate to that as well. One last question. How does one assess the treatment with beta blockers, diuretics, and combinations when the patients exhibit such great variations in the measurement of blood pressure at office visits? Dr. Wood; I wish to comment on that and on something that someone said earlier. One thing we have to remember as physicians is that all the risk data that relate to blood pressure came from office visits. It is fine to measure blood pressure throughout the day, but what of the patient who measures his blood pressure at home and tells me that it is terrific at home but that every time he comes to see me, he has a diastolic pressure of >lOO mm Hg? What does one do with that kind of patient? I think that, within reason, we have to view the blood pressure that patients have at the clinic as the pressure we shall treat-provided they are not having side effects from the blood pressure medicine at home. Presumably other stresses, such as seeing a physician or doing their job, are also associated with similar rises in blood pressure. Dr. Zanchetti: I certainly agree with that reasonable position. I would not take it to the point of saying that we should be satisfied with the crude evidence we have so far. Now that we have the means of measuring blood pressure in a more selective way, we should try to learn more. We still do not know whether the blood pressure measurement made in this emotional way-that is, the physician’s blood pressure measurement-is the best predictor. There might be better predictors, such as the measurements taken by the patients at home. Thus we need prospective
Volume Number
108 4, Part 2
studies, not only methodologies.Now that we have methodologies, we should verify them, but we should study them in a prospective way to discover more. Dr. Freis: Ambulatory blood pressures taken by nursesand physicians are a mixed bag.They include those of patients who are truly hypertensive in the long term and alsothose of patients whoseblood pressureswill drift down to normal over time without any treatment. Of course,we find in that mixed bag a higher morbidity and mortality risk than we would in completely normal people, probably because,and only because,of the presence of true hypertensive patients. It is our job, however, to try to separatethose people whosepressuresremain high from thosewhosepressuresdo not. It seemsthat the risk should be different in these two groups, and the need for treatment would also be different.
Discussion--Session
I
1097
Dr. Kaplan: It is obvious, from studies suchasthe one that Dr. Freis has reported, that the long-term washout and placebo periods used are an attempt to eliminate those labile patients from studies in which we are looking for sustained hypertension. The samething is clinically important: that patients should not be diagnosed and treated for hypertension unless thay have some fairly persistently elevated pressures-despite the fact, as Dr. Wood correctly points out, that the risk data from that first blood pressuremay be very important. I do think, however, that we would not start treating them with active medications unlessthere are sustained elevations.