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Roundtable discussion
Roundtable Discussion Moderator: J. Caulie Gunnells, Jr. DR. G U N N E L L S : As moderator, let me address the first question to Dr. Kaplan: One of the aims of this Symposium was to look at initial antihypertensive therapy and examine some of the controversies surrounding the widespread use of diuretics. We also wanted to consider other methods of treatment, and in particular to look at prazosin as a possible alternative as an initial therapeutic agent. Would you care to comment about physicians' patterns in choosing antihypertensive drugs, the rationale behind their choices, and where you think we stand at present in the selection of the initial agent to treat primary hypertension?
drugs other than diuretics for initial therapy, and specifically I see this as a very logical place for the increased use of prazosin. The possibility of reactive volume retention--which can happen with any of the nondiuretic drugs and is one of the reasons diuretics are often chosen first--needs to be considered. Whenever blood pressure is lowered, the kidney tends to retain fluid. This makes it important to institute a moderate restriction in dietary sodium as the first step in therapy; if drugs need to be used, a moderate restriction in dietary sodium becomes even more important.
DR. KAPLAN: We all grew up with the idea that diuretics were effective, that they were the easiest to use, and the least expensive agents. Effectiveness is one point that needs to be reemphasized since it has not been adequately stated. There is little difference, as far as therapeutic effectiveness is concerned, when one looks at careful comparisons between a diuretic in a reasonable daily dosage and any of the other drugs, including reserpine, methyldopa, clonidine, prazosin, and various beta-blocking agents. They all seem to have about the same effect on blood pressure. In general, therefore, the attitude has been that a single morning dose of a moderate to long-acting diuretic agent would be appropriate for beginning therapy. However, with the hazards and potential problems of diuretic therapy--which we all assume to be partly responsible for the lack of improvement in coronary disease that has been reported in most of the large therapeutic trials--the idea of using alternative drugs seems to have awakened a great deal of interest. I would predict that, in the future, increasing numbers of patients, particularly those with mild hypertension, are going to be treated with one of the alternative drugs. As to which alternative drug it will be, obviously we are blessed with multiple choices. Many physicians have been using beta-blocking agents. However, I believe we all harbor a certain concern about their negative effects on blood lipids, aside from the fact that probably 25 to 30% of all hypertensive patients have specific contraindications to the use of beta-blockers. Prazosin has an additional attraction in that it does not appear to adversely affect lipid levels. In addition, it offers a theoretical advantage in that it lowers the total peripheral resistance, whereas beta-blockers increase it, at least initially. Since high peripheral resistance is the hemodynamic hallmark of most essential hypertension, everyone would prefer that it be diminished rather than increased. Furthermore, in cold climates, many people notice cold extremities and have difficulties with their peripheral circulation while on beta-blocking therapy; that does not appear to be true with the use of prazosin. Thus, I foresee a continued increase in the use of
DR. CUTLER: I agree with what Dr. Kaplan has just said. My feeling is that some education will be needed to make physicians fully aware that other drugs do not have flat response curves like the diuretics, and they need to be titrated to get maximal benefits. DR. G U N N E L L S : That's a good point. Diuretics have always been easy to use, and we all like to do things the easiest possible way. However, we have a responsibility, based on an examination of the available data, to reeducate ourselves and other physicians. This should be a thinking process, not a conditioned reflex. Among the problems that everyone has mentioned regarding diuretics, a frequent and difficult problem is that of potassium depletion and its sequelae. DR. O K U N : This is a complex issue. Let me go back a step and say that, as we have heard repeatedly, diuretics have in the past been the first-line drugs. I, too, think this is going to change, and that we will see a decline in the use of diuretics, particularly in view of the data Dr. Ames and his co-workers have obtained. Other studies have added to this disquieting discrepancy of results between improvement in cerebrovascular disease and very little, if any, improvement in coronary disease despite blood pressure reduction. I am beginning to feel rather strongly that this may be due to a less than ideal choice of medication. In the past, one of my choices has often been to follow sodium restriction with the use of diuretics--primarily thiazide diuretics. I will have to rethink such an approach very seriously, because the risk-benefit ratio of early diuretic therapy has now shifted to the point where such therapy is no longer appropriate for a large number of patients. One of the problems posed by diuretics is that of potassium disturbance. Much has appeared in the medical literature in the past few years regarding the risks of even what was once considered modest hypokalemia. Some work indicates that there is indeed a significant risk of spontaneous arrhythmias in persons whose potassium levels tend to drop below 3.0 mEq/liter. Having witnessed some of these spontaneous arrhythmias, which do respond to potassium replacement, we now
657
658
ROUNDTABLEDISCUSSION
initiate potassium replacement very early in patients who are beginning diuretic therapy; if they are on a digitalis preparation, we institute administration of potassium immediately. The obvious reason is to avoid potentiating the toxic effects of digitalis. However, we have problems in patient acceptance of potassium supplements. In view of the data generated recently by McMahon and his group at Tulane, it seems that many of the potassium chloride substitutes that we have been using may cause problems in the gastrointestinal tract. We will have to restrict use of some of the potassium chloride preparations, and this makes potassium replacement even more difficult. But replace potassium we must, hopefully to the point of normal total body levels, a measurement that is not available to most clinicians, but can be approximated by a serum potassium determination. The use of drugs such as prazosin will probably make treatment much easier since there is no adverse effect on potassium levels at all. DR. COLUCCI: Cardiologists have always been impressed with the importance of a potassium level that is as stable (that is, free of large fluctuations) and as normal as possible, especially in patients with coronary artery disease. The data from the M R F I T study are relevant in this connection. The increased mortality rate in patients with preexisting electrocardiographic abnormalities who were aggressively treated with diuretics was impressive and reinforces the bias of many cardiologists that it is important to maintain adequate serum and total body potassium levels, especially in patients with preexisting heart disease. DR. G U N N E L L S : To summarize, most people would consider potassium depletion with diuretics a potential problem because hypertensive patients have an unknown amount of coronary heart disease, which places them at risk even with minor alterations in potassium levels. The usual physician is more likely than not to give potassium supplements when using diuretic agents. This adds to the expense, to the possibility of compliance problems, and to a need for more frequent laboratory tests in patients with hypertension. In the M R F I T study, thiazides, propranolol, methyldopa, hydralazine, reserpine, and guanethidine were all used. If one looks at the conclusions on mortality from coronary heart disease, none of these drugs seemed to have much of a beneficial effect. Could it be related to the hemodynamic and metabolic actions of these drugs? Or is there something else in that study that might throw some light on this issue? DR. AMES: I can only speculate in this regard. We just don't know why the patients treated with diuretics and antihypertensive therapy did not do as well as we had anticipated. Although there was an equal number of deaths in the special intervention group and the usual care group, we don't know the details. Were these sud~ den deaths, or were they deaths of individuals with documented myocardial infarction? This would be important to know, because if they were sudden deaths, without definite evidence of coronary disease or myocardial infarction, they might have an electrical origin
rather than being due to the build-up of atherosclerotic plaque. We need more information. The changes in lipids that may have occurred during therapy have not been looked at in great detail either, so that also remains speculative. I do know that at the 4-year interval, patients in the MRFIT trial who received antihypertensive therapy, specifically diuretic therapy, did not show as large a decrease in total cholesterol or triglycerides as the patients who had not received diuretic treatment. Diuretics thus appeared to counter the reduction in cholesterol that had been anticipated. The failure of cholesterol to decrease as much as expected in the hypertensive SI group could have lessened the mortality differential in comparison with the hypertensive UC group. Still, the hypertensive SI group had, in absolute terms, both lower blood pressure and lower total cholesterol than the hypertensive UC group throughout the program. The lipid hypothesis, therefore, does not seem to explain fully the failure of SI men to do better. Perhaps differences between SI and UC men in glucose tolerance or frank diabetes related to high-dose diuretic therapy could contribute to mechanisms causing the unexpected equivalence of CHD mortality in hypertensive SI and UC men. These suggestions are interesting but remain speculative. More detailed analyses of the M R F I T data are needed. DR. G U N N E L L S : We have talked a great deal about lipids this afternoon. This could be an important factor in connection with the problem of coronary heart disease and atherosclerosis in all hypertensives. If we're going to embark upon drug treatment, how much of a problem are the lipid effects of diuretics and betablockers, and how does prazosin come out in comparison? DR. C U T L E R : This is obviously a controversial area. You can't get 10 physicians together who will agree on that particular point. What we've talked here is taking data that are currently extant or being developed and comparing them with data from the past, namely the Framingham study, for the purpose of risk-factor calculation. The large clinical trials that we've talked about today have given us some food for thought, but they haven't truly answered the question for us. And it's not likely we will have the answers very quickly. All we can suggest at the present time is caution, in view of the. correlations that have been established in the past through epidemiologic methodology. The most we can say at this point is that antihypertensive agents that increase cholesterol and perhaps change the fractions in an adverse way by increasing the low density fractions and decreasing the high density ones may have an adverse effect on coronary heart disease. The underlying and conditional word is m a y . We won't know for sure until such studies are done. But in the meantime, as Stamler and others have said, the appropriate and prudent course of treatment is to implement dietary changes and to use drugs that do not have an adverse effect on lipid metabolism. As for a comparison between prazosin and other drugs, prazosin looks better because it doesn't seem to have any adverse effects on lipids.
February 24, 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 51
Diuretics seem to be more consistent in producing adverse effects that we believe may be atherogenic. DR. G U N N E L L S : Another important issue is that we seem to be in an exercise-oriented society. I'm constantly dodging joggers and bicycle riders on my way to the hospital. The use of drugs, specifically the betablockers, as first-line therapy in the physically active patient may be limiting. These agents have been advocated for the younger hypertensive patient. In these patients, the effect of the beta-blocker on the ability to exercise can often be an important side effect. DR. COLUCCI: Clearly, beta-blockers have multiple effects on the blood pressure, and the overall result is a combination of these effects. As I mentioned very briefly during my presentation, the beta-receptor in the vasculature, although frequently overlooked, is an important receptor. When it's blocked, the total peripheral resistance increases. This becomes clinically obvious when one treats a patient with Raynaud's disease or peripheral vascular occlusive disease, or just living in a cold climate. So we know that beta-blockers have an effect on total peripheral resistance that is the opposite of what we would want for an antihypertensive agent. One of the mechanisms by which beta-blockers lower blood pressure is through their reduction of renin release. They also tend to have effects on the heart. Cardiac output is diminished, and this may also contribute to their antihypertensive effect. In addition, betablockers seem to have a central effect, perhaps by reducing central sympathetic outflow. There may be other mechanisms, but it is somewhat paradoxical that beta-blockers were the first of the selective adrenergic antagonists to be used in hypertension, inasmuch as they do not seem to improve the main underlying problem in most primary hypertension, which is increased total peripheral resistance. The ability to exercise maximally is clearly decreased by beta-blockers. In part this is because the maximal heart rate is frequently lower, and therefore the maximal cardiac work that can be done is less. Beta-blockers may result in generalized fatigue, which may be related to this decrease in cardiac output. DR. OKUN: Our experience actually goes a little beyond that. Many youngsters who had been placed on beta-blockers for borderline or very mild hypertension have come to us later for other therapy because they found they couldn't exercise even to less than maximal capacity--jogging, tennis, and so on. They found themselves in difficult straits. Some animal data indicate that propranolol in particular will strikingly decrease skeletal muscle blood flow. This may be another mechanism for the easy fatigabillty. DR. G U N N E L L S : I'd like to set forth some of the features we might all agree are useful or favorable in an antihypertensive agent and see how they fit prazosin, the diuretics, and the beta-blockers. First is effectivehess. From what we've heard here, most antihypertensire drugs have equal effectiveness. In equipotent doses, prazosin is as effective as a diuretic or a beta-blocking
859
agent in reducing blood pressure. Second, we should look at hemodynamics and side effects: Prazosin's hemodynamic profile is a rational, reasonable, and appropriate one, relative to the underlying defect in primary hypertension, namely increased peripheral vascular resistance. Prazosin is free from the biochemical side effects that most of us have raised questions about. On the other hand, concern has been expressed about the hypokalemia induced by diuretics. Patients on prazosin do not have to worry about lowered serum potassium or increased uric acid levels. Equally important, prazosin does not appear to have any adverse effects on lipid metabolism. Another favorable feature of prazosin is its low incidence of sexual dysfunction, although some has been reported. Having said all that, I would then conclude that prazosin, as compared with diuretics and beta blockers, is an appropriate agent for consideration as initial therapy in mild or moderate hypertension. DR. OKUN: I agree with you, and I have 2 comments to make. First, I feel very strongly that correction of the pathophysiology of essential hypertension, normalization of the increased peripheral resistance, is a major benefit of prazosin and one that exists without any major counterbalancing effects in other areas. I have not seen this with any of the other drugs. That, to me, is a very positive aspect of prazosin. Second, I also feel very strongly about using prazosin more as initial therapy, along with a sodium-restricted diet. I think prazosin will be highly successful in controlling blood pressure in a great many patients without worsening risks--the other edge of the sword, so to speak. DR. COLUCCI: As Dr. Kaplan pointed out, given the choice of a number of drugs which have the same endpoint, namely the lowering of hypertension, the onus is now on the physician to choose the drug that will be safest in the long run. I certainly would be careful in my choice of agent. Clearly, of the agents currently available prazosin is the most specific in terms of pathophysiologic effects. Selective alpha blockade makes more sense than beta blockade or other more generalized methods of adrenergic suppression. A question usually arises about prazosin in regard to orthostatic hypotension and syncope. The overall incidence of syncope with the first dose of prazosin is about 0.1 to 0.2%, if one looks at a large series of patients and totals up the results. The incidence in any particular study will depend on a lot of factors. One of the factors identified as important was the dose of the drug used during the first administration. It is recommended that therapy be initiated with a I m g dose. Another important factor in determining whether a patient will have a syncopal or orthostatic reaction to the first dose is volume status. Patients who are volume contracted, whether because of diuresis or other reasons, are much more sensitive. This is presumably due to a lower initial venous filling pressure in these patients. The venous dilatation effects of prazosin then may result in a further decrease in preload. In the hypertensive patient without heart failure, when diuretics are withheld, syncope is rare. In one
860
ROUNDTABLEDISCUSSION
study, 12 out of 74 patients had either syncopal or significant orthostatic symptoms after the first administration of a 2-mg dose of prazosin. When these patients were withdrawn from prazosin for three weeks, then rechallenged with a lower dose (1 mg), none had severe symptoms, and only 2 had mild dizziness. Therefore, picking a low dose and avoiding diuresis are probably the 2 major things the physician can do to prevent this problem. In practice, good recommendations are to start with a low dose of 1 mg preferably at bed time when the patient can remain supine. If the patient is receiving diuretics, withhold the diuretics for 1 or 2 days, to allow the intravascular volume to reequilibrate. Diuretics can then be readministered. That raises an interesting question: If prazosin were to be used as first-line therapy, before diuretics, would we see the same incidence of syncope as when the drug is used as a Step 2 therapy? I speculate that we would not, and therefore this would be another good reason to consider prazosin as initial therapy before diuretics. DR. G U N N E L L S : With diuretic agents we still have the problem of potassium depletion and other effects not associated with prazosin. Among the antihypertensive drugs for which data are available, the treatment profile of prazosin--side effects and therapeutic effect i v e n e s s - i s extremely favorable. Therefore, prazosin is a very reasonable and rational drug as initial therapy for hypertension. I think it is fair to say there is general agreement on this among the panel members, and we all agree it is appropriate that we reexamined past practices and began to ask ourselves questions instead of just prescribing as a reflex. DR. C U T L E R : We've talked a lot about step therapy, but we should place it in perspective. It was very
useful in the beginning in training physicians. It was a good way to approach hypertension. The initial thrust in step care was provided by Wilkins many years ago with the advent of diuretics, reserpine, and vasodilators. We have now reached the point where the menu of therapeutic agents is quite large, and as when we visit a favorite restaurant, we probably need to pick and choose more appropriately, depending on the patient and the problem at hand. We can no longer deal simply with starting here and advancing to there, but rather we need to think of the clinical pharmacologic features of each agent, and use it as appropriately as we can in treating a particular patient. DR. G U N N E L L S : To summarize, we're not debating whether patients with mild hypertension should be treated with drug therapy, but rather what is the best way to treat them when drug therapy ~s chosen--how to provide the greatest benefit with the lowest risk. However, in discussing a new concept of therapy that provides an alternative to the traditional diuretic approach to initial therapy, a great deal of data are required on each specific agent. We have discussed the efficacy, hemodynamic profile, side effect profile, and effect on other risk factors for coronary heart disease (such as blood lipid levels) for at least 1 nondiuretic antihypertensive agent, namely prazosin, and it appears to fit a profile of an appropriate agent for the initial treatment of hypertension. If we are to make significant inroads into populations with hypertension, we cannot wait until they reach the point of target organ damage or of severe degrees of blood pressure, which will require more intensive and complicated therapy with greater likelihood of side effects and less than ideal control.
drugs other than diuretics for initial therapy, and specifically I see this as a very logical place for the increased use of prazosin. The possibility of reactive volume retention--which can happen with any of the nondiuretic drugs and is one of the reasons diuretics are often chosen first--needs to be considered. Whenever blood pressure is lowered, the kidney tends to retain fluid. This makes it important to institute a moderate restriction in dietary sodium as the first step in therapy; if drugs need to be used, a moderate restriction in dietary sodium becomes even more important.
DR. KAPLAN: We all grew up with the idea that diuretics were effective, that they were the easiest to use, and the least expensive agents. Effectiveness is one point that needs to be reemphasized since it has not been adequately stated. There is little difference, as far as therapeutic effectiveness is concerned, when one looks at careful comparisons between a diuretic in a reasonable daily dosage and any of the other drugs, including reserpine, methyldopa, clonidine, prazosin, and various beta-blocking agents. They all seem to have about the same effect on blood pressure. In general, therefore, the attitude has been that a single morning dose of a moderate to long-acting diuretic agent would be appropriate for beginning therapy. However, with the hazards and potential problems of diuretic therapy--which we all assume to be partly responsible for the lack of improvement in coronary disease that has been reported in most of the large therapeutic trials--the idea of using alternative drugs seems to have awakened a great deal of interest. I would predict that, in the future, increasing numbers of patients, particularly those with mild hypertension, are going to be treated with one of the alternative drugs. As to which alternative drug it will be, obviously we are blessed with multiple choices. Many physicians have been using beta-blocking agents. However, I believe we all harbor a certain concern about their negative effects on blood lipids, aside from the fact that probably 25 to 30% of all hypertensive patients have specific contraindications to the use of beta-blockers. Prazosin has an additional attraction in that it does not appear to adversely affect lipid levels. In addition, it offers a theoretical advantage in that it lowers the total peripheral resistance, whereas beta-blockers increase it, at least initially. Since high peripheral resistance is the hemodynamic hallmark of most essential hypertension, everyone would prefer that it be diminished rather than increased. Furthermore, in cold climates, many people notice cold extremities and have difficulties with their peripheral circulation while on beta-blocking therapy; that does not appear to be true with the use of prazosin. Thus, I foresee a continued increase in the use of
DR. CUTLER: I agree with what Dr. Kaplan has just said. My feeling is that some education will be needed to make physicians fully aware that other drugs do not have flat response curves like the diuretics, and they need to be titrated to get maximal benefits. DR. G U N N E L L S : That's a good point. Diuretics have always been easy to use, and we all like to do things the easiest possible way. However, we have a responsibility, based on an examination of the available data, to reeducate ourselves and other physicians. This should be a thinking process, not a conditioned reflex. Among the problems that everyone has mentioned regarding diuretics, a frequent and difficult problem is that of potassium depletion and its sequelae. DR. O K U N : This is a complex issue. Let me go back a step and say that, as we have heard repeatedly, diuretics have in the past been the first-line drugs. I, too, think this is going to change, and that we will see a decline in the use of diuretics, particularly in view of the data Dr. Ames and his co-workers have obtained. Other studies have added to this disquieting discrepancy of results between improvement in cerebrovascular disease and very little, if any, improvement in coronary disease despite blood pressure reduction. I am beginning to feel rather strongly that this may be due to a less than ideal choice of medication. In the past, one of my choices has often been to follow sodium restriction with the use of diuretics--primarily thiazide diuretics. I will have to rethink such an approach very seriously, because the risk-benefit ratio of early diuretic therapy has now shifted to the point where such therapy is no longer appropriate for a large number of patients. One of the problems posed by diuretics is that of potassium disturbance. Much has appeared in the medical literature in the past few years regarding the risks of even what was once considered modest hypokalemia. Some work indicates that there is indeed a significant risk of spontaneous arrhythmias in persons whose potassium levels tend to drop below 3.0 mEq/liter. Having witnessed some of these spontaneous arrhythmias, which do respond to potassium replacement, we now
657
658
ROUNDTABLEDISCUSSION
initiate potassium replacement very early in patients who are beginning diuretic therapy; if they are on a digitalis preparation, we institute administration of potassium immediately. The obvious reason is to avoid potentiating the toxic effects of digitalis. However, we have problems in patient acceptance of potassium supplements. In view of the data generated recently by McMahon and his group at Tulane, it seems that many of the potassium chloride substitutes that we have been using may cause problems in the gastrointestinal tract. We will have to restrict use of some of the potassium chloride preparations, and this makes potassium replacement even more difficult. But replace potassium we must, hopefully to the point of normal total body levels, a measurement that is not available to most clinicians, but can be approximated by a serum potassium determination. The use of drugs such as prazosin will probably make treatment much easier since there is no adverse effect on potassium levels at all. DR. COLUCCI: Cardiologists have always been impressed with the importance of a potassium level that is as stable (that is, free of large fluctuations) and as normal as possible, especially in patients with coronary artery disease. The data from the M R F I T study are relevant in this connection. The increased mortality rate in patients with preexisting electrocardiographic abnormalities who were aggressively treated with diuretics was impressive and reinforces the bias of many cardiologists that it is important to maintain adequate serum and total body potassium levels, especially in patients with preexisting heart disease. DR. G U N N E L L S : To summarize, most people would consider potassium depletion with diuretics a potential problem because hypertensive patients have an unknown amount of coronary heart disease, which places them at risk even with minor alterations in potassium levels. The usual physician is more likely than not to give potassium supplements when using diuretic agents. This adds to the expense, to the possibility of compliance problems, and to a need for more frequent laboratory tests in patients with hypertension. In the M R F I T study, thiazides, propranolol, methyldopa, hydralazine, reserpine, and guanethidine were all used. If one looks at the conclusions on mortality from coronary heart disease, none of these drugs seemed to have much of a beneficial effect. Could it be related to the hemodynamic and metabolic actions of these drugs? Or is there something else in that study that might throw some light on this issue? DR. AMES: I can only speculate in this regard. We just don't know why the patients treated with diuretics and antihypertensive therapy did not do as well as we had anticipated. Although there was an equal number of deaths in the special intervention group and the usual care group, we don't know the details. Were these sud~ den deaths, or were they deaths of individuals with documented myocardial infarction? This would be important to know, because if they were sudden deaths, without definite evidence of coronary disease or myocardial infarction, they might have an electrical origin
rather than being due to the build-up of atherosclerotic plaque. We need more information. The changes in lipids that may have occurred during therapy have not been looked at in great detail either, so that also remains speculative. I do know that at the 4-year interval, patients in the MRFIT trial who received antihypertensive therapy, specifically diuretic therapy, did not show as large a decrease in total cholesterol or triglycerides as the patients who had not received diuretic treatment. Diuretics thus appeared to counter the reduction in cholesterol that had been anticipated. The failure of cholesterol to decrease as much as expected in the hypertensive SI group could have lessened the mortality differential in comparison with the hypertensive UC group. Still, the hypertensive SI group had, in absolute terms, both lower blood pressure and lower total cholesterol than the hypertensive UC group throughout the program. The lipid hypothesis, therefore, does not seem to explain fully the failure of SI men to do better. Perhaps differences between SI and UC men in glucose tolerance or frank diabetes related to high-dose diuretic therapy could contribute to mechanisms causing the unexpected equivalence of CHD mortality in hypertensive SI and UC men. These suggestions are interesting but remain speculative. More detailed analyses of the M R F I T data are needed. DR. G U N N E L L S : We have talked a great deal about lipids this afternoon. This could be an important factor in connection with the problem of coronary heart disease and atherosclerosis in all hypertensives. If we're going to embark upon drug treatment, how much of a problem are the lipid effects of diuretics and betablockers, and how does prazosin come out in comparison? DR. C U T L E R : This is obviously a controversial area. You can't get 10 physicians together who will agree on that particular point. What we've talked here is taking data that are currently extant or being developed and comparing them with data from the past, namely the Framingham study, for the purpose of risk-factor calculation. The large clinical trials that we've talked about today have given us some food for thought, but they haven't truly answered the question for us. And it's not likely we will have the answers very quickly. All we can suggest at the present time is caution, in view of the. correlations that have been established in the past through epidemiologic methodology. The most we can say at this point is that antihypertensive agents that increase cholesterol and perhaps change the fractions in an adverse way by increasing the low density fractions and decreasing the high density ones may have an adverse effect on coronary heart disease. The underlying and conditional word is m a y . We won't know for sure until such studies are done. But in the meantime, as Stamler and others have said, the appropriate and prudent course of treatment is to implement dietary changes and to use drugs that do not have an adverse effect on lipid metabolism. As for a comparison between prazosin and other drugs, prazosin looks better because it doesn't seem to have any adverse effects on lipids.
February 24, 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 51
Diuretics seem to be more consistent in producing adverse effects that we believe may be atherogenic. DR. G U N N E L L S : Another important issue is that we seem to be in an exercise-oriented society. I'm constantly dodging joggers and bicycle riders on my way to the hospital. The use of drugs, specifically the betablockers, as first-line therapy in the physically active patient may be limiting. These agents have been advocated for the younger hypertensive patient. In these patients, the effect of the beta-blocker on the ability to exercise can often be an important side effect. DR. COLUCCI: Clearly, beta-blockers have multiple effects on the blood pressure, and the overall result is a combination of these effects. As I mentioned very briefly during my presentation, the beta-receptor in the vasculature, although frequently overlooked, is an important receptor. When it's blocked, the total peripheral resistance increases. This becomes clinically obvious when one treats a patient with Raynaud's disease or peripheral vascular occlusive disease, or just living in a cold climate. So we know that beta-blockers have an effect on total peripheral resistance that is the opposite of what we would want for an antihypertensive agent. One of the mechanisms by which beta-blockers lower blood pressure is through their reduction of renin release. They also tend to have effects on the heart. Cardiac output is diminished, and this may also contribute to their antihypertensive effect. In addition, betablockers seem to have a central effect, perhaps by reducing central sympathetic outflow. There may be other mechanisms, but it is somewhat paradoxical that beta-blockers were the first of the selective adrenergic antagonists to be used in hypertension, inasmuch as they do not seem to improve the main underlying problem in most primary hypertension, which is increased total peripheral resistance. The ability to exercise maximally is clearly decreased by beta-blockers. In part this is because the maximal heart rate is frequently lower, and therefore the maximal cardiac work that can be done is less. Beta-blockers may result in generalized fatigue, which may be related to this decrease in cardiac output. DR. OKUN: Our experience actually goes a little beyond that. Many youngsters who had been placed on beta-blockers for borderline or very mild hypertension have come to us later for other therapy because they found they couldn't exercise even to less than maximal capacity--jogging, tennis, and so on. They found themselves in difficult straits. Some animal data indicate that propranolol in particular will strikingly decrease skeletal muscle blood flow. This may be another mechanism for the easy fatigabillty. DR. G U N N E L L S : I'd like to set forth some of the features we might all agree are useful or favorable in an antihypertensive agent and see how they fit prazosin, the diuretics, and the beta-blockers. First is effectivehess. From what we've heard here, most antihypertensire drugs have equal effectiveness. In equipotent doses, prazosin is as effective as a diuretic or a beta-blocking
859
agent in reducing blood pressure. Second, we should look at hemodynamics and side effects: Prazosin's hemodynamic profile is a rational, reasonable, and appropriate one, relative to the underlying defect in primary hypertension, namely increased peripheral vascular resistance. Prazosin is free from the biochemical side effects that most of us have raised questions about. On the other hand, concern has been expressed about the hypokalemia induced by diuretics. Patients on prazosin do not have to worry about lowered serum potassium or increased uric acid levels. Equally important, prazosin does not appear to have any adverse effects on lipid metabolism. Another favorable feature of prazosin is its low incidence of sexual dysfunction, although some has been reported. Having said all that, I would then conclude that prazosin, as compared with diuretics and beta blockers, is an appropriate agent for consideration as initial therapy in mild or moderate hypertension. DR. OKUN: I agree with you, and I have 2 comments to make. First, I feel very strongly that correction of the pathophysiology of essential hypertension, normalization of the increased peripheral resistance, is a major benefit of prazosin and one that exists without any major counterbalancing effects in other areas. I have not seen this with any of the other drugs. That, to me, is a very positive aspect of prazosin. Second, I also feel very strongly about using prazosin more as initial therapy, along with a sodium-restricted diet. I think prazosin will be highly successful in controlling blood pressure in a great many patients without worsening risks--the other edge of the sword, so to speak. DR. COLUCCI: As Dr. Kaplan pointed out, given the choice of a number of drugs which have the same endpoint, namely the lowering of hypertension, the onus is now on the physician to choose the drug that will be safest in the long run. I certainly would be careful in my choice of agent. Clearly, of the agents currently available prazosin is the most specific in terms of pathophysiologic effects. Selective alpha blockade makes more sense than beta blockade or other more generalized methods of adrenergic suppression. A question usually arises about prazosin in regard to orthostatic hypotension and syncope. The overall incidence of syncope with the first dose of prazosin is about 0.1 to 0.2%, if one looks at a large series of patients and totals up the results. The incidence in any particular study will depend on a lot of factors. One of the factors identified as important was the dose of the drug used during the first administration. It is recommended that therapy be initiated with a I m g dose. Another important factor in determining whether a patient will have a syncopal or orthostatic reaction to the first dose is volume status. Patients who are volume contracted, whether because of diuresis or other reasons, are much more sensitive. This is presumably due to a lower initial venous filling pressure in these patients. The venous dilatation effects of prazosin then may result in a further decrease in preload. In the hypertensive patient without heart failure, when diuretics are withheld, syncope is rare. In one
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study, 12 out of 74 patients had either syncopal or significant orthostatic symptoms after the first administration of a 2-mg dose of prazosin. When these patients were withdrawn from prazosin for three weeks, then rechallenged with a lower dose (1 mg), none had severe symptoms, and only 2 had mild dizziness. Therefore, picking a low dose and avoiding diuresis are probably the 2 major things the physician can do to prevent this problem. In practice, good recommendations are to start with a low dose of 1 mg preferably at bed time when the patient can remain supine. If the patient is receiving diuretics, withhold the diuretics for 1 or 2 days, to allow the intravascular volume to reequilibrate. Diuretics can then be readministered. That raises an interesting question: If prazosin were to be used as first-line therapy, before diuretics, would we see the same incidence of syncope as when the drug is used as a Step 2 therapy? I speculate that we would not, and therefore this would be another good reason to consider prazosin as initial therapy before diuretics. DR. G U N N E L L S : With diuretic agents we still have the problem of potassium depletion and other effects not associated with prazosin. Among the antihypertensive drugs for which data are available, the treatment profile of prazosin--side effects and therapeutic effect i v e n e s s - i s extremely favorable. Therefore, prazosin is a very reasonable and rational drug as initial therapy for hypertension. I think it is fair to say there is general agreement on this among the panel members, and we all agree it is appropriate that we reexamined past practices and began to ask ourselves questions instead of just prescribing as a reflex. DR. C U T L E R : We've talked a lot about step therapy, but we should place it in perspective. It was very
useful in the beginning in training physicians. It was a good way to approach hypertension. The initial thrust in step care was provided by Wilkins many years ago with the advent of diuretics, reserpine, and vasodilators. We have now reached the point where the menu of therapeutic agents is quite large, and as when we visit a favorite restaurant, we probably need to pick and choose more appropriately, depending on the patient and the problem at hand. We can no longer deal simply with starting here and advancing to there, but rather we need to think of the clinical pharmacologic features of each agent, and use it as appropriately as we can in treating a particular patient. DR. G U N N E L L S : To summarize, we're not debating whether patients with mild hypertension should be treated with drug therapy, but rather what is the best way to treat them when drug therapy ~s chosen--how to provide the greatest benefit with the lowest risk. However, in discussing a new concept of therapy that provides an alternative to the traditional diuretic approach to initial therapy, a great deal of data are required on each specific agent. We have discussed the efficacy, hemodynamic profile, side effect profile, and effect on other risk factors for coronary heart disease (such as blood lipid levels) for at least 1 nondiuretic antihypertensive agent, namely prazosin, and it appears to fit a profile of an appropriate agent for the initial treatment of hypertension. If we are to make significant inroads into populations with hypertension, we cannot wait until they reach the point of target organ damage or of severe degrees of blood pressure, which will require more intensive and complicated therapy with greater likelihood of side effects and less than ideal control.