- Email: [email protected]
General group discussion
WHICH ELDERLY
PATIENTS
SHOULD WE TREAT?
P. S. Sever. The results of a number of clinical trials in the elderly have now been published and the evidence seems to support the benefits of active treatment in terms of a reduction in cardiovascular morbidity, if not mortality. Should we as physicians be treating all elderly patients? Should we be treating only some elderly ,patients and, if so, how do we decide which ones? F. Forette. I believe that there is a difference between what we shouEd do and what we actually do. In France, general practioners tend to treat all elderly hypertensive patients-they did not wait for the results of the European Working Party on Hypertension in the Elderly (EWPHE) study-but it is very important to know the effect of several drugs in this population. I am not sure that overall mortality is so important in very old patients: antihypertensive treatment is not a quest for immortality, especially when patients over 80 years old die of various other diseases, such as influenza. However, it is important to prevent stroke, and the EWPHE study has shown that treatment can decrease nonfatal strokes. We have no hard facts concerning isolated systolic hypertension, but in France we are continuing to treat it without waiting for the results of the Systolic Hypertension in Elderly People (SHEP) and EWPHE II studies. As you may know, the European Working Party is setting a protocol for isolated systolic hypertension, in which Professor Leonetti is participating, and first-line treatment will be a calcium channel blocker. We will therefore have, in many years’ time, data on the effects of calcium channel blockers on longterm morbidity and mortality. W. A. Littler. One of the problems is knowing at what age the benefits of therapy become disadvantageous. There are some persuasive data from Finland that showed that in a population whose average age was 85 years, patients with a blood pressure of 160/90 mm Hg fared much better. This was not simply because those with a lower blood pressure had more concomitant disease or poorer ventricular function, since patients were matched for this. All that the trials tell us is that up to the age of ‘75 years treatment for hypertension is beneficial. Our 270
present policy is that patients below 75 years of age with persistently elevated blood pressure (>160/95 mm Hg) should be treated, particularly if they have associated evidence of target organ damage such as heart failure, angina, or transient ischemic attacks. Increasingly, we are tending to treat them initially with a calcium channel blocker. L. R. Krakojf. I agree in general with what has already been said. In the US there is a tendency to divide the elderly into three groups: the “young elderly,” the “middle elderly,” and the “really elderly,” some of whom fall into Dr Forette’s study. Looking at all the trial data, it appears that in terms of benefit versus age at entry, the curve on the graph starts to accelerate over the age of 50 years. Perhaps I viewed the Hypertension Detection and Follow-Up Program (HDFP) data a little differently than some, and saw that at the upper end the survival curve starts to fall off again. I speculate that patients in the two younger categories will benefit most from therapy. In all our presentations and discussions so far, we have talked about blood pressure, side effects, mortality, morbidity, the detectable stroke, and so on. Yet, we have not mentioned using the available tools to assess silent ischemia in the cardiac patient-the regression or prevention of hypertrophy. Are there equivalent end points in the brain for which up-to-date technology such as serial computed tomography (CT), nuclear magnetic resonance imaging (NMR), and positron emission tomography (PET) scanning can be applied? We have not mentioned the means to refine our definition of pathologic end points effectively in this oldest group of patients where there is likely to be a lot of silent disease that precedes the overt, disabling condition. G. Leonetti. I was more inclined to treat all elderly hypertensive patients before seeing Dr Krakoffs results. He has shown the strong placebo effect in the elderly and this has reminded us that before defining old people as hypertensive, we should be wary of the high variability in blood pressure in this group. If we assume that the diagnosis of arterial hypertension is correct, I think that people older than 60 or 65 years with blood pressure greater than 160/95 mm Hg should be treated. Over
General
that age, I am a little more open-minded than Dr Littler and would push the upper limits to 80 years or so. Our European study showed that up to 80 years of age there were benefits from treatment, but above 80 years there was no benefit. Furthermore, we tend to have a more open-minded approach to treatment when using drugs with a low incidence of side effects. T, Santa. In Japan we do not usually prescribe antihypertensive drugs to patients over 80 years old because such drugs are not effective. We do treat ‘patients aged 60 to 80 years when there is a systolic blood pressure over 170 mm Hg. In addition, if the patient has diabetes, vascular damage, or a family history of cerebrovascular disease or ischemic heart disease, we would begin therapy at a blood pressure of 160 to 170 mm Hg. P. S. Seuer. Can I ask Dr. Flamm about his views on treating hypertension in the elderly who have already suffered a vascular event. E. S. Ftamm. Clearly, the most critical factor in the change in vascular disease in the past 20 or 30 years has been the control of hypertension, but I cannot really comment on what I would do with a hypertensive patient who has already had a stroke who is unlikely to be a surgical candidate. R. Carretta. The first criterion in treating the elderly patient. is that we should choose the patient who already has some complication of hypertension. The second is to look at the quality of life patients have on theralpy. If it is improved, we are on the correct track. F. Forette. ‘We must recognize that we have no evidence at all on the eventual beneficial effect of antihypertensive treatment in people over 80 years old, even with the EWPHE results, because in the latter study there were too few people over 80 years of age. Furthermore, patients aged 80 to 97 years were grouped together, yet an 80-year-old person is different from an 8byear-old. Most of the population over 80, around 90%) were in nursing homes or were institutionalized, and such patients are very different from ambulatory patients. P. S. Sever. We must be very careful we don’t take the subgroup analysis too far, because by the time the numbers are reduced you are unlikely to be able to show benefit,. I would like to add that there are no two patients in the elderly age group who have the same biologically aged vascular system. It is possible to have a 65:year-old who has the cerebral and coronary vessels of an 80-year-old and vice versa. I believe there may be a case for selecting out patients in terms of biological age rather than chronological we.
WHAT FACTORS THERAPY?
DETERMINE
group
discussiort 271
YOUR CHOICE OF
G. Leonetti. I use all kinds of drugs, and the first factor I consider is the presence or absence of a contraindication. L. R. Krakofi. It is the patient-that is, the overall status of the individual-that, in practice, determines the choice of drug. The elderly patient is complex and multifaceted, and until we obtain very good data on these subgroups I believe that is the best answer I can give. P. S. Sever. Consider the totally uncomplicated elderly hypertensive individual who is asymptomatic, who you discover has a sustained pressure of 180/120 mm Hg. L. R. Krakoff. We rarely meet such patients, but they are invariably complicated. We have a study presently going on with severe hypertension and many of these patients already have left ventricular hypertrophy and ischemic heart disease, so I think there is no simple way to answer the question. The isolated systolic (180 to 190 mm Hg) 80-year-old who is functioning very well perhaps does as well on placebo until we know better. W. A. Littler. For me the choice of drug depends on concomitant disease and the side effect profile of the agent. Increasingly in our hypertension clinic we are using calcium charmel blockers in the type of patient Professor Sever has described. We actually do see them, although perhaps not very frequently. F. Forette. We use all sort of drugs, but the fact that a drug is well tolerated, effective, and needs a less constraining laboratory monitoring is certainly an important plus in elderly patients. For these reasons, we now tend to use calcium channel blockers as first-line treatment. T. San&a. The degree of blood pressure and the concomitant disease are very important factors in choosing a drug. I use a calcium channel blocker. E. S. Flamm. With regard to subarachnoid hemorrhage, we have the adage that any drug used for the treatment of vasospasm works the first time. We have gone through a number of regimens and I would just stress the need for carefully controlled randomized trials to answer some of these very broad questions. R. Carretta. I believe it is very important to choose a drug on the basis of concomitant disease. Where there is little concomitant disease, a calcium channel blocker would be indicated because most cases of hypertension in the elderly are isolated systolic, and from the limited experience that we
272
General
group
discussion
American
have concerning the changes in blood vessels in these patients, it seems a rational approach. P. S. Sever. Before turning to the final question, I would like to mention the subject of drug disposition in the elderly. It seems that we need more data on this subject, in view of Dr Forette’s suggestion that the metabolism, distribution or disposition of the drug may be altered in the elderly. WHAT INITIAL DOSAGE AND DOSAGE NICARDIPINE WOULD YOU USE?
INTERVAL
OF
P. S. Sever. In answering this question, we should bear in mind that all the evidence points to the duration of action of nicardipine being relatively short. Certainly in terms of future design and development and drug delivery systems, an alternative formulation might well be an advantage. G. Leonetti. In the elderly it is common practice to start with lower doses than would be used in a younger adult, and I usually start with half the dose given to a younger patient. However, in our study we found that the final doses employed in the elderly were not actually lower than those employed in younger adults. Although the plasma levels are higher in the elderly, perhaps it is the amount that reaches the receptor that is the critical factor, and the elderly may be less sensitive. Concerning dosage interval, the same caution over the dosage applies to dosage interval, although there are occasions when blood pressure has to be lowered rapidly. L. R. Krakoff. In our study we did not do a comparison, so I can only reflect on Professor Leonetti’s observation that there appears to be less of an age effect, at least in the age range that we studied. The initial dose therefore seems to be similar for old and young. In our patients, 30 mg three times a day appears to be what is required for a therapeutic effect to begin to show. W. A. Littler. I agree with Dr Krakoff about the
January 1989 Heart Journal
initial dose, because a large dose may result in a large reflex response with tachycardia and flushing. Both patients and their doctors are frightened by this and the drug is stopped. I therefore believe that therapy should start with a smaller dose and that both the patient and his general practitioner should be warned that when a member of this class of drugs is used as monotherapy, there may initially be some side effects such as flushing, palpitations, and headache. In our experience, resetting of reflexes starts within 24 hours and it is usually complete at 1 week. In general terms, with all calcium channel blockers we have not been able to use substantially lower doses. However, there are data (some from the British study) that show that patients can be switched from three times a day to twice a day dosing with adequate blood pressure control. F. Forette. I agree that one should probably start with small dosage and raise the dosage if it is not effective in lowering blood pressure. The usual dose is 30 mg/day (10 mg three times a day), but one should not hesitate to raise dosage if necessary. T. Saruta. In Japan many doctors use 30 mg/day of nicardipine as the initial dose, and if there is insufficient reduction in blood pressure, this is increased to 60 mg/day. The maximum dose is 80 mg/day (20 mg four times a day). G. Leonetti. I believe it is important to start slowly and use the normal formulation of nicardipine. It is important to have thrice daily administration. We have little experience with the slow-release form. Parer&rally, we find fewer side effects, especially with regard to palpitations, and there is longer and better blood pressure control. R. Carretta. Depending on the effect of the dosage schedule upon a patient’s life-style, in patients who responded to 20 mg three times a day we try to reduce this to 20 mg twice a day, and about 80% of the population still respond.
PATIENTS
SHOULD WE TREAT?
P. S. Sever. The results of a number of clinical trials in the elderly have now been published and the evidence seems to support the benefits of active treatment in terms of a reduction in cardiovascular morbidity, if not mortality. Should we as physicians be treating all elderly patients? Should we be treating only some elderly ,patients and, if so, how do we decide which ones? F. Forette. I believe that there is a difference between what we shouEd do and what we actually do. In France, general practioners tend to treat all elderly hypertensive patients-they did not wait for the results of the European Working Party on Hypertension in the Elderly (EWPHE) study-but it is very important to know the effect of several drugs in this population. I am not sure that overall mortality is so important in very old patients: antihypertensive treatment is not a quest for immortality, especially when patients over 80 years old die of various other diseases, such as influenza. However, it is important to prevent stroke, and the EWPHE study has shown that treatment can decrease nonfatal strokes. We have no hard facts concerning isolated systolic hypertension, but in France we are continuing to treat it without waiting for the results of the Systolic Hypertension in Elderly People (SHEP) and EWPHE II studies. As you may know, the European Working Party is setting a protocol for isolated systolic hypertension, in which Professor Leonetti is participating, and first-line treatment will be a calcium channel blocker. We will therefore have, in many years’ time, data on the effects of calcium channel blockers on longterm morbidity and mortality. W. A. Littler. One of the problems is knowing at what age the benefits of therapy become disadvantageous. There are some persuasive data from Finland that showed that in a population whose average age was 85 years, patients with a blood pressure of 160/90 mm Hg fared much better. This was not simply because those with a lower blood pressure had more concomitant disease or poorer ventricular function, since patients were matched for this. All that the trials tell us is that up to the age of ‘75 years treatment for hypertension is beneficial. Our 270
present policy is that patients below 75 years of age with persistently elevated blood pressure (>160/95 mm Hg) should be treated, particularly if they have associated evidence of target organ damage such as heart failure, angina, or transient ischemic attacks. Increasingly, we are tending to treat them initially with a calcium channel blocker. L. R. Krakojf. I agree in general with what has already been said. In the US there is a tendency to divide the elderly into three groups: the “young elderly,” the “middle elderly,” and the “really elderly,” some of whom fall into Dr Forette’s study. Looking at all the trial data, it appears that in terms of benefit versus age at entry, the curve on the graph starts to accelerate over the age of 50 years. Perhaps I viewed the Hypertension Detection and Follow-Up Program (HDFP) data a little differently than some, and saw that at the upper end the survival curve starts to fall off again. I speculate that patients in the two younger categories will benefit most from therapy. In all our presentations and discussions so far, we have talked about blood pressure, side effects, mortality, morbidity, the detectable stroke, and so on. Yet, we have not mentioned using the available tools to assess silent ischemia in the cardiac patient-the regression or prevention of hypertrophy. Are there equivalent end points in the brain for which up-to-date technology such as serial computed tomography (CT), nuclear magnetic resonance imaging (NMR), and positron emission tomography (PET) scanning can be applied? We have not mentioned the means to refine our definition of pathologic end points effectively in this oldest group of patients where there is likely to be a lot of silent disease that precedes the overt, disabling condition. G. Leonetti. I was more inclined to treat all elderly hypertensive patients before seeing Dr Krakoffs results. He has shown the strong placebo effect in the elderly and this has reminded us that before defining old people as hypertensive, we should be wary of the high variability in blood pressure in this group. If we assume that the diagnosis of arterial hypertension is correct, I think that people older than 60 or 65 years with blood pressure greater than 160/95 mm Hg should be treated. Over
General
that age, I am a little more open-minded than Dr Littler and would push the upper limits to 80 years or so. Our European study showed that up to 80 years of age there were benefits from treatment, but above 80 years there was no benefit. Furthermore, we tend to have a more open-minded approach to treatment when using drugs with a low incidence of side effects. T, Santa. In Japan we do not usually prescribe antihypertensive drugs to patients over 80 years old because such drugs are not effective. We do treat ‘patients aged 60 to 80 years when there is a systolic blood pressure over 170 mm Hg. In addition, if the patient has diabetes, vascular damage, or a family history of cerebrovascular disease or ischemic heart disease, we would begin therapy at a blood pressure of 160 to 170 mm Hg. P. S. Seuer. Can I ask Dr. Flamm about his views on treating hypertension in the elderly who have already suffered a vascular event. E. S. Ftamm. Clearly, the most critical factor in the change in vascular disease in the past 20 or 30 years has been the control of hypertension, but I cannot really comment on what I would do with a hypertensive patient who has already had a stroke who is unlikely to be a surgical candidate. R. Carretta. The first criterion in treating the elderly patient. is that we should choose the patient who already has some complication of hypertension. The second is to look at the quality of life patients have on theralpy. If it is improved, we are on the correct track. F. Forette. ‘We must recognize that we have no evidence at all on the eventual beneficial effect of antihypertensive treatment in people over 80 years old, even with the EWPHE results, because in the latter study there were too few people over 80 years of age. Furthermore, patients aged 80 to 97 years were grouped together, yet an 80-year-old person is different from an 8byear-old. Most of the population over 80, around 90%) were in nursing homes or were institutionalized, and such patients are very different from ambulatory patients. P. S. Sever. We must be very careful we don’t take the subgroup analysis too far, because by the time the numbers are reduced you are unlikely to be able to show benefit,. I would like to add that there are no two patients in the elderly age group who have the same biologically aged vascular system. It is possible to have a 65:year-old who has the cerebral and coronary vessels of an 80-year-old and vice versa. I believe there may be a case for selecting out patients in terms of biological age rather than chronological we.
WHAT FACTORS THERAPY?
DETERMINE
group
discussiort 271
YOUR CHOICE OF
G. Leonetti. I use all kinds of drugs, and the first factor I consider is the presence or absence of a contraindication. L. R. Krakofi. It is the patient-that is, the overall status of the individual-that, in practice, determines the choice of drug. The elderly patient is complex and multifaceted, and until we obtain very good data on these subgroups I believe that is the best answer I can give. P. S. Sever. Consider the totally uncomplicated elderly hypertensive individual who is asymptomatic, who you discover has a sustained pressure of 180/120 mm Hg. L. R. Krakoff. We rarely meet such patients, but they are invariably complicated. We have a study presently going on with severe hypertension and many of these patients already have left ventricular hypertrophy and ischemic heart disease, so I think there is no simple way to answer the question. The isolated systolic (180 to 190 mm Hg) 80-year-old who is functioning very well perhaps does as well on placebo until we know better. W. A. Littler. For me the choice of drug depends on concomitant disease and the side effect profile of the agent. Increasingly in our hypertension clinic we are using calcium charmel blockers in the type of patient Professor Sever has described. We actually do see them, although perhaps not very frequently. F. Forette. We use all sort of drugs, but the fact that a drug is well tolerated, effective, and needs a less constraining laboratory monitoring is certainly an important plus in elderly patients. For these reasons, we now tend to use calcium channel blockers as first-line treatment. T. San&a. The degree of blood pressure and the concomitant disease are very important factors in choosing a drug. I use a calcium channel blocker. E. S. Flamm. With regard to subarachnoid hemorrhage, we have the adage that any drug used for the treatment of vasospasm works the first time. We have gone through a number of regimens and I would just stress the need for carefully controlled randomized trials to answer some of these very broad questions. R. Carretta. I believe it is very important to choose a drug on the basis of concomitant disease. Where there is little concomitant disease, a calcium channel blocker would be indicated because most cases of hypertension in the elderly are isolated systolic, and from the limited experience that we
272
General
group
discussion
American
have concerning the changes in blood vessels in these patients, it seems a rational approach. P. S. Sever. Before turning to the final question, I would like to mention the subject of drug disposition in the elderly. It seems that we need more data on this subject, in view of Dr Forette’s suggestion that the metabolism, distribution or disposition of the drug may be altered in the elderly. WHAT INITIAL DOSAGE AND DOSAGE NICARDIPINE WOULD YOU USE?
INTERVAL
OF
P. S. Sever. In answering this question, we should bear in mind that all the evidence points to the duration of action of nicardipine being relatively short. Certainly in terms of future design and development and drug delivery systems, an alternative formulation might well be an advantage. G. Leonetti. In the elderly it is common practice to start with lower doses than would be used in a younger adult, and I usually start with half the dose given to a younger patient. However, in our study we found that the final doses employed in the elderly were not actually lower than those employed in younger adults. Although the plasma levels are higher in the elderly, perhaps it is the amount that reaches the receptor that is the critical factor, and the elderly may be less sensitive. Concerning dosage interval, the same caution over the dosage applies to dosage interval, although there are occasions when blood pressure has to be lowered rapidly. L. R. Krakoff. In our study we did not do a comparison, so I can only reflect on Professor Leonetti’s observation that there appears to be less of an age effect, at least in the age range that we studied. The initial dose therefore seems to be similar for old and young. In our patients, 30 mg three times a day appears to be what is required for a therapeutic effect to begin to show. W. A. Littler. I agree with Dr Krakoff about the
January 1989 Heart Journal
initial dose, because a large dose may result in a large reflex response with tachycardia and flushing. Both patients and their doctors are frightened by this and the drug is stopped. I therefore believe that therapy should start with a smaller dose and that both the patient and his general practitioner should be warned that when a member of this class of drugs is used as monotherapy, there may initially be some side effects such as flushing, palpitations, and headache. In our experience, resetting of reflexes starts within 24 hours and it is usually complete at 1 week. In general terms, with all calcium channel blockers we have not been able to use substantially lower doses. However, there are data (some from the British study) that show that patients can be switched from three times a day to twice a day dosing with adequate blood pressure control. F. Forette. I agree that one should probably start with small dosage and raise the dosage if it is not effective in lowering blood pressure. The usual dose is 30 mg/day (10 mg three times a day), but one should not hesitate to raise dosage if necessary. T. Saruta. In Japan many doctors use 30 mg/day of nicardipine as the initial dose, and if there is insufficient reduction in blood pressure, this is increased to 60 mg/day. The maximum dose is 80 mg/day (20 mg four times a day). G. Leonetti. I believe it is important to start slowly and use the normal formulation of nicardipine. It is important to have thrice daily administration. We have little experience with the slow-release form. Parer&rally, we find fewer side effects, especially with regard to palpitations, and there is longer and better blood pressure control. R. Carretta. Depending on the effect of the dosage schedule upon a patient’s life-style, in patients who responded to 20 mg three times a day we try to reduce this to 20 mg twice a day, and about 80% of the population still respond.