Cardiovascular Drugs and Therapy 1992;6:571-573 © Kluwer Academic Publishers, Boston. Printed in U.S.A.
Treatment of Hypertension in the Elderly have We Learned from the Recent Trials?
What
Per L u n d - J o h a n s e n Department of Cardiology, University of Bergen, School of Medicine, Bergen, Norway
Summary. Treatment of hypertension in the elderly has so far mainly been based on clinical judgment and very few large controlled trials. During the last year several large new trials have been published, the so-called STOP-Hypertension, SHEP, and MRC trials. All have shown that drug treatment of hypertension in the elderly (65-85 years) with permanent diastolic hypertension or isolated systolic hypertension reduces stroke incidence. Most patients have needed combined drug treatment with diuretics and beta-blockers. When thiazide diuretics are used, serum postassium should be followed very closely and most likely amiloride should be added to the thiazide therapy, since this was done both in the STOP and the MRC trials. Since many elderly patients with hypertension suffer from other diseases that might represent contraindications to thiazide diuretics or beta-blockers, the choice of drug must be made after careful clinical evaluation. With the newer classes of antihypertensive agents (calcium antagonists, ACE inhibitors and alpha-blockers) side effects are probably seen less often, but long-term data on morbidity and mortality are still lacking.
Cardiovasc Drugs Ther 1992;6:571-573 Key Words. hypertension, elderly, antihypertensive therapy, diuretic, amiloride, triamterene, beta-blockers
Treatment of mild and moderately severe hypertension in the young and middle-aged has been debated for years and will most likely be discussed also in the years to come. Recent meta-analyses have shown that just a 5-mmHg difference in diastolic blood pressure during a 5-year period, strongly influences the risk of stroke and myocardial infarction in this age group [1], and another meta-analysis of 14 trials showed a significant reduction in stroke risk of 35-40% in treated patients [2]. In elderly subjects (>60 years) differences in opinion about when and how to treat have been even greater. Many have stressed that elderly patients should not be treated for hypertension, since high blood pressure is necessary to maintain adequate blood flow through narrow, stiff arteries. Lowering the blood pressure could be dangerous, and it has been suggested that the J-shape curve phenomenon [3] could be particularly evident in this age group. It has also been feared that there is a significant overtreatment of hypertension in the elderly [4]. On the other hand, epidemiological data show very
clearly that the risk of cardiovascular disease--and in particular stroke--increases much more dramatically with increasing blood pressure in the elderly than in the young [5]. It is also clear that high blood pressure in the systemic circulation indicates an increased load on the heart and vessels and, from this point of view, a reduction in systemic arterial blood pressures should be beneficial. Our dilemma--to treat or not to t r e a t - has so far been based mainly on clinical judgment and on relatively few controlled trials. The last year has given us new data that certainly will influence our guidelines. First, the European Working Party on Hypertension in the Elderly (EWPHE) has finally presented an analysis, including both advantages and disadvantages (side effects), and the major conclusion was that the benefit was greater than the risks [6]. This trial was based on initial therapy with hydrochlorothiazide plus triamterene. The most impressive results were seen in the Swedish STOP-Hypertension trial [7]. As in previous trials, there was a significant reduction in stroke, and also in total mortality, a rather unique finding in prevention trials. The trial is a very strong argument in favor of treating patients aged 70-84 years with permanently increased diastolic blood pressures above 100-105 mmHg. Also, this trial was based on using thiazide plus a potassium-spearing diuretic--amiloride or one of the three beta-blockers, metoprolol, atenolol, or pindolol. The majority of the patients needed combination treatment to achieve satisfactory blood pressure control. A beneficial effect was seen in all ages, but only 16% of the patients in the trial were above 80 years of age, so the number in the oldest group is small. A much bigger trial--The Medical Research Council (the MRC trial) [8]--was also based on hydrochlorothiazide plus amiloride and/or the beta-blocker atenolol. Treatment vs. placebo induced a 25% reduction in the incidence of stroke and a somewhat less reduction in coronary artery disease. So far, the results are
Address for correspondence and reprint requests: Per LundJohansen, Professor in Medicine, Department of Cardiology, Haukeland Hospital, 5021 Bergen, Norway.
571
572
Lund-Johansen
in agreement with previous trials. However, the big problem with the MRC trial comes from its attempt to determine what worked best, diuretics or betablockers. Surprisingly, the results showed that atenolol had no better effect than placebo, and that the mortality figures were much higher in the atenolol group than in the diuretic-treated group. The publication of the MRC trial led to a warning against the use of atenolol in Norway [9]. In my opinion, the publication of the results from the MRC trial was most unfortunate and confusing, and so was the design of the trial. First of all, if the intention is to compare two different classes of drugs in a long-term trial, one should not mix the two, but rather add a different class of agent as second-line treatment when monotherapy is not sufficient to induce satisfactory reduction in the blood pressure. In the MRC trial, the majority of the patients received both drugs, obviously making the analyses very difficult. The second major source of confusion was the statement that 25% of the patients were lost to follow-up. This, of course, leads one to question the value of this trial. At the Meeting of the International Society of Hypertension in Madrid in June 1992, one of the authors (A. Lever) pointed out that 25% "lost to follow-up" did actually not mean that the patients were lost to follow-up, but that the majority of those had not followed the protocol. However, mortality figures were availabile in that group [10]. Furthermore, it was pointed out that the high mortality in the atenolol group, which was caused by an increased incidence of cancer, could not be detected in two large analyses looking at cancer incidence in large groups of patients being treated with atenolol over a long period of time. The major conclusion was that the high mortality in the MRC atenolol-treated group was "a chance finding" [10], in other words, due to bad luck. Combined treatment was also necessary, to a large extent, in the American SHEP study, looking at the effect of treatment of isolated systolic hypertension [11]. The trial was based on chlorthalidrone plus atenolol 25-50 mg. Serum potassium was followed closely and potassium supplement was given if potassium fell to
Treatment of Hypertension in the Elderly have We Learned from the Recent Trials?
What
Per L u n d - J o h a n s e n Department of Cardiology, University of Bergen, School of Medicine, Bergen, Norway
Summary. Treatment of hypertension in the elderly has so far mainly been based on clinical judgment and very few large controlled trials. During the last year several large new trials have been published, the so-called STOP-Hypertension, SHEP, and MRC trials. All have shown that drug treatment of hypertension in the elderly (65-85 years) with permanent diastolic hypertension or isolated systolic hypertension reduces stroke incidence. Most patients have needed combined drug treatment with diuretics and beta-blockers. When thiazide diuretics are used, serum postassium should be followed very closely and most likely amiloride should be added to the thiazide therapy, since this was done both in the STOP and the MRC trials. Since many elderly patients with hypertension suffer from other diseases that might represent contraindications to thiazide diuretics or beta-blockers, the choice of drug must be made after careful clinical evaluation. With the newer classes of antihypertensive agents (calcium antagonists, ACE inhibitors and alpha-blockers) side effects are probably seen less often, but long-term data on morbidity and mortality are still lacking.
Cardiovasc Drugs Ther 1992;6:571-573 Key Words. hypertension, elderly, antihypertensive therapy, diuretic, amiloride, triamterene, beta-blockers
Treatment of mild and moderately severe hypertension in the young and middle-aged has been debated for years and will most likely be discussed also in the years to come. Recent meta-analyses have shown that just a 5-mmHg difference in diastolic blood pressure during a 5-year period, strongly influences the risk of stroke and myocardial infarction in this age group [1], and another meta-analysis of 14 trials showed a significant reduction in stroke risk of 35-40% in treated patients [2]. In elderly subjects (>60 years) differences in opinion about when and how to treat have been even greater. Many have stressed that elderly patients should not be treated for hypertension, since high blood pressure is necessary to maintain adequate blood flow through narrow, stiff arteries. Lowering the blood pressure could be dangerous, and it has been suggested that the J-shape curve phenomenon [3] could be particularly evident in this age group. It has also been feared that there is a significant overtreatment of hypertension in the elderly [4]. On the other hand, epidemiological data show very
clearly that the risk of cardiovascular disease--and in particular stroke--increases much more dramatically with increasing blood pressure in the elderly than in the young [5]. It is also clear that high blood pressure in the systemic circulation indicates an increased load on the heart and vessels and, from this point of view, a reduction in systemic arterial blood pressures should be beneficial. Our dilemma--to treat or not to t r e a t - has so far been based mainly on clinical judgment and on relatively few controlled trials. The last year has given us new data that certainly will influence our guidelines. First, the European Working Party on Hypertension in the Elderly (EWPHE) has finally presented an analysis, including both advantages and disadvantages (side effects), and the major conclusion was that the benefit was greater than the risks [6]. This trial was based on initial therapy with hydrochlorothiazide plus triamterene. The most impressive results were seen in the Swedish STOP-Hypertension trial [7]. As in previous trials, there was a significant reduction in stroke, and also in total mortality, a rather unique finding in prevention trials. The trial is a very strong argument in favor of treating patients aged 70-84 years with permanently increased diastolic blood pressures above 100-105 mmHg. Also, this trial was based on using thiazide plus a potassium-spearing diuretic--amiloride or one of the three beta-blockers, metoprolol, atenolol, or pindolol. The majority of the patients needed combination treatment to achieve satisfactory blood pressure control. A beneficial effect was seen in all ages, but only 16% of the patients in the trial were above 80 years of age, so the number in the oldest group is small. A much bigger trial--The Medical Research Council (the MRC trial) [8]--was also based on hydrochlorothiazide plus amiloride and/or the beta-blocker atenolol. Treatment vs. placebo induced a 25% reduction in the incidence of stroke and a somewhat less reduction in coronary artery disease. So far, the results are
Address for correspondence and reprint requests: Per LundJohansen, Professor in Medicine, Department of Cardiology, Haukeland Hospital, 5021 Bergen, Norway.
571
572
Lund-Johansen
in agreement with previous trials. However, the big problem with the MRC trial comes from its attempt to determine what worked best, diuretics or betablockers. Surprisingly, the results showed that atenolol had no better effect than placebo, and that the mortality figures were much higher in the atenolol group than in the diuretic-treated group. The publication of the MRC trial led to a warning against the use of atenolol in Norway [9]. In my opinion, the publication of the results from the MRC trial was most unfortunate and confusing, and so was the design of the trial. First of all, if the intention is to compare two different classes of drugs in a long-term trial, one should not mix the two, but rather add a different class of agent as second-line treatment when monotherapy is not sufficient to induce satisfactory reduction in the blood pressure. In the MRC trial, the majority of the patients received both drugs, obviously making the analyses very difficult. The second major source of confusion was the statement that 25% of the patients were lost to follow-up. This, of course, leads one to question the value of this trial. At the Meeting of the International Society of Hypertension in Madrid in June 1992, one of the authors (A. Lever) pointed out that 25% "lost to follow-up" did actually not mean that the patients were lost to follow-up, but that the majority of those had not followed the protocol. However, mortality figures were availabile in that group [10]. Furthermore, it was pointed out that the high mortality in the atenolol group, which was caused by an increased incidence of cancer, could not be detected in two large analyses looking at cancer incidence in large groups of patients being treated with atenolol over a long period of time. The major conclusion was that the high mortality in the MRC atenolol-treated group was "a chance finding" [10], in other words, due to bad luck. Combined treatment was also necessary, to a large extent, in the American SHEP study, looking at the effect of treatment of isolated systolic hypertension [11]. The trial was based on chlorthalidrone plus atenolol 25-50 mg. Serum potassium was followed closely and potassium supplement was given if potassium fell to
