Other views (commentary on "Antihypertensive therapy: beta-blockers and diuretics")

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Esmond Tucker
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1 BUMC Proceedings 2000;13: Other views (commentary on "Antihypertensive therapy: beta-blockers and diuretics") r. Messerli has advanced what, on the surface, appears to be a convincing argument that beta-blockers should not be used in the management of hypertension in the elderly and that diuretics should be used sparingly, if at all, in younger or middle-aged women (1). He bases his conclusions on meta-analyses that he and his colleagues have performed dealing with these subjects. He is critical of the recommendations of the Joint National Committee (JNC) for the use of diuretics and/or beta-blockers as initial therapy (2, 3) but admits that the use of diuretics, at least, has dramatically reduced the occurrence of strokes, heart attacks, heart failure, and progression to more severe disease in hypertensive individuals. Both JNC V (2) and the more current 1997 JNC VI (3) base their recommendations on good evidence from multiple prospective randomized trials that used diuretics or beta-blockers alone or in combination. Seventeen of the trials that were reviewed reported a statistically significant decrease not only in strokes but in coronary heart disease events and overall cardiovascular morbidity and mortality (4). At the time of JNC VI ( ), diuretics and beta-blockers were the only 2 classes of drugs that had been used in the large outcome trials, with the exception of 1 trial in the elderly, the Systolic Hypertension in Europe study (5). In this trial, a moderately long-acting calcium channel blocker, nitrendipine, was given as baseline therapy; strokes and overall cardiovascular events were reduced, but a statistically significant reduction in coronary heart disease events was not noted. There were no other prospective studies available at that time showing that blood pressure reduction with calcium channel blockers diminished cardiovascular morbidity and mortality. Only 1 trial prior to the Systolic Hypertension in Europe study examined long-term results of a calcium channel blocker in hypertensive subjects (6). In this study, the use of a calcium channel blocker, isradipine, resulted in more vascular events than the use of a diuretic. Since that study, several trials the Verapamil in Hypertension and Atherosclerosis Trial (7), using a long-acting, nondihydropyridine calcium channel blocker, verapamil SR, and the Japanese Trial in the Elderly (8) have reported that calcium channel blockers are as effective as diuretics in reducing cardiovascular events, but not more effective than diuretics. Thus, the implication that cardiovascular events have been reduced to a greater degree by calcium channel blockers than by the drugs recommended as initial therapy by JNC V and VI is not proven. Based on our observations through many years, diuretics have been at least as effective in reducing morbidity and mortality, not just in the young but in the elderly, as other agents tested to date. It is interesting to note that Dr. Messerli takes a strong position on the effectiveness of diuretics in reducing coronary heart disease events. For years, many investigators claimed that these agents were not effective in reducing myocardial infarctions.

2 BETA-BLOCKERS AND THE ELDERLY In reviewing data on the beta-blockers, Dr. Messerli has depended a great deal on the results of the Medical Research Council trial in the elderly (9). This reported a lack of benefit when beta-blockers were used as monotherapy compared to diuretics. As he noted, the dropout rate from adverse events from beta-blockers was more than double that in the placebo group or in patients on diuretics. The large number of dropouts greatly reduced the statistical power of the trial to show benefit. In the other trials, both in the young and the elderly, it is difficult to determine specific outcome with 1 medication compared to another. These are often not reported. JNC VI specifically states that in the treatment of hypertension in the elderly, thiazide diuretics or beta-blockers in combination with thiazide diuretics are recommended because they are effective in reducing morbidity and mortality in older persons with hypertension as shown in multiple randomized controlled trials. In making the case for not using betablockers, Dr. Messerli ignores the fact that the use of beta-blockers reduces the incidence of strokes and congestive heart failure in both young and elderly patients. In addition, the use of beta-blockers, in both the young and elderly, in patients with or without diabetes, has been effective in reducing morbidity and mortality in patients postmyo cardial infarction (10). When added to usual therapy, which includes diuretics, angiotensin-converting enzyme (ACE) inhibitors, and digitalis, these agents also have reduced the incidence of congestive heart failure, hospitalizations, and overall mortality (11). None of these benefits have been reported with calcium channel blockers, except for some decrease in reinfarction with the nondihydropyridine calcium channel blockers. The dosages of beta-blockers presently used in the treatment of hypertension in the elderly are considerably less than those used in the Medical Research Council trial and produce fewer side effects. In randomized, blinded trials, beta-blockers have been tolerated as well as or better than other medications (12, 13). Patients on beta-blockers have noted an improvement in quality-of-life scores similar to that seen with other agents. The Medical Research Council trial in the elderly was unique in the number and type of side effects reported. Sweeping conclusions regarding the use of beta-blockers should not be based primarily on this study. Dr. Messerli ignores a great deal of science when he states that millions of elderly hypertensive patients are needlessly exposed to the cost, inconvenience, and adverse effects of beta-blockers even though they will never harvest any benefits. TOXIC EFFECTS OF DIURETICS? Data supposedly establishing a relationship between diuretic use and renal cell carcinoma are based on retrospective case-control studies and cohort studies that were not designed to demonstrate this relationship. Patients with hypertension appear to have a higher incidence of renal cell carcinoma regardless of therapy. Dr. Messerli admits that carcinogenicity is low and that renal cell carcinoma is rare. It is a disservice to base a wide-ranging recommendation that young and middle-aged women should not be given diuretics despite their proven benefit in reducing strokes, myocardial infarctions, congestive heart failure, and overall morbidity and mortality based on these kinds of data. It may take as long as 15 to 20 years to develop this tumor, but some evidence should have been uncovered in careful follow-up studies of the more than 50,000 people who have participated in the diuretic

3 treatment trials. There has been no evidence in these carefully controlled studies of an increase in renal cell carcinoma. Additional and better data must be gathered before advising against the use of medications that have proven so helpful in reducing cardiovascular disease. Dr. Messerli might pause to reflect on the reserpine cancer scare based on case-control and retrospective studies. This proved not to be the case after careful review. He might reflect on the calcium channel blocker cancer connection, which he took a strong stand against because it was based on retrospective case-control data. There may or may not be some validity to some of these claims, but there are not enough data to warrant his recommendations. RECENT TRIALS WITH BETA-BLOCKERS Finally, to follow up on the argument that beta-blockers are relatively contraindicated in the elderly or in diabetic patients, it is of interest to review results of several recent studies. In 1 trial, a beta-blocker based treatment program was compared with an ACE inhibitor based treatment program in hypertensive type II diabetics (14). Large numbers of patients in both groups received a diuretic. The beta-blocker based treatment program produced a reduction in morbidity and mortality similar to that noted in the ACE inhibitor based program in patients who achieved lower blood pressures. In the other trial, a similar reduction in cardiovascular events was noted in a beta-blocker based compared with an ACE inhibitor based treatment program (15). It is difficult to divide patients in many of these trials into those on monotherapy and those on several medications. Almost all of the trials since the 1960s have been multidrug studies (hence the move today to use combination therapy rather than monotherapy). A careful review of the available evidence indicates that the use of beta-blockers reduces cardiovascular events and is not contraindicated in the elderly or in diabetic patients. WHY PHYSICIANS MAY NOT BE FOLLOWING GUIDELINES I believe that Dr. Messerli's explanation as to why physicians have not followed JNC guidelines to use beta-blockers or diuretics as initial treatment has very little to do with the analyses that he and his colleagues have performed. One reason for the lack of compliance may be that for many years he and others advised physicians that these agents, especially the diuretics, caused metabolic changes. Physicians were told to avoid their use because of lipid or glucose abnormalities or because the clinical trials in which they were used had failed to report a reduction in coronary heart disease events. In addition, there was heavy promotion of newer agents and lack of detailing and sampling of diuretics and betablockers. The fact that few symposia or monographs have highlighted these older medications also contributed to their declining usage. The use of diuretics and beta-blockers has increased in the past 6 to 9 months as more data from well-controlled comparative trials are published demonstrating that these drugs are as effective as other agents in reducing cardiovascular morbidity and mortality. MARVIN MOSER, MD Yale University School of Medicine

4 1. Messerli FH. Antihypertensive therapy: beta-blockers and diuretics why do physicians not always follow guidelines? BUMC Proceedings 2000;13: The fifth report of the Joint National Committee on detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1993;153: The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157: Moser M, Hebert PR. Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. J Am Coll Cardiol 1996;27: Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350: Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, Kappagoda T, Rocco MV, Schnaper HW, Sowers JR, Bond MG. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA 1996;276: Rosei EA, Dal Palu C, Leonetti G, Magnani B, Pessina A, Zanchetti A. Clinical results of the Verapamil in Hypertension and Atherosclerosis Study. VHAS Investigators. J Hypertens 1997;15: Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. National Intervention Cooperative Study in Elderly Hypertensives Study Group. Hypertension 1999;34: Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ 1992;304: Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27: The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353: Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, et al. Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group. JAMA 1993;270: Materson BJ, Reda DJ, Cushman WC. Department of Veterans Affairs single-drug therapy of hypertension study. Revised figures and new data. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Am J Hypertens 1995;8: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317: Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO,

5 Bjorck JE. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353: n his article, Antihypertensive therapy: beta-blockers and diuretics why do physicians not always follow guidelines? Dr. Messerli once again provides a reality check that should lead to a reexamination of current practices. He aims his criticisms mainly at 2 targets: first, the use of beta-blockers for hypertension in the elderly; second, the use of diuretics in less-than-elderly women with hypertension. I believe that Dr. Messerli's first criticism is correct and should lead to a change in the approach toward treatment of hypertension in the elderly. On the other hand, his second criticism should be taken with a large grain of salt, which in turn points out why diuretics will often need to be used in virtually all hypertensive patients: they consume too much salt. The use of beta-blockers in the elderly as monotherapy was known to be ineffective in the 1997 Joint National Committee report, in which they were recommended only in combination with a diuretic (1). Moreover, they were recommended, along with diuretics, as initial therapy only in patients with uncomplicated hypertension and with certain coexisting comorbidities, i.e., postmyocardial infarction, angina, atrial tachycardia, essential tremor, hyperthyroidism, migraine, and postoperative hypertension. Since Joint National Commission VI was composed, beta-blockers also have been found to be useful in congestive heart failure. Dr. Messerli describes the data denying their value in uncomplicated hypertension in the elderly. In truth, there are no such patients, since age >60 is a risk factor that immediately puts patients into a complicated class. In the Framingham population, only 2% of the entire hypertensive group were classified as uncomplicated, and they were all women with borderline hypertension (2). The use of beta-blockers, however, certainly can be defended in patients of any age with the comorbidities listed above. So, let's not throw out the baby with the beta-blockers: in the postmyocardial infarction patient, a beta-blocker should almost always be given, regardless of age. And, in passing, let's not blame them for erectile dysfunction: in the only comparative trial, diuretics and not beta-blockers were the only drugs that increased the frequency of impotence beyond that seen with placebo (3). As to the second major criticism, the use of diuretics in middle-aged and younger women, I have major reservations. Long-term diuretic use may increase the risk of renal cell cancer, although some find no such evidence (4) and others find increased cancers in hypertensive patients regardless of therapy (5). Even if diuretics do increase renal cell cancer, the relative risk is extremely small, so that many more patients would be helped than hurt. The situation is analogous to oral contraceptives and strokes: a few women are hurt but many more are saved by use of oral contraceptives.

6 Every day I see patients whose blood pressure is uncontrolled because they are not receiving a diuretic. Lack of a diuretic is the most common cause for resistant hypertension in patients who are compliant with their physician's prescribed regimen (6). In the absence of a diuretic, reactive sodium retention in the presence of excessive sodium intake and often coexisting renal damage overfills the intravascular volume, negating the antihypertensive efficacy of virtually all other drugs. If the middle-aged woman will restrict dietary sodium to half or less of usual intake, a diuretic may not be required. But, absent that maneuver, patients of either gender and at any age should not be denied a diuretic if it is needed to bring their hypertension under adequate control. NORMAN M. KAPLAN, MD Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas 1. Joint National Committee. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157: Lloyd-Jones DM, Evans JC, Larson MG, O'Donnell CJ, Wilson PW, Levy D. Cross-classification of JNC VI blood pressure stages and risk groups in the Framingham Heart Study. Arch Intern Med 1999;159: Grimm RH Jr, Grandits GA, Prineas RJ, McDonald RH, Lewis CE, Flack JM, Yunis C, Svendsen K, Liebson PR, Elmer PJ. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study. Hypertension 1997;29(1 Pt 1): Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr. Rising incidence of renal cell cancer in the United States. JAMA 1999;281: Shapiro JA, Williams MA, Weiss NS, Stergachis A, LaCroix AZ, Barlow WE. Hypertension, antihypertensive medication use, and risk of renal cell carcinoma. Am J Epidemiol 1999;149: Kaplan NM. Treatment of hypertension. In Clinical Hypertension, 7th ed. Baltimore: Williams & Wilkins, 1998:181.

Large therapeutic studies in elderly patients with hypertension

(2002) 16 (Suppl 1), S38 S43 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Large therapeutic studies in elderly patients with hypertension Centro Clinico Profesional