The thiazide diuretics and more recently the

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1 1-119 Traditional First-Line Therapy Overview of Medical Benefits and Side Effects Ray W. Gifford Jr. and Raymond A. Borazanian When diuretic-based stepped care was first advocated for the treatment of hypertension, there were fewer classes of antihypertensive medication than there are today. In 1984, the third Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC) for the first time suggested an alternative initial treatment with a /3-blocker in selected hypertensive patients, and the fourth JNC report has recommended the alternatives of calcium channel blockers or angiotensin converting enzyme inhibitors for step-one therapy as well. However, only the diuretic drugs and /3-blockers have been shown to reduce cardiovascular morbidity and mortality in prospective, long-term, controlled trials. Moreover, 30 years' experience with diuretic agents and 20 years' experience with /3-blockers have defined the advantages, disadvantages, and potential side effects of these drugs more precisely than is possible for newer agents. The diuretic drugs and /3-blockers remain excellent choices in the management of hypertension. {Hypertension 1989;13(suppl I):I-119-I-124) The thiazide diuretics and more recently the /3-blockers have been the traditional firststep agents in the stepped care approach to therapy of arterial hypertension. Stepped care therapy was not intended to be a rigid algorithm for selection of drugs that had to be followed in all cases, but rather, this therapeutic approach was intended as a set of guidelines for treatment based on experience and arrived at by consensus. When stepped care was introduced, the only options other than diuretic agents for initial therapy were methyldopa, reserpine, guanethidine, or hydralazine, and the diuretic drugs were much preferable to any of the other drugs. In 1984, the third Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC) suggested an alternative: either a thiazide diuretic drug at less than a full dose or a /3-blocker at less than a full dose. 1 The fourth JNC report recommends other alternatives for step one, including calcium channel blockers and angiotensin converting enzyme inhibitors. 2 Nevertheless, 30 years after the introduction of thiazide diuretic agents and 20 years after the introduction of /3-blockers, these agents remain a viable choice for step-one therapy and possess many attributes of the ideal step-one drug (Table 1). From the Department of Hypertension and Nephrology, The Cleveland Clinic Foundation, Cleveland, Ohio. Address for reprints: Ray W. Gifford Jr., MD, Department of Hypertension and Nephrology, Desk A-101, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH Advantages of Diuretic Agents and /3-Blockers as Step-One Drugs Diuretic drugs are effective as monotherapy in at least 50% of unselected mildly hypertensive patients (Table 2). In the Veterans Administration doubleblind study comparing propranolol and hydrochlorothiazide for the initial treatment of hypertension in men with diastolic blood pressures between 95 and 114 mm Hg, 65.5% of those receiving hydrochlorothiazide achieved a goal diastolic blood pressure of less than 90 mm Hg compared with 52.8% of those receiving propranolol (p<0.03). 3 Black patients responded better to hydrochlorothiazide than to propranolol. 4 /3-Blockers seem to be more effective in younger patients than in older patients. 5 Diuretic agents are easy to titrate and are less expensive than the alternatives including the /3- blockers. The usual initial dosage is 12.5 or 25 mg/ day of hydrochlorothiazide or its equivalent in other diuretic drugs. If this dose is not effective, the dosage can be increased to 50 mg/day. Above the 50-mg/day dosage, the dose-response curve becomes flat, and most authorities agree that there is no advantage to a further increase. 6-9 The next step is to add another drug to the regimen or to use a substitute. This approach results in fewer office visits for the patient and consequent lower health care costs. Unfortunately, cost is a real concern for many patients, particularly those on limited incomes. Most diuretic agents and some /3-blockers can be given as a once-daily dose, a regimen that enhances patient compliance. Titration usually requires more than two or three steps for most j8-blockers except for atenolol ( mg).

2 1-120 Supplement I Hypertension Vol 13, No 5, May 1989 TABLE 1. Characteristics of the Ideal Step-One Drug Safe Effective as monotherapy (should normalize blood pressure as the sole agent for 50% of patients with mild hypertension) Well tolerated by the majority of patients (few side effects that necessitate cessation of therapy) Inexpensive Dose easy to titrate (no more than a two- or three-step titration) Desirable hemodynamic effects (for most hypertensive patients, this means a reduction in total peripheral resistance with little or no change in cardiac output; for the few patients who have hyperkinetic circulation, it would mean a reduction in cardiac output with little or no effect on total peripheral resistance) Should reduce cardiovascular morbidity and mortality in controlled treatment trials Minimal drug-drug interactions Should augment the effect of other antihypertensive agents that might be necessary subsequently Should not produce pseudotolerance (occult salt and water retention, expansion of extracellular fluid volume, and elevation of blood pressure) Long-acting (one dose daily is a distinct advantage to enhance compliance) Minimal contraindications In cases where diuretic drugs are not effective as monotherapy, they have the virtue of potentiating the effect of any agent that may subsequently be added to the regimen. In the case of the direct vasodilators and the sympathetic inhibitors (other than the /3-blockers), concomitant use of a diuretic drug will prevent the gradual accumulation of sodium and water that leads to the pseudotolerance that occurs when the vasodilators or sympathetic inhibitors are used alone. 10 Prevention of salt and water accumulation cannot entirely explain this enhancing effect of the diuretic drugs, since such enhancement also occurs when the diuretic drugs are given in combination with /3-blockers, calcium channel blockers, and converting enzyme inhibitors, which do not cause pseudotolerance. In any event, when a diuretic drug is included in the regimen, lower doses of other drugs are effective, and side effects of other drugs can be minimized. This is also true to a lesser extent for the /3-blockers. TABLE 2. Advantages of Diuretic Drugs and /3-Blockers as Step-One Therapy Advantages of a Diuretic Drug Inexpensive Effective in 50% of mild hypertensive patients One dose daily Easy to titrate Well tolerated Enhances potency of all other agents Effective in reducing cardiovascular mortality No pseudotolerance The precise mechanism of the hypotensive action of the diuretic agents is not known. It has been established that these drugs reduce plasma volume during the first few weeks of therapy; thereafter, the decrease in plasma volume is less obvious but seems to persist as long as the diuretic drug is administered." During chronic therapy, diuretic agents reduce total peripheral vascular resistance but have no effect on cardiac output. This effect makes a diuretic drug hemodynamically appropriate for most patients with essential hypertension, which is characterized by increased total peripheral resistance and normal cardiac output. Most /3-blockers reduce blood pressure by reducing cardiac output and by leaving total peripheral resistance unchanged, making them ideal for the treatment of young hypertensive individuals with hyperkinetic circulation characterized by increased cardiac output. The /3-blockers with intrinsic sympathomimetic activity (pindolol and acebutolol) and especially the /3-blocker with a-adrenergic receptorblocking properties (labetalol) decrease total peripheral resistance with a lesser effect on cardiac output than do the /3-blockers without these properties. The major advantage of the /3-blockers that is not shared by any other class of antihypertensive drugs is the /3-blockers' unique cardioprotective effect after a myocardial infarction, although /3-blockers with intrinsic sympathomimetic activity may not have this cardioprotective effect. /3-Blockers also have an antianginal effect, some have a prophylactic effect against migraine, and they may also be helpful in controlling senile tremor. Only the diuretic agents and the /3-blockers 12 -' have been shown to decrease total cardiovascular morbidity and mortality in long-term prospective trials (Table 3). The European Working Party on Hypertension in the Elderly trial 21 is the only placebo-controlled clinical trial that demonstrated a significant reduction in coronary mortality No placebo-controlled trial with a /3-blocker as step-one therapy has shown a primary protective effect against coronary events, although these agents have been shown to be effective in the secondary prevention of coronary events Nevertheless, it is impressive that between 1970 and 1985 the US age-adjusted death rate for coronary disease and Advantages of a /3-Blocker Effective in =50% of mild hypertensive patients Cardioprotective after myocardial infarction Antianginal drug Reduces cardiac output in hyperkinetic circulation Reduces cardiovascular mortality One dose daily No pseudotolerance Migraine prophylaxis Reduces senile tremor

3 Gifford and Borazanian Traditional First-Line Therapy TABLE 3. Large, Randomized, Clinical Trials Showing a Significant Reduction in Cardiovascular Morbidity or Mortality Diuretic-based stepped care VA Cooperative Trial, 1966* 16 VA Cooperative Trial, 1970* 17 US Public Health Service Trial* 18 Hypertension Detection and Follow-Up Program 19 Australian National Trial* 20 European Working Party on Hypertension in the Elderly* 21 Diuretic and f}-blocker-based stepped care Medical Research Council Trial* 22 /3-Blocker-based stepped care Coope and Warrender 23 VA, Veterans Administration. *Placebo-controlled. stroke, conditions associated with uncontrolled hypertension, decreased by 35% and 48%, respectively. The decrease in the mortality rates for these diseases can be attributed to a variety of factors, one of which is the control of hypertension, and during this time, most hypertensive patients were treated with diureticbased stepped care. No other class of drugs has been as intensely scrutinized for so long as the diuretic drugs, and today, they are the standard against which other classes of agents must be measured. Side Effects With the possible exception of the calcium channel blockers and converting enzyme inhibitors, diuretic agents and /3-blockers produce fewer symptomatic side effects than other classes of antihypertensive drugs and are well tolerated by most patients. In the Medical Research Council trial 25, the most troublesome side effect of bendrofluazide was sexual dysfunction, which was reported by 22.6% of the men receiving this diuretic agent for 2 years TABLE 4. Prevalence of Symptoms at 2 Years in the Medical Research Council Trial Subjects Men Dizziness Muscle pain Slowed walking Exertional dyspnea Headaches Cold or numb digits Paresthesias Dry mouth Blocked or runny nose Vomiting or nausea Impotence (Percent,* n=l,130) Bendrofluazide Propranolol t t compared with 10.1% of the men receiving placebo (p<0.05) and 13.2% of the men receiving propranolol. This side effect, however, was reversible. Sexual dysfunction was the most frequent reason that men withdrew from diuretic therapy, while nausea, dizziness, or headache were the most frequent side effects cited by women. In all, 17.1% of men and 12.8% of women were withdrawn from diuretic therapy during the 5-year period of the trial, although not all subjects were withdrawn because of symptomatic side effects. In the propranolol group, 15.5% of the men and 18% of the women were withdrawn. Table 4 lists the most common side effects reported by participants in this study. In the Systolic Hypertension in the Elderly Program 1-year feasibility trial, 26 none of the symptomatic side effects reported by subjects receiving chlorthalidone mg/day were significantly more frequent than those in the placebo group. Only six of 443 participants on chlorthalidone and two of 108 participants in the placebo group were withdrawn from the study because of symptomatic side effects. Diuretic drugs were reserved for the second step if blood pressure could not be controlled by monotherapy in a double-blind study that compared the effects of propranolol, methyldopa, and captopril on various parameters of quality of life in 626 men. 27 The investigators found that captopril interfered with quality of life less frequently than did the others. The addition of a diuretic agent detracted from the quality of life, but without the diuretic, the study might not have been completed because 36%, 31%, and 22% of patients in the captopril, methyldopa, and propranolol groups, respectively, required the addition of a diuretic agent by the 16th week to maintain normotension. Disadvantages of Diuretic Agents and /3-Blockers as Step-One Drugs The major concern about diuretic agents concerns their metabolic side effects: hypokalemia, Women (Percent,* n=958) Placebo Bendrofluazide Propranolol t lt t Placebo *Reported in questionnaire. tp<0.05. Significance levels refer to prevalence rates for each active drug separately compared with those for all control patients. The figures do not indicate comparisons between the two active drugs. Reprinted from The Lancet (1981 ;2: ), Copyright 1981, Little, Brown and Company.

4 1-122 Supplement I Hypertension Vol 13, No 5, May 1989 TABLE 5. Disadvantages of a Diuretic Drug as Step-One Therapy Metabolic side effects Decreases potassium and magnesium Increases urate, calcium, glucose, and lipids Disadvantages of a /3-Blocker as Step-One Therapy Does not reduce total peripheral resistance Central nervous system side effects Metabolic side effects Decreases high density lipoprotein cholesterol Increases glucose Sexual dysfunction in men Multiple contraindications and precautions Greater than first-degree heart block Asthma Congestive heart failure Intermittent claudication Insulin-dependent diabetes mellitus hyponatremia, hyperuricemia, hyperglycemia, and hyperlipidemia. Hypokalemia is not usually a problem because it can easily be avoided by the concomitant use of a potassium-sparing diuretic agent if the patient is at risk of ventricular ectopy due to digitalis therapy, a history of cardiac arrhythmias, or an abnormal resting electrocardiogram, particularly left ventricular hypertrophy. If the patient is not at particular risk, diuretic-induced hypokalemia has not been harmful. 28 Hyperuricemia is not harmful if the patient is asymptomatic, 29 and hypercalcemia is not life-threatening and occurs only infrequently. Long-term use of thiazide diuretic agents can increase the concentration of fasting plasma glucose and can impair glucose tolerance, but these changes usually do not reach abnormal levels. Glucose tolerance is not usually impaired during the 1st year of thiazide treatment, 30 although impairment was apparent at 10 weeks in a Veterans Administration study 31 but was only apparent at 2-3 years in the European Working Party on Hypertension in the Elderly trial 32 and after 6 years in a Medical Research Council study. 33 At 14 years, glucose tolerance had deteriorated even more than at 6 years. 34 These changes were reversible after the diuretic agent was discontinued 31 even after 14 years. 34 On the other hand, Berglund and Andersson 35 found that fasting blood glucose and 1-hour blood glucose concentrations decreased after 6 years of treatment with bendroflumethiazide. Although the thiazide diuretic agents can aggravate preexisting diabetes in some susceptible patients and can precipitate diabetes in predisposed persons, 36 most diabetic patients can tolerate a thiazide diuretic drug with little or no change in the control of their diabetes. The most serious criticism of diuretic agents concerns their effects on serum lipids. Most shortterm studies have shown an increase in serum cholesterol, triglycerides, and low density lipoprotein cholesterol in previously untreated individuals when diuretic therapy is started These effects occur in about 60% of patients, with the other 40% experiencing no adverse effect on their serum lipid levels. 37 These effects are blunted by adjustments in the diet 38 and appear to be dose related. 37 In most studies, higher doses of diuretic agents were used than are now customarily prescribed. It is now unusual to use more than 50 mg hydrochlorothiazide or its equivalent per day. In long-term trials, serum cholesterol concentrations have decreased to or below baseline after the 1st year The /3-blockers have the disadvantage of producing a high incidence of central nervous system side effects, which may not be related to relative lipophilicity. 43 In the Veterans Administration Trial, 3 propranolol caused significant increases in the concentrations of total cholesterol and serum triglycerides, which (unlike the effect of hydrochlorothiazide) persisted for the duration of the 58-week trial. In this same study, the adverse effect of propranolol on glucose tolerance persisted longer than that produced by hydrochlorothiazide after conclusion of the trial. 31 The high density lipoprotein cholesterol has been suppressed by /3-blocker therapy even when the total serum cholesterol concentration has not been significantly altered. The intrinsic sympathomimetic activity /3-blockers and the a- and js-blocking drug labetalol apparently do not have an adverse effect on serum lipids, yet these agents have not been shown to have the cardioprotective effect after a myocardial infarction that the conventional /3-blockers have. Summary The traditional drugs for initial therapy of hypertension, the diuretic agents and /3-blockers, have many of the desirable attributes of the ideal step-one drug, not the least of which is their demonstrated effect in reducing cardiovascular morbidity and mortality. Time and experience may well temper the original enthusiasm for calcium channel blockers and converting enzyme inhibitors as step-one agents. References 1. The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure: The 1984 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1984; 144:

5 Gifford and Borazanian Traditional First-Line Therapy The Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure: The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: Veterans Administration Cooperative Study Group: Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. II. Results of long-term therapy. JAMA 1982;248:20O4-20ll 4. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. I. Results of short-term titration with emphasis on racial differences in response. JAMA 1982;248: Buhler FR, Burkart F, Lutold BE, Rung M, Marbet G, Pfisterer M: Antihypertensive /3-blocking action as related to renin and age: A pharmacologic tool to identify pathogenetic mechanisms in essential hypertension. Am J Cardiol 1975; 36: Berglund G, Andersson P: Low doses of hydrochlorothiazide in hypertension. Antihypertensive and metabolic effects. EurJ Clin Pharmacol 1976;10: Tweedale MG, Oglivie RI, Ruedy J: Antihypertensive and biochemical effects of chlorthalidone. Clin Pharmacol Ther 1977;22: Materson BJ, Oster JR, Michael UF, Bolton SM, Burton ZC, Stambaugh J, Morledge J: Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose. Clin Pharmacol Ther 1978;24: Vardan S, Mehrotra KG, Mookherjee S, Willsey GA, Gens JD, Green DE: Efficacy and reduced metabolic side effects of a 15-mg chlorthalidone formulation in the treatment of mild hypertension. A multicenter study. JAMA 1987; 258: Finnerty FA, Davidov M, Mroczek WJ, Gavrilovich L: Influence of extracellular fluid volume on response to antihypertensive drugs. Circ Res 1970;26/27(suppl I):I Tarazi RC: Diuretic drugs: Mechanisms of antihypertensive action, in Onesti G, Kim KE, Moyer JH (eds): Hypertension: Mechanisms and Management. Orlando, Fla, Grune & Stratton, Inc, 1973, pp /3-Blocker Heart Attack Trial Research Group: A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 1982;247: /3-Blocker Heart Attack Trial Research Group: A randomized trial of propranolol in patients with acute myocardial infarction. II. Morbidity results. JAMA 1983;253: Norwegian Multicenter Study Group: Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981,304: Pedersen TR, for the Norwegian Multicenter Study Group: Six-year follow-up of the Norwegian Multicenter Study on timolol after acute myocardial infarction. N Engl J Med 1985;313: Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. I. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202: Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressures averaging 90 through 114 mm Hg. JAMA 1970; 213: Smith WM: Treatment of mild hypertension. Results of a 10-year intervention trial. US Public Health Service Cooperative Study Group. Circ Res 1977;4O:98-IO4 19. Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the Hypertension Detection and Follow-up Program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979;242: Report by the Management Committee: The Australian Therapeutic Trial in Mild Hypertension. Lancet 1980;l: Amery A, Birkenhager W, Brixko P, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Dollery C, Fagard R, Forette F, Forte J, Hamdy R, Henry JF, Joossens JV, Leonetti G, Lund-Johansen P, O'Malley K, Petrie J, Strasser T, Tuomilehto J, Williams B: Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet 1985;1: Medical Research Council Working Party: MRC trial of treatment of mild hypertension: Principal results. Br Med J 1985;291: Coope J, Warrender T: Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J 1986;293: MacMahon SW, Cutler JA, Furberg CD, Payne GH: The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: A review of randomized controlled trials. Prog Cardiovasc Dis 1986; 29(suppl 1): Report of the Medical Research Council Working Party on Mild to Moderate Hypertension: Adverse reaction to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981 ;2: Hulley SB, Furberg CD, Gurland B, McDonald R, Perry HM, Schnaper HW, Schoenberger JA, Smith WM, Vogt TM: Systolic Hypertension in the Elderly Program (SHEP): Antihypertensive efficacy of chlorthalidone. Am J Cardiol 1985;56: Croog SH, Levine S, Testa MA, Brown B, Bulpitt CJ, Jenkins CD, Klerman GL, Williams GH: The effects of antihypertensive therapy on the quality of life. N Engl J Med 1986;314: Madias JE, Madias NE, Gavras H: Nonarrhythmogenicity of diuretic-induced hypokalemia. Its evidence in patients with uncomplicated hypertension. Arch Intern Med 1984; 144: Langford HG, Blaufox MD, Borhani NO, Curb JD, Molteni A, Schneider KA, Pressel S: Is thiazide-produced uric acid elevation harmful? Analysis of data from the Hypertension Detection and Follow-up Program. Arch Intern Med 1987; 147: Kohner EM, Dollery CT, Lowy C, Schumer B: Effect of diuretic therapy on glucose tolerance in hypertensive patients. Lancet 1971 ;l: Veterans Administration Cooperative Study Group on Antihypertensive Agents: Propranolol or hydrochlorothiazide alone for the initial treatment of hypertension. IV. Effect on plasma glucose and glucose tolerance. Hypertension 1985; 7: Amery A, Berthaux P, Bulpitt C, Deruyttere M, De Schaepdryver A, Dollery C, Fagard R, Forette F, Hellemans J, Lund-Johansen P, Mutsers A, Tuomilehto J: Glucose intolerance during diuretic therapy. Results of trial by the European Working Party on Hypertension in the Elderly. Lancet 1978;l: Lewis PJ, Kohner EM, Petrie A, Dollery CT: Deterioration of glucose tolerance in hypertensive patients on prolonged diuretic treatment. Lancet 1976;l: Murphy MB, Lewis PJ, Kohner E, Schumer B, Dollery CT: Glucose intolerance in hypertensive patients treated with diuretics: A fourteen-year follow-up. Lancet 1982; 2: Berglund G, Andersson A: /3-Blockers or diuretics in hypertension? A six year follow-up of blood pressure and metabolic side effects. Lancet 1981 ;1: Goldner MG, Zarowitz H, Akgun S: Hyperglycemia and glycosuria due to thiazide derivatives administered in diabetes mellitus. N Engl J Med 1960;262: Ames RP, Hill P: Elevation of serum lipids during diuretic therapy of hypertension. Am J Med 1976;61: Grimm RH, Leon AS, Hunninghake DB, Lenz K, Hannan P, Blackburn H: Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients. A doubleblind trial. Ann Intern Med 1981;94:7-11

6 1-124 Supplement I Hypertension Vol l3, No 5, May Goldman Al, Steele BW, Schnaper HW, Fritz AE, Frohlich ED, Perry HM: Serum lipoprotein levels (luring chlorthalidone therapy VA-NHLB1 cooperative study on antihypertensive therapy: Mild hypertension. JAMA 1980; 244: Helgeland A, Hjermann I, Leren P, Enger S, Holme I: High-density lipoprotein cholesterol and antihypertensive drugs: The Oslo study. Br Med J 1978;2: Williams WR, Schneider KA, Borhani NO, Schnaper HW, SlotkoffLM, Ellefson RD: The relationship between diuretics and serum cholesterol in Hypertension Detection and Follow-up Program participants. Am J Prev Med 1986; 2: Amery A, Birkenhager W, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Doliery C, Fagard R, Forette F, Forte J, Hamdy R, Leonetti G, O'Malley K, Tuomilehto J: Influence of antihypertensive therapy on serum cholesterol in elderly hypertensive patients. Results of trial by the European Working Party on High Blood Pressure in the Elderly (EWPHE). Ada Cardiol 1982;37: Gengo FM, Huntoon L, McHugh WB: Lipid-soluble and water-soluble /3-blockers. Comparison of the central nervous system depressant effect. Arch Intern Med 1987; 147:39-43 KEY WORDS stepped care diuretic therapy adrenergic receptor blockade /3-blockers