Controversies in Hypertension: Mild Hypertension, Isolated Systolic Hypertension, and the Choice of a Step One Drug

Transcription

1 Clin. Cardiol. 6, 1-10 (1983) Clinical Cardiology Publishing Co., Inc. Brief Review Controversies in Hypertension: Mild Hypertension, Isolated Systolic Hypertension, and the Choice of a Step One Drug M. D. CRESSMAN, D. 0., R. W. GIFFORD, JR., M.D. Department of Hypertension and Nephrology, Cleveland Clinic Foundation, Cleveland, Ohio, USA Summary: The realization that cardiovascular morbidity and mortality increases in patients with mild elevation of either systolic or diastolic blood pressure has led to a consideration to treat millions of patients with mild diastolic or isolated systolic hypertension. The cost of administering a successful antihypertensive treatment program and the potential adverse effects of pharmacologic agents is of great concern. It has been emphasized that the risk of premature mortality differs in individual patients according to the number of associated cardiovascular risk factors at any level of blood pressure. This has led to a suggestion that only high risk patients be treated. However, a significant number of low risk patients with mild hypertension develop a more severe or complicated form of their disease even over a follow-up period of five to ten years. There is no good way to identify these patients. Trials of antihypertensive therapy suggest a beneficial effect of blood pressure lowering in mild hypertension. No trials of antihypertensive therapy in elderly patients with isolated systolic hypertension have been reported, but the elevation in systolic blood pressure appears to be an independent risk factor for cardiovascular mortality. Even the choice of the first step agent in treatment is debatable. Diuretics or beta blockers effectively lower blood pressure in the majority of hypertensive patients, particularly if modest dietary Address for reprints: Ray W. Gifford, Jr., M.D. Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 42106, USA Received: November 18, 1982 Accepted: November 24, 1982 sodium restriction is achieved. The incidence of side effects, either symptomatic or biochemical, is similar but diuretics are unquestionably cheaper and probably more effective. Successful application of an antihypertensive treatment program may continue to reduce our unacceptably great incidence of cardiovascular disease. Key words: hypertension, systolic, diastolic, treatment, diuretics, beta blockers, isolated, elderly Introduction There has been a growing awareness by both physicians and the community that hypertension is a major treatable health problem. Epidemiologic data clearly indicate that even mild hypertension (diastolic blood pressure mmhg) is associated with premature mortality. Elderly patients with isolated systolic hypertension share this risk. The cost of administering a successful antihypertensive treatment program to some 30 million Americans with mild diastolic hypertension and the risks of drug toxicity have led to considerable debate regarding the efficacy of drug treatment in the management of this large group of patients. Even the choice of the first step of drug therapy (diuretics versus beta blockers) continues to be debated. Some clinical trials of drug therapy in patients with mild diastolic hypertension suggest that blood pressure reduction reduces cardiovascular mortality (Hypertension Detection and Follow-up Program Cooperative Group, 1979a). A controlled trial of antihypertensive therapy in elderly

2 2 Clin. Cardiol., Vol. 6, January 1983 patients with isolated systolic hypertension has only recently been initiated. and the effects of blood pressure reduction on mortality have not been reported. The decision to treat patients with mild diastolic or isolated systolic hypertension requires a knowledge of the risks of untreated hypertension when balanced against the costs, benefits, and potential hazards of antihypertensive therapy. Should Mild Diastolic Hypertension be Treated? Hypertension and Premature Mortality The largest body of epidemiologic data relating mild hypertension to premature mortality has been obtained by the insurance industry. In 1980, the Society of. Actuaries and the Association of Life Insurance Medical Directors of America published the results of their analysis of the relationship between blood pressure elevation and mortality in over four million policy holders (Society of Actuaries and the Association of Life Insurance Medical Directors of America, 1980). The data underscore the role of even small increments in systolic or diastolic blood pressure in the generation of premature mortality (Table I). Men with diastolic blood pressures (DBP) ranging from 88 to 92 mmhg had a 37% increase in the ratio of actual to predicted mortality when compared to men whose diastolic blood pressures were mmhg. Similar trends were apparent in women. Pooling of data from several population studies (the Albany Civil Servant, Chicago Peoples Gas Company, TABLE I Actual to predicted mortality by systolic and diastolic blood pressures combined for all ages li Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) Percent actual to predicted mortality Men Women III I g I II Blood Pressure Study Society of Actuaries and Association of L.ife Insurance Medical Directors of America (Nov. 1990). Relationship of diastolic blood pressure to mortal- TABLE II itya Death ratel 1000 Coronary Diastolic Sample heart (mmhg) size disease Stroke All < ~ a The Pooling Project adapted from Circulation 42. A-55. ( 1970) Chicago Western Electric Company, Framingham community, Tecumseh community) supports the impression that mild hypertension adversely affects prognosis (Pooling Project Research Group, 1978). All-cause mortality over a I O-year period of follow-up increased from 5.4% in middle-aged men (30-59 years at entry) when diastolic blood pressures were mmhg to 8.2% when diastolic blood pressures were 10 mmhg higher (Table II). Coronary heart deaths occurred in 2% and 3.8%, respectively, of the men at these blood pressure levels (Atherosclerosis Study Group and Epidemiology Study Group, 1970). Advocates of an aggressive approach to blood pressure reduction point to the fact that mortality was 50% higher in patients at the higher level of DBP. Critics wold emphasize that the difference is less than 3%. The Pooling Project Research Group emphasized that the bulk of the excess in coronary heart deaths occurred in patients whose diastolic blood pressures were less than 105 mmhg. Thus, the greatest potential for a reduction in coronary heart mortality for the entire population exists in the group of patients with mild hypertension. Considerable variability in the risk of high blood pressure exists among individual patients at a given blood pressure level depending on the presence or absence of associated cardiovascular risk factors such as age, sex, smoking habits, hypercholesterolemia, glucose intolerance, and/or left ventricular hypertrophy by electrocardiography (Kannel, 1974). Madhavan and Alderman (1981) have analyzed this variability in risk among patients at a given blood pressure level utilizing data obtained from the Framingham study. They deduced that only I of year-old nonsmoking females with normal electrocardiograms, normal cholesterol levels, and normal glucose tolerance would benefit from having systolic blood pressure reduced from 165 mmhg to 135 mmhg over a 15-year follow-up period. Although this may be true, it should not be used as a reason to withhold therapy in mildly hypertensive patients. Fifteen years is

3 M. D. Cressman and R. W. Gifford: Controversies in hypertension 3 not a lifetime for a 35-year-old woman and silent atherosclerosis may progress in this time period. It must be emphasized that we have no good way to identify those patients who will develop evidence of target organ involvement which then adversely effects prognosis. Trials of Drug Thenpy in Mild Hypertension Those who oppose aggressive management of mild hypertension have argued that blood pressure reduction, particularly with pharmacologic agents, does not necessarily alter prognosis. They point to the cost, inconvenience, or potential hazards and toxicity of antihypertensive agents. Indeed, the decision to treat involves a major commitment by both the patient and the physician if the treatment program is to be effective. Over the last two decades, a number of trials of drug therapy have been conducted to determine the safety and efficacy of pharmacologic therapy in the management of patients with mild hypertension. In 1970, the Veterans Administration reported the results of a placebo controlled trial of antihypertensive therapy in patients with diastolic blood pressures ranging from mmhg (Veterans Administration Cooperative Study Group, 1970). Among the 523 patients entered into this study, 170 had DBPs ranging from mmhg. Of these patients, 86 received active drug therapy while 84 placebo-treated patients served as controls. After 3 1 /2 years of follow up, 16.3% of the drug treated patients with mild hypertension developed "morbid events" related to hypertension. This compared favorably to the 25% incidence of morbid events in the placebo-treated group. However, complications of coronary artery disease were not prevented and only patients who were over the age of 50 years or had cardiovascular-renal abnormalities at the time of entry derived significant benefit from drug therapy (Veterans Administration Cooperative Study Group, 1972). The Oslo study was a trial of drug therapy in men aged years with DBPs less than 110 mmhg who were free of evidence of cardiovascular disease at the time of entry (Helgeland, 1980). Patients with hypercholesterolemia or glucose intolerance were excluded from the study. The group consisted of 406 patients who received active drug therapy while 379 untreated patients served as controls. Over 17% of the untreated patients developed blood pressures exceeding 180/110 mmhg requiring therapy during the 5-year period of follow up. Major cerebrovascular events, fatal aortic dissection, congestive heart failure, and/or left ventricular hypertrophy developed in 4.5% of the untreated patients. These complications did not occur in the drug treated group. Thus, over 20% of these untreated low risk patients developed a more severe form of their disease or experienced serious hypertensive complications over a brief period of follow up. However, major coronary events occurred more frequently in the drug treated patients and minimized the benefit of drug therapy in the group as a whole. Helgeland (1980) speculated that the minor increases in serum cholesterol and triglyceride levels in the drug treated group accounted for the lack of prevention of coronary-related events. The National Heart Foundation of Australia conducted a prospective, placebo controlled trial of antihypertensive therapy in patients with mild hypertension (DBPs mmhg) in 3427 men and women aged years of at the time of entry into the study (The Management Committee, National Heart Foundation of Australia, 1980). The 1721 actively treated patients and 1706 placebo treated controls were free of evidence of cardiovascular disease at the beginning of the trial and were well matched for associated cardiovascular risk factors. Diastolic blood pressure was reduced by an average of 12.2 mmhg in the drug treated patients and 6.6 mmhg in the placebo treated group during a 4-year period of follow up. Diastolic blood pressure averaged 88.3 mmhg in the drug treated patients and 93.9 mmhg in the placebo treated patients. For the group of patients with diastolic blood pressures ranging from mmhg (756 drug treated and 763 placebo treated patients), all-cause mortality and hypertensive complications were reduced by 30% in the drug treated group. Freis (1982) has pointed out that the Australian trial did not include the important subgroup of patients with diastolic blood pressures ranging from mmhg. Women and patients less than 50 years of age did not derive a statistically significant benefit from drug therapy. Additionally, the apparent benefit of drug therapy noted after four years of follow up was not apparent after three years and eight months of follow up. It should be pointed out that the benefit of blood pressure reduction may have been underestimated in the Australian trial. Of the 763 placebo treated patients with diastolic blood pressures ranging from mmhg at the time of randomization, 33% had their blood pressure reduced to less than 90 mmhg during the trial. In this group, 9% of the drug treated patients did not achieve any blood pressure reduction during the course of the trial. Thus, a considerable overlap in blood pressure status was apparent in the placebo and drug treated groups. The recent report of the Hypertension Detection and Follow up Program Cooperative Group (HDFP) provides the best evidence that a systematic approach to blood pressure reduction in patients with mild hypertension decreases mortality (Hypertension Detection and Follow-up Program Cooperative Group, 1982). Of the 10,940 hypertensive patients identified in screening, 7825 had diastolic blood pressures ranging from mmhg (Hypertension Detection and Follow-up Program Cooperative Group, 1979a). Patients were randomly assigned to receive a free standardized program of antihypertensive therapy in specialized HDFP centers (SC group) or were referred to the usual sources of health care in the community (RC group).

4 4 C1in. Cardiol., Vol. 6, January 1983 TABLE III Comparison of stepped care (SC) and referred care (RC) in patients with diastolic blood pressures from mmhga % Cumulative % Reduction Sample size % Treated %at goal Average DBP All deaths mortality by Year SC RC SC RC SC RC SC RC SC RC SC RC SC group I a Hypertension Detection and Follow-up Program study adapted from JAMA 242,2562 (1979) The stepped care approach to antihypertensive therapy involved the sequential administration of diuretics, antiadrenergic agents, and vasodilators in order to reduce diastolic blood pressure to 90 mmhg or less in patients whose initial DBP was 100 mmhg or greater. A 10 mmhg reduction in DBP was the goal of therapy for patients with DBPs ranging from mmhg at entry. A diastolic blood pressure goal of 90 mmhg or less was attempted in the 25% of patients already receiving antihypertensive therapy at the time of randomization. A greater percentage of the SC patients received drug therapy and achieved their goal diastolic blood pressure in each year of follow up when compared to the RC group. The difference in DBP of approximately 5 mmhg between the SC and RC patients at the end of five years of follow up was associated with a 20.3% reduction in cumulative mortality in the SC group (Table III). The benefit of blood pressure reduction was apparent even when multivariate adjustments for the minor differences in entrance characteristics of the two groups were analyzed. Cerebrovascular and coronary heart deaths were reduced by 45 and 20%, respectively, in the SC group when compared to the RC group. Stepped care therapy reduced mortality by 27.6% in patients with diastolic blood pressures ranging from mmhg when target organ involvement was absent at the time of randomization (Hypertension Detection and Follow-up Program Cooperative Group, 1982). The presence of target organ involvement adversely affected prognosis in both the SC and the RC groups. Five-year mortality increased from 4.9% to 18.1 % in the entire subgroup (SC plus RC group) of patients with baseline diastolic blood pressures ranging from mmhg. Mortality was reduced by only 7.9% in the SC compared to the RC patients with diastolic blood pressures ranging from mmhg if target organ involvement was present at the initiation of the study. Freis (1982) has questioned the validity of considering the RC group as a "control" population because of differences in medical care that were provided to the SC and RC patients. Indeed, noncardiovascular mortality was reduced by 13% in the SC group compared to the RC group. Some of the mildly hypertensive patients originally randomized to the RC group may have developed more severe hypertension which adversely affected their prognosis. Nevertheless, no one can argue with the fact that blood pressure reduction utilizing a standardized approach to antihypertensive therapy was associated with a substantial reduction in mortality in the SC group. The data clearly demonstrates the danger of waiting for target organ involvement to develop before attempting to reduce blood pressure in patients with uncomplicated, mild hypertension. A significant percentage of untreated mildly hypertensive patients developed hypertensive retinopathy or increasingly severe hypertension. Successful antihypertensive therapy undoubtedly prevents this progression. In the Veterans Administration trial, 12% of the placebo treated patients developed hemorrhagic retinopathy or diastolic blood pressures exceeding 124 mmhg over a 38-month period of follow up. This never occurred in the actively treated patients (Veterans Administration Cooperative Study Group, 1970). During the 10-year trial of antihypertensive therapy conducted by the U.S. Public Health Service, approximately 18% of untreated patients with diastolic blood pressures ranging from mmhg developed hypertensive retinopathy or diastolic blood pressures greater than 130 mmhg. Drug treatment reduced the incidence to 0.5% (Smith, 1977). In the Australian trial, 12% of the placebo treated patients developed hypertensive retinopathy, systolic blood pressures greater than 199 mmhg, and/or diastolic blood pressures greater than 109 mmhg. This occurred even though 33% of the placebo group had their diastolic blood pressure reduced to less than 90 mmhg during the course of the trial. Progression occurred in only 0.3% of the actively treated patients (The Management Committee, National Heart Foundation of Australia, 1980). Nonpharmacologic approaches to blood pressure reduction (diet, exercise, transcendental meditation, and other relaxation techniques) are obviously attractive alternatives to pharmacologic therapy in mildly hypertensive patients because the benefit of drug treatment

5 M. D. Cressman and R. W. Gifford: Controversies in hypertension 5 is still being debated. The behavioral techniques have never convincingly been demonstrated to produce sustained blood pressure reduction and should be considered experimental (Shapiro, 1977). Dietary modification is potentially effective in reducing blood pressure, particularly in obese patients or in patients who ingest large amounts of sodium. Vigorous dietary sodium restriction effectively lowers arterial blood pressure and enhances the efficacy of other antihypertensive agents. Hunt and Margie (1980) were able to reduce DBP to less than 90 mmhg in 85% of patients with mild hypertension (DBP mmhg) with a diet containing less than 75 meq/d of sodium. Unfortunately, the limitations imposed by adherence to this level of sodium restriction are unacceptable to the majority of patients. Of more practical importance is the 38% response to modest ( meq) dietary sodium restriction. When a thiazide diuretic or propranolol was combined with modest sodium restriction, adequate blood pressure control was achieved in 64% and 77% of the patients, respectively. An attempt to reduce sodium intake without imposing unacceptable changes in the patient's lifestyle would appear to be a reasonable goal. We feel that drug therapy should commence after a 6-month trial of dietary modification if diastolic blood pressure is not reduced to less than 90 mmhg. The epidemiologic evidence relating mild hypertension to premature mortality is so strong that drug therapy designed to reduce diastolic blood pressure to mmhg or less is a reasonable goal. Concern for drug related side effects and long-term toxicity is obviously warranted but these undesired side effects can be minimized with a rational treatment program (Gifford, 1980). Diuretics,s Beta Blockers as the First Step in Drug Therapy Diuretics or beta blockers are nearly always used as the first step in drug therapy for hypertension. Either class of agents will reduce arterial blood pressure without causing excessive volume expansion and attenuation of their antihypertensive effect. Berglund and Andersson (1981) found no difference in the blood pressure lowering effect of bendroflumethiazide or propranolol in mildly hypertensive patients treated for six years. The response to either of these agents is enhanced by modest dietary sodium restriction (Hunt and Margie, 1980). Some physicians fear the biochemical abnormalities (hyperglycemia, hyperlipidemia, hypokalemia, and hyperuricemia) which may develop during chronic diuretic therapy. Others point to the added cost of using beta blockers as the first step in drug therapy. Cost consideration is obviously important because of the huge number of patients with mild hypertension. A few centers advocate renin/sodium profiling to make a more "rational" choice between diuretics and beta blockers as initial therapy for hypertension. Recently, the Veterans Administration Cooperative Study Group on Antihypertensive Agents reported their findings of a prospective, double-blind trial of diuretics (hydrochlorothiazide mg twice daily) or beta blockers (propranolol mg twice daily) in the management of 683 men with diastolic blood pressures ranging from mmhg (Veterans Administration Cooperative Study Group, 1 982a). Dose titrations were made at two-week intervals over the next 8 weeks and at weekly intervals until week 10. The goal of therapy was to reduce seated diastolic blood pressure to 90 mmhg or less. During this titration phase, 64.1 % of the hydrochlorothiazide treated patients and 57.0% of the propranolol treated patients achieved their diastolic blood pressure goal. This difference did not reach statistical significance. Diuretics appeared to be more effective than propranolol in blacks (71.3% hydrochlorothiazide treated vs 53.5% propranolol treated patients at goal); this difference reached statistical significance. The goal blood pressure was achieved in approximately 15%ofthe patients treated with 80 mg propranolol per day while 50% of the patients treated with 50 mg per day of hydrochlorothiazide decreased their diastolic blood pressure to 90 mmhg or less during the 10-week titration phase. After the titration phase, patients received continuous therapy and regular clinic follow up for a 48-week period. The superior efficacy of hydrochlorothiazide compared to propranolol was evident during the long-term trial by a number of criteria (Veterans Administration Cooperative Study Group, 1 982b). Of 394 patients completing the long-term study, diastolic blood pressure was reduced to 90 mmhg or less in 65% of the hydrochlorothiazide treated and 52.8% of the propranolol treated patients. This response rate for propranolol treated patients correlates well with the 52% response rate observed in an earlier trial of propranolol monotherapy where approximately 40% of the patients received 480 mg of propranolol per day (Veterans Administration Cooperative Study Group, 1977). Comparative dose requirements were much lower and dose titrations were required less frequently with hydrochlorothiazide than with propranolol. Hydrochlorothiazide reduced systolic and diastolic blood pressure to a greater degree in both whites and blacks during the long-term evaluation. Hydrochlorothiazide was particularly more effective than propranolol in blacks. More propranolol treated patients had to terminate their treatment program compared to hydrochlorothiazide treated patients because of an increase in diastolic blood pressure to 120 mmhg or greater (25 propranolol treated and 3 hydrochlorothiazide treated patients). However, biochemical abnormalities developed more frequently in patients treated with diuretics.

6 6 Clin. Cardiol., Vol. 6, January 1983 The metabolic derangements that develop during chronic diuretic therapy have been recognized for many years, but the significance of these changes is still uncertain. The European Working Party on Hypertension in the Elderly found a mean increase in fasting blood glucose of 9.6 mg/dl after one year of treatment with bendroflumethiazide in 119 patients over the age of 60 years (European Working Party on Hypertension in the Elderly, 1978). The fasting blood glucose fell by 3.1 mg/dl in the placebo treated group. After two years, the blood glucose was increased by 26.6 mg/dl one hour after a 50 g oral glucose load in the thiazide treated group and decreased by 5.3 mg/dl in the placebo treated group. A positive correlation between hypokalemia and glucose intolerance was noted. Beta blockers may also impair glucose tolerance. The administration of propranolol to normal volunteers has been shown to decrease glucose mediated insulin release (Cesari et al., 1969). Propranolol or metoprolol may adversely effect diabetic control in noninsulin dependent (type II) diabetics (Wright et al., 1979). Beta blockers have been reported to precipitate hyperosmolar nonketotic coma (Podolsky and Pattavina, 1973). Berglund and Andersson (1981) did not observe a significant change in glucose tolerance in the majority of 53 bendroflumethiazide or 53 propranolol treated hypertensive patients over a six-year treatment period. Clinically overt diabetes mellitus developed in one thiazide and one propranolol treated patient. There is also concern that the changes in lipid metabolism induced by thiazide diuretics will minimize their potential to decrease the progression of and complications related to coronary atherosclerosis. Thiazide diuretics increase triglyceride levels and sometimes increase total serum cholesterol. The ratio of low density lipoprotein (LDL) to high density lipoprotein (HDL) does not change significantly (Johnson, 1982). Ames and Hill (1982) have shown that therapy which does not alter glucose metabolism has little effect on blood lipids in thiazide treated patients. Abnormalities in lipid metabolism also develop in patients treated with beta blockers. Day and co-workers (1979) observed a significant increase in plasma triglyceride levels in patients treated with propranolol or atenolol for periods of three to six months. Serum cholesterol was unchanged. In the Oslo study, propranolol was shown to decrease HDL while total serum cholesterol was unchanged (Leren et al., 1980). Serum cholesterol decreased in patients treated with thiazide diuretics or beta blockers in the six-year trial conducted by Berglund and Andersson (1981), but these patients were given dietary advice in an attempt to reduce serum cholesterol. In the Veterans Administration study, statistically significant increases in fasting glucose, cholesterol, and triglyceride levels were noted in propranolol treated patients. Fasting glucose rose slightly in hydrochlorothiazide treated patients but cholesterol and triglyceride levels actually fell during therapy (Veterans Administration Cooperative Study Group, 1982b). Thus, the abnormalities in glucose and lipid metabolism that had been noted during treatment with thiazide diuretics cannot be used as a reason for choosing beta blockers over diuretics as the first step in drug therapy since similar metabolic events have been shown to occur when beta blockers are utilized. The recent report of the Multiple Risk Factor Intervention Trial (MRFIT) has generated much controversy regarding the potential toxicity of antihypertensive medications, particularly the thiazide diuretics, in the management of hypertensive patients with abnormalities on the resting electrocardiogram (Multiple Risk Factor Intervention Trial Research Group, 1982). This trial was designed to assess the effects of risk factor modification (smoking, hypercholesterolemia, hypertension) in middle-aged men who were designated to be at "increased risk" for cardiovascular disease based on risk factor scores derived from the Framingham Heart Study. Nearly 13,000 patients were randomized to receive a special intervention (SI) program designed to decrease blood pressure (by a stepped care approach to therapy), limit smoking, and control serum cholesterol by dietary modification; or were referred to the usual sources of health care in the community (UC). Physicians of the UC patients were informed that these men were at high risk for cardiovascular disease. In each group, 62% of the patients had hypertension (DBP of mmhg or were on antihypertensive medications) at the time of entry into the study. Several unexpected findings emerged from this trial after six years of follow up. First, patients in the UC group significantly reduced their risk factor levels (but not to the same degree as the SI patients) during the course of the trial. All-cause mortality and deaths due to coronary heart disease were 50% and 44% less, respectively, than expected in the UC patients based on Framingham risk assumptions. Secondly, there was no difference in mortality between the SI and the UC patients. The lack of benefit of the SI program in hypertensive patients was due to a 65% increase in mortality among SI patients compared to the UC patients with abnormalities of the resting electrocardiogram (30% of the hypertensive patients). Electrocardiographic abnormalities included Q waves, ST-segment elevations and depressions, negative T waves, frequent and infrequent ventricular premature contractions. complete atrioventricular and bundle-branch block. high R waves, and left axis deviation. Mortality was reduced by 24% in the SI hypertensive patients without resting electrocardiographic changes when compared to the hypertensive patients without electrocardiographic changes in the UC group. Kolata (1982) suggested that the adverse effect of the SI treatment program in the hypertensive patients with

7 M. D. Cressman and R. W. Gifford: Controversies in hypertension 7 TABLE IV Percentage of patients reporting symptoms at two years after entry with diuretic, beta blocker, and placebo therapy in mild hypertension Men {n= 1130! Women {n,",958~ Symptom Bendrofluazide Propranolol Placebo Bendrofluazide Propranolol Placebo Dizziness Muscle pain / Exertional dyspnea / Headaches Cold/numb digits / Paresthesias Dry mouth /1 \ Blocked or runny nose Nausea/vomiting Impotence 22.6/ /I Connotes a significant difference (p<0.05) for each active drug compared to all placebo patients. Adapted from the Medical Research Council Working Party on Mild to Moderate Hypertension. Lancet 2, 539 (1981). abnormal electrocardiograms was generated largely from the group of patients who were receiving large doses of thiazide diuretics. The SI patients received up to 100 mg of hydrochlorothiazide or chlorthalidone. Possibly, a higher incidence of diuretic-induced hypokalemia was associated with an increased incidence of sudden death in the SI patients. Although this explanation is speculative, it deserves careful consideration in our management of hypertensive patients with abnormalities in the resting electrocardiogram. Perhaps, our "national obsession with potassium" is not completely unjustified in this group of patients. (Harrington et 01., 1982). Tweedale and co-workers (1977) have demonstrated that dosages of 25, 50, 100, and 200 mg of chlorthalidone produce similar degrees of blood pressure reduction, but the degree of hypokalemia associated with therapy are dose related. The 25 mg chlorthalidone dose decreased serum potassium by 0.43 meq/liter while the 100 mg chlorthalidone dose decreased serum potassium by 0.89 meq/liter. The reduction of blood pressure was maximal in 67% of the patients on a 25 or 50 mg chlorthalidone dose. Materson et 01. (1978) have confirmed this relationship between chlorthalidone dose and response in terms of blood pressure and potassium depletion. The incidence of reported symptoms which occur during chronic therapy with diuretics, beta blockers, or placebo has been analyzed by the Medical Research Council Working Party on Mild to Moderate Hypertension (1981). Impotence was reported in 22.6%, 13.2%, and 10.1 % of men treated with diuretics, beta blockers, or placebo, respectively. The difference between diuretics and placebo was statistically significant. Dry mouth was noted more frequently in women treated with diuretics. Men treated with propranolol noted exertional dyspnea more frequently than placebo treated patients. A statistically significant increase in the incidence of cold/ numb digits was observed in propranolol treated women when compared to patients receiving placebo. Overall, the incidence of the most commonly reported side effects of antihypertensive therapy occurred just as frequently in patients taking placebo as in patients taking diuretics or beta blockers (Table IV). This study offers little evidence to suggest that the incidence of drug-related symptoms confers an advantage to either diuretics or beta blockers as the first step in drug therapy. Renin Profiling It has been suggested that a more rational and scientific approach to choosing diuretics or beta blockers is provided by the renin/sodium profile (Buhler et 01., 1972). This requires measurement of plasma renin activity and a 24-h urinary sodium excretion. It is assumed that patients with normal or high renin levels (when adjusted for the 24-h sodium excretion) will have a more favorable response to beta blockade. "Low renin" patients are given diuretics. There are several difficulties with this approach, not the least of which is obtaining an accurate 24-h urine collection and deciding at what level renin is high, normal, or low. Bravo et 01. (1975) found no consistent relationship between changes in plasma renin activity and the response to beta blockade in patients treated with propranolol alone or in combination with a diuretic. Furthermore, the cost of applying this method would be enormous and utilization of renin/ sodium profiling as a method to choose initial drug therapy cannot be recommended (Gifford, 1980). For practical purposes, comparative cost favors diuretics over beta blockers as the first step agent, particularly in view of the large numbers of patients who would appear to benefit from drug therapy. Expense can endanger compliance, detracting from the effectiveness of any treatment regimen. Although beta blockers may

8 8 Clin. Cardiol., Vol. 6, January 1983 be preferred in patients with gout, evidence of a hyperkinetic circulation, or ischemic heart disease (especially following myocardial infarction), diuretics are the most logical first step in drug therapy in the majority of patients with mild uncomplicated hypertension because they are more cost effective (B-blocker Heart Study Group, 1981). Isolated Systolic Hypertension in the Elderly The HDFP data provide evidence that drug therapy decreases mortality in elderly patients with diastolic hypertension (Hypertension Detection and Follow-up Program Cooperative Group, 1979b). Five-year mortality was reduced by 16.4% in the SC patients aged years at the time of entry. An important subgroup of elderly patients have isolated systolic hypertension (~160 mmhg systolic and <90 mmhg diastolic). Systolic blood pressure progressively increases with age while diastolic blood pressure stabilizes after the age of 60 (Stamler el al., 1976). Thus, the prevalence of isolated systolic hypertension increases with age. There is ample evidence that isolated systolic hypertension is an adverse cardiovascular risk factor, but no controlled trials of antihypertensive therapy have been reported to indicate that blood pressure reduction alters this risk (Dyer et al., 1977). The increased level of systolic blood pressure in elderly patients has been attributed to loss of elasticity in the aorta and large arteries due to arteriosclerosis. It would be logical to assume that the increased cardiovascular risk which has been noted in elderly patients with pure systolic hypertension relates solely to the presence of pre-existing atherosclerosis with systolic hypertension serving as a marker of arterial disease rather than an independent cardiovascular risk factor. The finding that isolated systolic hypertension is associated with cardiac complications is not surprising since cardiac work is a function of systolic blood pressure, stroke volume, and heart rate. Thus, even isolated systolic hypertension will increase myocardial work demands and oxygen consumption and theoretically predispose to congestive heart failure and manifestations of ischemic heart disease (O'Malley and O'Brien, 1980). Kannel and co-workers ( 1981) analyzed pulse wave tracings as a measure of arterial rigidity in 1825 patients with pure systolic hypertension during the Framingham study. They found that systolic hypertension was an adverse risk factor for stroke even when taking age, diastolic blood pressure, and pulse configuration into account. This would indicate that systolic pressure per se is an independent risk factor for stroke and not merely a marker for pre-existing atherosclerotic vascular disease. Much of the reluctance to treat hypertension in elderly patients, either systolic or diastolic, stems from the false assumptions that elderly patients tolerate elevated levels of blood pressure better than young patients and that blood pressure lowering will precipitate coronary or cerebral ischemia in the elderly. Neither of these assumptions has been supported by the Framingham data or the HDFP trial (Hypertension Detection and Follow-up Program Cooperative Group, 1979b; Kannel, 1974). It is true that elderly patients may be more sensitive to antihypertensive agents because of suppressed baroreceptor function and decreased intravascular volume which occur with advancing age (Messerli et al., \981). Blood pressure reduction should proceed cautiously in elderly patients. Modest dietary sodium restriction may reduce blood pressure in patients with isolated systolic hypertension. When the starting dosage of antihypertensive agents is decreased (by about 50%) and additions of new drugs are made at intervals of 4-6 weeks, systolic blood pressure reduction to levels of mmhg can usually be achieved safely with minimal side effects in elderly patients with isolated systolic hypertension (Gifford, 1982). Since the risk of isolated systolic hypertension has been so firmly established, a cautious attempt to gradually reduce systolic blood pressure in elderly patients appears to be indicated. Conclusion The epidemiologic data from the insurance industry, the pooling project, and the Framingham community leave no doubt that mild hypertension is a precursor to premature cardiovascular morbidity and mortality. Although the magnitude of the risk varies in individual patients according to a variety of demographic characteristics, we have no good way to identify which of the "low risk" patients may develop hypertensive complications during a prolonged period of observation. Controlled clinical trials of antihypertensive therapy utilizing a stepped care approach to drug therapy beginning with oral diuretics has been shown to decrease mortality even in patients with mild uncomplicated hypertension. Oral diuretics continue to be the preferred first step agent in the majority of patients because they are less expensive than beta blockers. Although reduction of systolic blood pressure in patients with isolated systolic hypertension has not been shown to decrease mortality, it reduces myocardial work and oxygen consumption. Cautious reduction of systolic blood pressure in elderly patients with pure systolic hypertension is justifiable because we know the risk of the untreated disease. Cardiovascular mortality has declined in the last decade since antihypertensive agents have become more available and widely utilized (Whelton, 1982). Despite this decline, cardiovascular morbidity and mortality remain unacceptably high. An aggressive approach to blood pressure reduction in the large group of patients

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