Superiority of nonpharmacologic therapy compared to propranolol and placebo in men with mild hypertension: A randomized, prospective trial We compared the effects of nonpharmacologic therapy, propranolol monotherapy, and placebo on blood pressure, metabolic, exercise, and quality of life variables in a lBweek, randomized, placebo-controlled trial of 79 male patients with hypertension. A significant reduction in diastolic blood pressure was observed with both nondrug therapy (-8.0 + 1.08 mm Hg) and propranolol (-9.5 f 1.46 mm Hg) compared to placebo (-0.1 i- 2.01 mm Hg). However, only patients receiving nonpharmacologic therapy showed a reduced body mass index, lower total and low-density lipoprotein serum cholesterol levels, and increased exercise tolerance compared to both propranolol and placebo. Patients receiving propranolol felt less anxious and unsure but showed a significant decrement in nocturnal penile tumescence compared to both placebo and nondrug therapy. Patients receiving nondrug therapy felt more energetic and reported improved sexual arousal and greater sexual satisfaction after treatment. Reductions in blood pressure in the nondrug treatment group were related to both weight reduction and improved fitness. We conclude that nondrug therapy is effective in controlling blood pressure in men with mild hypertension and is associated with improvements in weight, lipoprotein levels, and exercise tolerance compared to both propranolol and placebo. Quality of life assessments further support the use of nondrug therapy in this context. (AM HEART J lgg2;123:466.)

John B. Kostis, MD, Raymond C. Rosen, PhD, Elizabeth Brondolo, Lynn Taska, MS, Delia E. Smith, PhD, and Alan C. Wilson, PhD. New Brunswick, N.J.

Nonpharmacologic treatment of mild hypertension has been advocated by both the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure1 and the World Health Organization.2 However, few studies to date have specifically compared nondrug treatment with either pharmacologic therapy or placebo.3 In addition, previous reports have been limited to either studying the effects of single interventions such as weight loss or exercise or comparing different modalities of nonpharmacologic therapy.4y 5 We performed a randomized, placebo-controlled,

From the University Johnson Medical

of Medicine School.

Supported

by grant

Received

for publication

Reprint requests: One Robert Wood 08903-0019. 4/1/33940

466

HL

33960 Feb.

and Dentistry from

the National

25, 1991;

John B. Kostis, Johnson Place,

accepted

of New Jersey, Institutes July

Robert

Wood

of Health.

1, 1991.

MD, Department of Medicine-0419, UMD-New Jersey, New Brunswick,

Nd

PhD,

prospective trial comparing a combined nonpharmacologic approach to propranolol monotherapy in patients with mild hypertension, who were studied in a comprehensive, multidimensional fashion. A 12-week combined nonpharmacologic intervention consisting of a reduced-calorie, low-salt diet, low-intensity exercise, and mental relaxation was compared with both propranolol monotherapy and double-blind, parallel placebo. This is the first study of this type to evaluate the impact of these two treatment regimens on a broad range of outcome measures, including exercise performance, lipoprotein levels, and quality of life variables such as mood state, cognitive performance, and sexual function. Adverse drug effects on these latter parameters are a major source of patient noncompliance in the treatment of mild hypertensi0n.s METHODS Patients.

Men with hypertension (diastolic blood pressure, 95 to 105 mm Hg), aged 30 years or more, who had no history of myocardial infarction or aortocoronary bypass

Volume

123

Number

2

Table

Nonpharmacologic

467

I. Baselinevalues (meansf SD) in the study groups Nondrug (N = 33)

Age

56.5 162.3 100.7 76.5 88.1 28.3 9.8 19.3 238.8 155.6 47.7 166.4

(yr)

SBP (mm Hg) DBP (mm Hg) Heart rate Total weight (kg) Body mass index (kg/m2) Maximum METS Peak VOs (ml)/kg Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) SBP,

therapy in mild hypertension

Systolic

blood pressure;

DBP,

diastolic

t k + t + f + f k f + f

8.1 18.7 6.7 7.9 11.0 3.0 3.8 5.5 42.7 32.7 9.6 77.8

Propranolol (N = 23) 57.8 164.8 100.2 78.1 87.2 28.2 10.1 19.4 238.1 146.1 43.5 176.6

f + * k + + -t* + * + *

8.1 11.7 9.7 11.6 11.5 3.1 4.1 4.5 56.1 43.3 10.9 78.8

Placebo (N = 23) 58.2 167.0 101.0 80.0 87.0 28.0 10.1 17.9 230.0 153.2 44.4 159.2

zk 9.6 k 22.4 + 7.9 _t 12.2 + 22.8 f 6.1 ” 3.3 c 6.0 k 41.2 + 37.6 -?r 9.4 -t 79.9

blood pressure.

surgery, who were not taking medications, and who intended to residein central New Jersey for at least 1 year, were invited to be screenedfor the study. Blood pressure eligibility was established during the course of three screening clinic visits, during which the average of two blood pressuremeasurementsin the sitting position, using mercury sphygmomanometers,wasusedfor blood pressure determinations. Patients with an average diastolic blood pressureof 95to 105mm Hg at all three visits wereaccepted for study. Measurementsobtained at the third visit were used as baselinevalues. Before being randomly assignedto groups, all patients were evaluated by means of medical history, physical examination, resting ECG, completeblood count, biochemical profile, and urinalysis. Men with marked obesity defined as a body weight greater than 135% of idea&l evidence of congestiveheart failure, atria1 fibrillation, or recurrent tachyarrhythmias, second- or third-degree atrioventricular heart block, sinus bradycardia ( 110mm Hg at any time during the courseof the study or diastolic blood pressure>105 mm Hg for two consecutive visits (blood pressureescapecriteria) was withdrawn and placedon open-labelpharmacotherapy. The study was approved by the Committee for the Protection of Human Subjects in Research. Study design. After baselineassessment,eligible men were randomly assignedto one of three treatment groups: nonpharmacologictherapy (consistingof a 12-weekcombined program of weight loss,sodiumrestriction, low-level exercise, and relaxation), propranolol monotherapy, or double-blind placebo. Consideringthe possibility of an in-

creasednumber of dropouts in the group receiving nonpharmacologic therapy, the randomization schedule was designedto yield more patients in this group at a ratio of 3:2:2 (i.e., nonpharmacologic therapy:propranolol:placebo). Patients randomly assignedto propranolol were given 40 mg twice a day for 2 weeks.If the sitting diastolic blood pressuremeasuredaspreviously describedremainedabove 90 mm Hg, the doseof propranolol wasincreasedto 80 mg twice a day for 2 weeks, then to 120 mg twice a day in a stepped-caremanner. A similar sham stepped-careregimen that usedmatching placebowasemployed in patients randomly assignedto the placebo group. Treatment was continued for 3 months, after which all patients underwent a secondassessmentof all study measures. Nonpharmacologic therapy. Nonpharmacologic therapy consisted of an intensive 12-week intervention program.All subjects(N = 33) were required to attend weekly intervention sessions,which were conducted in a group treatment format and included spouseparticipation where possible. Weight loss was strongly emphasized for all patients weighing more than 115% of ideal body weight. For these patients weight lossgoalsof approximately one pound per week were established,for a total goal of 12 to 15 pounds during the 3-month intervention. Dietary changeswere accomplishedthrough educational instruction, group support, and application of behavior modification principles.8 During the first 4 weeks, emphasiswas placed on weight loss and subjects were required to self-monitor caloric intake, after which subjects recorded both caloric and sodium intake for the remainder of the program. Participants were encouragedto restrict sodium intake to 1500mglday and to decreasealcoholintake to two drinks or lessper day. In addition, participants were provided instruction in aerobic exercise training and stress managementtechniques. A period of graduated exerciseduring the first 2 weeks allowed subjectsto becomeaccustomedto increasedactivity and to scheduleexercisetime into their daily routine.g After this subjectswere encouragedto exercise3 to 5 days per week at an exercise level not to exceed 70% of the

468

Kostis

et al.

Table

II. Changes

American

in blood pressure

and metabolic Nondrug

Resting DBP (mm Hg) Resting SBP (mm Hg) Heart rate (beats/min) Submaximum DBP (mm Hg) Submaximum SBP (mm Hg) Submaximum heart rate (beats/min) Maximum DBP (mm Hg) Maximum heart rate (beats/min) Maximum SBP (mm Hg) Weight (kg) Body mass index (kg/m2) Maximum METS Peak VOslkg Resting insulin (IV) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Groups

with a common

and exercise measures (N = 33)

Propranolol

-8.0a ( + 6.2) -12.4 (k 14.6) -4gasb (“95) -8:8a (9.0) . -15.6 (20.3) -5.58 (9.1) -4.5 (10.8) 8.2a (19.0) -4.5 (18.5) -6.55a (k 5.0) -2.0a (+ 1.6) +1.11a (-c 1.3) +3.2a (k4.6) -6.8 (16.3) -19.9a (+ 35.9) +2.2 (k6.2) -11.2a (+ 19.6) -35.38 ( + 66.0)

letter (a or b) are not significantly

different

February 1992 Heart Journal

(means + SD in the study groups (N = 23)

-9.5a ( rt 7.0) -12.2 (I 15.2) -10.08 (2 14.0) -7.1a,b (9.9) -13.5 (17.2) -12.7b (13.6) -6.7 (8.8) -13.6b (22.0) -13.5 (26.0) +0.55b ( f 2.9) +0.2b (+- 0.9) -0.33b (-+ 0.9) -1.2b (k3.1) -0.6 (27.1) +2.5b (+ 35.0) +2.6 (T 7.5) +7.5b (k 24.6) +15.4b (k86.3)

Placebo

(N = 23)

-0.1e (k9.7) -4.9 (+ 18.9) -1.7b (* 7.5) -2.5b (9.9) -5.4 (18.0) -4.3a (8.8) -4.7 (11.0) -9.0= (25.3) -5.9 (19.5) -O.lb ( + 2.3) -0.lb (LO.7) +0.30b (+2.1) +l.lasb (k6.0) 1.1 (12.5) +8.5b (k 25.4) +2.8 ( + 7.1) +3.7b (+ 18.9) -4.78,b (t81.1)

P

0.0001 NS 0.02 0.0553 NS 0.0157 NS 0.0021 NS 0.0001 0.0001 0.001 0.005 NS 0.005 NS 0.01 0.05

at p < 0.05.

maximum ascertained during the baseline stress test evaluation. Simple, easily performed exercise regimens such as vigorous walking and swimming or use of a stationary bicycle were prescribed. Subjects experiencing exerciserelated symptoms or difficulties were advised to contact the study nurse. Compliance was assessed by attendance at intervention meetings, patient recording of home practice sessions and caloric and sodium intake, and continued monitoring of blood pressure and weight throughout the treatment period. Laboratory assessments. A comprehensive laboratory evaluation was conducted on all patients before randomization and at the end of the 3-month study period. Clinical and laboratory evaluations were made in an “observer blind” fashion beginning at 4 PM on each test date. The last meal before laboratory evaluation was between noon and 1 PM. Measurement of weight and blood pressure and exercise stress testing were followed by a comprehensive battery of self-report questionnaires, mood scales, and cognitive and perceptual-motor testing. Sexual function was evaluated by means of both subjective measures and objective laboratory recordings of nocturnal penile tumescence (NPT).‘O, l1 Multistage exercise stress testing on a bicycle was performed as follows: 50 W for 3 minutes, 75 W for 3 minutes, 100 W for 3 minutes, 125 W for 3 minutes, 150 W for 3 minutes, and 175 W for 3 minutes. Heart rate, systolic blood pressure, diastolic blood pressure, minute ventilation, oxygen consumption, and respiratory quotient with the use of a Beckman Metabolic Cart (Beckman Instruments, Inc., Fullerton, Calif.) were measured at rest, at the end of each 3-minute exercise phase, and at maximum exercise. Peak exercise intensity and peak VOs (maximum exercise) at the point of volitional termination were also determined.

Serum cholesterol and triglyceride levels were measured with automated procedures.12 High-density lipoprotein (HDL) cholesterol was determined by the heparin-manganese chloride (92 mmol/L) precipitation method.13 Lowdensity lipoprotein (LDL) cholesterol was estimated by the Friedewald equation. I4 The lipid laboratory participates in the Centers for Disease Control-National Heart, Lung, and Blood Institute lipid standardization program. Glucose levels were determined by the method of Trinder15 and insulin by radioimmunoassay.16 Mood state was assessed by means of a standardized self-report scale, the bipolar Profile of Mood States questionnaire.17 Cognitive and psychomotor function was assessed by a brief battery of neuropsychological tests that included the Trail Making Test (parts A and B),18 Rey Auditory Verbal Learning Test,lg Embedded Figures Test,20 Federation of American Scientists Test of Verbal FluenTest.22 Sexual function CY, 21 and Benton Visual Retention was evaluated by a self-report questionnaire23 and overnight laboratory assessment of NPT.ll To familiarize the patients with testing procedures and to minimize training effects on the dependent variables, a set of psychometric evaluations and exercise testing procedures was performed before patients were entered into the study. Statistical analysis. A within-subjects design was used to assess the effects of treatment. Pre- to posttreatment change scores were computed for each of the cardiovascular, metabolic, and lipoprotein measures of interest. Oneway analysis of variance was used to test significance of change on each of these dependent variables. Duncan’s multiple-range test was used for all post hoc comparisons. Regarding the cognitive and psychomotor measures, a principal components analysis was performed on baseline test scores to reduce the number of dependent variables for analysis. 24 Change scores in the resulting factors were

Volume

123

Number

2

Nonpharmacologic

therapy in mild hypertension

469

CHANGE

I -

q PLACEBO &j NON-DRUG u PROPRANOLOL rest

sue max max

resr

SUD max max

rest

SUD max max

1. Comparison of changesin exercise tolerance and hemodynamic measuresduring exercise after treatment. Open bars represent placebo; hatched bars , nondrug therapy; solid bars, propranolol. Values represent mean heart rate (beats/min), diastolic and systolic blood pressure(mm Hg), exercise intensity (METS x4), and oxygen consumption(VO.&g X2); for standard deviation and exact statistical significance of different changes,seeTable II. *p < 0.05; **p < 0.005; ***p < 0.0005compared with placebo.

Fig.

tested for significance by meansof a similar analysis of variance as above. To evaluate pre- to posttreatment changesin ordinal, nonparametric data (i.e., subjective ratings of sexual function), the McNemar sign test25was used. All p values reported refer to probabilities derived from two-tailed tests.

total cholesterol, LDL cholesterol, and triglycerides. Baseline values for these variables were not significantly different among the three treatment groups.

RESULTS Subjects.

weight and body mass index, exercise variables, and A total of 192 men were screened for pos-

sible inclusion in the study. Ninety-two patients who met all inclusion criteria were randomly assigned to one of the three treatment groups. Thirteen patients were withdrawn from the study after randomization because of uncontrolled hypertension (blood pressure escape criteria described previously) or adverse treatment reactions. Five of these patients were receiving propranolol, three were receiving placebo, and five were receiving nondrug therapy. Results of the analyses presented below are based on a total of 79 patients who completed treatment and who underwent both pre- and posttreatment laboratory assessments as described. Seventy-two patients were white and seven were black (three randomly assigned to nondrug therapy, two to propranolol, and two to placebo). As indicated in Table I, randomization resulted in similarities in weight, blood pressure, exercise tolerance, and lipid levels in the three groups at baseline. As a group, subjects were moderately overweight, with mild to moderate elevations of systolic and diastolic blood pressure, and mild elevations of

Changes in blood bolic and exercise

pressure, body weight, and metaparameters after treatment. The

mean changes in blood pressure, heart rate, body lipid levels after treatment are shown in Table II and Fig. 1. The nondrug group had an 8.0 mm Hg reduction in diastolic blood pressure compared with 9.5 mm Hg with propranolol and 0.1 mm Hg with placebo. The overall difference between groups was highly significant (p < O.OOOl), with no significant difference between propranolol and nonpharmacologic therapy, both of which were significantly different from findings with placebo (Fig. 1). Similar changes in systolic pressure were observed. The resting heart rate was significantly reduced by propranolo1 (p < 0.03). A gradual loss of weight and lowering of blood pressure was seen in the nondrug group. Weight reduction or change in body mass index was significantly greater with nondrug treatment (p < 0.001) compared with both propranolol and placebo (Fig. 2). A small weight gain was seen in the propranolol group. Similarly nondrug treatment was associated with significantly decreased total cholesterol, LDL cholesterol, and triglyceride levels. Insulin levels showed a trend toward a decrease in the nondrug group. Significant changes in the glucose/

470

Kostis et al.

American

February 1992 Heart Journal

CHANGE

INSULIN

Fig. 2. Comparisonof changesin body weight (pounds), total serum cholesterol (TCHOL, mg/dl), lowdensity lipoprotein cholesterol(LDL-C, mg/dl), triglycerides (TG), and insulin (IU) after treatment. Open. bars represent placebo; hatched bars, nondrug therapy; solid bars, propranolol. Values represent mean changes; for standard deviation and exact statistical significance of different changes, see Table II. *p < 0.05; **p < 0.005; ***p < 0.0005 comparedwith placebo and propranolol.

Table III. Quality of life measures:Changesin mood state, sexual function, and psychomotor performance after treatment

Nondrug Profile

of mood

(N = 33)

Propranolol

(N = 23)

Placebo (N = 23)

P

states

Energetic/tired Clearheaded/Confused Confident/Unsure Composed/Anxious Elated/Depressed Sexualfunction-NPT No. of episodes of full tumescence No. of episodes of partial tumescence Sexualfunction-subjective ratings* Sexualarousalrating Erectionsatisfaction Orgasmsatisfaction Psychomotorperformance-factorscores Reactiontime Cognitivescore

+3.48 (t6.3) +2.1a ( f 6.4) +0.3a~ b ( t 6.2) +1.3a*b (k5.2) t1.7 (k5.6)

+1.2a,b (i6.8) +2.2s (* 9.2) +3.&3 (* 5.7) +5.2a (+ 7.2) +2.5 (+7.7)

-2.lb (k8.9) -2.6b ( f 2.6) -1.5b (k8.0) -1.4b (_t 10.2) -1.2 ( * 8.7)

0.03 0.05 0.03 0.02 NS

+0.1a -0.1a

(+ 1.1) ( f 0.8)

-l.Ob +0.3b

+1.2a (+- 1.0) -l.Oa (kO.6)

0.006 0.01

+5.44; +3.57; +7.0;

p = 0.02 p = 0.06 p = 0.01

+0.14; +0.14;

(k1.1) (kO.5)

+O.O; NS

-3.67 (+ 10) +12.2 (-+ 24.0)

NS NS

-2.79 (rt9.4) +3.7 (F 15.2)

+7.0; p = 0.01 +l.o; NS +0.14; NS -3.76 (t 12.4) +10.1 ( t 14.5)

NS NS

Groups with a common letter (a or h) are not significantly different at p < 0.05. *Subjective ratings of sexual function were analyzed by means of within-group x2 tests.

insulin ratio or plasma renin activity were not observed. Compared with propranolol, nonpharmacologic therapy resulted in a significant increase in exercise tolerance (maximum METS = p < 0.001; peak VOn/ kg = p < 0.005) (Fig. 1). At peak exercise the heart rate was higher for nondrug therapy and lowest for propranolol (p < 0.003) (Table II). At submaximal exercise the heart rate and VOz/kg were significantly lower in the propranolol group (p < 0.05). Changes

in mood

state,

sexual

function,

and

cognitive

after treatment. Significant effects of treatment were observed on four of the five mood scales assessed(Table III, Fig. 3). Compared with those randomly assigned to the placebo group, patients receiving nondrug therapy rated themselves as significantly more energetic (p < 0.03) than at baseline. Both patients receiving propranolol and nondrug therapy reported improvement in feeling more clearheaded (p < 0.05) than those receiving placebo. Patients in the propranolol group also rated themselves as feeling less anxious (p < 0.02) and unsure performance

Volume

123

Number

2

Nonpharmucologic

therapy in mild hypertension

47 1

CHANGE 6 0

5- q

PLACEBO NON-DRUG

-3

1 ENERGETIC

CLEARHEADED

CONFIDENT

COMPOSED

ELATED

Fig. 3. Comparisonof changesin quality of life parametersmeasuredon five profile of mood state scales after treatment. Open bars representplacebo;hatched bars, nondrug therapy; solid bars, propranolol. Values represent mean changes;for standard deviation and statistical significanceof different changes,see Table III. *p < 0.05 compared with placebo.

SUBJECTIVE* NPT

CHANGE

CHANGE I 10.0

2.0

q

PLACEBO

n

PROPRANOLOL

2.5

-0.5 -l.O-

t -5.0 FULL ERECTION (NW

PARTIAL ERECTION (NW

AROUSAL’ RATING

EJACULATION’ RATING

ORGASM’ RATING

Fig. 4. Comparisonof changesin objective nocturnal penile tumescence(NPZ’) and subjective measures of sexualfunction after treatment. Open bars representplacebo;hatched bars, nondrug therapy; solid bars, propranolol. Values represent mean changes;for standard deviation ‘and exact statistical significanceof different changes,seeTable III. *p < 0.05 compared with placebo; +p < 0.05 comparedwith propranolol.

(p < 0.03) than those in the placebo control group. Differences between propranolol and nondrug therapy with regard to these latter measures were not statistically significant. On measures of sexual function, nondrug therapy generally produced beneficial effects, as opposed to certain adverse effects observed with propranolol (Table III and Fig. 4). For example, on subjective

measurements of sexual function, patients receiving nondrug therapy reported more arousal during sexual activity (p < 0.02), more satisfying ejaculations 0, < 0.02), and increased frequency of orgasm (p < O.Ol), whereas significant changes in these variables were not seen in subjects randomly assigned to the propranolol group. Objective evaluation of sexual function by NPT testing showed that propranolol

472

Kostis et al.

was associated with a significant decline in the frequency of full erections (p < 0.006) and an increased number of partial erections (p < 0.01) compared with both nondrug therapy and placebo (Table III and Fig. 4). Significant differences in the measures of cognitive function used in this study were not observed, although patients receiving nondrug therapy showed a trend toward improved performance on the cognitive factor score compared with patients in both the placebo and propranolol groups. Correlates of change in diastolic blood pressure in nondrug therapy. Multiple regression techniques were

used to evaluate possible predictors of change in diastolic blood pressure associated with nondrug therapy. Specifically changes in diastolic blood pressure, weight, exercise tolerance, maximum VOz/kg, glucose/insulin ratio, and plasma insulin levels were entered into a stepwise multiple regression analysis. Changes in diastolic blood pressure were found to be significantly related to submaximum changes in heart rate (p < 0.024, F = 6.58) and to weight loss (p < 0.044, F = 5.09). The combination of these two variables accounted for 53% of the variance of the change in diastolic blood pressure (p = 0.0001). Additionally a significant correlation was found between the change in maximum VOz/kg and submaximum heart rate (p < 0.002, r = 0.58). The correlation between changes in weight and insulin concentrations (p < 0.089, r = 0.31) was not statistically significant. Follow-up evaluation of nondrug therapy. An attempt was made to evaluate all patients in the nondrug therapy group at a follow-up visit conducted 9 months after termination of treatment (i.e., approximately 1 year after initial randomization). Patients receiving nondrug therapy were advised to continue life style changes for 1 year and not to use pharmacotherapy unless their physician advised them to do so. Thirty-one subjects (94%) returned for this follow-up visit and were not receiving drug therapy. Mean diastolic blood pressure in this group continued to be significantly reduced compared with pretreatment levels (p < 0.05), as was the average body massindex (p < 0.05). Compared with diastolic blood pressure levels immediately after treatment, however, an average increase of 3.9 mm Hg was noted at follow-up. Body mass index was essentially unchanged at follow-up (mean = 26.7) compared with posttreatment evaluation (mean = 26.1). DISCUSSION

This randomized, placebo-controlled study demonstrates that nondrug therapy is effective in lowering blood pressure to a similar extent as propranolol monotherapy. Compared with placebo nondrug ther-

American

February 1992 Heart Journal

apy was associated with lower total cholesterol, LDL cholesterol, and triglyceride levels, weight loss, increased exercise tolerance and lower submaximum heart rate, a tendency toward lower insulin levels, and improved measures of mood and sexual function, as assessedby both subjective and objective means. Directionally opposite effects were noted with propranolol therapy, with the exception of certain mood effects such as decreased anxiety, which were observed with the drug. Similar effects on mood with propranolol treatment have been reported by other investigators.26 The generalizability of these results is enhanced by the fact that consecutive patients who were eligible for the study were enrolled by random assignment of these patients to drug or nondrug therapy or placebo groups and by the low dropout rate. Our findings suggest that properly administered nonpharmacological therapy should be effective in the average patient with mild-to-moderate hypertension and that in contrast to drug therapy nondrug therapy results in significant additional benefits in the areas of cardiovascular risk+ overall health effects, and quality of life. With respect to the risk of coronary atherosclerotic events, it has been postulated that the lack of beneficial effects of antihypertensive pharmacotherapy may be related to the adverse effects of the drugs used (e.g., diuretics or P-blockers) on plasma lipid levels.27.28 Significant changes in HDL cholesterol values were not observed in our study, perhaps because of the small magnitude (i.e., a few mg/dl) of the expected effect and the low levels of exercise used.2g On the other hand, the fact that nondrug interventions did not include strenuous exercise, but well-tolerated activities such as walking, swimming, or riding a stationary bicycle, further emphasizes that such methods of blood pressure control may be used by a majority of patients with hypertension.30 The patients in this study were predominantly white, middle-aged men who were mildly overweight and leading a largely sedentary life style, characteristics of the average patient with hypertension. Women were not included to minimize patient variability and to make possible a uniform study methodology, particularly in the assessment of sexual function. Middle-aged Caucasian men are more likely to respond to propranolol monotherapy compared to other patient subsets, such as black or elderly persons with hypertension, suggesting that our study is not biased in favor of nondrug therapy by the selection of propranolol as the drug for comparison. Propranolol, the first p-blocker to become available, is still widely prescribed, has been routinely used in large trials of

Volume Number

123 2

antihypertensive therapy, and is used as a basis of comparison for P-blocker therapy. However, it should be noted that other P-blockers (e.g. ,&-selective or hydrophilic agents) or pharmacologic agents of different classes may yield results different from those presented here. Nonetheless, the efficacy of nondrug therapy is clearly demonstrated in this randomized, parallel, placebo control trial. The choice of nonpharmacologic procedures was guided by the ease of administration, absence of need for highly specialized personnel or facilities, and expectations of good adherence by the majority of patients. A combined nondrug approach, rather than reliance on a single intervention such as weight loss, was selected in view of our intention to maximize the blood pressure-lowering effect while ensuring a high level of compliance. Similar methods of combined nondrug intervention are currently being used by other clinical hypertension prevention trials, for example, the Trial of Mild Hypertension, Trial of Hypertension Prevention. 31,32 However, these studies lack placebo control groups, a limitation of major importance given the previous findings of significant antihypertensive effects associated with placebo administration.33 In addition, none of the studies to date have employed a comprehensive, multidimensional assessment methodology such as that used in the present study. In the present study alcohol intake was restricted to two drinks or less per day. This may have had an antagonistic effect on HDL cholesterol to that of exercise. In addition, alcohol restriction may have affected sexual function. The observed effect on sexual function after nondrug therapy could have been due to exercise, dietary changes, alcohol restriction, or changes in blood pressure. Nonpharmacologic treatment approaches for mild hypertension acquire special importance when viewed from an epidemiologic perspective. Large numbers of hypertensive patients must be treated to benefit relatively few, and there is the enormous aggregate monetary cost of drug therapy for hypertension. The fact that nondrug therapy can be implemented without specialized facilities, and the associated health benefits from improved lipid and exercise tolerance levels, mood changes, and other quality of life benefits, underscores the superiority of nondrug approaches as the initial therapy of choice for hypertension. These findings render strong support for the recommendations regarding nonpharmacologic therapy of the World Health Organization and the Joint National Committee for the Detection, Evaluation, and Treatment of High Blood Pressure. Weight loss, regular exercise, a low-sodium diet, and restriction of alcohol intake all exert an antihy-

Nonpharmacologic

therapy in mild hypertension

473

pertensive effect. This study was not designed to elucidate the specific mechanisms of blood pressurelowering effects by nondrug means. However, post hoc analyses suggest that weight loss and exercise conditioning with lower sympathetic activity and lower insulin levels may be interrelated mechanisms in our patients. Further research on this issue, as well as studies on the role of different components of nondrug intervention, are desirable. More information is also needed on the long-term maintenance of treatment gains. However, our results to date indicate that a carefully structured nonpharmacologic treatment approach is feasible and effective for blood pressure control in the average white male with hypertension and that this approach is associated with significant metabolic, mood, exercise, and quality of life benefits.

REFERENCES

1. The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988;148:1023-38. 2. Memorandum from the WHO/ISH. 1986 Guides for the Treatment of Mild Hypertension. Hypertension 1986;8:9573. & erman A, Wassertheil-Smoller S, Langford HG, et al. Pharmacologic and nutritional treatment of mild hypertension: changes in cardiovascular risk status. Ann Intern Med 1990;112:89-95. 4. Blanchard EB, Martin JE, Dubbert PM. Non-drug treatments for essential hypertension. New York: Pergamon Press, 1988. 5. Chesney MA, Agras WS, et al. Nonpharmacological approaches to the treatment of hypertension. Circulation 1987$76:104-9. 6. Lyles MF. Adverse effects of antihypertensive therapy. Clin Geriatr Med 1989;5:691-702. 7. Van Itallie TB. Health implications of overweight and obesity in the United States. Ann Intern Med 1985;103:983-8. 8. Rosen RC, Kostis JB, Brondolo E. Nondrug treatment approaches for hypertension. Clin Geriatr Med 1989;5:791-9. 9. Martin JE, Dubbert PM. Exercise in hypertension. Ann Behav Med 1985;7:13-8. 10. Karacan I, Salis PJ, Williams RL. The role of the sleep laboratory in diagnosis and treatment of impotence. In: Williams RL, KaracanI, eds. Sleep disorders: Diagnosis and treatment. New York: John Wilev & Sons. Inc: 1978246-63. 11. Rosen RC, Goldstein L, Scoles’V, Lazarus C. Psychophysiological correlates of nocturnal penile tumescence in normal males. Psychosom Med 1986;48:423-9. 12. Lipid Research Clinics Program. Manual of laboratory operations. Lipid and lipoprotein analysis. vol 1. National Heart, Lung, and Blood Institute, 1975; DHEW publication no. 75286. 13. Warnick GR, Albers JJ. A comprehensive evaluation of the heparin-manganese precipitation procedures for estimating high density lipoprotein cholesterol. J Lipid Res 1978;19:6576. 14. Friedewald WT, Levy RI, Frederickson DS. Estimation of the concentration of low density lipoprotein in plasma without the use of the preparative ultracentrifuge. Clin Chem 1972;18:499502. 15. Trinder P. Determination of glucose using I-aminophenazone. J Clin Path01 1969;22:240-44. 16. Crowley MF, Garbien KJT. Insulin: a comparison of the

474

17.

18.

19. 20. 21. 22. 23.

24. 25. 26.

Kostis et al.

results of plasma and serum assays using a double antibody technique-Clin Chim Acta 1974;51:345-52. McNair DM, Lorr M, Droppelman LF. Manual for Profile of Mood States. San Diego: Educational and Industrial Testing Service, 1971. Harley JP, Leuthold CA, Matthews CG, Bergs LE. Wisconsin neuropsychological test battery. Madison, Wis: CG Matthews, 1980. Rey A. L’Examen clinique en psychologie. Paris: Presses Universitaires de France, 1964. Benton AL, Spreen OS. Embedded figures test. Victoria, Canada: Neuropsychology Laboratories,l969. Eslineer PJ. Damasio AR. Neuroasvcholoeic detection of abnorm:1 mental decline in older persons. JAMA 1985;253:670-4. Benton AL. Revised visual retention test. New York: Psychological Corporation, 1974. Reynolds CF, Frank E, Thase ME. Assessment of sexual function in depressed, impotent, and healthy men: factor analysis of a brief sexual function questionnaire for men. Psychiatr Res 1988;24:231-50. Stevens J. Applied multivariate statistics for the social sciences. Hillsdale, NJ: Lawrence Erlbaum, 1986. Siegel S. Nonparametric statistics for the behavioral sciences. New York: McGraw Hill Book Company, Inc, 1956. Rosen RC, Kostis JB, Biohavioral sequellae associated with

American

27. 28.

29.

30.

31.

32.

33.

February 1992 Heart Journal

adrenergic-inhibiting antihypertensive agents. Health Psychol 1985;4:597-604. Kaplan NM. Nonpharmacological therapy of hypertension. Med Clin North Am 1987;71:921-33. Heyden S, Schneider KA, Fodor GJ. Coronary heart disease in hypertensives: a need to reduce cholesterol. Int J Epidemiol 1988;17:784-8. Schwartz RS. Effects of exercise training on high density lipoproteins and apolipoprotein A-I in old and young men Metabolism 1988;37:1128-33. Harris SS, Caspersen CJ, DeFriese GH, Estes Jr EH. Physical activity counseling for healthy adults as a primary preventive intervention in the clinical setting. Report for the US Preventive Services Task Force. JAMA 1989;261:3588-98. Meinert CL, Borhani NO, Langford HG. Design, methods, and rationale in the Hypertension Prevention Trial. Hypertension Prevention Trial Research Trial Research Group. Controlled Clin Trials 1989;10:(3 suppl):lS-29s. Stamler R, Stamler J, Gosch FC, Civinelli J, Fishman J, McKeever P, McDonald A, Dyer AR. Primary prevention of hypertension by nutritional-hygienic means. Final report of a randomized, controlled trial. JAMA 1989;262:1801-7. Gould BA, Mann S, Davies AB, Altman DG, Raftery EB. Does placebo lower blood-pressure? Lancet 1981;2:1377-81.