comparison of enalapril and atenolol in mild to moderate hypertension

Comparison of Enalapril and Atenolol in Mild to Moderate Hypertension ARIANNEL. HERRICK, M.R.c.P., PATRICKC. WALLER,M.R.C.P., KATHARINE E. BERKIN,M.R.C.P., STUART D. PRINGLE,M.R.C.P.,JOHNS.CALLENDER,M.R.~.P~Y~~., MAUREEN P. ROBERTSON,S.R.N.,JANETG. FINDLAY,B.SC.,GORDON D. MURRAY,P~.D.,JOHN L. REID, F.R.c.P., ANDREWR. LORIMER, F.R.c.P., RONALDJ.WEIR,F.R.C.P., HUGHA.CARMICHAEL,F.R.C.P.,JAMESI.S. ROBERTSON,F.R.C.P.,STEPHEN G. BALL,M.R.C.P., GORDONT. MC~NNES,F.R.C.P. Glasgow, Scot/and

PURPOSE: Short-term therapy with angiotensin converting enzyme (ACE) inhibitors for hypertension is effective and well tolerated, and compared with beta blockers, may cause fewer adverse reactions. Furthermore, enalapril has been observed to have a greater effect on systolic blood pressure than beta blockers. We therefore decided to com- pare the ACE inhibitor enalapril and the beta blocker atenolol as monotherapy in a double-blind study of patients with mild to moderate hypertension.

PATIENTS AND METHODS: After a four-week placebo run-in period, 162 patients were allocated randomly to receive atenolol(50 to 100 mg daily) or enalapril(20 to 40 mg daily) for 12 weeks. To assess the influence of these drugs on quality of life, a se- ries of psychologic tests was performed, and a subset of patients also underwent treadmill exercise and pulmonary function tests.

RESULTS: In 147 patients who completed the study, enalapril reduced supine blood pressure by 19/12 mm Hg, compared with 9/7 mm Hg for aten- 0101 (p <0.001/p <0.005). The modest blood pressure response to atenolol was not due to poor compliance. A target blood pressure of 140/90 mm Hg or less was achieved by 35 percent of enalapril-treated patients and by 14 percent of those treated with atenolol (p <O.Ol). The frequency and severity of adverse effects with the two drugs were similar, and few important differences emerged from the quality-of-life assessments.

CONCLUSION: At the doses used, enalapril induced a greater short-term blood pressure response than atenolol; long-term studies of its safety and efficacy are required.

From the Glasgow Blood Pressure Clinic and the Department of Psychologi- cal Medicine, University of Glasgow, Glasgow, Scotland. This work was supported in part by Merck Sharp & Dohme Ltd. Requests for reprints should be addressed to G.T. Mclnnes, F.R.C.P., Glasgow Blood Pressure Clinic, Western Infirmary, Glasgow Gil 6NT, Scotland. Manuscript submit- ted July 27, 1988, and accepted in revised form January 16, 1989.

B eta blockers are established treatment for hypertension, and long-term studies have demonstrated

their safety and beneficial effect on outcome [1,2]. Al- though in general these drugs appear to be well tolerated, 15 to 20 percent of patients withdraw from treatment within five years because of side effects [3], and adverse effects on pulmonary function [4], psychomotor performance [5,6], and quality of life [7,8] have been reported. Angiotensin converting enzyme (ACE) inhibitors such as enalapril are effective and well tolerated in the short term [9,10]. Compared with beta blockers, ACE inhibitors may cause fewer adverse reactions, particularly those affecting mental function [9,11]. It has also been claimed that enalapril has an effect on systolic blood pressure greater than that of beta blockers [12-151.

Our aim was to evaluate enalapril and atenolol as monotherapy for patients with mild to moderate hypertension. The study was designed to have sufficient power to provide a precise comparison of the drugs with respect to their effects on blood pressure and adverse effects, including measurements of mental well-being, psychomotor performance, exercise toler- ance, and respiratory function. Three centers partici- pated in the trial: The Royal Infirmary and Western Infirmary, Glasgow, and the Vale of Leven Hospital, Alexandria, Strathclyde.

PATIENTS AND METHODS Patients

Hypertensive patients aged 18 to 70 years with supine blood pressure 140 to 220 mm Hg systolic and/or 90 to 119 mm Hg diastolic on three occasions during four weeks of treatment with placebo alone, and who gave informed consent, were eligible to participate. Persons with known secondary hypertension, acceler- ated-phase hypertension, cerebrovascular disease, myocardial infarction within the previous six months, renal impairment (serum creatinine level more than 144 ~mol/liter), or any contraindication to either of the trial treatments, as specified by their data sheets, were excluded.

Study Design After a four-week placebo run-in period, patients

whose blood pressure fulfilled the aforementioned cri- teria were randomly assigned to receive either enalapril or atenolol in parallel groups. Each center had a separate randomization process that was stratified for previous drug treatment. The study was conducted in a double-blind fashion using a double-dummy tech- nique. Treatment was continued for 12 weeks and patients were reviewed at two, four, eight, and 12 weeks after randomization. The aim was to reduce systolic

April 1989 The American Journal of Medicine Volume 86 421

COMPARISON OF ATENOLOL AND ENALAPRIL FOR HYPERTENSION / HERRICK ET AL

TABLE I Comparability of the Two Treatment Groups at Randomization

Atenolol (n = 76)

Enalapril (n = 86)

Age (years)* Sex (M:F) Weight (kg)*

5w;-” 4;;,5;.3)

74.2’(1.5) 76.5’(1.6)

Supine’ Blood pressure (mm Hg)

Systolic Diastolic

Pulse rate (/minute)

170.8(1.7) 167.8(1.5) 98.2 (1 .O) 80.2(1.1)

Standing* Blood pressure (mm Hg)

Systolic Diastolic


162.3 (1.7) 158.8(1.5) 101.6(1.2)

84.2 (1.6) 102.8(1.0)

86.7 (1.1)

ilalues are mean (SEM).

blood pressure to 140 mm Hg or less and diastolic blood pressure to 90 mm Hg or less. The initial dose was enalapril20 mg or atenolol50 mg, each taken once daily in the morning. If blood pressure did not reach the stated target at four or eight weeks after randomization, the dose was increased to enalapril40 mg once daily or atenolol 100 mg once daily.

Measurements For each person, all assessments were made at ap-

proximately the same time of day, three to eight hours after drug administration. At every visit, patients were weighed and had their blood pressure and pulse rate recorded supine and erect in the right arm after 15 minutes of rest. Blood pressure was measured with the arm supported at heart level using a random-zero sphygmomanometer, recording phase V diastolic pressure. Tablet counts were carried out at each visit, and urinary drug assay was performed on two occasions, four and 12 weeks after randomization. Hematologic and biochemical monitoring, including measurement of plasma renin [16], was performed after 30 minutes supine at the end of the placebo period and during randomized treatment. Subjective side effects were assessed by the response to a standard non-leading question at each visit, and by a questionnaire based on that devised by Bulpitt and Dollery [17] at entry to and exit from the trial.

Psychologic Testing In 134 patients, psychologic tests were performed at

the end of the placebo phase and after 12 weeks of randomized treatment, under the supervision of a psy- chiatrist or clinical psychologist trained in their use. Patients who had a history of mental illness or neuro- logic disturbance were excluded from these tests. Psy- chiatric morbidity was measured using the 60-item General Health Questionnaire [18]. Verbal memory was assessed by subtests of the Weschler memory scale [19], and non-verbal memory by the Complex Figure Test [20]. A Digit Symbol Substitution Test [21] and Paced Auditory Serial Addition Task [22] were used as measures of speed, co-ordination, and attention. So- cial functioning was also evaluated, using the self-report form of the Social Adjustment Scale [23].

422 April 1989 The American Journal of Medicine Volume 86

Pulmonary Function and Exercise Testing Measurements of pulmonary function at rest were

made during the placebo period and after eight weeks of randomized treatment in 118 patients, using a spi- rometer and a heated pneumotachograph. Tests in- cluded measurement of forced expiratory volume in one second (highest of three readings used in the analysis) and maximum flow rate at 25 percent of vital capacity (mean of three readings used in the analysis). At two centers, a subset of 64 patients also underwent treadmill exercise testing at the same visits, using a graded Bruce protocol with three-minute stages [24]. At the end of each stage, blood,pressure, pulse rate, oxygen consumption, and minute ventilation were measured and dyspnea and tiredness assessed using lo-cm visual analogue scales. The results were analyzed using data for the last stage of exercise that was completed on both occasions.

Statistical Methods The sample size was determined in order to provide

a power of 0.8 to detect a difference between the drugs in blood pressure response of 8/5 mm Hg, with statistical significance at the 5 percent level. A single planned interim analysis was performed with the intention that exercise or psychologic testing would be stopped if clear treatment differences (p <O.OOl) were demonstrated. The stopping rule was so stringent that no adjustment to allow for the interim analysis has been made. Differences between the drugs in changes from the placebo period were compared using two-sample t- tests, except for data from psychologic testing, which were analyzed using the Mann-Whitney U-test, with corresponding confidence intervals. All p values refer to the two-tailed significance of between-group differences. Age adjustment was performed using analysis of covariance.

RESULTS Characteristics of patients at random assignment to

atenolol (n = 76) or enalapril (n = 86) are shown in Table I. The groups were well matched for important variables except for age, with atenolol-treated patients being, on average, four years older, Fifteen patients withdrew from the trial (atenolol, n = 7; enalapril, n = 8) and blood pressure findings refer to the 147 patients who completed 12 weeks of treatment. The mean final daily doses used were atenolol91 mg, and enalapri133 w.

Blood Pressure and Pulse Rate Decreases in supine systolic and diastolic blood

pressure were significantly greater with enalapril than with atenolol (Figure 1). At 12 weeks, the mean reduction with enalapril was 19.0 (SEM 1.6)/12.4 (1.1) mm Hg, compared with 8.8 (2.1)/7.4 (1.2) mm Hg for ateno- 101 (p <0.001/p <0.005). For standing blood pressure, the mean reduction with enalapril was 20.1 (1.9)/12.3 (1.4) mm Hg, compared with 13.3 (2.2Y9.1 (1.4) mm Hgfor atenolol (p = 0.02/p = 0.10). Adjustment for age had no important effect on blood pressure responses (Table II). For example, the difference between enalapril and atenolol for mean reduction in supine systolic blood pressure was 10.2 mm Hg (95 percent confidence interval 5.0 to 15.4 mm Hg), with the corresponding difference after age adjustment 9.8 mm Hg (95 percent confidence interval 4.5 to 15.1 mm Hg).


Thirty of 86 patients (35 percent) randomly assigned to enalapril achieved target blood pressure (140 mm Hg systolic or less and 90 mm Hg diastolic or less) at 12 weeks, compared with 11 of 76 patients (14 percent) randomly assigned to atenolol (p <O.Ol). Target blood pressure was achieved by 21 patients taking enalapril 20 mg daily and by four patients taking atenolol50 mg daily. Atenolol reduced the mean supine pulse rate by 16.6 (1.2) beats/minute, compared with an increase of 0.8 (1.1) beats/minute with enalapril (p <O.OOl).

Adverse Effects Eight patients withdrew from the trial because of

adverse effects that they attributed to randomized treatment; the other seven withdrawals were for rea- sons unrelated to the trial. In the atenolol group, three patients withdrew, respectively, because of tiredness, dizziness, or impotence. In the enalapril group, five patients withdrew because of tiredness (two patients), chest pain, wheeze, or cold extremities. The most common volunteered side effects with atenolol were tiredness (16 percent) and dizziness (9 percent). For enalapril, common volunteered side effects were tiredness (17 percent), dizziness (14 percent), and headache (8 percent). Cough was reported by four patients taking enalapril and two patients taking atenolol.

Symptom questionnaires showed no significant difference between the drugs in the average number of symptoms reported per patient (atenolol, 3.2; enalapril, 3.0). Patients reported an average of 0.5 symptoms less during atenolol treatment and 0.1 symptoms less with enalapril (95 percent confidence interval for difference: -1.0, +0.3), compared with placebo treatment. As assessed by volunteered information and symptom questionnaires, no particular symptom occurred significantly more frequently with either drug.

Psychologic Tests Findings from the psychologic tests are summarized

in Table III. Scores increased significantly more with enalapril than with atenolol for the Digit Symbol Sub- stitution Test (p <0.005) and Paced Auditory Serial Addition Task (p <0.05). In these tests, increased scores indicate beneficial effects. There were no other significant differences between the groups.

Pulmonary Function and Exercise Testing As assessed by changes in forced expiratory volume

in one second and maximum flow rate at 25 percent of vital capacity, resting pulmonary function altered lit- tle with either treatment and differences between the drugs were not significant (Table IV). Exercise duration increased by 25 seconds with enalapril but did not change with atenolol, a difference that also was not significant (Table V). Atenolol attenuated the rise in systolic blood pressure and pulse rate with exercise by 15 mm Hg more than enalapril (p <O.Ol). There were no significant differences between the drugs as regards oxygen consumption, minute ventilation, and subjective dyspnea and tiredness, as assessed by visual analogue scales (Table V).

During placebo treatment, patients subsequently randomly assigned to receive atenolol seemed to be less fit (shorter duration of exercise), more dyspneic, and more tired (visual analogue scales). None of these differences was statistically significant: exercise time, t = 1.05 (62 df), p = 0.30; dyspnea, t = 1.56 (62 df), p =

Figure 1. Mean (SEM) effects of 12 weeks of treatment with atenolol (n = 69) or enalapril (n = 78) on supine blood pressure (BP) (mm Hg). Mean daily doses of atenolol at zero, two, four, eight, and 12 weeks were 0, 50, 50, 87, and 91 mg, respectively. Mean daily doses of enalapril at zero, two, four, eight, and 12 weeks were 0, 20, 20, 31, and 33 mg, respectively.

TABLE II

Differences between Patients Treated with Atenolol (n = 69) and Enalapril (n = 78) in Mean Unadjusted and Age- Adjusted Blood Pressure and Heart Rate Reductions*

Unadjusted Age-Adjusted

Supine Blood pressure (mm Hg)

Systolic Diastolic

+10.2t+5.0, +15.4) $5.1 (+1.9, +8.3)

$9.8 (+4.5, f15.1)

Pulse rate (/minute) +4.3 (+l.l, +7.5)

-17.4(-20.5, -14.2) -17.3(-20.5,-14.0)

Standing Blood pressure (mm Hg)

Systblic -’ Diastolic

+6.8(+1.1, +12.6)

Pulse rate (/minute) +3.2 (-0.6, +7.1)

+6.0(+0.2, +11.8) f2.7 (-1.2, +6.6)

-22.9(-26.7, -19.0) -23.0(-26.9, -19.0) * Results are expressed as enalapril minus atenolol (95 percent confideno intervals).

0.12; tiredness, t = 0.90 (62 df), p = 0.37. In view of the multiple tests, such trends would be expected to arise simply due to chance.

Other Variables Body weight increased by an average of 0.57 kg with

atenolol and decreased by an average of 0.8 kg with enalapril (p <O.OOl). Compliance was satisfactory in both groups, as judged by tablet counts and urinary drug assays. Tablet counts suggested that 86 percent of patients treated with atenolol and 82 percent of patients treated with enalapril took more than 90 percent of their tablets. One patient in the atenolol group and three in the enalapril group were found to have taken less than 80 percent of their tablets. As expected, plasma renin concentration increased markedly with enalapril and decreased with atenolol, a difference that was highly significant (p <O.OOl; Table VI). Serum uric acid increased by 30 pmol/liter in the aten- 0101 group compared with a 5 pmol/liter increase in the enalapril-treated patients (p <O.Ol). There were no


CONPARISON OF ATENOLOL AND ENALAPRIL FQR HYPERTENSION / HERRICK ET AL

TABLE III

Median Results for Psychologic Testing of Patients Treated with Atenolol or Enalapril*

General Health Questionnaire

Social Adjustment Scale

Atenolol (n = 64) Placebo Change

1.0 0.0

148 0.0

Enalapril (n = 70) Placebo Change

0.0 0.0

140 -3.0

Difference (95 percent confidence intervals)

Complex Figure (copy)

Complex figure (immediate recall)

33.0 0.0 33.0 0.0 (-5.06;7.0)

20.0 +1.0 18.5 +1.5 ybyo

Complex Figure (delayed recall)

Digit forward

18.5

7.0

0.0 16.5 +2.0

0.0 7.0 0.0

(-Wi2.5)

(-o.5b$.o)

Digit backward

Logical memory

Paired Associate Learning

Digit Symbol Substitution Test

Paced Auditory Serial Addition Task

10.0 +1.0

14.0 0.0

47 +2.0

60.5 +5.5

10.0

14.5

49

55.0

+0.5

-0.3

+4.0

+10.0

Units are arbitrary; for the General Health Questionnaire and Social Adjustment Scale, an increase in score is adverse; for all other tests, an increase in score i 8 . . , ^.,, . ..I oenencrar. umerences are expressea as enaiaprri minus atenoiot. t p <0.005. * p <0.05.

TABLE IV

Mean (SEM) Results of Resting Pulmonary Function Tests in Patients Treated with Atenolol or Enalapril*

Atenolol (n = 54) Placebo Change

Enalapril (n = 64) Difference (95 percent Placebo Change confidence intervals)

Forced expiratory volume in one 2.77 second (liters) 0;;’

Maximum flow at 25 percent of vital capacity (0.06)

* Differences are expressed as enalapril minus atenolol.

-0.12 2.97 -0.03 +0.09 (g5) ‘y.;:’ (0.03)

(0:04) (0:ll) -0.07

(-O.(J?$I21)

(0.04) (-0.18, +0.04)

TABLE V

Mean (SEM) Duration of Exercise, Blood Pressure, Pulse Rate, Pulmonary Function Test Results, and Visual Analogue Scale Findings during Graded Treadmill Exercise in 64 Patients Treated with Atenolol or Enalapril*

Atenolol (n = 32) Enalapril (n = 32) Placebo Change Placebo Change


Duration of exercise (seconds)

Systolic blood pressure (mm Hg)

Diastolic blood pressure (mm Hg)


586 639 +25 +25

13:1 (19)

-35 YOJ -20 (yi5;73)

I2 ‘“i”Q

1’2 5;’ “;1+28)

ki; (221 (3)

156 ’ y ‘y&l1

(3) (2.7) (5) (2.7) (+22, +37)

Pulmonary Function Tests Oxygen consumption

(ml/kg/minute) Minute ventilation

(liters)

22.7 -1.3 22.8 -0.3 +1.0

42’ (0.6) (0.6) -3.3 42 -2.6 (-0$;2.7)

(1.9) (1.1) Q.8) (1.4) (-2.9, +4.3)

Visual Analogue Scales Dyspnea (cm) 4.54 +0.03 3.44 +0.62 +0.59

Tiredness (cm) ‘:::l !% ‘3 (0.5)

+0.15 (-O.f$+$.87)

(0~3 (0.5) (0.5) (0.5) (-1.88, +0.94) L * For Visual Analogue Scales, an increased score reflects increased symptom severity. Differences are expressed as enalapril minus atenolol. tp <O.Ol. *p <O.DDl.



TABLE VI

Median Results of Hematologic and Biochemical Tests in Patients Treated with Atenolol or Enalapril

White blood cell count (X log/liter)

Serum potassium (mmol/liter)

Serum creatinine (rmol/liter)

Serum urate (pmol/liter)

Plasma renin concentration W/ml)

Atenolol (n = 69) Enalapril (n = 78) Placebo Change Placebo Change

6.5 +0.3 6.3 +o. 1

4.3 +0.1 4.3 +o. 1

85.0 0.0 86.5 -2.0

300 +20 305 +5

18 -5 21 +80


-0.2 (-0.5.0&II.2)

(-o.$t;.2)

(-410i5+3.0)

(-i$5;40)

(f65, f147) * Differences are expressed as enalapril minus atenolol. tp <O.Ol. * p <O.OOl.

other important changes in hematologic or biochemical variables (Table VI).

COMMENTS At the doses used, enalapril clearly reduced supine

systolic and diastolic blood pressure more than ateno- 101 did, and levels of significance suggest that it is most unlikely that these findings occurred by chance. Dif- ferences between the drugs for standing blood pressure were less marked and non-significant for diastolic blood pressure. Significantly more patients achieved target blood pressure in the enalapril group and 70 percent of those whose blood pressure was controlled by enalapril did not require the dose to be increased above 20 mg daily. Previous studies have suggested that enalapril may have a greater effect than atenolol on systolic blood pressure [12-X], but hitherto no significant difference in diastolic blood pressure has been reported. However, blood pressure was measured at only one time point during the dosage interval and, therefore, the findings may not reflect 24-hour blood pressure control. Measurements were intended to co- incide with the peak antihypertensive effect of each drug, but if the time courses of action of enalapril and atenolol differed, the results may be biased towards one or other of the agents. At the doses used in this study, enalapril and atenolol have 24-hour durations of action, leading us to believe that the observed differences are of clinical relevance.

Attenuation of exercise-induced increases in systolic blood pressure and heart rate were significantly greater with atenolol. This has been observed previously [25], but the importance of such a difference is not known.

Atenolol had only a modest effect on resting blood pressure in this study, with a mean supine response of 917 mm Hg. This was unlikely to be due to poor compliance, as shown by tablet counts, urinary drug and plasma renin assays, and a mean reduction in pulse rate of 17 beats/minute. It was also unlikely to be due to recruitment of a population of patients who were not responders to beta blockers, since only 26 percent of patients had been treated previously with a beta blocker, and their average response was similar to that of the whole group. The degree of hypertension in this study was relatively mild (mean initial supine blood pressure 171/96 mm Hg) and a 95 percent confidence interval for the mean blood pressure reduction with

atenolol shows that the true response could be as large as 13110 mm Hg. Low rates of achievement of target blood pressure in both groups reflected the deliberate- ly stringent target (140 mm Hg systolic and 90 mm Hg diastolic).

The frequency and severity of side effects were similar during treatment with atenolol or enalapril and, in general, both drugs were well tolerated. Previous work has shown that cardioselective beta blockers may reduce pulmonary function [4], but only a small decrease in mean forced expiratory volume in one second was observed with atenolol and there was no change in the maximum flow rate at 25 percent of vital capacity. These measurements were not significantly different between the groups, and 95 percent confidence intervals show that an important difference in their effects on pulmonary function is unlikely to occur. In response to a non-leading question about side effects, cough was reported by four patients who took enalapril in our study (5 percent). Cough is an increasingly recognized side effect of treatment with ACE inhibitors [26]. The true incidence is not known, although prescription event monitoring suggests that at least 2 percent of patients are affected [27].

The duration of graded treadmill exercise increased by 4 percent after enalapril, but compared to atenolol, this was not significant. The 95 percent confidence interval shows that a difference of more than 12 percent in favor of enalapril is improbable. Although long-term treatment with beta blockers reduces exercise capacity [28], this may be less marked with cardioselective agents [29] ,,and our study suggests that enalapril is unlikely to have an important advantage over atenolol in this respect. During exercise, measurements of respiratory function, and subjective tiredness and dyspnea showed no large differences between patients treated with enalapril and patients treated with atenolol.

Interpretation of the psychologic findings could be confounded by observed differences in blood pressure response, although recent evidence from the Framing- ham study suggests that blood pressure may not be related to cognitive performance [30]. For two tests (the Digit Symbol Substitution Test and the Paced Auditory Serial Additon Task), differences between the drugs were significant, favoring enalapril. Both these tests assessed attention and mental speed, and increased alertness has been reported with enalapril in healthy volunteers [31]. Cautious interpretation of our



findings is necessary because a large number of statistical comparisons were made and some significant results might have been expected to occur by chance, even if the drugs were truly no different. This seems less likely for the Digit Symbol Substitution Test, as the difference was highly statistically significant (p <0.005). The clinical significance of a median difference in score of less than 5 percent is uncertain, however, and this would probably only be important in occupations where a high degree of mental acuity is required. Overall, tests of psychologic function suggested that enalapril may be preferable to atenolol, but this difference is unlikely to be large and is not necessarily important.

In conclusion, enalapril, 20 to 40 mg daily, had a greater antihypertensive effect than atenolol, 50 to 100 mg daily, in the short term. This advantage may not be applicable to smaller doses of enalapril, and since the study was designed, it has become common practice to use lower doses of this drug (the British National For- mulary suggests an initial dose of 5 mg daily). Mea- surements of quality of life also tended to favor enalapril, but these differences were small and the overall tolerability of the two drugs was similar. When choos- ing between a beta blocker and an ACE inhibitor for the treatment of hypertension, the probable short- term advantages of ACE inhibition must be balanced against the relatively limited long-term safety data and lack of evidence that such therapy prevents hypertensive complications.

ACKNOWLEDGMENT We thank V. Gray, E. Brannigan, and Sisters L. Robertson and M. McGowan for technical assistance.

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comparison of enalapril and atenolol in mild to moderate hypertension

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