Comparison of Bevantolol and Atenolol for Systemic Hypertension

G.J. FAIRHURST, MD

In an international, randomized, double-blind trial involving 229 patients, 400 mg of bevantolol was compared with 100 mg of atenolol (both in single daily doses) in the management of mild to moderate hypertension (diastolic blood pressure [BP] 95 to 115 mm Hg after a 4-week placebo washout period). Patients were then randomized to 12 weeks of treatment with either drug. Patients were evaluated at 2, 4, 8 and 12 weeks during the drug treatment period. Efficacy measurements were based on sitting and standing BP and heart rate. Adverse experiences were recorded on patient checklists, by spontaneous complaints and by 12- lead electrocardiography and funduscopy. A subgroup of 104 patients had heart rate and BP determinations every 24 to 26 hours after drug ingestion. Overall results showed both drugs to be comparably effective; no real difference was shown after 12 weeks of treatment. Bevantolol caused a

more gradual BP decrease than atenolol. Both regimens were associated with decreased heart rate (less marked with bevantolol, p <O.OOl). Data from the 24-hour assessment subgroup showed similar results for both drugs, with a somewhat lower decrease in BP for bevantolol, which persisted throughout the study. Both drugs lowered sitting BP; the decrease was significantly less with bevantolol after the second week of therapy. The mean number of adverse experiences was similar for both drugs; cardiovascular side effects were less frequent with bevantolol. Patients taking bevantolol showed a higher incidence of digestive system side effects. Bevantolol maintained a 24-hour antihypertensive effect. Although atenolol showed a more rapid onset of action, at 12 weeks, there was no difference in the clinical efficacy of bevantolol and atenolol.

(Am J Cardiol 1986;58:25E-27E)

T herapy using a single 100-mg daily dose of atenolol has been shown to be effective in the management of mild to moderate hypertension1 The cardioselective ,8 blocker bevantolol reportedly has a clinical profile similar to that of atenolol, but unlike atenolol, bevanto- 101 has also been reported to have activity at cy receptor sites2 A randomized, double-blind parallel study was designed to compare these agents in the management of mild to moderate hypertension, using a single, 400- mg daily dose of bevantolol. Seven institutions in the United Kingdom, the Netherlands, France, Finland and South Africa participated.

Methods The trial design provided for a 4-week placebo

washout, after which those meeting the study criterion for mild to moderate hypertension (defined as systolic

Address for reprints: G.J. Fairhurst, MD, 348 Newton Road, Lowton, Warrington, Cheshire, United Kingdom WA3 IJD.

blood pressure [BP] between 95 and 115 mm Hg) were randomized to receive either bevantolol or atenolol. The active drug was administered in the morning and therapy was continued for 12 weeks. In addition to the assessment at the end of the placebo period, BP was evaluated at the end of weeks 2, 4, 3, and 12 of the study.

A total of 229 patients (150 men, 70 women) were entered into the trial; 222 met criteria for entry into the active phase of the study. No patient with systolic BP >200 mm Hg was included in the study.

Therapeutic efficacy was gauged on the basis of sitting and standing BP and heart rate, using the aver- age of 3 readings and Korotkoff’s fifth sound for BP. A subgroup of 104 patients at 3 centers had BP and heart rate determinations taken every 24 to 26 hours after drug ingestion. This subgroup was evaluated separate- ly and is included in the overall assessment of the study.

Adverse experiences were assessed by means of a patient checklist and on the basis of spontaneous pa-

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FIGURE 1. Adjusted mean silting systol- ic blood pressure (BP) for all patients. There were no significant differences between treatments, and both bevanto- lol and atenolol were significantly effec- tive (p <O.OOl) at all assessments com- pared with baseline BPS.

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FIGURE 2. Adjusted mean sitting diastol- ic blood pressure (BP) for all patients. Significant differences (p <0.05) oc- curred between treatments at all as- sessments. Both bevantolol and atenolol were significantly effective (p <O.OOl) at all assessments compared with base- line BPS.

FIGURE 3. Mean sitting systolic blood pressure (BP) in 104-patient subgroup that was assessed daily. There were no significant differences in response be- tween the 2 groups. Both treatments were significantly effective (p <O.OOl) at all assessments compared with base- line BPS.

FIGURE 4. Mean sitting heart rate in 104-patient subgroup monitored daily. Both treatments lowered heart rate sig- nificantly (p <O.OOl) compared with baseline levels. ** = significant differ- ences (p <O.OOl) occurred between be- vantolol and atenolol at all assessments. BPM = beats/min.

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November 26, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 58 27E

tient complaints. In addition, 12-lead electrocardiogra- phy and funduscopy were used to assess possible ad- verse effects. Laboratory studies done in all patients included hematologic, biochemical and urinalysis tests.

Patient characteristics: Entered into the active phase of the study were 146 men and 76 women. There were 75 men and 36 women randomized to bevantolol therapy, and i’l men and 40 women randomized to atenolol. The 2 groups were closely comparable in terms of sex, age, weight and severity of hyperten- sion-demographic features that could affect study outcome. There were more smokers in the atenolol group (29 vs 20). The number of patients in each treat- ment group completing 12 weeks of therapy was essen- tially the same: 97 for bevantolol, 99 for atenolol.

Results On the basis of actual recorded values and on the

basis of adjusted mean values, both drugs resulted in similar decreases in systolic BP by the end of the 12- week treatment period (Fig. 11. The onset of action, however, was more gradual in the bevantolol group.

Similar analyses, using diastolic BP values, showed very similar results: comparable decrease in BP at the end of the l&week therapy period, but with a much more gradual decrease in the bevantolol patients (Fig. 2).

Both drugs were associated with a reduced heart rate over the 12 weeks of therapy. However, the be- vantolol-associated decrease was less than that seen with atenolol, particularly at the week 4 and week 12 evaluations. The difference was statistically signifi- cant at the p <O.OOl level.

Both drugs lowered BP in the subgroup of 104 pa- tients who had BP and heart rate determinations ap- proximately every 24 hours (52 patients in each drug group). But by the end of 12 weeks of therapy, it was apparent that there was no significant difference be- tween the 2 treatments (Fig. 3).

When the BP determinations at 24 hours were ex- amined, it was again apparent that both drugs lowered BP during the course of the day.

The 24-hour evaluations also showed that both drugs were associated with a decrease in heart rate; however, the bevantolol-associated decrease was less marked than that seen with atenolol throughout the 12- week treatment period [Fig. 41.

Adverse effects: The overall incidence of adverse effects was similar in the 2 treatment groups (2.84% for the bevantolol group, 2.52% for atenolol). Neither was markedly higher than the incidence observed during the placebo phase (2.08%).

When evaluated on the basis of body systems af- fected, however, bevantolol was associated with a higher incidence of digestive system side effects (27.0% vs 13.5% for atenolol and 2.6% for placebo]. There was a somewhat higher incidence of dermato-

logic side effects with bevantolol (4.5% vs 0.9% for atenolol and 0.4% for placebo). Atenolol was associ- ated with a higher incidence of cardiovascular side effects (11.7% vs 3.6% for bevantolol and 2.2% for placebo].

While the incidence of diarrhea was 9.0% in the bevantolol group compared with 0.9% in the atenolol group, no patient discontinued medication. Further, it is interesting to note that diarrhea is also a part of the clinical profile of peripheral CY blockers like prazosin.

The incidence of hypotension was higher in the atenolol group (1.8%); no hypotension was recorded for either the bevantolol or the placebo group. Periph- eral vascular side effects in the atenolol group also exceeded those in the others (5.4% compared with 1.8% for bevantolol and 0.9% for placebo].

Dosage reduction proved necessary in 12 bevanto- lol-treated and 6 atenolol-treated patients. Adverse events were probably responsible for 9 of the dosage reductions in the bevantolol group, and 3 of the reduc- tions in the atenolol group.

Laboratory tests showed no hematologic changes in either treatment group. Similarly, there were no alter- ations in either funduscopy or in electrocardiographic assessments in either group. No atrioventricular block or arrhythmia was detected in either group during the study. One patient who received atenolol and 2 who received bevantolol showed an increase in phosphatase at the end of the 12-week trial. tion, 9 bevantolol- and 4 atenolol-treated showed an increase in blood urea levels.

Discussion

alkaline In addi- patients

Results of this trial clearly show that a single daily dose of either 400-mg bevantolol or 100-mg atenolol is effective in the management of mild to moderate hy- pertension. Bevantolol as a single daily dose taken in the morning maintained an antihypertensive effect for 24 hours. It also controlled hypertension to the same degree as atenolol by the end of the U-week trial period, even though it has a slower onset of action.

Bevantolol also resulted in a significant decrease in heart rate [although not as great a decrease as with atenolol), and was associated with a lower incidence of peripheral vascuIar side effects. These 2 attributes suggest that bevantolol might be especially suitable for the management of mild to moderate hypertension in patients for whom compliance may be difficult, be- cause of either too rapid or too profound antihyperten- sive effects leading to hypotensive side effects,

References 1. Castleden CM. Dathan IR. Georee CF. A comtxxison of once and twice daily atenolol in hypertenskxx Post&ad Med f 19+7:53:625,679-682. 2. Kaplan HR. Bevontolol hydrochloride preclinicol pharmacologic profile. Angiology 1986:37:254-262.