Eur J Clin Pharmacol (1990) 38: S 143-S 146

@ Springer-Verlag 1990

Safety and antihypertensive efficacy of carvedUol and atenolol alone and in combination with hydrochlorothiazide L. Widmann , R. van der Does , M. H 6 r r m a n n , and M. Machwir th

Boehringer Mannheim GmbH, FRG

Summary. Carvedilol has been shown to be effective and safe in patients with essential hypertension when given as monotherapy. In this double-blind, randomized, group- comparat ive study, 2 groups of 59 patients with mild to modera te essential hypertension [median supine sys- tolic/diastolic blood pressure at baseline (SBP/DBP), 168/105 m m Hg] were treated with either 25 mg carvedilol once daily (o. d.) or 50 mg atenolol o. d. for 4 weeks. Re- sponders at 4 weeks (DBP, < 90 m m H g ) terminated the study. Nonresponders continued the study. Hydrochloro- thiazide (HCTZ) was added at 25 mg o.d. for a further 6 weeks. The median blood pressure decreased under monotherapy with carvedilol (n = 59) from 167/105 at baseline to 155 /94mmHg after 4weeks , and in the atenolol group (n=59 ) it decreased f rom 168/105 to 162/97 m m H g . The patients who received carvedilol in combination with H C T Z and were evaluated for efficacy (n = 38) showed a decrease in SBP/DBP f rom 156/97 at the end of monothe rapy to 145/88 m m H g af ter 10 weeks; the combination of atenolol with H C T Z (n = 44) reduced BP f rom 162/97 to 147/88. Both carvedilol and atenolol were safe when given either alone or in combination with H C T Z . In conclusion, after long-term administration, 25 mg carvedilol o. d. and 50 mg atenolol o. d. significantly reduced both SBP and D B P over 24 h. The addition of H C T Z led to a further increase in antihypertensive effi- cacy. Combined t reatment with carvedilol or atenolol and H C T Z was very well tolerated, without hypotensive events or relevant changes in objective safety parameters .

Key words: carvedilol, atenolol, hydrochlorothiazide, safety, efficacy, essential hypertension

Carvedilol, with its balanced dual mode of action consist- ing of beta-blockade and vasodilation in the same dose range, has been shown in a series of well-controlled studies to be effective and safe in the t rea tment of mild to

modera te essential hypertension when given as mono- therapy.

The purpose of the present study was to investigate further its antihypertensive efficacy and safety when given alone and in combination with hydrochlorothiazide (HCTZ) . The reference drug in this controlled trial was atenolol alone and in combination with HCTZ. The doses of the antihypertensive agents were based on the results of previous studies with carvedilol [1] and on the currently approved average dosing regimens for atenolol and H C T Z in patients with mild to modera te essential hyper- tension.

Materials, methods, and subjects studied

Study design

This was a randomized, double-blind, multicentre group-com- parative trial in patients with mild to moderate essential hyperten- sion. After a wash-out period of at least 2 weeks for patients pre- viously treated with antihypertensive agents and a 2-week placebo run-in period for all other eligible patients, a dose of either 25 mg carvedilol once daily (o. d.) or 50 mg atenolol o. d. was assigned in a randomized, double-blind manner for 4 weeks. Patients with DBP of < 90 mmHg after 4 weeks of treatment terminated the study. Pa- tients with a DBP of > 90 mmHg received 25 mg HCTZ o. d. in ad- dition to their existing study medication. The combined treatment was given for a further 6 weeks. The study design is shown in Fig. 1.

Patients

A total of 126 patients (76 men and 50 women aged 23-73 years) were enrolled and randomized. Patients were included if they had mild to moderate essential hypertension (WHO grade I or II) with a mean supine DBP of between 100 and 115 mmHg when measured on 2 consecutive clays during the placebo run-in period. Informed consent was obtained from all patients before their entry into the study.

S 144

|

Carvedilol [Carvedilol + HCTZ Placebo 25 mgo.d. 725 mgo.d. 25 mgo.d.

o.d. I Atenolol ~Atenolol + HCTZ ~0 mgo.d. ]50 n~g o.d. I 25 mgo.d.

- L t

Visit 0 1 2 3 4 5 6 7

Week - 2 0 2 4 5 6 8 10

Medical history X

Randomisation X

B. weight X X X X X X X X

BE HR at trough X X X X X X X X

BP, HR 2 h after reed. X X X

ECG X X X X

Laboratory X X X X

Tablet/ Capsule count X X X X X X X

Fig.1. Responder (mean DBP in supine and standing positions < 90 mmHg) terminated study at week 4. Additional administra- tion of Hydrochlorothiazide (HCTZ): 25 mg o. d. to nonresponders during weeks4-10. BP=blood pressure; HR=hear t rate; B. weight = body weight; reed = medication; o. d. = once daily

Criteria for exclusion were: contraindications for beta-blockers, vasodilators and HCTZ; renal or hepatic impairment; stroke or myocardial infarction (MI) within the preceding 12 months; un- stable angina pectoris; pregnancy and lactation; or participation in another study within the preceding 30 days,

Measurements

A complete medical history was taken and a physical examination was performed for each patient before enrollment in the study and at the final visit. Whenever possible, blood pressure was measured by the same person and at the same time in the morning, using a cali- brated sphygmomanometer with an inflatable cuff. On the first visit it was determined on both arms; if a difference existed, at the follow- ing visits the blood pressure was taken on the arm with the higher value. Phases I and V of the Kdrotkoff sounds were used as end points for systolic and diastolic pressure. Supine blood pressure was recorded after patients had spent l0 min at rest, and the mean of three subsequent readings taken at 1-min intervals was calculated. In addition, a single reading was taken after patients had stood for 2 min. The pulse rate was counted for 60 s directly after each blood pressure measurement and the mean was then calculated.

At weeks 0, 4 and 10, the blood pressure was measured in the same way both before and 2 h after drug administration, at the ex- pected peak of the study drugs efficacy [2, 3]. Response was defined as supine and standing DBP of < 90 mm Hg. Before their enrollment in the study and at the final visit, blood was collected from patients for safety laboratory tests. Before the start of the study, at weeks 0 and 4 and at the final visit, a 12-lead electrocardiogram was obtained with patients at rest in the supine position. All adverse events (AE) were recorded.

Statistical analysis

Quantitative data were expressed by median and range if not stated otherwise. Comparisons between the groups were made by calcu- lated P-values according to the Wilcoxon-Mann-Whitney test. With-

L. Widmann et al.: Safety and antihypertensive efficacy of carvedilol and atenolol

in-group comparisons were done by means of P-values using the Wilcoxon signed rank test. Results were considered to be significant if P-value was < 0.05.

Resul t s

Assignment of patients

126 patients were enrolled and randomized to monother- apy with either carvedilol or atenolol. Of these 126 pa- tients, all of whom were evaluated for safety, 118 were in- cluded in the p e r - p r o t o c o l analysis of eff icacy at the conclus ion of the four w e e k m o n o t h e r a p y phase . A f t e r 4 to 5 weeks , 26 pa t i en t s (17 in the ca rved i lo l g roup and 9 in the a t eno lo l g roup) were wi thdrawn: 13 and 8 pa t i en t s on ca rved i lo l and a teno lo l , respect ively , were r e sponde r s wi th supine and s t and ing D B P < 90 m m H g . O n e pa t i en t on a t e n o l o l + H C T Z was w i thd rawn af ter 5 w e e k s (1 w e e k on c o m b i n a t i o n t r e a t m e n t ) when it was dis- c o v e r e d tha t he was a r e s p o n d e r at the end of m o n o t h e r - apy, and t he r e fo re shou ld no t have con t inued with combi - na t i on t r ea tmen t .

100 pa t i en t s e n t e r e d the six w e e k c o m b i n a t i o n t rea t - m e n t p h a s e wi th 46 rece iv ing c a r v e d i l o l + H C T Z and 54 rece iv ing a t eno lo l + H C T Z .

D u r i n g c o m b i n a t i o n t r e a t m e n t wi th H C T Z (weeks 4-10) four pa t i en t s in the ca rved i lo l g roup and six pa t i en t s in the a t eno lo l g roup were wi thdrawn. T h e r ea son was n o n c o m p l i a n c e in two ca rved i lo l + H C T Z pa t i en t s and in five a t e n o l o l + H C T Z pat ients . O n e pa t i en t in the car- ved i lo l g roup was los t to fo l low-up, and one pa t i en t in each g roup was w i t h d r a w n be c a use of AEs . A l l 100 pa- t ien ts rece iv ing c o m b i n a t i o n t h e r a p y were e v a l u a t e d for safe ty and, of the 97 pa t i en t s who c o m p l e t e d the study, 82 pa t i en t s were inc luded in the p e r - p r o t o c o l analysis of efficacy.

Table L Patients' demographic and anamnestic data

Carvedilol Atenolol

Number of patients 59 59

Age(years) 57 (26-73) 55 (23-69)

Sex (male/female) 33/26 39/20

Height(cm) 170 (156-187) 172 (153-189)

Body weight (kg) 76 (51-96) 81 (62-99)

Hypertension since 1987 13 13 since 1984 19 15 before 1984 27 31

Smokers 13 18

Concomitant diseases: Hypercholestcrolemia 15 20 Hypertriglyceridemia 10 15 Diabetes mellitus 7 8 Hyperuricemia 8 8 Coronary heart disease 3 11 Compensated heart failure 5 2 Cerebral vascular disease 2 2 Peripheral vascular disease 4 5

No maj or data differences in patients excluded from efficacy analysis were found. Data represent median values; numbers in parentheses represent minimal and maximal values

L. Widmann et al.: Safety and antihypertensive efficacy of carvedilol and atenolol $145

mmHg

210-

190-

170 -

150-

130-

110-

90-

supine standing supine standing supine standing week 0 week 4 week 10

~g.2. Systolic and diastolic blood pressure. Antihypertensive effi- cacy o125 mg carvedilol o. d. and 50 mg atenolol o.d. either alone or in combination with 25 nag HCTZ o.d. in weeks 0, 4 and 10 before and 2 h after administration. ~ , carvedilol + HCTZ ( _> week 4) be- fore and 2h after morning medication; ~ , atenolol + HCTZ (> week 4) before and 2 h after morning medication. For A to week0 within groups, * P<0.05; ** P<0.01; *** P<0.001. ForA to week4 within groups, + P<0.05; ++ P<0.01; + + + P < 0.001. Data points represent median values; bars represent minimal and maximal values

Systolic and diastolic blood pressure and heart rate

During the first 4 weeks of therapy, the median DBP measured with patients in the supine position decreased from 105 to 94 m m H g (P < 0.001) in the carvedilol group and from 105 to 97 m m H g ( P < 0.001) in the atenolol group. The supine SBP decreased from 167 to 155 m m H g (P<0.001) in the carvedilol group and from 168 to 162 m m H g (P < 0.001) in the atenolol group. The heart rate changed from 74 to 72 beats/min (P < 0.01) on carve- dilol and from 74 to 70beats/min (P<0.001) during atenolol treatment.

Of those patients included in the efficacy analysis at the end of monotherapy, 13 out of 59 patients in the car- vedilol group and 8 out of 59 in the atenolol group were re- sponders.

The data on patients who continued the trial with com- bined treatment with H C T Z are shown in Fig. 2. Supine SBP decreased from week 4 to week 10 from 156 to 145 m m H g (P < 0.001) in the carvedilol plus H C T Z group and from 162 to 147 m m H g (P < 0.00l) in the atenolol plus H C T Z group.

The supine DBP decreased from 97 to 8 8 m m H g (P < 0.001) in both groups.

In the per-protocol analysis at week 10, 15 out of 38 pa- tients in the carvedilol + H C T Z group and 22 out of 44 in the atenolol + H C T Z group were responders.

The demographic and clinical history data of the pa- tients are given in Table 1.

Laboratory results

Discussion

Diuretics are widely used in antihypertensive therapy and are very frequently used in combination with other agents. This trial was carried out to obtain data on the efficacy and safety of carvedilol in combination with HCTZ.

No clinically relevant changes were seen with respect to the laboratory data at the end of the study. No differences between groups were detected.

Adverse events

Adverse events (AE) occuring during monotherapy with carvedilol or atenolol and during the combination treat- ment are listed in detail in Table 2. The Table also pro- vides information on AEs considered possibly or prob- ably drug related.

An increase in serum cholesterol was reported as AE for 2 patients on atenolol monotherapy and I patient on carvedilol monotherapy. 4 patients on atenolol + H C T Z had this event, 2 of whom were the same 2 with this A E on atenolol monotherapy. An increase in triglycerides was reported in 2 patients on atenolol monotherapy. During the combined treatment period i patient on carvedilol + H C T Z and 3 patients on atenolol + H C T Z had this AE, 2 of whom had the same event on monotherapy.

No severe AEs that could have been interpreted as study-drug-related were recorded with either combina- tion.

Table 2. Adverse events

C A C+H A + H

Events Bradycardia 1 a 1 ~ Dizziness 1 a 2 "' ~ 1" Tremor I a Headache 1 N a u s e a l a 1 a

Decrease in potassium 1 Increase in cholesterol i s 2 a 4 ~ Increase in triglycerides 2 a i a 3" Increase in gamma-GT 2 ~ Increase in uric acid 1 1 Common cold 2 2 Acute bronchopneumonia 1 Peribronchitis 1 Cystitis 1 1 Cholecystitis 1 Fracture of the femur 1 b, c

Total patients with AE(S) 2 6 9 9

Total patients with AE(S) possibly or probably related 1 4 4 8

a Possibly or probably related to study medication. b Serious AE. c One patient withdrawn because of this AE. (C Carvedilol; A Atenolol; H HCTZ)

S 146 L. Widmann et al.: Safety and antihypertensive efficacy of carvedilol and atenolol

The data show a clinically relevant reduction in sys- tolic and diastolic blood pressure after acute and chronic administration of carvedilol and atenolol as monotherapy. The addition of H C T Z led to an increase in antihyperten- sive efficacy in both groups. With respect to safety pa- rameters, no hypotensive events occurred and the general incidence of AEs was very low for both agents alone and in combination with HCTZ.

Compared with results from previous studies, the re- sponse rate was unexpectedly low for both carvedilol and atenolol [1, 4]. There are several possible explanations: in this trial response was defined as "BPD < 90 mmHg" . Furthermore, titration was not allowed for either drug ac- cording to the trial protocol, as an increase of dosage could have influenced the rate of response. Finally, poor compliance might be considered as a source of bias in this multicentre trial in general practice. However, a full inves- tigation of the case report forms did not reveal any abnor- malities in the drug accountability.

The first administration of trial medication and H C T Z took place in the practice under direct supervision. There- fore, data after acute combined treatment may be con- sidered to be valid anyway. No major AEs occurred with combination treatment, which was given to 100 patients.

Our conclusions are, first, that a combination of ateno- lol plus H C T Z or carvedilol plus H C T Z results in an addi- tive response and secondly, that a combined treatment is well tolerated.

References

1. Rittinghausen R (1988) Response rate with respect to the blood pressure lowering effect of the vasodilating and ~-blocking agent carvedilol. Drugs 36 [Suppl 6]: 92-101

2. De Cesaris R, Ranieri G, Chiarappa R, Assereto R, Garganzelli P, Martignoni U, Nazzaron R, Pettroccione A, Bedoschi D (1988) Comparison of antihypertensive efficacy of carvedilol, a new vasodilating ]~-blocker, versus atenolol. Drugs 36 [Suppl 6]: 102- 105

3. Tomlinson B, Cronin CA, Graham BR, Prichard BNC (1987) Haemodynamics of carvedilol in normal subjects compared with propranolol, pindolol, and labetolol. J Cardiovasc Pharmacol 10 [Suppl 11]: 69-75

Dr. L. Widmann Boehringer Mannheim GmbH Sandhofer Stra6e 116 D-6800 Mannheim 31 FRG