SYSTEMIC HYPERTENSION

Celiprolol in Systemic Hypertension William H. Frishman, MD, Walter Flamenbaum, MD, James Schoenberger, MD,

Gary L. Schwartz, MD, Donald G. Vidt, MD, Gilbert0 S. Neri, MD, Steven Greenberg, MD, Eliot Lazar, MD, John C. Godfrey, PhD, Annette Stevenson, MS, Kim D. Lamon, MD, PhD,

Yueh Chang, PhD, and David J. Magner, MSHyg

The safety and efficacy of orally administered celiprolol, a new &-selective adrenergic blocking drug with peripheral &-agonist properties, were assessed in 91 patients with mild to moderate sys- temic hypertension (supine diastolic blood pressure [BP] 95 to 114 mm Hg without medication) using a placebo-controlled, double-blind, randomized, titra- tion-to-effect study design. All patients received placebo for 4 weeks and were then randomized to receive placebo (n = 46) or once-daily celiprolol (n = 45), which was titrated every 2 weeks (200, 400,600 mg/day) over a 6-week period to achieve a reduction in supine diastolic BP to 190 mm Hg. Plasma lipids and lipoproteins were also assessed at baseline, during placebo and after randomization to active therapy in a subgroup of patients. Com- pared with placebo, celiprolol reduced supine and standing BP (reduction of supine BP -0.4/-2.1 mm Hg with placebo, -5.7F6.4 with celiprolol, p <0.05; reduction of standing BP -1.7/-1.0 with placebo, -7.2/-4.9 with celiprolol, p <O.OS). &I- pine heart rate was reduced by 6.8 beats/min with celiprolol compared with 2.0 beats/min with place- bo (p <O.OS). No differences were seen when the effects of placebo and celiprolol on plasma lipopro- teins were compared. Celiprolol is a safe, effective and well tolerated once-daily antihypertensive drug and has no detrimental effects on plasma lipids.

(Am1 Cardiol 1989;63:639-642)

From the Albert Einstein College of Medicine, Bronx, New York; Pharm Evaluation Services, Englewood Cliffs, New Jersey; Rush-Pres- byterian-St. Luke’s Medical Center, Chicago, Illinois; Mayo Clinic and Mayo Foundation, Rochester, Minnesota; the Cleveland Clinic Foun- dation, Cleveland, Ohio; and Rorer Central Research, Rorer Pharma- ceutical Corp., Horsham, Pennsylvania. This study was supported by a grant from Rorer Pharmaceuticals, Horsham, Pennsylvania. Manu- script received September 20, 1988; revised manuscript received De- cember 30,1988, and accepted January 3,1989.

Address for reprints: William H. Frishman, MD, 1825 Eastchester Road, Bronx, New York 10461.

eta-adrenergic blocking agents have been proven to B be safe and effective antihypertensive drugs.t However, there are differences between drugs re-

garding hemodynamic profiles, adverse reaction rates and dosing schedules.1-3 Celiprolol is a new and unique &selective adrenergic blocker with additional peripher- al &agonist activities4J (Figure 1). It can be adminis- tered once daily, and has been shown to be effective in patients with hypertension6-s and with stable angina pectorisgJO We report on the results of a multicenter study comparing once-daily celiprolol with placebo. The trial was designed to evaluate the efficacy and safety of the drug, the appropriate dosing range and the effects of the drug on plasma lipids and lipoproteins.

METHODS Patients with mild to moderate systemic hyperten-

sion were enrolled in this multicenter trial after written informed consent was obtained.

Patient selection: All patients entered into the study had stable supine resting diastolic blood pressure (BP) of 95 to 114 mm Hg without medication. Study candi- dates were seen before the study and were entered into a 4-week placebo run-in period after all antihyperten- sive medications had been discontinued. To qualify for admission, supine diastolic BP (average of 3 readings) had to be within the previously defined range at both weeks 3 and 4, and to vary by no more than 4 mm Hg between the 2 visits.

Patients were excluded from the study if they had significant cardiovascular disease other than essential hypertension, history of adverse reaction to fi-adrenergic blocking agents, cerebrovascular insufficiency or cere- brovascular accident within 6 months, severe chronic obstructive pulmonary disease, allergic rhinitis, signifi- cant hepatic or renal dysfunction, hemolytic disease, in- sulin-dependent diabetes mellitus, known alcohol or drug abuse, or treatment with rauwolfia alkaloid or guanethidine within 1 month of the first visit.

Experimental design: The study was conducted as a multicenter trial (Figure 2). A single-blind, placebo run-in screening period of 4 weeks was used to establish baseline BP. Eligible patients were then randomized to treatment with celiprolol or placebo in a double-blind parallel fashion. A titration period of 6 weeks then fol- lowed, with patients given increasing doses of celiprolol (200 to 600 mg) or additional identical placebo tablets until a goal response was obtained. Goal response was defined as a reduction in supine diastolic BP to 190 mm Hg. Full participation in the study included 4

THE AMERICAN JOURNAL OF CARDIOLOGY APRIL 1, 1989 839

CELIPROLOL IN SYSTEMIC HYPERTENSION

TABLE I Baseline Demographic Summary

Placebo (n = 46) Cellprolol (n = 45)

M/F 31/15 33/12

Age Ws) 54f9 53f8 Height (cm) 177f9 172 f 10 Weight (kg) 85f 13 87+ 15 Black/nonblack 8/38 3/42 Hypertension duration (yrs) 12f8 10*7

Values are mea” zt standard dewatmn

weeks of placebo run-in and 6 weeks of randomized, double-blind treatment, for a total of 10 weeks.

Methods of observation: BP and heart rate at rest were measured 3 times each in the supine position and then after standing for 2 minutes. Measurements were taken approximately 24 hours after the previous dose of medication and just before the next dose.

Safety was monitored during the placebo and active treatment phases by side effect profiling, complete blood counts, blood chemistry determinations and elec- trocardiograms. Blood samples were also drawn from a subgroup of 20 patients at the end of placebo treatment (week 4) and at the end of active treatment (week 10) for determinations of total cholesterol, high density lipo- protein cholesterol and triglycerides. Low density lipo- protein cholesterol was calculated according to the for- mula: low density lipoprotein cholesterol = total choles- terol - (0.20 X triglycerides) + high density lipoprotein cholesterol.

Statistical analysis: Comparisons of mean changes were based upon a 2-way analysis of variance fixed ef- fects model, with treatment and investigator as main effects and no interaction term. The 2 treatment groups were compared at a 5% level of significance using a l- sided t test for blood pressure variables and a 2-sided t test for heart rate variables. The mean changes reported here are least square means.

For the therapeutic response rates, comparisons were made using unadjusted chi-square tests for proportions, pooling the patients from all centers.

RESULTS Patients: A total of 124 patients was enrolled. Thir-

ty-three were disqualified because of early placebo screening failures. Of the remaining 91 patients who were randomized, 9 were discontinued before visit 7. Of these 9 patients, 3 (2 placebo, 1 celiprolol) were discon- tinued due to ineffective therapy, 4 (3 placebo, 1 celi-

CHs 0

CH-p,,~-C$-CH2-0 -

-9

11 ,Ws \ , -NH-C-N,C2H5.HCI

‘3 ,c=o

CH3

FIGURE 1. Celiprold HCI (REV 5320-A) 3-(3-acetyl-4-3 (tert-hutylamino)-2-hydroxpropoxylphenyl~-l,l-diethykrrea hydrochloride.

prolol) due to adverse clinical experiences and 2 were lost to follow-up. Data from these patients are included in the safety analysis. The remaining 82 patients were analyzed for both safety and efficacy parameters. The baseline demographic characteristics of the randomized patients are listed in Table I. No differences were ob- served between placebo and active treatment groups in demographic characteristics.

Compliance and titratable dosage: Patient compli- ance (based on tablet count) was good throughout the study. Twenty-three percent of patients were receiving 200 mg/day of celiprolol at the end of this study, 26% were receiving 400 mg/day and 5 1% were receiving 600 Wdw.

Blood pressure and heart rate: Compared with pla- cebo, celiprolol resulted in significant reductions in su- pine and standing diastolic BPS at the end of the study (Table II). When all patients were analyzed, over 40% achieved the treatment goal with celiprolol versus 17% of those receiving placebo (p <0.05).

Celiprolol did produce small reductions in heart rate that were statistically significant. The decrease in heart rate was not clinically relevant, as no bradycardia was seen in any patient and mean heart rates remained >70 beats/min.

Plasma lipids: In the subgroup of patients who un- derwent lipid studies, a nonsignificant reduction trend in total cholesterol and low density lipoprotein cholesterol was observed when celiprolol was compared with place- bo baseline.

Safety: Electrocardiograms were assessed before and after treatment. In the celiprolol group, 5 patients developed nonsignificant abnormalities during treat- ment.

Routine laboratory chemistry and hematology stud- ies were obtained before and during treatment. One pa- tient receiving celiprolol developed an increased antinu- clear antibody titer and 2 patients developed slight ele- vations of triglycerides. In the placebo group, 1 patient developed an increased antinuclear antibody titer and 4

I I I PLACEBO TITRATION

I I I Single-Blind Double-Blind

I I I

1 RON-IN I I (WASB-OUT)

I I 3 Tablets 1 Q.D. (cl

I I

1 1 Tablet I 2 Tablets I Q.D. Q.O. (b) > 9omldlg

I I I

I I > 9otmdfg < 9omEg 1

I 1 Tablet Q.D. (a) <9ollmwg

+ I I I VISITS 1 2 3 4 5 6 7

WEFXS 0 2 3 4 6 8 10

FIGURE 2. Study protocol.

840 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

patients developed slight elevations of triglycerides. There were no systematic laboratory changes observed during the study.

Adverse experiences: Eighteen of the 45 patients (40%) in the celiprolol group and 20 of the 46 patients (43%) in the placebo group had adverse experiences, which resulted in discontinuation of treatment in 1 celi- pro101 patient and 4 placebo patients. The celiprolol pa- tient experienced leg cramps beginning on day 31 of treatment with 200 mg/daily. In the placebo group, 1 patient was discontinued because of severe epistaxis, 1 because of moderate dyspnea (although this patient ac- tually completed the study), 1 because of severe sneez- ing and nasal stuffiness, and 1 because of mild dyspnea and wheezing. The most frequently reported adverse ex- perience was headache, which occurred in 7 patients in the celiprolol group and 2 patients in the placebo group. Edema was noted in 4 patients in the placebo group but did not occur in the celiprolol group.

DISCUSSION Beta-adrenergic blockers have been shown to be

both safe and effective in the treatment of patients with systemic hypertension.’ However, there are significant pharmacologic differences among the various agents in this class that may be of clinical importance. These in- clude hemodynamic profiling, adverse reaction rates, ef- fects on plasma lipids, metabolism and dosing inter- vals.2v3J 1

Celiprolol is excreted unchanged from the body.12 The pharmacologic properties of celiprolol may provide advantages over existing P-adrenergic blocking drugs. The drug does not have a measurable myocardial de- pressant effect when administered to dogs.13 It appears to have no central nervous system effects in human be- ings. I4 Unlike propranolol, celiprolol decreases peripher- al vascular resistance, resulting in a lower propensity to induce cold extremities,15-l7 and has bronchosparing ef- fects in patients with reversible airways disease.18-23 Studies in human beings with intravenous celiprolol have failed to show a significant effect on the conduc- tion system of the heart, other than a small increase in the AV nodal refractory period.24

The drug has been used once daily in patients with systemic hypertension,6-8,25-27 and appears to be as ef- fective as atenolol26,27 and propranolol* in comparative studies. The drug is equally effective in black and white patients25 and has been used successfully in elderly sub- jects.19 Our group and others have previously shown the drug to be effective in patients with angina pecto- ris,9Jo*28 and to have comparable efficacy when com- pared with atenolol29 or propranolo130y31 on angina1 fre- quency and exercise tolerance. The present study dem- onstrates the efficacy and safety of celiprolol under conditions of use (that is, titration to response) which, unlike assigned-dose, parallel-group studies, closely re- flect the manner in which this type of drug is adminis- tered in practice.

In this multicenter study, celiprolol proved to be more effective than placebo when administered once

TABLE II Blood Pressure and Heart Rate at the End of Monotherapy

Change Between No. of Baseline from Group

Parameter Group Pts Value Basehe Value

Supine diastolic P 40 101 f 1 -2&l BP(mm Hg) C 42 101 f 1 -6fl

0.005*

Supine systolic P 40 155f2 04f2 BP(mm Hg) C 42 151f2 -6f2

0.022s

Standing diastolic P 40 lOOf -1 f 1 BP(mm Hg) C 42 100&l -5fl

0.016*

Standing systolic P 40 150f3 -2f2 BP(mm Hg) C 42 146f2 -7f2

0.025*

Suplne HR P 40 75f2 -2f2 (beats/min) C 42 78f2 -7fl

0.0140

Standing HR P 40 8Of2 -1f2 (beats/min) C 42 81 f 2 -6fl

0.009’

Values are mean f standard de&bon. * p <O 05 for l-talled t test (BP variables) or Z-t&d t test (HR variables) dewed

from the P-way man effects analysis of variance model: changes from basellne are adjusted for imbalances between treatment groups and nwesbgators

BP = blood pressure; C = celiprolol; HR = heart rate: P = placebo.

daily in doses of 200 to 600 mg/day to patients with mild to moderate systemic hypertension. The drug had minimal effects on heart rate, and its safety profile was comparable to that observed with placebo-except for an increased incidence of headache. In addition, celipro- 101 demonstrated a tendency to reduce both total choles- terol and low density lipoprotein cholesterol values in a subgroup of patients. This effect on lipids differs from that observed with other nonselective /? blockers and PI- selective blockers.32 This observation needs to be veri- fied in larger numbers of patients.

Celiprolol appears to be a safe and effeetive antihy- pertensive agent. However, its role in clinical practice should be clarified further in comparative studies with other first-line antihypertensive drugs, including diure- tics, angiotensin converting enzyme inhibitors and calci- um antagonists.

REFERENCES 1. Frishman WH. Clinical Pharmacology of the Beta-Adrenergic Blocking Drugs. Second Ed. Norwalk: Appleton-Century-Crofts, 1984:71-99. 2. Frishman WH. Clinical differences between beta-adrenergic blocking agents: implications for therapeutic substitution. Am Heart J 1987;113:1190-1198. 3. Frishman WH. Beta-adrenergic receptor blockers: adverse effects and drug interactions. Hypertension 1988;ll @art II):II-21-M-29. 4. Smith RD, Wolf PS. Celiprolol. In: Scriabine A, ed. New Drugs Annual: Cardiovascular Drugs. Volume 2. New York: Raoen Press, 1984:19-35. 5. Van Inwegen R, Khandwala A, Ingram R, Kharode Y, Sutherland C, Coutts S, Weinryb I, Puss T. Effects of celiprolol in the interactions of serotonin and post- synaptic alphaz-receptors in isolated cat tracheal rings (abstr). Fed Proc 1984;43:745. 6. Craickshank JM, Prichard BNC. Beta-Blockers in Clinical Practice. Edin- burgh: Churchill-Livingstone, 1988:946-949. 7. Capone P, Mayo1 R. A comparative study of celiprold and placebo in the treatment of hypertension. Br J Clin Pratt 1985;39:65-69. 8. Taylor S, Beattie A, Capone P. A comparison of celiprolol and propranolol in the treatment of hypertension. Br J Clin Prod 1985;39:76-81. 9. Eff .I, Godfrey J, Garutti R, Capone P. Celiprolol in angina pectoris: a con- trolled study. J Cardiouasc Pharmacol 1986;8(suppl 4):S132SI34. 10. Soberman J, Frishman WH. Celiprolol in angina pectoris. Am Heart J 1988;116:1422-1425. 11. Frishman W. B-adrenoceptor antagonists. New drugs and new indications. N

Engl J Med 1981:305:SO&506. 12. Hitzenber VG, Takacs F, Pittner H. Pharmacokinetics of the &adrenergic

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CEUPROLOL IN SYSTEMIC HYPERTENSION

receptor blocking agent celiprolol after single intravenous and oral administra- tions to man. Arznermittelforschung 1983:33.50-52 13. Shlevin HL, Barrett JA. Thompson GF, Wolf PS, Pruss TP, Smith RD. Celiprolol HCI: propranolol-insensitive cardiostimulatory effects in anesthetized dogs (abstr). Pharmacologist 1983,25:263. 14. Hofner KJ, Klebel E. Experimental psychologic tests on the effects of celipro- 101 with special reference to the effects on driving competency. LJL/4334 (Internal Report). Rarer Pharmaceuticals. 15. Solomon T, Gemini G, Dater C, Caruso F. Celiprolol: a hemodynamic appraisal in comparison with propranolol. Br J Clin Pharmacol 1985;40,43A- 44A. 16. Ehringer H, Konecny U, Rasser W. The effect of celiprolol on pertpheral cuculation in healthy volunteers. Br J Clm Pharmacol 1985;40:91S99S. 17. Gensini G, Dater C, Esente P, Caruso FS, Solomon T. Comparison of the acute hemodynamic effects of intravenous celiprolol and propranolol in patients with suspected coronary disease. J Cardiouasc Pharmacol1986;8(suppl4):S83- S85. 16. Matthys H, Doshan HD, Ruble KH, Baig H, Pohl M, Applin WJ, Caruso FS, Neiss ES. The bronchosparing effect of celiprolol, a new betai, alphaa- receptor antagonist on pulmonary function of propranolol-sensitive asthmatics. J Clin Pharmacol 198X25:354-359. 19. Hitzenberger G. Celiprolol, clinical dosage, efficacy and safety tn asthmatic and elderly pattents Br J Clin Pratt 1985;39.25-32. 20. Hitzenberger G. The cardiovascular effects of celiprolol in healthy volunteers and patients with coronary heart disease. Br J Clin Pratt 1985;29:46-52. 21. Schindl R, Wurtz J, Hoffmann H. The effect of the cardioselective beta blocker celiprolol on pulmonary function in asthmatic patients. J Cardiouasc Pharmacol 1986;8(suppl4)S99-S101 22. Dorow P, Clauzel AM, Capone P. Mayo1 R, Mathieu M. A comparison of

cehprolol and chlorthahdone in hypertenswe patients with reversible bronchial obstructton. J Cardiouasc Phnrmacol 1986;8(suppl 4):SlO2S104. 23. Doshan HD, Brown R, Apphn WJ, Kapoor M, Caruso FS. Effects of high doses of celiprolol in asthmatic patients. J Cardiouasc Pharmacol 1986;8(suppI 4):SIO9-Sl Il. 24. Estes NAM, Lm SK, Caruso FS, Solomon TA. Clinical cardiac electrophysi- ologic study of celiprolol. J Cardiovasc Pharmacol1986;8(strppl4):Sl16-S118. 25. Leary P, Mayo1 R, Capone P. A compartson of celiprolol and propranolol in the treatment of hypertension in one hundred and seventy-nine SubJects. Br J Clin Pratt 1985.39:70-72. 26. Silke B, Rosenthal F, Taylor S A randomized double-blind study of atenolol and celiprolol in mdd to moderate hypertension. J Cardiovasc Pharmacol 1986,8(suppl4):Sl22-S126. 27. Stumpe K, Kollach R, Mathieu M, Capone P. A comparison of cehprolol and atenolol in the treatment of hypertension: a placebo-controlled double-blind study. Br J Clin Pratt 1985;39:73-75. 26. Harston WE, Eff J, Capone P. A double-blind placebo-controlled study of celiprolol in the treatment of angina pectoris. Br J Clrn Pratt 1985;39:55-61. 29. Jackson NC, Lee PS, Taylor SH. A singleblind randomized comparison of the 24 hour antianginal efficacy of celiprolol versus atenolol. J Cardiooasc Phar- macol 1986:8(suppl4).Sl45-S147. 30. Klein W, Fluch N, Brandt D. Double-blind placebo-controlled trial of pro- pranolol versus celiprolol in stable effort angina: antianginal efficacy and side effects. Wien Kiin Wochenschr 1982;94:258-261. 31. Niederberger M, Ebm W, Panzer S. Antiangmose therapie mu dem kardiose- lektiven beta-rezeptoren-blocker celiprolol. Arzneimirtelforschung 1983;33:63- 66. 32. Lardinois CK, Neuman SL. The effect of hypertenstve agents on serum hpids and lipoproteins. Arch Intern Med 1988:148:1280-1288.

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