336 1

MEDICAL SCIENCE

Xamoterol in severe heart failure

THE XAMOTEROL IN SEVERE HEART FAILURE STUDY GROUP*

516 patients with New York Heart Associationclass III and IV heart failure despite treatment withdiuretics and angiotensin converting enzymeinhibitors were randomised in a double-blind

between-group comparison to xamoterol 200 mg(352) or placebo (164) twice daily for 13 weeks.There was no difference between the treatmentsin loss of clinical signs. Visual analogue scale andLikert scores indicated that breathlessness wasless severe with xamoterol, but there was nodifference in exercise duration or total work done.Xamoterol reduced maximum exercise heart rateand systolic blood pressure, did not affect thenumber of ventricular premature beats afterexercise, showed no arrhythmogenic activity, andhad variable (agonist and antagonist) effects on24 h heart rate. On intention-to-treat analysis 32(9·1%) patients in the xamoterol group and 6

(3·7%) patients in the placebo group died within100 days of randomisation (p=0·02).

Introduction

Xamoterol (’Corwin’, ICI 118,587) is a &bgr;1-selective partialagonist which stabilises the cardiac response to sympatheticdriver The overall effect is one of a mild &bgr;1-adrenoceptoragonist at rest and during light exercise. At high levels ofsympathetic tone or during heavy exercise &bgr;1-adrenoceptorantagonism is more prominent.2 In patients with mild tomoderate left ventricular dysfunction due to ischaemic heartdisease or idiopathic dilated cardiomyopathy, xamoterolimproves left ventricular systolic and diastolic function,reduces left ventricular end-diastolic pressure, and

improves the rate of left ventricular relaxation.3-5 In patientswith mild to moderate heart failure it has beneficial effectson symptoms and exercise tolerance .6,7 In a large placebo-controlled comparison of digoxin and xamoterol in mildchronic heart failure, xamoterol increased exercise durationand improved breathlessness and tiredness whilst no similarbenefits were observed with digoxin. 8

Only limited information is available concerning theeffects of xamoterol in heart failure of greater severity.McAlpine et al9 did a randomised double-blind cross-overstudy with 6-week treatment periods of xamoterol versusplacebo in 15 patients who had severe heart failure despitetherapy with captopril. Xamoterol increased resting systolicblood pressure and reduced the double product duringexercise. Exercise duration was improved or unchanged in11 patients and reduced in 4 patients. Pouleur et all showedthat in 9 patients with severe heart failure (New York HeartAssociation class III) despite therapy with angiotensinconverting enzyme inhibitor, further haemodynamicimprovement (left ventricular filling pressure, systolicfunction, and diastolic function) was obtained by addition ofxamoterol.We undertook the present study to test the hypothesis,

based on the preliminary evidence of Pouleur and

McAlpine, that xamoterol was a safe and effective treatmentfor heart failure which was moderate to severe despitetreatment with diuretics and angiotensin converting enzymeinhibitors.

*The names of organisers and participants are printed at the end of thepaper. Correspondence to Prof Lars Rydén, MD, Division of Cardiology,Department of Medicine, Thoracic Clinics, Karolinska Hospital,S-104 01 Stockholm, Sweden.

2

Materials and methods

DesignThe study was a double-blind, randomised, between-group

comparison of xamoterol (200 mg twice daily) and placebo,conducted at 66 centres in ten countries. After a 1-3 week

single-blind placebo run-in period the patients were randomised todouble-blind treatment for 13 weeks in the ratio xamoterol 2,placebo 1.

It was estimated that 228 patients would have to complete thestudy to give a 90% chance of detecting a 30-second difference inexercise duration between placebo and xamoterol at the 5% level ofsignificance. The aim was therefore to recruit at least 255 patients toallow for withdrawals. A blinded re-evaluation of the variance of theexercise data after the first 63 patients had completed the study, anda higher drop-out rate (15%) than expected (10%), caused thesteering committee (in agreement with the safety committee) torevise the recruitment figure to at least 450.The study protocol, which was approved by independent

hospital ethics committees at each of the participating centres, wasin accordance with the 1964 Declaration of Helsinki as amended inVenice in 1983. All patients gave their written informed consentbefore entering the study.

Patients

Male or female patients above the age of 18 years were eligible forinclusion if they had moderate to severe heart failure (New YorkHeart Association class 111-IV) despite stable therapy with diureticsand an angiotensin converting enzyme inhibitor, the latter for atleast two months. The diuretic dosage was not to have been changedduring the 2-week period before inclusion.The diagnosis of heart failure was made clinically and was

confirmed by at least one of the following criteria: a cardiothoracicratio on the chest radiograph of > 0-55; fractional shortening onM-mode echocardiogram of < 20%; left ventricular diastolicdimension > 60 mm; ejection fraction < 35%. The patients couldbe in either sinus rhythm or atrial fibrillation treated with digitalis.Patients were excluded from the study if they were women ofchildbearing potential, had had a myocardial infarction in the past 8weeks, had pronounced renal impairment (serum creatinine> 250

&micro;mol/1), had exercise limitation due to non-cardiac disease, hadaortic or pulmonary obstructive valvular disease, had hypertrophicobstructive cardiomyopathy, were receiving concurrent therapywith any drug which has its activity through &bgr;-adrenoreceptors,were capable of less than 1 min of exercise on testing, had a greaterthan 25% variability in baseline exercise duration between thebeginning and the end of the run-in period, or had chest pain as thesole limiting symptom during the exercise test.

Methods

_

At the first recruitment visit the patients were examined, werefamiliarised with the symptom questionnaire, and underwent anexercise test. After the single-blind placebo run-in period thepatients were reassessed, blood was taken for haematological andbiochemical testing, a symptom questionnaire was completed, and asecond exercise test was undertaken. The patient was randomised todouble-blind treatment only if the duration of exercise on thesecond test was within 25% of the previous test, and a maximum offour exercise tests was permitted. Data from the last exercise testbefore randomisation were regarded as baseline data for futurecomparisons. If the entry criteria were satisfied, patients wererandomly assigned in a ratio of 2:1 to receive xamoterol 200 mgtwice daily or matching placebo. The doses of all concurrentcardioactive therapy remained fixed throughout the study, wherepossible.An intermediate visit, at which a clinical examination was

performed, was scheduled for 2 weeks after randomisation. At theend of the treatment period of 13 weeks, patients underwent a repeatof the baseline assessments. If patients withdrew from the study

investigators were asked, where possible, to perform the final studyassessments at the time of withdrawal.

Exercise tolerance was measured on an electrically braked bicycleergometer (Bosch ERG 551). Exercise was initiated at a workload of10 W and increased by 10 W every minute until the symptom-limited maximum exercise tolerance was reached. Heart rate (fromthe electrocardiogram) and cuff blood pressure were measured atrest directly after the end of exercise. The patient’s ECG wasrecorded continuously during the exercise test. The number ofventricular premature beats was measured in the first 5 min after theend of exercise.

Subjective symptoms during daily life were assessed by visualanalogue and Likert scales, which included questions relating tobreathlessness, tiredness, chest pain, and palpitations. For theLikert scales the physician rated the answers given by the patientson a 4 or 5 point scale. The visual analogue scales required thepatient to put a cross on a 100 mm horizontal line marked at the twoextremes by "not at all" and "very much".

48 h Holter ECG-monitoring was performed in a subgroup ofpatients at 40 centres. Recordings were made at baseline and at theend of the double-blind randomised part of the study. The numberof ventricular premature beats per 24 h was assessed. The numberof episodes per 24 h of non-sustained ventricular tachycardia (morethan 3 consecutive beats but less than 30 s at a rate greater than 120

beats/min) or periods of sustained ventricular tachycardia (> 30 s)were also assessed. Only Holter ECG recordings with more than22 h of analysable data were included in the analysis.

Serious adverse experiences were evaluated by reference tohospital records. For patients who died, the mode of death wasdetermined from records and an interview with the physicianconcerned. The mode of death has been given as progression ofheart failure, sudden death, or other cause. To cover a possibleuntoward effect of withdrawal of the study drug, serious adverseexperiences were included if they occurred within the study periodof 91 days and during a further 9 days, covering 100 days offollow-up.

Routine haematological and biochemical tests were done onblood. In a subgroup of patients plasma noradrenalineconcentrations were also measured, blood samples being taken atbaseline and at the end of the double-blind randomised period afterthe patients had rested supine for at least 10 min.

Statistical analysisAvailable data on all relevant patients were analysed. The efficacy

analysis dealt with all patients who fulfilled the entry criteria. In theanalysis of safety all 516 randomised patients were included.The exercise data, resting blood pressure and heart rate, and

patient subjective assessment data were examined by analysis ofcovariance. The statistical significance of the differences betweentreatment means was assessed by "F" tests. Standard errors and95% confidence intervals were also calculated for all differencesbetween treatment means.As the analysis of covariance is based on assumptions of normal

distribution of data, these were examined and were found to beadequately fulfilled. Furthermore, no outlying values were

sufficiently extreme to affect the conclusions.The exercise data were also investigated by intention-to-treat

analysis to ensure that all eligible patients were included and henceto confirm that no serious bias had arisen from missing data. Thisinvolved classification of patients into one of the followingcategories based on exercise times: improved, no change, anddeterioration. Patients who withdrew and did not have a finalexercise test performed, and those who died, were classified for thispurpose as having deteriorated.The survival data were analysed on an intention-to-treat basis.

Cox’s regression model was used and hazard ratios and confidenceintervals were calculated.The 48 h Holter data were totalled and converted to hourly

rates. These were found to be skewed and unsuitable for parametricanalysis. The data were therefore summarised in terms of medians,minima, and maxima. The percentage change for each patient from

3

Recruited

Randomised

Entry

Double-blind treatmentwithdrawals includingdeath

Completed

Fig 1-Outcome for all patients.

Note, in 25 xamoterol and 9 placebo patients data were generated attime of withdrawal.

baseline to the end of the study was also calculated and summarised.The hourly heart rate data were analysed in bands of 4 h. In each4 h band the mean heart rate for each patient was calculated.The mean in each band was subjected to analysis of covariancewhere the baseline value was the covariable.

Results

Recruitment

The study started in November, 1987. When recruitmentwas complete in March, 1989, a total of 516 patients hadbeen randomised-352 to xamoterol and 164 to placebo. InMay, 1989, the safety committee reported to the steeringcommittee that there was an excess of deaths in thexamoterol group (see below) and requested that the study bestopped. Accordingly, the steering committee instructedthat all remaining patients should have their final

assessment, that the study medication be withdrawn, andthat the study be terminated. The average length oftreatment during the randomised phase was 87 days onxamoterol and 86 days on placebo.

Demography

Fig 1 shows the outcome for all patients. 39 (25 xamoterol,14 placebo) patients were excluded from the efficacy analysisbecause they did not fulfil the entry criteria. The causes ofviolation of entry criteria were exercise not limited by acardiac cause or repeatable within &plusmn;25% (11 xamoterol, 4placebo), drug treatment exclusions at entry (14 xamoterol,8 placebo), and patients not fulfilling the criteria for ejectionfraction, chest radiograph, left ventricular end-diastolic

dimension, or fractional shortening (2 placebo). Safety dataare reported from all 516 patients randomised.Demography and baseline clinical status are shown in

table I. The populations were similar with respect to allbaseline demographic and clinical characteristics.Concomitant cardiac drug treatments were balancedbetween the placebo and xamoterol groups for short andlong acting nitrates (15 and 24; 52 and 128 patients,respectively), calcium antagonists (19 and 50), digitalis (77and 159), and amiodarone (19 and 51 patients). Therapywith diuretics and angiotensin converting enzyme inhibitorsis shown in table 11.

Clinical assessment

When corrected for baseline variation the adjusted meansupine resting heart rate for the xamoterol group was 79beats/min compared with 83 bpm for the placebo group

TABLE I-BASELINE CHARACTERISTICS OF PATIENTS

*n = 150 for placebo and 327 for xamoterol unless otherwise stated Protocolviolators excluded

(p < 0-01). There were no statistically significant differencesbetween the treatments with respect to changes in restingblood pressure.The presence of clinical signs did not differ between the

two treatment groups at the end of the study. There was nosignificant change in body weight during the study periodfor either treatment group.

SymptomsBreathlessness was less severe with xamoterol than with

placebo, on both visual analogue scale (p < 0-02, 11 % vs 0%increase) and Likert scale (p=0-02, 8% vs 2% increase).There was no difference in the symptom of fatigue (visualanalogue scale) or total Likert scale score.

TABLE II-CONCOMITANT ANGIOTENSIN CONVERTING ENZYME

INHIBITOR AND DIURETIC THERAPY

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TABLE III-TREATMENT EFFECT ON EXERCISE TOLERANCE:ADJUSTED MEANS AND CONFIDENCE INTERVALS

Pre-ex = pre-exercise.

Exercise test data

After correction for baseline variation, exercise durationdid not differ between the xamoterol and placebo groups atthe end of the study period (table III). There was nosignificant difference in the amount of work done on exercisetesting at the end of the treatment period for the twotreatment groups and the groups were comparable in termsof reasons for stopping exercise. Maximum heart rate andsystolic blood pressure on exercise were both reduced byxamoterol (p<0-01). There was no difference betweentreatment groups in the number of ventricular prematurebeats during the 5 min immediately after the end of exercise.To ensure that patients without final exercise data did notbias the analysis of exercise duration in favour of xamoterol,an intention-to-treat analysis of all randomised patients wasmade: the interpretation was unaltered.

Continuous ambulatory monitoring188 patients underwent Holter monitoring. The data

presented are from the 106 patients (76 xamoterol, 30placebo) who had more than 22 h of analysable data both atbaseline and at the end of the study period. Median hourlyrates for total ventricular extrasystoles, couplets, andnon-sustained ventricular tachycardia did not differbetween the two treatment groups. No patients in eithertreatment group had or developed sustained ventriculartachycardia.At baseline the two treatment groups had comparable

mean heart rates over the 24 h period. Fig 2 shows the meanheart rates during 24 h at the end of the study period. Duringthe 16 h of wakefulness the maximum heart rate was lower inthe xamoterol treated group than in the placebo group

Time (24-hour clock)

Fig 2-Mean heart rate (beats per minute) over 24 h periodrecorded by Holter monitoring at end of the study for thetwo treatment groups.

Placebo (&Dgr;-&Dgr;); xamoterol ([]-[]).

TABLE IV-COMMONEST ADVERSE EXPERIENCES WITH

XAMOTEROL TREATMENT COMPARED WITH PLACEBO, GREATERTHAN OR EQUAL TO AN INCIDENCE OF 2% FOR EITHER

TREATMENT

TABLE V-DEATHS WITHIN 100 DAYS OF RANDOMISATIONACCORDING TO INTENTION-TO-TREAT ANALYSIS

(p < 0-05), whereas during the 8 h of sleep the minimumheart rate was higher in the xamoterol treated group(p < 005).

Noradrenaline concentrations

Plasma noradrenaline was measured in a total of 52

patients (37 xamoterol, 15 placebo). The mean (SE)concentration at baseline and at the end of the study was 776(107) pg/ml and 592 (108) pg/ml for the placebo group and678 (60) pg/ml and 647 (63) pg/ml for the xamoterol group(reference range 130-550 pg/ml).

Adverse experiences and withdrawals

More patients withdrew from the xamoterol group (67;19%) than from the placebo group (19; 12%). Of thewithdrawals due to adverse experiences on xamoterol (41;12%) or placebo (8; 5%) most were the result ofcardiovascular changes (xamoterol 30, 73%; placebo 5,62%). A small number of patients (4% in each group) were

Number of Days

Fig 3-Three-month survival probabilities for the placebo andxamoterol groups.

Placebo n=164 (- - -), xamoterol n=352 (-). ).p=0’02; hazard ratio 2 54 (confidence interval 1 ’06 to 6 08).

5

TABLEVI-DISCRIM I NANTANALYSIS: FACTORS IN DECREASINGORDER OF IMPORTANCE

withdrawn because of inadequate response or disease

deterioration, whilst drop-outs and other miscellaneouswithdrawals accounted for 11 (3%) xamoterol and 4 (2%)placebo patients.The most common of the adverse experiences are shown

in table IV. Adverse experiences not leading to withdrawalwere balanced between the two groups.The haematological and biochemical tests, including

serum creatinine, showed no gross disturbances with eitherxamoterol or placebo.

Survival

On intention-to-treat analysis 32 (9-2%) patients in thexamoterol group and 6 (3-7%) in the placebo group diedwithin 100 days of randomisation (p = 0.02). The hazardratio was 2-54 with a 95% confidence interval of 1-04-6-18.The mode of death-namely, progression of heart failure,sudden unexpected death, or other cause-is given for bothtreatment groups in table v. 12 of the patients had stoppedtaking xamoterol, and 1 placebo, more than 9 days beforedeath. The 3-month survival probabilities for the xamoterolgroup and the placebo group are 91 % and 96 %, respectively(fig 3).A discriminant analysis was performed to investigate

whether specific patient characteristics could be identifiedthat could be used to predict poor outcome. This was donein two steps (table VI). Firstly, all patients were evaluatedand six variables were identified. Table VI shows these inorder of importance: they relate principally to disease

severity and concomitant medication. Secondly, thexamoterol group alone was investigated; this analysisprovided similar factors, although in a slightly differentorder, and introduced other factors relating to disease

severity (presence of hepatomegaly, peripheral oedema) andto treatment (concomitant therapy with calcium

antagonists).Discussion

The modest symptomatic relief and lack of improvement ofexercise tolerance in patients with more severe heart failurein this study contrasts with previous experience gained withxamoterol in patients with mild to moderate heart failure.8In earlier studies few patients received angiotensinconverting enzyme inhibitors and a substantial proportionof patients had ischaemic heart disease. Accordingly, theremay be at least two important explanations for these

findings. In patients with ischaemic heart disease the main

effect may have been relief of symptoms of myocardialischaemia rather than improvement in congestive heartfailure. Xamoterol, because of its &bgr;-blocking action, lessensheart rate and therefore probably also myocardial oxygenconsumption during exercise. Another reason could be thatpatients in mild to moderate heart failure respond differentlyto xamoterol from those in severe heart failure, in line withthe pharmacological action of the compound.2 There arereports of individual patients with severe heart failure inwhom the haemodynamic response to xamoterol has beenunfavourable.5,7 Furthermore, the clinical condition of thepatients in the present study was in many cases worse than inthe two studies9,10 that formed the basis for our initial

hypothesis. Many of the patients at entry into the presentstudy were clinically deteriorating and some patients wereincluded as a last treatment resort; a few were awaitingtransplantation.The study was designed to compare exercise tolerance

and subjective symptoms after xamoterol and placebo butnot to study possible differences in mortality. Nonetheless,on intention-to-treat analysis 32 in the xamoterol group and6 in the placebo group died within 100 days ofrandomisation. Even if the repeated examinations of themortality data (three in all) by the steering committee aretaken into consideration, there remains a statisticallysignificant higher mortality among xamoterol-treated

patients. The CONSENSUS Study recruited only patientsin NYHA functional group IV before initiation of the

angiotensin converting enzyme inhibitor." In that study theenalapril-treated patients had a three-month survival of81 %. In a captopril survival study with 105 patients inNYHA groups II and III, there was a 96% three-monthsurvival among the captopril-treated patients. 12 The presentstudy focused on individuals who, despite treatment withangiotensin converting enzyme inhibitors, remained inNYHA functional groups III and IV, and the three-monthsurvival was 96% in the placebo group and 91 % in thexamoterol group. Accordingly, the overall mortality of thepresent study was not high, although it was higher in thexamoterol arm.

The design of the present study has several limitationsthat hamper the search for possible mechanisms behind theincreased mortality among xamoterol-treated patients. Firstof all, there was no predetermined requirement to record theexact time of death or classification of the mode of death.

Secondly, the 2:1 randomisation meant that there were veryfew deaths among the placebo patients so it is difficult tomake detailed comparisons between those who survived andthose who died. There was no recorded information onblood pressure, heart rate, and the clinical condition duringthe first few days after institution of drug. Despite theseshortcomings some comments can be made that may berelevant for future studies of both &bgr;-agonist and&bgr;-antagonist drugs in the treatment of heart failure.The &bgr;-blocking action of xamoterol was more

pronounced in this population than expected: heart rate, forexample, was reduced throughout the hours of wakefulnessand not only during exercise. In previous mild-to-moderateheart failure studies no net reduction in heart rate at rest wasseen with xamoterol. Our patients may have had highersympathetic tone, and the plasma noradrenalineconcentrations in a subpopulation of our patients supportthis hypothesis. Previous studies2 have shown xamoterol toact as a &bgr;-blocker in these circumstances. Sudden

&bgr;-blockade would be a likely reason for haemodynamic

6

deterioration and resultant decompensation, since, instudies where beneficial effects of &bgr;-blockers have beenreported in patients with dilated cardiomyopathy, onlysmall slowly increased doses of &bgr;-blockers were instituted. 13Again, however, although &bgr;-blockade seems to improvecongestive cardiomyopathy the same may not be true insevere heart failure of ischaemic origin. It is possible thatdose titration and individualisation of the final dose mighthave resulted in a more favourable outcome in this study.However, if the &bgr;-blocking effect of the drug was theessential part of the increased mortality observed one wouldhave expected withdrawals, adverse experiences, and

mortality to be closely related in time to the introduction ofxamoterol. This was not so, and indeed some of the studydeaths occurred in patients previously randomised to

xamoterol but off treatment at the time of death.From the results of Holter monitoring it is clear that

xamoterol acted as a &bgr;-agonist during the night. In anotherplacebo-controlled trial in which dobutamine was givenintermittently for 48 h of each week, there was an excessmortality among actively treated patients.14 One explanationfor the excess mortality in the present study might be thatperiods of &bgr;-stimulation became increasingly deleteriouswith time. Data from the Holter-monitored group of

patients do not, however, point to an arrhythmia-promotingeffect.

Angiotensin converting enzyme inhibitors reduce

mortality in severe congestive heart failure." If xamoterolinteracted with the ACE inhibitor in the present study,increased mortality could be due to elimination of thelife-saving effects of the ACE inhibitor, but the low overallmortality seen within the xamoterol arm makes this

explanation unlikely. Discriminant analysis did not revealany particular subgroup prone to an unfavourable outcomeon xamoterol. This leads to the general advice thatxamoterol must be avoided in all patients with severe heartfailure.

We thank ICI Pharmaceuticals for the financial support. Study organisersand participating centres were as follows:

Organisation

Steering committee. Prof G. Nicholas, Umversity Hospital of Nantes, Nantes, France;Dr C. Oakley, Hammersmith Hospital, London UK; Dr H. Pouleur, University ofLouvain, Brussels, Belgium; Prof M. F. Rousseau, University of Louvain, Prof L. E.Ryden (chairman), Karolinksa Hospital, Stockhohn, Sweden; Prof H. Wellens,University of Limburg, Maastricht, Holland.

Safety committee. Dr W. M. Castle, ICI Pharmaceuticals, Macclesfield, UK; Dr H.Dargie (chairman), Western Infirmary, Glasgow, UK; Dr I. Ford, Glasgow University,Glasgow, UK; Prof D. G. Julian, British Heart Foundation, London, UK; Prof P. A.Poole-Wilson, National Heart and Lung Institute, London, UK.

Pnncipal mvestigators and participating centres (no of patients)Austria. Prof F. Kaindl, Dr H. D. Glogar, and Dr H. Sochor, University Clinic, Vienna

(13).Belgium. Dr J. M. Chaudron, H&ocirc;pital de Jolimont, Haine-St-Paul (14); Dr P. Cheron,

Clinique N. D. de la Misericorde, Libramont (4); Dr G. Jouret, IMC de Peruwelz,P&eacute;ruwelz (8); Dr J. Leonard, Centre Hospitalier des Fagnes, Chimay (4); Dr P. Mengeot,Hopital St Joseph, Gilly (5); Dr K. Mitri, Clinique St Joseph, Arlon; Dr E. Schroeder,Cliniques Universitaires de Mont-Godine, Yvoir (2); Dr J. L. Urbain, Centre Hospitalierdu Grand Homu, Homu (6); Dr P. Vanrobbays, Hopital St Joseph, St Vith (5)

France. Prof F. Cherrier and Dr C. Suty-Selton, CHU Brabols, Nancy (5); Prof J. P.Delahaye and Dr J. P. Gare, Hopital Louis Pradel, Lyon (3); Dr A. Juillard, HopitalLouise Michel, Evry, Paris (2); Dr J. C. Kahn and Dr M. Pathe, CHI de Poissy, Paris (6);Prof A. Serradimigni and Dr M. Lambert, CHR de la Timone, Marseille (7); DrH. Lardoux, CH Gilles de Corbeil, Pans (3); Dr P. Maribas, CHP de Juvisy sur Orge,Juvisy sur Orge (1).

Netherlands. Dr Th. J. J. M. Bloem, Marie Ziekenhuis, Tilburg (4); Dr F. el Deeb, DrM. H. H. el Gamal, and Dr J. Hoogsteen, Cathanna Ziekenhms Eindhoven (12); DrH. J. M. Dohmen and Dr H. W. M. Lijnsveld, Groot Ziekengasthuis, Hertogenbosch(16); Dr I. Letsch and Dr F. Vermeer, Academisch Ziekenhuis, Maastricht (9); Dr J. A.Kragten, "De Wever" Ziekenhuis, Heerlen (10); Dr H. Olthof and Dr J. P. Zijlstra, StLambertus Ziekenhuis, Helmond-Deume (3); Dr H. J. A. M. Penn, St Jans-Gasthuis, BeWeert (12).

Luxembourg. Dr L. Boisante, H&ocirc;pital de la Ville, Esch-sur-Alzette (4).Norway. Dr V. V. Bonarjee and Dr F. V. Shammas, Sentral Sykehus i Rogaland,

Stavanger (9); Dr J. W. Haerem, Hamar Sykehus, Hamar (12); Dr T. Hole,

Fylkessykehuset i Alesund, Alesund (4), Dr T. Holm, Sentral Sykehuset i 0stfold,Fredrikstad (4); Dr 0. Tenstad, Ringerike Sykehus, Honefoss (3); Dr H. Tj&oslash;nndal,Regionsykehuset, Trondheim (13); Dr B. Wik, Sentral Sykehus, Kristiansand (4).South Africa. Dr E. Beale, Dr D. G. Levison, Dr M. K. Malin, Dr C. Meyerowitz and

Dr P. Sareh, Baragwanath Hospital, Johannesburg (27); Prof A. C. Otto, Dr M. E.Coetzee, and Dr A. Krieger, University of the Orange Free State, Bloemfontein (12); ProfP. J. Commerford, Dr G. D. Gordon, and Dr H. Nell, Groote Schuur Hospital, CapeTown (8); Dr D. Nathan, City Park Medical Centre, Cape Town (9).Sweden. Dr P-A. Bostrom and Dr H. Lecerof, Allmana Sjukhuset, Malmo (8); Dr A.

Dahlberg, Lasarettet Nykopmg (1); Dr L. R. W. Erhardt, Dr H. Persson, and Dr B.Lindvall, Danderyds Slukhus, Stockholm (8); Dr L. Ljungdahl, Lasarettet, Helsingborg(8); Dr P. Smedgard, Kamsjukhuset, Skovde (10); Dr K. Swedberg and Dr A. Sigurdson,Ostra Sjukhuset, Goteborg (5).

West Germany. ProfJ. Cyran, Krankenanstalten, Heilbronn (4); ProfH. Simon, Dr T.Ezzeldin, and Dr W. Wehler, Stadtisches Krankenhaus, Duren (13); Prof G. Wambachand Dr R. Jacob, Krankenhaus Koln, Merheim, Koln (11); Prof J. Senges, Dr H. Nohl,and Dr J. Rusuge, Staedtisches Krankenhaus, Ludwigshafen (8).

United Kingdom Dr N. D. S. Bax, Royal Hallamshire Hospital, Sheffield (4); Dr D. H.Bennett and Dr J. Dhawan, Wythenshawe Hospital, Manchester (16); Dr K. K Bhallaand Dr L. B. Sharma, Bolton General Hospital, Bolton (13); Dr R. Blackwood, Dr J.O’Donnell, and Dr M. Sarjudeen, Wexham Park Hospital, Slough (12); Dr N. A. Boon,Royal Infirmary, Edinburgh (4); Dr C. Bucknall, Dulwich Hospital, London (3); Dr V.Challenor and Dr D. G. Waller, Southampton General Hospital, Southampton (8); Dr C.Davidson and Dr S. Doyle, Birch Hall Hospital, Rochdale (8); Dr S. Fletcher, PooleGeneral Hospital, Poole (4); Dr J. Gaddie, The Borders General Hospital, Roxburghshire(2); Dr M. Joy, St Peter’s District General Hospital, Surrey (13); Dr M. M. Kubic and DrN. H. Stentiford, Russells Hall Hospital, Dudley (6); Dr A. A. McLeod, Poole GeneralHospital (14) and Dulwich Hospital, London (3); Dr A. Nathan and Dr C. Wong, StBartholomew’s Hospital, London (22); Dr D. Moore, Hammersmith Hospital, London(22); Dr M. T. Rothman and Dr H. Nouriel, London Hospital (Whitechapel), London(29); Dr S. Short and Dr P. Siklos, West Suffolk Hospital, Bury-St-Edmunds (8); Dr J.Stoker, St James’ Hospital, Leeds (8); Dr C. A. Sykes, Furness General Hospital,Barrow-in-Furness (13); Dr I. Wilson, William Harvey Hospital, Ashford (2); Dr R.Wray, Dr. ’.; P T Travis and Dr M Bradley Cr t Helen’s Hospital Haennoc (15)

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