DOUBLE-BLIND PLACEBO-CONTROLLEDCOMPARISON OF DIGOXIN AND XAMOTEROL
IN CHRONIC HEART FAILURE
THE GERMAN AND AUSTRIAN XAMOTEROL STUDY GROUP
Summary 433 patients aged 29-80 with mild to
moderate heart failure entered a
multicentre double-blind randomised between-patientcomparison of xamoterol 200 mg twice daily, digoxin 0·125mg twice daily, and placebo. Patients were assessed atbaseline and after three months. Of 349 who completed thedouble-blind phase, 300 had valid exercise tests. Comparedwith placebo, xamoterol significantly increased exerciseduration and work done on a bicycle ergometer andimproved breathlessness and tiredness during daily life asassessed by visual analogue scale and by Likert scale.
Digoxin showed no statistically significant advantage overplacebo on any of the measures except the Liken scale.Exercise performance and work done were significantlyhigher with xamoterol than with digoxin.
Introduction
HEART failure affects 1 % of the population of Europe andthe United States and its incidence is increasing. Few of theestablished treatments have been subjected to double-blindplacebo-controlled trials of efficacy.2 Most commonly usedtreatments do not directly affect impaired myocardialcontractility. Digitalis is one therapy that does so, but itsvalue in patients with sinus rhythm is the subject ofcontinued debate. 3-6
Xamoterol (’Corwin’; ’Xamtol’; ICI 118,587) is a partialagonist at the &bgr;1-adrenoceptor which stabilises the responseof the heart to sympathetic drive.7 Haemodynamic studies inpatients have shown that xamoterol increases ventricularcontractility and improves diastolic function by increasingthe rate of ventricular relaxation, thus decreasing ventricularfilling pressure.8,9 Small short-term studies havedemonstrated an improvement in exercise capacity andsymptoms in mild to moderate heart failure and a reductionin the degree to which the heart rate increases withexercise.10,11 We therefore set out to study xamoterol anddigoxin longer term in patients with mild to moderate heartfailure.
Patients and Methods
DesignThe study was a double-blind randomised between-patient
comparison of placebo, xamoterol (200 mg twice daily), and digoxin(0 125 mg twice daily) conducted at 32 centres in Germany and 2 inAustria. There was a single-blind placebo run-in period of 1 weekfollowed by a double-blind treatment period of three months.Patients were randomised to receive placebo, xamoterol, or digoxinin the ratio 1:2:1.
Results of a pilot study indicated that a total of 360 patients wouldbe needed to give a 90% chance of detecting a 60 s difference inexercise duration between placebo and xamoterol at the 5% level ofsignificance, when the treatment ratio of 2:1 was taken into account.The protocol was reviewed by an independent ethical committee
and all patients gave informed consent to take part. The study wasconducted in accordance with the revised Declaration of Helsinki.
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TABLE I-CHARACTERISTICS OF PATIENTS AT BASELINE
Patients
Patients aged 29-80 years with breathlessness and/or fatigue onexercise-ie, mild to moderate heart failure (New York HeartAssociation class II-III)--were selected. Patients with severe heartfailure (NYHA class IV) were excluded, as were those with
pulmonary disease causing breathlessness or fatigue on exercise,and all premenopausal women. Other exclusion criteria included:sinus tachycardia > 90 beats per minute; any arrhythmia requiringtherapy; aortic or mitral stenosis; hypertrophic obstructive
cardiomyopathy; serious non-cardiac diseases; inability to completethe first 2 min of the exercise protocol; concurrent therapy withdigitalis, p-blockers, vasodilators with arteriolar action, angiotensinconverting enzyme (ACE) inhibitors, calcium antagonists, or
antiarrhythmics. Thiazides at any dose were permitted, but doses ofloop diuretics were limited to frusemide 80 mg daily or equivalent.
Methods
At entry the patients were familiarised with the bicycle exercisetest, and each had a clinical assessment and chest X-ray. After theplacebo run-in (visit 2), baseline assessments were made, includingsymptom-limited exercise test, questionnaires about symptoms andactivities in their daily lives, and recording of any comments aboutadverse experiences. Randomised treatment was then started.Further visits for monitoring safety were made after 1 and 6 weeksof randomised treatment. After three months the full assessments asat baseline were repeated (visit 5).
Effort tolerance was assessed by symptom-limited exercise on abicycle ergometer starting at 20 W for the first minute and
increasing every minute by another 20 W to a maximum of 240 W.Heart rate and blood pressure were measured during the last 15 s ofeach 2 min period and immediately after cessation of exercise.
TABLE II-WITHDRAWAL INFORMATION
*1 convulsion due to alcohol withdrawal; 1 cerebral embolism due tointracardiac thrombosis.
tHeadache, anxiety, allergy, pain in limbs, accident.
Symptoms during daily life were assessed by Likert and visualanalogue scale (VAS) questionnaires, each of which includedquestions about breathlessness, tiredness, chest pain, and
palpitations. For the Likert scales, the physician rated the answersgiven by the patients on a 4 or 5 point scale. Visual analogue scalesrequired the patient to make a vertical mark through a 100 mmhorizontal line marked at the two extremes "not at all" and either
"very much" or "a great deal".Routine haematology and serum biochemistry tests were made,
and plasma concentrations of xamoterol and digoxin were measuredduring the study.
Statistical AnalysisFor each variable, analysis was confmed to those patients who had
data at baseline (visit 2) and after three months’ randomisedtreatment (visit 5). Analysis of covariance was used for exercisetolerance data, which yielded adjusted means. In the case of dataconcerning symptoms during daily life, analysis of variance wasapplied to the difference between baseline and three months’treatment (visit 5). The statistical significance of the differencebetween treatment means was assessed by conventional F tests and ttests. Significance (p < 0-05) of an overall F test was required beforeuse of paired t tests.
Results
Characteristics at Baseline
433 patients entered the study. Their median age was 62years and 57% were female. 63% had class II and 13% classIII I heart failure (NYHA). 25% were initially categorised ashaving class I heart failure but were reassigned to class IIafter exercise testing.The three treatment groups were similar in respect of age,
weight, NYHA class, diuretic use, cardiovascular drugsstopped at some time before entry, and other baselinecharacteristics (table l). 44% had been taking a cardiac
TABLE IV-PRINCIPAL EFFICACY FINDINGS (MEANS AND SEM)
Exercise duration and heart rate are given to the nearest unit; work done,VAS, and Likert scores to the first decimal place. Likert scores are recorded in arbitrary units.The higher the figure shown for VAS or Likert score, the greater the improvement between visit 2 and visit 5.
glycoside before entry. During randomised treatment, 5patients violated the protocol by increasing diuretic dosage(placebo 2, xamoterol 1, digoxin 2): 1 patient on xamoterolreduced diuretic dosage. Concomitant isosorbide dinitratewas increased for 2 patients on xamoterol and was varied for1 on placebo and 1 on digoxin. Data from these patients areincluded in the analyses.
Withdrawals
16 patients were withdrawn during the run-in and 68during the double-blind phase. Of the 68 withdrawn duringthe double-blind phase 33 did not have the intended visit 5assessments. The analysis therefore includes data from 384patients whereas only 349 can be said to have completed thefull double-blind phase (table 11).
Exercise Test
Exercise continued until either symptoms or cardiac
safety criteria prevented continuation. During therandomised-treatment period 33 patients did not reach final(visit 5) assessment; for these, therefore, no exercise datawere available. A further 12 patients at final assessmentwere, at clinical discretion, not subjected to exercise testingand for these no exercise data were produced. For a further72 patients an exercise test was performed (visit 5) but thesetests were not as defined by the protocol (eg, exercise insupine rather than erect posture, discontinuous exercise test,workload or time increments not as specified). There werethus 300 patients with valid exercise tests at both baselineand after three months’ randomised treatment. At baselinetheir commonest reasons for stopping exercise were
breathlessness (93%), tiredness (66%), and chest pain(22%). Exercise was often curtailed for more than onereason. The groups were comparable in terms of baselineexercise and reasons for stopping exercise. Both activetreatments tended to reduce the incidence of breathlessness.Chest pain was reduced in the xamoterol group (table III) aswas the, albeit small, number of arrhythmias terminatingexercise tests. Xamoterol increased both exercise durationand work done more than did placebo (p < 0’001), and heartrate at maximum exercise was lower (p < 0’01) despite theincreased workload (table IV). Digoxin produced a similartrend but none of the changes differed significantly fromthose seen with placebo. Both exercise duration and workdone were significantly higher with xamoterol than withdigoxin (p < 0-05).
The accompanying figure shows the results of pooling, intreatment groups, percentage changes in exercise capacityfrom baseline to three months for each patient. Thexamoterol group improved by 33%, the digoxin group by17%, and the placebo group by 5%. There was nosignificant difference between treatments with respect tosystolic blood pressure at maximum exercise.
Symptoms During Daily LifeBreathlessness and tiredness during daily life were
significantly better with xamoterol than with placebo onboth the Likert and the VAS assessments. Digoxinproduced similar results except that the difference fromplacebo on the VAS was not statistically significant.Xamoterol was significantly better than digoxin fortiredness on the VAS and the trend was similar on the Likertscale although the difference was not statistically significant.In comparison with placebo, xamoterol produced a
significant improvement in palpitations and chest pain asassessed by Likert and VAS. These symptoms were alsoimproved by digoxin, although the difference in VAS scorewas not statistically significant (table IV).
Clinical Assessments
There were no significant differences between thetreatments with respect to changes in resting heart rate andblood pressure. The most common change in NYHAclassification was a reduction by one class, which occurred in
Work done:mean percentage change over 3 months’ treatment.
Mean % changes in individuals pooled for each treatment group.
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TABLE V-CLINICAL SIGNS OF HEART FAILURE
n = 93 placebo, 199 xamoterol, 92 digoxin. -
28 3% on xamoterol, 23-6% on digoxin, and only 5-5% onplacebo.
Signs of Heart Failure
One or more signs of heart failure were present in 52% ofpatients on entry to the study. The numbers of patientsshowing each sign of failure are shown in table v. The mostfrequent sign was peripheral oedema (27%). The’
percentage of patients who improved with respect to eachsign of heart failure was greater in the xamoterol and digoxingroups than in the placebo group; this difference reachedstatistical significance (chi-squared test) with respect tocrepitations and peripheral oedema. There were no
significant differences between the xamoterol and digoxingroups. A small number of patients acquired a sign of heartfailure between visit 2 and visit 5 in each of the threetreatment groups.
Patients’ weight (adjusted mean) was reduced 0-47 kg byxamoterol compared with (p < 005), and 0,99 kg by digoxincompared with placebo (p < 0-001). The reduction in weightwith digoxin was significantly greater than that withxamoterol (p < 0-05).
Radiographic Assessments
In the majority of patients the cardiothoracic (CT) ratiowas unchanged (placebo 78-8%; xamoterol 73-8%; digoxin697%). A greater percentage of patients had a reduced CTratio with xamoterol (20-0%) and with digoxin (22-7%) thanwith placebo (9-1 1 % ). The active treatments also produced a
greater percentage of patients with improvements in otherradiographic signs (one or more of: upper lobe diversion;pulmonary congestion; pulmonary oedema)-xamoterol17-3%; digoxin 18-9%; placebo 7-9%.
Adverse ExperiencesAdverse experiences that resulted in withdrawal are
shown in table n. Most of them affected the cardiovascular
system (table vi). The commonest single event was adeterioration in heart failure, which occurred in a lower
proportion of xamoterol patients than would be expected bychance. Nausea with or without vomiting occurred in 5
patients who received digoxin, 1 who took xamoterol, and 1 onplacebo. The proportion of patients withdrawn from double-blind treatment because of adverse experiences was 15-8% fordigoxin, 16-7% for placebo, and 9-9% for xamoterol.
There was no detectable pattern to suggest a differencebetween active treatments in the responses given by patientswhen asked about their general health and wellbeing at eachvisit, except in respect of nausea (placebo 4 patients,xamoterol 4, digoxin 10).There was no clinically significant disturbance of blood
picture or serum biochemistry, or of urine findings,attributable to study therapy.
Concentrations of Study Drugs in Plasma
The mean concentration of xamoterol in plasma at the endof 3 months’ treatment was 72-37 ng/ml SD 8-37; and that ofdigoxin was 0-87 ng/ml SD 0-05 (therapeutic range 0-7-1 -7).
Discussion
This study of xamoterol in heart failure is also the largestdouble-blind placebo-controlled study of the efficacy ofdigoxin yet reported. We have shown that, at a standard doseof 0-25 mg daily, digoxin has at best a modest effect onexercise tolerance (not significant for comparison withplacebo) in this group of patients with cardiac failure, thegreat majority of whom were in sinus rhythm. Xamoterolwas significantly more effective than either placebo ordigoxin, and was better tolerated than digoxin.The mean plasma concentration of digoxin (0-87 SD 0-05
ng/ml) was within the therapeutic range,12 yet despite thisthere was a notable incidence of nausea among patients whoreceived digoxin. However, withdrawals due to adverseexperience were no more frequent in the digoxin group thanin the placebo group.
Several investigations have been unable to detect anyclinical deterioration in patients after withdrawal of long-term digoxin therapy13-19 whilst others have demonstratedeither a haemodynamic deterioration2O or a haemodynamicdeterioration with a clinical deterioration in about half the
patients.21 The design of these studies has been criticised.’ 2Pitt, in a double-blind study of digoxin versus captopril andplacebo, detected no difference between digoxin andplacebo in exercise duration or functional status, but did findan increased ejection fraction with digoxin; it is unclearwhether certain subsets of patients may have benefitedfunctionally.22 Lee and colleagues reported clinical
improvement in 14 out of 25 patients receiving digoxin in aprospective controlled randomised study. Their patientscould be characterised as having more severe heart failurethan those in our own study as judged by ejection fraction,heart size, and the presence of 3rd heart sound.23 Similarly,haemodynamic improvements from short-term digoxinafter myocardial infarction are greater the more pronounced
493
the left ventricular dysfunction.z’ Most patients in our studyhad mild heart failure of ischaemic aetiology; only about athird had radiological evidence of cardiomegaly. Whilst thismay be one reason for the modest effects of digoxin in thisstudy, in clinical practice these characteristics, together withfluid retention, are the commonest presentation of mild andmoderate heart failure. Fluid retention in such patients canusually be controlled with diuretics.6
It was implicit in the selection criteria for entry into thisstudy that breathlessness and fatigue occurred at an
abnormally low level of exercise when compared with thatachievable by a healthy population of similar age and sexdistribution. The maximum work rate of such a populationshould be within the range 35-75 kj ’1-127 whereas the meanin our patients was 16 33 kj. Clearly, exercise capacity in thepatients we studied was substantially below normal.The improvement in exercise capacity brought about by
both xamoterol and digoxin may be considered either interms of the actual work done or as the percentage change ineach individual patient. Both methods have been used in thisreport (table iv and figure). A merit of percentage change isthat improvements are related directly to each patient’sbaseline exercise capacity and are not influenced by the largebetween-patient variation in exercise capacity. In thiscontext, the increase in exercise capacity brought about byxamoterol was similar to that seen with captopril added todiuretic in a recent double-blind study of patients with heartfailure.22The most frequent reasons for stopping exercise were
breathlessness and fatigue in the symptom-limited test andthis was so in all three treatment groups. However, it isnoteworthy that both xamoterol and digoxin tended toreduce the incidence of breathlessness whilst the incidenceof chest pain and palpitations on exercise testing was alsoreduced in the xamoterol group.52% of patients had one or more signs of congestive heart
’ failure on entry into the study. The protocol permitteddiuretic treatment but that dosage was kept constant duringthe study. Despite this, the incidence of signs of heartfailure, especially peripheral oedema and crepitations, was
, reduced in both the xamoterol and digoxin groups relative tothe placebo group. The observation of weight loss in theactive treatment groups is consistent with the improvementseen in signs of congestion and might reflect additional fluidloss in consequence of these treatments.The changes in exercise capacity, in reasons for stopping
exercise, and in clinical signs of heart failure, are inaccordance with the changes in the patients’ symptomsduring everyday activities as assessed by the patient’s VASand physician Likert scales. These showed that bothxamoterol and digoxin had beneficial effects on the cardinalsymptoms-breathlessness and fatigue-in those patients(table iv). Though the changes in the xamoterol group werelarger and of greater statistical significance, randomisationincluded more patients on xamoterol than digoxin; thus it ispossible that the trend for clinical improvements seen withdigoxin in these study indices would also have reachedstatistical significance had larger numbers of patients beenstudied on the glycoside.Our conclusions are that digoxin has at best a modest
effect in patients with mild to moderate heart failure who arein sinus rhythm; it has some effect on symptoms but nomajor benefit on exercise capacity. Xamoterol seems to be apromising alternative to digoxin in the treatment of mild tomoderate heart failure.
The following physicians took part in the study:Germany.-Dr C. Baran, Dachau; Dr M. Baumuller, Dachau; Dr G.
Bohm, Neufahm; Dr W. Bohn, Petershausen; Dr H. D. H. Breitfelder,Burglengenfeld; Dr C. Buckert, Heidelberg; Dr W. Erhard, Stockdorf; ProfC. A. Geser, Garmisch-Partenkirchen; Dr V. Greifenstein, Langen; ProfK. D. Hahn, Hannover; Dr E. Haringer, Miinchen; Prof P. U.
Heuckenkamp, Munchen; Prof K. Jork, Langen; Dr P. Junger, Karlsfeld; DrJ. Kandziora, Troisdorf (2 centres); Dr H. D. Klimm, Kuppenheim; Prof B.Konig, Mainz-Finthen; Dr B. Krakow, Ilversheim; Dr H. A. Kraus,Waiblingen-Neustadt; Dr T. Kusus, Miinchen; Prof K. Lossnitzer,Puttlingen Saar; Dr W. Michel, Ludwigshafen; Dr B. Muller-Wittig, Bruhl;Prof K. E. von Olshausen, Mainz; Dr G. Prager, Regensburg; Dr J. Rauh,Domstadt; Dr W. Rudroff, Munchen; Dr H. J. Schaumann, Mannheim; DrR. Schorten, Dachau; Prof B. Stegaru, Mannheim; Dr B. Stolzki, Dachau.
Austria. Prof W. Klein, Graz; Prof K. Steinbach, Wien.
We thank ICI Pharmaceuticals for providing the trial materials andfinancial support. The data were analysed by statisticians at ICIPharmaceuticals in the UK. Digoxin was supplied as ’Lanoxin’ tablets by theWellcome Foundation Ltd.
Correspondence should be addressed to Prof K. E. von Olshausen,Elisabeth Krankenhaus, Schulgasse 20, 8440 Straubing, Federal Republic ofWest Germany, who prepared this report with the technical guidance of DrH. F. Marlow, Medical Research Department, ICI, UK.
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