Effect pimobendan capacity - Heart · phosphodiesterase inhibition.8 It is rapidly absorbed, the peak plasma concentration is reached after 1-5 hours, and the effect lasts eightto

Heart 1996;76:223-231

Effect of pimobendan on exercise capacity inpatients with heart failure: main results from thePimobendan in Congestive Heart Failure (PICO)trial

The Pimobendan in Congestive Heart Failure (PICO) Investigators

AbstractPrimary objective-To determine theeffects of pimobendan 2 5 and 5 mg dailyon exercise capacity in patients withchronic heart failure.Design-A randomised, double blind,placebo controlled trial of the addition ofpimobendan to conventional treatmentwith a minimmum follow up of 24 weeks.Setting-Outpatient cardiology clinics insix European countries.Patients-317 patients with stable symp-tomatic heart failure, objectivelyimpaired exercise capacity, and an ejec-tion fraction of 45% or lower who were

treated with at least an angiotensin con-verting enzyme inhibitor and a diureticand who tolerated a test dose ofpimoben-dan.Results-Compared with placebo, bothpimobendan 2*5 and 5 mg daily improvedexercise duration (bicycle ergometry) by6% (P = 0-03 and 0.05) after 24 weeks oftreatment. At that time 63% of patientsallocated to pimobendan and 59% ofthoseallocated to placebo were alive and able toexercise to at least the same level as atentry (P = 0.5). No significant effects on

oxygen consumption (assessed in a sub-group of patients) and on quality of life(assessed by questionnaire) wereobserved. Pimobendan was well tolerated.Proarrhythmic effects (24-hour electro-cardiography) were not observed. In bothpimobendan groups combined the hazardof death was 1*8 (95% confidence interval0 9 to 3.5) times higher than in theplacebo group.Conclusions-Pimobendan improvesexercise capacity in patients with chronicheart failure who are also on conventionaltreatment. The balance between benefitand risk of treatment with this compoundremains to be established however.

(Heart 1996;76:223-231)

Keywords: pimobendan; heart failure; exercise capac-ity; clinical trials

Correspondence to:ProfJ Lubsen, SOCARResearch SA, Domaine deLeydefeur, CH-1271Givrins, Switzerland.

Accepted for publication30 April 1996

Despite optimal treatment with diuretics andangiotensin converting enzyme inhibitors'many patients with chronic heart failure sufferfrom persistent symptoms, limited exercisetolerance, and impaired quality of life. Alsothe prognosis continues to be poor. Hence, the

treatment of this condition remains a thera-peutic challenge.

Inotropic stimulation has met with littlesuccess. That digitalis glycosides improveexercise performance and quality of life is gen-erally accepted but their effect upon mortalityremains to be established. More recently phos-phodiesterase inhibitors with both inotropicand vasodilating properties have been intro-duced.23 Much has been expected of this classof substances4 but long-term trials have shownthat, although a moderate improvement inquality of life and exercise capacity can beachieved, mortality is increased.5-7 A novelapproach to inotropic stimulation is the directsensitisation of cardiac myofilaments tocytosolic calcium. Pimobendan (UDCG 115BS) combines this effect with myocardialcyclic adenosine monophosphate dependentphosphodiesterase inhibition.8 It is rapidlyabsorbed, the peak plasma concentration isreached after 1-5 hours, and the effect lastseight to 10 hours. Its main metabolite, UDCG212, has similar pharmacodynamic propertiesas the parent compound. In patients withheart failure, oral or intravenous pimobendanproduces lasting and dose dependent benefi-cial haemodymic effects. Myocardial energet-ics seem to be favourably influenced becausethe ratio between cardiac work and oxygenconsumption remains unchanged or is evenimproved.9 Systemic blood pressure is reducedslightly with higher doses of pimobendan.Although the phosphodiesterase inhibitingproperties of pimobendan suggest arrhythmo-genic potential, no important proarrhythmiceffect has been observed in the clinical studiesperformed so far.

Several earlier trials in chronic heart failurepatients showed beneficial effects whenpimobendan was added to an optimal basicregimen with or without digitalis.'1"2 Also, atrial comparing pimobendan with theangiotensin converting enzyme inhibitorenalapril was performed."3 To confirm theseearlier findings, another placebo-controlledtrial focusing on exercise capacity, oxygenconsumption, and quality of life was under-taken with a longer (at least 24 weeks) treat-ment duration and in a larger group of patientsthan in previous trials.

Patients and methodsPATIENTSIn 30 centres (see Appendix) patients wererecruited if they had chronic moderate (New

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Table 1 Exercise protocol (maximal bicycle ergometry in sitting position) and limits ofexercise time allowed at entry

Age (years)

Men < 65 65-69 70-74 > 75Women < 50 50-59 60-64 65-69 70-74 > 75

Workload (w):1 st minute 0 0 0 0 0 0 02nd minute 30 20 20 10 10 10 10Each next minute +10 +10 +10 +10 +10 +10 +10

Limits (min:s):At least 3:00 3:00 3:00 3:00 3:00 3:00 3:00Less than 10:00 10:00 10:00 10:00 9:00 8:00 7:00

York Heart Association class II-III) heart fail-ure and had given written informed consent.All patients were at least 18 years of age, hadbeen clinically stable without importantchanges in background medication for at least30 days, and had an ejection fraction of 45%or lower. At two maximal exercise tests at leasttwo weeks apart, exercise times were withinthe age and sex-specific limits shown in table 1and no more than one minute apart.

Exclusion criteria were: stenotic, obstruc-tive, or infectious cardiac disease; exercisecapacity limited by angina; on waiting list fortransplantation; suspicion of digitalis toxicity;acute myocardial infarction, coronary revascu-larisation, or episode of syncope or cardiacarrest during the last three months; automaticcardiac defibrillator implanted; primary renalor hepatic disease; haemodynamically signifi-cant pulmonary embolism or severe pul-monary disease; any other still presentlife-threatening condition; previous participa-tion in a trial with pimobendan; and antici-pated problems with follow up or compliance.Women were excluded unless they had beensterilised or were at least two years post-menopause. Baseline serum potassium had tobe above 3-8 mmol/l, serum creatinine below194,mol/l, and aspartate aminotransferasebelow 100 U/1.The day before double blind medication

was started, all patients were given a single testdose of pimobendan and were excluded if thisdose produced significant symptoms or signsof intolerance.

MEDICATION REGIMEN

Background medication consisted of at leastan angiotensin converting enzyme inhibitorand a diuretic. In addition, digitalis, nitrates,and molsidomine were allowed. Otherinotropic agents, phosphodiesterase inhibitors,ibopamine, ,B blockers, calcium antagonists,and other vasodilators could not be given. Theonly antiarrhythmic agent allowed was amio-darone, which had to have been started at leastthree months before entry. In patients receiv-ing amiodarone, the QT interval corrected forheart rate'4 (QTc) was monitored and the doseof this compound was reduced if QTcexceeded 480 ms.

Double blind medication consisted of eitherplacebo or pimobendan 2-5 or 5 mg daily,divided in two equal doses. Allocation was

randomised and blocked by centre.Medication was also taken on the days of exer-

cise testing. Investigators were instructed tohalve the dose when serum creatinine rose toat least 2-5 mg/dl (220 fmol/l), or aspartateaminotransferase to at least 150 U/l; and towithdraw double blind medication if suchincrease(s) persisted. Compliance was moni-tored by pill counts and was judged to havebeen good when at least 80% of the predictednumber of double-blind medication capsuleshad been used without interruption for morethan 48 hours.

TRIAL DESIGNThe screening phase consisted of a minimumof two outpatient clinic visits at least twoweeks apart and was followed by a 24 weekefficacy phase on double blind medicationconsisting of clinic visits after 2, 4, 8, 12, and24 weeks. Clinical status permitting, allplanned follow up assessments (includingexercise testing) were completed irrespectiveof deviations from the double blind medica-tion regimen (intention-to-treat principle).After completion of the efficacy phase,patients who were still alive at that momentwere followed for further clinical events until acommon stopping date. Patients who con-sented continued to take double blind medica-tion (extended follow up phase).The primary outcome was exercise time

measured at least twice during screening, and4, 12, and 24 weeks after the start of doubleblind medication. The same age and sex spe-cific maximal bicycle ergometry protocol inthe sitting position (table 1) was used in allcentres. In a sub-study, gas exchange mea-surements were also performed.

Baseline ejection fraction was assessed bythe investigator from a two dimensionalechocardiogram, which was recorded on videotape and re-analysed later at the co-ordinatingcentre. If no analysable echocardiogram wasavailable, a value obtained by another methodwas accepted. At each visit, the symptomaticstate was assessed by the New York HeartAssociation classification.'5 Quality of life wasevaluated by the Minnesota Living with HeartFailure questionnaire'6 administered twiceduring screening and after four, 12, and 24weeks. Patient safety was assessed by monitor-ing vital signs (every visit), standard 12 leadelectrocardiography preceding exercise testing,standard laboratory tests (screening, four, 12,and 24 weeks), and 24 hour electrocardiogra-phy (screening, four, and 24 weeks). ECGswere analysed at the co-ordinating centre.Proarrhythmia was assessed by criteriadescribed previously.'7

While the trial was ongoing, patients werewithdrawn when a clinically relevant violationof the selection criteria was detected at the co-ordinating centre. The decision to do so wastaken by the steering committee before themedication code was broken. Cause of deathwas classified by the critical events committee,which had no access to the medication code.Sudden death was defined as witnessed deathwithin one hour of onset of symptoms orunexpected, unwitnessed death.'819 This com-mittee also assessed whether missed exercise

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Effect ofpimobendan on exercise capacity in patients with heart failure

Table 2 Entry characteristics*

Pimobendan (daily dose)

Characteristics Placebo 2 5 mg 5 mg Total

Numberofpatients 108 (100%) 106 (100%) 103 (100%) 317 (100%)Age (years) 65-1 (10-3) 64 8 (9-1) 66-6 (9-1) 65 5 (9 5)Male 79% 78% 83% 80%History:

Ischaemic aetiology 72% 67% 67% 69%Documented MI 65% 63% 57% 62%Coronary bypass grafting 18% 26% 21% 22%Treated for high blood pressure 23% 36% 20% 26%Diabetes 14% 15% 20% 16%Median (range) duration ofHF (months) 34 (1-225) 35 (2-480) 35 (2-284) 35 (1-480)Hospitalised > 24 hours for HF 73% 66% 70% 70%NYHA II/III 51%/49% 56%/44% 50%/50% 52%/48%

Basic regimen:ACE inhibitor and diuretic 100% 100% 100% 100%Digitalis glycosides 63% 55% 59% 59%Nitrates 43% 44% 46% 44%Molsidomine 7% 7% 5% 7%Amiodarone 9% 11% 17% 12%Anticoagulants 56% 46% 51% 51%

Observations:Regular sinus rhythm 78% 74% 73% 75%Ejection fraction (%)t 28 (7) 26 (6) 28 (7) 27 (7)End diastolic volume (ml)t 312 (104) 315 (95) 308 (113) 312 (104)Exercise time (s) 435 (97) 417 (100) 416 (110) 423 (102)Drop of SBP during exercise 3% 4% 7% 4%Total MLHF score§ 27-9 (18-4) 26-5 (16-8) 25 8 (19-1) 26-8 (18 1)QTc interval > 480 ms 14% 18% 18% 17%

*Data are given either as a percentage or as a mean (SD); unless indicated otherwise. ACE, angiotensin converting enzyme; HF,heart failure; MI, myocardial infarction; MLHF, Minnesota Living with Heart Failure questionnaire; NYHA, New York HeartAssociation classification; SBP, systolic blood pressure; QTc, QT-interval corrected for heart rate.tNo entry value was available for one patient assigned to pimobendan 5 mg/day (local values were accepted when central analysiswas not possible).tNo entry values were available for 11 patients assigned to placebo, 7 patients assigned to pimobendan 2-5 mg/day and 10 patientsassigned to pimobendan 5 mg/day.§No entry value was available for one patient assigned to pimobendan 2 5 mg/day.

tests were due to the patient's cardiovascularcondition.

ETHICSThe trial was carried out in accordance withthe Declaration of Helsinki,20 had beenapproved by the institutional review board ofeach centre, and was monitored according toEuropean Union standards of Good ClinicalPractice. For patient safety, episodes of ven-tricular tachycardia in excess of three consecu-tive beats observed in centrally analysed 24hour electrocardiograms were reported to theinvestigator. Data on serious adverse eventswere regularly reviewed by an independentmonitoring committee, which was in the pos-session of the treatment code from the start ofthe trial onwards.

Table 3 Exercise testing and medication compliance during efficacy phase

Pimobendan (daily dose)

Placebo 2 5 mg 5 mg Total

Number of patients 108 106 103 317Exercise test done:

4 weeks 103 99 98 30012 weeks 97 92 88 27724 weeks 94 86 88 268

Exercise test done and good compliance:4 weeks 101 97 94 2924 and 12weeks 93 82 82 2574, 12, and 24 weeks 88 73 79 240

Exercise test not done due to death:4 weeks 2 3 3 812 weeks 5 5 10 2024weeks 6 13 11 30

Exercise testing contraindicated:4weeks 1 3 2 612 weeks 3 4 4 1124 weeks 4 2 3 9

Exercise test not done for other reasons:4weeks 2 1 0 312 weeks 3 5 1 924 weeks 4 5 1 10

STATISTICAL METHODSSample size estimation was based on theresults of an earlier trial with the same com-pound and the same primary outcome." Forexercise time and for the physical dimension ofthe Minnesota Living with Heart Failure ques-tionnaire, 70 patients per group were requiredfor a power of 90% at a two-sided significancelevel of 5% (based on charts of the powerfunction for analysis of variance tests2' andsums of squared treatment effects estimatedfrom the earlier trial"). For peak oxygen con-sumption 45 patients per group were required.No interim analyses for efficacy were per-formed.

All patients who complied with the selectioncriteria and had started double blind medica-tion were included in intention-to-treat analy-ses; no patient was excluded for protocolviolations which had occurred during followup. The primary pre-specified analysis of exer-cise time was limited to those patients whohad at least the first follow up (four week)exercise test carried out and had shown goodcompliance (see medication regimen) up tothe day of the test. If subsequent tests were notperformed, whatever the reason, or were per-formed although compliance between testshad been poor, the last exercise time valueobtained while compliance was good was car-ried forward. Tests of significance were per-formed by fixed-effects analysis of variance forrepeated measurements.22 All P values quotedare two-sided.As a secondary analysis, changes in exercise

time at 24 weeks were ranked and all patientsassigned to placebo were compared by a stan-dard non-parametric test with all patientsassigned to pimobendan on an intention-to-treat basis. If the patient had died or if there

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had been a cardiovascular contraindication forexercise testing, the rank assigned was thatbelow the patient with the lowest rank basedon exercise time changes actually observed. Ifexercise time was missing for other reasons,the last available value was carried forward incalculating the rank.

Percentages were compared between groupsby chi-squared tests with one or two degrees offreedom for comparisons between two or threegroups respectively. Hazards of all-cause mor-tality and of the combined event death or hos-pital admission for cardiovascular reasonswere calculated by dividing the total numberof events that had occurred by the number of

person-years of follow up that patients hadbeen at risk of the event considered. The timeof first intake of double-blind medication wasregarded as the beginning of follow up, andthe day the patient was last known to be alive,as the end. Medication groups were comparedby hazard ratios and their 95% confidenceintervals.23 To assess whether the hazard ratioestimates for the combined endpoint of deathor hospital admission for cardiovascular rea-sons were distorted by imbalance betweentreatment groups for clinical predictors of thisevent at baseline, the same hazard ratios werealso estimated by Cox multivariate propor-tional hazard analysis.24

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(A) Mean (SEM) ofchange in exercise time afterfour, 12 and 24 weeks relative to baseline (per protocol analysis) in 292patients entered in the primary analysis (101 placebo, 97pimobendan 2 5 mglday, and 94 5 mglday; table 3). The lastavailable value was carriedforward when data for 12 or 24 weeks was missing. For the 101 patients on placebo in thisanalysis, the mean entry exercise time was 437 seconds and the mean changes were: + 25 (7) afterfour weeks, + 32 (8) after12 weeks, and + 30 (9) seconds after 24 weeks. In the pimobendan 2-5 mglday group the mean changes were + 38 (7),+ 59 ( 8), and + 59 ( 9) and in the 5 mglday group + 44 (7), + 49 (11), and + 58 ( 10) seconds respectively (overall P= 0-06; 2 5 mglday versus 5 mglday P = 0 9; 2 5 mglday versus placebo P = 0 03, 5 mglday versus placebo P = 0 05;allpimobendan versus placebo P = 0-02).

(B) Cumulative distributions ofchanges in exercise time at 24 weeks based on intention-to-treatfor placebo (108 patients)andfor both pimobendan groups combined (209 patients). In ten cases in theformer group (6 + 4, table 3) and 29 in thelatter group (13 + 11 + 2 + 3; table 3, P = 0-2) the 24-week exercise test was missing because ofdeath or a cardiovascularcontraindication to exercise testing. Hence, for placebo the curve starts at the 10 2th (11/108) andforpimobendan at the14-4th (301209) percentile. Whenever the 24-week test was missingfor other reasons (4 placebo, 5 + 1 pimobendan; table3), the last available value was carriedforward. The medians do not differ significantly (difference between medians = 18seconds, P = 0 5) but in this trial patients assigned to pimobendan showed more improvement in exercise time than patientsassigned to placebo, despite their higher incidence of death or contra-indications to exercise testing.

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Table 4 Clinical events (excluding extendedfollow up)

Number ofpatients with event* Ranked clinical outcome at 24 weekst

Pimobendan Pimobendan Pimobendan PimobendanPlacebo 2 5mg/day 5 mg/day Placebo 2 5 mglday 5 mglday

Event (n = 108) (n = 106) (n = 103) (n = 108) (n = 106) (n = 103)

Death (all causes) 6 13 11 6 13 11Acute myocardial infarction 2 1 1 1 0 1Admission to hospital for

worsening heart failuret 0 1 4 0 1 2Admission to hospital for

arrhythmia§ 4 3 5 3 1 5Admission to hospital for

other cardiovascular reasons 14 17 16 8 10 5Medication for heart failure

added or increasedll 29 25 22 17 12 10Anti arrhythmic agents added 6 7 6 1 3 0Other cardiac medication

added or increased¶f 3 5 0 1 0 0Double-blind medication

stopped by physician 1 1 21 16 5 5 2Double-blind medication

reduced by physician 8 13 13 4 5 7Admission to hospital for

non-cardiovascular reasons** 12 13 18 3 1 4None of the above - - - 59 55 56

*Each patient with at least one of the events listed counted.tEach patient counted once and assigned to the uppermost applicable event listed.tIn-hospital addition of intravenous inotropics (including digitalis).§In-hospital addition of an anti arrhythmic agent (including digitalis).IlDiuretics, ACE inhibitors, intravenous inotropics, digitalis, nitrates, or molsidomine added or increased at any time.¶rCalcium antagonists, 3 blockers, or other vasodilators added or increased at any time.**Except admission to hospital for procedures already planned before entry.

ResultsPATIENTS, CONDUCT, AND COMPLIANCEThe trial was completed as planned. FromMarch 1993 to June 1994, 333 patients com-pleted the screening phase and had one testdose of pimobendan administered. None ofthese patients showed acute intolerance buttwo were subsequently excluded (one forhypokalaemia, one for worsening heart fail-ure). Thus 331 patients were started on dou-ble-blind medication. Before the medicationcode was broken 14 of these were excluded forviolations of the selection criteria (fourplacebo, six pimobendan 2-5 mg/day, fourpimobendan 5 mg/day; one excluded patientassigned to placebo died nine months afterrandomisation). Hence, 317 patients (108allocated to placebo, 106 to pimobendan 2-5mg/day, and 103 to 5 mg/day) are the basis ofthis report. All but one had been followeduntil November 1994 for clinical events.Selected entry characteristics are presented intable 2. Given the relatively small numbers ineach treatment arm, randomisation resulted inwell balanced groups.

Table 5 Mortality and mortality orfirst hospital admission for cardiovascular reasons(intention-to-treat; including extendedfollow up)

Pimobendan HR 251 Pimobendan HR 51Placebo 2 5 mglday placebo * 5 mglday placebo *(n = 108) (n = 106) (95% CI) (n = 103) (95% CI)

Deaths (all causes): 11 20 - 16 -

Sudden cardiact 7 15 - 7Other cardiovasculart 3 5 6Non-cardiovasculart 1 - - 1Unknown - - - 2 -

Hazard t (per 100person-years) 10 8 21 3 2-0 17 4 1-6

(0-9 to 4-1) (0 7 to 3 4)No of deaths or 1st

admission to hospital 27 40 - 33 -

Hazard t (per 100person-years) 29-5 48-5 1-6 41-2 1-4

(1 0 to 2 7) (0-8 to 2-3)

*Hazard ratios (HR) comparing patients assigned to pimobendan 2-5 mg/day and topimobendan 5 mg/day respectively with patients assigned to placebo; with 95% confidenceintervals (CI).tAs assessed by the Critical Events Committee.tNumber of events divided by person-time of follow up until event or until end of extendedfollow up.

Table 3 summarises the extent to whichexercise testing was performed in relation tocompliance with the double-blind medicationregimen. For the primary analysis of exercisetime 92% of patients (292/317) were available.In 76% (240/317) all three exercise tests wereperformed and compliance was good through-out the efficacy phase. One or more exercisetest results was carried forward in the primaryanalysis for 52 patients. In 10 patients therewas a reason other than death or a contra-indi-cation for not performing the planned 24 weekexercise test. For these the last exercise testresult was carried forward in the ranked sec-ondary analysis of change in exercise capacityat 24 weeks (see statistical methods).

Based on the same criteria for inclusion asfor the primary analysis of exercise time, 35patients on placebo, 34 on pimobendan2-5 mg/day, and 34 on pimobendan 5 mg/dayrespectively were available for analysis of gasexchange measurements. Similarly, 103patients on placebo, 100 on pimobendan2-5 mg/day, and 94 on pimobendan 5 mg/daywere available for a per-protocol analysis ofMinnesota Living with Heart Failure ques-tionnaire scores.

EXERCISE CAPACITY AND PEAK OXYGENCONSUMPTIONThe mean changes in exercise time (relative tothe last baseline test) for the patients includedin the primary analysis are shown in figure (A).After four, 12, and 24 weeks respectively, themean treatment effects of pimobendan2-5 mg/day relative to placebo were 13, 27,and 29 seconds (P = 0 03); and of pimoben-dan 5 mg/day 19, 17, and 28 seconds (P =0 05).

Figure (B) shows the cumulative distribu-tions of changes in exercise time at 24 weeksfor the 108 patients assigned to placebo andthe 209 patients assigned to pimobendan(both dose groups combined), based on inten-

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tion-to-treat and taking into account exercisetests which were not possible because of deathor a contraindication. Of the 209 patientsassigned to pimobendan, 63% were able toexercise at 24 weeks to at least the same levelas at entry. Among the 108 patients assignedto placebo, this was the case in 59% (P = 0 5,non-parametric test).

In the subgroup of 35 patients allocated toplacebo who had gas exchange measurementsthe mean peak oxygen consumption was 13-1ml/min.kg at entry; and 13-7, 13-3, and 13-9ml/min.kg after four, 12, and 24 weeks respec-tively. At these time points, the mean effects ofpimobendan 2-5 mg/day (relative to placebo,per-protocol analysis) on this variable were0-2, 0-8, and 0-4 (P = 0 4) and of pimoben-dan 5 mg/day 0-6, 0'8, and 0 3 ml/min.kgrespectively (P = 0-4).

NEW YORK HEART ASSOCIATION CLASS ANDQUALITY OF LIFEOf those assigned to placebo, 4% (4/108) werein a better New York Heart Association classat least once during follow up than at entryand never worsened or died before the 24week visit. The corresponding figure for thoseassigned to pimobendan was 10% (20/209; P- 0 06).For the 103 patients on placebo analysed

for Minnesota Living with Heart Failure ques-tionnaire scores, the mean total score at entrywas 27-7 units; and 25-0, 25-6, and 26d1 unitsafter four, 12 and 24 weeks respectively. Atthese time points, the mean effects ofpimobendan 2-5 mg/day (relative to placebo,per-protocol analysis) were - 04, - 1 6, and- 1 2 (P = 0 5) units and of pimobendan 5mg/day -0 0, +0 7, and -1 0 units respec-tively (P = 0 9).

CLINICAL OUTCOMEDuring the efficacy phase proarrhythmia basedon 24-hour electrocardiography was observedin 20 patients assigned to placebo, 15 topimobendan 2-5 mg/day, and 14 to pimoben-dan 5 mg/day. When sudden cardiac deathwas regarded as proarrhythmia also, thesenumbers became 24, 22, and 19 respectively(P = 05).

Data on the clinical outcome at the end ofthe efficacy phase (that is, at 24 weeks) is givenin table 4. Double-blind medication wasstopped or reduced significantly more often inpatients allocated to pimobendan than toplacebo (11 + 8 = 19 placebo, 21 + 13 = 34pimobendan 2-5 mg/day, 16 + 13 = 29pimobendan 5 mg/day; P = 0 04).

Data on mortality and hospital admissionfor cardiovascular reasons during the entiretrial (that is, efficacy and extended follow upphase combined) based on intention-to-treatare given in table 5. The mean follow up was11 months and 44% of patients were followedfor at least one year. In total, 47 patientsdied. While taking double-blind medication,eight died on placebo, 14 on pimobendan2 5 mg/day and 11 on pimobendan 5 mg/day.The causes of death are also given in table 5.More than half of all deaths were classified as

sudden. Cardiovascular deaths were caused bymyocardial infarction (one in each treatmentgroup), worsening heart failure (one placebo,two pimobendan 2-5 mg/day, and fivepimobendan 5 mg/day), multiple organ failure(one placebo), cerebrovascular accident (onepimobendan 2-5 mg/day), and peripheral vas-cular disease (one pimobendan 2-5 mg/day).The two non-cardiac deaths were caused bybladder cancer (placebo) and pneumonia(pimobendan 5 mg/day).Although there was a trend towards a higher

mortality hazard among patients allocated topimobendan, neither comparison with placebowas statistically significant at the 5% level(each 95% confidence interval includes one,table 5). In both pimobendan groups com-bined, the mortality was 1 8 times higher (0 9to 3 5) than in the placebo group. Similarly,there was a non-significant trend towardshigher hazards of the combined event death orfirst hospital admission for cardiovascular rea-sons.The adjusted estimates from the Cox

regression model of the hazard ratios for deathor hospital admission for cardiovascularreasons were 1-5 comparing pimobendan2-5 mg/day with placebo (95% confidenceinterval 0 9 to 2-5) and 1-2 (07 to 2 1) com-paring pimobendan 5 mg/day with placebo.Conditionally independent and significant(P < 0 05) covariates associated with areduced risk in the Cox model were (hazardratios between brackets): change of systolicblood pressure during exercise (0-983/mm Hgrise), resting systolic blood pressure(0-980/mm Hg), exercise time (0 998/s), andprevious coronary bypass grafting (0 5).Covariates associated with an increased riskwere previous hospital admission for heart fail-ure (2-6), history of symptomatic arrhythmia(1 6) and history of high blood pressuretreated with drugs (1-7). The adjusted esti-mates are similar to those given in table 5.Conditional on the covariates mentioned, age,sex, NYHA class, ejection fraction, and use ofdigitalis were not associated with the risk.

DiscussionThe main finding of this trial confirms earlierfindings that pimobendan improves exercisecapacity.'s"2 Relative to placebo, the magni-tude of this effect seemed to increase until 12weeks of treatment and then to persist at thesame level at 24 weeks (figure A). This is notonly the largest placebo-controlled trial to datebut also the first one with a treatment periodof this duration. This sustained effect hastherefore not been reported before.The largest earlier placebo-controlled trial

studied 198 patients in NYHA class III whowere treated for 12 weeks with either placebo,or 2-5, or 5, or 10 mg/day of pimobendan."Mean exercise duration increases (rounded towhole seconds) of 30, 68, 122, and 81 respec-tively were observed. Adding these meanincreases to the mean entry exercise time inthe placebo group (536 seconds) yields meanfollow up exercise durations of 566, 604, 658,

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and 617 seconds respectively for placebo or2-5, or 5, or 10 mg/day of pimobendan.Hence, in that trial the effect of treatmentexpressed as the percentage difference com-pared with placebo was ((604- 566) x100)/566 or 7% for treatment with 2-5 mg/dayof pimobendan. Calculated in the same way,the treatment effects for 5 and for 10 mg/dayof pimobendan were 16% and 9% respec-tively. In another smaller earlier trial,'0 inwhich treatment effects were calculated in asimilar manner results of 16% and 13% for 5and 10 mg/day of pimobendan respectivelywere observed.

Based on the data given in table 2 and fig-ure (A) and by the same method of calcula-tion, treatment effects at 24 weeks in this trialwere 6% for 2-5 and also 6% for 5 mg/day ofpimobendan. Thus the magnitude of the effectof 2-5 mg/day of pimobendan in this trial wassimilar to that in the largest earlier trial" butthe effect of 5 mg/day was considerably lessthan observed before. 10 1' Because of the dose-response relations observed in these earlier tri-als, the 10 mg/day dose was not studied in thistrial. Contrary to the largest earlier trial," nodifference was observed between the 2-5 and5 mg/day dosages with respect to their effecton exercise duration. One can only speculatewhy the effect on exercise duration of the5 mg/day dose in this trial was less markedthan observed earlier. In the largest earliertrial," all patients were in NYHA class III. Inthe present trial that was the case in 48%(table 2). We found no relation between theeffect of pimobendan and NYHA class atentry. Hence, it seems unlikely that this canexplain the difference between this and theearlier result. Similarly, it is unlikely that thedifference in angiotensin converting enzymeinhibitor use (80% in the largest earlier trial,all patients in the present one) or digitalis use(88% in the largest earlier trial, 59% in thepresent one) can explain the difference.Whether there is a relation between the use ofangiotensin converting enzyme inhibitors andthe effect of pimobendan is not known and inour data there was no relation between theeffect of pimobendan and use of digitalis. Afactor may have been that patients in this trialwere older than in the earlier trial (65-5 meanage in this one, 61 in the largest earlier trial)and that ischaemic heart disease was a morefrequent aetiology (69% in this trial and 44%in the largest earlier trial). This, and the differ-ent exercise methodology used,25 may haveinfluenced the results. Alternatively, the largerefficacy of pimobendan 5 mg/day relative to2-5 and 10 mg/day in the largest earlier trial"may to a certain extent have been a chancefinding. An argument in favour of this is thatthe 10 mg dose has produced the largesthaemodynamic improvement.'0 In any case,this trial together with earlier trials'0" suggeststhat the therapeutic range of pimobendan is2-5 to 5 mg/day.

This trial did not reproduce the statisticallysignificant effects of pimobendan on peak oxy-gen consumption'0"1 and on the MinnesotaLiving with Heart Failure questionnaire"

scores seen in earlier trials. Again, one canonly speculate about the reasons. Peak oxygenconsumption was measured only in a sub-group of patients and the power may havebeen insufficient. The Minnesota Living withHeart Failure questionnaire may be less sensi-tive to changes in patient wellbeing and/or lessreproducible when used in different culturalsettings than the one for which it was origi-nally developed and validated.

This trial followed a classic pattern for exer-cise capacity trials in heart failure. Severaladditional design features, however, allowedus to clarify further the efficacy and safety ofadding pimobendan to the prevailing basicheart failure regimen. As in the largest earliertrial," we randomised only those patients whotolerated a test dose of pimobendan. Nopatient was excluded because of acute intoler-ance. In fact, the present data show thatpimobendan in the dosages studied is well tol-erated. The number of patients in whom treat-ment had to be discontinued was small (table4). No clinically relevant signs of proarrhyth-mia were observed. The number of patients inwhom proarrhythmia was observed by 24-hour electrocardiography based on acceptedcriteria'7 was highest in the placebo group evenwhen sudden cardiac death in the absence ofproarrhythmia based on 24-hour electrocar-diography was also regarded as proarrhythmia.When the clinical situation permitted, fol-

low-up exercise testing was performed inpatients in whom pimobendan had been dis-continued. This allowed for the ranking ofpatients based on exercise capacity at 24 weeksand on intervening clinical events as shown infigure (B). We believe this to be an importantadditional evaluation of the efficacy of chronicheart failure treatment. Effects on clinical out-come may either dilute or enhance effects onexercise capacity.26 In the present case, thetrend towards a higher mortality in patientsstarted on pimobendan raises the questionwhether the benefit related to the positiveeffect of pimobendan on exercise capacity inthe survivors is negated by the higher mortalityrisk associated with this treatment. The rank-ing in figure (B) shows that patients started onpimobendan have a higher chance of surviving24 weeks and improving their exercise capacitythan patients started on placebo. The differ-ence was, however, not statistically significant.The major limitation of this trial is thereforethat it does not allow a definitive conclusionabout the benefit:risk ratio of treatment withpimobendan and it is this benefit:risk ratiowhich would merit further study in a largertrial.To collect further data on the safety of

pimobendan, all patients were followed until acommon stopping date after they completedthe 24-week efficacy phase, and those whoconsented were kept on medication. Thisdesign feature optimises the number ofpatient-years of follow up which can be accu-mulated within a given time. Hence it was pos-sible to evaluate mortality and the combinedrate of death or first hospital admission forcardiovascular reasons over a mean follow up

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of 11 months based on intention-to-treat.Even though the differences were not signifi-cant, the hazards of both events were higher inthe pimobendan than in the placebo groups(table 5). This was largely due to an increasedincidence of sudden cardiac death, in particularin the pimobendan 2-5 mg/day group. Theresults of Cox multivariate proportional haz-ard analysis showed that these differences areunlikely to be related to imbalance betweentreatment groups in important predictors ofclinical outcome.

Because of its different mechanism ofaction,9 the trend towards a higher mortality inpatients treated with pimobendan in this trialis unexpected despite earlier findings with pre-dominantly cyclic adenosine monophosphatedependent phosphodiesterase inhibitors suchas milrinone and enoximone.67 Our findingsmay be attributable to chance because thetrend observed was not statistically significant.Another potential explanation is a hithertounknown interaction between digitalis and apositive inotropic compound such aspimobendan. The excess mortality in thepimobendan groups in this trial occurred pre-dominantly in patients who were also on digi-talis at entry. Thirty five of the 47 deathsobserved (table 5) occurred in patients on dig-italis at entry, divided as follows over the treat-ment groups: eight placebo, 15 pimobendan2-5 mg/day, and 12 pimobendan 5 mg/day.The corresponding numbers of deaths amongpatients not on digitalis at entry were three,five, and four respectively. The number ofevents in each subgroup was small: this sub-group analysis had not been specified inadvance and the apparent interaction betweenthe effect of pimobendan on mortality and theuse of digitalis at entry was not statistically sig-nificant. Nevertheless, our data raise the ques-tion whether the benefit:risk ratio of treatingheart failure patients with positive inotropicagents depends on co-treatment with digitalis.Theoretically, calcium sensitisation enhancesthe effects of digitalis, which acts by increasingthe ionised calcium concentration within themyocardial cell.27 Possibly, this leads to over-stimulation. Rather than being dependent onco-treatment with digitalis, the benefit:riskratio may also depend on the prognosis in gen-eral. In this trial, patients on digitalis weresicker (as evidenced by lower ejection frac-tions) and had a worse prognosis than patientsnot on digitalis. In any case, these potentialsources of effect modification of pimobendan,and possibly of other positive inotropic agents,warrant further investigation. The extent towhich such questions can be answered inplacebo controlled trials will depend to a largeextent on the outcome of the currently ongo-ing large-scale digitalis trial.

In conclusion, as regards exercise capacitythis trial confirmed the efficacy of the additionof pimobendan to the basic regimen ofpatients with chronic heart failure. The effectof pimobendan as monotherapy has not beenstudied in controlled trials thus far.Pimobendan was well-tolerated and clinicallyrelevant proarrhythmia was not observed.

There was a trend towards an improved clinicalcondition in patients treated with pimoben-dan, but also towards a higher mortality.Hence, the balance between benefit and risk,which may depend also on concomitant use ofdigitalis, remains to be established.

AppendixThe Pimobendan in Congestive Heart Failure (PICO)Investigators consisted of:

CLINICAL INVESTIGATORSBelgium: G Heyndrickx (O-L Vrouwziekenhuis, Aalst),M Renard (IJLB Hopital Erasme, Brussels). Germany: SBeil, W Doering (Stadt. Krankenhaus Munchen-Schwabing); E Kauder (Kreiskrankenhaus Tuttlingen),H Klepzig, C Schacherer (Klinikum der JohannWolfgang Goethe-Universitat, Frankfurt), M Haass, CKruger (Abt Innere Medizin III, UniversitatsklinikumHeidelberg), P Limbourg (Stadtkrankenhaus Worms),E Liomin (Stadt. Krankenhaus Singen), B. Maisch(Klinikum der Philipps-Universitat, Marburg), MSchartl (Universitatsklinikum Rudolf Virchow, Berlin),H Simon (Stadt. Krankenhaus Duren). The Netherlands(*member of Working Group on CardiovascularResearch): PJLM Bernink* (Martini Ziekenhuis,Groningen), PhW Fels* (Drechtsteden Ziekenhuis,Dordrecht), HJM Dohmen* (Groot Ziekengasthuis,Den Bosch), PHJM Dunselman*, MRP Baselier(Ignatius Ziekenhuis, Breda), NJ Holwerda* (StElisabeth Ziekenhuis, Tilburg), GJ Laarman* (O-LVrouwe Gasthuis, Amsterdam), CM Leenders(Havenziekenhuis, Rotterdam), K van Leeuwen*(Ziekenhuis Overvecht, Utrecht), HR Michels*(Catharina Ziekenhuis, Eindhoven), M van der Ent,WJ Remme (Sticares Cardiovascular ResearchFoundation, Rotterdam); AJAM Withagen* (R deGraaf Gasthuis, Delft). Norway: T Gundersen (Aust-Agder Central Hospital, Arendal), JE Otterstad, GFr0land (Vestfold Sentralsykehus, Toensberg), TRPedersen (Aker Sykehus, Oslo). Portugal: JRG Ferreira,E Prazeres de Sa (Hospital de Santa Maria, Lisbon), RSeabra-Gomes, V Gil (Hospital Santa Cruz,Carnaxide). Sweden: N-J Abdon (Uddevalla Hospital,Uddevalla), J Jonsson (Varberg Hospital, Varberg).

STEERING COMMITTEEH Just, chairman (Freiburg, Germany). ACHjalmarsson (Gothenburg, Sweden), WJ Remme(Rotterdam, The Netherlands).

DATA MONITORING AND ETHICAL REVIEW COMMITTEESJ Pocock (London School of Hygiene and TropicalMedicine, UK), T Meinertz (Universitats-krankenhausEppendorf, Hamburg, Germany).

CO-ORDINATING CENTRE, CORE LABORATORY FORECHOCARDIOGRAPHY AND 24 HOURELECTROCARDIOGRAPHY AND ON-SITE MONITORINGSociete pour la Recherche Cardiologique (SOCAR)SA, Givrins, Switzerland (Hi van Dalen, J-M Dumont, PJonkers, BA Kirwan, D La Framboise, L Le Roux, JLubsen; M-J Roulin, M St John Sutton; D Sekarski, ASublet, X-F Suckow).

SPONSORBoehringer Ingelheirn Deutschland GmbH (M Haehl;J Heinrich-Nols)

REPORT PREPARED BY:

J Lubsen, H Just, AC Hjalmarsson, D La Framboise,WJ Remme, J Heinrich-Nols, J-M Dumont, P Seed(London School of Hygiene and Tropical Medicine,UK), X-F Suckow.

1 Packer M. Treatment of chronic heart failure. Lancet1 992;340:92-5.

2 Kulka PJ, Tryba M. Inotropic support of the critically illpatient. A review of the agents. Drugs 1993;45:654-67.

3 Scholz H, Meyer W. Phosphodiesterase-inhibiting pro-

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Effect ofpimobendan on exercise capacity in patients with heartfailure

perties of newer inotropic agents. Circulation 1986;73:III-99-108.

4 Colucci WS, Wright RF, Braunwald E. New positiveinotropic agents in the treatment of congestive heart fail-ure. NEnglJMed 1986;314:349-58.

5 The xamoterol in severe heart failure study group.Xamoterol in severe heart failure. Lancet 1990;336:1-6[Erratum, Lancet 1990;336:698].

6 Uretsky BF, Jessup M, Konstam MA, Dec GW, Leier CV,Benotti J, et al. Multicenter trial of oral enoximone inpatients with moderate to moderately severe congestiveheart failure. Lack of benefit compared with placebo.Circulation 1990;82:774-80.

7 Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBiancoR, Zeldis SM, et al for the PROMISE Study ResearchGroup. Effect of oral milrinone on mortality in severechronic heart failure. NEnglJMed 1991;325:1468-75.

8 Hagemeijer F. Calcium sensitization with pimobendan:pharmacology, haemodynamic improvement, and sud-den death in patients with chronic congestive heart fail-ure. EurHeartJ7 1993;14:551-66.

9 Hasenfuss G, Holubarsch C, Heiss W, Just H. Influence ofUDCG-1 15 on hemodynamics and myocardial energet-ics in patients with idiopathic dilated cardiomyopathy.Am HeartJ 1989;118:512-9.

10 Katz SD, Kubo SH, Jessup M, Brozena S, Troha JM, WahlJ, et al. A multicenter, randomized, double-blind,placebo-controlled trial of pimobendan, a new car-diotonic and vasodilator agent, in patients with severecongestive heart failure. Am HeartJ 1992;123:95-103.

11 Kubo SH, Gollub S, Bourge R, Rahko P, Cobb F, JessupM, et al for the Pimobendan Multicenter ResearchGroup. Beneficial effects of pimobendan on exercise tol-erance and quality of life in patients with heart failure.Results of a multicenter trial. Circulation 1992;85:942-9.

12 Sasayama S, Asanoi H, Kihara Y, Yokawa S, Terada Y,Yoshida S, et al. Clinical effects of long-term administra-tion of pimobendan in patients with moderate congestiveheart failure. Heart Vessels 1994;9: 113-20.

13 Remme WI, Krayenbuhl HP, Baumann G, Frick MH,Haehl M, Nehmiz G, et al for the Pimobendan-EnalaprilStudy Group. Long-term efficacy and safety of pimoben-dan in moderate heart failure. A double-blind parallel 6-month comparison with enalapril. Eur Heart J 1994;15:947-56.

14 Bazett HC. An analysis of the time-relations of electrocar-diograms. Heart 1920;7:353-8.

15 The Criteria Committee of the New York HeartAssociation. Nomenclature and criteria for diagnosis of dis-eases of the heart and great vessels. 9th ed. Boston: Little,Brown;1994:253-6.

16 Rector TS, Kubo SH, Cohn JN. Patient's self-assessmentof their congestive heart failure: Part 2. Content, reliabil-ity and validity of a new measure, the Minnesota Livingwith Heart Failure Questionnaire. Heart Failure 1987;3:198-209.

17 Morganroth J, Borland M, Chao G. Application of a fre-quency definition of ventricular proarrhythmia. Am JCardiol 1987;59:97-9.

18 Myerburg RJ, Castellanos A. Cardiac arrest and suddencardiac death. In: Braunwald E, ed. Heart disease. A text-book of cardiovascular medicine. 4th ed. Philadelphia: WBSaunders, 1992:756-89.

19 Cleland JGF, Erhardt L, Hall AS, Winter C, Ball SG onbehalf of the AIRE Study Investigators. Validation of pri-mary and secondary outcomes and classification of modeof death among patients with clinical evidence of heartfailure after a myocardial infarction: a report from theAcute Infarction Ramipril Efficacy (AIRE) StudyInvestigators. J Cardiovasc Pharmacol 1993;22 (suppl 9):S22-7.

20 Declaration of Helsinki. The World Medical Assembly,Inc. Femey-Voltaire, France, September 1989.

21 Pearson ES, Hartley HO. Charts of the power function foranalysis of variance tests derived from the non-CentralF-distribution. Biometrika 1951;38: 112-30.

22 Armitage P, Berry G. Statistical methods in medical research.3rd ed. London: Blackwell, 1994:207-32.

23 Rothman KJ. Modern epidemiology. Boston: Little, Brown,1986:170-1.

24 Armitage P, Berry G. Statistical methods in medical research.3rd ed. London: Blackwell, 1994:484-7.

25 Narang R, Swedberg K, Cleland JGF. What is the idealstudy design for evaluation of treatment for heart failure?Insights from trials assessing the effect ofACE inhibitorson exercise capacity. Eur HeartJ1 1996;17:120-34.

26 Lubsen J. Exercise testing as outcome in congestive heartfailure trials. Drugs 1994;7(suppl 4):25-30.

27 Feldman AM. Classification of positive inotropic agents. J7Am Coll Cardiol 1993;22:1223-7.

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Effect pimobendan capacity - Heart · phosphodiesterase inhibition.8 It is rapidly absorbed, the peak plasma concentration is reached after 1-5 hours, and the effect lasts eightto