Br Heart _1994;72 (Supplement):S 57-62

Diuretic induced changes in symptoms andquality of life

B Silke

Quality of life merits increasing attention as ameans of evaluating the impact of drug treat-ment on patients during long-term treatmentfor a variety of clinical conditions.' Quality oflife is an abstract concept and as such no singlevariable is adequate to fully describe it.Quality of life may be considered a variable ofmultiple dimensions encompassing a range ofhuman experiences. It describes importantaspects of physical, social, and emotionalhealth that are important to patients.2

As no single variable can fully evaluatequality of life, it is usually assessed in terms ofindividual components that may includesymptomatic and psychological well being,general level of activity, aspects of intellectualand cognitive function, and general satisfac-tion with life. These individual componentsthat contribute to quality of life can be indi-vidually assessed and from them a compositescore may be derived that allows an overallassessment of the impact of treatment onquality of life to be computed. In many casesthis will yield numerical data that may betested statistically; the relevance of such mea-sures to the clinical condition and the clinicalimportance of the findings may be difficult tointerpret.

In general questionnaires are used to collectinformation for quality of life analyses andthese are often termed "instruments". Theseinstruments have to be validated, that is to saythey must be shown to provide reliableanswers to the questions asked. In general thequestionnaires should be clearly written andsimple to administer and interpret. Theyshould also be sensitive to small changes inthe patient's condition and be capable ofdetecting subtle influences of drug treatment.A number of problems can be anticipated

with the information gathering process forquality of life questionnaires. It is uncertainwhether it is best to use a self administeredquestionnaire or trained interviewers. Thetraining for interviewers, if these are used,must be detailed and specific. Also the inter-viewers should have specific expertise in theparticular questionnaire used. It is recognisedthat the use of an interviewer may indeed pro-duce misleading results. In one study withmainly female interviewers, impotence wasreported far less commonly with the directinterviewer rated method than with thepatient self assessment questionnaire.3

It is recognised that bias may be introducedby the perspective of the interviewer. Forexample, the study by Jachuck et al used aquality of life impairment scale to assess the

impact of hypotensive drugs in essentialhypertension.4 The quality of life issue, duringthe chronic treatment of 75 controlled hyper-tensive patients, was assessed by a scale withexcellent validity and high internal reliability.Compared with the physicians' view of 100%improvement, patients or their close compan-ions showed a considerable discrepancy fromthis view of the impact of treatment on qualityof life variables (fig 1). Thus unlike the physi-cians' view of universal benefit, only 48% ofthe patients considered themselves improvedby treatment and 8% were worse. The ques-tionnaires returned by relatives suggested that25% had had mild adverse effects, 45% mod-erate, and 30% severe. These deteriorationswere attributed to undue preoccupation withsickness, decline in energy, general, and sex-ual activity, and irritability. Thus the deterio-ration in quality of life found was not evidentto the doctor; however the data suggested thatfrom a patients' or relatives' viewpoint, thenegative impact of treatment on quality of lifecreated problems in social, marital, and occu-pational readjustment.The use of self rated assessments may

exclude those with poor literacy. The ques-tionnaires may be given in a clinic or labora-tory situation under time constraints that mayadversely affect their completion; if thepatient is allowed to take the questionnairehome then other family members may influ-ence the responses.A well designed quality of life instrument

should look at the acute and long-term

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Figure 1 Effect of antihypertensive treatment on qualityof life; difference in perceived outcome between physician,patient, and relative. Graph plotted with data fromreference 4.

Department ofTherapeutics andPharmacology,Queen's University ofBelfast, BelfastB SilkeCorrespondence to:Dr B Silke, Department ofTherapeutics andPharmacology, Queen'sUniversity of Belfast, WhitlaMedical Building,97 lisbum Road, BelfastBT9 7BL.

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influence of treatments in a large number ofpatients who have received treatment for areasonable period of time. It is important toemphasise that a questionnaire that is appro-priate for one clinical situation may fail or beinappropriate in a different condition. Thus avalid and specific instrument in essentialhypertension may be not translatable toanother clinical situation such as angina pec-toris or chest pain and its impact on activitylevel may not be assessed. The conclusionsabout the impact of a particular drug on qual-ity of life may also be specific to a particularclinical situation and not be universal for thattreatment. Thus for example, if one looks atthe effects of diuretics in an asymptomaticcondition such as essential hypertension thenadverse effects such as gout and impotencemay rate highly in terms of negative impact onquality of life. In chronic heart failure, how-ever, a dramatic improvement in dyspnoea,reduced frequency of admissions to hospital,and improved exercise capacity may lead to acontrary conclusion, a positive outcome ofdiuretic actions on quality of life. One canalso envisage that use of a /3 blocker drug foressential hypertension may result in sideeffects being frequently reported, such as coldperipheries and tiredness (perhaps resulting ina reduced exercise capacity or cold intoler-ance) and therefore have a negative impact onquality of life. In patients whose ischemicheart disease results in angina, the druginduced reduction in frequency of angina andincreased exercise capacity may result in amuch higher threshold for reporting thesesymptoms, due to the perceived improve-ments in symptoms. Therefore valid instru-ments may not be readily translatable fromone clinical condition to another, and the con-clusions from one. clinical area may be irrele-vant to a different therapeutic area.

In conclusion, study design suggests that alarge sample size should be interrogated overa reasonable period with a validated question-naire or instrument that is appropriate for thatspecific condition.' Caution should be the

Figure 2 Reported adverse reaction rate in men and women in MRC trial of mildhypertension. Graph plotted with data from reference 8.

watchword when extrapolating from one clini-cal condition to another even within the samedrug category.

Overview ofimpact of diuretics onquality of life in hypertensive patientsAfter the paper by Croog et al there has been agradual increase in the development of instru-ments to assess the impact of drugs on qualityof life to allow the risk benefit ratio to be morefully assessed during chronic treatment.3 Theimpact of drug treatment in a variety of anti-hypertensive trials was analysed by van Hoofet al.5 Quality of life data from six studies withindapamide was reviewed. These were openstudies without a control group; the quality oflife data were based on self administeredquestionnaires with modifications of the tec-niques of Croog et al 3 or Bulpitt and Dollery.6Perceptual measurements were also madewith a visual analogue scale.The lack of control groups in these studies

means that the improvement in most of thevariables assessed might well have been due towithdrawal of previous threatments, the non-specific effect of inclusion in a clinical trial, orto the hypotensive effect of indapamide. Thesensitivity of the studies to detect particulareffects was not described and a large numberof commonly anticipated side effects ofdiutetics such as gout, lethargy, musclecramps, constipation, and impotence wereabsent from these studies. Thus althoughthere was a reasonable database on quality oflife for indapamide, the lack of a controlgroup minimised the value of these data.The Medical Research Council mild hyper-

tension study7 did not provide specific data onquality of life although it reported the pres-ence of subjective and metabolic side effects.8The cumulative withdrawal of adverse reac-tions in men was highest in the diuretic groupand lower in the ,B blocker and placebo groups(fig 2). In women the picture was slightlydifferent. Compared with placebo there was asignificant increase in impaired glucose toler-ance, constipation, lethargy, nausea, dizzi-ness, headaches, and gout. The cumulativewithdrawal rate for adverse reactions inwomen was highest in the fl blocker group.The European Working Party study on

high blood pressure in the elderly reportedquestionnaire data.9 There was little evidenceof the impact of diuretic treatment on qualityof life. The Australian trial on mild hyperten-sion'0 reported use of a questionnaire modi-fied from Bulplitt and Dollery.6 Sleepinessand self assessed depression were found to bemore common in the actively treated groupafter age and sex adjustment of the data.Active treatment could have consisted ofeither chlorothiazide (up to 1 g daily), propra-nolol (up to 320 mg), methyldopa (up to 2 g),or a combination.The hypertension detection and follow up

programme looked at two methods of treat-ment, regular care where the patients weremainly followed up in their routine care sys-tems, or stepped care where the patients were

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Diuretic induced changes in symptoms and quality of life

more closely followed up in specialist clinics.Long-term surveillance data indicated thatchlorthalidone caused treatment to end due toside effects less commonly than did otherdrugs (diuretics chlorthalidone 5%, reserpine9-9%, methyldopa 9%, hydralazine 7%, andguanethidine 7%).11Van Hoof et al concluded that although

indapamide improved quality of life in mostvariables measured, in five studies this was insharp contrast with the results obtained withother diuretics in the main studies reportedsubsequently. The limited controlled data onquality of life with diuretics would lead one toquestion whether, on the available evidence, areliable conclusion about the impact of diuret-ics on the quality of life could be drawn.The treatment of mild hypertension study

(TOMHS) looked at optimal treatment ofpatents with mild hypertension comparing sixfirst line treatments including placebo,diuretic (chlorthalidone), J blocker (acebu-tolol), a, antagonist (doxazosin), calciumantagonist (amlodipine), or angiotensin con-verting enzyme (ACE) inhibitor (enalapril).12Blood pressure control with any of the activetreatment regimens was better than withnutritional hygienic advice alone. Data onseven indices of quality of life were reportedwith higher levels corresponding to improvedquality of life. At entry the average levels formost of the scales were close to the upperlimit of the scale. Most indices of quality oflife after 12 months of follow up wereimproved but the energy fatigue and generalfunctioning indices showed smaller averageincreases for participants given doxazosinthan for those given acebutolol or chlorthali-done. General functioning indices of partici-pants given acebutolol and chlorthalidone alsoshowed significantly greater improvementthan those given doxazosin or placebo. Theoverall tests that combined the seven qualityof life indices showed greater improvement inquality of life for participants given a fi blocker(acebutolol) or diuretic (chlorthalidone) thanfor those given placebo.A meta analysis of the impact of quality of

life in hypertension studies was attempted byBeto and Bansal.'3 All studies that fulfilledcertain criteria such as patients who acted astheir own control and that used blind and ran-domised trials were included. Change in thestudy was measured by self or interviewerassisted evaluation, standardised psychomotoror cognitive tests, or sleep laboratory observa-tions. Between 1970 and 1990 nine publishedtrials of 27 population groups (n = 1620)identified six pharmacological groups that metthe criteria. These were analysed for five qual-ity of life variables: sexual function, sleep, psy-chomotor finction, general well being, andmood. With the meta-analysis technique ofHedges and Olkin"4 a size of effect was com-puted for each study (by dividing the meanchange between baseline and treatment by thestandard deviation). The standard deviationadjustment in the denominator of the size ofeffect formula allowed studies with differentmeasurement scales to be compared and com-

ACE 1

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Figure 3 Impact of six different drug groups on quality oflife variables in essential hypertension. Graph plotted withdata from reference 13.

bined. Sizes of effect and 95% confidenceintervals (95% CIs) for each construct groupwere computed. When the CI excludes zero,improvement (<0) or deterioration (>0) withtreatment can be concluded. With Cohen'sdefinition15 a small effect in mathematicalterms is <0-2, a medium effect 0 2-0 5, and alarge effect size > 0 8. Overall there weresmall positive effects seen for sleep, psy-chomotor function, general wellbeing, andmood, but no effect on average was found forsexual function. None of the drug groups had aclearly superior effect but a more frequentpositive effect was seen with ACE inhibitorsand [3 blockers (fig 3). The narrower demo-graphics and small sample size for diureticsand calcium channel blockers may havebiased the outcome; however, diuretics wereaccompanied by an appreciable positive effectfor psychomotor function and mood (fig 4).Diuretics had no overall action on sexualfunction, sleep, or general level of wellbeing.The use of a mathematical method of com-

bining the studies is useful and allows an esti-mate of effect to be computed. This does not,however, give information on the likely clini-cal relevance of the statistical finding. The useof only published studies may further biasoutcome by underestimating the contribution

SexualF

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Figure 4 Impact of diuretic treatment on quality of lifevariables in essential hypertension. Graph plotted withdata from reference 13.

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Figure S Action of onemonth's treatment withtorasemide (5 or 10 mg)on symptoms in patientswith chronic heartfailure.Assessment expressed interms ofNYIHA classbefore and after onemonth's treatment. Graphplotted with data fromreference 16.

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from negative studies. The limited controlleddata on diuretics in particular mean that onecannot have great confidence in the reliabilityof the effects described.

Actions of diuretics in heart failureAlthough there are no data on the use ofdiuretics on quality of life variables in heartfailure is seems not unreasonable to use symp-toms as a surrogate for quality of life. Severalstudies have shown the overall improvementin symptoms after diuretic treatment (fromone to three months) in patients with NewYork Heart Association (NYHA) class II toIII heart failure.

Data on torasemide (fig 5) seem to suggest a

direct relation between the severity of symp-toms (judged by NYHA class) and responseto diuretic treatment.'6 This would suggestthat the symptomatically worse patients arelikely to gain the greatest improvement inquality of life from diuretic treatment. Thesefindings are supported by those of Oversohl etal.'7 Muzolimine treatment, in 36 patientswith heart failure, gradually (three to fourweeks) reduced systolic blood pressure andbody weight. Concomitant with the average 2kg reduction in body weight and the 11 mmHg fall in systolic blood pressure, there were

overall improvements in symptom scores.With a Framingham heart failure ratingmethod, which summates symptoms (maxi-

Figure 6 Actions offourweek's treatment withmuzolimine on overallsymptoms (see text) inpatients with chronic heartfailure. Graph plotted withdata from reference 17.

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Symptom score

mum severity score = 10) including oedema,paroxysmal nocturnal dyspnoea, neck veindystension, rales, cardiomegaly, hepatojugularreflux, night cough, pleural effusion, tachycar-dia, and dyspnoea on exertion, the extent ofthe improvement is clearly documented (fig6).A controlled, double blind, clinical trial of

the efficacy and tolerance of torasemide incontrast with frusemide in patients with con-gestive heart failure indicated that symptomsof peripheral oedema, dyspnoea, and centralcongestion shown by raised jugular venouspressure were dramatically reduced aftertorasemide (fig 7).16 Objective findings suchas hepatomegaly and cardiomegaly were lessamenable to treatment after four weeks withtorasemide (either 5 or 10 mg daily). A similarsymptomatic improvement was noted afterfrusemide treatment (40 mg). Dusing andPiesche who used torasemide for second linetreatment of congestive heart failure foundsimilar symptomatic and objective evidence ofimprovement after four weeks of treatmentwith 5 or 10 mg of torasemide daily in con-trast with frusemide (40 mg daily).'8 Thussymptomatic improvement after four weeks ofsustained treatment with loop diuretics maypossibly act as a surrogate of quality of life.These findings both for the conventional andnewer loop diuretics support dramaticimprovement in symptoms and quality of lifevariables.One would anticipate that improvement in

symptoms of such magnitude might beaccompanied by objective evidence ofimproved exercise capacity during chronictreatment. It is well known that loop diuretics,particularly frusemide in acute coronary caresituations are associated with an average fallin resting pulmonary wedge pressure from20-7 to 15-7 mm Hg (-24%) and usuallywith an associated fall in cardiac output from2.77 to 2-46 l/min/12 (- 11%). These effectsare usually maintained during chronic treat-ment.'9 Several haemodynamic studies evalu-ated the immediate or sustained actions oftorasemide on cardiac performance in severeheart failure. Fiehring and Achhammer com-pared intravenous torasemide (10 mg) withfrusemide (20 mg) at rest and during bicycleergometry in a controlled double blind andrandomised trial of chronic heart failure.20Eight patients received torasemide and sevenfrusemide. All pulmonary pressures werereduced on exercise and the pulmonary dias-tolic pressure was lower at the two highest lev-els of exercise with a concomitant fall in ratepressure product. Isbary et al compared 20 mgof intravenous torasemide with frusemide (20mg) in a randomised double blind study of 21patients with NYHA class III or IV acuteheart failure.2' Onset of diuresis averagedeight minutes and there was a gradual, equiva-lent, and progressive fall in pulmonary wedgepressure over 24 hours (torasemide, 23-6 to18-1 mm Hg (-23%): frusemide, 23-6 to16-3 mm Hg (-31%). Cardiac index was

s unaltered on either treatment.Langbehn et al compared the actions of

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Hepatomegaly Removed

Figure 7 Improvement in symptoms in patients with chronic heart failure afterfour weeksof treatment with torasemide (5 or 10 mg daily). _iVP, jugalar venous pressure. Graphplotted with data from reference 16.

torasemide (20 mg) and frusemide (20 mg)on cardiac performance in 19 patients withseverely impaired cardiac function due toischaemic heart disease.22 Within 12 min ofthe drug, left ventricular end diastolic pres-sure was reduced from 15-0 to 12-0 mm Hg(-20%) by torasemide and from 12 5 to 11 0mm Hg (- 14%) after frusemide. Cardiacoutput was not determined. Podszus andPiesche examined the actions of oraltorasemide (10 mg) on haemodynamics in 12patients with NYHA classes II and III heartfailure.23 Rest and supine exercise haemody-namics were assessed after acute treatmentand after 28 days of sustained treatment. Thepulmonary wedge pressure on chronic treat-ment was lower during exercise (20.3 to 14-6mm Hg: -28%) and cardiac index was higher(5 9 to 6 7 1/min/m2: + 14%). Interestinglythe systemic arterial pressure during exercisewas 9 mm Hg lower at the same workloadafter treatment. This indicates perhaps a

decrease in systemic vasoconstriction. Eight ofthe 12 patients improved their symptom score

by one NYHA class.Thus there seems to be little doubt that at

rest and during exercise acute doses ofdiuretics lower cardiac filling pressures, whichmay contribute to the relief of central conges-tion and relief of symptoms of dyspnoea.Undoubtedly of greater interest is the longerterm actions of these drugs, their impact ofsymptoms, exercise capacity, and quality oflife. Several studies have examined this ques-

tion. The longer term (three weeks) actions ofpiretanide were investigated by Haerer et al.24In 46 patients with NYHA class II or III heartfailure 3 mg of piretanide produced an aver-

age weight loss of 1 6 kg (baseline 77 kg) bodyweight by three weeks. Echocardiographicallythere was an associated improvement in frac-tional shortening (+ 5-6%: baseline 25-9%)with a fall in cardiac volumes. The 26 patientsstudied at baseline after 6 mg of intravenouspiretanide showed a fall in pulmonary wedgepressure from 20-2 to 11-9 mm Hg with a

small concomitant reduction in cardiac index(3-2 to 3 0 1/min/m2). After three weeks treat-ment there was no attenuation of the haemo-

dynamic actions of piretanide; exercise toler-ance increased from 135 to 249 W (+84%).In contrast a control group showed no changein pulmonary wedge pressure (20-0 to 22-8mm Hg). Radiographic heart volumedecreased from 1012 ml to 936 ml (-7 5%).This well conducted study concluded that theacute actions of piretanide were similar to thedescribed actions of frusemide; the improvedechocardiographic measures of cardiac perfor-mance were probably secondary to alteredloading conditions (preload). The actionswere well maintained over at least one monthof treatment; increased exercise capacity con-tinued.The haemodynamic actions of the potas-

sium sparing agent amiloride were determinedin a double blind placebo controlled crossoverstudy of 11 patients with stable chronic heartfailure.25 The actions of placebo or amiloride(5 or 10 mg) were compared over seven dayswhen added to background treatment ofdigitalis and hydrochlorothiazide. Haemo-dynamic variables were measured at rest andat three levels of supine bicycle exercise. Themain findings were noted for exercise haemo-dynamics; amiloride significantly reducedexercise pulmonary wedge pressure (28&6 to22 1 mm Hg: - 22 7%) with an augmentedcardiac stroke index (+3%) and stroke workindex (+ 12%). The improved cardiac func-tion was most evident from the change inhaemodynamic variables from rest to peakexercise; the increase in pulmonary wedgepressure (placebo/amiloride; + 18-7/ + 13-7mm Hg: P < 0 001) and left ventricular strokework index (+15-0/+27A4 gm.m-2: P < 0 005)suggesting a much improved cardiac perfor-mance.

It would therefore be reasonable to con-clude that the initial haemodynamic activity ofdiuretic treatment that favourably reducedcentral haemodynamic filling pressures ismaintained during long-term treatment andthat overall exercise cardiac output is usuallyaugmented at a lower left ventricular fillingpressure. This improved cardiac performanceis usually accompanied by increased exercisecapacity or duration. If symptoms may beused as a surrogate for quality of life, thereseems to be a substantial short and mediumterm improvement; it would seem reasonableto conclude that the balance of probabilitysuggests that long term diuretic treatmentimproves quality of life dramatically forpatients with chronic heart failure.

1 Hollenberg NK, Testia M, Williams GH. Quality of life asa therapeutic end-point. Drug Saf 1991;6:83-93.

2 Bulpitt CJ, Fletcher AE. Quality of life evaluation of anti-hypertensive drugs. PharmacoEconomics 1992;1:95-102.

3 Croog SH, Levine S, Testa MA, Brown B, Bulpitt CJ,Jenkins D, et al. The effects of antihypertensive therapyon the quality of life. N EnglJ_7Med 1986;314:1657-64.

4 Jachuck SJ, Brierly H, Jachuck S, Willcox PM. The effect ofhypotensive drugs on the quality of life. J R Coll GenPract [Occas Pap] 1982;32:103-5.

5 Van Hoof R, Amery A, Fagard R, Staessen J. Quality oflife during treatment of hypertensive patients withdiuretics. Acta Cardiologica 1990;45:393-401.

6 Bulpitt CJ, Dollery CT. Side-effects of hypotensive agentsevaluated by a self-administered questionnaire. BMJ1973;3:485-90.

7 Medical Research Council Working Party. MRC trial of

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mild hypertension: principal results. BMJ 1 985;291:97-104.

8 Miall WE, Greenberg G, eds. An account of the MRCtrial-mild hypertension: is there pressure to treat?Cambridge: Cambridge University Press, 1988.

9 Fletcher AE, Staessen J, Thijs L, Bulpitt CJ. Risk andbenefit in the European Working Party on hypertension inthe elderly trial (EWPHE). Abstracts of the 4th europeanmeeting on hypertension 1989. Milan: Universita degliStudi di Milano Ricerca Scientifica ed EducazionePermanente, suppl 76;263A.

10 Management Committee. The Australian therapeutic trialin mild hypertension. Lancet 1980;i: 1261-7.

11 Curb JD, Borhani NO, Blaszkowski TP, Zimbaldi N,Fotiu S, Williams W. Long-term surveillance for adverseeffects of antihypertensive drugs. JAMA 1985;253:3263-8.

12 The Treatment of Mild Hypertension Research Group.The treatment of mild hypertension study (TOMHS).Ann Intern Med 1991;151:1413.

13 Beto JA, Bansal VK. Quality of life in treatment of hyper-tension. Am I Hypertens 1992;5:125-33.

14 Hedges LV, Olkin I, eds. Statistical methods for meta-analysis. New York: Academic Press, 1985.

15 Cohen J, ed. Statistical power analysis for the behavioralsciences. New York: Academic Press, 1969.

16 Stauch M, Stiehl L. Controlled double-blind clinical trialof the efficacy and tolerance of torasemide in compari-son with furosemide in patients with congestive heartfailure. In: Kruck F, Mutschler E, Knauf H, eds.Torasemide: clinical pharmacology and therapeuticapplications. Stuttgart and New York: Gustav Fischer,1990;121-6. (Progress in pharmacology and clinicalpharmacology; vol 8).

17 Oversohl K, Mehrabian G, Hanisch M, Schmitz H.Muzolimine as monotherapy in the treatment of patientswith congestive heart failure. Z Kardiol 1985;74(suppl2):27-31.

18 Dusing R, Piesche L. Second line therapy of congestiveheart failure with torasemide. In: Kruck F, Mutschler E,Knauf H, eds. Torasemide: clinical pharmacology andtherapeutic applications. Stuttgart and New York:Gustav Fischer, 1990;105-120. (Progress in pharmacol-ogy and clinical pharmacology; vol 8).

19 Silke B. Central haemodynamic effects of diuretic therapy inchronic heart failure. Cardiovasc Drugs Ther 1993;7:45-53.

20 Fiehring H, Achhammer I. Influence of 10 mg torasemidei.v. and 20 mg furosemide i.v. on the intracardiac pres-sures in patients with heart failure at rest and duringexercise. In: Kruck F, Mutschler E, Knauf H, eds.Torasemide: clinical pharmacology and therapeuticapplications. Stuttgart and New York: Gustav Fischer,1990;97-104. (Progress in pharmacology and clinicalpharmacology; vol 8).

21 Isbary J, Achhammer I, Wetzels E. The influence of 20 mgtorasemide i.v. and 20 mg furosemide i.v. on hemody-namics and diuresis in patients with high grade left heartfailure. In: Kruck F, Mutschler E, Knauf H, eds.Torasemide: clinical pharmacology and therapeuticapplications. Stuttgart and New York: Gustav Fischer,1990;137-46. (Progress in pharmacology and clinicalpharmacology; vol 8).

22 Langbehn AF, Achhammer I, Bolke T. Acute hemody-namic effects of 20 mg torasemide and 20 mgfurosemide given intravenously to patients with conges-tive heart failure. In: Kruck F, Mutschler E, Knauf H,eds. Torasemide: clinical pharmacology and therapeuticapplications. Stuttgart and New York: Gustav Fischer,1990;147-55. (Progress in pharmacology and clinicalpharmacology; vol 8).

23 Podszus T, Piesche L. Effect of torasemide on pulmonaryand cardiac haemodynamics after oral treatment ofchronic heart failure. In: Kruck F, Mutschler E, KnaufH, eds. Torasemide: clinical pharmacology and thera-peutic applications. Stuttgart and New York: GustavFischer, 1990;157-66. (Progress in pharmacology andclinical pharmacology; vol 8).

24 Haerer W, Bauer U, Sultan N, Cernoch K, Mouselimis N,Fehske KJ, et al. Acute and chronic effects of a diureticmonotherapy with piretanide in congestive heartfailure-a placebo-controlled trial. Cardiovasc Drugs Ther1990;4:515-22.

25 Cheitlin MD, Byrd R, Benowitz N, Liu E, Modin G.Amiloride improves hemodynamics in patients withchronic congestive heart failure treated with chronicdigoxin and diuretics. Cardiovasc Drugs Ther 1991 ;5:719-26.

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