Heart Failure:PharmacologicManagement

EDITED BY

Arthur M. Feldman, MD, PhD

Heart Failure:Pharmacologic Management

Dedication toSusan, Emilykate, Elizabeth Willa

Heart Failure:PharmacologicManagement

EDITED BY

Arthur M. Feldman, MD, PhD

© 2006 by Blackwell Publishing

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Heart failure : pharmacological management / edited by Arthur M.

Feldman.

p. ; cm.

Includes bibliographical references.

ISBN-13: 978-1-4051-0361-9

ISBN-10: 1-4051-0361-2

1. Congestive heart failure–Chemotherapy. I. Feldman, Arthur

M. (Arthur Michael), 1949–.

[DNLM: 1. Heart Failure, Congestive–drug therapy. WG 370 H436535 2006]

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concerning new drugs.

Contents

Contributors, vii

Introduction, ix

1 Diuretics in congestive heart failure, 1Alicia Ross, Ray E. Hershberger &David H. Ellison

2 Use of digoxin in the treatment ofheart failure, 17Deborah DeEugenio & Paul J. Mather

3 Renin–angiotensin system andangiotensin converting enzymeinhibitors in chronic heart failure, 30Rimvida Obeleniene & Marrick Kukin

4 Angiotensin receptor blockers inthe treatment of heart failure, 44Anita Deswal & Douglas L. Mann

5 Beta blockers, 57Peter F. Robinson & Michael R. Bristow

6 Aldosterone antagonism inthe pharmacological management ofchronic heart failure, 82Biykem Bozkurt

7 Inotropic therapy in clinical practice, 104Sharon Rubin & Theresa Pondok

8 Antiarrhythmic therapyin heart failure, 120Igino Contrafatto & Leslie A. Saxon

9 Treating the hypercoagulablestate of heart failure: modifyingthe risk of arterial and venousthromboembolism, 135Geno J. Merli & Howard H. Weitz

10 Vasodilator and nitrates, 144Abdul Al-Hesayen & John D. Parker

11 Natriuretic peptides forthe treatment of heart failure, 154Jonathan D. Sackner-Bernstein,Hal Skopicki & Keith D. Aaronson

12 Immune modulatory therapiesin heart failure: usingmyocarditis to gainmechanistic insights, 174Grace Chan, Koichi Fuse,Mei Sun, Bill Ayach &Peter P. Liu

13 The role of vasopressin andvasopressin antagonists inheart failure, 187Olaf Hedrich, Marvin A. Konstam &James Eric Udelson

14 Role of erythropoietin in thecorrection of anemia inpatients with heart failure, 205Rebecca P. Streeter &Donna M. Mancini

15 Endothelin antagonism incardiovascular disease, 217Srinivas Murali

v

vi Contents

16 Pharmacogenetics, 236Richard Sheppard & Dennis M. McNamara

17 Management of diastolicdysfunction, 250Arthur M. Feldman & Bonita Falkner

18 Multidrug pharmacy for treatment ofheart failure: an algorithm forthe clinician, 266Mariell Jessup

Index, 275

Contributors

Keith D. Aaronson, MD, MScAssociate Professor of Internal MedicineMedical Director, Cardiac Transplant ProgramUniversity of Michigan Health SystemAnn Arbor, MI, USA

Abdul Al-Hesayen, MD, FRCPCAssistant Professor of MedicineUniversity of TorontoDivision of CardiologySt. Michael’s HospitalToronto, Ontario, Canada

Bill Ayach, MScFRWQ and Heart and Stroke Foundation Doctoral FellowHeart & Stroke/Richard Lewar Centre for ExcellenceUniversity of TorontoToronto, Ontario, Canada

Biykem Bozkurt, MD, FACCAssociate Professor of MedicineAction Cheif, Section of CardiologyDepartment of MedicineMichael E. DeBakey Veterans AffairsMedical Center & Winters Center for

Heart Failure ResearchBaylor College of MedicineHouston, TX, USA

Michael R. Bristow, MD, PhDCo-director, CU-CVI, DenverBoulder and Aurora, ColoradoS. Gilbert Blount Professor of Medicine (Cardiology)University of Colorado at Denver and Health Sciences CenterDenver, CO, USA

Igino Contrafatto, MDKeck School of MedicineUniversity of Southern CaliforniaLos Angeles, CA, USA

Deborah DeEugenio, Pharm DJefferson Heart InstitutePhiladelphia, PA, USA

Anita Deswal, MD, MPHAssistant Professor of MedicineWinters Center for Heart Failure ResearchBaylor College of MedicineMichael E. DeBakey Veterans Affairs Medical CenterHouston, TX, USA

David H. Ellison, MDHead, Division of Nephrology & HypertensionProfessor of Medicine and Physiology & PharmacologyOregon Health & Science UniversityPortland, OR, USA

Bonita Falkner, MDProfessor of MedicineDivision of NephrologyJefferson Medical CollegePhiladelphia, PA, USA

Arthur M. Feldman, MD, PhDMagee Professor and ChairmanDepartment of MedicineJefferson Medical CollegePhiladelphia, PA, USA

Grace ChanHeart & Stroke/Richard Lewar Centre for ExcellenceUniversity of TorontoToronto, Ontario, Canada

Koichi Fuse, MD, PhDCIHR/HSF TACTICS Research FellowHeart & Stroke/Richard Lewar Centre for ExcellenceUniversity of TorontoToronto, Ontario, Canada

Olaf Hedrich, MDDivision of CardiologyDepartment of MedicineTufts-New England Medical Center

and Tufts University School of MedicineBoston, MA, USA

vii

viii Contributors

Ray E. Hershberger, MDProfessor of MedicineDirector, Heart Failure and Transplant CardiologyOregon Health & Science UniversityPortland, OR, USA

Mariell Jessup, MDProfessor of MedicineUniversity of Pennsylvania School of MedicineMedical Director, Heart Failure/Transplant programUniversity of Pennsylvania Health SystemPhiladelphia, PA, USA

Marvin A. Konstam, MD, FACCChief of CardiologyProfessor of Medicine and RadiologyTufts-New England Medical CenterBoston, MA, USA

Marrick Kukin, MDDirector, Heart Failure ProgramSt. Luke’s Roosevelt HospitalProfessor of Clinical MedicineColumbia University College of Physicians & SurgeonsNew York, NY, USA

Peter P. Liu, MDHeart and Stroke/Polo Chair Professor

of Medicine and PhysiologyDirector, Heart and Stroke/Richard LewarCentre of Excellence in Cardiovascular ResearchUniversity of Toronto/Toronto General HospitalToronto, Ontario, Canada

Donna M. Mancini, MDProfessor of MedicineCollege of Physicians and SurgeonsColumbia University Columbia

Presbyterian Medical CenterNew York, NY, USA

Douglas L. Mann, MDDon W. Chapman ChairProfessor of Medicine, Molecular

Physiology and BiophysicsChief, Section of CardiologyBaylor College of MedicineHouston, TX, USA

Paul J. Mather, MDAssociate Professor of MedicineDirector, Advanced Heart Failure & Cardiac

Transplant CenterJefferson Heart InstituteJefferson Medical CollegePhiladelphia, PA, USA

Dennis M. McNamara, MD, FACCAssociate Professor of MedicineDirector, Heart Failure/Transplantation ProgramUniversity of Pittsburgh Medical CenterPittsburgh, PA, USA

Geno J. Merli, MD, FACPLudwig A. Kind ProfessorDirector, Division of Internal MedicineVice Chairman of Clinical AffairsDepartment of MedicineJefferson Medical CollegePhiladelphia, PA, USA

Srinivas Murali, MDProfessor of MedicineUniversity of Pittsburgh School of MedicineAssociate Director, Clinical ServicesCardiovascular Institute Director, Heart Failure NetworkDirector, Pulmonary Hypertension ProgramPittsburgh, PA, USA

Rimvida Obeleniene, MDSt. Luke’s Roosevelt HospitalNew York, NY, USA

John D. Parker, MD, FRCP(C), FACCPfizer Chair in Cardiovascular ResearchProfessor of Medicine and PharmacologyUniversity of TorontoHead, Division of CardiologyUHN and Mount Sinai HospitalsToronto, Ontario, Canada

Theresa Pondok, MDHeart Failure FellowJefferson Heart InstituteThomas Jefferson University HospitalPhiladelphia, PA, USA

Peter F. Robinson, MDInterventional Cardiology FellowUniversity of Colorado at Denver

and Health Sciences CenterDenver, CO, USA

Alicia Ross, MDFellow, Cardiovascular MedicineOregon Health & Science UniversityPortland, OR, USA

Sharon Rubin, MDAssociate Professor of MedicineJefferson Heart InstituteThomas Jefferson University HospitalPhiladelphia, PA, USA

Contributors ix

Jonathan D. Sackner-Bernstein, MDDirector of Clinical ResearchDirector of the Heart Failure Prevention ProgramNorth Shore University HospitalLong Island, NY, USA

Leslie A. Saxon, MDProfessor of Clinical MedicineDirector, Cardiac ElectrophysiologyKeck School of MedicineUniversity of Southern CaliforniaLos Angeles, CA, USA

Richard Sheppard, MDAssistant Professor of MedicineMcGill UniversityDivision of CardiologySir Mortimer B. Davis-Jewish General HospitalMontreal, Quebec, Canada

Hal Skopicki, MD, PhDDirector of the Center for Cellular

and Molecular CardiologyNorth Shore-LIJ Research InstituteNorth Shore University HospitalLong Island, NY, USA

Rebecca Streeter, MDClinical Cardiology FellowCollege of Physicians and SurgeonsColumbia UniversityColumbia Presbyterian Medical CenterNew York, NY, USA

Mei Sun, MD, PhDHeart and Stroke/ Richard Lewar Centre of ExcellenceUniversity of TorontoToronto, Ontario, Canada

James Eric Udelson, MD, FACCAssociate Chief, Division of CardiologyDirector, Nuclear Cardiology LaboratoryDepartment of Medicine/Division of CardiologyTufts-New England Medical CenterAssociate Professor of Medicine and RadiologyTufts University School of MedicineBoston, MA, USA

Howard H. Weitz, MD, FACC, FACPProfessor of MedicineSenior Vice Chairman for Academic AffairsDepartment of MedicineCo-Director, Jefferson Heart InstituteJefferson Medical CollegePhiladelphia, PA, USA

Introduction

Twenty years ago in the twenty-first edition of thePrinciples and Practice of Medicine, the authorsdescribed what was then the practice for the phar-macologic therapy of patients with heart failure,which included digoxin and a diuretic [1]. In addi-tion, the authors noted that recent studies hadsupported the potential use of vasodilators in thetreatment of this population of patients. Over thepast two decades – a very short period of time inthe evolution of science – enormous changes haveoccurred in our therapy for patients with this dev-astating disease. These changes have occurred inlarge part because of an explosion in our under-standing of the basic biology of heart muscledisease, an increased level of sophistication in per-forming clinical research to evaluate the efficacy ofnew drugs and devices for the treatment of heartfailure, and an improving understanding of howdifferent genetic, racial, and gender backgroundscan influence a given patient’s response to a givendrug or device.

Epidemiologic studies have suggested that heartfailure is a disease of epidemic proportions [2].For example, it is estimated that over 550 000new cases occur each year in the United Statesand that heart failure accounts for nearly 287 000deaths (2002 Heart and stroke statistical update.Dallas: American Heart Association, 2001). Cross-sectional studies from large data sets have shownan increase in the point prevalence of heart failurein both the United States and Europe over the pastthree decades [3–5]. In addition, analyses of theNational Health and Nutrition Examination Survey(NHANES) II showed similar trends and showed aprevalence estimate of 1.04% by subject self-reportand 1.78% clinical evaluation in the US popula-tion [6]. More recently, McCullough and colleaguesused administrative data sets from a large verticallyintegrated mixed model managed care organization

to assess the incidence of heart failure in a com-munity setting [7]. They found that heart failurewas a disease of epidemic proportion whose pre-valence had increased over the previous decade. Inaddition, it has recently been demonstrated thatthe lifetime risk for developing heart failure is onein five for both men and women with risks beingone in nine for men and one in six for women in theabsence of a history of a myocardial infarction [8].

Despite the marked incidence of heart failurein the US population, recent epidemiologic stud-ies suggest that 20 years of drug discovery hashad an impact on the outcomes associated withthis disease (and potentially on disease incidenceby better control of risk factors). For example,the Framingham Heart Study demonstrated thatover the past 50 years, the incidence of heart fail-ure declined among women but not among men[9]. More importantly, survival after heart failureimproved for both sexes with an overall improve-ment in the survival rate after the onset of heartfailure of 12% per decade. Indeed, survival hasimproved to such an extent that clinicians havecalled for a reevaluation of the listing criteria forpatients undergoing cardiac transplantation [10].However, heart failure remains a progressive dis-ease. Thus even patients with asymptomatic leftventricular dysfunction are at risk for symptomaticheart failure and death, even when only a mildimpairment in ventricular function is present [11].

As will be described in the chapters of thistext, a series of clinical trials have also demon-strated significant improvements in survivals as thebaseline therapy for each of these trials changed.For example, the 2-year mortality rate in patientswho had chronic heart failure, an ejection fractionof <45%, cardiac dilation, and reduced exer-cise tolerance and who were receiving digoxinand a diuretic in the Veterans Administration

xi

xii Introduction

Cooperative Study was 34% [12]. In the consensustrial, patients with severe heart failure symptomswho were receiving digoxin and a diuretic (andin some cases a vasodilator) had a 1-year moral-ity of 52% and a 6-month mortality of 44%. Bycontrast, patients with moderate to severe heart fail-ure symptoms receiving an angiotensin convertingenzyme (ACE) inhibitor and a beta-blocker in theBEST trial had an annual mortality of 15% [13].Furthermore, patients with moderate to severeheart failure symptoms receiving an ACE inhibitor,a beta-blocker, and an aldosterone antagonist in therecent COMPANION trial had a 1-year mortality of<10% [14]. Thus, while heart failure remains a dis-ease of epidemic proportions in the United States,our opportunity to improve both the length of lifeas well as the quality of the life of patients with thisdisease has improved remarkably over the past twodecades.

An important concept that has received increas-ing attention is the finding that a large proportionof patients with the signs and symptoms of heartfailure, that is, shortness of breath, edema, andfatigue actually have preserved left ventricular func-tion. Indeed, recent studies suggest that nearlyhalf of all patients with symptoms of heart fail-ure have preserved left ventricular systolic function[15–17]. This finding is most commonly attrib-uted to patients who are older and are female [18].Despite the fact that these patients have preservedfunction, their risk of readmission, disability, andsymptoms subsequent to hospital discharge arecomparable to that of heart failure patients withdepressed systolic performance [19]. Indeed, inpatients hospitalized with worsening heart failure,long-term prognosis was worse for patients withnormal systolic function that for those with dimin-ished systolic performance despite a lower numberof comorbidities [20]. Despite the increasing evid-ence of the importance of heart failure in patientswith preserved systolic performance – and presum-ably diastolic dysfunction – there is little consensusregarding appropriate treatment strategies in thesepatients. Most studies that have been carried outto date are either small in size, nonrandomized oranecdotal. Thus, in this book we will focus largelyon patients with heart failure secondary to systolicdysfunction, in whom seminal clinical trials havepointed the way in terms of treatment strategies.

However, where appropriate we will point out thepotential role for pharmacologic agents in the ther-apy of patients with heart failure and preserved leftventricular function.

Despite the advances that have been made inthe pharmacologic treatment of heart failure, theincreasing armamentarium that is now in the handsof the practicing physician provides an interest-ing conundrum – how does one choose betweenthe increasingly large number of treatment options,where does one start in a newly diagnosed patient,how does one monitor treatment once it is begun,and what are the side-effect profiles of these agents.Thus, the objective of this textbook is to act asan informative guide for the practicing physicianin order that they be able to optimize their use ofpharmacologic therapy in the treatment of patientswith heart failure. In the chapters that follow,we have attempted to provide both the biologicand pathologic underpinning for the use of eachpharmacologic agent currently recommended forthe treatment of patients with heart failure, aswell as provide an in depth presentation of theclinical investigations that have led to our under-standing of the risks and benefits associated withthe use of these drugs. While the initial chaptersfocus on agents that have been well-characterizedand are considered “standard care” for the patientwith heart failure (i.e. diuretics, ACE inhibitors,angiotensin receptor antagonists, aldosterone ant-agonists, and beta-blockers), we have also includeddiscussions of several agents that are currentlyunder investigation (e.g. Vasopressin antagonists,erythropoietin) – but which we believe will havean important impact in the future. In addition,we have provided didactic discussion regarding theuse of a group of agents about which there issome controversy, including inotropic agents, anti-arrhythmic drugs, and anticoagulants. We have alsoincluded a discussion on the emerging field of phar-macogenetics and how studies of the genetic profileof patients help us understand which patient pop-ulations are most likely to respond to a given classof drugs. Indeed, it is hoped that the emergenceof pharmacogenetics will allow physicians to tailordesign a pharmacologic regimen – avoiding thosedrugs (and their attendant risks) that will not addbenefit and allowing the practitioner to optimizethe dosing of those drugs that will add benefit based

Introduction xiii

on a patients genotype. Finally, in the penultimatechapter of this book we have provided an algorithmfor the physician that will help them utilize what hasnow become multidrug pharmacy for heart failuretherapy.

This book could not have been completedwithout the commitment of each of the authors toprovide a text that was informative and substant-ive and could provide the reader with up-to-dateinformation that could allow them to understandthe biologic and investigative basis for the rationaluse for heart failure drugs. In addition, the authorthanks Marianne LaRussa for her technical andadministrative assistance, editorial assistance andproof-reading.

References

1 Harvey AM, Osler W. The Principles and Practice of

Medicine. 21st edn. Conn.: Appleton-Century-Crofts,

Norwalk, 1984.

2 Redfield MM. Heart failure – an epidemic of uncertain

proportions. N Engl J Med 2002;347:1442–1444.

3 Hoes AW, Mosterd A, Grobbee DE. An epidemic of

heart failure? Recent evidence from Europe. Eur Heart

J 1998;19:L2–9.

4 Kannel WB, Ho K, Thom T. Changing epidemiological

features of cardiac failure. Br Heart J 1994;72:S3–9.

5 Parameshwar J, Shackell MM, Richardson A, Poole-

Wilson PA, Sutton GC. Prevalence of heart failure in three

general practices in north west London. Br J Gen Pract

1992;42:287–289.

6 Schocken DD, Arrieta MI, Leaverton PE, Ross EA. Preval-

ence and mortality rate of congestive heart failure in the

United States. J Am Coll Cardiol 1992;20:301–306.

7 McCullough PA, Philbin EF, Spertus JA, Kaatz S,

Sandberg KR, Weaver WD. Confirmation of a heart fail-

ure epidemic: findings from the Resource Utilization

Among Congestive Heart Failure (REACH) study. J Am

Coll Cardiol 2002;39:60–69.

8 Lloyd-Jones DM, Larson MG, Leip EP et al. Lifetime risk

for developing congestive heart failure: the Framingham

Heart Study. Circulation 2002;106:3068–3072.

9 Levy D, Kenchaiah S, Larson MG et al. Long-term trends

in the incidence of and survival with heart failure. N Engl

J Med 2002;347:1397–1402.

10 Butler J, Khadim G, Paul KM et al. Selection of patients

for heart transplantation in the current era of heart failure

therapy. J Am Coll Cardiol 2004;43:787–793.

11 Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC,

Vasan RS. Natural history of asymptomatic left ventricu-

lar systolic dysfunction in the community. Circulation

2003;108:977–982.

12 Cohn JN, Archibald DG, Ziesche S et al. Effect of vas-

odilator therapy on mortality in chronic congestive heart

failure. Results of a Veterans Administration Cooperative

Study. N Engl J Med 1986;314:1547–1552.

13 A trial of the beta-blocker bucindolol in patients

with advanced chronic heart failure. N Engl J Med

2001;344:1659–1667.

14 Bristow MR, Saxon LA, Boehmer J et al. Cardiac-

resynchronization therapy with or without an implant-

able defibrillator in advanced chronic heart failure. N Engl

J Med 2004;350:2140–2150.

15 Senni M, Tribouilloy CM, Rodeheffer RJ et al. Congestive

heart failure in the community: a study of all incident

cases in Olmsted County, Minnesota, in 1991. Circulation

1998;98:2282–2289.

16 Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK,

Levy D. Congestive heart failure in subjects with normal

versus reduced left ventricular ejection fraction: preval-

ence and mortality in a population-based cohort. J Am

Coll Cardiol 1999;33:1948–1955.

17 Kitzman DW, Gardin JM, Gottdiener JS et al. Import-

ance of heart failure with preserved systolic function in

patients ≥65 years of age. CHS Research Group. Cardi-

ovascular Health Study. Am J Cardiol 2001;87:413–419.

18 Masoudi FA, Havranek EP, Smith G et al. Gender, age,

and heart failure with preserved left ventricular systolic

function. J Am Coll Cardiol 2003;41:217–223.

19 Smith GL, Masoudi FA, Vaccarino V, Radford MJ,

Krumholz HM. Outcomes in heart failure patients with

preserved ejection fraction: mortality, readmission, and

functional decline. J Am Coll Cardiol 2003;41:1510–1518.

20 Varadarajan P, Pai RG. Prognosis of congestive heart

failure in patients with normal versus reduced ejection

fractions: results from a cohort of 2,258 hospitalized

patients. J Card Fail 2003;9:107–112.

1 CHAPTER 1

Diuretics in congestive heartfailure

Alicia Ross, MD, Ray E. Hershberger, MD & David H. Ellison, MD

Introduction

Diuretics (see Table 1.1 for a physiological classi-fication) remain an important part of the med-ical therapy for patients with congestive heartfailure (CHF). They control fluid retention andrapidly relieve the congestive symptoms of heartfailure (HF). The American College of Cardi-ology/American Heart Association assigned thema class I indication in patients with symptomaticheart failure who have evidence of fluid reten-tion [1]. Indeed, diuretics are the only drugsused in the treatment of HF that control fluidretention and that rapidly produce symptomaticbenefits in patients with pulmonary and/or peri-pheral edema. Because diuretics alone are unableto effect clinical stability in patients with HF,they should always be used in combination withan angiotensin converting enzyme (ACE) inhib-itor and a β-blocker. Despite the widespread useof diuretics, there have yet to be large random-ized clinical trials that evaluate their effects onmortality or morbidity (with the exception ofaldosterone antagonists, which will be consideredseparately). Furthermore, care must be exercised inthe use of diuretics as both hypovolemia second-ary to over-diuresis and hypervolemia secondaryto under-diuresis have profound effects on car-diac pathophysiology. Therefore, questions remainabout appropriate diuretic use [2]. This chapter willexplore the effects, pharmacokinetics, and clinicalutility of diuretics in patients with congestive heartfailure.

Vascular effects of diuretics

Diuretics are believed to improve symptoms ofcongestion by several mechanisms. Loop diuret-ics induce hemodynamic changes that appear tobe independent of their diuretic effect. They actas venodilators and, when giving intravenously,reduce right atrial and pulmonary capillary wedgepressure within minutes [3,4]. This initial improve-ment in hemodynamics may be secondary to therelease of vasodilatory prostaglandins [5]. Stud-ies in animals and humans have demonstrated thatthe loop diuretic furosemide directly dilates veins;this effect can be inhibited by indomethacin, sug-gesting that local prostaglandins may contribute toits vasodilatory properties [6]. In the setting ofacute pulmonary edema from myocardial infarc-tion, Dikshit et al. measured an increase in venouscapacitance and decreasing pulmonary capillarywedge pressure within 15 min of furosemide infu-sion, while the peak diuretic effect was at 30 min [7].Numerous other investigators have found similarresults [8]. Other loop diuretics, such as bumetan-ide, have been reported to have differing effects[9]. There have also been reports of an arteriolarvasoconstrictor response to diuretics when givento patients with advanced heart failure [10]. A risein plasma renin and norepinephrine levels leads toarteriolar vasoconstriction, resulting in reductionin cardiac output and increase in pulmonary capil-lary wedge pressure. These hemodynamic changesreverse over the next several hours, likely due tothe diuresis. The vasoconstrictor response to loop

1

2 CHAPTER 1

Table 1.1 Physiological classification of diuretic drugs.

Proximal diuretics Loop diuretics DCT diuretics CD diuretics Aquaretics

Carbonic anhydrase

inhibitors

Acetazolamide

Na–K–2Cl (NKCC2)

inhibitors

Furosemide

Bumetanide

Torsemide

Ethacrynic acid

Na–Cl (NCCT) inhibitors

Hydrochlorothiazide

Metolazone

Chlorthalidone

Indapamide∗Many others

Na channel blockers

(ENaC inhibitors)

Amiloride

Triameterene

Aldosterone antagonists

Spironolactone

Eplerenone

Vasopressin

receptor

antagonists

Tolvaptan

Lixivaptan

∗Indapamide may have other actions as well.

DCT: Distal convoluted tubule. CD: Collecting duct. Aquaretics are pending approval for clinical use.

diuretic administration occurs more commonlyin patients treated chronically with loop diuret-ics [10]. In this situation, chronic stimulation ofthe renal renin/angiotensin/aldosterone axis mayprime the vascular system to vasoconstriction. Itis likely that different diuretics have complex andmultifactorial actions on the vascular system.

Neurohormonal effects of diuretics

Diuretic drugs stimulate the renin–angiotensin–aldosterone (RAA) axis via several mechan-isms. Loop diuretics stimulate renin secretion byinhibiting NaCl uptake into macula densa cells.Sodium/chloride uptake via the loop diuretic-sensitive Na+–K+–2Cl− cotransport system is acentral component of the macula densa-mediatedpathway for renin secretion [11]. Blocking Na+–K+–2Cl− uptake at the macula densa stimulatesrenin secretion directly, leading to a volume–independent increase in angiotensin II and aldos-terone secretion. Loop diuretics also stimulaterenal production of prostacyclin, which furtherenhances renin secretion. All diuretics can alsoincrease renin secretion by contracting the extra-cellular fluid (ECF) volume, thereby stimulatingthe vascular mechanism of renin secretion. ECFvolume contraction also inhibits the secretion ofatrial natriuretic peptide. Among its other effects,atrial natriuretic peptide inhibits renin release.Interestingly, the combination of aggressive vas-odilator therapy and diuresis to achieve improvedhemodynamic parameters in turn led to diminishedneurohormonal activation [12].

Clinical use of diuretics incongestive heart failure

The mortality benefit of ACE inhibitors (orangiotensin receptor blockers) and β-adrenergicblockers in patients with systolic dysfunction is welldocumented (see Chapter 4). However, all recentheart failure mortality trials have included patientswho were treated with diuretics as diuretics remainan important part of heart failure management.According to the SOLVD (Studies of Left Ventricu-lar Dysfunction) registry, diuretics are the mostcommonly prescribed drugs for heart failure, usedby 62% of patients [13].

When loop diuretics were introduced in the1960s, they had a significant impact on heart failuretreatment. They allowed the physician to aggress-ively treat fluid retention. However, few multicenterand randomized trials were carried out to assessthe efficacy of diuretics and they rapidly became astandard part of the management of patients withthis disease [14]. Indeed, it was not until the intro-duction of ACE inhibitors and elucidation of theneurohormonal pathophysiology of heart failurethat regulatory mandates required that new drugsbe evaluated with large randomized and placebo-controlled trials. By that time, it was clear toclinicians that diuretics dramatically improve thesymptoms of congestion and they had become aninseparable part of the heart failure pharmacopeia.

Although diuretics have not been shown toimprove survival in patients with heart failure(a trial that would now be considered uneth-ical), investigators have attempted to gain a betterunderstanding of the long-term benefits and risks

Diuretics in congestive heart failure 3

of diuretic use from smaller clinical trials. Forexample, Odemuyiwa et al. [15] demonstrated thatdiuretic requirements did not decline after the addi-tion of ACE inhibitors in patients with stable heartfailures symptoms. Similarly, Grinstead et al. [16]evaluated 41 patients with stable, but symptomaticheart failure. After discontinuing diuretic therapy,patients were randomized to either lisinopril orplacebo. Of this, 71% of patients restarted diuretictherapy because of worsening symptoms; how-ever, there was no significant difference betweenthe number of patients who restarted therapy inthe placebo or lisinopril group. Interestingly, abaseline daily furosemide dose of >40 mg, a leftventricular ejection fraction <27%, and a his-tory of systemic hypertension were independentlypredictive of the need for diuretic reinitiation.

It is tempting to think that ACE inhibitors wouldreduce extracellular fluid volume in the absenceof other pharmacologic agents; however, in manycases they require the synergistic action of otherdrugs. The explanation for this paradox lies in thefact that, while diuretics shift the renal functioncurve to the left (Figure 1.1), permitting sodiumexcretion to increase at a constant mean arter-ial pressure and constant dietary salt intake, ACEinhibitors not only shift the renal function curveto the left but also reduce mean arterial pres-sure through peripheral vasodilation. Thus, in theabsence of diuretics, ACE inhibitors are unable toeffect a change in urinary sodium excretion becausethe shift in the renal function curve is offset by thereduction in blood pressure.

In another study that evaluated the effectivenessof diuretic therapy in patients with heart failure,Walma and colleagues evaluated the effects of diur-etic withdrawal in a group of 202 elderly patientswho were minimally symptomatic and who had nothad a recent episode of worsening heart failure [17].The subjects in this study were randomized toeither continued therapy with a diuretic or dis-continuation of their diuretic therapy. Diureticreinstitution was required in 50 of 102 patients inthe withdrawal group and 13 of 100 patients in thecontrol arm. Heart failure was the most frequentcause of reinitiating diuretic therapy and 65% ofpatients who were originally prescribed diureticsfor heart failure needed reinitiation of diuretic ther-apy during the trial. The authors concluded that

0

200

400

600

70 80 90Mean arterial pressure (mm Hg)

Na

excr

etin

(m

mol

/day

)

A

B

C

Dietary Na

ControlACE inhibitor

Diuretic

Figure 1.1 Comparison of diuretic and ACE inhibitor effectson sodium (Na) excretion and mean arterial pressure. Thefigure shows two ‘chronic renal function curves’ relatingdietary Na intake (grey line), urinary Na excretion(ordinate) and mean arterial pressure (abscissa). Atbaseline (point A), the urinary Na excretion equals dietaryNa intake. Both diuretics and ACE inhibitors shift the renalfunction curve to the left (from the solid to the dottedline). Diuretics do not reduce arterial pressure directly,therefore urinary Na excretion rises (move from point A topoint B). In contrast, ACE inhibitors reduce mean arterialpressure as well as shift the renal function curve, so urinaryNa excretion is unchanged (move from point A to point C).

clinicians should be cautious while withdrawingdiuretic therapy and when withdrawal is required itshould be accompanied by assiduous monitoring,especially during the first 4 weeks after therapy isdiscontinued.

Important information regarding the use of diur-etics also come from a number of large multicenterclinical trials that evaluated chronic therapy withdiuretics in patients with hypertension, an import-ant risk factor in the development of heart failure.In the Stop Hypertension in the Elderly Program(SHEP) [18], 4736 persons with isolated systolichypertension were randomized to receive chlorthal-idone, a thiazide-like diuretic, versus placebo, ina stepwise approach. The incidence of heart fail-ure was reduced in the active group by 53% with48 events being seen in the active treatment groupand 102 events in the placebo group. Treatmentwith a diuretic compared to a calcium channelblocker or an ACE inhibitor was also evaluatedin the Antihypertensive and Lipid-Lowering Treat-ment to Prevent Heart Attack Trial (ALLHAT)[19]. Chlorthalidone was superior to amlodipine

4 CHAPTER 1

in preventing the development of heart failure.The amlodipine group had a 38% (p < 0.001)higher risk of heart failure and a 6-year absoluterisk difference of 2.5%. When all major long-term hypertension treatment trials were reviewedto evaluate the effects of diuretics on the devel-opment of heart failure, diuretics were found todecrease the risk of heart failure by 52% [20,21].Thus, though indirect, the experience in hyper-tension supports the hypothesis that diuretics arebeneficial in patients with heart failure as well asthose at high risk of its development.

Adverse effects associated withdiuretic use

The adverse effects associated with the use ofdiuretics are reviewed in Table 1.2. However, thetwo most serious consequences of diuretic useare the development of arrhythmias and electro-lyte abnormalities – the two being linked in manyinstances.

ArrhythmiasNumerous studies have demonstrated an increasedincidence of arrhythmias with the use of

non-potassium-sparing diuretics [22]. Siscovicket al. demonstrated in a population-based case-control study that the presence and dose of thiazidediuretics was associated with an increased risk ofprimary cardiac arrest [23]. The SOLVD invest-igators similarly found that the baseline use ofnon-potassium-sparing diuretics was associatedwith an increased risk of arrhythmic death, whilepotassium-sparing diuretic use was not associatedwith an increased risk [24]. The presence or absenceof ACE inhibitors or potassium supplementationdid not affect this relationship and there was nota significant difference in potassium levels betweenpatients who were receiving or not receiving an ACEinhibitor.

Electrolyte abnormalities and othermetabolic sequelae of diureticsHyponatremiaHyponatremia develops in the setting of congest-ive heart failure because of the accumulation ofexcess free water within the vascular spaces. Freewater retention occurs in the setting of increasedtubular absorption of sodium and activation ofthe renin–angiotensin–aldosterone axis [2]. Waterretention is caused at least in part by increased

Table 1.2 Complications of diuretics.

Complications Preventive measures

Electrolyte abnormalities

Hypokalemia

Hyponatremia

Hypomagnesemia

Periodic electrolyte monitoring when actively

diuresing or adjusting ACE inhibitor dose

Caution with potassium-sparing diuretics

Arrhythmias Keep serum K 4.0–5.0

Extracellular fluid volume depletion

Metabolic alkalosis

Daily weights

Regular assessment by clinician

Azotemia Regular assessment by clinician

Medication review, that is, NSAIDs, etc.

Glucose intolerance

Hyperlipidemia

Hyperuricemia

Erectile dysfunction

Regular assessment by clinician

Otoxicity Limit rapid boluses, especially in uremia,

use of aminoglycosides

Limit rate of furosemide infusion to less

than 240 mg/h

Progressive heart failure Regular assessment by clinician

Diuretics in congestive heart failure 5

levels of vasopressin and subsequent activation ofvasopressin receptors in the kidney. Diuretics cancontribute to the stimulation of vasopressin byreducing effective arterial volume [25,26]. Indeed,it has been recognized clinically that many patientsenter the hospital with normal serum sodium,but develop hyponatremia after receiving aggress-ive diuresis with loop diuretics. Recent studieshave demonstrated that even modest decreases inserum sodium (130 to 135 mEq/L) are associatedwith a worse outcome in patients hospitalized forworsening heart failure.

The management of hyponatremia includesefforts to improve cardiac function, decreasevolume overload, and to restrict free water intake.Some patients may require intravenous inotropicsupport and/or low doses of dopamine to improverenal perfusion. Because hyponatremia is driven atleast inpart by an impairment in effective arterialblood volume, the addition of an ACE inhibitormay lead to an improvement in the serum sodiumlevel [27]. The recent development of vasopressinreceptor antagonists (so-called aquaretic agents)shows promise in treating the water retention ofheart failure and may become an important com-ponent of the treatment regimen for hyponatremicpatients with heart failure [28,29]. The potentialrole for vasopressin antagonists will be discussed inChapter 13.

Disorders of potassium balanceActivation of the renin–angiotensin–aldosteronesystem leads to hypokalemia because of augmen-ted exchange of sodium for potassium in therenal tubule [2]. Non-potassium-sparing diuret-ics potentiate this hypokalemia by presenting anincreased sodium load to the distal tubule. Thisleads to urinary excretion of potassium, whichhas been associated with further activation ofthe renin–angiotensin–aldosterone axis [30]. Asa result, many patients with chronic heart fail-ure develop a reduction in whole-body potassiumstores as potassium is released from intracellularstorage pools in order to help balance the levels ofpotassium in the peripheral circulation. Aggress-ive diuresis in the setting of chronic hypokalemiacan further reduce serum potassium levels. Hypo-kalemia is a significant risk factor for the devel-opment of malignant arrhythmias [4]. Although

not evaluated in a randomized, prospective trial,many experts believe that in patients with CHF,potassium concentrations should be maintainedin the range of 4.5 to 5.0 mEq/L [2]. Historic-ally, most heart failure patients who were receivinga loop diuretic were prescribed a potassium sup-plement. However, the incidence of hypokalemiain heart failure patients appears to be decreasing,with the wide utilization of ACE inhibitors/ARBstogether with β-blockers and aldosterone antag-onists. Indeed, a recent survey showed substantialincreases in the rates of hospitalization for poten-tially harmful hyperkalemia as a result of increasedutilization of aldosterone antagonists [31], an areathat will be discussed in further detail in the chapteron the use of aldosterone antagonists. Preexistingserum potassium concentrations above 4 mM oreven mild chronic kidney disease should promptspecial caution in the use of potassium-sparingagents.

HypomagnesemiaHypomagnesemia develops by similar mechan-isms to hypokalemia; however, the importanceof hypomagnesemia in heart failure is less wellestablished. Hypomagnesemia has been associatedwith an increase in ectopy and mortality is somesmall trials; however, hypomagnesaemia was notassociated with an increase in mortality in thelarge Prospective Randomized Milrinone SurvivalEvaluation (PROMISE) trial. Parenthetically, thepresence of hypomagnesaemia is difficult to assessas there is poor correlation between serum and tis-sue magnesium concentrations [32]. Magnesiumdeficiency is less common in mild to moderateHF; however, there are several populations thatare more susceptible including post cardiac trans-plant patients, patients in intensive care units, andpatients with moderately severe to severe symptomsrequiring hospitalization, high dose diuretic ther-apy, or patients who have coexisting hypokalemia[2]. Magnesium replacement should be stronglyconsidered in these populations.

Progressive heart failureBecause diuretic use is associated with activationof the renin–angiotensin–aldosterone system, thereis reason to believe that its use may promote theprogression of heart failure. In a retrospective

6 CHAPTER 1

analysis of the SOLVD trial, the risk of hospital-ization for, or death from, worsening CHF wassignificantly increased in patients receiving non-potassium sparing diuretics (i.e. loop diuretics)compared to those patients not being treated witha diuretic or receiving a potassium sparing diuretic[13]. The investigators proposed that loop diuret-ics induce a loss of sodium that in turn activatesthe renin–angiotensin system and thereby contrib-utes to disease progression. Thus, diuretics shouldalways be used in conjunction with inhibitors of therenin–angiotensin system including ACE inhibit-ors, β-blockers, and an aldosterone inhibitor whenappropriate.

Practical considerations for the useof diuretics

Diuretic choice and dosingMost patients with a current evidence of volumeoverload or a history of fluid retention should betreated with a diuretic in combination with an ACEinhibitor and a β-blocker. In patients with newonset of fluid retention, a diuretic should be thefirst drug used as it will provide the most rapidimprovement in symptoms. Some authors suggestthat patients with mild symptoms should initiallybe treated with a thiazide diuretic [33]; however,there are no objective data to support this approachand many heart failure specialists believe that thethiazide diuretics have too little potency in a heartfailure population. When patients have moderate tosevere heart failure symptoms or renal insufficiency,a loop diuretic is required. Outpatient treatmentshould begin with low doses of diuretic with incre-mental increases in the dose until urine outputincreases and weight decreases (∼1.0 kg/day). Somepatients may develop hypotension or azotemia dur-ing diuretic therapy. While the rapidity of diuresisshould be slowed in these patients therapy shouldbe maintained at a lower level until euvolemia hasbeen attained, as persistent volume overload maylimit and/or compromise the effectiveness of otheragents and persistently high filling pressures canenhance maladaptive cardiac remodeling.

A typical starting dose is 20 mg of furosemide inpatients with normal renal function, although dosesof 40–80 mg may be necessary. Further increases

in dose may be required to maintain urine outputand weight loss. In patients with renal insufficiency,larger starting doses are often necessary, such as40–80 mg of furosemide that may be increasedup to 160 mg. Ceiling doses of loop diuretics intreating heart failure, single doses that appear tobe maximally effective, have been described [33].For furosemide, the maximal doses are 40–80 mgIV (160–240 mg PO). For torsemide, the maximaldoses are 20–50 mg IV or PO. For bumetanide, themaximal doses are 2–3 mg IV or PO. Because ofthe steep dose-response curve for loop diuretics, anadequate dose is necessary that causes a clear diur-etic response. Some experts recommend doublingthe dose until this effect is demonstrated.

Although furosemide is the most commonly usedloop diuretic, there are several limitations to itsuse. For example, its oral bioavailability is onlyapproximately 50% and there is significant intra-and interpatient variability [34]. In patients withhepatic and bowel edema, the bioavailability offurosemide may be markedly decreased becauseof decreased gastric absorption. Therefore, someclinicians favor the use of bumetanide or torsemidebecause of their increased and more predictablebioavailability [35].

All of the commonly used loop diuretics areshort acting. In CHF, the half-lives of these drugsare increased, but still less than 3 h [34]. Afterthe period of diuresis, the diuretic concentrationdeclines below its threshold and renal sodium reab-sorption is no longer inhibited and “postdiureticNaCl retention” begins [36]. If a patient is notrestricting sodium intake, this retention can over-take the original diuresis. For this reason, loopdiuretics usually need to be given at least twicedaily and salt restriction is an important com-ponent of therapy. In addition, patients receivingdiuretic therapy should monitor their weight on adaily basis.

Diuretic resistance

An edematous patient may be deemed resistant todiuretic drugs when moderate doses of a loop diur-etic do not achieve the desired reduction in ECFvolume as noted by a change in weight, the amountof edema, the degree of liver enlargement, or thejugular venous pressure. Before labeling the patient

Diuretics in congestive heart failure 7

as ‘resistant’ to diuretics and considering intens-ive diuretic therapy or combination therapy, it isimportant to exclude reversible causes. An inad-equate ECF volume reduction does not necessarilyindicate an inadequate natriuretic response (seeFigure 1.1), Loop diuretics may induce natriur-esis without contracting the ECF volume, if dietaryNaCl intake is excessive. It should also be emphas-ized that the ‘desired’ ECF volume may not leadto an edema-free state; some patients may requirea modest amount of peripheral edema to main-tain adequate cardiac output: such patients mayneed to be counseled regarding local measuresto reduce edema (support stockings, keeping thefeet elevated) and the willingness to tolerate mildedema. When needed, however, intensive diur-etic treatment is usually effective in reducing theECF volume; each of the different approaches tointensive therapy is best employed under specificcircumstances.

Combination diuretic therapy

A common and useful method for treating the diur-etic resistant patient is to administer two classesof diuretic drug simultaneously. For this discus-sion, it is assumed that the patient is already beinggiven a loop diuretic at maximal or near max-imal doses. Although some authors have advocatedalternating two members of the same diuretic classtogether (such as ethacrynic acid and furosemide)controlled trials suggest little or no benefit fromsuch an approach [37]. In contrast, adding a prox-imal tubule diuretic or a distal convoluted tubulediuretic (DCT) to a regimen of loop diuretics isoften dramatically effective [38–40]. DCT diuret-ics (thiazides and the like) are the class of drugsmost commonly added to loop diuretics and thiscombination has proven remarkably effective. Thecombination of loop and DCT diuretics has beenshown to be synergistic (the combination is moreeffective than the sum of the effects of each drugalone) in formal permutation trials [41].

Adding a DCT diuretic to a regimen that includesloop diuretics may enhance NaCl excretion by sev-eral mechanisms, none of which is mutually exclus-ive. DCT diuretics do not appear to potentiate theeffects of loop diuretics by altering their pharma-cokinetics or bioavailability [42], but DCT diuretics

do have longer half-lives than do loop diuretics. Thefirst mechanism responsible for the efficacy of com-bination therapy is that DCT diuretics may preventor attenuate postdiuretic NaCl retention. As shownin Figure 1.2, the natriuretic effects of a single doseof furosemide, bumetanide, and to a lesser extenttorsemide, generally cease within 6 h. Before thenext dose of diuretic is administered, intense renalNaCl retention frequently occurs (so called postdi-uretic NaCl retention); this NaCl retention can beattenuated by DCT diuretics, which will continue toinhibit renal NaCl absorption after the loop diuretichas worn off. A second mechanism by which DCTdiuretics potentiate the effects of loop diuretics is byinhibiting salt transport along the proximal tubule.When the kidney is strongly stimulated to retainNaCl, proximal NaCl reabsorption is enhanced.Most thiazide diuretics inhibit carbonic anhydrase,thereby reducing Na and fluid reabsorption alongthe proximal tubule. This leads to increase Na andfluid delivery to the loop of Henle [43], which leadsto increases in delivery of Na+ and Cl− into thecollecting duct system. Because the loop diureticdrug is inhibiting loop segment solute reabsorp-tion, the delivery of solute to the distal nephronwill be greatly magnified. The importance of car-bonic anhydrase inhibition in diuretic synergism isdocumented by the efficacy of carbonic anhydraseinhibitors (e.g. acetazolamide) when added to loopdiuretics. Although carbonic anhydrase inhibitorsare relatively weak diuretics when administeredalone, they can be very potent when added to aregimen of a loop diuretic [44].

A third mechanism by which DCT diuretics maypotentiate the effects of loop diuretics is by inhib-iting NaCl transport along the distal convolutedtubule. Chronic loop diuretic administration leadsto hypertrophy and hyperplasia of distal convolutedtubule cells, increasing their NaCl reabsorptivecapacity by up to threefold [45–47]. Because DCTdiuretics can inhibit thiazide-sensitive Na+/Cl−cotransport completely even under these stim-ulated conditions [45], the effects of the DCTdiuretics will be greatly magnified in the patientwho has developed distal nephron hypertrophyfrom high doses of loop diuretics. Loon and col-leagues [48] showed that the effect of chlorothiazideon urinary Na+ excretion in humans is enhancedby one month’s prior treatment with furosemide.

8 CHAPTER 1

Short term adaptation‘PostdiureticNaCl retention’

0

20

40

60

80

100

120

140

160

180

200

UN

aV (

mm

ol/6

h)

D D D D D D

Chronic adaptation‘The brakingphenomenon’

Dietary Na intake(140 mmol/day)

70

72

74

76

78

80(a)

(b)

0 2 4 6 8 10 12W

eigh

t (kg

)Time (days)

Diuretic

Time (6-h period)

Figure 1.2 Effects of diuretics on urinary Na excretion and ECF volume. (a) Effect of diuretic on body weight, taken as anindex of ECF volume. Note that steady state is reached within 6–8 days despite continued diuretic administration.(b) Effects of loop diuretic on urinary Na excretion. Bars represent 6-h periods before (in Na balance) and after doses loopdiuretic (D). The dotted line indicates dietary Na intake. The solid portion of the bars indicate the amount by which Naexcretion exceeds intake during natriuresis. The hatched areas indicate the amount of positive Na balance after thediuretic effect has worn off. Net Na balance during 24 h is the difference between the hatched are (postdiuretic NaClretention) and the solid area (diuretic-induced natriureisis). Chronic adaptation is indicated by progressively smaller peaknatriuretic effects (The braking phenomenon) and is mirrored by a return to neutral balance [as indicated in (a)] wherethe solid and hatched areas are equal. As discussed in the text, chronic adaptation requires ECF volume depletion.

These data suggest that daily oral furosemide treat-ment, even in modest doses, may be sufficient toinduce adaptive changes along the distal nephron,changes that may be treated with combination drugtherapy.

The choice of drugs for combination diuretictherapy has been controversial [40,44,49–53]. Inmost cases, it is appropriate to add a DCT diur-etic to a regimen of a loop diuretic. Alternativeapproaches, however, are appropriate in some cir-cumstances and will be discussed later. In general,when a second class of diuretic is added, the dose ofloop diuretic should not be altered. The shape of thedose-response curve to loop diuretics is not affectedby the addition of other diuretics and the loop diur-etic must be given in an effective or maximal safedose. The choice of DCT diuretic that is to be addedis arbitrary. Many clinicians choose metolazone

because its half-life, in the commonly employedformulation, is longer than that of some other DCTdiuretics and because it has been reported to remaineffective even when the glomerular filtration rate islow. Yet, direct comparisons between metolazoneand several traditional thiazides have shown littledifference in natriuretic potency when includedin a regimen with loop diuretics in patients withcongestive heart failure [51].

The DCT diuretics may be added in full doses(50–100 mg/day hydrochlorothiazide or 10 mg/daymetolazone, see Table 1.3) when a rapid and robustresponse is needed, but such an approach is likely tolead to complications unless follow-up is assiduous.This approach should be reserved for hospital-ized patients since fluid and electrolyte depletionmay be excessive. Indeed, in one review of com-bination diuretic therapy, side effects were noted

Diuretics in congestive heart failure 9

Table 1.3 Combination diuretic therapy.

To a maximal dose of a loop diuretic add

Distal convoluted tubule diuretics:

metolazone 2.5–10 mg PO daily∗hydrochlorothiazide (or equivalent) 25–100 mg PO daily

chlorothiazide 500–1000 mg IV

Proximal tubule diuretics:

acetazolamide 250–375 mg daily or up to 500 mg

intravenously

Collecting duct diuretics:

spironolactone 100–200 mg daily

eplerenone 25–100 mg/day

amiloride 5–10 mg daily

∗Metolazone is generally best given for a limited period of time

(3–5 days) or should be reduced in frequency to three times per week

once extracellular fluid volume has declined to the target level. Only

in patients who remain volume expanded should full doses be con-

tinued indefinitely, based on the target weight. Be very cautious

with higher doses of spironolactone or eplerenone in the setting of

angiotensin converting enzyme inhibitors or angiotensin receptor

blockers, hyperkalemia can occur [31].

to have occurred in about two-thirds of patientsreceiving therapy [39]. One rational approach tocombination therapy is to achieve control of ECFvolume by adding full doses of DCT diuretics ona daily basis initially and then to maintain con-trol by reducing the dose of the DCT diuretic tothree times weekly. However, many clinicians titratethe dose of the DCT diuretic in each patient andhave found that in some patients only a singleweekly dose is required to maintain an appro-priate level of diuresis. A physiological rationalefor such an approach is provided by the obser-vation that chronic treatment with DCT diureticsdown-regulates Na+/K+-ATPase activity [54] andtransport capacity [55] along the distal convolutedtubule of rat. Thus, it may be speculated that addinga DCT diuretic to a regimen including a loop diur-etic may decrease the structural and functionalcompensatory effects of loop diuretics.

Another approach to combination therapy is touse combination therapy for only a short fixedcourse. A comparison of different combinationdiuretic regimens suggested that a limited courseof combination therapy may be as effective andperhaps safer than more prolonged courses [51].Thus, for the outpatient, either a small dose ofDCT diuretic, such as 2.5 mg/day metolazone or

a limited and fixed course of a higher dose (3 daysof 10 mg/day metolazone) may be recommendedas effective therapy that is less likely to lead to sideeffects. Because DCT diuretics are absorbed moreslowly than loop diuretics, it may be reasonable toadminister the DCT diuretic 1/2 to 1 h prior to theloop diuretic, although rigorous support for thiscontention is lacking.

Drugs that act along the collecting duct, such asamiloride and spironolactone, can be added to aregimen of loop diuretic drugs but their effects aregenerally less robust than those of DCT diuretics.For example, the combination of spironolactoneand loop diuretics has not been shown to be syn-ergistic but aldosterone antagonists can prolonglife and help prevent hypokalemia [56]. Corticalcollecting duct diuretics also reduce magnesiumexcretion, relative to other diuretics, making hypo-magnesemia less likely than when loop diureticsare combined with DCT diuretics [57–60]. How-ever, there is far less experience with these types ofdiuretics in heart failure patients.

One situation in which aggressive diuretic ther-apy is often indicated is for hospitalized patients,especially those in an intensive care unit whoneed urgent diuresis. While the causes of diur-etic resistance delineated above may be present inthese patients, many also receive obligate fluid andsolute loads, some develop electrolyte complica-tions, and many cannot take medications by mouth.Two IV drugs are available to supplement loopdiuretics for combination therapy. Chlorothiazide(500–1000 mg once or twice daily) and acetazol-amide (250–375 mg up to four times daily) areboth available for IV administration: chlorothiazidehas relatively potent carbonic anhydrase inhibit-ing capacity in the proximal tubule. It also blocksthe ‘thiazide-sensitive’ Na–Cl cotransporter in thedistal tubule; and chlorothiazide has a longerhalf-life than some other DCT diuretics. Bothchlorothiazide and acetazolamide have been shownto act synergistically with loop diuretics when givenacutely. Acetazolamide is especially useful whenmetabolic alkalosis and hypokalemia complicatethe treatment of edema. Alkalosis may make itdifficult to wean a patient from a ventilator andmake it impossible to correct K+ depletion. Theuse of acetazolamide can often correct these dis-orders [61] without the need to administer saline,

10 CHAPTER 1

which would otherwise be used to correct alkalosisin these patients. In other situations, combinationdiuretic therapy may be targeted at the underly-ing disease process. Low doses of dopamine areoften employed to potentiate the action diureticsby improving renal perfusion. However, one studyhas suggested that dopamine is not effective as anadjunct to diuretic treatment unless it increasescardiac output [62].

A newer approach may include combining brainnatriuretic peptide (nesiritide) with loop diur-etic treatment. In animals, this combination wasrecently shown to result in enhanced natriuresiswithout stimulating aldosterone secretion [63].This combination makes it attractive as an optionfor acutely ill patients, but awaits confirmatorystudies in humans and will be discussed in detailin Chapter 11.

High dose diuretic therapy

High doses of loop diuretics are frequentlyemployed to treat severe volume overload, espe-cially when treatment is urgent. Maximal effectivedoses of furosemide, bumetanide, and torsemidehave been estimated (see “diuretic choice and dos-ing” discussed earlier), although some have usedhigher doses [64]. In diuretic sensitive patients,the most common complications of loop diuret-ics result directly from the diuresis and natriur-esis. Hypokalemia, hyponatremia, and hypotensionfrequently result because of excessive fluid andelectrolyte losses. For diuretic resistant patients,however, drug toxicity, most commonly ototoxicity,may also occur and is an important considerationduring high dose or prolonged therapy. All loopdiuretics have been reported to cause ototoxicityin experimental animals and clinical ototoxicityhas been reported following ethacrynic acid, fur-osemide, and bumetanide administration [65,66].Ototoxicity is usually reversible, but has been irre-versible occasionally; its incidence may be increasedin patients exposed to other ototoxic agents, such asthe aminoglycosides. Ototoxicity may be especiallycommon following ethacrynic acid administration.It appears to be related to the serum concentra-tion of the drug. It has been suggested, and clinicalexperience seems to confirm, that ototoxicity of fur-osemide can be minimized by administering it no

faster than 15 mg/min [67]. Comparable data arenot available for bumetanide and torsemide, but itseems reasonable to avoid rapid bolus administra-tion of loop diuretics in general. Myalgias appear tobe more common following high doses of bumetan-ide [68]. The avoidance of high peak levels and theconcomitant toxicity is one reason that continuousinfusion of diuretics (discussed later) has becomepopular as an alternative approach to treat diureticresistant patients.

It has long been appreciated that many patientssuffering from CHF experience symptomatic relieffrom IV boluses of loop diuretics before significantvolume and NaCl losses have occurred. In somepatients, loop diuretics reduce pulmonary capil-lary wedge pressure acutely [7]. Loop diuretics arealso known to stimulate secretion of vasodilatoryprostaglandins. Pretreatment of animals with indo-methacin greatly attenuates furosemide-inducedvenodilation, suggesting that prostaglandin secre-tion contributes importantly to the effects of loopdiuretics by altering vascular reactivity. Althoughvenodilation and improvements in cardiac hemo-dynamics frequently result, other reports suggestthat the hemodynamic response to IV loop diureticsmay be more complex. In two series, 1–1.5 mg/kgfurosemide boluses, administered to patients withchronic CHF, resulted in transient deteriorations inhemodyanamics during the first hour [10,69] andexacerbation of CHF symptoms. These changeswere related to activation of both the sympatheticnervous system and the renin–angiotensin systemby the diuretic. Although these data provide cau-tionary information concerning the use of loopdiuretics in acute cardiogenic pulmonary edema,it should be emphasized that IV loop diureticsremain the most important and useful form of ther-apy for these patients because they rapidly ameli-orate symptoms in most patients. Furthermore,they contribute to symptomatic improvement oncenatriuresis begins, an effect that should beginwithin 15 to 20 min of diuretic administration.

Another interesting complication of high dosefurosemide treatment may be thiamine deficiency[70–74]. Studies in experimental animals haveshown that chronic furosemide administrationcan lead to thiamine deficiency. In humans, sev-eral groups have reported thiamine deficiency inpatients treated chronically with furosemide [74].

Diuretics in congestive heart failure 11

In one study, patients with CHF who receivedfurosemide 80 mg daily for at least 3 monthswere randomized to receive IV thiamine orplacebo. Intravenous thiamine led to improvedhemodynamics and a natriuresis, compared withplacebo, and to an improvement in the thiamine-pyrophosphate effect on erythrocyte transketolaseactivity [72].

Continuous diuretic infusionFor hospitalized patients who are resistant to diur-etic therapy, another approach is to infuse diureticscontinuously. Continuous diuretic infusions haveseveral potential advantages over bolus diureticadministration. First, because it avoids troughs ofdiuretic concentration, continuous infusion pre-vents intermittent periods of positive NaCl balance(postdiuretic NaCl retention). When short-actingdiuretics, such as the loop diuretics, are admin-istered by bolus infusion or by mouth once or twicea day, a period of natriuresis and diuresis lastingabout 6 h ensues. When diuretic serum concen-trations decline, urine NaCl concentrations alsodecline to levels below basal. Because 24-h renalNaCl excretion is the sum of the natriuretic andantinatriuretic responses, negative salt balance maybe limited, especially when dietary salt intake ishigh. Clearly, a constant infusion that leads to con-stant serum diuretic concentrations will minimizeperiods of sodium retention and might be expectedto be more efficacious. Second, constant infusionsappear to be more efficient than bolus therapy. Inone study of patients with chronic renal failure, acontinuous infusion of bumetanide was 32% moreefficient than a bolus of the same drug when theamount of NaCl excreted per milligram of admin-istered drug was compared [68]. In a crossoverstudy of nine patients with NYHA class III–IV CHF(see Figure 1.2), 60–80 mg/day was more effect-ive when given as a continuous infusion followinga loading dose (30–40 mg) than when given asboluses three times daily (30–40 mg/dose) [75].Third, some patients who are resistant to largedoses of diuretics given by bolus have respondedto continuous infusion [64]. Most studies of effic-acy in diuretic resistant patients have not comparedstrictly equivalent doses or administered them isa randomized manner. Regardless, several studiesdo provide suggestive evidence that continuous

infusion may elicit diuresis in some patients resist-ant to large boluses. Fourth, diuretic response canbe titrated; in the intensive care unit where obligatesolute and fluid administration must be balancedby solute and fluid excretion, control of NaCl andwater excretion can be obtained by titration ofdiuretic dose. While this is important in everypostoperative patient, it is especially important inpatients who are hemodynamically compromised.Magovern reported successful diuresis of hemo-dynamically compromised patients after cardiacsurgery by continuous furosemide infusion [76].Because continuous infusion of loop diuretics mayreduce the sympathetic discharge and activationof the renin–angiotensin system, continuous infu-sions may be the preferred mode of therapy forhemodynamically unstable patients in need of diur-esis. Finally, drug toxicity from loop diuretics, suchas ototoxicity (observed with all loop diuretics) andmyopathies (with bumetanide), appear to be lesscommon when the drugs are administered as con-tinuous infusions. In fact, total daily furosemidedoses exceeding 2 g have been tolerated well whenadministered over 24 h. Dosage regimens for con-tinuous IV diuretic administration are shown inTable 1.4. Of note, although natriuretic efficacy mayvary linearly with loop diuretic dose, high infusionrates (e.g. 2 g per day of furosemide) might leadto toxic serum concentrations if continued for pro-longed periods. This is especially true in patientswith renal failure, in whom larger doses are oftenrequired to initiate diuresis. Special care shouldbe taken when administering large daily doses ofloop diuretics over prolonged periods; in patientswith renal failure, a drug such as torsemide thatis cleared, in part, by hepatic metabolism, maybe preferred when high or prolonged therapy isattempted.

Ultrafiltration

In contrast to loop diuretics, ultrafiltration hasmuch more modest effects to stimulate the renin–angiotenin–aldosterone axis because it does notactivate the macula densa mechanism [77]. Sub-sequent reports have corroborated that ultrafiltra-tion is safe and can be an effective adjunct todiuretics, but controlled trials are still lacking [78].

12 CHAPTER 1

Table 1.4 Continuous infusion of loop diuretics.

Infusion rate (mg/h)

Bolus (mg) <25 mL/min 25–75 mL/min >75 mL/min

Furosemide 40 20 then 40 10 then 20 10

Bumetanide 1 1 then 2 0.5 then 1 0.5

Torsemide 20 10 then 20 5 then 10 5

At high continuous doses, toxicity may develop, especially during furosemide infusion

in patients with impaired renal function. Doses derived from Brater [88].

Table 1.5 Adequacy of diuresis.

Adequacy of diuresis

Jugular venous distension

Hepatojugular reflex

Hepatomegaly

Ascites, peripheral and sacral edema

Pulmonary rales

Cough, dyspnea on exertion

Orthopnea, paroxysmal nocturnal dyspnea

Documented elevated filling pressures by cardiovascular

testing (i.e. cardiac catheterization, echo cardiography)

Evaluation of adequacy of diuresis

Clinicians use various methods to determine theextent and adequacy of diuresis (Table 1.5). How-ever, some of the more commonly used signs, suchas resolution of pulmonary rales, are insensitivewhen determining adequacy of diuresis in patientswith chronic heart failure. Many clinicians usemeasures of renal function as an indicator of over-diuresis; however, increased blood urea nitrogen(BUN)/serum creatinine ratio can be a marker forrapid diuresis rather than overdiuresis. Patientsmay be temporarily intravascularly depleted whileevidence of increased total body fluid still remains.In patients with azotemia or hypotension but con-tinued evidence of fluid retention, diuresis shouldcontinue, although at a slower rate. Overdiur-esis that leads to hypotension may contribute torenal insufficiency in patients on vasodilators andACE inhibitors. In this setting, hypotension canbe managed by reducing the dose or frequency ofdiuretics. In some patients with advanced, chronicheart failure, elevated BUN and creatinine concen-trations may be necessary to maintain control of

congestive symptoms. Once patients are believedto be adequately diuresed, it is important to doc-ument this “dry weight” and have patients weighthemselves daily.

Natriuretic peptides are increasingly being usedas both diagnostic and prognostic tools in CHF.Some investigators have encouraged their useto titrate therapy. Both b-type natriuretic pep-tide (BNP) and N-terminal-pro-BNP plasma con-centrations have been demonstrated to improvewith heart failure pharmacologic therapy [79–82]In a study by Troughton et al. [82], patientswith impaired systolic function and symptomaticheart failure were randomized to receive treatmentguided by either N-BNP concentration (N-BNP <

200 pmol/L) or standardized clinical assessment.After a median of 9.5 months, there were fewertotal cardiovascular events (death, hospital admis-sion, or heart failure decompensation) in the BNPgroup compared to the clinical group (19 versus54, p = 0.02). However, titration of heart failuretherapy was accomplished by a predetermined pro-tocol that first maximized ACE inhibitors and thenincreased the dose of the loop diuretics. Unfortu-nately, there have not been studies that investigatethe role of natriuretic peptides in titration of diuret-ics in patients already maximized on ACE inhibitorsand β-blockers.

Monitoring the efficacy of diuretictherapy

Patients with CHF who are on diuretics should bemonitored for complications of diuretics on a reg-ular basis (Table 1.2). The interval for reassessmentshould be individualized based on severity of ill-ness, recent medication changes, past history ofelectrolyte imbalances, or need for active diuresis.

Diuretics in congestive heart failure 13

The earliest indication of volume retention isusually a consistent or dramatic increase in weight.In some patients, they can be instructed to take anextra dose of their routinely prescribed loop diur-etic. Metolazone or other long-acting thiazide diur-etics also can be used to improve diuresis. A dose of2.5 to 5.0 mg of metolazone in addition to routineloop diuretics can be used periodically. Whilethe effectiveness of volume management by heartfailure nurses and multidisciplinary heart failureclinics is well established [83–85], this commonlyprescribed practice of patient-guided managementof diuretics has not been adequately studied [86].Some clinicians in cognitively intact and motivatedpatients have used this practice in order to preventheart failure hospitalizations [87]; however, thispractice could lead to over treatment with diuretics.Therefore, it should be reserved for those patientswho are hemodynamically stable, well motivated,and consistently compliant. Routine use of extradiuretics should prompt reevaluation by a clinician.

Summary

Diuretics are a mainstay of therapy in patients withheart failure. They rapidly produce an improve-ment in symptoms, can be effective in alleviat-ing pulmonary and peripheral edema, and canadequately control fluid retention with chronictherapy. However, diuretics most be utilized withcare. First and foremost, they must be used in com-bination with an ACE inhibitor and a β-blocker inorder to optimize their effectiveness and decreaserisk. Furthermore, care must be taken to avoid inap-propriately high doses of diuretics and resultantvolume contraction as well as to avoid underutil-ization and associated hypervolemia. Furthermore,care should be taken to avoid alterations in serumelectrolyte levels that can accompany diuretic use.Although appropriate cautions are warranted, itshould be recognized that an optimal use of diur-etics serves as a cornerstone in the treatment ofpatients with heart failure.

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