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European Heart Journal (1996) 17 (Supplement B), 43-56

Congestive heart failure

Towards a comprehensive treatment

S. H. Taylor

University Department of Cardiovascular Studies, Department of Medical Cardiology, The General Infirmary,Leeds, U.K.

Heart failure constitutes an increasing health hazard withmajor demands on health care resources. Recent majoradvances in drug treatment have yet to be translated intoincreased survival of heart failure patients in the commu-nity at large. Failure of diagnosis is a major factor indelaying early and adequate treatment. Echocardiographyprobably provides the most reliable and inexpensive instru-ment to confirm the diagnosis and pinpoint the mechanicalcomponents of the syndrome.

The targets for therapeutic intervention may be categorized(i) haemodynamic, neuroendocrine and metabolic disorders(ii) symptoms and quality of life, (iii) morbidity and mor-tality risks. Symptoms and quality of life are the primeconcerns of the physician in the treatment in the individualpatient. Selection of anti-heart failure drugs used should bebased on knowledge of the impact on the pathophysiologi-cal disorders and on the morbidity and mortality risks.

Diuretics, vasodilators and ACE-inhibitors are now ac-cepted as standard treatment, particularly when used incombination. Controversy continues to surround the

efficacy of digitalis glycosides; they improve symptoms insome patients but their impact on morbidity and mortalityrisks is still uncertain. Even with standard treatments, maypractical therapeutic questions remain, one of which is whatis the most efficacious dose of each anti-heart failure drugwhich, when used in combination, will give the maximumimprovement in quality of life and greatest extension ofsurvival? Despite available treatment with diuretics, digi-talis, vasodilators and ACE-inhibitors, the morbidity andmortality risks of congestive heart failure remain high.None of these drug groups significantly modulates theexcessive excitation of the sympathoadrenal system, one ofthe two major neuroendocrine hazards of heart failure. Forthis reason, amongst the many newer drugs in develop-ment, the beta-adrenoceptor antagonists hold considerablepromise as the next step towards a more comprehensivetreatment of congestive heart failure.(Eur Heart J (1996); 17 (Suppl B): 43-56)

Key Words: Congestive heart failure, diagnosis, treatment,symptoms, survival.

Introduction

Knowledge of the basic pathophysiological processesand the mechanisms whereby they induce the clinicalexpressions of heart failure continues to increase,spurred on, not only by the development of new drugs,but also by increasing refinement of methods of evalu-ating their efficacy. In recent years, the major clinicalinterest in this field has centred on the results of formallarge-scale survival trials many of which — with variousdrugs, to a varying extent, and in a variety ofpatients — have demonstrated a reduction in the overallmortality risk. However, the hopes they raised must betempered by the widening gap between the knowledge sogained and its application to the treatment of theindividual patient in heart failure. The evidence suggests

Correspondence: S. H. Taylor, Aberford Court, Aberford, WestYorkshire, LS25 3AH, U.K.

that maximum therapeutic benefit in terms of amelior-ation of symptoms, improvement in quality of life,reduction in morbid events and extension of life-spanis achieved in only a small number of such patients.Moreover, the advances made in large-scale clinicaltrials have yet to be translated into a longer life-span inthe population at risk in the community at large (Fig. 1).Heart failure now afflicts over 1% of the general popu-lation and nearly 1 in 10 of the elderly and is continuingto increase in frequency in most industrial societies(Fig. 2fl\ This places considerable demands on thephysician and other health-care resources; 5% of allhospital admissions are for heart failure and 1 in 3patients are re-admitted within a year of discharge.Overshadowing all other considerations, however, is thesevere and detrimental impact of the symptoms of heartfailure on the quality of life of the patient.

The prime objective of the majority of trials ofdrug therapy in chronic heart failure has been directed

0195-668X/96/OB0043+14 $18.00/0 © 1996 The European Society of Cardiology

44 S. H. Taylor

4 6Years after CHF

10 4 6Years after CHF

10

Figure 1 Comparison of the age-adjusted survival rates after first diagnosis of congestiveheart failure in the periods 1948-74 ( ) and 1975-88 ( ). (From1", reproduced withpermission).

45-54 85-94

Figure 2 Incidence of clinical heart failure by age andsex: 36 year follow-up of the Framingham Study. (From1'1,reproduced with permission).

to their effects on survival but the gains in life-quality sofar recorded in the various trials have been less thanimpressive. The impact of therapy on mortality risk is ofprime concern in the global evaluation of drug therapy,but the physician facing the individual patient with heartfailure can only be concerned with the impact of treat-ment on symptoms and overall quality of life of the

patient. Whether such treatment will prolong their life orfail to do so will never be known in the case of theindividual. For this reason, it is beholden not only tore-examine continually and critically new pharmaco-therapeutic information derived from formal clinicaltrials, but also to determine how far such informationmay be applied to the far broader populations met inpractice than those specifically selected for finite clinicaltrials.

The ultimate treatment undoubtedly resides inprevention, but this is unlikely to reverse the increasingincidence of heart failure in the foreseeable future. Thephysician will therefore still have to contend with asyndrome which will come to his notice only when thepatients presents with symptoms i.e. at a relatively latestage of the syndrome in life-span terms. The earlier thatheart failure is detected with certainty, the better theprospects for retarding its natural history by optimumtreatment and, thus, the amelioration of symptoms andprolongation of survival'2'3'. The first consideration,therefore, is the precision of the diagnostic detection ofheart failure in routine clinical practice.

Diagnostic dilemmas in heart failure

The clinical diagnosis of heart failure in the later stagesof the syndrome is both highly specific and highlysensitive. For the experienced physician, the presence ofthe symptoms of breathlessness and fatigue, togetherwith the clinical signs of raised jugular venous pressure,pulmonary congestion, tachycardia with gallop rhythm,hepatomegaly and angle oedema are of sufficient diag-nostic validity to require little further evaluation. In

Eur Heart J, Vol. 17 Suppl B 1996

Comprehensive treatment of CHF 45

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Figure 3 Natural history of heart failure. (From1131, reproduced withpermission).

earlier stages of heart failure, however, when symptomsare likely to be nonspecific and accompanied by a dearthof physical signs, the clinical diagnosis is more open tofault and often missed. Studies in general practice havedisclosed that the diagnosis of heart failure may be inerror in up to 50% of the patients, even in those withsymptoms'4'51. Moreover, there is widespread under-investigation of patients with possible heart failure inthis environment161. The most reliable and relativelyinexpensive investigation to confirm the diagnosis ofheart failure, at least in patients with cardiac dilatationat rest, is undoubtedly provided by the echocardio-gram'71. It is also useful to describe the mechanicalcomponents of the syndrome, namely systolic or dias-tolic dysfunction, which are difficult to differentiatesolely on the basis of clinical signs and symptoms'8'91.Diuretics, positive inotropes, vasodilators and ACE-inhibitors are particularly useful in patients withpredominant systolic dysfunction. In contrast, beta-blocking drugs and calcium antagonists are of primevalue in diastolic dysfunction, the former augmentingdiastolic filling by slowing the heart rate and the latterby enhancing myocardial relaxation. Echocardiographynot only furnishes a valid and reliable confirmationof the diagnosis of established heart failure but alsoprovides a ready instrument to monitor therapeuticprogress1101. Unfortunately, its clinical utility in thisregard is still not widely appreciated, accounting for itsunder-utilization in open general practice1"1.

Therapeutic objectives in the treatment ofheart failure

The pharmacotherapeutic targets in heart failure mustbe considered in relation to the natural history of thesyndrome (Fig. 3)[l2il3]. Damage to the heart muscle or

work overload of the heart is immediately countered byintrinsic changes in the myocardium which attempt tosustain contractile activity. Initially, increased stretchof the cardiac myocytes enhances their sensitivity tocytosolic calcium and augments their contraction. How-ever, if overstretching is maintained, the reuptake ofcalcium by the sarcoplasmic reticulum is progressivelyimpaired with dire consequences not only for the con-tractile activity of the myocyte but also for its electricalstabilty114'151. At this point, when the failing ventriclecannot maintain its ouptut without permanent increasesin volume and pressure, many neuroendocrine reflexesare alerted, but predominantly those employingthe sympathoadrenal system and renin-angiotensin-aldosterone axis'16' 21]. Sympathoadrenal stimulation ofthe heart is at its most intense in the earliest stages ofheart failure, but the results of such stimulation arerapidly attenuated by the failure ('down-regulation')of myocardial beta-adrenoceptors'221. The role ofangiotensin is also complex. The direct and indirectfunctional consequences for the failing heart as a resultof genetically determined differences in angiotensin-converting enzyme activity due to the possession ofthe deletion geneotype (DD) are still unclear1231. Fromthe clinical veiwpoint, however, in the earliest stages ofheart failure, heightened neuroendocrine activity may besufficient to maintain the pumping performance of thedamaged heart. Eventually however, myocardial failureprogresses inexorably to the point at which, despite boththe intrinsic cardiac adaptations and the extrinsic neuro-endocrine activation, the pumped output of the heartis incapable of maintaining circulatory integrity andnutritional supply of the metabolically active tissues.These pathophysiological developments translate intodistinct, if overlapping, stages in the clinical presen-tation and hazardous consequences of heart failure.In the earliest stages, (New York Heart Association


46 S. H. Taylor

Classification I and Ha), with a paucity of symptoms orsigns, the immediate clinical hazards are small, althoughfirmly predictive of the future progression of thesyndrome. In the stage when cardiac dilatation andsymptoms ensue during exercise the main threat is thatof electrical instability of the damaged and overstretchedmyocardium and the precipitation of life-threateningarrhythmias (NYHA Class lib and Ilia). In the terminalstages of the syndrome, when symptoms are presenteven at rest, the heart is grossly dilated and accompaniedby all the traditional peripheral signs of 'congestiveheart failure' (NYHA Class Illb and IV).

The mechanisms responsible for the symptoma-tology of the syndrome are complex and complicated bythe fact that symptoms in patients with heart failure maynot quantitively correlate with changes in the haemo-dynamic, neuroendocrine or metabolic profiles of thepatient and there is wide and unpredictable vari-ability between these profiles and symptoms betweenpatients'241. The cardinal symptom of patients with con-gestive heart failure is their restricted exercise capacitywhich is primarily limited by breathlessness during fastexercise and by fatigue during slow exertion1251. Thesensation of breathlessness is accompanied by an abnor-mal increase in ventilation at any workload'26'271 and atany level of carbon dioxide production1281. The increasedventilation helps to maintain normal systemic arterialoxygenation despite pulmonary congestion and in-creased dead space*29'301. The sensation of breathlessnessis closely correlated with changes in the pulmonaryvascular pressures'3'1. It is also complexly associatedwith lung water, compliance and dead space and theincreased work of the respiratory muscles in terms ofboth force and rate, although the exact relationships andmechanisms involved remain to be clarified'321. In con-trast, fatigue is due to a wide variety of discordantdisorders including deconditioning of striated muscle'331,short-stepping gate'341, changes in the striated muscleand the micro-circulation'35-361, defective utilization ofmuscle metabolic substrates'371 and elevated energyexpenditure even at rest'381. Above all, the relationship ofsuch symptoms to the patients routine life-style adds afactor that only the individual physician can utilize toevaluate the impact of drug therapy.

Many trials are now investigating the influenceof drugs in the earlier stages of heart failure, but in thesestudies the objectives are primarily concentrated onlengthening life-span. But in the later stages of thesyndrome the prime objective of therapy is the amelio-ration of symptoms (Fig. 4)1391. This overview willtherefore concentrate on the goals of drug therapyand the clinical expectations of treatment in the latersymptomatic stages of the syndrome.

Major objectives of therapyThe first major objective of pharmacotherapy in thepatient in heart failure is correction or ameliorationof the haemodynamic, neuroendocrine and metabolicdisorders present, all of which are important determi-nants of the ultimate prognosis'40'411. Fortunately, the


Priority in therapeutic aims

NYHA Class

Figure 4 Clinical priority in therapeutic objectivesaccording to severity of heart failure.

group results of formal clinical trials of drug therapyare sufficiently uniform for the practising physician toassume with reasonable certainty the pharmacodynamicactivity of the anti-failure drugs prescribed.

The second major objective in the treatment ofheart failure is the reduction in the high morbidity andmortality risk of the syndrome. This has been the subjectof a number of pivotal trials'42^491. But, however attrac-tive the results of large-scale group trials of anti-heartfailure drugs, they impose considerable limitations whenattempting to apply them in clinical practice. Patientsincluded in formal prospective survival trials are oftenhighly selected and there is usually insufficient statisticalpower to validate sub-group analysis. Thus the numberof patients who particularly benefited, and as impor-tantly, the patients who did not benefit or who weredisadvantaged by the drug treatment under test, remainsunclear. This is highlighted by the fact that many studieshave included patients with widely different degrees ofdisability so that the averaged improvement is difficultto apply to any particular individual. The majority oftrials have also been relatively short-term, particularlywhen one considers the relative longevity of patientswith less severe heart failure. Ideally, the practisingphysician should attempt to mimic these results bymatching his patients with those included in the pub-lished trials and use the same medications and dosages.However, it is over-ambitious to expect that at best morethan a few physicians will adhere to such severe limita-tions on their clinical practice, partciularly when it isrealized that it will never be known if a treatmentprolongs or shortens life in the individual patient.

The third major, and most important, therapeu-tic objective for the practising physician is the amelio-ration of symptoms and improvement in quality of lifeof the individual patient with congestive heart failure.This overriding practical objective of drug treatment israrely given the attention it warrants. Just as it wouldbe inconceivable to use drugs that had not beenshown to have measurable effects on one or more of


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Figure 5 A perspective for adjudging clinical impact ofdrug therapy in heart failure.

the prime pathophysiological disorders in heart failure,so it would be clinically reprehensible to use drugswhich could not be expected to improve a patient'ssymptoms.

Considered against this background, there arethree ways by which the efficacy to the treatment ofcongestive heart failure may be monitored: by haemo-dynamic improvement, by attenuation of the heightenedneuroendocrine activity, and by improvement in thepatients symptoms and quality of life. Under the usualconditions of clinical practice, it is only the latter avenueof persistent monitoring which is possible. However,amalgamating the information from survival trials withthat directly obtained from the clinic, may crystalizefor the physician the benefits of each drug treatmenthe or she may expect in the patient with congestiveheart failure (Fig. 5). This overview will be particularlydevoted to this specific aspect, namely the impact ofdrug treatments on symptoms and survival prospects ofpatients with congestive heart failure.

Drug treatment of congestive heartfailure

Traditional treatments most widely used in the treat-ment of heart failure comprise diuretics, digitalis glyco-sides, vasodilators and ACE-inhibitors. Althoughconfirmation is awaited from other large-scale trials inprogress, the positive results of the GESICA (GrupoEspanol para el Seguimiento del Injerto Coronario)Trial also suggest that the anti-arrhythmic amiodaroneshould now be considered for inclusion in the routinedrug treatment of the syndrome'49'. Although it is stillundecided at what stage each drug should be com-menced, there is little doubt that in the later stages of thesyndrome (NYHA Classes III and IV) all five classes ofdrugs should be prescribed if the patient can toleratethem (Fig. 6). Multi-drug therapy has been shown to

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- Life-span

Figure 6 Schematic summary of the results of large scaletrials of drugs in patients in severe heart failure in terms ofthe inter-relationship of their impact on quality of life andlife-span; for explanation see text.

extend life-span in many patients in a number of large-scale prospective randomized clinical trials'42^*91; butthese trials have given no information on the mostefficacious balance of drug doses to be used. Likewise,there is no information on the proportionate effective-ness of different individual anti-heart failure drugs inrelieving symptoms, as multi-drug therapy is the ruleboth in practice and in clinical trials. The final prescrip-tion can ony be decided by the physician in eachindividual patient and only determined from the impactof such therapy on their symptoms.

Diuretics

There is a sound theoretical and practical basis for theuse of diuretics in the treatment of heart failure150"551.The increased diuresis and consequent reduction of theexpanded blood volume is accompanied by improve-ment in cardiac pumping performance due to the reduc-tion in both preload and afterload[56i57]. Although neverformally compared, it would appear that the thiazidesand loop diuretics produced directionally similarhaemodynamic changes which are maintained duringdynamic exercise157"591. Diuretic stimulation of renalrenin release and subsequent activation of the vasocon-strictor angiotensin and salt-retaining aldosterone mayoccur when large doses of diuretics are used, althoughthis appears to be less of a problem in the elderly heartfailure patient than in a younger subject'201. This isprobably of little clinical importance, however, as bothpotentially adverse effects are completely countered bythe ACE-inhibitors that the majority of patients withcongestive heart failure are prescribed'21'. Diuretics act-ing on the ascending limb of the loop of Henle in thenephron have long been the drug of choice in thetreatment of heart failure. Thiazides, are however, noless efficacious. Contrary to some clinical opinions, it is


48 S. H. Taylor

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Figure 7 Improvement in symptoms in patients with chronic heart failure after 4 weekstreatment with torasemide 5 or 10 mg daily. (From1651, reproduced with permission).

now clear that a combination of small doses of diureticsacting on different parts of the nephron are moreefficacious in terms of salt and water excretion thanlarger doses of a single compound'601. The combinedprescription of small doses of different diuretics alsopreludes the development of diuretic resistance to asingle drug*61'. The clinical utility of the diuretics hasbeen greatly extended by the development of compoundswith high absorption, high bioavailability and longduration of action'621.

The diuretics have undoubtedly achieved theirpre-eminent first-line role in the treatment of heartfailure based solely on their ability of relieve symptomsin the majority of patients to whom they are adminis-tered. In this regard they are the equal, or even superiorto all other currently available anti-heart failure drugsincluding the ACE-inhibitors[63]. The diuretic-inducedimprovement in symptoms is invariably associated witha substantial diuresis which is certainly the predominantand perhaps sole mechanism by which the diureticsattenuate symptoms and improve quality of life1641. Anumber of recent clinical trials have clearly defined thebenefits of diuretics on the symptom profile of patientswith congestive heart failure. The majority of informa-tion stems from studies with loop-diuretics. A double-blind trial with the loop diuretic torasemide (5 or 10 mgdaily in 119 patients with congestive heart failure)demonstrated a significant improvement in symptomsand clinical signs during 48 weeks of sustained treat-ment[62). Another double-blind placebo-controlled clini-cal trial of 4 weeks with the same loop diuretic alsodemonstrated a significant improvement in symptomsof breathlessness and peripheral oedema althoughcardiomegaly and hepatomegaly were less amenableto treatment (Fig. 7)[65]. A double-blind randomizedparallel design study in 120 patients with mild andmoderate heart failure treated with either furosemide or

NYHAII NYHA IIIFunctional state

Figure 8 Results of 4 weeks treatment with torasemide 5or 10 mg daily related to severity of heart failure assessedaccording to New York Heart Association FunctionalClassification (From1661, reproduced with permission.(• = better; 0=unchanged; n = l5 l ) .

torasemide demonstrated a significant improvement intheir symptomatic disability as judged by the New YorkHeart Association Classification1661. In this study, as inothers with furosemide, musolamine and bumetanide alldemonstrated that the clinical improvement was concen-trated in the more severely ill patients (Fig. 8). In allof these studies, diuretics were added to backgrounddigitalis therapy. In one study in untreated patientswith mild heart failure, furosemide induced a markedincrease in exercise capacity1671. Although there is noformal information on the influence of diuretic treat-ment on accepted quality of life variables in patientswith heart failure it is probably reasonable to accept



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Figure 9 Schematic illustration of the impact of diuretictreatment on the inter-relationship between quality of lifeand life-span in patients with different degrees of heartfailure.

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Figure 10 Schematic illustration of the impact of treat-ment with digitalis on the inter-relationship between qual-ity of life and life-span in patients with different degrees ofheart failure and the potential influence of other variables.

symptoms as surrogate representatives for changes inquality of life. On this basis there is little doubt thatdiuretics have a major impact on improving quality oflife in patients with chronic heart failure which isinversely related to the severity of the clinical syndrome(Fig. 9).

No major trial has been directed to ascertainingthe influence of diuretics on the morbidity and mortalityrisks of patients in severe heart failure (NYHA class IIIand TV). It is unlikely that such studies will be under-taken considering that diuretics are so firmly establishedas first-line drugs in symptomatic heart failure that themajority of physicians would find it ethically unaccept-able for diuretics to be excluded from any treatmentgroup. Although there is no substantive clinical trialevidence that diuretics reduce morbidity and extendsurvival of patients with congestive heart failure, itshould be remembered that in all the major survivaltrials in heart failure so far undertaken many of thepatients in all arms of the various trials received diureticsas well as the drug under test.

Positive ino tropes

For many physicians, digitalis glycosides together withthe diuretics, continue to remain a mainstay of thetreatment of symptomatic heart failure. The sympto-matic benefits conferred by digitalis may be less clear-cutthan those induced by the diuretics but this may be dueto their nearly universal combined prescription. Noformal large-scale clinical trial has been mounted toquestion this point and a number of smaller studieshave not shown completely convincing evidence of thesymptomatic benefits of digitalis therapy. Some studieshave indicated that the addition or withdrawal ofdigitalis has led to clinical improvement or deteriora-tion, respectively'68"75'. A major pharmacotherapeutic

drawback of digitalis is its narrow dose-responserelationship so that the fixed-dose selected in orderto avoid toxicity often falls short of the effectivetherapeutic range.

The effects of the digitalis glycosides on morbid-ity and mortality risks of patients with symptoms ofheart failure is unknown, but is now the subject of amajor clinical trial in North America in combinationwith diuretics, vasodilators and ACE-inhibitors. Shouldthe trial results indicate no particular prognosticbenefits, but no harm, then physicians will be left tomake the difficult individual decision as to whether toprescribe digitalis based entirely on the potential symp-tomatic benefits it may afford. They may be influencedin this regard by the finding that in a number of smallstudies the digitalis glycosides improved patients feelingsof well-being more than either placebo or even ACE-inhibitors (Fig. 10). But the future clinical popularity ofthe digitalis glycosides will undoubtedly be greatly influ-enced by the outcome of the large scale survival trialbeing undertaken in North America.

Many drugs with positive inotropic activity havefailed formal survival trials. However, a number haveclearly demonstrated a beneficial impact on symptomsand quality of life of patients with severe congestiveheart failure despite the failure to prolong sur-vival'72'76'771. However, none has yet achieved sufficientoverall efficacy to be accepted into clinical practice,which leaves the digitalis glycosides as the only positiveinotrope than is widely prescribed for heart failure.

Vasodilators

The introduction of the vasodilator era, some 25 yearsago, constituted the second major advance in the treat-ment of heart failure of recent times'78'791. Their haemo-dynamic effectiveness and clinical efficacy in patients


50 5. H. Taylor

with heart failure is now beyond question. However, theterm 'vasodilators' encompasses a wide range of differ-ent pharmacological groups which have widely diverseactivities in the peripheral and central circulations.These range from the earliest alpha-1 adrenoceptorantagonists through such groups as the direct act-ing peripheral vasodilators, nitrates, hydralazine andminoxadil and other imidazolines, the slow calcium-channel antagonists which only dilate the systemic arte-riolar resistance vessels, dopaminergic agonists such asibopamine, atrial natriuretic peptidase inhibitors such ascandoxidril, flosequinan, with combined arteriolar andvenodilator activities, and potassium-channel activatorswith similar combined vasodilator effects. Many drugswhich dilate the systemic resistance and capacitancevessels also have other significant circulatory activities.For example, flosequinan has some direct positive ino-tropic activity, the calcium antagonists have negativeinotropic effects and ibopamine has diuretic activity.Thus, the vasodilators comprise a heterogenous groupof drugs with the only common property being dilata-tion of the vessels of the systemic vascular system. Allvasodilators have the universal property of reducingcardiac afterload and/or the preload, and some, such asthe nitrates, have dose-dependent activity; at low dosesnitrates dilate the systemic venous capacitance systemand in high doses also dilate the arterial resistancevessels. As a heterogenous group, vasodilators improvethe haemodynamic profile of the patients with heartfailure but their individual effects on the neuroendocrineand metabolic profiles are less well documented.

The majority of vasodilators have been shown toattenuate symptoms and improve exercise capacity to agreater or lesser extent in patients with symptomaticheart failure. In many the effects are dose-dependent andwith many, pharmacodynamic tolerance is a problem,e.g. nitrates, alpha-1 adrenoceptor antagonists. More-over, many induce side-effects, particularly hypotension,and particularly in the elderly. There are few formalstudies of the influence of any of the vasodilators on thequality of life of patients with heart failure. This makesit difficult to predict the impact of the addition of avasodilator to other anti-heart failure treatments of thequality of life of a patients with symptomatic heartfailure. There is some evidence, however, from twolarge-scale studies, that additional clinical benefitmay be expected when a direct-acting vasodilator suchas flosequinan is added to conventional treatmentsincluding ACE-inhibitors[80>8l].

The influence of vasodilators on morbidity andsurvival has been the subject of two large-scale studies.The first, a placebo-controlled comparative trial, un-equivocally demonstrated that fixed doses of hydralazineand isosorbide dinitrate (ISDN) added to diuretics anddigitalis extended life-span in patients with moderatecongestive heart failure (NYHA III) compared toplacebo, although alpha-1 adrenoceptor blockade withprazosin did not (Fig. 6)[42]. A more recent multi-centreplacebo-controlled trial with two doses of flosequinandemonstrated no improvement in survival with either

dose and the trial was prematurely terminated with thehigher dose of drug used resulted in increased mortalityrisk'801. Thus it would appear that irrespective of theirability to induce an improvement in the haemodynamicprofile and, in many instances, improvement in patients'symptoms, it cannot be assumed that all drugs withvasodilator activity will increase the life-span of patientswith symptomatic heart failure. This can only be ascer-tained by subjecting each drug to a rigorous formalclinical trial.

There are two aspects of particular clinicalimportance from the practical view point. The V-HeFTI trial demonstrated some extension in life-span forthe group of patients as a whole, but the sample sizesof patients precluded the demonstration of benefit ordisadvantage of treatment in any particular subgroupdefined by age, gender, aetiology or other objectivevariable'421. A practical therapeutic drawback in apply-ing the result of the V-HeFT I trial is that vasodilatorshydralazine and ISDN were given in a fixed dose, aprescription which may not be suitable for all patients,particularly the elderly.

A CE-inhibitors

The introduction of the ACE-inhibitors was the thirdmajor drug development which has done much to revo-lutionize the treatment of congestive heart failure inrecent years. They are considered an obligatory additionto diuretics in the drug therapy of congestive heartfailure for a number of reasons. They improve leftventricular pumping performance by directly reducingleft ventricular afterload through dilatation of thesystemic arteriolar resistance vessels. How much ofthis dilatation results from reduction of circulatingangiotensin-U and how much from reduction of angio-tensin in the vascular wall is unknown. These directvasodilator effects are augmented by (a) the reduction ofsympathoadrenal activity which is a result of modu-lation of the central vasomotor centre tone responsiblefor sympathoadrenal discharges; and (b) blockadingangiotensin-II receptors in sympathetic nerve terminalsresponsible for enhancing the release of noradrenaline.The ACE-inhibitors are also of direct clinical utility inthat they blockade one of the major disadvantagesof concomitant treatment with diuretics, namely therelease of renin and activation of angiotensin-II andlater the increased stimulation of aldosterone release.During long-term administration the ACE-inhibitorscan also be expected to reduce left ventricular hyper-trophy, particularly in patients with the ACE genedeletion allele1821. ACE-inhibitors undoubtedly improvesymptoms and quality of life in patients with severeheart failure {Fig. 6). However, in many instances, thesebenefits are relatively modest and less than that achievedwith diuretics. ACE-inhibitors have all been shown toimprove exercise capacity but in none of the reportedstudies did the patients' exercise tolerance return tonormal.



Undoubtedly however, the major clinical interestin the use of ACE inhibitors in heart failure resides intheir ability to improve morbidity and mortality risk inpatients with moderate and severe heart failure143"^'.The major improvement in mortality risk exerted by theACE-inhibitors is predominantly related to retardationof the progression to terminal heart failure; the risk ofsudden death, a major contributor to death in patientswith severe heart failure appears to be little influencedby ACE-inhibitor treatment. The various mechanismsby which the ACE-inhibitors retard the progressionof heart failure remains to be clarified but certainlyinvolves remodelling of the ventricular myocardium,improvement in peripheral blood flow, reduction insympathodrenal tone and many other synergistic influ-ences. In patients with heart failure the ACE-inhibitorscaptopril and ramipril have been demonstrated toreduce significantly the risk of further coronary events.This is of crucial importance considering that in patientswith congestive heart failure the incidence of myocardialinfarction is increased by up to six times.'1'. All ACE-inhibitors are effective in improving symptoms inpatients with congestive heart failure particularly whenused in combination with other anti-heart failure drugs,e.g. the diuretics. Side effects, particularly hypotensionand non-productive cough, limit their prescription in asmall proportion of patients and with the drugs cur-rently available there is no cross-independence of eitherefficacy for adverse reactions. Despite the fact thatACE-inhibitors cannot be tolerated in all patients withcongestive heart failure, together with the diuretics, theyform the first-line drugs of choice in the majority.

From the theoretical viewpoint a number ofmajor issues await solution. There is increasing evidencethat in some patients with congestive heart failure thereis a gradual escape from ACE-inhibition with time.Whether this is a universal phenomenon, whether it isdue to too small dose or poor compliance, or whether itafflicts only a particular patient subgroup is unknown.The optimum dose to prolong survival is also unknownand it is also unclear whether the effect on survivalis age-dependent. For the practising physician theseissues are of importance but only of theoretical interest.Current evidence would suggest that ACE-inhibitorsshould be prescribed, in combination, with diuretics inthe highest dose the patient with heart failure cantolerate without side-effects. Unfortunately, althoughthe majority of physicians are aware of the improve-ment in survival prospects in heart failure affordedby ACE-inhibitors, it is only a minority of patients thatare afforded such treatment, at least in the UnitedKingdom'84' and many are treated with doses outside therange associated with a reduction in mortality risk'851.

Anti-arrhythmics

The efficacy of anti-arrhythmic drugs in the treatment ofheart failure has long been a matter of contention. Incongestive heart failure, ventricular arrhythmias are

frequent and associated with increased mortalityrisks'861. Sudden death is a cause of demise in perhapsone in three patients with congestive heart failure.Doubts were raised about the role of anti-arrhythmicdrugs in the routine treatment of heart failure by theresults of the CAST trial'871. The GESICA trial, how-ever, clearly points to the potential benefit specifically ofamiodarone in the routine treatment of severe heart-failure'49'. In this prospective randomized trial in whichamiodarone was added to diuretics, digitalis and ACE-inhibitor, the drug significantly reduced mortality. Fur-ther confirmatory studies are undoubtedly essential, anda further large-scale multicentre trial is now underway inEurope (EMIAT) to address this point albeit in post-infarction patients'88'. The results of the GESICA trialtaken together with the results of many smaller studies,are persuasive enough for the physician to consider theprescription of amiodarone in all patients with sympto-matic heart failure (NYHA Class HI and IV) (Fig. 6).Unexpectedly, in the GESICA trial, there was a signifi-cant improvement in the functional capacity of thepatients on amiodarone, the reasons for which areobscure'491.

Pharmacotherapy of heart failure — thenext step

Whatever their impact on the various surrogate end-points of improvement, such as the haemodynamic,neuroendocrine and metabolic profiles, the final arbitorsof acceptance of a drug for the treatment of heart failureare its ability to improve symptoms and quality of life,and extend lifespan. Many compounds have been devel-oped or the treatment of heart failure, and many haveimproved various aspects of the haemodynamic, neuro-endocrine, metabolic and symptom profiles of patientsin heart failure. Such preliminary studies in small groupsof highly selected patients are essential to define theinitial pharmacotherapeutic potentials of a compoundbut they can never replace formal survival trials. Onlywhen such studies are completed and the drug in ques-tion has been shown beyond reasonable doubt to extendlife-span, can it be recommended for universal prescrip-tion in the treatment of heart failure. However, thisshould never preclude the individual physician's decisionto use a drug in the terminal phase of heart failure whichmay improve the patients symptoms without guaranteethat it will extend life-span.

The drug treatment of congestive heart failurehas undergone substantial evolution during the past fewyears but when considered in the overall context of thehigh morality risk of the syndrome, despite such treat-ment, there is much further to go (Fig. 11). Many drugsare now under scrutiny and opinions differ as to thosewhich hold most promise — certainly few will becomeestablished in the routine drug treatment of heart failure.Those under test embrace many novel pharmacologicalapproaches targeted at specific pathophysiological


52 S. H. Taylor

100

0-75 -

0-50 -

.3a<o

•J3CO

PL,

0-25 -

12 18 24 30 36 42Time (months)

48 64 60 68

Figure 11 Cumulative suvival curves in patients with congestive heart failure treatedwith diuretics, digitalis, vasodilators and ACE-inhibitors; results for V-HeFT I and II.( = hydralazine-isosorbide (V-HeFT I); =hydralazine-isosorbide dini-trate (V-HeFT II); = placebo (V-Heft I); =prazosin (V-HeFT I);^^—=hydralazine-isosorbide dinitrate+enalapril (V-HeFT II)).

disorders in heart failure. The heightened activity of thesympathoadrenal system furnishes one of the two majorneuroendocrine targets for therapy in heart failure,particularly as it carries such sinister prognostic impli-cations'891. For this reason, beta-adrenoceptor antago-nists, long regarded as totally contra-indicated, are nowamongst the major contenders for acceptance in thedrug therapy of congestive heart failure. There are anumber of theoretical and practical reasons for thischange in cardiological opinion. It is now recognizedthat however vital in the acute situation, chronic sym-pathetic stimulation of the failing heart is deleteriousnot only from the direct mechanically induced oxygen-wasting effects, but also from the electrical instabilityprecipitated by such stimulation. Excessive stimulationalso results in progressive deterioration of myocardialbeta-adrenoceptor sensitivity, which leads to diminish-ing inotropic support of the heart. Chronically raisedplasma catecholamines are also directly injurious to themyocardium; such sympathetically induced cardiomy-opathy almost certainly involves calcium overload1901

and the generation of harmful free radicals19'1. Thesesympathetically mediated hazards to the failing heartmay obviously be countered by beta-adrenoceptorblockade, particularly non-selective blockade of bothbeta-1 and beta-2 receptors. At a practical level the

correction of myocardial wall asynergy and high heartrate, and suppression of release of renal renin by beta-blockade, may all contribute to benefit in the patientswith heart failure. Sympathoadrenal activity is probablyalso intimately involved in the genesis of life-threateningventricular arrhythmias particularly, in patients withcoronary heart disease1921. Ventricular tachycardia iscommon in ischaemic heart failure and sudden deathaccounts for more than a third of the deaths in heartfailure1931; beta-adrenoceptor antagonists are an obviousremedy1941. These many facets of sympathoadrenalstimulation of the heart may mean that beta-blockadehas an important role to play in attenuating thesepotentially deleterious consequences of heart failure.Moreover, coronary heart disease is by far the common-est cause of congestive heart failure in Western society,and sub-group analysis of post-infarction beta-blockertrials has shown that the greatest reductions in mortalitywere seen in patients with clinical evidence of heartfailure*95'961.

The evidence from clinical studies impressive ifnot entirely conclusive. The majority of the randomizeddouble-blind, controlled studies have demonstratedhaemodynamic improvement, and in many an improve-ment in symptoms and exercise capacity was recordedalthough neither of these surrogate endpoints was



substantial197 " ' . Although the many studies reporteddiffered in design, beta-blocking drug prescribed, dura-tion of treatment and patient characteristics, they fairlyconsistently demonstrated an improvement in symptomsand exercise capacity, and attenuation of the elevatedneuroendocrine profile. Moreover, the late with-drawal of beta-blockers usually resulted in clinical andhaemodynamic deterioration t'oo-ioi]

There are, however, two major hurdles to beovercome before these drugs can be advised or theroutine treatment of patients with heart failure. First, nolarge-scale valid clinical trial has demonstrated beyondreasonable doubt that beta-blocking drugs improvesymptoms and quality of life and do not incur seriousside-effects in some sub-groups of patients with conges-tive heart failure. Second, their impact on morbidity andmortality risks are unproven. In the BHAT post-infarction trial the greatest reductions in mortality wereseen in patients with mild or moderate heart failure butthe trial specifically excluded patients with congestiveheart failure (NYHA Class IV) and the finding arosefrom post hoc sub-group analysis'951. A trial with meto-prolol in 383 patients with dilated cardiomyopathy didnot achieve a statistically significant reduction in deathsin the active treatment group compared to those onplacebo'1021. Zamoterol in 516 patients with congestiveheart failure of mixed aetiology was associated with asignificant increase in mortality11031. More recently, theSWORD trial with d-sotalol in 3000 patients withpost-infarction left ventricular dysfunction was discon-tinued because an interim analysis revealed a 39%death-rate on the beta-blocker compared to 20% in theplacebo group. These discouraging results must cautionagainst speedy acceptance of beat-blocking drugs as aconventional addition to currently available agents, par-ticularly as they have little clinically discernible impacton symptoms. For these reasons it is imperative that theeffect of these drugs, both on quality of life and on thehigh mortality risk of patients with congestive heartfailure, be clearly determined as the next step to theirrecommendation for routine clinical practice.

From the practical viewpoint, a number of im-portant clinical considerations arise. The first relates tothe functional disability of the patients to whom thesedrugs may be administered. In the majority of studiesreported, the patients have been those with mild ormoderate symptomatic disability, namely New YorkHeart Association Classification II or III. This is acrucial consideration as the administration of beta-blocking drugs, even in very small doses, to patients withsevere heart failure (NYHA Class IV) has been shownto result in further depression of cardiac dysfunc-tion'104'1051. For this reason, the clinical results of beta-blockade may differ widely between patients withdifferent degrees of functional disability; possible benefitin patients with milder degrees of heart failure cannotbe translated into similar benefits in more severely illpatients. None of the reported trials have includedelderly patients. As the incidence of heart failure isage-dependent and as the elderly are more sensitive to

the cardiovascular consequences of beta-blockade, thisglaring pharmacotherapeutic omission awaits clarifi-cation. With regards to the aetiology of the heart failure,it is important to emphasize that the majority of thestudies so far reported with a range of beta-blockingdrugs have predominantly been concerned with theirefficacy in patients with idiopathic dilated cardiomy-opathy196"981. Such patients comprise the minority ofthose presenting with heart failure in clinical practice. Afurther point of practical clinical importance relates toconcomitant treatment. In all the clinical trials so farreported, beta-blocking drugs have only been adminis-tered to patients already pre-treated with diuretics,digitalis and often a vasodilator; they have never beengiven as first-line treatment. The starting dose of beta-blocking drug and dose titration also requires particularattention. It would appear from published studies thatthe clinical efficacy of beta-blockade in patients withsymptomatic heart failure is best achieved when theseare introduced in a low dose and only gradually titratedunder close clinical monitoring. Unfortunately, there isno ready clinical test with which to monitor suchprogress. The primary reason for the administration ofbeta-blocking drugs in the treatment of heart failure is toreduce morbidity and extend life-span; in the trials so farreported, beta-blockade has had no substantial effect onsymptoms.

Considerable debate has concerned the efficacystature of different beta-blocking drugs in the treatmentof severe heart failure, but with the paucity of datacurrently available it is a question still without a definiteanswer. The first generation of these drugs, the arche-type of which was propanolol, caused profound depres-sion of cardiac pumping, not only due to their negativeinotroptic activity but also due to the reflexly increasedperipheral vascular resistance and aortic impedancewhich further depressed cardiac function. The secondgeneration of these drugs, archetypes of which areatenolol and metoprolol, are relatively beta-I selectivebut in the doses used in clinical practice this selectivityis frequently eroded to the point of extinction. The latestgeneration are those which possess peripheral vasodilat-ing activities in addition to their prime function ofbeta-adrenoceptor blockade. The vasodilatation is de-signed to offset the increase on systemic vascular resist-ance and further depression of cardiac function. In thisregard, therefore, it is reasonable to argue that this thirdgeneration of beta-adrenoceptor antagonists, namelythose with ancillary vasodilating activity, may well turnout to be the beta-blocking drugs of choice should thiscategory of drug eventually be accepted as an adjunct toother conventional treatments of heart failure.

At the present time many outstanding questionsof practical importance remain to be answered beforethese drugs can be safely recommended for general usein the treatment of congestive heart failure. Not leastamongst these questions are the age of the patient to betreated, the aetiology of the heart failure, the degree offunctional disability and the adequacy of concomitantanti-failure treatment. Hopefully, the extensive clinical


54 S. H. Taylor

research programmes and large-scale survival trials nowunderway with a variety of beta-blocking drugs willfurnish sufficient positive evidence for them to beaccepted as yet another important pharmacotherapeuticstep towards the goal of a comprehensive treatment ofthe patient with congestive heart failure.

References[1] Kannel WB, Ho K, Thorn T. Changing epidemiological

features of cardiac failure. Br Heart J 1994; 72: (Suppl): S3-9.[2] The SOLVD Investigators. Effect of enalapril on mortality

and the development of heart failure in asymptomaticpatients with reduced left ventricular ejection fractions.N Engl J Med 1992; 327: 685-91.

[3] Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ,Cuddy TE. Effect of captopnl on mortality and morbidity inpatients with left ventricular dysfunction after myocardialinfarction. Results of the survival and ventricular enlargementtrial N Engl J Med 1992; 327: 669-77.

[4] Remes J, Miettinen H, Reunanen A, Pyorala K. Validity ofclinical diagnosis of heart failure in primary health care. EurHeart J 1991; 12- 315-21.

[5] Wheeldon NM, MacDonald TM, Flucker CJ, McKendrickAD, McDevitt DG Struthers AD. Echocardiography inchronic heart failure in the community. Q J Med 1993; 86:17-23.

[6] Clarke (CW, Gray D, Hampton JR. Evidence of inadequateinvestigation and treatment of patients with heart failure. BrHeart J 1994; 71: 584-7.

[7] Albin G, Rahko PS. Comparison of echocardiographicquantification of left ventricular ejection fraction to radio-nuclide angiography in patients with regional wall motionabnormalities. Am J Cardiol 1990; 65: 1031-2.

[8] Gaasch WH. Diagnosis and treatment of heart failure basedon left ventricular systolic or diastolic function. JAMA 1994;271: 1276-80.

[9] Thomas JD, Weyman AE. Echocardiographic Dopplerevaluation of left ventricular diastolic function. Physics andphysiology. Circulation 1991; 84: 977-90.

[10] Dargie HJ, McMurray JJV. Diagnosis and management ofheart failure. Br Med J 1994; 308: 321-8.

[11] Francis CM, Caruana L, Kearney P, Love M, Sutherland GR,Starkey IR, Shaw TRD, McMurray JJV. Open accessechocardiography in management of heart failure in thecommunity. Br Med J 1995; 310: 634-6.

[12] Taylor SH, Silke B, Nelson GIC. Principles of treatment ofleft ventricular failure. Eur Heart J 1982; 3 (Suppl D): 19-43.

[13] Packer M, Pathophysiology of chronic heart failure. Lancet1992; 340: 88-92.

[14] Parmley WW, Chatterjee MB. Congestive heart failure andarrhythmias: an overview. Am J Cardiol 1986; 57: 34B-37B.

[15] Campbell RWF. Electrophysiological disturbances in heartfailure. Br Heart J 1994; 72 (Suppl): S31-5.

[16] Thomas J, Marks B. Plasma norepinephrine in congestiveheart failure. Am J Cardiol 1978; 41: 233^»3.

[17] Goldsmith S, Francis GS, Cowley A, Levine T, Cohn J.Increased plasma anginine vasopressin level in patients withcongestive heart failure. J Am Coll Cardiol 1983; 1: 1385-90.

[18] Cody R, Atlas S, Laragh J, Kubo SH, Covit AB, Ryman KS.Atrial natriuretic factor in normal subjects and heart failurepatients. J C1in Invest 1986; 78: 1362-74.

[19] Francis GS. Neuroendocrine manifestations of congestiveheart failure. Am J Cardiol 198S; 62: 9A-13A.

[20] Rieggar AJG. Neuroendocrine excitation in heart failure. BrHeart J 1994; 72 (Suppl): S28-30.

[21] Sigurdsson A, Amtorp O, Gundersen T, Nilsson B, Remes J,Swedberg K. Neurohormone activation in patients with mildor moderately severe congestive heart failure and the effects oframipril. Br Heart J 1994; 72- 422-7.

[22] Bristow MR, Herhberger RE, Port JD. Beta-adrenergicpathways in non-failing and failing human ventricularmyocardium. Circulation 1990; 82 (Suppl 1): 12-25.

[23] Morgan K. Diverse factors influencing angiotensin metab-olism during ACE inhibition; insights from molecular biologyand genetic studies. Br Heart J 1994; 72 (Suppl): 3-10.

[24] Poole-Wilson PA. Origin of symptoms in patients withchronic heart failure. Eur Heart J 1988; 9 (Suppl H): 49-53.

[25] Coats AJS, Clark AL, Piepoli M, Volterrani M, Poole-WilsonPA. Symptoms and quality of life in heart failure: the musclehypothesis. Br Heart J 1994; 72 (Suppl): S36-39.

[26] Rubin SA, Brown HV. Ventilation and gas exchange duringexercise in severe chronic heart failure. Am Rev Resp Dis1984; 129 (Suppl): S63-S64.

[27] Sullivan MJ, Higginbothman MB, Cobb FR. Increased exer-cise ventilation in patients with chronic heart failure; intactventilatory control despite haemodynamic and pulmonaryabnormalities. Circulation 1988; 77: 552-9.

[28] Buller NP, Poole-Wilson PA. Mechanism of the increasedventilatory response to exercise in patients with chronic heartfailure. Br Heart J 1990; 63: 281-3.

[29] Rubin SA, Brown HV, Swan HJC. Arterial oxygenation andarterial oxygen transport in chronic myocardial failure at rest,during exercise and after hydralazine treatment. Circulation1982; 66: 143-8.

[30] Clark AL, Coats AJS. Mechanisms of increased ventilation inchronic heart failure. Eur Heart J 1992; 13: 1698-708.

[31] Franciosa JA, Leddy CL, Wilen M, Schwartz DE. Relationbetween haemodynamic and ventilatory responses in deter-mining exercise capacity in severe congestive heart failure. AmJ Cardiol 1984; 53: 127-34.

[32] Clark AL, Coats AJS. Usefulness of arterial blood gas esti-mation during exercise in patients with chronic heart failure.Br Heart J 1994; 72- 528-30.

[33] Buller NP, Jones D, Poole-Wilson PA. Direct measurement ofskeletal muscle fatigue in patients with chronic heart failure;Br Heart J 1991; 65: 20-^.

[34] Davies SW, Grieg CA, Jordan SL, Grieve DW, Lipkin DP.Short-stepping gait in severe heart failure. Br Heart J 1992; 68:469-72.

[35] Lipkin DP, Jones DA, Round JM, Poole-Wilson PA. Abnor-malities of skeletal muscle in patients with chronic heartfailure. Int J Cardiol 1988; 18: 187-95.

[36] Drexler H, Riede U, Munzel T, Konig H. Alterations ofskeletal mucle in chronic heart failure. Circulation 1992; 85:1751-9.

[37] Massie B, Conway M, Yonge R, Frostick BM, Ledingham J,Sleight P, Radda G, Rajagopalan B. Skeletal muscle metab-olism in patients with congestive heart failure; relation toclinical severity and blood flow. Circulation 1987; 76: 1009-19.

[38] Riley M, Elborn JS, McKane WR, Bell N, Stanford CF,Nicholls DP. Resting energy expenditure in chronic heartfailure. Clin Sc. 1991; 80: 633-9.

[39] Cleland JGF, Dutka DP. Optimising heart failure pharmaco-therapy: the ideal combination. Br Heart J 1994; 72: (Suppl):S73-97.

[40] Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D,Francis GS et al Plasma norepinephrine as a guide toprognosis in patients with chronic congestive heart failure.N Engl J Med 1984; 311: 819-23.

[41] Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen I, for theCONSENSUS Trial Study Group. Hormones regulating car-diovascular function in patients with severe congestive heartfailure and the relation to mortality. Circulation 1990; 82:1730-6.

[42] Cohn JN, Archibald DG, Ziesche S. Effect of vasodilatortherapy on moartality of chronic congestive heart failure:results of a Veterans Administration cooperative study (V-HeFT). N Engl J Med 1986; 314: 1547-52.

[43] CONSENSUS (Cooperative North Scandinavian EnalaprilSurvival Study) Trial Study Group. Effects of enalapril onmortality in severe congestive heart failure. N Engl J Med1987; 316: 1429-35.



[44] Cohn JN, Johnson G, Ziesche S. A comparison of enalaprilwith hydralazine — isosorbide dinitrate in the treatent ofchronic congestive heart failure. N Engl J Med 1991; 325:303-10.

[45] SOLVD (Studies of Left Ventricular Dysfunction) Investiga-tors. Effect of enalapril on survival in patients with reducedleft ventricular ejection fractions and congestive heart failure.N Engl J Med 1992; 325: 293-302.

[46] SOLVD (Studies of Left Ventricular Dysfunction) Investiga-tors. Effect of enalapril on mortality and the development ofheart failure in asymptomatic patients with reduced left ven-tricular ejection fractions. N Engl J Med 1992; 327: 685-91.

[47] Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ,Cuddy TE et al. Effect of captopril on mortality and morbid-ity in patients with left ventricular dysfunction after myocar-dial infarction. N Engl J Med 1992; 327: 669-77.

[48] AIRE (Acute Infarction Ramipril Efficacy) InvestigatorsEffect of ramipril on mortality and moridity of suvivors ofacute myocardial infarction with clinical evidence of heartfailure. Lancet 1993; 342: 821-8.

[49] Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR,Curiel R. Randomised trial of low-dose amiodarone in severecongestive heart failure. Lancet 1994; 344. 493—8.

[50] Abraham AS. Diuretics and intracellular cations. Drugs 1986;31 (Suppl4): 109-11.

[51] Brater DC. Pharmacokinetics of loop diuretics in congestiveheart failure. Br Heart J 1994; 72 (Suppl): S40-43.

[52] Taylor SH, Storstein L. Diruetics in the treatment of heartfailure. Herz 1983; 8: 11-22.

[53] Taylor SH. Diuretics in heart failure; some knowns andunknowns. J Cardiovasc Pharmacol 1993; 22 (Suppl 3).540-50.

[54] Taylor SH. Efficacy of diuretics in chronic heart failure. ProgPharmacol Clin Pharmacol 1995; 9: 91-103.

[55] Taylor SH. Refocus on diuretics in the treatment of heartfailure. Eur Heart J 1995; 16 (Suppl F): 7-15.

[56] Raftery EB. Haemodynamic effects of diuretics in heartfailure. Br Heart J 1994; 72 (Suppl): S44-^t7.

[57] Verma SP, Silke B, Reynolds G, Muller P, Frais MA, TaylorSH. Effects of bumetamide on systemic haemodynamics andleft ventricular volume in acute and chronic heart failure. Br JClin Pharmacol 1978; 24: 21-32.

[58] Stampfer M, Epstein SE, Beiser D, Braunwald E. Haemody-namic effects of diuresis at rest and during intense uprightexercise in patients with impaired cardiac function. Circula-tion 1968; 37: 900-11.

[59] Wilson JR, Reichek N, Dunkman WB, Goldberg S. Effect ofdiuresis on the failing left ventricle in man. Am J Med 1981;70: 234-9.

[60] Knauf H, Mutschler E. Functional state of the nephron anddiuretic dose-response — rationale for low-dose combinationtherapy. Cardiology 1994; 84 (Suppl 2): 18-26.

[61] Brater DC. Resistance to loop diuretics; why it happens andwhat to do about it. Drugs 1985; 30: 427-43.

[62] Achhammer I. Long-term efficacy and tolerance of torasemidein congestive heart failure. Prog Pharmacol Clin Pharmacol1990; 8 (Suppl): 127-36.

[63] Richardson A, Byliss J, Scriven AF. Double-blind comparisonof captopril alone against frusemide plus amiloride in mildheart failure. Lancet 1987; 2: 709-11.

[64] Silke B. Diuretic induced changes in symptoms and quality oflife. Br Heart J 1994; 72 (Suppl): S57-62.

[65] Stauch M, Stiehl L. Controlled double-blind clinical trial ofthe efficacy and tolerance of torasemide in comparison withfrusemide in patients with congestive heart failure. ProgPharmacol Clin Pharmacol 1990; 8: 121-6.

[66] Dusing R, Piesche L. Second-line therapy of congestive heartfailure with torasemide. Prog Pharmacol Clin Pharmacol1990; 8 (Suppl): 105-20.

[67] Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole-Wilson P. Untreated heart failure; clinical and neuroendocrineeffects of introducing diuretics. Br Heart J 1987; 57: 17-22.

[68] Lee DCS, Johnson RA, Bingham JB et al. Heart failure inoutpatients: a randomized trial of digoxin versus placebo.N Engl J Med 1982; 306: 699-705.

[69] Taggart AJ, Johnston GD, McDevitt DG. Digoxin with-drawal after cardiac failure in patients with sinus rhythm.J Cardiovasc Pharmacology 1983; 5: 229-34.

[70] Aronow WS, Starling I, Etienne F. Lack of efficacy of digoxinin treatment of compensated congestive heart failurewith third heart sound and sinus rhythm in elderly patientsreceieving diuretic therapy. Am J Cardiol 1986; 58: 168-9.

[71] Guyatt GH, Sullivan MJJ, Fallen EL et al. A controlled trialof digoxin in congestive heart failure. Am J Cardiol 1988; 61:371-5.

[72] DiBianco R, Shabetai R, Kostuk W et al. A comparison oforal milnnone, digoxin and their combination in the treatmentof patients with chronic heart failure. N Engl J Med 1989; 20:677-83.

[73] Fleg JL, Rothfeld B, Gottlieb SH. Effect of maintenancedigoxin therapy on aerobic performance and exercise leftventricular function in mild ot moderate heart failure due tocoronary artery disease: a randomized, placebo-controlledcrossover trial J Am Coll Cardiol 1991; 17: 713-51.

[74] Uretsky BF, Young JB, Shahidi FE, Yellen LG, HarrisonMC, Jolly KM. Randomized study assessing the effect ofdigoxin withdrawal in patients with mild to moderate chroniccongestive heart failure- results of the PROVE trial. J Am CollCardiol 1993; 22: 955-62.

[75] Packer M, Gheorghiade M, Young JB et al. Withdrawal ofdigoxin from patients with chronic heart failure treated withangiotensin-converting enzyme inhibitors. N Engl J Med1993; 329: 1-7.

[76] Packer M, Carver JR, Rodenheffer RJ. Effect of oral milri-none on mortality m severe chronic heart failure N Engl JMed 1991; 325: 1468-75.

[77] Cowley AJ, Skene AM. Treatment of severe heart failure;quantity or quality of life? A trial of enoximone. Br Heart J1994; 72: 226-30.

[78] Majid PA, Sharma B, Taylor SH. Phentolamine for vasodila-tor treatment of severe heart failure. Lancet 1971; ii: 719-24.

[79] Cohn JN, Franciosa JA. Vasodilator therapy of cardiacfailure. N Engl J Med 1977; 297: 27-31 and 24-58.

[80] Pitt B and the REFLECT II Study Group A randomisedmulti-centre double-blind placebo controlled study of theefficacy of Flosequinan in patients with chronic heart failure.Circulation 1991, 84 (Suppl II): 1-311).

[81] Massie BM, Berk MR, Brozenas S. Can further benefit beachieved by adding a vasodilator to triple therapy in conges-tive heart failure? Circulation 1992; 86 (Suppl I): 1-64.

[82] Raynolds MV, Bristow MR, Bush EW, Abraham WT.Angiotensin-converting enzyme DD genotype in patients withischameic or idiopathic dilated cardiomyopathy. Lancet 1993;342: 1073-5.

[83] Parmley WW, Chattergee K. Congestive heart failureand arrhyhmias — an overview. Am J Cardiol 1986; 57:34B-37B.

[84] McMurray J, Hart W, Rhodes G. An evaluation of thecost of heart failure to the National Health Service In UK..Br Med Econ 1993; 6: 99-110.

[85] Clark AL, Coats AJS. Severity of heart failure and dosage ofangiotensin converting enzyme inhibitors. BMJ 1995; 310:973-^.

[86] Chakko S, DeMarchena E, Kessler KM, Myerburg RJ. Ven-tricular arrhythmias in congestive heart failure. J Clin Cardiol1989; 12: 525-30.

[87] The Cardiac Arrhythmia Supression Trial (CAST) Investiga-tors. Effect of encainide and flecainide on mortality in arandomised trial of arrhythmia suppression after myocardialinfarction. N Eng J Med 1989; 321: 406-12.

[88] Schwartz PJ, Camm AJ, Frangin G, Janse MJ, Julian DG,Simon P. Does amiodarone reduce death and cardiac mortal-ity after myocardial infarction (EMIAT)? Eur Heart J 1994;15:620-4.


56 S. H. Taylor

[89] Cohn JN, Levine TB, Olivari MT. Plasma norepinenphrineas a guide to prognosis in patients with congestive heartfailure. N Engl J Med 1984; 311: 819-23.

[90] Fleckenstein A, Janke J, Doring HJ, Pachinger O. Calciumoverload as a determinant factor in the production ofcatecholamine-induced myocardial lesions. Rec Adv StudCardiac Struct Metab 1973; 2: 455-68.

[91] Yates JC, Beamish RE, Dhalla NS. Ventricular dysfunctionand necrosis produced by adrenochrome metabolite ofepinephrine: relationship to pathogensis of catecholaminecardiomopathy. Am Heart J 1981; 102; 210-21.

[92] Podrid PJ, Fuchs T, Candinas R. Role of the sympatheticnervous system in the genesis of ventricular arrhythmia.Circulation 1990; 82 (Suppl 1): 103-13.

[93] Bigger JT. Why patients with congestive heart failure die:arrhythmias and sudden cardiac death. Circulation 1987; 75(Suppl IV): 28-35.

[94] Venditti FJ, Garan H, Ruskin JN. Electrophysiologic effectsof beta-blockers in ventricular arrhythmias. Am J Cardiol1987; 60: 3D-9D.

[95] Chadda K, Goldstein S, Byington R, Curb JD. Effect ofpropranolol after acute myocardial infarction in patientswith congestive heart failure. Circulation 1986; 73: 503-10.

[96] The Norwegian Multicenter Study Group. Timolol-inducedreduction in mortality and reinfarction in patients survivingacute myocardial infarction. N Engl J Med 1981; 304: 801-7.

[97] Bashir Y, McKenna WJ, Camm AJ; Beta-blockers and thefailing heart: is it time for a U-turn? Br Heart J 1993; 70:8-12.

[98] Waagstein F. Beta-blockers in heart failure. Cardiomyop-athy 1993; 82 (Suppl 3): 13-8.

[99] Hampton JR. Beta-blockers in heart failure — evidence fromclinical trial. Eur Heart J 1996; 17 (Suppl A): 17-20.

[100] Waagstein F, Caidahl K, Wallentin I, Berhg CH,Hjalmarson A. Long-term beta-blockade in dilated cardio-myopathy; effects of short and long-term metoprolol treat-ment followed by withdrawal and readministration ofmetoprolol. Circulation 1989; 80: 551—63.

[101] Swedburg K, Hjalmarson A, Waagstein F, Wallentin I.Adverse effects of beta-blockade withdrawal in patients withcongestive cadiomyopathy. Br Heart J 1980; 44: 134-42.

[102] Waagstein F, Bristow MR, Swedberg K el al. For theMetoprolol in Dilated Cardiomyopathy (MDC) Trial StudyGroup. Beneficial effects of metroprolol in idiopathic dilatedcardiomyopathy. Lancet 1993; 342: 1441-56.

[103] The Xamoterol in Severe Heart Failure Study Group. Lancet1990; 336: 1-6.

[104] Ikram H, Chan W, Bennett SI, Bones PJ. Haemodynamiceffects of acute beta-adrenergic receptor blockade in conges-tive cardiomyopathy. Br Heart J 1979; 42: 311-5.

[105] Taylor SH, Silke B. Haemodynamic efects of beta-blockadein ischaemic heart failure. Lancet 1981; ii: 835-7.


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