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Consensus on Heart Failure

Management?

THE LANCET

VASODILATOR therapy has been routine for severalyears in patients with severe heart failure. The theoryis simple: venous dilatation reduces filling pressure(pre-load) and arteriolar dilatation reduces theresistance against which the heart has to pump(after-load). By manipulating the tone of the venousand arterial circulations the failing heart can be madeto pump more effectively, and centrally measuredhaemodynamic variables such as pulmonary capillarywedge pressure and cardiac output are improved.Exercise tolerance is increased in the long term,although for some reason there is only a poorcorrelation between haemodynamic improvementand change in exercise capability. It is unclearwhether the ideal vasodilator for use in heart failureshould have its main action on the venous or arterialside of the circulation; in the USA a combination ofhydralazine (primarily an arteriolar dilator) andnitrates (which act predominantly on the venous side)has been commonly used whereas in the UK

angiotensin converting enzyme (ACE) inhibitors havebeen the drugs of choice. 2-4 ACE inhibitors affect boththe arterial and the venous circulation, and preventingthe increased effect of the vasoconstrictor angiotensinII in heart failure seems a logical approach.

Several small studies have suggested thatvasodilators reduce fatality from heart failure,s but

1 Franciosa JA, Goldsmith SR, Cohn JV. Contrasting immediate and longterm effectsof isosorbide dinitrate on exercise capacity in congestive heart failure. Am J Med1980; 67: 557-60.

2 Leier CV, Magorien RD, Desch CE, et al. Hydralazine and isosorbide dinitrate:comparative central and regional haemodynamic effects when administered aloneor in combination. Circulation 1981; 63: 102-09.

3 Levine TB, Franciosa JA, Cohn JN. Acute and long-term response to an oralconverting-enzyme inhibitor, captopril, in congestive heart failure. Circulation1980; 62: 35-41.

4. Cowley AJ, Rowley JM, Stainer KL, Hampton JR. Captopril therapy for heartfailure. A placebo controlled study. Lancet 1982; ii: 730-32.

5 Lipkin DP, Poole-Wilson PA. Treatment of chronic heart failure: a review of recentdrug trials. Br Med J 1985; 291: 993-96.

two trials designed specifically to investigate this

possibility have now been published. The effect of theACE inhibitor enalapril was studied in a trial with thetortuous acronym "CONSENSUS" (CooperativeNorth Scandinavian Enalapril Survival Study).6 256patients with heart failure causing symptoms at restwere randomly allocated to receive either enalapril(2-5-40 mg daily) or placebo in addition to othertherapy. The diuretic dose was "optimal" and themean dose of frusemide was 200 mg in each group; useof other vasodilators was allowed, and about a third ofthe patients received nitrates and hydralazine. After 6months the case fatality rate in the placebo group was44%, compared with 26% in the group givenenalapril; after one year the respective rates were 50 %and 36%. The differences between treatment groupswere highly significant, and the trial was discontinuedprematurely on the advice of the ethical committee,who felt that it was unreasonable either to recruit more

patients or to continue double-blind treatment inthose already in the study. For this reason follow-upranged from 1 day to 20 months, with a mean of 188days.

It is highly unusual for a study to be stopped earlybecause a treatment is more effective than had been

anticipated, and in general it is extremely undesirablenot to let a trial run its intended course. In this case thenumber of patients involved is small; at the time theethical committee made its decision there were 22more deaths in the placebo group than among thepatients given enalapril, and this difference wasreduced to 18 by the end of the study. However, thedecision to stop was undoubtedly right. It appears thatno patients were withdrawn from placebo treatmentand given enalapril, and the investigators were

evidently determined not to do so. The effects ofenalapril on mortality had to be viewed by the ethicalcommittee in the context of the undoubted efficacy ofACE inhibitors on the symptoms of heart failure.Patients included in the CONSENSUS study wereextremely ill, and when the study began in 1985 itwould probably have been considered unreasonable towithhold ACE inhibitors from such patients in theUK. No further mortality-endpoint trials comparingvasodilators with placebo in patients with severe heartfailure will now be undertaken-this form oftreatment should be routine in such patients. There isprobably nothing special about enalapril bycomparison with captopril, or probably with any otherACE inhibitor.7,8 The main questions posed by theCONSENSUS results are whether ACE inhibitorshave any advantages over other vasodilator drugs, andwhich patients with heart failure should be treatedwith vasodilators.

6. The CONSENSUS Trial Study Group. Effects of enalapnl on mortality in severecongestive heart failure. N Engl J Med 1987; 316: 1429-35.

7. Cleland JGF, Dargie HJ, Hodsman GP, et al. Captopril m heart failure. A doubleblind controlled trial. Br Heart J 1984; 52: 530-35.

8. Cleland JGF, Dargie HJ, Ball SG. Effects of enalapril in heart failure: a double blindstudy of effects on exercise performance, renal function, hormones and metabolicstate. Br Heart J 1985; 54: 305-12.

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The Veterans Administration (VA) heart failuretrial provides some answers.9 643 patients withmoderate heart failure were randomly allocated totreatment with prazosin, hydralazine plus isosorbidedinitrate, or placebo in addition to diuretics. Prazosinhad no effect, but at 1 year case fatality in the

placebo group was 19% compared with 12% in thehydralazine/nitrate group; the corresponding rateswere 34 % and 26 % at 2 years and 47 % and 36 % at 3

years. Whilst the number of patients followed for 4years was small, the difference between groupsappeared to diminish by this time. It therefore seemsthat although not all vasodilators affect fatality inpatients with heart failure, the beneficial effects are notlimited to ACE inhibitors. Patients included in the VA

study were obviously far less ill than those in

CONSENSUS, as is shown by the much lower casefatality rate in the placebo group and by the fact thatthe VA patients could exercise for about 9 min beforethe trial began. The dose of diuretics needed by theVA patients is not stated, but they were clearly fairly illfor their maximum oxygen uptake was about 13ml/kg/min, which is approximately equivalent toexercise on a treadmill at 2.7 kph and 4° of slope.Thus vasodilator drugs are apparently useful both

for fatality reduction and for relief of symptoms inpatients with moderate or severe heart failure.However, it does not necessarily follow that they havethese effects in patients with mild failure. ACEinhibitors are not very effective in patients with mildsymptoms,to perhaps because the renin-angiotensinsystem is not strongly activated. In patients whoalready take 40 mg of frusemide and who needadditional treatment, an increased dose of diureticshas a very similar effect on symptoms to the additionof captopril. 11 It is therefore possible that good controlof heart failure is what matters, and the means bywhich control is achieved is unimportant. In patientswith mild failure, death may not result from

progressive heart failure,-45% of the patients in theVA study died suddenly-and in the CONSENSUSstudy enalapril prevented only death from progressivefailure, not death from other causes.A different approach to the management of patients

with heart failure will soon be possible with theintroduction of a new range of drugs with bothinotropic and vasodilator properties.12 These drugsmay not reduce fatality, 13 but the heart failure storyclearly has some way to run before there can be a trueconsensus of views about the best form of treatment.

9. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality inchronic congestive heart failure. Results of a Veterans Administration CooperativeStudy. N Engl J Med 1986; 314: 1547-52.

10. Richardson A, Striven AJI, Parameshwar T, Bayliss J, Poole-Wilson PA, Sutton GC.Can angiotensin converting enzyme inhibitors replace diuretics as the sole

treatment of mild heart failure? Br Heart J 1987; 57: 80.11. Cowley AJ, Stainer H, Wynne MD, Rowley JM, Hampton JR. Symptomatic

assessment of patients with heart failure: double-blind comparison of increasingdoses of diuretics and captopril in moderate heart failure. Lancet 1986; ii: 770-72.

12. Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in the treatmentof congestive heart failure. N Engl J Med 1986; 314: 349-57.

13. Packer M, Leier CV. Survival in congestive heart failure during treatment with drugswith positive inotropic actions. Circulation 1987; 75 (suppl IV): 55-63.

Antibiotics by DesignTHE history of antibiotics documents an

undeniable therapeutic triumph, but with onlymodest contributions from basic science. Fleming’sdiscovery of penicillin was the result of a chanceobservation; streptomycin emerged from an

essentially random programme of screening of soilmicroorganisms, a process so successful that it formedthe basis of the subsequent discovery of nearly all thetherapeutically useful groups of antimicrobial agentsand is today still the most fruitful source of new

compounds. True, many of these discoveries havebeen brilliantly developed and exploited by chemistsand biological scientists, but the oft pursued goal ofdesigning antimicrobial agents by premeditated attackon unique bacterial structures has proved singularlyelusive. It has sometimes seemed as though naturewere set on exposing the efforts of man as merefoolishness: the first real antimicrobial breakthrough,sulphanilamide, was discovered accidentally throughtests of azo dyes 2 The scientific approach wasunexceptionably rational. Bacteria exhibited a greataffinity for azo dyes and these compounds oftenpossessed antibacterial activity; sulphonamide-containing dyes bound with great avidity to silk andwool and might similarly bind to bacteria. A series ofmoderately non-toxic azo derivatives was synthesisedand tested in infected mice. One derivative, prontosil,produced astonishingly good results.3 However, therationality of the exercise evaporated when ’it wasdiscovered that the curative properties came not fromthe dye, which was inactive, but from the unsuspectedsulphanilamide that was liberated in the body.

It is an affront to scientific vanity to suggest thatman is not clever enough to beat bacteria in a battle ofwits, but a therapeutic agent that has been rationallydesigned from scratch is still awaited. The nearest

approximation to such a compound is the

diaminopyrimidine, trimethoprim, which was

specifically sought as a selective inhibitor of bacterialdihydrofolate reductase.4 But even in this case thevulnerable pathway had already been indicated bysulphonamides and by the discovery that theantimalarial compound proguanil acted on the folatepathway and was converted in the body to a

diaminopyrimidine analogue. 5Two new efforts to bring rationality to the design of

antimicrobial agents have lately been reported.6,7 Bothgroups of workers focused their attention on thebacterial cell wall, a structure that is lacking inmammalian cells. Girodeau and co-workers6 chose

1. Omura S. Philosophy of new drug discovery Microbiol Rev 1986, 50: 259-792. Schreiber W. Vor 50 Jahren: Entdeckung der Chemotherapie mit Sulfonamiden Dt

Med Wschr 1985; 110: 1138-42.3. Domagk G. Ein Beitrag zur Chemotherapie der bakteriellen Infektionen Dt Med

Wschr 1935; 61: 250-53.4. Bushby SRM, Hitchins GH Trimethoprim, a sulphonamide potentiator. Br J

Pharmacol Chemother 1968; 33: 72-90.5. Falco EA, Goodwin LG, Hitchins GH, Rollo IM, Russell PB. 24

diaminopyrimidines—a new series of antimalarials. Br J Pharmacol Chemother1951; 6: 185-200