European Heart Journal (2002) 23, 1322–1323doi:10.1053/euhj.2002.3225, available online at http://www.idealibrary.com on

See doi:10.1053/euhj.2001.3112 for the article to whichthis Editorial refers

The clinical syndrome of heart failure results inimpaired quality of life, exercise intolerance, frequenthospital admissions and high mortality. Each of thesecan be of importance for a patient with heart failure.Ideal drug treatment for heart failure should result inimprovement in all of these end-points. However, it isnow well established that there can be dissociationbetween short- and long-term effects of pharmaco-logical agents. For example, both enoximone andmilrinone can improve symptoms in the short termbut result in increased mortality, mainly due to anincrease in sudden presumed arrhythmic death[1,2]. Asa result of this and the dominance of survival data fordrug regulatory requirements, the effects of manydrugs on end-points other than survival are relativelyunstudied. However, improvement in symptoms,quality of life and ability to exercise rather thansurvival, may be a higher priority for heart failurepatients, particularly the elderly.

ACE inhibitor therapy provides a good example ofthis data disparity, with clear evidence of survivalbenefit but conflicting information on the effects onexercise. The study in this edition by Cooke et al.again raises the issue of the optimal dose of ACEinhibitor therapy in heart failure[3]. The study relatesthe pathophysiology of exercise intolerance in heartfailure to vasodilator therapy with ACE inhibitors.The study was performed with a small sample of 12heart failure patients in a crossover design, testing theeffects of 5 mg and 20 mg of lisinopril on exercisecapacity. The low-dose of lisinopril had more favour-able effects on aerobic exercise capacity than the20 mg dose. Although this is an elegant study, severalissues relevant to the application of these findings toheart failure patients remain uncertain. For example,although the study demonstrated beneficial effects onaerobic exercise capacity, there were no data tosupport extension of these benefits to overall im-provements in quality of life. Many heart failurepatients are severely limited by concomitant con-ditions and thus data on exercise capacity alone arenot convincing enough to mandate this dose. Inaddition, how the effects observed in this study willtranslate to the patient receiving standard beta-blocker therapy is uncertain.

Other studies have compared different doses ofACE inhibitors in heart failure patients. A recentcomparison of low (5 mg . day�1) and high dose

� 2002 The European Societ

enalapril (40 mg . day�1) in heart failure patientsdemonstrated no greater suppression of angiotensinII, aldosterone or catecholamines with the high dosecompared with the low dose[4]. There were no differ-ences in exercise duration or VO2 between the twogroups. However, there was a trend for a reduction ina pre-specified clinical composite end-point (hospitaladmission, emergency room visit, death, sustainedincrease in diuretic) in the high-dose group. TheATLAS trial compared (very) low-dose lisinopril (2·5to 5 mg . day�1) with (very) high-dose lisinopril(35 mg . day�1) in 3614 patients with heart failure[5].There was no statistically significant difference insurvival (primary end-point) between the two groupsalthough there was a significant reduction in hospitaladmissions for heart failure and the combined end-point of death or hospital admission with the highdose. These data support a beneficial effect on clinicaloutcome with higher dose ACE inhibitor therapy butdo not preclude a similar advantage with an inter-mediate dose which may be more practical andefficient.

Thus, while it is clear that ACE inhibitor therapyshould be used to treat patients with heart failure,uncertainty remains regarding the optimal dose. Howdo we incorporate this information into the clinicaldecision making for individual patients? A fundamen-tal concept of evidence-based medicine is that weshould take the overall clinical trial results obtainedfrom various heterogeneous patient groups and applythese to individual patients. There are many circum-stances where we must make assumptions beyondthe available evidence until such time as (hopefully)further evidence gaps are filled. One argument is toassume that the apparent beneficial effects of highdose ACE inhibitor therapy on expensive hospitalreadmissions should outweigh any lesser effect onaerobic exercise capacity and be justified on thebasis of cost effectiveness. Worsening heart failureoccurs commonly in heart failure patients and willcontribute to the impaired quality of life for theseindividuals. Thus, this argument for higher-dosetherapy is reasonable. No clear evidence-based rec-ommendations can be made regarding the effects ofACE inhibitors at different doses on survival alone.The practical reality though is that many patientswith heart failure may not tolerate the high doses ofACE inhibitor required to achieve these benefits.Thus, we may end up with many patients receiv-ing intermediate doses, such as the equivalent oflisinopril 20 mg daily, where the effects on hospital

Optimization of ACE inhibitor therapy in heart failure

y of Cardiology. Published by Elsevier Science Ltd. All rights reserved.

Editorials 1323

readmissions and worsening heart failure may be lesspronounced. This moderate approach is more inkeeping with the average dose actually achieved in thelarge-scale ACE inhibitor survival trials[6,7] and in ourview is a reasonable target.

A more attractive future option would be to tailortherapy to the individual patient. This would allowoptimization of drugs and dosage to achieve theoptimal outcomes for that individual patient. Tailor-ing therapy to achieve a desired neurohormonalresponse and improve outcomes has been demon-strated[8] and further large-scale clinical trials areongoing in this area. In the meanwhile we shouldensure that evidence-based therapies are more widelyapplied in general to all patients with heart failure,continue to debate dosage while supportingadditional more definitive studies.

R. N. DOUGHTYN. SHARPE

Division of Medicine,Faculty of Medical and Health Sciences,

The University of Auckland,Auckland,

New Zealand

European Heart Journal (2002) 23, 1323–1325doi:10.1053/euhj.2002.3178, available online at http://www.ide

Home-based management offailure — focus on content not

See doi:10.1053/euhj.2001.3114 for the article to whichthis Editorial refers

Chronic heart failure is common, costly, dangerousand treatable, and is a syndrome mainly foundamong elderly patients. Its management is oftencomplex and involves the use of several pharmaco-logical agents, in particular, neurohormonal antagon-ists. The significance of lifestyle modifications has notbeen studied carefully, but is recognised to be import-ant. The value of chronic heart failure managementhas been outlined in several recent Guidelines[1,2].Treatment of chronic heart failure, as transmittedby these documents, shows the need for monitoringof patients during initiation of therapy as well asduring follow-up. With modern therapy, prognosishas improved markedly with reduction of mortality,morbidity and improved quality of life.

� 2002 The European Society of C

References[1] Cowley AJ, Skene AM on behalf of the Enoximone Investi-

gators. Treatment of severe heart failure: quantity or quality oflife? A trial of enoximone. Br Heart J 1994; 72: 226–30.

[2] Packer M, Carver JR, Rodeheffer RJ et al. for the PROMISEStudy Research Group. Effect of oral milrinone on mortality insevere heart failure. N Engl J Med 1991; 325: 1468–75.

[3] Cooke GA, Williams SG, Marshall P et al. A mechanisticinvestigation of ACE inhibitor dose effects on aerobic exercisecapacity in heart failure patients. Eur Heart J 2002; 23:1358–66.

[4] Tang WHW, Vagelos RH, Yee Y-G et al. Neurohormonal andclinical responses to high-versus low-dose enalapril therapy inchronic heart failure. J Am Coll Cardiol 2002; 39: 70–8.

[5] Packer M, Poole-Wilson Armstrong PW et al. Comparativeeffects of low and high doses of the angiotensin-convertingenzyme inhibitor, lisinopril, on morbidity and mortality inchronic heart failure. ATLAS Study Group. Circulation 1999;100: 2312–8.

[6] The CONSENSUS Trial Study Group. Effects of enalapril onmortality in severe congestive heart failure. Results of theCooperative North Scandinavian Enalapril Survival Study(CONSENSUS). N Engl J Med 1987; 316: 1429–35.

[7] The SOLVD Investigators Effect of enalapril on survival inpatients with reduced left ventricular ejection fractions andcongestive heart failure. N Engl J Med 1991; 325: 293–302.

[8] Troughton RW, Frampton CM, Yandle TG, Espiner EA,Nicholls MG, Richards AM. Treatment of heart failure guidedby plasma aminoterminal brain natriuretic peptide (n-BNP)concentrations. Lancet 2000; 355: 1126–30.

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patients with chronic heartjust form!

How do we implement treatment as outlined inthese Guidelines? Unfortunately, many patients withchronic heart failure are not offered optimal treat-ment. In Euro-HF, primary care physicians from sixEuropean countries were asked about chronic heartfailure treatments[3]. Knowledge of ACE-inhibitorswas wide, but perceived dose levels were lower thanrecommended. The beneficial effects of beta-blockerswere not familiar. In IMPROVEMENT, primarycare physicians from 24 countries were also askedabout chronic heart failure treatment[4]. The use ofACE-inhibitors and beta-blockers were more com-mon in this study than in Euro-HF. However, theirprescription varied widely and were mostly initiatedother than by primary care physicians. The limitedtake-up of these beneficial therapeutic options maybe explained by the complexity of their use. Neuro-hormonal blockers, for example ACE-inhibitors and

ardiology. Published by Elsevier Science Ltd. All rights reserved.