REVIEW
MALAWI MED JOURNAT ;16(l )t 22-26 March 2004
Pharmacological managementof chronicheart failure in adults:a reviewof the literature RichardAuty Departmentof Medicine,QueenElizabethCentralHospitaland Collegeof Medicine,Blantyre,Malawi.
Introduction Heart failure is a common, life threatening condition Table 1. encounteredin patientsof all agesand in all clinical settings. The New York Heart Association (NYHA) Classification of Heart Failure It may be due to any of a wide variety of causes- in Malawi, Class I Asymptomatic Left Ventricular Dysfunction cardiomyopathies,hypertension and rheumatic heart disCardiac diseasebut no undue dyspnoea on exercise. easeare probably the commonestcausesof heart failure. In Class II Mild Heart Failure more affluent societies,ischaemicheart diseaseis an imporCardiac diseasecausing slight limitation ofphysical activity, with dyspnoea on ordinary activity. tant factor. Chronic heart failure (CHF) causessignificant morbidity: it reducesexercisecapacity,interfereswith sleep Class III Moderate Heart Failure Cardiac diseasecausing marked limitation of physical activity, with and producesunsightly and uncomfortableoedema. dyspnoea on less than ordinary activity. The syndrome also carries substantial mortatity, worse than that of many malignant tumours: 20 -30% of patientswith Chss fV Severe Heart Failure Cardiac diseasecausing dyspnoea at rest. mild or moderately severeheart failure will die every year if left untreated. The life expectancyof a patient with untreat- Figure 1. Flow diagram illustrating the treatment options ed severeheart failure is only about 6 months. Table 1 availablefor the managementof chronic heart explains the symptomatic classificationof the severity of failure. heart failure. Objective measurementsof cardiac function, of Chronic Heart Failure suchas Left Ventricular Ejection Fraction (LYEF) or chamber filling pressures,correlate poorly with symptomsand New York Heart Association(NYHA) classification. Many of the problems experiencedby a patient with heart failure are due to a (yiciouscircle'of eventsin which pathophysiologicalresponsesto the falling cardiac output cause further deterioration in cardiac function over time. These responsesinclude ventricular remodeling, neurohumoural activation (increasedsympatheticactivity; increasedatrial natriuretic peptide; increased angiotensin II), increased activity of the renin-angiotensin-aldosterone system(RAAS) causingfluid retention, yasoconstrictionand sodium retention.
TreatmentGoals Traditionally, treatmentsfor heart failure have concentratedon relieving the effects of fluid retention (pulmonary and peripheral oedema) with diuretics and on increasing contractility of the myocardium with digoxin. Now a wider range of approachesis available to modulate most of the various compensatorysystems that are activated in heart failure. The aims of treatment are: - to improve symptoms - to improve functional capacity - to improve quality of life - to increase survival. Much can be done to improve the condition and prognosis of a patient with heart failure without using drugs. Dietary salt restriction, avoidanceof alcohol, a planned exerciseprogramme and weight loss have all been shown to be beneficial. Both surgical reconstruction of the myocardium and sophisticated biventricular pacing devices can also play a part. However, drug treatment forms the cornerstone of the management of a patient with chronic heart failure and very significant advances have been made in the last 20 years in our understanding of which drugs to use in particular circumstances. This increasedunderstanding has led to dramatic improvements in the outlook for patients with heart failure: the annual mortality rate for patients Malawi Medical Journal
with moderate (Class II-[I) heart failure has fallen by more than 5O7oin 20 years., The evidence-baseis reviewed in this paper regarding the different pharmacological approachesto the managementof heart failure. An attempt to draw all the data together to provide somerecommendationson how the various drugs may be used alone or in combination to the best effect in different types of patient has also been done. Some important questions remain unanswered, particularly about the relevance of the (largely American and European) evidence-baseto Malawian patients.
Diuretics Diuretics have been a fundamental part of the treatment of heart failure for decades. In facl becausethe use of diuretics was well establishedbefore the advent of controlled clinical trials and evidence-basedpractice, there is little formal evidence of their effectiveness. But virtually all patients with heart failure receive diuretics and all those who took part in the trials that have demonstrated the effectiveness of Angiotensin Concerting Enzyme (ACE) inhibitors, B-blockers and the other drugs discussedbelow were taking diuretics in addition to the test drug. So it is standardpractice to give a patient with heart failure a thiazide or loop diuretic, with the addition of the potassium sparing
managementof chronicheart failure 23 Pharmacoloqical bo) in the ffeatment of mild to moderate heart failure, with most of the benefit being attributed to the reduction in risk of death due to progressive heart failure. The risk of death or hospitalization for progressive heart failure was also lower in the treated group. enalapril Vasodilators pre-load and after-load reduce The SOLVD Prevention trial looked at the use of enalapril in Venous and arterial vasodilators relieve heart patients with asymptomatic left ventricular dysfunction (LVEF< on the heart, respectively. They should thereby failure. Two groups of vasodilatorshave been studied systemat- 36Vo)who were not receiving any drug ffeatment for their heart ically: a combination of hydralazine and isosorbidedinitrate and failure.' Combined mortality and casesof heart failure were sigthe ACE inhibitors. The latter have many other effects in addi- nificantly lower in the enalapril group compared with placebo tion to vasodilatation. (relative risk reduction 297o). However, the reductions in allTwo large, controlled studiesperformed in the USA determined cause mortality and death from cardiovascular causes with the effects of hydralazine 75 mg four times a day (37.5 mg qid enalapril were not significantly different from placebo. The for first two weeks) and isosorbide dinitrate 40 mg four times a absolute survival benefit of enalapril over placebo in the three day (20 mg qid for first two weeks). The Vasodilator-Heart year course of the SOLVD trials was aboutsZo,equivalentto one Failure Trial I (VHeFT I) compared the vasodilators (and pra- life savedfor every 300 patients treated per year. zosin) with placebo in patients with NYHA Class I-III heart fail- An overview of the effects of ACE inhibitors on mortality and ure (LVEF 3;45Vo)who were allowed to continue using digoxin morbidity in patients with heart failure from 32 randomised triand diuretics but who were not allowed long-acting nitrates, cal- als and a total of 7,105 patients has been published.* A number cium antagonists,B-blockers or antihypertensivedrugs. 3 After of ACE inhibitors were used in these trials and the analysis was one year, mortality in the placebo treated patients was 2O7o conductedwith the assumptionthat an ACE inhibitor class-effect while it was only l27o in the patients treated with the was responsiblefor the effects observedin the trials. This is not hydralazine and isosorbide. It is interesting to note that black necessarily the case.nHowever, overall there was a statistically (American) patients benefited more from the vasodilators than significant reduction in total mortality (odds ratio 0.77, p
MALAWI MED JOURNAT ;16(l )t 22-26 March 2004
Pharmacological managementof chronicheart failure in adults:a reviewof the literature RichardAuty Departmentof Medicine,QueenElizabethCentralHospitaland Collegeof Medicine,Blantyre,Malawi.
Introduction Heart failure is a common, life threatening condition Table 1. encounteredin patientsof all agesand in all clinical settings. The New York Heart Association (NYHA) Classification of Heart Failure It may be due to any of a wide variety of causes- in Malawi, Class I Asymptomatic Left Ventricular Dysfunction cardiomyopathies,hypertension and rheumatic heart disCardiac diseasebut no undue dyspnoea on exercise. easeare probably the commonestcausesof heart failure. In Class II Mild Heart Failure more affluent societies,ischaemicheart diseaseis an imporCardiac diseasecausing slight limitation ofphysical activity, with dyspnoea on ordinary activity. tant factor. Chronic heart failure (CHF) causessignificant morbidity: it reducesexercisecapacity,interfereswith sleep Class III Moderate Heart Failure Cardiac diseasecausing marked limitation of physical activity, with and producesunsightly and uncomfortableoedema. dyspnoea on less than ordinary activity. The syndrome also carries substantial mortatity, worse than that of many malignant tumours: 20 -30% of patientswith Chss fV Severe Heart Failure Cardiac diseasecausing dyspnoea at rest. mild or moderately severeheart failure will die every year if left untreated. The life expectancyof a patient with untreat- Figure 1. Flow diagram illustrating the treatment options ed severeheart failure is only about 6 months. Table 1 availablefor the managementof chronic heart explains the symptomatic classificationof the severity of failure. heart failure. Objective measurementsof cardiac function, of Chronic Heart Failure suchas Left Ventricular Ejection Fraction (LYEF) or chamber filling pressures,correlate poorly with symptomsand New York Heart Association(NYHA) classification. Many of the problems experiencedby a patient with heart failure are due to a (yiciouscircle'of eventsin which pathophysiologicalresponsesto the falling cardiac output cause further deterioration in cardiac function over time. These responsesinclude ventricular remodeling, neurohumoural activation (increasedsympatheticactivity; increasedatrial natriuretic peptide; increased angiotensin II), increased activity of the renin-angiotensin-aldosterone system(RAAS) causingfluid retention, yasoconstrictionand sodium retention.
TreatmentGoals Traditionally, treatmentsfor heart failure have concentratedon relieving the effects of fluid retention (pulmonary and peripheral oedema) with diuretics and on increasing contractility of the myocardium with digoxin. Now a wider range of approachesis available to modulate most of the various compensatorysystems that are activated in heart failure. The aims of treatment are: - to improve symptoms - to improve functional capacity - to improve quality of life - to increase survival. Much can be done to improve the condition and prognosis of a patient with heart failure without using drugs. Dietary salt restriction, avoidanceof alcohol, a planned exerciseprogramme and weight loss have all been shown to be beneficial. Both surgical reconstruction of the myocardium and sophisticated biventricular pacing devices can also play a part. However, drug treatment forms the cornerstone of the management of a patient with chronic heart failure and very significant advances have been made in the last 20 years in our understanding of which drugs to use in particular circumstances. This increasedunderstanding has led to dramatic improvements in the outlook for patients with heart failure: the annual mortality rate for patients Malawi Medical Journal
with moderate (Class II-[I) heart failure has fallen by more than 5O7oin 20 years., The evidence-baseis reviewed in this paper regarding the different pharmacological approachesto the managementof heart failure. An attempt to draw all the data together to provide somerecommendationson how the various drugs may be used alone or in combination to the best effect in different types of patient has also been done. Some important questions remain unanswered, particularly about the relevance of the (largely American and European) evidence-baseto Malawian patients.
Diuretics Diuretics have been a fundamental part of the treatment of heart failure for decades. In facl becausethe use of diuretics was well establishedbefore the advent of controlled clinical trials and evidence-basedpractice, there is little formal evidence of their effectiveness. But virtually all patients with heart failure receive diuretics and all those who took part in the trials that have demonstrated the effectiveness of Angiotensin Concerting Enzyme (ACE) inhibitors, B-blockers and the other drugs discussedbelow were taking diuretics in addition to the test drug. So it is standardpractice to give a patient with heart failure a thiazide or loop diuretic, with the addition of the potassium sparing
managementof chronicheart failure 23 Pharmacoloqical bo) in the ffeatment of mild to moderate heart failure, with most of the benefit being attributed to the reduction in risk of death due to progressive heart failure. The risk of death or hospitalization for progressive heart failure was also lower in the treated group. enalapril Vasodilators pre-load and after-load reduce The SOLVD Prevention trial looked at the use of enalapril in Venous and arterial vasodilators relieve heart patients with asymptomatic left ventricular dysfunction (LVEF< on the heart, respectively. They should thereby failure. Two groups of vasodilatorshave been studied systemat- 36Vo)who were not receiving any drug ffeatment for their heart ically: a combination of hydralazine and isosorbidedinitrate and failure.' Combined mortality and casesof heart failure were sigthe ACE inhibitors. The latter have many other effects in addi- nificantly lower in the enalapril group compared with placebo tion to vasodilatation. (relative risk reduction 297o). However, the reductions in allTwo large, controlled studiesperformed in the USA determined cause mortality and death from cardiovascular causes with the effects of hydralazine 75 mg four times a day (37.5 mg qid enalapril were not significantly different from placebo. The for first two weeks) and isosorbide dinitrate 40 mg four times a absolute survival benefit of enalapril over placebo in the three day (20 mg qid for first two weeks). The Vasodilator-Heart year course of the SOLVD trials was aboutsZo,equivalentto one Failure Trial I (VHeFT I) compared the vasodilators (and pra- life savedfor every 300 patients treated per year. zosin) with placebo in patients with NYHA Class I-III heart fail- An overview of the effects of ACE inhibitors on mortality and ure (LVEF 3;45Vo)who were allowed to continue using digoxin morbidity in patients with heart failure from 32 randomised triand diuretics but who were not allowed long-acting nitrates, cal- als and a total of 7,105 patients has been published.* A number cium antagonists,B-blockers or antihypertensivedrugs. 3 After of ACE inhibitors were used in these trials and the analysis was one year, mortality in the placebo treated patients was 2O7o conductedwith the assumptionthat an ACE inhibitor class-effect while it was only l27o in the patients treated with the was responsiblefor the effects observedin the trials. This is not hydralazine and isosorbide. It is interesting to note that black necessarily the case.nHowever, overall there was a statistically (American) patients benefited more from the vasodilators than significant reduction in total mortality (odds ratio 0.77, p
