Pharmacological management of chronic heart failure in adults: a review of the literature

Introduction

Heart failure is a common, life threatening condition encountered in patients of all ages and in all clinical settings. It may be due to any of a wide variety of causes - in Malawi, cardiomyopathies, hypertension and rheumatic heart disease are probably the commonest causes of heart failure. In more affluent societies, ischaemic heart disease is an important factor. Chronic heart failure (CHF) causes significant morbidity: it reduces exercise capacity, interferes with sleep and produces unsightly and uncomfortable oedema.

The syndrome also carries substantial mortatity, worse than that of many malignant tumours: 20 –30% of patients with mild or moderately severe heart failure will die every year if left untreated. The life expectancy of a patient with untreated severe heart failure is only about 6 months. Table 1 explains the symptomatic classification of the severity of heart failure. Objective measurements of cardiac function, such as Left Ventricular Ejection Fraction (LYEF) or chamber filling pressures, correlate poorly with symptoms and New York Heart Association (NYHA) classification.

Many of the problems experienced by a patient with heart failure are due to a ‘vicious circle’ of events in which pathophysiological responses to the falling cardiac output cause further deterioration in cardiac function over time. These responses include ventricular remodeling, neurohumoural activation (increased sympathetic activity; increased atrial natriuretic peptide; increased angiotensin II), increased activity of the renin-angiotensin-aldosterone system (RAAS) causing fluid retention, vasoconstriction and sodium retention.

Table 1.

The New York Heart Association (NYHA) Classification of Heart Failure

Class I	Asymptomatic Left Ventricular Dysfunction Cardiac disease but no undue dyspnoea on exercise.
Class II	Mild Heart Failure Cardiac disease causing slight limitation of physical activity, with dyspnoea on ordinary activity.
Class III	Moderate Heart Failure Cardiac disease causing marked limitation of physical activity, with dyspnoea on less than ordinary activity.
Class IV	Severe Heart Failure Cardiac disease causing dyspnoea at rest.

Treatment Goals

Traditionally, treatments for heart failure have concentrated on 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 approaches is available to modulate most of the various compensatory systems 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, avoidance of alcohol, a planned exercise programme 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 increased understanding has led to dramatic improvements in the outlook for patients with heart failure: the annual mortality rate for patients with moderate (Class II–III) heart failure has fallen by more than 50% in 20 years.

The evidence-base is reviewed in this paper regarding the different pharmacological approaches to the management of heart failure. An attempt to draw all the data together to provide some recommendations on 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-base to Malawian patients.

Diuretics

Diuretics have been a fundamental part of the treatment of heart failure for decades. In fact, because the use of diuretics was well established before the advent of controlled clinical trials and evidence-based practice, 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, β-blockers and the other drugs discussed below were taking diuretics in addition to the test drug. So it is standard practice to give a patient with heart failure a thiazide or loop diuretic, with the addition of the potassium sparing agents amiloride, or triamterene depending on the degree of oedema and the intensity of the effect that is required - as well as another drug.^1,2

Vasodilators

Venous and arterial vasodilators reduce pre-load and after-load on the heart, respectively. They should thereby relieve heart failure. Two groups of vasodilators have been studied systematically: a combination of hydralazine and isosorbide dinitrate and the ACE inhibitors. The latter have many other effects in addition to vasodilatation.

Two large, controlled studies performed in the USA determined the effects of hydralazine 75 mg four times a day (37.5 mg qid for first two weeks) and isosorbide dinitrate 40 mg four times a day (20 mg qid for first two weeks). The Vasodilator-Heart Failure Trial I (VHeFT I) compared the vasodilators (and prazosin) with placebo in patients with NYHA Class I–III heart failure (LVEF ≤45%) who were allowed to continue using digoxin and diuretics but who were not allowed long-acting nitrates, calcium antagonists, β-blockers or antihypertensive drugs. ³ After one year, mortality in the placebo treated patients was 20% while it was only 12% in the patients treated with the hydralazine and isosorbide. It is interesting to note that black (American) patients benefited more from the vasodilators than the white patients did. There was no benefit from prazosin.

VHeFT II compared the same hydralazine-isosorbide regimen with the ACE inhibitors enalapril 5–10mg twice daily in a similar population. Enalapril produced a lower mortality at two years (18%) than the hydralazine-isosorbide combination (25%). The lower mortality with Enalapril was due to a reduction in sudden death and was more prominent in patients with less severe heart failure (Class I or II). White patients responded very much better to the ACE inhibitors than black patients.⁴ Unfortunately, the benefits of treatment with hydralazine and isosorbide have not been studied in depth since these VHeFT trials were reported some 15 years ago. We are therefore left to speculate about the possibility that these two drugs could be particularly helpful to black (Malawian) patients with heart failure.

ACE inhibitors

ACE inhibitors have many properties that make them very effective drugs for the treatment of heart failure. By virtue of their ability to reduce circulating angiotensin II levels, they are vasodilators that reduce both preload and afterload; they reduce sympathetic stimulation; they have an anti-proliferative effect and thereby affect ventricular remodeling and reduce left ventricular mass.

In addition to VHeFT II, there have been four, important, large studies of the effects of ACE inhibitors in heart failure. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) showed a 40% (p = 0.002) reduction in mortality at 6 months in Class IV patients treated with enalapril 5–20mg twice daily. At 1 year, mortality was reduced by 31% (p = 0.001). The effect on mortality was due to a reduction in death from progression of heart failure rather than sudden death.⁵ All the patients received diuretics in addition to the trial treatment, 94% also received digitalis and 50% received vasodilators, mainly isosorbide.

The SOLVD (Studies of Left Ventricular Dysfunction) Treatment trial⁶ showed that enalapril (2.5 – 10mg twice daily), added to conventional therapy (though an effort was made to discontinue use of non-ACE inhibitor vasodilators) significantly reduced mortality risk by 16% (35.2% enalapril v. 39.7% place bo) in the treatment 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 enalapril treated group.

The SOLVD Prevention trial looked at the use of enalapril in patients with asymptomatic left ventricular dysfunction (LVEF< 36%) who were not receiving any drug treatment for their heart failure.⁷ Combined mortality and cases of heart failure were significantly lower in the enalapril group compared with placebo (relative risk reduction 29%). However, the reductions in all-cause mortality and death from cardiovascular causes with enalapril were not significantly different from placebo. The absolute survival benefit of enalapril over placebo in the three year course of the SOLVD trials was about 8%, equivalent to one life saved for every 300 patients treated per year.

An overview of the effects of ACE inhibitors on mortality and morbidity in patients with heart failure from 32 randomised trials and a total of 7,105 patients has been published.⁸ A number of ACE inhibitors were used in these trials and the analysis was conducted with the assumption that an ACE inhibitor class-effect was responsible for the effects observed in the trials. This is not necessarily the case.⁹ However, overall there was a statistically significant reduction in total mortality (odds ratio 0.77, p<0.001) and in the combined end-point of mortality plus hospitalization for CHF (odds ration 0.65, p=0.001). Patients with the lowest left ventricular ejection fraction appeared to gain the greatest benefit. The greatest effect was seen during the first three months of treatment but additional benefit was seen during further treatment. The reduction in death was mainly due to the reduction in deaths due to progressive heart failure.

There is good evidence, therefore, to support the use of ACE inhibitors in patients with moderate or severe congestive heart failure. There are some concerns, however. A reanalysis of the data from the SOLVD studies has just been published¹⁰, suggesting that there may be racial differences in the response of patients to ACE inhibitors. Enalapril treatment in this trial was associated with a 44% reduction in the risk of hospitalization for heart failure in the white patients (p<0.001) but was without significant effect in black patients. Similarly, enalapril treatment produced significant reductions in systolic and diastolic blood pressure in the white patients but not in the black patients.

Compliance with ACE inhibitors treatment is also disappointing. Many doctors are failing to give these drugs to their patients with heart failure, even though their useful effects have been known for over five years. And patients who are prescribed them often fail to take them - maybe because of the common occurrence of a troublesome cough, a side-effect of ACE inhibitors that has been attributed to their effect on kinin degradation.

When ACE inhibitors are prescribed for heart failure they are often given in doses which may be appropriate for the treatment of hypertension but which are lower than those studied in the definitive heart failure trials.¹¹ Thus, CONSENSUS, VHeFT II and SOLVD used doses of enalapril of about 15mg daily, whereas doses of 2.5–5mg are routinely used in clinical practice. One study of lisinopril has explored this issue. The ATLAS (Assessment of Treatment with Lisinopril and Survival) trial in patients with moderate or severe heart failure (LVEF £30% despite treatment with diuretics for ≥2 months) added a low or a high dose of lisinopril to the treatment of patients who were already receiving diuretics and digoxin. The higher dose of the drug (about 35mg daily) reduced all cause mortality and all cause hospitalization by 12% compared with the low dose (about 5mg).¹²

Spironolactone

Aldosterone has many properties in addition to promoting sodium reabsorption in the distal nephron. Many of its effects may precipitate or exacerbate heart failure. Aldosterone increases the excitability and contractility of cardiac myocytes; it increases the reactivity of vascular smooth muscle; it promotes the growth of fibroblasts; it increases the turnover of collagen.^13,14 There are good grounds, therefore, to expect an aldosterone antagonist to have useful effects in patients with heart failure. The RALES (Randomised Aldactone Evaluation Study) trial took 1663 patients with symptomatic congestive heart failure (LVEF ≤35%), receiving standard care with a diuretic plus an ACE inhibitor and compared the effects of addition of spironolactone (mean dose 25mg daily) or placebo. Spironolactone reduced the overall risks of death, death due to progressive heart failure and sudden cardiac death all by about 30%. It also reduced rates of hospitalization.¹⁵ This is a very impressive result, which led to early termination of the study, and it would argue for inclusion of spironolactone in the treatment regimen for most patients with heart failure, were it not for the relatively high incidence of side effects (gynaecomastia etc) experienced by the patients in this trial. Eplerenone is a “selective” aldosterone receptor antagonist that should be free of those side effects of spironolactone which are due to the latter's antagonism of oestrogen and androgen receptors. A mortality study is currently being performed with eplerenone in patients with symptomatic heart failure.¹⁶

β- blockers

Activation of the sympathetic nervous system plays an important part in the pathogenesis of heart failure and therapeutic modulation of sympathetic activity has a correspondingly important role in the management of the syndrome. Some effects of sympathetic activity are beneficial to the patient with heart failure and it is for this reason that β-adrenoreceptor blocking drugs were contra-indicated in patients with heart failure, particularly on account of their negative inotropic activity. Thus, nor-adrenaline has a positive inotropic effect and it causes vasoconstriction of non-essential blood vessels. However, it is now appreciated that prolonged increases in sympathetic drive are harmful. Chronic elevations in the levels of circulating noradrenaline damage the myocardium by causing it to hypertrophy (leading to decreased compliance), they cause myocardial ischaemia, and they are directly toxic to cardiac myocytes. Even effects that used to be thought to be beneficial are now seen to be generally harmful, for example peripheral vasoconstriction increases afterload.

For these reasons β-blockers have now been used extensively in the management of heart failure due to left ventricular dysfunction and there is very good evidence of their effectiveness, at least in the milder forms of this disease.^17,18 There has been a lingering concern that sympathetic drive may be essential to keep the heart working at all in very severe heart failure and the use of β- blockers at this end of the heart failure spectrum has therefore been very limited. Now, new mixed _- and β-adrenoreceptor blocking drugs have been shown to be useful even in severe heart failure. For mild or moderately severe heart failure, metaanalyses of trials of β- blockers involving more than 15,000 patients and more than 2000 deaths have provided convincing evidence of a marked effect of β- blockers on both morbidity and mortality from heart failure. ^17,18 These meta-analyses suggest that for every 100 patients treated for one year about 4 lives will be saved and four admissions to hospital will be avoided.^18,19 β-blockers have an effect as great as or greater than that of ACE inhibitors. Most patients however, in trials of β- blockers were already taking ACE inhibitors, so the benefits of β- blockade appear to be additional to those of the ACE inhibitors. A recent study in patients with heart failure has shown that concentrations of angiotensin II are lower in patients who are taking β- blockers as well as ACE inhibitors than they are in patients taking the latter alone - providing support for the use of combinations of these two classes of drug.²⁰ Cardio-selectivity does not influence the effects of the β- blockers in this situation; thus propranolol a non-selective β- blocker and atenolol and metoprolol, β1 (cardio) selective β- blockers, all of which are available in Malawi may be helpful to patients with Class I–III heart failure, although they are not approved for this use in the UK or the USA. β- blockers are of limited use, and may be dangerous, in acute exacerbations of heart failure, so initiation of β- blocker therapy is not recommended in patients with no haemodynamic reserve, as indicated by obvious fluid retention, symptoms at rest or recent admission to hospital for decompensated heart failure.¹⁸ They are best reserved as part of a strategy for preventing heart failure; they are best used in patients with milder symptoms to delay deterioration and to increase the length and quality of life. Like ACE inhibitors, β- blockers need to be started in low doses¹⁸; they also require slow titration over weeks or months before patients can attain maintenance doses: start low and go slow.¹⁷ Once again there are suggestions of racial differences in the patients' responses to these drugs. In this case, black patients appear to benefit less from β- blockers than white patients do.

Carvedilol is a non-selective β- blocker, an _1- blocker and an endothelin ET-1 antagonist. It is the only β- blocker that has received regulatory approval for use in heart failure. It has been compared with placebo in a double-blind trial in 2289 patients with severe heart failure (LVEF < 25%) over a mean duration of 10.4 months.^21,22 The patients continued to receive diuretics and ACE inhibitors or an All antagonist but were excluded if they had required an _-blocker, a β- blocker, a Class I antiarrythmic drug or a calcium channel blocker in the previous few weeks. The trial was stopped early because of the very good effects of carvedilol, which produced a 35% mean reduction in risk of death (cumulative risk of death at one year 18.5% placebo v. 11.4% carvedilol) and a halving in the risk of worsening of heart failure. White and black patients derived roughly equal benefit from this drug.²³ There have been no direct comparisons of carvedilol and metoprolol, which is the β- blocker most commonly prescribed for heart failure in the USA but one authority believes that such data as are available do not suggest any major clinical difference between the two drugs.¹⁸

One recent study has examined the effects of carvedilol, metoprolol and placebo on myocardial gene expression in patients with heart failure due to idiopathic dilated cardiomyopathy.²⁴ The effects of the treatments on three different groups of genes involved in the regulation of contractility were examined. Gene expression in all three groups was initially abnormal in these patients. Both β- blockers improved left ventricular function (Ejection Fraction) and produced favourable changes in the genes implicated in loss of contractile function and in pathological hypertrophy of the myocardium. There were no qualitative differences between metoprolol and carvedilol in their effects on any measurement, and both were better than placebo. The uthors suggest that β- adrenergic stimulation contributed to induction of pathological gene expression which was reversed by β- blockade more comprehensively and more frequently than by placebo treatment.

Digoxin

After years of controversy digoxin is regaining credibility as a treatment for heart failure. Its place in the management of atrial fibrillation has never been seriously challenged. The rehabilitation of digoxin follows from the results of the DIG (Digitalis Investigation Group) study performed in the USA.²⁵ In this study, digoxin increased cardiac contractility, increased cardiac output, decreased filling pressures and volumes and decreased peripheral resistance. It did not reduce all-cause mortality in heart failure but it reduced mortality due to worsening heart failure, and hospitalization for worsening heart failure was also significantly reduced. It appears that digoxin increased the risk of sudden death (arrythmias and myocardial infarction) but reduced mortality due to worsening heart failure - leaving patients with a choice to make between quality and duration of life expectancy. The best responses were found in patients with more severe heart failure.

Inotropic agents

Digoxin is still the only positive inotrope available for long-term oral use and its role is only just being redefined. Other drugs have been tried too, in the expectation that positive inotropic stimulation of the failing heart would improve cardiac performance. In fact there has been a long series of disappointments (vesnarinone, milrinone, flosequinan, etc.) and some evidence that inotropic drugs can increase mortality rather than reduce it. With the exception of digoxin, positive inotropic drugs have no place in the management of chronic heart failure.²⁶

Conclusions

How should we be managing our patients with heart failure? Before reaching any conclusions we should remember two weaknesses in the data available to help us. First, the evidence to support the use of diuretics is weak by modern standards. Second, from the perspective of the Malawian patient there is virtually no directly relevant evidence to support the use of ACE inhibitors, β- blockers, vasodilators, digoxin or aldosterone antagonists. This is because all the definitive trials with these drugs have been performed in the USA, Europe or Australasia. There is some evidence that black and white patients respond differently to each of these types of drug, but the “black” patients who took part in the trials may have been at least as different from Malawians as they are from the white participants in the trials. The differences in response are, presumably, due to genetic polymorphisms and until the studies are repeated in the appropriate population it is as well to remember that we are extrapolating results from one population to another, and possibly a very different one.

With these caveats, there is a wealth of evidence that demonstrates the effectiveness - and safety - of β- blockers, ACE inhibitors and vasodilators in patients with chronic congestive heart failure. Only a couple of trials support the use of spironolactone or digoxin but they are convincing.

Diuretics remain the first-line treatment in these patients, an ACE inhibitor, titrated to high dose, should be added for the patient with moderate degrees of heart failure or for the patient who does not respond well to the diuretic. Addition of a β-blocker, such as atenolol or metoprolol, may help the patient whose heart failure is still poorly controlled or in whom ACE inhibitors are contraindicated.

ACE inhibitors substantially reduce the risk of death for heart failure patients. One death is prevented for every 74 patients who are treated with an ACE inhibitor for one year. The combination of an ACE inhibitor plus a β- blocker prevents one death for every 21 patients treated for one year.¹⁷

The two-year mortality rate in patients with mild or moderately severe heart failure and who are treated with a diuretic plus digoxin is about 34%. Addition of an ACE inhibitor to this regimen reduces the rate to about 22% and adding a β- blocker as well brings the rate down to 14%. Alternatively, adding a combination of hydralazine and isosorbide dinitrate to the diuretic and digoxin is associated with a two-year mortality rate of 26%. Hydralazine and isosorbide should be considered for the black patient who does not respond well to either ACE inhibitor or β-blockers - or who cannot afford ACE inhibitors.

For the patient with severe heart failure the outlook is less encouraging. Treatment with a diuretic and digoxin alone carries a six month mortality of 44%. This may be reduced to about 20% by the addition of an ACE inhibitor and to 5–15% by further addition of spironolactone and/or a β- blocker. However, the outcome in these patients is very variable and it probably depends at least as much on individual patient characteristics as it does on the treatment regimen that is chosen. Diuretics and ACE inhibitors are the mainstay of treatment in these patients, with the addition of a β- blocker (preferably carvedilol), spironolactone and digoxin depending on response.

Figure 1.

Flow diagram illustrating the treatment options available for the management of chronic heart failure