Systolic heart failure

Dr Graham Jackson
Consultant Cardiologist, Guy’s Hospital, London, UK

When buying or selling a property, the agent always emphasizes ‘location, location, location’. Cardiologists approaching heart failure would do well to begin with ‘prevention, prevention, prevention’. The prognosis for the patient with heart failure is poor, but it worsens alarmingly with deteriorating left ventricular systolic function, so that the mortality rate may be as high as 60% at 1 year for New York Heart Association (NYHA) class III/IV heart failure (Table 1).[1] 

Table 1. Classification of heart failure (NYHA).

Prevention is therefore paramount — preventing left ventricular dysfunction occurring and preventing it worsening once it has developed.
We are all aware that modern treatments have improved survival and reduced morbidity, but we are probably seduced into a false sense of security by benefits being presented as relative rather than absolute differences. For example, a relative reduction in events of 30% sounds more convincing than an absolute change of say 5–7%. As we treat our heart failure patients we need to keep a sense of perspective: the presentation of current benefits may disguise continuing problems of increasing morbidity and mortality over time. Whilst we need to be critical of the evidence, we also need to embrace the positive aspects so that we can offer currently established optimal care while continuing to seek further improvements. Both the neurohormonal compensatory but counterproductive overactivation of the renin-angiotensin system and the sympathetic nervous system have formed the basis for intervention to improve the long-term outcome for systolic heart failure patients.[2]
The angiotensin-converting enzyme (ACE) inhibitors attack one part of the neurohormonal basis of systolic heart failure and their use has led to significant improvements in both morbidity and mortality. The Co-operative North Scandinavian Enalapril Survival Study (CONSENSUS) was the breakthrough study.[3] Enalapril was compared with placebo in addition to conventional digoxin and diuretics in patients with severe heart failure (NYHA IV). In doses of up to 40 mg daily, enalapril reduced mortality from 52% in the placebo group to 36%, and the symptoms and signs of heart failure also improved. Presented as a 27% reduction in mortality, we could be forgiven for overlooking the high residual 36% death rate in spite of ACE inhibition. It is also important to note the high doses of enalapril used in this study because of the dose-related benefits demonstrated in the ATLAS study using lisinopril.[4] 
Recently, in similarly severe cases, spironolactone was compared with placebo and added to conventional therapy including ACE inhibitors.[5] The spironolactone group reported a reduction in all-cause mortality from 46 to 35% with a significant reduction in morbidity. The interesting similar residual mortality to that in the enalapril group in the CONSENSUS Trial was attributed to a beneficial effect of spironolactone whereas the possibility of suboptimal doses of ACE inhibitors influencing the result was not considered (mean daily doses of captopril 63.4 mg, enalapril 13.5 mg, lisinopril 15.5 mg). This begs the question as to whether angiotensin II antagonists, by having a more complete and selective endpoint inhibition of the angiotensin II receptor, will offer or improve on the combined benefit of spironolactone and ACE inhibition; with a residual mortality of 35% we clearly need to make further progress.
Preventing the progression of left ventricular dysfunction by early intervention at the time of acute myocardial infarction in patients with clinical heart failure using ramipril in comparison with placebo reduced 15-month mortality from 23 to 17% (relative risk reduction 27%).[7] In the Survival and Ventricular Enlargement (SAVE) Study,[8] postinfarction patients who were asymptomatic but with an ejection fraction of less than 40% were treated with high-dose captopril (up to 50 mg t.i.d.) or placebo. Captopril reduced the all-cause mortality at 42 months from 24.6 to 20.4% (relative risk reduction of 19%). These two studies have led to the recommendation that ACE inhibitors be adopted as standard therapy when there is evidence of left ventricular dysfunction (symptomatic or not) following myocardial infarction. By using ACE inhibitors early, prior to the development of class III/IV failure, we have one means of reducing the grim morbidity and mortality of severe heart failure.
Beta-blockade may be another means.[9] Once more in common with ACE inhibition, beta-blockers attack one aspect of the neurohormonal pathophysiology of heart failure. Patients who were clinically stable (and in general not NYHA IV) with left ventricular systolic dysfunction and established on standard therapy were randomized to carvedilol, bisoprolol, metoprolol or placebo in separate studies. The MERIT-HF Trial[10] of metoprolol is the largest study and included NYHA II-IV patients, although one has to be cautious when interpreting ‘stable class IV’ patients. The trial was stopped early because of a reduction in overall annual mortality from 11.0 to 7.2% (relative risk reduction 34%) in the metoprolol group — figures similar to those in a meta-analysis of beta-blocker studies which demonstrated a 9.7–7.5% mortality reduction (relative risk reduction 31%).[11] By 18 months, cumulative mortality was approximately 16% on placebo and 11% on metoprolol. The curves, as in all heart failure studies, showed a relentless progression in the incidence of sudden death, worsening heart failure, cardiovascular and overall mortality, though the pharmacological benefit was sustained. 
The curves should, however, remind us that life itself is a kind of dose-response curve with an inevitable endpoint. The 10-year follow-up of the CONSENSUS Trial[12] of 253 patients identified only five long-term survivors, all of whom had been in the enalapril group. Thus the long-term prognosis remained poor although ACE inhibition prolonged survival by 50% to 781 days from 521 days.
New avenues are needed. More vigorous control of diabetes and hypertension should not be forgotten and some evidence exists for the preventative role of lipid-lowering therapy. The metabolic aspects of heart failure and their modification have not been explored to the same degree as the neurohormonal aspects. There is no room for complacency or comfort from reassuring relative risk benefits. We can optimize our use of diuretics, ACE inhibitors, digoxin and beta-blockers and hope that further studies of newer agents will reduce the burden of heart failure. In the meantime we can construct a management checklist to allow us to optimize the evidence-base we have to date (Figure 1).