Improving outcomes in heart failure: a personal perspective

When I was a medical student and junior doctor in the early 1980s I saw many patients on the wards in hospital with this terrible illness for which we could do little. When the heart fails as a pump one of the main manifestations is accumulation of fluid due to retention of sodium and water by the kidneys which also malfunction as a result of reduced blood flow and other mechanisms. Fluid accumulation in the legs and lungs leads to swelling (peripheral oedema) and breathlessness. Reduced blood flow to the muscles also causes intense fatigue. Back in these early days diuretics which caused the kidneys to produce more urine and relieve fluid intention) and digoxin, a 200 year old plant-extract thought to stimulate contraction of the failing heart, were the only two treatments we had, except for the rare, young, patient who was lucky enough to get a transplant. Otherwise, I knew that around 7 out of 10 of those men and women I saw would be dead within a year. Even worse the last months of their lives were characterized by disabling symptoms and exercise intolerance making even ordinary everyday activities a struggle, if not impossible. Often patients were also readmitted to hospital because of acute worsening of their symptoms. Around the time I graduated from medical school USA and European investigators such as Jay Cohn, Gary Francis, Peter Harris, and Philip Pool-Wilson were beginning to unravel the pathophysiology—the disease mechanisms—of heart failure and starting to explore the possibility of finding new treatments for this condition.1,2 The picture that emerged was remarkable. Although the primary problem was of course weakness and failing of the contraction of the heart muscle, it was the secondary responses (and their effects on the blood vessels, kidneys, and failing heart) that were key to the understanding of why heart failure progressively worsened over time and to effective new treatments. It was realized that inappropriate activation of a key hormonal pathway, the renin-angiotensin-aldosterone system (RAAS), occurs in patients with heart failure, contributing to the progressive worsening I have mentioned and, ultimately, death. One of my most formative experiences as a young Cardiology trainee was seeing Dr Karl Swedberg, as he was then, from Gothenburg University present the results of the first trial (CONSENSUS) in heart failure to show that we could reduce the risk of death in this terrible illness.3 That trial, conducted in around 250 people with very advanced heart failure, showed that a drug which blocked the RAAS, enalapril, had a dramatic and early effect on mortality. Later another, larger, trial showed that the same drug also improved survival in patients with less severe symptoms; one of the leaders of that trial was Salim Yusuf (Figure 1).4 Another less well publicized discovery around that time was that the heart was not just a mechanical pump but also an endocrine organ that secreted peptide hormones which stimulated the kidneys to excrete sodium and water.5 I was fascinated by this discovery and in 1986 went to work with one of the pioneers studying these newly described hormones in humans, Professor Allan Struthers at the University of Dundee in Scotland. We showed that these natriuretic peptides, as well as promoting urine production by the kidneys, also inhibited the RAAS.6–8 We also hypothesized that because of these actions, boosting natriuretic peptide levels might be a useful way to treat patients with heart failure.8 While working in Dundee I heard that Dr Henry Dargie in Glasgow was working with a new drug that blocked an enzyme (neutral endopeptidase or neprilysin) which breaks down natriuretic peptides (thereby increasing natriuretic peptide levels).9–11 Because of that I moved to Glasgow in 1988 in the hope of becoming involved in the further development of this exciting new compound. Unfortunately, for reasons we did not understand at the time, the effect of this agent was not sustained over time and it was abandoned. However, that story did not end there, as I will come back to. I pursued additional lines of research, finding that angiotensin II could be produced in human tissues by non-angiotensin-converting enzyme (ACE) pathways.12,13 This provided some of the rationale to add a new type of RAAS antagonist, an angiotensin receptor blocker, to an ACE inhibitor and that an ARB might be as good as or even better than an ACE inhibitor. With Karl Swedberg, Marc Pfeffer (Brigham and Women's Hospital, Boston), Christopher Granger (Duke University), and Salim Yusuf I conducted a series of trials in patients with chronic heart failure (CHARM) and a large trial in patients with heart failure after myocardial infarction (VALIANT, where I became friends with Rob Califf, Lars Køber, Aldo Maggioni, Eric Velazquez, Faiez Zannad, among others) using two of these new drugs.14–17 Together we showed that ARBs were an effective alternative to ACE inhibitors (important because some patients cannot tolerate an ACE inhibitor) and that in heart failure adding an ARB to an ACE inhibitor further reduced the risk of death and hospital admission. With ACE inhibitors and β-blockers which had also been shown to be of benefit in heart failure, we now had three drugs that used together led to much better outcomes for our patients with heart failure than could have been dreamt of twenty years early. I had also been interested in a different type of RAAS blocker spironolactone, which is a mineralocorticoid receptor antagonist (MRA) blocking the actions of aldosterone rather than angiotensin II. Spironolactone had been shown by Bert Pitt (Ann Arbor Michigan) and Faiez Zannad (Nancy, France) to reduce the risk of death in patients with severe heart failure when added to an ACE inhibitor but this was before we had learnt about the value of β-blockers and ARBs (the famous RALES trial).18 I and others showed that MRAs also seemed to have beneficial actions in patients with milder symptoms and was lucky enough to team up with Drs Pitt, Zannad, Swedberg, and Henry Krum from Melbourne in Australia among others, to lead a new mortality/morbidity trial with the MRA eplerenone in patients with heart failure and mild symptoms, by this stage adding the MRA not only to an ACE inhibitor but also a β-blocker.19,20 We were delighted to be able to show that this treatment led to a striking improvement in outcome with both an improvement in survival and decrease in hospital admissions. Now we had a treatment that was even better than an ARB when added to an ACE inhibitor and β-blocker and a triad of treatments capable of transforming the lives of all patients with this type of heart failure (Figure 2).

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