The changing landscape of heart failure outcomes

Hospital Universitario La Paz
IdiPaz Research Institute
Madrid, SPAIN

The changing landscape of heart failure outcomes

by J. López-Sendón and N. Montoro, Spain

Heart failure is a highly prevalent, lethal, and costly condition. For many years, treatment was focused on improvement of symptoms. Sodium restriction, diuretics, digoxin, and nitrates were the principal (and only) therapies employed to alleviate symptoms and improve functional capacity. Then, the CONSENSUS trial (COoperative North Scandinavian ENalapril SUrvival Study) demonstrated that medical therapy could also prolong life, a concept that changed clinical practice and research objectives in heart failure. Since then, β-blockers, angiotensin II receptor blockers, aldosterone antagonists, and If current blockers were included in the first-line treatment of patients with heart failure, along with nonmedical therapies such as implantable defibrillators, resynchronization, and other therapeutic strategies that also demonstrated a clear benefit in outcomes of selected populations. Research has been intensive and fraught with failures. The majority of major clinical trials have yielded neutral or even negative results. Trials with inotropic drugs, antiarrhythmic drugs, some vasodilators, and other drugs had to be prematurely discontinued because of an unexpected increase in mortality. Nevertheless, the landscape of heart failure treatment has changed completely. Guidelines have been prepared to recommend evidence-based therapies to improve survival and reduce hospitalization. Research continues, but the immediate challenge is to follow the guidelines’ recommendations for treatments that prolong survival, reduce hospitalization, and improve ventricular function and quality of life.

Medicographia. 2015;37:125-134 (see French abstract on page 134)

The increasing burden of heart failure

Heart failure is one of the most important contemporary medical and social problems. It is highly prevalent. It shortens life and greatly impairs quality of life, and the management-related cost is very high (Table I, page 126). The European Heart Failure Association estimates that 26 million people have heart failure worldwide and 3.6 million people are newly diagnosed with heart failure every year in Europe alone.1 In the United States, heart failure may affect up to 3% of the adult population.2 The absolute numbers are increasing due to the longer life expectancy of the population, a steady increase in risk factors related to ischemic heart disease and heart failure (age, diabetes, obesity, sedentary lifestyle, etc), and the longer survival of patients with heart diseases in general and after myocardial infarction in particular with modern therapy strategies.3 There are important differences between countries regarding prevalence, hospitalizations, and mortality for heart fail- ure.3 Indeed, generally speaking, in the United States, hospitalization is stable or decreasing while mortality remains stable4,5; however, in most European countries, the number of hospitalizations is increasing and rehospitalization is becoming perhaps the major problem related with chronic heart failure (Figure 1),3 with a high impact on the increase in direct and indirect costs associated with heart failure.6 Heart failure represents the greatest negative impact on quality of life as compared with other major chronic diseases, such as diabetes, arthritis, and hypertension. Patients with heart failure, especially after the first hospitalization, suffer disabling symptoms— the most common being fatigue and dyspnea—and the end stage of the disease can only be compared to that of terminal cancer.

Figure 1
Figure 1. Hospitalizations for heart failure in Europe and the United States.

All data shown include planned admissions.
Abbreviations: HF (1º /2º), number of hospitalizations for heart failure as primary/secondary diagnosis; HF (any), number of hospitalizations for heart failure as any diagnosis; HF/total, heart failure hospitalizations as a proportion of all hospitalizations; LOS, average
length of hospital stay; Total, total number of hospitalizations.
After reference 3: Cowie et al. Improving care for patients with acute heart failure – Before, during and after hospitalization. London, United Kingdom: Oxford PharmaGenesis Ltd; 2014. © 2014, Oxford PharmaGenesis™ Ltd.
Available from:

Table I
Table I. Heart failure burden in numbers.

Based on data from various sources.

Table II shows the predicted projections of prevalence as well as the direct costs (medical care, hospitalization, treatment) and the indirect costs (loss of productivity) attributed to heart failure for the years 2010 to 2030 in the United States.6 The increase in prevalence will be relatively small, but within a 10- year period will be equivalent to a 25% increase, a figure that implies a terrible social and economic burden. These estimates may even be conservative; if there is a change in lifestyle leading to an increase in risk factors with a strong impact on heart failure, such as diabetes and obesity, we may see a greater increase in cardiovascular diseases, heart failure, and associated costs.7,8 In countries with an economy in transition, there may be more dramatic eventualities.9 The control of communicable diseases, the expected steep increase in life expectancy, and the change in lifestyle mainly due to a shift from rural to urban communities may lead to a steady increase in cardiovascular diseases, such that the heart failure pandemic will be, simply, global. The only solution to prevent this growing epidemic is through control of risk factors.

Table II
Table II. Projections of prevalence, and direct and indirect costs
of heart failure in the United States for the years 2010-2030.

Direct costs: medical care, hospitalization, treatments. Indirect costs: loss of
productivity. Cost is in billions 2008$.
After reference 6: Heidenreich et al. Circulation. 2011;123:933-944. Source: American
Heart Association, Inc.

Accurate diagnosis is one of the major issues in heart failure.1-3 Symptoms may be misleading. The diagnosis of heart failure with depressed systolic ventricular function is elusive and the correct diagnosis of diastolic heart failure is a real clinical challenge.10,11 This chapter focuses on outcomes in general, though the evidence in the literature mainly refers to heart failure with depressed left ventricular ejection fraction.

Outcomes in heart failure

The aim of therapies in heart failure is to prolong life, reduce hospitalization, and improve functional capacity. These main outcomes have been the target and have served as measures of efficacy in therapies for clinical trials in heart failure. Table III (page 128) details the most important outcomes in heart failure, along with their advantages and drawbacks in clinical practice and in clinical trials.

The long-term prognosis associated with heart failure is poor.1-4 Half of all patients diagnosed with heart failure die within 4 years, and the 5-year survival rate is lower than that associated with myocardial infarction and the majority of key malignancies. Accordingly, mortality has been the most important outcome to be included in clinical trials. The importance of total mortality is self-evident, but includes heart failure–related as well as other cardiovascular and noncardiovascular mortalities. This may be important in patients with heart failure and preserved systolic function, a clinical setting where comorbidities have an important impact on outcomes, making the evaluation of therapy strategies very difficult in this form of heart failure. Sudden death is the single most common form of death in heart failure, but decreasing sudden death without improving overall prognosis simply implies a change in the mode of death and is a useless achievement. Mortality directly related to heart failure itself is probably the best single outcome measure to evaluate the efficacy of new therapies and should be included in all heart failure trials designed to explore outcomes. The main problem with this outcome measure is the need for adjudication, as comorbidities often contribute to the cause of death.

Hospitalization for heart failure is now recognized to be one of the most important outcomes in cardiology.3 Worsening heart failure resulting in hospitalization may be associated with cardiac and/or renal injuries that may contribute to progression of heart failure, comorbidities, changes in lifestyle, and compliance with medication. Hospitalizations are associated with unacceptably high postdischarge mortality and rehospitalization rates12 and are the single most important parameter related to cost of care in heart failure patients. Besides, the need for hospitalization objectively defines quality of life. However, hospitalization for heart failure itself is difficult to ascertain, and is influenced by social, cultural, and economic reasons.

Nevertheless, hospitalization remains one of the principal outcome measures and should be included in all clinical trials evaluating outcomes in this population. Comprehensive planning of hospital discharge, adequate patient education, and initiation and continued optimization of disease-modifying therapies are crucial opportunities for improving postdischarge outcomes and preventing repeated events in these patients.

Other clinical outcomes
Stroke and myocardial infarction are relatively frequent in patients with heart failure and have been included in some outcome trials, but the relationship with heart failure therapies is uncertain. Undoubtedly, renal failure plays a key role in the progression of the disease. It is associated with hospitalizations and prognosis and may be a target for treatment; however, some therapies may have an adverse influence on renal function.1-3 Renal function is not a clinical outcome itself except when it forces hospitalization, dialysis, or other clinically relevant action, and this should be included as a clinical outcome measure in patients with heart failure.

Symptoms and quality of life
Improvement in functional capacity and reduction in symptoms may be perceived as the most important target for many patients with heart failure13 and will remain among the top priorities in the measurement of outcomes for this condition.

Table III
Table III. Desirable outcomes in heart failure clinical

Abbreviations: BNP, B-type natriuretic peptide; EMA, European Medicines
Agency; ICU, intensive care unit; LVEF, left ventricular ejection fraction.

However, neither functional capacity nor symptom improvement has been related to major outcomes, and symptoms are subjective and difficult to evaluate. For these reasons, symptoms and functional capacity will probably remain to be considered important, but second-line, outcomes in the measurement of therapy efficacy.

No surrogates in heart failure?
Surrogates are parameters related to major outcomes. Improvements in these parameters would have a favorable impact on clinical outcomes. An example would be hypercholesterolemia and hypertension. Both are well-recognized prognostic factors and reducing hypercholesterolemia and hypertension levels improves outcomes.

For years, surrogates in heart failure have been a deception. Many therapies that improve symptoms, ventricular function, and arrhythmias related to sudden cardiac death, and even therapies that decrease neurohormonal activation not only failed to demonstrate a benefit, in some cases they were associated with an increase in mortality. The lack of reliable surrogates is one of the most important barriers to identifying new therapies in heart failure.

More recently, it has been demonstrated that B-type natriuretic peptide levels (BNP and N-terminal proBNP) are increased in heart failure and are closely related with prognosis. Changes in BNP levels may represent a reliable surrogate, but this concept is still controversial.

Heart rate is clearly related to outcomes in heart failure14,15 and heart rate reduction has been associated with an improvement in outcomes. Furthermore, heart rate reduction induced with ivabradine, with no inotropic or vasoactive effects, improved outcomes in the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial), reducing heart failure mortality and the need for hospitalization and recurrent hospitalizations as well as improving ventricular function and quality of life.16-18 The information available supports the concept of heart rate as a reliable surrogate for outcomes in heart failure; in fact, it may be considered not only as a prognostic factor, but also as a therapeutic target.

With more aggressive therapies and multiple-drug combinations, safety becomes an issue in patients with heart failure and different parameters must be monitored during follow-up. These include all types of secondary effects previously reported in patients with heart failure; among others: mortality (over 6 months) in trials not designed to measure outcomes, arrhythmias, corrected QT interval (QTc) prolongation, hypotension, ischemic events, renal function (over 6 months), bradycardia and atrioventricular conduction abnormalities, and exaggerated pharmacological response in special groups (children, women, elderly) that may be related to single- or multiple-drug therapy.

Impact of therapies designed to improve clinical outcomes
Spurred on by a high prevalence, mortality, and morbidity, research in heart failure has been extraordinary through the last 30 years. New pathophysiological mechanisms were identified and therapies with new drugs, devices, and management strategies have been tested with the aim to improve clinical outcomes in different clinical settings.1,2 Some trials demonstrated unequivocal benefit, including a reduction in mortality, while others had to be prematurely discontinued because of unacceptable secondary effects or unexpected increase in mortality. Nevertheless, all yield important information to better understand the disease. Overall, the concept, diagnosis, and management of heart failure have completely changed the prognosis and quality of life in patients with heart failure.

Therapies associated with an improvement in outcomes in clinical trials
The first trial to demonstrate an improvement in survival was the CONSENSUS trial (COoperative North Scandinavian ENalapril SUrvival Study), adding enalapril to the standard treatment of heart failure with digoxin and diuretics.19 This outstanding achievement changed the way physicians looked at heart failure: prognosis could be improved with medical therapy. Improving outcomes became a clear target in clinical practice and in the objectives of clinical research. After the CONSENSUS trial, many other trials with angiotensin-converting enzyme (ACE) inhibitors, including captopril, lisinopril, ramipril, and trandolapril, confirmed the benefit in different clinical settings, including asymptomatic left ventricular dysfunction and postinfarction heart failure.20 Since then, ACE inhibitors have become the cornerstone of heart failure with reduced left ventricular function. Table IV (page 130) includes a list of strategies showing clear evidence of improvement in major clinical outcomes in such patients.1,2,14-19

After accepting that medical treatment could dramatically change outcomes, the next huge change in the strategy of heart failure management came from the clear demonstration that β-blockers (contraindicated in heart failure due to the negative inotropic effect) further improve the outcomes. Carvedilol, metoprolol, bisoprolol, and to some extent bucindolol were clearly associated with a further improvement in outcomes when added to ACE inhibitors.21 The limitations of the use of β-blockers are derived from some side effects, in particular hypotension.

Table IV
Table IV. Strategies with unequivocal evidence of major clinical outcomes improvement in patients with heart failure and reduced left ventricular ejection fraction.

Abbreviations: ACE, angiotensin-converting enzyme; aldo, aldosterone; AV, atrioventricular; bpm, beats per minute; CRT, cardiac resynchronization therapy; HF, heart failure; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; LV, left ventricular; ms, milliseconds.
Based on references 1,2,14-19.

Angiotensin II receptor blockers (ARBs) were also extensively investigated, but without the success needed to dramatically change clinical practice; the role of ARBs is currently perceived as an alternative to ACE inhibitors.1,2 Aldosterone blockers, spironolactone, and eplerenone were the third group of drugs that demonstrated an extra benefit on top of ACE inhibitors and β-blockers and are now recommended in all patients without contraindication, mainly severe renal failure. Heart rate is directly related to heart failure outcomes and selective heart rate reduction with ivabradine, an If current inhibitor, further improves outcomes, introducing a new concept in the heart failure management strategy.1,2,15-18 The last achievement, yet to be implemented in clinical practice, comes from the PARADIGM-HF trial (Prospective comparison of Angiotensin Receptor–neprilysin inhibitor with ACE inhibitors to Determine Impact on Global Mortality and morbidity in Heart Failure).22 In this study, the new drug LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure, challenging the accepted paradigm of ACE inhibition as the cornerstone for heart failure treatment.

Somehow, diuretics should be included in this selected list of first-line medical therapies. There is not clear evidence of clinical benefit using diuretics in heart failure. Certainly, no major trial could demonstrate an improvement in outcomes and some large contemporary trials with new diuretic drugs were a failure, including vasopressin inhibitors (tolvaptan) and adenosine inhibitors (rolofylline).

Failures of medical therapy in clinical research
More often than not, clinical trials in heart failure fail to demonstrate the hypothesis and yield neutral results. This includes important groups of drugs with different mechanisms of action, including levosimendan,23 vasopressin inhibitors (tolvaptan),24 statins,25 new antiarrhythmic drugs (celivarone),26 darbepoietin,27 dihydropyridines and other calcium channel blockers,28,29 nesiretide,30 adenosine inhibitors (rolofylline),31 and others. Furthermore, in many trials, new therapies were actually related to an increase in mortality, including inotropes23,32-36 (xamoterol, vesnarinone, enoximone, pimobendan, ibopamine), antiarrhythmic drugs37-41 (propafenone, sotalol, dronedarone), fluosequinan, prostacyclins (epoprostenol), calcium antagonists28 (mibefradil), and endothelin antagonists. Table V (page 131) includes a list of therapies with neutral outcomes or negative results in clinical trials well designed to explore the effect of therapies on heart failure outcomes.1,2,23-57

Table V
Table V. Therapies with failure to demonstrate unequivocal evidence to improve outcomes in heart failure with reduced left ventricular
ejection fraction. Based on references 1,2,23-57.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; HF, heart failure; ICD, implantable cardioverter defibrillator.

The reasons for these failures are not completely clear (Table VI) and do not necessarily indicate that the tested drug itself was the reason for failure.

Nonpharmacological therapies
Other management strategies have also demonstrated a significant clinical benefit, and have been included in the current recommendations in heart failure guidelines. Some may be applied universally; such is the case for exercise and team work in heart failure clinics. Others, such as implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT), and implantable ventricular assist devices should be reserved for very selected populations with specific characteristics.1,2

Lessons learned
Through this extraordinary research journey 2 important lessons should be recognized:
– Heart failure outcomes may improve with a combination of strategies. Guideline recommendations should be followed.
– Well-defined hypotheses must be tested in outcomes trials before incorporating new treatments in clinical practice.

Future needs
New research
More research is needed as mortality and rehospitalizations remain a major problem in heart failure. New mechanisms of action and new drugs are currently being investigated58 and the results of ongoing clinical trials along with new management strategies and technology improvement of ventricular assist devices will provide further evidence to modify the landscape of heart failure outcomes.

Two clinical settings are of particular interest for future research: heart failure with preserved ventricular function and acutely decompensated heart failure where demonstrating evidence of benefit remains a challenge.

Table VI
Table VI. Reasons for failure in heart failure clinical trials.

Abbreviation: LVEF, left ventricular ejection fraction.

Figure 2
Figure 2. Indications for first-line medical treatment
in patients with heart failure.

Abbreviations: ACE, angiotensin-converting enzyme; ARBs,
angiotensin receptor blockers; BP, blood pressure; contraindic,
contraindication; Cr: creatinine; HR, heart rate; inh, inhibitors;
K+, potassium ion; Na+, sodium ion; SR, sinus rhythm.
Based on reference 59: Lopez et al. Diagnóstico y tratamiento
de la insufficiency cardiac. iPad application. 2014. © CARDIOSESAMO.

Guideline implementation
However, implementation of what we have learned so far is of paramount importance and following the guideline recommendations improves outcomes. Figure 2 simplifies the current guideline recommendation for medical therapy in heart failure patients.59

Redefining clinical research
Traditional components of efficacy measurement in clinical trials include mortality and hospitalization for cardiovascular reasons, but require a large number of patients to ensure the reliability of results. However, the size, duration, complexity, and costs associated with new, contemporary trials make clinical research ever more difficult and challenging. A more pragmatic approach simplifying the trials and maintaining relevant clinical outcome measures should be agreed upon between the scientific community and health care authorities.60

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Keywords: heart failure; hospitalization; mortality; outcome