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José LÓPEZ-SENDÓN, MD, PhD

Heart failure constitutes an important medical, social, and economic problem. Although reliable estimates are lacking in many countries, the prevalence of heart failure is estimated as 2%-3% of the adult population and increases with age. Over 26 million people suffer from heart failure around the world and over 3.5 million people are newly diagnosed with heart failure every year in Europe alone. The long-term prognosis associated with heart failure is worse than that associated with the majority of cancers, with 50%mortality after 4 years. Patients suffer disabling symptoms that often become refractory to treatment and need hospitalization, having the greatest negative impact on quality of life compared with other chronic conditions. The cost ofmedical care ismeasured in billions of dollars. The prevalence of heart failure progressively increased from the early 1950s onwards for 30 years, eventually reaching a plateau. However, it is likely we will observe a new increase in the future mainly because of the aging of the population and because of the trend showing an increasing prevalence of major heart risk factors, including obesity and diabetes. The challenge of preventing a heart failure pandemic in the future is important for all countries, but especially those with economies in transition, where traditional healthy lifestyles are quickly changing. The only way of avoiding this new pandemic is through prevention, which is the collective responsibility of everyone: physicians, education and health authorities, and patients.

Although not a heart disease itself, heart failure (HF) is a heart condition with a high social, sanitary, and economic impact. Reliable estimates of HF are lacking in many countries because of the absence of reliable surveillance programs to track the incidence, prevalence, outcomes, as well as the key causes of HF. According to estimates from the European Heart Failure Association, 26 million people have HF worldwide and 3.6 million people are newly diagnosed with HF every year in Europe alone. Similar figures are reported by the National Institute of Health in the United States, and an absolute increase is expected in future years.

The long-term prognosis associated with HF is poor. Half of all patients diagnosed with HF die within 4 years, and the 5-year survival rate is lower than that associated with myocardial infarction and the majority of major malignancies. HF has the greatest negative impact on quality of life compared with other major chronic disease, such as diabetes, arthritis, and hypertension. Patients with HF suffer disabling symptoms, especially after their first hospitalization, the most common of which are fatigue and dyspnea, while in terms of disability, the end stage of the disease is comparable to that of terminal cancer.

The economic cost of HF is estimated in billions of dollars per year, the need for repeated hospitalization being the most powerful contributing factor to direct costs associated with the disease. The longer life expectancy of the population, better treatment of heart diseases, and increase in risk factors for ischemic heart disease, particularly in countries with economies in transition, account for a growing incidence and prevalence of HF around the world. The only way to decrease the oncoming pandemic is by reducing the risk factors for cardiovascular diseases and HF through treatment, education of the population, and legislation for a healthier lifestyle. This is a responsibility that concerns not only physicians, but also teachers, health care providers, and patients.

Figure 1. The progression of heart failure.

The difficulties of defining and classifying heart failure

HF is a complex syndrome, clinically characterized by signs and symptoms secondary to abnormal cardiac function.^1,2 It includes patients with impaired (systolic HF) or preserved systolic left ventricular function (diastolic HF). Left ventricular function is below normal limits in a significant number of otherwise normal individuals (asymptomatic left ventricular dysfunction),^3,4 and the process itself may be considered as a progressive disorder ranging from risk factors to heart disease, asymptomatic impaired ventricular function, symptomatic HF, and finally refractory or advanced HF (Figure 1).^1,2 In some epidemiological studies, the most representative being the Framingham Study,⁵ patients were considered as having HF when 2 major criteria or 1 major and 2 minor criteria of HF (major criteria: rales, jugular ingurgitation and third heart sound; minor criteria: dyspnea, peripheral edema, and hepatomegaly) were present.

None of the above clinical manifestations are pathognomonic of HF and may be related to other conditions, some of which are common comorbidities associated with HF. Other studies used algorithms and scores based on clinical data, physical findings, and chest x-ray or even specific drug treatments^{3- 9} with different sensitivity and specificity results,^8,10 ICD-9 codes,¹¹ or even the simple, direct opinion of physicians.⁶ There is no agreement over a simple definition of HF for epidemiologic studies.

Incidence and prevalence

Incidence (number of new cases per year) and prevalence (proportion of the general population with HF) figures reported in the medical literature vary widely, mainly because different sets of diagnostic criteria have been used. Contemporary studies estimate the overall prevalence of HF in the US population to be about 2%-3%.^10,12-14 The prevalence is higher in men than in women and increases with age as shown in Figure 1.¹⁰ The prevalence of HF may be even higher in Europe.^15,16 Although significant differences have been noted between studies in different countries (Figure 2),^16-19 in general, HF prevalence in Western European populations is estimated to range from 0.4% to 2%.^1,16

_ Systolic versus diastolic heart failure
Asymptomatic diastolic left ventricular dysfunction, manifested by severe left ventricular hypertrophy and/or abnormal echocardiographic parameters,^20-22 is frequently found in patients with hypertension and other clinical conditions, such as ischemic heart disease. Although the majority of these patients never present signs or symptoms of HF,^3,4 there is a clear relationship between diastolic functional abnormalities and long-term hospital admission for HF and, in general, worse outcomes compared with patients with normal diastolic function.^22-27

If the diagnosis of HF with depressed systolic ventricular function is considered elusive, then the correct diagnosis of diastolic HF is a real clinical challenge. Both European and American cardiology associations offer recommendations for the correct diagnosis of diastolic HF that go well beyond the tandem of HF symptoms in the presence of normal left ventricular ejection fraction (LVEF).^20,21 The relative complexity of the diagnosis may be a problem in everyday clinical practice, but it is a real challenge to ascertain the type of HF, either systolic or diastolic, when conducting epidemiologic studies. Accordingly, the information relative to this type of HF is found mainly in registries rather than in prospective, populationbased epidemiologic studies. With all the aforementioned limitations, the incidence and prevalence of diastolic HF is probably about the same as HF with depressed left ventricular contractility.^16,22

Figure 2. Prevalence of heart failure by age and sex in the USA.

_ Incidence
In the Olmsted County study (Minn, USA), 137 patients with new HF presenting in 1991 had a recent echocardiogram assessing LVEF, which showed that 43% of them had an LVEF above 50%, qualifying as HF with preserved systolic function.²⁸ However, in another population-based study, Cowie et al in London¹⁸ performed an echocardiogram in 93% of all new, local cases of HF and only 16% presented a normal LVEF, while there was a mild to moderate reduction in LVEF in 68%, and a severe reduction in LVEF in 16%. Again there was the problem of defining normal limits of systolic function parameters.

Figure 3. Prevalence of heart failure.

_ Prevalence
In cross-sectional population studies, the proportion of patients with preserved systolic function HF range from 40% to 70%, with an average of about 50% (Figure 3).¹⁶ In the Euro- Heart Failure Survey I, 51% of men, but only 28% of women, had an LVEF <40%.29 In contrast, in the EuroHeart Failure Survey II in patients hospitalized with acute HF, preserved LVEF ≥45% was present in 34.3% of the whole study population (42.8% in de novo acute HF vs 29.6% in acutely decompensated chronic HF patients).³⁰ In addition, patients with diastolic HF are older and present more comorbidities than patients with left ventricular systolic dysfunction, and treating patients with diastolic HF remains a diagnostic and therapeutic challenge in clinical practice.^22,23,25

Figure 4. Low left ventricular ejection fraction in normal individuals with previously
unknown heart disease.

Table I. The heart failure pandemic in numbers.

_ Asymptomatic left ventricular dysfunction
A surprisingly large number of otherwise normal individuals in the general population present systolic function indexes well below the normal limits, the majority without signs or symptoms of HF. In the Glasgow study, part of the MONICA (MONItoring CArdiovascular disease) project, 2.9% of 1467 normal individuals without previously known heart disease, aged 25 to 75 years, presented a LVEF <30%, of whom about 50%were completely asymptomatic (Figure 4).³

In the Rotterdam study,⁴ which included 5540 participants aged over 55 years, the prevalence of HF was 3.9%, and 3.7% presented a left ventricular fractional shortening <25%, a measure of systolic left ventricular dysfunction. Curiously, only 20% of patients with systolic dysfunction presented clinical HF, and 60% of patients with left ventricular systolic dysfunction had no symptoms or signs of HF at all.^3,4

A true epidemic

HF statistics all over the world are overwhelming (Table I). It is estimated that 26 million people have HF worldwide, up to 6 million American and as many Europeans suffer from HF, and 1 million people are newly diagnosed with HF every year in the USA and the European Union alone. These figures imply that the risk of having HF in a lifetime is 1 in 5.^10,12-19

Past, present, and future prospects

The worldwide prevalence of HF has been increasing during the last few decades, something that could be attributed to several factors: an increase in the incidence of cardiovascular diseases; an aging population; better and more effective treatment of heart disease in general and acute coronary syndromes in particular, leading to a reduction in short-term mortality and HF occurring over a longer time frame.

A higher awareness of the problem and the widespread use ofmore reliable and sensible diagnostic tools, especially echocardiography, could certainly also explain a “false” increase in the incidence and prevalence of HF.

Figure 5A shows the hospitalization rates for congestive HF in USA over a span of 35 years.¹³ For people younger than 65 years, HF prevalence increased from 1971 to 1993 and remained stable until 2006. Rates for those 65 years and older increased from 1970 to 1998 and remained somewhat stable until 2006.¹³ In contrast, hospital mortality has progressively decreased during the last 25 years, contributing to the observed increase in the prevalence of HF (Figure 5B).

Figure 5A. Hospitalization rates for congestive
heart failure in the USA from 1971-2006.

Figure 5B. Mortality rates for congestive heart
failure in the USA from 1982-2006.

Despite an increasing prevalence, the majority of evidence indicates that the incidence of HF has plateaued and might even be decreasing in some groups.^14,31,32 In Western countries, including Canada, the USA, and countries in Western Europe, the incidence and prevalence of HF as well as the hospital admissions for HF has decreased during the last decade when corrected for age.^10,12-14,31 This trend has not been observed in many other countries where the prevalence of heart disease remains very high (as in Eastern European countries)³² or is still increasing (as in some Asian and South American countries).^33,34

What is expected in future years is controversial and depends mostly on the success we have in controlling risk factors and on the change in life expectancy of the population. Most estimates predict a steady increase in the total number of cases, even in countries where cardiovascular diseases and cardiovascular mortality is declining.^14,35 Again, the aging of thepopulation explains the otherwise contradictory epidemiologic predictions. Table II shows the predicted prevalence of HF, as well as the direct costs (medical care, hospitalization, treatments) and the indirect costs (loss of productivity) attributed to HF, for the years 2010 to 2030 in the United States.³⁵ The increase in prevalence will be relatively small, but over a 20-year period is equivalent to 25%, a figure that implies a terrible social and economic burden, with a cost increase of over 200%. These estimates may be conservative; if changing lifestyles lead to an increase in risk factors that have a strong impact on HF, such as diabetes and obesity, we may see an even greater increase in cardiovascular diseases and HF and their associated costs.^11,36-38

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

In countries with an economy in transition, the possibilities are even more dramatic.33,34 The control of communicable diseases, the expected steep increase in life expectancy, and the changes in lifestyle (mainly due to a shift from rural to urban communities) may lead to a steady increase in cardiovascular diseases and HF, causing a pandemic that will be, put simply, global. The only hope is in the control of risk factors.

Preventing an epidemic outbreak

_ Risk factors
A number of risk factors, such as ischemic heart disease, hypertension, smoking, obesity, atrial fibrillation, diabetes, and tachycardia, among others, have been identified to both predict the incidence of HF as well as its severity.^11,36-39

The risk of HF is particularly high in coronary disease (the incidence of HF is highest after myocardial infarction) and diabetes. Needless to say, prevention of cardiovascular diseases, changing lifestyle and diet (or maintaining healthy lifestyles and diets in some populations), and using appropriate medications are the best and most rewarding strategies to control the growing medical, social, and economic burden of HF.

_ Role of the patient
HF is a chronic disease, and the role of the patient in prevention and treatment is crucial. Although the awareness of the problem of HF is very low,⁴⁰ the majority of citizens from developed countries are aware of the negative effects of major classic risk factors, such as obesity, hypercholesterolemia, smoking, hypertension, sedentary lifestyle, etc. In spite of this awareness, the control of some factors is lower than expected,^41,42 while others are clearly increasing, especially obesity and diabetes, both of which are related to modern lifestyles and HF. Education and legislation will be crucial to control the growing global burden of cardiovascular heart diseases, HF included. _

References
1. Dickstein K, Cohen Solar A, Filipatos G, et al; Task Force for the Diagnosis and Treatment of Heart Failure. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2008;29:2388-2442.
2. Jessup M, Abraham W, Casey D, et al; Task Force on Practical Guidelines. 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults. J Am Coll Cardiol. 2009;53;1343-1382.
3. McDonagh TA, Morrison CE, Lawrence A, et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet. 1997; 350:829-833.
4. Mosterd A, Hoes AW, de Bruyne MC, et al. Prevalence of heart failure and left ventricular dysfunction in the general population. The Rotterdam Study. Eur Heart J. 1999;20:447-455.
5. McKee PA, CastelliWP, McNamara P, KannelWB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285:1441-1446.
6. Carlson KJ, Lee DCS, Goroll AH, Leahy M, Johnson RA. An analysis of physicians’ reasons for prescribing long-term digitalis therapy in outpatients. J Chron Dis. 1985;38:733-739.
7. Eriksson H, Caidhal K, Larsson B, et al. Cardiac and pulmonary causes of dyspnea— validation of a scoring test for clinical-epidemiological use: the study of men born in 1913. Eur Heart J. 1987;8:1007-1014.
8. Mosterd A, Deckers JW, Hoes AW, et al. Classification of heart failure in population based research: An assessment of six heart failure scores. Eur J Epidemiol. 1997;13:491-502.
9. Di Bari M, Pozzi C, Cavallini MC, et al. The diagnosis of heart failure in the community. Comparative validation of four sets of criteria in unselected older adults: the ICARe Dicomano Study. J Am Coll Cardiol. 2004;44:1601-1608.
10. Lloyd-Jones D, Adams RJ, Brown TM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation. 2010;121:e46-e215.
11. Goyal A, Norton CR, Thomas TN, et al. Predictors of incident heart failure in a large insured population a one million person-year follow-up study. Circ Heart Fail. 2010;3:698-705.
12. National Center for Health Statistics. 2006 National Hospital Discharge Survey. Hyattsville, MD: National Center for Health Statistics; 2008. National Health Statistics Reports. No. 5. Available at: http://www.cdc.gov/nchs/data/nhsr/ nhsr005.pdf. Accessed August 9, 2011.
13. National Institutes of Health—National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2009 Chart Book on Cardiovascular, Lung and Blood Diseases. Available at: www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf. Accessed August 9, 2011.
14. Bui AL, Horwich TB, Fonarow GC. Nature Rev Cardiol. 2011;8:30-41.
15. Cowie MR, Mosterd A, Wood DA, Poole-Wilson PA, Sutton GC, Grobbee DE. The epidemiology of heart failure. Eur Heart J. 1997;18:208-225.
16. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function. epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol. 2004;43:317-327.
17. Otero-Ravina F, Grigorian-Shamagian L, Juanatey JR, et al. Galician study of heart failure in primary care (GALICAP study). Rev Esp Cardiol. 2007;60;373-383.
18. Cowie MR, Fox KF, Wood DA, et al. Hospitalization of patients with heart failure: a population-based study. Eur Heart J. 2002;23:877-885.
19. Baena-Diez JM, Vidal-Solsona M, Byram AO, et al. The epidemiology of cardiovascular disease in primary care. The Zona Franca Cohort Study in Barcelona, Spain. Rev Esp Cardiol. 2010;63:1261-1270.
20. Nagueh S, Appleton C, Gillebert T, et al; American Society of Echocardiography. Recommendations for the Evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echo. 2009;22:109.
21. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:2359-2550.
22. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I. Diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002;105:1387-1393.
23. Meta-Analysis Research Group in Echocardiography (MeRGE) AMI Collaborators. Independent prognostic importance of a restrictive left ventricular filling pattern after myocardial infarction an individual patient meta-analysis: Meta- Analysis Research Group in Echocardiography Acute Myocardial Infarction. Circulation. 2008;117:2591-2598.
24. Lam CSP, Donal E, Kraigher-Krainer E, et al. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail. 2011;13:18-28.
25. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251-259.
26. Smith GL, Masoudi FA, Vaccarino V, Radford MJ, Krumholz HM. Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline. J Am Coll Cardiol. 2003;41:1510-1518.
27. Senni M, Redfield MM. Heart failure with preserved systolic function. A different natural history? J Am Coll Cardiol. 2001;38:1277-1282.
28. Dunlay SM, Weston SA, Jacobsen SJ, et al. Risk factors for heart failure: a population- based case-control study. Am J Med. 2009;122:1023-1028.
29. Cleland JG, Swedberg K, Follath F, et al. The EuroHeart Failure Survey programme— a survey on the quality of care among patients with heart failure in Europe. Eur Heart J. 2003;24:442-463.
30. Nieminen M, Brutsaert D, Dickstein K, et al; EuroHeart Survey Investigators. EuroHeart Failure Survey II (EHFS II). A survey on hospitalised acute heart failure patients. Description of population. Eur Heart J. 2006;27:2725-2736.
31. Shafazand M, Rosengren A, Lappas G, et al. Decreasing trends in the incidence of heart failure after acute myocardial infarction from 1993-2004: a study of 175216 patients with a first acute myocardial infarction in Sweden. Eur J Heart Fail. 2011;13:135-141.
32. Allender S, Scarborough P, Peto V, et al. European cardiovascular disease statistics 2008. www.ehnheart.org/cvd-statistics.html. Accessed August 9, 2011.
33. Paradis G, Chiolero A. The cardiovascular and chronic diseases epidemic in low- and middle-income countries: a global health challenge. J Am Coll Cardiol. 2011;57:1775-1777.
34. Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A. Growing epidemic of coronary heart disease in low- and middle-income countries. Curr Probl Cardiol. 2010;35:72-115.
35. Heidenreich PA, Trogdon JG, Khavjou OA, et al; American Heart Association Advocacy Coordinating Committee, Stroke Council, Council on Cardiovascular Radiology and Intervention, Council on Clinical Cardiology, Council on Epidemiology and Prevention, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Cardiovascular Nursing, Council on the Kidney in Cardiovascular Disease, Council on Cardiovascular Surgery and Anesthesia, and Interdisciplinary Council on Quality of Care and Outcomes Research. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123:933-944.
36. Loehr LR, Rosamond WD, Poole C, et al. The potentially modifiable burden of incident heart failure due to obesity. The atherosclerosis risk in communities study. Am J Epidemiol. 2010;172:781-789.
37. Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937-952.
38. Lim SS, Gaziano TA, Gakidou E, et al. Prevention of cardiovascular disease in high-risk individuals in low-income and middle-income countries: health effects and costs. Lancet. 2007;370:2054-2062.
39. Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823-830.
40. Remme WJ, McMurray JJV, Rauch B, et al. Public awareness of heart failure in Europe: first results from SHAPE. Eur Heart J. 2005;26:2413-2414.
41. EUROASPIRE I and II Group. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. Lancet. 2001;357:995- 1001.
42. Euroaspire III Investigators. European Society of Cardiology. www.escardio.org/ guidelines-surveys/ehs/prevention/Pages/Euroaspire3-survey.aspx. Accessed August 9, 2011.

Keywords: heart failure; epidemic; life expectancy; prevention; risk factor

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M. R. COWIE, MD, FRCP, FRCP (Edin), FESC
National Heart and Lung Institute
Imperial College London and Royal Brompton Hospital
London, UNITED KINGDOM

Around 2% of the adult population in the developed world have heart failure (HF), the prevalence of which rises steeply with age. Male gender, advanced age, more severe symptoms, coronary artery disease (particularly acute coronary syndrome), hypotension, impaired renal function, hyponatremia, and elevated plasma brain natriuretic peptide concentration are all factors associated with poorer prognosis. In Europe, HF accounts for 5% of adult internal medicine and geriatric hospitalizations, and the median duration of hospitalization is 11 days. Readmission rates are high, with one third to one half of patients being readmitted within 12 months. Although the prognosis of the syndrome is still severe, available data suggest that it is improving even though it remains worse than that of many common malignancies. The improving prognosis, coupled with a rapidly aging population, is driving a steep increase in the total number of people with HF: conservative estimates suggest that 6 million Europeans have this syndrome. It is a costly condition to treat: between 1% and 2% of national health care budgets are spent on HF, with more than 60% of this cost related to hospitalization. The condition has a major impact on many aspects of an individual’s quality of life, which is regarded as being worse in HF than in chronic lung disease, arthritis, or diabetes.

The epidemiology of heart failure (HF), and its impact on health services, has been well described, at least for the developed world. Published studies, which have used a range of methodologies, have been supplemented by data from surveys of hospital practice in North America and Europe. The literature on quality of life in HF is limited, but suggests that the syndrome has a major impact on many aspects of daily life.

Incidence

Reliable estimates of the incidence of HF are available from studies such as the Framingham Heart Study in the United States,¹ and the Hillingdon and Bromley Heart Failure Studies in London, UK.^2,3 The Framingham Study employed set criteria at biennial examinations of a cohort of individuals initially free of HF. The London studies employed an expert panel approach that reviewed all the available data for those with a new diagnosis of HF within a geographically defined population, using a systematic method of assessment that included imaging of the heart by Doppler echocardiography. Table I summarizes the results of these and other key incident studies.⁴

Table I. Incidence of heart failure in a selection
of population-based studies.

The crude incidence rate in the general population ranges from 1 to 5 cases per 1000 population per year, with a steep increase with advancing age: the annual incidence is estimated to be 0.2%-0.3% in those aged 50-59 years; in those aged 80-89,⁵ this rises tenfold (Figure 1).⁶ The median age at first presentation in most recent studies (in the developed world) is the mid-70s, with a higher incidence in men than in women at all ages (male:female ratio is ≈1.8:1).^7,8 It is not clear whether the incidence of HF has changed in the past few decades. The Framingham Heart Study reported no change during the period from 1950 to 1999 for men, but a small decrease in the early stages of HF during the same period for women.⁹ Elsewhere, data from Olmsted County, Minnesota, showed no change in the incidence of HF from 1979 through 2000,^10,11 while the Kaiser Permanente database in the Pacific Northwest of the United States suggests an increase of 14% in the HF incidence rate between 1970 and 1994.¹²

Prevalence

Studies from both Europe and North America suggest that the prevalence of HF is approximately 2% of the adult population, with a steep rise with age. Few adults aged younger than 40 years of age have HF. Early studies used a range of methods to estimate prevalence, including medical record reviews that were supplemented by direct questioning and/or examination of individuals within the general population, drug prescription data analysis, monitoring of general practice activity, and appropriately sampled cohorts from the general population. The results of some key studies are shown in Table II (page 372).⁴

The first population-based study to use two-dimensional Doppler echocardiography was in Glasgow, UK. The prevalence of HF was reported as 1.5% in 1647 participants aged 25 to 74 years.¹³ The definition of HF was left ventricular ejection fraction (EF) less than 30% and cardiac shortness of breath on questionnaire or use of a loop diuretic. Asymptomatic left ventricular systolic dysfunction was almost as common as HF, at 1.4% in this population. A population-based study in Rotterdam, The Netherlands, reported a prevalence of HF of 0.7% in those 55 to 64 years of age, 2.7% at 65 to 74 years of age, 13% at 75 to 84 years of age, and over 10% in those 85 years of age or older.¹⁴ A trained nonmedical interviewer administered a standardized questionnaire, a clinician detected pulmonary rales and ankle edema in a subsample of individuals, and an electrocardiograph and echocardiogram were recorded. HF was considered present if the individual did not have chronic pulmonary disease, but had evidence of cardiac disease and at least two of the following three characteristics: history of dyspnea, ankle edema, or pulmonary rales.

Figure 1. Incidence of heart failure by age group and gender in the Hillingdon Heart
Failure Study, London, from 1995 to 1997 (cases per 1000 population per year).

Table II. Prevalence of heart failure in a selection of populationbased studies.

Definite HF, defined as individuals who were breathless on exertion and who had objective evidence of underlying cardiac dysfunction, such as EF <40%, atrial fibrillation, or moderate-to-severe valve disease, was present in 2.3% of the general population 45 years of age and older in Birmingham, UK.¹⁵ Probable HF was reported in a further 0.8%.

In North America, several studies have reported similar figures, including the Cardiovascular Health Study16 and the National Health and Nutrition Examination Survey.17 In Olmsted County, Redfield and colleagues recently reported a prevalence of 2.2% in the population aged 45 years or older, applying the Framingham criteria to data in community- and hospital-based medical records.¹⁸ Of the 45 participants with a validated diagnosis of HF, 20 (44%) had an EF ≥50%. The prevalence of HF increased steeply with age: 0.7% for those 45 to 54 years of age; 1.3% in those 55 to 64 years of age; 5% in those 65 to 74 years of age; and 8.4% for those 75 years of age or older.

On the basis of these studies, a conservative estimate of the burden of HF would be that 4 million Americans and 6 million Europeans have HF out of a total population of 300 million and 460 million, respectively.

Prognosis

Despite the current use of life-prolonging therapies, such as angiotensin-converting enzyme inhibitors, β-blockers, and aldosterone receptor antagonists, a new diagnosis of HF carries a prognosis similar to that of bowel cancer, which is worse than that of breast cancer.^19,20 The comparative survival from HF and a variety of malignancies in the United States is shown in Figure 2.^21,22 Factors associated with a poorer prognosis include male gender, advanced age, more severe symptoms (higher New York Heart Association [NYHA] class), coronary artery disease (particularly acute coronary syndrome), hypotension, impaired renal function, hyponatremia, and elevated plasma BNP concentration.^19,23-25

The overall in-hospital mortality for patients admitted with HF is between 4% and 7%.²⁶ Those presenting with cardiogenic shock (low cardiac output with organ hypoperfusion) have a particularly high in-hospital mortality of ≈40%. Within 12 weeks of initial discharge, 1 in 4 acute HF patients are readmitted to hospital and ≈15% are dead, rising to 30% at 12 months from discharge. Death is most likely to occur due to progressive HF in the more severe grades of HF (often after several decompensations requiring hospitalization), but sudden death can occur at any time. Predicting likely life expectancy is more difficult than in terminal malignancies, making management decisions more difficult. Although HF prognosis is today better than it once was, the long-term mortality rate remains high.

Figure 2. Comparative 5-year mortality rates of heart failure and a number of malignant
conditions in the United States from 1990 to 2000.

Figure 3. Cumulative survival of the 552 individuals with incident (new) heart failure identified in the Hillingdon and Bromley (London) Heart Failure Studies from 1995 to 1998.

Figure 3 shows long-term survival in a cohort of 552 new cases of HF identified in the London Heart Failure Studies from 1995 to 1998. The survival of incident cases was similar in the Rotterdam Study, with 1-, 2-, and 5-year survival rates of 63%, 51%, and 35%, respectively.²⁷ Mortality is particularly high in the 3 months after diagnosis. The most recent data from the Framingham Heart Study shows a similar picture, but with evidence of improvement in prognosis in the past 30 years (Figure 4).⁹ Recent epidemiological data from the Olmsted County Rochester Epidemiology Project¹¹ and the United Kingdom confirm this improvement.^28,29

Temporal trends in heart failure

The number of people living with HF in Europe and North America is set to increase steeply. The rapid aging of the population in developed countries, lack of a fall in incidence, and improving prognosis of HF are all acting to increase the number of people with chronic HF—with no likely decrease anticipated in the near future. In 2002, 12.6% of the population was older than 65 years of age in the United States. This is expected to rise to 16.3% in 2020, 19.6% in 2030, and 22.4% in 2040.³⁰ Similar population projections have been made for Europe.³¹

Health-care burden

In the United States, HF continues to be the most common cause of hospitalization in people older than 65 years of age,^22,32 with a reported 26% rise in hospital discharge rates from 877 000 in 1996 to 1 106 000 in 2006. In Europe, 5% of adult internal medicine and geriatric hospitalizations occur as a result of HF—a larger proportion than those that occur as a result of myocardial infarction.³³ The age-adjusted rates for hospitalization may have peaked.³⁴ The duration of hospitalization for HF, particularly in Europe, is long with a median duration in the Euroheart Heart Failure survey of 11 days.³⁵ The typical duration of hospitalization in the United States is closer to 5 days.^36,37

Figure 4. Secular trends in survival of incident (new) heart failure in the Framingham Heart Study.

The readmission rate is also high, with one third to one half of patients being readmitted within 6 months in the United States32 or 12 months in Europe.^33,38 Mortality after hospitalization is also high, with 13% dying within 12 weeks in Europe. 35 Not all admissions are as a result of HF, but 20% to 50% of the emergency readmissions are likely to be so,^38,39 with some patients being readmitted multiple times.

Hospitalization is the main driver of the cost of HF to the health service. Approximately 60% of the total direct costs of HF relate to hospitalization, 1% to 2% of the total health care budget of many developed countries.^39,40 Added to the direct health care costs are the economic consequences of HF to patients and their families: the total (direct and indirect) cost of HF was estimated to be $39.2 billion in the United States for 2010.²²

From an individual perspective, the diagnosis of HF is associated with annual costs of approximately $8500 per patient according to data from the National Heart and Lung Institute cardiovascular health study.⁴¹ These estimates may underestimate the real costs as they are based on data featuring HF as the primary diagnosis; HF treatment costs also need to be taken into account for the many patients primarily hospitalized for one of the multiple comorbidities that typically accompany HF, such as hypertension, diabetes, and renal or lung disease. Whellan et al⁴² studied almost 1.4 million Medicare beneficiaries after their initial hospitalization for HF and found that 66% made a subsequent in-patient claim the following year. HF hospitalizations accounted for 15% of total in-patient costs, while 57% of costs were associated with noncardiovascular diagnoses.

Quality of life

HF has a major impact on many aspects of health-related quality of life. Studies from Europe have reported that people with HF have more severe physical impairment than those with chronic lung disease, arthritis, or diabetes and similar impairment to those with Parkinson’s disease or motor neuron disease (Figure 5).^43-45

Figure 5. Forest plot showing the mean EuroQOL (EQ-5D index) score of patients enrolled in the CARE-HF study compared with the mean EuroQol scores of patients with other chronic diseases and those of a sample of the UK population.

HF affects mobility and the ability to carry out usual activities. Mental health is affected, but less so than in patients with depression, although this can often coexist in patients with HF.^43,46 Assessment of quality of life is not routine in clinical practice, although NYHA class appears to correlate relatively closely with overall health-related quality of life, as assessed by the Short Form-36 questionnaire.⁴³ Work from the United States⁴⁷ suggests that a disease-specific questionnaire (the 23-item Kansas City Cardiomyopathy Questionnaire) is more sensitive to changes in overall clinical condition, than the EQ- 5D (a more generic, and much simpler, quality of life instrument),⁴⁸ or NYHA class. Narrative meta-analysis of the small number of published qualitative studies of HF suggests that social isolation, living in fear, and the loss of a sense of control are very common consequences of HF.⁴⁹

Conclusions

HF remains a major public health issue that is likely to increase in importance as the world’s population ages and survival from the syndrome continues to improve. The already huge cost of delivering care is also likely to increase. At a personal level, a diagnosis of HF will have an important impact on the individual’s length and quality of life, particularly where chronic disease management is poor. _

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19. Cowie MR, Wood DA, Coats AJ, et al. Survival of patients with a new diagnosis of heart failure: a population based study. Heart. 2000;83:505-510.
20. Quinn M, Babb P, Brock A, Kirby L, Jones J. Cancer Trends in England and Wales 1950-1999. London, UK: The Stationery Office, Office for National Statistics; 2001.
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Keywords: heart failure; epidemiology; economics; quality of life

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Luigi TAVAZZI, MD, PhD
GVM Care & Research
Fondazione Ettore Sansavini per la Ricerca Scientifica
Health Science Foundation Onlus
Cotignola, ITALY

Observational research today, particularly in the form of surveys and registries, which are widely used by the clinical/scientific community, has several applications.Well-definedmethodologies, which vary according to the specific aim(s) of the research, must be applied. This paper reports some observational findings on heart failure (HF) that were collected in a recent survey conducted by the European Society of Cardiology (ESC). This survey, with a multinational European network structure, was based on the principles of observational research. Its aim was to get a picture of real clinical profiles of both acute and chronic HF patients and to compare current therapeutic regimens in HF with ESC guideline recommendations. The main observations are as follows: (i) the clinical profiles of acute HF suggested by the ESC broadly identify small subsets of subjects with different outcomes, but this still leaves large clinical areas that are not fully characterized; (ii) acute HF therapy has remained practically unchanged in the last few decades, and we require proper randomized controlled trials for a better understanding of pathophysiological profiles; and (iii) although chronic HF therapy is evidence-based, drug doses currently used in clinical practice are far from recommended doses. In spite of these shortcomings, recently tested new drugs have been found to be both effective and safe, and with rapid incorporation in guidelines these should improve patient outcomes.

Over a decade has passed since Sakett advised, “If you find that a study was not randomized, we’d suggest that you stop reading it and go on to the next article.” What was the case in 1997 is not the case today. Today, observational research, particularly in the form of surveys and registries, which are widely used by the clinical/scientific community, has several applications, even though randomized controlled trials (RCTs), which protect against otherwise unavoidable bias, remain essential. RCTs are still the key to reliably evaluating the efficacy and safety of new drugs and diagnostic/therapeutic procedures and interventions.

It is important that this point is clear because many of the reservations concerning observational research derive from its inappropriate use. Observational research has its own objectives and well-defined methodologies that vary with the specific aim(s) of the research. This paper reports a few observational findings on heart failure (HF) collected in a recent survey conducted in several European countries.¹ Firstly, a few criteria that should be taken into consideration when designing an observational clinical study to obtain reliable and informative data are discussed. These criteria have been applied in the above-mentioned survey.

Table I. Preliminary questions that should be answered before starting an observational study.

Table II. In-hospital mortality registries.

General outline of a registry

Some preliminary questions that should be answered before starting an observational study are listed and briefly commented on below (Table I).

Outline of heart failure in Europe today

Several registries and surveys have been conducted in patients with either chronic or acute HF, but they all had one or some of the limitations highlighted above. In response to these shortcomings, the European Society of Cardiology (ESC) planned a new registry that attempted to overcome these limitations.¹ This study was conducted in 136 centers in 12 European countries. The countries, selected on the basis of their geographical distribution, provide a reasonably accurate representation of Europe overall. The centers, selected in each country according to a defined hospital/inhabitant ratio to provide an appropriate balance, were hospitals with dif- ferent types of cardiology facilities (with or without cardiac surgery and interventional facilities). The aim of this selection was to provide an up-to-date picture of HF in Europe by establishing a network with a broad spectrum of cardiology units capable of consecutively enrolling and following outpatients with HF and admitting patients with acute/worsening HF. From October 2009 to May 2010, 5118 patients were included in a pilot phase of this registry, and follow-up is ongoing. A few of the findings recorded at the enrollment of these patients, which are worthy of further consideration, are discussed below.¹

Hospital in-patients

Some 1892 patients were admitted to hospital for acute/ worsening HF. Mean age was 70 years, and about a third of the patients enrolled were female. More than half of the patients (64%) had an ischemic etiology confirmed by coronary angiography. At hospital entry, either pulmonary or peripheral congestion was detected in 82% of cases, and clinical signs of peripheral hypoperfusion were reported in 9% of the patients.

Atrial fibrillation was detected in 35% of the patients as well as a large QRS (≥120 ms). An echocardiographic examination was performed in 75% of the patients. The median ejection fraction (EF) was 38% (interquartile range [IQR] 27%- 52%); 39% of the patients had preserved EF, defined as EF >40%.Moderate-to-severemitral regurgitation was diagnosed in 43% of the patients. Echocardiograms were performed during hospitalization, but not necessarily on admission. As a result, we do not know what the EF value was when the clinical status of the patient was at its worst. However, the proportion of patients with preserved or mildly compromised ventricular systolic function observed in this cohort of acute or worsening HF patients (approximately 40%) is similar to that found in other comparable surveys,^2-5 confirming that a drop in ventricular systolic contractile performance is not necessarily the precipitating cause of decompensation.

Comorbidities were frequent. Anemia, defined as a hemoglobin level <12 g/dL, was detected in 31% of patients; an estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m² and <30 mL/min/1.73 m² was reported in 33% and 10% of patients, respectively. Over a third (35%) of patients had a history of diabetes, while 54% had hyperglycemia on admission.

N-terminal prohormone of brain natriuretic peptide (NT-pro- BNP) and brain natriuretic peptide (BNP) were measured at entry in 489 and 204 patients only. The median values were 4007 pg/mL (IQR 2043-9487 pg/mL) and 870 pg/mL (IQR 423-1950 pg/mL), indicating the severity of patients’ clinical condition at hospital admission. Troponin (I or T) was measured in 987 patients with a median value of 0.04 ng/mL (IQR 0.01-0.29 ng/mL). These important markers of ventricular stress and compromise have not so far been fully incorporated in clinical practice.

The definition of acute HF reported in international guidelines is quite vague,^6,7 which has led to the inclusion of heterogeneous populations under the umbrella of “acute heart failure.” This is one of most important reasons for the failure to have developed active drugs in the setting of acute HF, as most RCTs adopted an “all comers” approach. The current European guidelines for the diagnosis and treatment of HF propose a stratification of patients admitted for acute HF.² Figure 1A (page 380) shows the stratification of patients enrolled in the ESC-HF (European Society of Cardiology Heart Failure) survey, according to the clinical profiles in the ESC guidelines.¹ Decompensated HF was most frequent clinical profile (75% of the cases), while pulmonary edema and cardiogenic shock were reported in 13% and 2% of patients, respectively. Figure 1B shows the overall rate of in-hospital mortality stratified by clinical profile. As expected, patients with cardiogenic shock have the worst short-term prognosis. For this reason, patients presenting with this clinical profile should be managed with specific, intensive approaches. Patients with hypertensive HF are the other extreme, showing the most favorable in-hospital survival.

It is unlikely that the inclusion of both these patient categories in the same trial testing the same drug could lead to meaningful and applicable results. Whether the category of “decompensated heart failure” (75% of patients) represents a homogeneous group of patients is difficult to envisage, and to believe. There is the need, in future, to better clarify the relationship between clinical pictures and the definitions of profiles suggested by the guidelines to obtain a patients’ categorization that allows both individual decision-making and the identification of patient populations appropriate for testing specific new drugs.

Overall, 71 patients died during their hospital stay. When age and two major markers of cardiovascular function (systolic blood pressure and reduced renal function) were considered, 93% of deaths could be explained by the presence of at least one of these factors. The median length of hospitalization was 8 days (IQR 5-11 days), and 48% of patients were managed in the intensive care unit for amedian of 4 days (IQR 2-7 days). The median body weight reduction during the hospital stay was 2 kg. At discharge, pulmonary congestion, peripheral congestion, or both were still present in 10%, 18%, and 24% of cases, respectively.

Figures 1A and 1B. Clinical profiles and in-hospital mortality rates of patients with acute/worsening heart failure.

The mean duration of hospitalization, compared to that recorded in a previous ESC survey on acute HF,⁴ was shortened by a day (from 9 to 8 days). The length of hospitalization in Europe remains approximately twice the length of hospitalization reported in US surveys.^8,9 However, the number of patients showing clinical signs of congestion at discharge is still elevated and may account, at least in part, for the high rates of hard events and rehospitalizations observed in the few months after discharge in previous studies.^10,11

Intravenous diuretics were used in 85% of cases. The median dose of furosemide used during the hospital stay was 60 mg per day (IQR 40-100 mg per day). Nitrates and inotropes were administered in 18% and 10% of patients. Of the inotropes, the most used was dobutamine (in 4.6% of patients) followed by levosimendan (in 2.4% of patients). In fact, in spite of many trials testing a number of new drugs in acute HF patients in the last decade, these patients are still treated in the same way today as the same patients were 20 years ago.

Chronic heart failure in outpatients

In this population (3226 patients enrolled), the rates of moderate (New York Hospital Association [NYHA] class I-II) and severe HF (NYHA class III-IV) were 72% and 28%, respectively. Ischemic etiology accounted for just 40% of cases, with angiographic confirmation in 85% of cases. EF was available for 2857 patients (89%): its median value was 36%(IQR 30%- 46%) and preserved EF (>40%) was reported in 36% of cases, a figure not far from that observed in patients with acute/ worsening HF. A hemoglobin level <12 g/dL was reported in 19% of cases, and an eGFR <60 and <30 mL/min/1.73 m² was reported in 41% and 5% of patients. NT-proBNP and BNP were measured in a minority of cases (747 and 285 patients). Median values were 1387 pg/mL (IQR 485-3381 pg/ mL) and 390 pg/mL (IQR 133-870 pg/mL).

The use of pharmacological treatments is reported in Table III. A blocker of the renin-angiotensin system, β-adrenergic blockers, and aldosterone blockers were prescribed in 88%, 87%, and 44% of cases, respectively. The combination of renin-angiotensin system blockers, β-adrenergic blockers, and aldosterone blockers was prescribed in 35% of patients, where- as the combination of β-adrenergic blockers, angiotensinconverting enzyme (ACE) inhibitors, and angiotensin receptor blockers was reported in just 3% of patients. Table IV reports the doses of evidence-based treatments prescribed.

Table III. Prescribed pharmacological treatment for chronic heart failure (n=3226 patients).

Table IV. Doses of evidence-based treatments used in the ESC-HF Pilot Survey with respect to the recommended target doses.

Prescribed doses of recommended treatments represent a major issue in chronic HF therapy. Ramipril (never tested in HF patients in RCTs) and enalapril were the most prescribed ACE inhibitors; the target dose of these drugs (assuming the target dose advised for ischemic heart disease for ramipril) was achieved in 38% and 46% of cases. For angiotensin receptor blockers, the target dose of candesartan, losartan, and valsartan was reached in 28%, 19%, and 17% of cases.

The target dose of carvedilol, bisoprolol, and metoprolol was reached in 37%, 21%, and 21% of patients, whereas the target dose of spironolactone, canrenone, and eplerenone was prescribed in 22%, 61%, and 33% of patients, respectively. Overall, beside a much improved rate of prescription of recommended treatments compared to previous European surveys, the drugs’ doses did not change at all. They actually correspond to about a third of the suggested optimal dose, according to current guidelines.

This behavior of physicians, which is common to all European countries, should be seriously considered. The first obvious question to ask is whether the expected drug effects, from the results of RCTs in which most patients were treated at target doses, are actually achieved. We have no answer to this key question. A second question is why do physicians not uptitrate drug doses as they are consistently recommended to? Are they not properly informed? If this was the case, unlikely though this possibility is, the matter could be dealt with via education and our goal would be to find more effective approaches in continuous medical education. Alternatively, perhaps physicians are satisfied with the clinical results achieved with the doses prescribed? If this is the case, we should consider and test whether lower doses than those recommended may be enough in the polypharmaceutical approach that we nowadays implement in HF therapy. Finally, could it be that full recommended doses are not tolerated by most HF patients in the real world?

We know that patients enrolled in clinical trials according to a number of inclusion/exclusion criteria represent a small, selected portion of the universe of HF patients. Moreover, the RCTs that tested recommended drugs against placebo were performed many years ago, with a background therapy that was markedly different to that which is currently used. The target doses recommended today were defined in those trials, which were not validated afterwards. Maybe, contrary to our expectations, these doses are not optimal for many patients.

This may particularly be the case for β-blockers. The history of β-blocker implementation is represented in Figure 2 (page 381),¹² showing data recorded in a long-term Italian registry since 1995. Gradually, the prescription of the β-blockers increased until now about 80% of patients are taking these drugs. However, the doses have remained unchanged, at about one third of those recommended. A recent instructive experience occurred during SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial), which tested ivabradine, a pure bradycardic agent, versus placebo on top of recommended treatments, including β-blockers.

Because both ivabradine and β-blockers reduce heart rate, an important goal of the trial (both for safety and efficacy) was to investigate the tested drug—ivabradine—when added to the highest tolerated dose of β-blockers. All the investigators were kept aware of this important condition and they were encouraged to modulate the β-blocker dose according to guideline recommendations, and required to report the reasons for not achieving target dose if this was not reached. In spite of this cogent approach, only 56% of patients were treated with at least half the target dose of β-blocker¹³—44% of patients were given less than half target dose. The main reasons for the failure to reach the goal were collateral effects, such as hypotension, asthenia, or comorbidities. The association of ivabradine with the best tolerated dose of β-blocker improved outcome without increasing undesired effects.

Figure 2. Yearly prescription rate of β-blockers in patients with chronic heart failure recorded in the Italian IN-CHF registry over time (1995- 2010). Based on data from reference 12.

Interestingly, a similar dissociation between recommendations and clinical practice was noted in a European survey of electrical device implantation. According to current guidelines,5 37% of patients had clinical characteristics that suggested an implantable cardioverter-defibrillator (ICD) was potentially suitable. Of these patients with a theoretical indication for the implant, only one third (33%) actually received an ICD implant. Similarly, of the 6% of patients with a clinical profile suitable for a CRT (cardiac resynchronization therapy) device, only 2.2% actually received an implant.

The ESC-HF survey commented on above provides a clear picture of the clinical profiles of both acute and chronic HF patients in Europe, the rate of use of guideline-recommended evidence-based treatments, and detailed data on the proportion of patients in whom target dose was reached, as well as the adherence to recommendations on device implantation. New therapeutic options have been shown to be as effective and safe in two recent large trials. The EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) trial¹⁴ showed that eplerenone, a selective aldosterone receptor blocker, proved to be as effective on hard end points in patients with postacute myocardial infarction and left ventricular dysfunction and is also beneficial in patients with mild-to-moderate HF of any etiology.

The SHIFT trial showed that ivabradine, an I_f current blocker that selectively decreases heart rate, significantly reduces the incidence of both HF mortality and hospitalization in a broad population of patients with HF of any etiology and any severity.¹³ The important incremental knowledge provided by this trial is that the modulation of heart rate per se, independent of any other effect, can delay the progression of HF and prevent HF-related adverse events.¹⁵ Future guidelines on HF management will probably include this new information in terms of recommendations, and future observational studies will show the impact of their incorporation in clinical practice. _

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12. Fabbri G, Gorini M, Maggioni AP, Cacciatore G, Di Lenarda A, Tavazzi L. Unpublished.
13. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.
14. Zannad F, McMurray J, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011; 364:11-21.
15. Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376: 886-894.

Keywords: observational research; heart failure

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Forough RASHIDI, MB ChB
GVM Care & Research
Fondazione Ettore Sansavini per la Ricerca Scientifica
Health Science Foundation Onlus
Cotignola, ITALY

Kenneth DICKSTEIN, MD, PhD
University of Bergen
Stavanger University Hospital
NORWAY

The objective of this paper is to review the evidence provided by the major clinical trials that have yielded new advances in heart failure management. Heart failure is a major public health burden associated with high morbidity and mortality, frequent hospitalization, and substantial cost. Prevalence is increasing through the combined effects of an aging population and the efficacy of heart disease therapies, in particular the prolonged survival associated with coronary artery disease. The cornerstone of the pathophysiology of heart failure is the activation of key neurohormonal systems (reninangiotensin- aldosterone system and sympathetic nervous system). Landmark trials have established renin-angiotensin-aldosterone blockade using angiotensin- converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor blockers, along with sympathetic blockade using β-blockers, as the mainstays of current treatment, conferring significant morbidity and mortality benefit. Recently, the Systolic Heart failure treatment with If inhibitor ivabradine Trial (SHIFT) demonstrated that heart rate reduction with ivabradine added to adequate β-blockade improved clinical outcomes in patients with heart failure.

Heart failure is a common clinical syndrome dominated by signs and symptoms of fluid retention, even if many patients are asymptomatic. As the end stage of various cardiac conditions, it is associated with high morbidity and mortality, frequent hospitalization, and substantial socioeconomic cost. It affects an estimated 5 million Americans, with over 550 000 new patients being diagnosed annually,¹ and a total of 15 million European patients, equivalent to 2% to 3% of the total population and 10% to 20% of the over-70s.² Prevalence is increasing because of population aging and improved management of heart disease, in particular coronary artery disease.^2-4

Heart failure can be divided into two types, depending on whether it is associated with systolic dysfunction (the more studied variant) or diastolic dysfunction. However, some consider the distinction arbitrary.⁵ Most trials have included only patients with left ventricular (LV) systolic dysfunction defined by an ejection fraction (EF) below 35% to 40%. Current drug therapy is based on our understanding of the pathophysiology behind heart failure progression. This review focuses on the drug management of heart failure as recommended in current guidelines^2-4 on the basis of the evidence garnered from pivotal trials, and it includes prevention of acute decompensation that often requires hospitalization. We shall not be considering the lifestyle changes and dietary measures that are an integral part of heart failure management, nor the treatment of cardiac conditions leading to heart failure. Nor will our review encompass recently introduced nondrug approaches, such as implantable cardioverter defibrillators and cardiac resynchronization therapy using biventricular pacing.

Drug therapy remains the mainstay of management. Its key objectives are symptom relief, slowing of disease progression (even reversal of myocardial dysfunction, if possible), and prolongation of survival.

The management of heart failure patients is based on two main pathophysiological mechanisms: inhibition of the reninangiotensin- aldosterone system and inhibition of the sympathetic nervous system. Current guidelines recommend a number of medications that improve patient symptoms, including angiotensin-converting enzyme (ACE) inhibitors, β-blockers, diuretics, digoxin, angiotensin II receptor blockers (ARBs) (in patients who cannot tolerate ACE inhibitors), and vasodilators, such as nitrates.^2-4 Among these, some medications have been shown to improve survival, such as ACE inhibitors, β-blockers, ARBs, and in some subsets of patients spironolactone and eplerenone.

Inhibition of the renin-angiotensin-aldosterone system

_ ACE inhibitors in heart failure and their effect on mortality
Several trials have shown ACE inhibitors to prolong survival in various disease stages ranging from severe heart failure to asymptomatic LV dysfunction.^6-9

_ CONSENSUS
The COoperative North Scandinavian ENalapril SUrvival Study (CONSENSUS) investigated the effect of adding enalapril 40 mg to diuretics, digitalis, and spironolactone, but not β-blockers, in 253 patients with severe heart failure. Enalapril improved symptoms and life expectancy compared with placebo, but had no impact on sudden cardiac death.⁶

_ V-HeFT-II
The Vasodilator-Heart Failure Trial II (V-HeFT-II) randomized 804 men with New York Heart Association (NYHA) class II and III heart failure to receive enalapril 20 mg (n=403) or hydralazine/ isosorbide dinitrate (n=401) for 2 years. Sudden death was 14% and mortality from progressive heart failure 12% in the enalapril group compared with 23% and 10% in the hydralazine/ isosorbide dinitrate group.⁷

_ SOLVD
The Studies Of Left Ventricular Dysfunction–Treatment (SOLVDTreatment) randomized 2569 patients with NYHA class II to III heart failure and EF <35% to enalapril 20 mg or placebo. After an average of 41 months, there were 16% fewer deaths in the enalapril group (P=0.0036), primarily deaths attributed to progressive heart failure, and 26% fewer hospitalizations (P<0.0001).8 SOLVD-Prevention randomized 4228 asymptomatic patients with EF ≤35% to enalapril 2.5 mg-20 mg or placebo. At an average of 37 months, total mortality was 8% lower in the enalapril group (nonsignificant [NS]) and there were fewer deaths and hospitalizations due to heart failure (P<0.001).⁹

_ Other trials
The Survival And Ventricular Enlargement (SAVE) trial with captopril,¹⁰ the Acute Infarction Ramipril Efficacy (AIRE) trial with ramipril,¹¹ and the TRAndolapril Cardiac Evaluation (TRACE) trial with trandolapril¹² all showed that ACE inhibition significantly improves survival and reduces morbidity and mortality due to major cardiovascular events in patients with heart failure and/or a low EF.

The above trials were consistent in showing that ACE inhibitors should be the basis for therapy, along with a diuretic and digoxin as necessary, in all patients with symptomatic LV dysfunction, unless contraindicated or not tolerated. However, they also showed, and clinical experience has confirmed, that potassium and creatinine levels need to be monitored in patients receiving ACE inhibitors.

Treatment may be associated with side effects such as hypotension and cough. ARBs are an alternative to ACE inhibitors for patients who cannot tolerate an ACE inhibitor.

_ Angiotensin II receptor blockers
ARBs are indicated mainly in patients in whom ACE inhibitors are contraindicated. The key trials in this regard include the Valsartan Heart Failure Trial (Val-HeFT), which showed that valsartan significantly reduced the combined end point of mortality and morbidity and improved the signs and symptoms of heart failure versus placebo13; the CHARM-Added trial (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity—in patients with LV dysfunction already taking ACE inhibitors), which revealed that candesartan (target dose 32 mg/day) significantly improved outcomes versus placebo in patients already receiving an ACE inhibitor or β-blocker¹⁴; the CHARM-Alternative trial (CHARM—in patients with LV dysfunction intolerant to ACE inhibitors), in which candesartan at the same target dose of 32 mg/day significantly reduced cardiovascular mortality and hospitalization for heart failure in patients unable to tolerate an ACE inhibitor¹⁵; and the VALIANT trial (VALsartan In Acute myocardial iNfarc- Tion), which found valsartan 160 mg to be as effective as captopril 150 mg in all-cause mortality in patients with myocardial infarction complicated by heart failure (the combination of valsartan plus captopril, however, provided no added survival benefit, serving only to increase the rate of adverse events).¹⁶

_ Aldosterone antagonists
Aldosterone antagonists are recommended in patients with NYHA class III or IV heart failure associated with systolic dysfunction in the absence of hyperkalemia and renal dysfunction.² The recommendation is based on three placebo-controlled trials: the Randomized ALdactone Evaluation Study (RALES) in class III and IV heart failure patients with systolic dysfunction (EF ≥35%), which reported a 30% reduction in the relative risk (P<0.001) of all-cause mortality in the group taking spironolactone¹⁷; the Eplerenone Post-AMI Heart failure Efficacy and SUrvival Study (EPHESUS) in a total of 6632 patients with low EF (≤40%), which showed reductions in all-cause mortality (P=0.008) and the combined end point of cardiovascular mortality and hospitalization for cardiovascular events (P=0.002) over a mean follow-up of 16 months¹⁸; and, most recently, the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF), which confirmed the reductions observed in all-cause mortality (P=0.008) and cardiovascular mortality plus hospitalization for heart failure (P<0.001), only this time in patients with mild symptoms, over a median follow-up of 21 months (the trial was stopped prematurely according to prespecified rules).¹⁹

Inhibition of the sympathetic nervous system with β-blockers

The European and American guidelines recommend β-blockers in symptomatic heart failure unless contraindicated or not tolerated. As with ACE inhibition, the recommendations are based on a number of large-scale randomized trials.

_ US Carvedilol Heart Failure Trials Program
In 1996, the US Carvedilol Heart Failure Trials Program was the first to demonstrate the benefit of added β-blockade in heart failure, with reductions versus placebo of 65% in overall mortality and 38% in the combined risk of death or hospitalization (both P<0.001), leading the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion.²⁰

_ CIBIS-II
The Cardiac Insufficiency Bisoprolol Study II (CIBIS II) randomized 2647 patients with class III to IV heart failure and EF ≤35% to bisoprolol 1.25-10 mg or placebo. The trial was stopped after the second interim analysis due to the lower overall mortality on bisoprolol (n=156 [12%] vs n=228 [17%] on placebo; P<0.0001), as well as significantly fewer sudden deaths and all-cause hospital admissions.²¹

_ COPERNICUS
In 2002, the CarvedilOl ProspEctive RaNdomIzed CUmulative Survival (COPERNICUS) trial reported reductions versus placebo of 27% (P<0.00002) in the combined risk of death or hospitalization for a cardiovascular cause and of 40% in the number of days in hospital for heart failure (P<0.0001) after a mean 10.4 months in 1156 patients with severe heart failure randomized to carvedilol (3.125-50 mg target dose).²²

_ SENIORS
The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure (SENIORS) addressed the hitherto neglected topic of the safety and efficacy of &beta-blockade in patients aged 70 years or older with a broad range of EF values. Over a mean duration of 21 months, the primary outcome (a composite of all-causemortality or cardiovascular hospital admission) occurred in 31.1% of patients on nebivolol compared with 35.3% on placebo (P=0.039), leading the authors to conclude that β-blockade with nebivolol is safe and effective in elderly patients with heart failure.²³

Heart rate reduction by sinus node inhibition

In 1986, the Norwegian cardiologist John Kjekshus tested the hypothesis that the degree of potential benefit of β-blockade after myocardial infarction depends quantitatively on the re duction in heart rate it achieves. Exhaustive and stringent review of acute and long-term intervention trials revealed a relation between the actual reduction in resting heart rate and the percentage reduction in mortality in each trial (r=0.60, P<0.05). Kjekshus also uncovered a near-similar relation between the reduction in resting heart rate and nonfatal reinfarction (r=0.59, P<0.05).²⁴

These studies set the theoretical stage for the development of agents that would be devoid of the unwanted effects of &beta- and calcium blockade. They would lower heart rate while having little or no activity elsewhere in the body. First-in-class of these pure heart rate–lowering drugs was ivabradine, a specific inhibitor of the I_f current in the sinoatrial node.²⁵

_ SHIFT
The recent Systolic Heart failure treatment with If inhibitor ivabradine Trial (SHIFT) randomized 6558 patients with moderate- to-severe heart failure and systolic dysfunction (EF ≤35%) to ivabradine or placebo.26 All patients received concomitant guideline therapy with ACE inhibitors, ARBs, β-blockers, aldosterone antagonists, and diuretics. The primary end point was a composite of cardiovascular death and hospitalization for worsening heart failure. Over a mean follow-up of 23 months, 793 patients in the ivabradine group (24%) had a primary end point event compared with 937 (29%) of those taking placebo (P<0.0001). The effects were driven mainly by fewer hospitalizations for worsening heart failure (P<0.0001) and fewer deaths due to heart failure (P=0.014). The hazard ratio for cardiovascular death or hospitalization for worsening heart failure was 18%lower than in the placebo group. Serious adverse events rates were also fewer in the active treatment group (P=0.025), leading the authors to conclude that ivabradine was effective and well tolerated and should have an important role to play in the treatment of heart failure in the future.

Conclusion

Insights into the fundamental mechanisms of heart failure, dominated by activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, have driven the major advances in drug therapy achieved in recent decades, namely the addition to therapy of ACE inhibitors, ARBs, and aldosterone inhibitors, on the one hand, and β-blockers on the other. More recently, a novel approach to reducing heart rate by sinus node inhibition with ivabradine has been shown to improve clinical outcomes and emphasizes the importance of achieving adequate heart rate reduction in patients with heart failure. _

References
1. American Heart Association. Heart Disease and Stroke Statistics: 2005 Update. Dallas, Tex: American Heart Association; 2005.
2. Dickstein K, Cohen-Solal A, Filippatos G, et al; Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of European Society of Cardiology. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-2442.
3. Swedberg K, Cleland J, Dargie H, et al; Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J. 2005;26:1115-1140.
4. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90.
5. Aurigemma GP, Gaasch WH. Clinical practice. Diastolic heart failure. N Engl J Med. 2004;351:1097-1105.
6. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435.
7. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine- isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303-310.
8. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302.
9. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685-691.
10. Pfeffer MA, Braunwald E, Moye LA, et al; SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327:669-677.
11. Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-828.
12. Kober L, Torp-Pedersen C, Carlsen JE, et al; Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 1995;333:1670-1676.
13. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675.
14. McMurray JJ, Ostergren J, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771.
15. Granger CB, McMurray JJ, Yusuf S, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772-776.
16. Pfeffer MA, McMurray JJ, Velazquez EJ, et al; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906.
17. Pitt B, Zannad F, Remme WJ, et al; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717.
18. Pitt B, Remme W, Zannad F, et al; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.
19. Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011; 364:11-21.
20. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349-1355.
21. CIBIS II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13.
22. Packer M, Fowler MB, Roecker EB, et al; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194-2199.
23. Flather MD, Shibata MC, Coats AJ, et al; SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26:215-225.
24. Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F.
25. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757-1765.
26. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.

Keywords: angiotensin-converting enzyme inhibitor; angiotensin receptor blocker; _-blocker; diuretic; heart failure; ivabradine; systolic dysfunction

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Michel KOMAJDA, MD
Department of Cardiology
Pierre and Marie Curie University
Assistance-Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital
Paris, FRANCE

Heart failure with reduced ejection fraction (EF) is associated with poor outcomes, and heart rate is a risk factor for cardiovascular events in this condition. SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) enrolled 6505 chronic heart failure patients in sinus rhythm with a recent heart failure hospitalization, low EF ≤35%, and elevated heart rate ≥70 bpm to investigate the role of heart rate in heart failure. Patients were randomized to either the specific heart rate–reducing agent ivabradine, an If current inhibitor, or to placebo, on top of the best possible recommended heart failure therapy. The addition of ivabradine resulted in a highly significant 18% reduction in the occurrence of the primary composite end point, cardiovascular mortality or heart failure hospitalization. This beneficial effect was mainly driven by significant 26% reductions in heart failure deaths and heart failure hospitalizations. Overall, the safety of ivabradine was good; in particular, the number of bradycardic adverse effects was low. This good cardiac tolerability was recently confirmed in a 24-hour Holter monitoring substudy. Ivabradine also improved quality of life. In patients with reduced EF, elevated heart rate, and in sinus rhythm, the addition of ivabradine on top of recommended heart failure medications improves cardiovascular outcomes. Special attention should be paid to heart rate measured under standardized conditions, and efforts should be made to reduce elevated heart rate to <60 bpm.

Heart rate is recognized as a strong predictor of mortality and morbidity in the general population as well as in patients with a broad spectrum of cardiovascular disorders, including hypertension, myocardial infarction, coronary artery disease, and chronic heart failure (with reduced as well as preserved ejection fraction).^1-6 The underlying mechanism of the deleterious effect of elevated heart rate remains partially unknown. Elevated heart rate creates an imbalance in oxygen supply/ expenditure to the myocardium, but it is also is associated in experimental models with vascular oxidative stress, endothelial dysfunction, acceleration of atherogenesis, and coronary plaque instability.⁷

In heart failure, β-blocker therapy is associated with a marked improvement in outcomes that seems proportional to the magnitude of heart rate reduction and might involve a reverse remodeling effect.^8,9 However, since β-blockers have multiple mechanisms of action, it was not known until the recent publication of SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) whether specific heart rate reduction obtained by a heart rate–reducing agent devoid of any other significant pharmacological properties, the If channel inhibitor ivabradine, would be beneficial in this condition. This question is all the more important as recent surveys conducted in Europe suggest that more than 50% of patients with heart failure have an elevated heart rate, despite the wide dissemination of β-blockers, suggesting therefore that underdosage is common in real life.^10,11

Figure 1. Kaplan-Meier cumulative event curves for different end points in SHIFT.

Major findings from SHIFT

In a population of 6505 chronic heart failure patients with reduced ejection fraction, who had experienced a recent heart failure hospitalization, were in sinus rhythm, and with elevated heart rate ≥70 bpm, the addition of ivabradine 5 mg to 7.5 mg bid on top of the best possible recommended therapy provided additional benefit and significantly reduced the occurrence of the primary composite outcome, cardiovascular mortality or heart failure hospitalizations, by 18%. This effect is driven mainly by a significant reduction in heart failure hospitalizations (-26%) and heart failure deaths (–26%) (Figure 1).¹²

This beneficial effect was observed in a well-treated population: 93% of the patients were taking an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker, and 89% were receiving a β-blocker. Moreover, 56% of these patients were receiving at least 50% of the β-blocker target dose recommended by the European Society of Cardiology guidelines and 26% were at target dose.

The baseline characteristics of the population show that this was a relatively young, predominantly male (76%) population with a mean age of 60 years and with ischemic etiology (68%). The mean ejection fraction was markedly diminished (29%), and patients were almost evenly distributed in terms of heart failure severity, based on NYHA (New York Heart Association) class (49% in class II, 51% in class III/IV).

The beneficial effect on the outcomes detailed above occurred rapidly, and the survival curves show that the separation was rapid after randomization. This mirrored heart rate reduction, which occurred early on: heart rate decreased from 80 to 64 bpm 1 month after randomization in the ivabradine group, and the difference, corrected for placebo, was 11 bpm. The difference in heart rate between the two groups was 8 bpm at the end of the trial.

The reduction in the occurrence of the primary composite end point was consistent in all prespecified subgroups, including age, sex, etiology of heart failure, and use/nonuse of β-blockers, with one notable exception: the magnitude of benefit derived from ivabradine was significantly greater in the subgroup with baseline heart rate above the median value (77 bpm in the SHIFT population).

In the subgroup of patients receiving at least 50% of the target dose of β-blockers, the effects of ivabradine were consistent with those observed in the overall population, although less marked, probably due to a lower rate of cardiovascular events and therefore a limited power.

Table I. Adverse events leading to treatment discontinuation in
the ivabradine and in the placebo arms of SHIFT.

There was also a small but significant improvement in quality of life, assessed by change in NYHA class and patient and physician reported assessment at the last visit, in ivabradinetreated patients. This was recently confirmed by a subanalysis of health-related quality of life using the Kansas City cardiomyopathy questionnaire, a self-reported instrument that includes several dimensions, such as symptoms, quality of life, and social limitations.¹³

Overall, the tolerability of ivabradine was good and serious adverse effects were less frequent in the active arm than in the placebo arm (Table I).¹² Symptomatic and asymptomatic bradycardia were reported in 5% and 6% of patients, respectively, in the ivabradine arm, but led to treatment discontinuation in only 1% of cases for each of these two adverse effects. Visual side effects were also uncommon and led to treatment discontinuation in only a few cases. Overall, approximately 70% of the patients in the ivabradine arm were at target dose (7.5 mg bid) and less than 10% had to be downtitrated to the lowest dosage (2.5 mg bid).

This excellent cardiac tolerability was recently confirmed by a 24-hour Holter substudy conducted in 602 patients: in the 501 patients suitable for analysis after 8 months of treatment, the number of pauses was similar in both groups; while in the ivabradine group the number of second or higher degree atrioventricular blocks was smaller (4 vs 9); there were no cases of third degree AV block; and only the number of heart rate episodes <40 bpm increased (54 vs 21).¹⁴

Clinical implications

The first lesson from SHIFT is therefore that the addition of the selective heart rate–reducing agent ivabradine on top of the best possible recommended therapy, including βblockers in 90%of cases, significantly improves cardiovascular outcomes and particularly hospitalizations or deaths related to heart failure, with good tolerability.

The SHIFT study also demonstrates that heart rate is not only a risk marker, but also a risk factor in heart failure: the risk of cardiovascular outcomes increases with heart rate and every 5 bpm increase in baseline heart rate is associated with a 16% increase in the risk of primary outcome in the placebo arm. The beneficial effect of ivabradine is solely accounted for by heart rate reduction, since the adjustment for change in heart rate at 28 days in the active arm neutralizes the effect of the drug for subsequent outcomes.¹⁵ Another important finding is that in the active arm, minimal risk is observed in patients who reach a target heart rate <60 bpm at 28 days.

SHIFT suggests therefore that greater attention should be paid to a simple biomarker, resting heart rate, a powerful predictor of outcomes in chronic heart failure. Indeed, epidemiological studies suggest that despite the dissemination of β-blocker therapy, heart rate remains elevated >70 bpm in a substantial proportion of patients.^10,11

This is at least partially the result of underdosage of this therapy as a result of poor tolerance, prescribers’ reluctance, or lack of awareness of recommended target doses in real life. In the Heart Failure pilot study, comprising 3226 patients with chronic heart failure enrolled in twelve European countries, only 21% to 37% of patients were at β-blocker target dose (of carvedilol, bisoprolol or metoprolol). In CIBIS-ELD (Cardiac Insufficiency BIsoprolol Study in Elderly), the primary objective of reaching and maintaining target dose of carvedilol or bisoprolol was observed in only 25% of patients.¹⁶

_ What should the optimal heart rate in chronic heart failure be?
Since the analysis of the relationship between heart rate reduction achieved at 28 days with ivabradine and subsequent outcomes suggests that patients with the lowest risk reached a heart rate <60 bpm, it is reasonable to recommend this target in daily practice when tolerated. There is no information available on the potential benefit/harm of lowering heart rate further, although it should be remembered that cardiac output is the product of heart rate and stroke volume, so that very low heart rates result in a significant decrease in cardiac output and therefore in reduced oxygen delivery to the body. Empirically, achieving a target heart rate at rest of 50-60 bpm therefore seems a reasonable objective.

_ Is uptitrating &btea;-blockers or combining ivabradine with low/medium doses of β-blockers the best strategy?
There is no clear answer yet to this important practical question from the SHIFT results, since more than 50% of the patients enrolled in this trial were taking at least half of the target recommended dose and 26% were at target dose. The investigators were repeatedly encouraged by the Executive Committee to provide the best possible therapy to their patients, including β-blockers at target dose. The SHIFT results should therefore be interpreted as heart rate reduction by ivabradine bringing an incremental benefit in patients with elevated heart rate who are unlikely to tolerate maximal doses of β-blockers, as frequently observed in daily practice.

_ Can ivabradine replace β-blocker therapy in chronic heart failure?
SHIFT provides no insights into this question, since the overwhelming majority of patients included in this trial were on β-blocker therapy (90%). It was not a trial designed to compare ivabradine face to face with β-blocker therapy, and the only scientifically valid conclusion that can be drawn from SHIFT is that in chronic heart failure patients treated with β-blockers whose heart rate remains elevated for any reason, ivabradine should be considered on top of their existing therapy in order to improve outcomes, particularly heart failure events, regardless of efforts to maximize β-blocker dose. This course of action has indeed been proposed in the recently published Australian and New Zealand Guidelines.¹⁷ However, the magnitude of the benefit provided by ivabradine was similar in the small subgroup who did not receive a β-blocker (10% of the population) to that observed in the rest of the population, suggesting that reducing heart rate with ivabradine in chronic heart failure patients intolerant to β-blockers provides a similar benefit to that observed in other patients and could be considered as an alternative.

_ Can the results be generalized to the overall heart failure population?
Patients in SHIFT were selected on the basis of several criteria: high resting heart rate >70 bpm, normal heart beat (sinus rhythm), and reduced ejection fraction (≤35%). In addition, the proportion of elderly patients was limited. Therefore, the effects of ivabradine cannot be generalized to apply in the overall heart failure population, nor in particular to patients with permanent atrial fibrillation (where there is no indication for ivabradine due to the mechanism of action of this drug) or to patients with heart failure and preserved ejection fraction.

Conclusion

SHIFT has brought new insights into the role of heart rate as a risk factor in chronic heart failure and on the importance of heart rate reduction—when elevated—in improving outcomes in heart failure in sinus rhythm and with reduced ejection fraction. The addition of a specific bradycardic agent, ivabradine, to the best possible recommended heart failure therapy provides a significant improvement in cardiovascular outcomes in this population and should be considered to further reduce the burden of chronic heart failure and the risks related to this disorder. The tolerability of the combination of this new heart rate–reducing agent with β-blockers was good, particularly with regards to cardiac safety. _

References
1. Kannel WB, Kannel C, Paffenbarger RSJR, Cupples LA. Heart rate and cardiovascular mortality: the Framingham study. Am Heart J. 1987;113:1489- 1494.
2. Kolloch R, Legler UF, Champion A, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the International Verapamil SR/transdolapril Study (INVEST). Eur Heart J. 2008;29: 1327-1334.
3. Hjalmarson A, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol. 1990;65:547-553.
4. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
5. Lechat P. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation. 2001;103:1428-1433.
6. Komajda M, Carson PE, Hetzel S, et al. Factors associated with outcome in heart failure with preserved ejection fraction: findings from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE). Circ Heart Fail. 2011;4:27-35.
7. Custodis F, Schirmer SH, Baumhakel M, Heusch G, Bohm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010;56:24.
8. McAlister FA, Wieber N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction and death in patients with heart failure. Ann Intern Med. 2009;150:784-794.
9. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol. 2008;101:865-869.
10. De Groote P, Isnard R, Assyag P, et al. Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO Survey. Eur J Heart Fail. 2007;9:1205-1211.
11. Maggioni P, Dahlström U, Filippatos G, et al; Heart Failure Association of the ESC (HFA). EURObservational Research Programme: the heart failure pilot survey (ESC-HF Pilot). Eur J Heart Fail. 2010;12:1076-1084.
12. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo controlled study. Lancet. 2010;376:875-885.
13. Ekman I. SHIFT: patient-related outcomes. In: ESC Heart Failure Congress 2011; May 22, 2011; Gothenburg, Sweden. Late breaking trial.
14. Camm I, Talagic C, Komajda M, et al. Cardiac safety of selective heart rate reduction with ivabradine in chronic heart failure: insights from the SHIFT ECG – Holter substudy. Eur J Heart Fail Suppl. 2011;10(S1):S134. Abstract P797.
15. Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376: 886-894.
16. Düngen HD, Apostolovic S, Inkrot S, et al. CIBIS-ELD Investigators and Project Multicentre Trials in the Competence Network Heart Failure. Titration to target dose of bisoprolol vs carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. Eur J Heart Fail. 2011;13:670-680.
17. Krum H, Jelinek MV, Stewart S, Sindone A, Atherton JJ; National Heart Foundation of Australia; Cardiac Society of Australia and New Zealand. 2011 update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Med J Aust. 2011;194:405-409.

Keywords: chronic heart failure, heart rate, clinical trial, heart rate reduction

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Jeffrey S. BORER, MD
Waqas KHAN, MD
Division of Cardiovascular Medicine, Department of Medicine, State University of New York Downstate
Medical Center and College of Medicine
Brooklyn and New York
NY, USA

Heart rate (HR) is an easily measured parameter employed universally in clinical evaluation. Multiple studies during the past 65 years have established the utility of HR as a riskmarker for cardiovascular events and for total mortality in unselected (“nondiseased”) populations, as well as in cohorts with coronary artery disease, hypertension, and heart failure. However, to establish a risk marker as a risk factor, it is necessary to demonstrate not only that outcome is quantitatively related to the factor, but also thatmodification of the putative risk factor similarly modifies disease outcome. In order to demonstrate that HR is a risk factor for heart failure, it is necessary, first, to have a therapeutic modality that modifies HR, but no other cardiovascular parameter, and then to apply the therapy in patients with heart failure. Ivabradine meets the first criterion, and SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) showed that ivabradine is markedly superior to placebo in improving cardiovascular outcomes when administered on a background of guideline-based standard pharmacological therapy for heart failure. Thus, based on SHIFT, HR should be considered a risk factor for heart failure. Modulation of HR, specifically with ivabradine, should be considered in the management of patients with moderate-to-severe systolic heart failure.

Heart rate (HR), a simple and easily measured clinical parameter, is now known to hold a substantial amount of independent prognostic information in the free-living population as a whole,^1,2 and in a number of subpopulations with various forms of heart disease. The latter include those with coronary artery disease (CAD), hypertension, and chronic heart failure (HF) (Figure 1).^3-5 Much of the supporting information is derived from epidemiological studies and, thus, suggests that HR is a risk factor for these conditions, but in the absence of prospective demonstration from randomized clinical trials, cannot definitively establish HR as a risk factor. Nonetheless, this association is biologically plausible: experimentally, HR has been shown to be directly related to the progression of coronary atherosclerosis^6,7; clinically, HR is directly related to the likelihood of disrupting preexisting atherosclerotic plaque.⁸ Most recently, in a large placebo-controlled clinical trial, HR was found to be directly associated with outcome among patients with HF.9,10 The latter association also has biological plausibility: failing myocardium has a negative force-frequency association and is energetically starved.^11,12 HR reduction can improve contractility, perhaps by reducing energy expenditure, decreasing myocardial oxygen consumption, and enhancing the relationship between energy requirements and energy availability.^13,14 Therefore, it is possible that HR-slowing therapies may hold a particular advantage for patients with various forms of cardiovascular disease (CVD). Indeed, guidelines from the European Society of Cardiology and European Society of Hypertension for the prevention of CVD already recommend recognition of HR as a cardiovascular risk factor.^15,16 This review article aims to assess the accumulating evidence in support of HR as a risk factor for cardiovascular mortality and morbidity, specifically in HF.

Figure 1. Heart rate as a predictor of outcome in patients with coronary artery disease receiving placebo.

Heart rate and mortality in different populations

_ Unselected populations
Beginning as early as 1945, many epidemiological studies have reported that HR is strongly and directly associated with all-cause and cardiovascular mortality in unselected (“nondiseased”) populations.^1,2,17-20 For example, in a Framingham cohort of 5070 subjects free from clinically apparent CVD at study entry, cardiovascular and noncardiovascular mortality increased progressively with resting HR, irrespective of age.¹ Similarly, in three studies organized in Chicago, all in males, HR at rest was directly associated with sudden cardiac death.2 More recently, two large prospective studies have confirmed the strong and graded relationship between resting HR and cardiovascular and total mortality.^18,19 In the Paris Prospective Study of >5000 men aged 42 to 53 years, HR was measured at rest every year for 5 consecutive years.¹⁸ Those participants whose HR decreased during the 5 years had a 14% (P=0.05) decrease in mortality risk compared with those whose HR was unchanged; men with increased HR during the 5 years had a 19% (P<0.012) increase in mortality. Among 21 853 men and women in the prospective national FINRISK study (Finland Cardiovascular Risk Study), a strong, graded, independent relationship between resting HR and incident CVD was also demonstrated.¹⁹

A resting HR of more than 90 beats per minute (bpm) was associated with an almost twofold increase in cardiovascular mortality rate in men and a threefold increase in women, compared with a resting HR of less than 60 bpm. These results confirmed findings from other studies indicating the independence of HR effect from sex.¹⁹ Finally, in a prospective study of Chinese adults followed on average for 8.3 years, HRs of 75-89 bpm and ≥90 bpm in men resulted in a 1.12- fold and 1.32-fold increase in the risk of CVD, respectively, compared with lower HR.²⁰ Similarly, in women, there was a 1.23-fold increase in risk if HR exceeded 90 bpm. A unique finding in this study was increased stroke risk in subjects with HR ≥90 bpm, not found in Western populations.^21,22

Figure 2. Data from the Framingham cohort demonstrating the relationship between heart rate and death from all causes, cardiovascular disease, and coronary heart disease among individuals with hypertension.
Abbreviations: bpm, beats per minute; CHD, coronary heart disease; CVD, cardiovascular disease.

_ Hypertension
HR varies directly with sympathetic activity and therefore could be directly related to the proclivity for hypertension. This may be one explanation for the observation that, in subjects with hypertension, cardiovascular mortality risk increases directly with HR (Figure 2).^21,23,24 One of the strongest relationships in hypertensive patients was found by Benetos et al, who studied more than 12 000 French men aged 40 to 69 years. During 20 years of follow-up, the investigators found that HR was directly related to cardiovascular death, with hazard ratios of 1.35 (95% confidence interval [CI], 1.01-1.80) for HR of 60 to 80 bpm, 1.44 (95% CI, 1.04-2.00) for HR of 81 to 100 bpm, and 2.18 (95% CI, 1.37-3.47) for HR >100 bpm, compared with HR <60 bpm.²¹ In the Systolic Hypertension in Europe (Syst-Eur) trial, clinic and ambulatory HR was directly associated with all-cause, cardiovascular, and noncardiovascular mortality among both elderly hypertensive men and women.²³ In addition to the association between initial study HR and outcome, HR while on treatment in hypertensive patients also predicts likelihood of subsequent cardiovascular or all-cause mortality, independent of treatment modality.²⁴ In a study of 9190 hypertensive patients with echocardiogramindicated left ventricular hypertrophy followed for almost 5 years while being treated with losartan-based or atenololbased regimens, HR increments of 10 bpm while on treatment were associated with a 25% increment in cardiovascular death and a 27% increment in all-cause mortality. In an alternative analysis, persistence or development of HR ≥84 bpm (upper quintile of baseline HR) was associated with an 89% greater risk of cardiovascular death and a 97% increased risk of all-cause mortality compared with lower HR. These findings support the value of serial assessment of HR for risk stratification in hypertensive patients.

The relationship between resting HR and adverse outcomes in patients with hypertension and CAD was examined in INVEST (INternational VErepamil-SR/trandolapril STudy).⁴ In this study of 22 576 hypertensive patients with CAD randomized to either verapamil SR-based or atenolol-based treatment strategies, baseline HR was directly associated with adverse outcomes, which were twofold greater among patients with HR >100 bpm than among those with HR <100 bpm. A linear relationship was observed between baseline HR and risk of adverse outcomes: 5-bpm increments were associated with 6% risk increments.

_ Diabetes
Impaired autonomic function is associated with abnormal concentrations of serum insulin and abnormal insulin resistance, independent of blood glucose concentrations.²⁵ This suggests that autonomic dysfunction may be a consequence and also a precursor to hyperglycemia. The relationship between autonomic dysfunction and development of diabetes was further explored in the ARIC study (Atherosclerosis Risk In Communities).²⁶ The authors demonstrated that individuals with autonomic dysfunction, determined by low HR variability and high resting HR, were at a relatively high risk of developing diabetes over the succeeding 9 years, even when body mass index and physical activity were taken into account. Furthermore, in a post hoc analysis of the Diabetes Prevention Program (DPP) randomized trial of more than 3000 nondiabetics with abnormal fasting and postload plasma glucose concentrations, who were assigned to placebo, metformin, or a lifestyle-modification program, lower HR was associated with lower risk of developing diabetes, independent of weight change.²⁷

HR is also a powerful predictor of cardiovascular outcomes in established diabetics. This was clearly demonstrated in a study of 475 patients (aged 55 to 75 years) with type 2 diabetes who were followed over the course of 5 years, during which 57 (13.5%) died due to cardiovascular causes.28 In this population, HR >75 bpm was associated with an odds ratio for cardiovascular death of 3.3 (95% CI, 1.33-8.19) compared with the risk at lower HR. In another study of 14 992 Medicare participants aged 35 to 64 years who were free from diabetes at baseline (1992), over the next 10 years, HR was associated with diabetes mortality in those aged 35 to 49 years at baseline when adjustment was made for postload glucose and body mass index.²⁹

_ Coronary artery disease
Experimental data suggest that tachycardia results in development and progression of atherosclerosis. Reasons may include the direct relation of HR to hemodynamic shear stress (possibly due to shortening of diastole and changes in flow direction), which may damage intercellular junctions, increasing the permeability of endothelial cells and facilitating the ingress of atherogenic particles into the tunica media.³⁰ Tachycardia also tends to increase mean arterial pressure by shortening diastole, thus increasing pulse pressure. The result is an increase in cardiac workload and thickening of arteriolar smooth muscle.³¹ HR is also inversely related to arterial compliance.³² Studies in experimental animals support the relationship between HR and CAD. Beer et al ablated the sinus node in adult monkeys and also studied an equal number of nonablated monkeys, all fed on an atherogenic diet for 6 months.6 The controls, with persistently higher HR, had a significantly higher number of and more serious coronary artery atherosclerotic lesions than the test animals (P<0.02). Similar relationships have been reported in other studies.³³

A direct relationship between HR and progression of coronary atherosclerosis has also been shown in humans. Perski et al observed that HR on 24-hour ambulatory electrocardiogram predicted progression of CAD, independently of (and, indeed, more predictively than) conventional risk factors.⁷ Huikuri et al described the association between HR and progression of focal coronary atherosclerosis in patients with coronary artery bypass grafts.³⁴

The prognostic importance of HR in patients with known chronic CAD and in those surviving after myocardial infarction has been repeatedly demonstrated. In a large cohort of Israeli patients hospitalized for acute myocardial infarction in 1985-1986, Disegni et al recorded all deaths during initial hospitalization and at 1 year post discharge.³⁵ On multivariate analysis, admission HR was an independent predictor of in-hospital and 1-year postdischarge mortality. The CASS (Coronary Artery Surgery Study) registry investigated the longterm prognostic value of resting HR in nearly 25 000 patients with suspected or proven CAD.³⁶ Cardiovascular mortality increased progressively with increasing HR: resting HR ≥83 bpm was a strong predictor of overall mortality (hazard ratio, 1.32; 95% CI, 1.19-1.47; P<0.0001) and cardiovascular mortality (hazard ratio, 1.31; 95% CI, 1.15-1.48; P<0.0001), independent of known risk markers such as hypertension, diabetes, smoking, left ventricular ejection fraction, and the number of hemodynamically significantly diseased coronary vessels. In INVEST, in patients with hypertension and CAD, baseline and follow-up resting HR were directly associated with risk of adverse outcomes.⁴ Hjalmarson et al demonstrated that admission HR in patients with myocardial infarction is directly related to clinical outcome: they reported all-cause mortality at 1 year of 14% when admission HR was <60 bpm, 41% when admission HR was >90 bpm, and 48% when admission HR was >110 bpm.³⁷ Meta-analyses of the GISSI-2 and GISSI-3 trials (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico), which included about 20 000 patients, found that in-hospital mortality rates after myocardial infarction rose from 3.3% for patients with admission HR <60 bpmto 10.1%for patients with admission HR >100 bpm.³⁸ As a corollary, both mean HR and failure of HR to fall between hospital days 1 and 7 carry a poor prognosis.³⁹ HR is also an independent prognosticator in patients with acute ST-segment– elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. An analysis of 6- month follow-up data from 2477 consecutive patients with STEMI treated by primary percutaneous coronary intervention revealed that HR >80 bpm was associated with more than a twofold increased risk of death compared with lower HR.⁴⁰

The value of HR as a prognostic factor was also evaluated in the 5438 patients in the placebo arm of BEAUTIFUL (mor- Bidity-mortality EvAlUaTion of the I_f inhibitor ivabradine in patients with coronary artery disease and left ventricULar dysfunction).³ This large cohort with stable CAD and left ventricular dysfunction was divided into those with HR ≥70 bpm and those with HR <70 bpm at study entry. The group with higher entry HR had significantly higher adverse cardiovascular outcome rates compared with those who entered with lower HR (34%greater cardiovascular death, and higher hospital admissions for HF, myocardial infarction, and revascularization [53%, 46%, and 38%, respectively]). These findings have recently been corroborated by results from the TNT trial (Treating to New Targets).⁴¹ An analysis of 9580 subjects followed for a median of 4.9 years revealed a major cardiovascular event rate of 11.9% in those with a baseline HR of ≥70 bpm compared with a rate of 8.8%in those with a baseline HR <70 bpm.

Congestive heart failure

The prognostic value of resting HR extends to patients with chronic HF. HF is common, disabling, and serious, affecting roughly 2% to 3% of the population in developed countries.⁴² Standard pharmacological treatment for HF includes β-blockers and renin-angiotensin-aldosterone system antagonists. β-Blockers, amainstay of therapy, are associated with reduced morbidity and mortality beyond that achieved with renin-angiotensin- aldosterone system antagonists.⁴³ These benefits seem to be linked, at least in part, to their HR-lowering properties.^44,45 HR reduction may be particularly important in chronic HF, as it decreases energy expenditure,¹⁴ increases coronary blood supply by prolonging diastole, and improves in vivo⁴⁶ and in vitro¹² force-frequency associations. Furthermore, HR is directly related to vascular elastance, and thus, ventricular loading.⁴⁷ Thus, HR reduction unloads the ventricle, with the greatest effect in diseased hearts.⁴⁸ The effect of β-blocker–induced HR reduction has been analyzed in different studies.^44,49,50 HR reduction in these studies was fairly similar, and the results suggested that mortality benefits were directly related to magnitude of HR reduction. However, these studies could not separate the effects of HR reduction from those of other potentially important actions of β-blockers, such as antiarrhythmic effects, inhibition of maladaptive β-adrenergic signaling pathways producing apoptosis,⁵¹ or reduction of β-adrenergic signaling dysregulating contractility.

Figure 3. Ivabradine improves outcomes in heart failure.

Figure 4. Ivabradine significantly reduces death from heart failure.
Abbreviations: HF, heart failure; HR, hazard ratio.
After reference 9: Swedberg K et al. Lancet. 2010;376:875-885. © 2010,
Elsevier Ltd.

Figure 5. Data from the placebo group in SHIFT.
Data show that heart rate is a predictor of cardiovascular death and/or heart failure hospitalizations in
chronic heart failure. Increase in risk of 2.9% per 1 bpm, 15.6% per 5 bpm.
Abbreviations: bpm, beats per minute; SHIFT, Systolic Heart failure treatment with the If inhibitor ivabradine Trial.
After reference 10: Boehm et al. Lancet. 2010;376:886-894. © 2010, Elsevier Ltd.

The impact of SHIFT

In recent decades, the association between HR and cardiovascular morbidity and mortality in HF has been increasingly appreciated, but the impact of HR modulation has remained less than totally clear because of the relationship between HR and conventional CVD risk factors.⁵² Thus, it has been unclear as to whether HR is a marker of underlying hemodynamic and metabolic abnormalities and therefore, of risk, or whether HR is truly an independent risk factor, downward modification of which is associated with reduction in risk. Assessment of this issue required a therapeutic modality that could reduce HR without affecting other aspects of cardiovascular function and pathophysiology. Ivabradine, as a selective HR-reducing agent (via blockade of the sinoatrial nodeIf current [“funny” current, mediated by voltage-dependent cyclic AMP interactions] with no other apparent cardiovascular effects), provided a unique opportunity to define the impact of pure HR reduction in HF. To address this, SHIFT (Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial) investigated the effects of HR reduction with ivabradine on clinical outcomes in HF.^9,10 SHIFT was an event-driven, randomized, double-blind, placebo-controlled trial in which either ivabradine or placebo was administered for a median of 22.9 months to 6505 patients who were also receiving a background of guideline-defined standard multidrug therapy on evidence-based recommended doses ormaximally achievable dosages if lower than recommended. The primary outcome event in SHIFT was the composite of death or HF hospitalization in patients with moderate-to-severe chronic HF and left ventricular systolic dysfunction.9 The results of SHIFT were compelling: the primary outcome was 18% lower (P<0.0001) among patients receiving ivabradine than among those receiving placebo (Figure 3).^9,10 The effect on the primary outcome was predominantly driven by a 26% reduction in hospital admissions for worsening chronic HF (^P<0.0001) and deaths due to HF, which were also reduced by 26% (^P=0.014, Figure 4). There was a trend toward a reduction in cardiovascular death (hazard ratio, 0.91; P=0.128) and mortality (hazard ratio, 0.90), and fewer allcause hospital admissions with ivabradine (hazard ratio, 0.89; P<0.003). Ivabradine was well-tolerated: health-related quality of life, assessed with the Kansas City Cardiomyopathy Questionnaire, was significantly improved with ivabradine relative to placebo, a finding not reported in any of the β-blocker trials. The findings were consistent across several prespecified subgroups. Among these was etiology of HF. Although the underlying cause of HF in two thirds of the study population was CAD/ischemic heart disease, one third had idiopathic cardiomyopathy as the underlying etiology. The benefits of ivabradine versus placebo were statistically indistinguishable across these etiologies. Importantly, among patients who had the highest HR at study entry and were, therefore, at greatest risk, those on ivabradine had the largest reduction in HR and outcome events relative to placebo. In a companion analysis focusing specifically on HR effects, it was demonstrated that event frequency in the placebo group was 2.9% higher with every 1-beat increase from the admission HR minimum of 70 bpm.¹⁰ The finding of this direct relationship betweenpretreatment HR and adverse outcome in the placebo group confirms the importance of HR as a risk marker (Figure 5). More importantly, the reduction in outcome events with ivabradine relative to placebo within each quintile of pretreatment HR ranges indicates that HR is, in fact, a risk factor for HF; ie, that it not only indicates risk, but that its therapeutic downward modulation reduces risk. The results of SHIFT clearly establish that HR reduction is an important part of the management of HF.

Conclusions

To establish the clinical validity of epidemiological association between a risk factor and any CVD, several criteria should be satisfied.⁵³ The risk factor must have a direct relation with the likelihood of a disease, should contribute to the development of the disease regardless of sex, age, or race, should manifest a relationship with outcome that is statistically independent of other known or previously accepted risk factors and, most importantly, when it is modified to reduce its magnitude, this modification must similarly modify the outcome (beneficially) of the disease. In addition, to be clinically useful, the risk factor must be readily measurable and there must be considerable evidence linking the risk factor to the disease.

As noted previously, many studies have shown that HR, an easily measured clinical variable, is a significant predictor of total mortality and cardiovascular mortality. This relationship is strong, graded, and independent of other prognostic factors. Confirmation from SHIFT that HR reduction reduces cardiovascular events in patients with HF9,10 clearly establishes HR as a true risk factor for this disease, as it also appears to be for CAD.⁵³ Therefore, it is reasonable and appropriate to consider HR in risk stratification and as a guide for medical therapy, specifically that involving the administration of ivabradine in addition to other already established HF therapies, in patients with HF. _

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40. Parodi G, Bellandi B, Valenti R, et al. Heart rate as an independent prognostic risk factor in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Atherosclerosis. 2010;211:255-259.
41. Ho JE, Bittner V, Demicco DA, Breazna A, Deedwania PC, Waters DD. Usefulness of heart rate at rest as a predictor of mortality, hospitalization for heart failure, myocardial infarction, and stroke in patients with stable coronary heart disease (Data fromthe Treating to New Targets [TNT] trial). Am J Cardiol. 2010;105: 905-911.
42. Dickstein K, Cohen-Solal A, Filippatos G, et al; ESC Committee for Practice Guidelines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail. 2008;10:933-989.
43. Gheorghiade M, Colucci WS, Swedberg K. Beta-blockers in chronic heart failure. Circulation. 2003;107:1570-1575.
44. Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation. 2001;103:1428-1433.
45. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150:784-794.
46. Hasenfuss G, Holubarsch C, Hermann HP, Astheimer K, Pieske B, Just H. Influence of the force-frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J. 1994;15:164-170.
47. Kelly RP, Ting CT, Yang TM, et al. Effective arterial elastance as index of arterial vascular load in humans. Circulation. 1992;86:513-521.
48. Reil JC, Reil GH, Böhm M. Heart rate reduction by If-channel inhibition and its potential role in heart failure with reduced and preserved ejection fraction. Trends Cardiovasc Med. 2009;19:152-157.
49. Gullestad L, Wikstrand J, Deedwania P, et al; MERIT-HF Study Group. What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker? Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERITHF). J Am Coll Cardiol. 2005;45:252-259.
50. Metra M, Torp-Pedersen C, Swedberg K, et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial. Eur Heart J. 2005;26:2259-2268.
51. Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation. 1998;98:1329-1334.
52. Palatini P, Julius S. Heart rate and the cardiovascular risk. J Hypertens. 1997; 15:3-17.
53. Borer JS. Heart rate: from risk marker to risk factor. Eur Heart J. 2008;10(suppl F):F2-F6.

Keywords: cardiovascular disease; coronary artery disease; heart failure; heart rate; ivabradine; risk factor; risk marker

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Maurizio VOLTERRANI, MD
Cristiana VITALE, MD, PhD
Department of Medical Sciences, IRCCS San Raffaele
Pisana, Rome, ITALY
Ilaria SPOLETINI, PhD
Center for Clinical Research
San Raffaele Sulmona
Sulmona, ITALY

Heart failure (HF) is a major challenge for health care systems. In acute HF, themain aimof clinicalmanagement is to stabilize the clinical condition, clarify the etiology and precipitating factors, and provide quick symptom relief. In both acute and chronic HF, it is advisable to use a multimarker approach, factoring in several diagnostic and therapeutic pathways simultaneously. The pharmacological approach recommended by current guidelines is a step-by-step procedure. Angiotensin-converting enzyme inhibitors and diuretics are the mainstay of therapy. The next step is β-blockers, which should be uptitrated to the maximum dosage possible. This therapeutic strategy is supported by several large-scale trials, which have shown a significant improvement in survival. Most patients, however, cannot tolerate maximum β-blockade and for these, ivabradine is a life-saving therapeutic option, to be used either in combination with β-blockers or alone in patients with comorbidities. Once these therapies have been implemented, aldosterone antagonists, angiotensin II receptor blockers,metabolic therapy, and iron therapy can all be considered. Furthermore, resynchronization therapy and cardioverter defibrillators should be implanted in all eligible patients. In spite of these clear guidelines, most patients with HF continue to receive suboptimal care, and most of them remain moderately or severely symptomatic. Multidisciplinary management programs have been developed to promote further improvement and implementation of appropriate HF management. Close monitoring of patients during the entire course of the disease encourages self-care management and, consequently, adherence to medication and diet, ensures better symptom recognition, and thus has a considerable impact on symptoms, well-being, and prognosis.

Heart failure (HF) is a common disease that is increasingly recognized as a major health burden, with a dramatic impact in terms of consumption of human and economic resources, and is one of the major challenges for health care systems throughout the world.^1,2 The worldwide prevalence of HF is 2% to 2.5%; it affects close to 6 million people in the US and 14 million people in Europe. HF is the first cause of morbidity and mortality due to cardiovascular disease and results in more hospitalizations than all forms of cancer combined.³ HF remains disabling even after discharge from the hospital, as it considerably impairs quality of life and constitutes a risk factor for stroke, renal failure, and early readmission.⁴

HF prevalence increases with age, from 1% to 2% in individuals aged 45 to 54 years to >10% in those aged ≥75 years.⁵ Approximately 80% of patients hospitalized due to HF are older than 65 years. With a population that continues to age and (paradoxically) with the continuing improvement in the treatment of hypertension and myocardial infarction, HF is the fastest-growing clinical cardiac disease entity in all countries³ and its management is therefore assuming pivotal importance.

HF is often caused by ischemic cardiomyopathy, but may also occur in the presence of normal or nearly normal cardiac function. Its clinical presenting signs include shortness of breath and fatigue (left ventricular failure) or physical signs of fluid retention (right ventricular failure).⁶

Management of heart failure

The current guidelines of the European Society of Cardiology for the diagnosis and treatment of HF call for a quick and efficient approach.⁶ This is especially true for acute HF, in the context of urgent, unplanned hospitalization. In this case, HF management begins in the Emergency Department, continues during hospitalization, and extends after discharge.⁷ In the Emergency Department, the management of acute HF aims to stabilize the patient’s clinical condition, clarify the etiology and the precipitating factors, and initiate treatment to provide quick symptom relief. Respiratory support with use of oxygen if necessary, and noninvasive positive pressure ventilation should be provided, in order to avoid intubation.⁷ Admissions for worsening HF represent a significant health care burden and lead to significant impairment of patient quality of life; they are associated with increased short-term and long-term mortality. This is why special emphasis should be laid on ensuring the best possible management of chronic HF, in order to reduce the need for (re)hospitalization and improve prognosis.

According to current guidelines, the first step in HF management is taking a comprehensive history and carrying out a thorough physical examination in search of causal factors such as the presence of prior or current evidence of myocardial infarction, valvular disease, or congenital heart disease.^6,8,9 In addition to history and physical examination, imaging techniques such as chest x-ray and echocardiography of the cardiac chambers or great vessels are used to identify causal structural abnormalities.⁹ Transesophageal echocardiography, stress echocardiography (exercise or dobutamine echocardiography), cardiac magnetic resonance imaging, cardiac computed tomography, or radionuclide imaging should be used only if the nature of HF is unclear.⁶ Coronary arteriography should be performed in HF patients with angina or significant ischemia unless the patient is not eligible for revascularization.⁹ Pulmonary function tests may be useful in assessing potential respiratory causes of dyspnea.

Evaluation of dyspnea and fatigue, as well as exercise capacity and exertional symptoms relies on exercise testing (determination of mixed venous oxygen saturation [MVO₂] or 6-minute walk test [6MWT]).^6,10 Physical training improves symptoms and quality of life in patients with chronic HF and is associated with positive effects on morbidity and mortality.¹¹ Therefore, assessment of exercise performance should always be performed in patients with chronic HF in order to monitor the effectiveness of medical and rehabilitative therapies. Exercise training is a core component of HF management, as it induces positive changes in vessel structure, attenuates left ventricular dilation, regresses cellular hypertrophy, and slows the progression of coronary artery disease.¹² Thus, physical activity appears to have “pleiotropic” actions on the cardiovascular system.¹¹

To conclude, HF risk stratification requires a multimarker approach based on making an adequate selection of biomarkers known to be individually associated with HF, taking into account several biochemical pathways simultaneously. This allows better prediction of the incidence of HF and of the response to treatment.¹³

Pharmacological treatment

In spite of the variety of pathophysiological causes, HF is consistently characterized by the presence of neurohumoral activation, metabolic disorders such as testosterone deficiency and insulin resistance, and a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function.¹⁴ Consequently, therapeutic strategies targeted to these pathophysiological processes have been developed over the last decades, which have resulted in a substantial improvement in survival rate of patients with HF.¹

Current guidelines recommend pharmacological treatment based on a stepped-care approach. The first step involves angiotensin-converting enzyme inhibitors (ACE inhibitors) and diuretics. The second step calls for the introduction of β-blockers. The third step consists in uptitrating β-blocker therapy to reach the maximum dosage possible.

Figure 1. The beneficial effect of
-blockers is proportionally related to resting heart
rate reduction.

_ ACE-inhibitors and diuretics
ACE inhibitors are the cornerstone of treatment of patients with HF and are recommended as first-line therapy in all patients with current or prior symptoms of HF and reduced left ventricular ejection fraction (LVEF), unless contraindicated.9 They exert beneficial effects on cardiac and systemic hemodynamics the neuroendocrine system, and vascular function, leading to reduction in blood pressure, preload, and afterload. ACE inhibitors also have structural effects on the myocardium, resulting in regression of left ventricular hypertrophy, reduction in interstitial collagen deposition and fibrosis, and prevention of cardiac remodeling.¹⁵

In patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention, diuretics and salt restriction are indicated, concurrently with ACE inhibitors.⁹ In patients with congestive HF, diuretics are of pivotal importance in the presence of symptoms and signs of volume overload.¹⁶ Diuretics are often the mainstay of the treatment of the elderly and patients with diastolic dysfunction, as they allow to generate low-normal to normal cardiac output in these patients who are extremely sensitive to changes in volume and preload.

_ &beta-Blockers
As step-two therapy, β-blockers are recommended in all stable patients with current or prior symptoms of HF and reduced left ventricular EF, unless contraindicated.⁹ CIBIS III (Cardiac Insufficiency BIsoprolol Study–III) clearly showed that β-blocker therapy should be implemented only after adequate diuretic and ACE-inhibitor therapy has been instituted.¹⁷ The study failed to show noninferiority of implementation of β-blocker
first versus ACE-inhibitor–first strategy, but showed that initiation of β-blockers before optimization of ACE inhibition was associated with increased risk of hospitalization for HF. The beneficial effects of β-blockers in patients with HF involve a number of mechanisms: (i) they slow the heart rate (increasing left ventricular filling time and reducing myocardial oxygen consumption); (ii) they modify the hemodynamic response to exercise; (iii) they lower the blood pressure. These effects combine to regress left ventricular hypertrophy and reverse ventricular remodeling. In patients with HF adequately treated with ACE inhibitors, the favorable effects of β-blockers are mediated by the heart rate–lowering effect,¹⁸ as shown by a meta-analysis of 17 randomized, placebo-controlled trials of long-term treatment with β-blockers or calcium channel blockers in patients surviving myocardial infarction (Figure 1).

The randomized controlled trials (RCTs) on β-blockers in HF have been exhaustively reviewed.^6,9 One of the three β-blockers that have been proven to reduce mortality (viz, bisoprolol, carvedilol, and sustained release metoprolol succinate) should be administered whenever possible.^19-22 However, although β-blockers represent the mainstay of treatment of patients with HF, these drugs are most often undertitrated for various reasons, despite the lack of real contraindications.⁴ Our group has recently reported that, among patients with coronary artery disease, 43% of those with HF were not on β-blocker therapy (Figure 2, page 404).²³

Similarly, ACE inhibitors are often prescribed at lower dosages than those known to be clinically effective.³ Thus, β-blockers and, to a lesser extent, ACE inhibitors are often not adequately prescribed in patients with HF, most of whom remain moderately or severely symptomatic, because treatment is suboptimal.²⁴ The major problem in implementing the therapeutic dosages of these drugs is hypotension due to the concomitant effect of drugs with hemodynamic action.

Figure 2. Heart rate by β-blocker use in heart failure and coronary
artery disease patients.

_ Ivabradine
In these patients, ivabradine plays a central role. This specific and selective I_f inhibitor has been found to improve ischemiarelated end points, either alone or in association with β-blockers. SHIFT (Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial) has shown a significant reduction in mortality and hospitalization for HF with ivabradine.²⁵ The prognosticbenefit is related to the magnitude of heart rate reduction and, indeed, patients achieving an heart rate <60 beats/minute are those with the greater survival benefit. Our group has recently consistently shown that in patients receiving inadequate ACE-inhibitor dosages and in those naive to β-blockers, ivabradine alone or in combination with carvedilol was superior to carvedilol alone in improving exercise capacity and quality of life (Figure 3).²¹ As aforementioned, patients with HF who are candidates for ivabradine are those without atrial fibrillation and not on β-blockers (or receiving inadequate dosagesof β-blockers) because of hypotension and other side effects. In these patients, ivabradine improves symptoms, quality of life, and prognosis. Given the fact that β-blockers are so often not used at adequate dosage, their combination with ivabradine may represent an effective alternative strategy for reducing heart rate in patients with HF.^25,26

Once these therapies have been implemented, angiotensin II receptor blockers (ARBs), aldosterone antagonists, metabolic therapy, and iron therapy can be considered.

Figure 3. Changes in heart rate, systolic blood pressure, and diastolic
blood pressure at rest at 4-week follow-up in the bisoprolol
and carvedilol groups.

Additional pharmacological therapies

_ Angiotensin receptor blockers
ARBs may have a small additional protective effect in patients with HF who are intolerant to ACE inhibitors and/or in those who remain symptomatic despite maximally uptitrated therapy with ACE inhibitors and β-blockers. Use of ARBs should be limited to these patients only, since it is preferable to achieve maximal uptitration of effective therapies such as ACE inhibitors and β-blockers in patients with HF.

ARBs are also recommended in patients with current or prior symptoms of HF and reduced LVEF who are intolerant to ACE inhibitors.⁹ Addition of an ARB may be considered in persistently symptomatic patients with reduced LVEF already being treated with maximally uptitrated conventional therapy.²⁷ OPTIMAAL (OPtimal Trial In Myocardial infarction with the Angiotensin II Antagonist Losartan) failed to show noninferiority of losartan to captopril in patients with HF and acute myocardial infarction, but found that fewer patients discontinued the study medication when allocated to losartan (Figure 4).²⁸ Thus, although ACE inhibitors should remain the first-choice treatment in HF patients, losartan can be considered in those who are intolerant to ACE inhibitors.

_ Hydralazine–isosorbide dinitrate combination
Combination treatment with hydralazine and isosorbide dinitrate is an alternative in patients intolerant to both ACE inhibitors and ARBs. This combination should be considered in all patients with HF and persistent symptoms despite maximal treatment. It is effective in reducing the risk of death, and this is particularly true in black patients, known to have reduced sensitivity to ACE inhibitors.⁹ It is also useful in patients with current or prior symptoms of HF and reduced LVEF in whom ACE inhibitors and ARBs are contraindicated because of drug intolerance, hypotension, or renal insufficiency.²⁹

_ Aldosterone receptor blockers
Aldosterone receptor blockers may be considered in selected patients with moderately severe to severe HF and reduced LVEF who can be carefully monitored for renal function and potassium concentration. Aldosterone receptor blockers are potentially able to improve cardiac function by blocking the effects of aldosterone and thus interfering with collagen deposition and cardiac fibrosis.³⁰

Figure 4. OPTIMAAL trial.

_ Digoxin
Digoxin is effective in controlling ventricular rate, especially when combined with calcium channel blockers or β-blockers, in patients with current or prior symptoms of HF, reduced LVEF, and atrial fibrillation,³¹ which is a frequent occurrence in older patients.^32-34

_ Trimetazidine
Trimetazidine (TMZ) is an effective strategy for treating HF by improving myocardial substrate use through inhibition of oxidative phosphorylation and by shifting energy production from free fatty acids to glucose oxidation.³⁵ A recent meta-analysis of RCTs in HF has confirmed that TMZ improves cardiac function in ischemic and nonischemic HF and reduces mortality, cardiovascular events, and hospitalization.³⁶

_ RLY5016
Hyperkalemia, anemia, hyponatremia, and reduced renal function are common in patients treated with diuretics and ACEinhibitor/ ARB/aldosterone antagonist therapy.6 Hyperkalemia, in particular, may result in discontinuation of a renin-angiotensin- aldosterone system inhibitor/blocker and/or β-blocker or chronic kidney disease. The PEARL-HF study (Evaluation of RLY5016 in Heart Failure Patients) study has recently shown that a nonabsorbed, orally administered, potassium [K+]-binding polymer (RLY5016) may be useful for both prevention and treatment of hyperkalemia in HF patients with or without concomitant chronic kidney disease.³⁷

_ Treatment of iron deficiency
Treatment of anemia has not been established so far as routine therapy in HF.⁶ However, there is growing evidence that iron deficiency is a valid independent therapeutic target in HF. It is now recognized that iron deficiency in HF patients with or without anemia attenuates aerobic performance and is accompanied by fatigue and exercise intolerance. The FERRICHF trial (Ferric Iron Sucrose in Heart Failure) has shown that intravenous iron sucrose therapy was associated with better exercise capacity and symptom status, especially in anemic HF patients.³⁸ The FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure) trial has consistently found that treatment with intravenous iron (ferric carboxymaltose) improved symptoms, functional capacity, and quality of life in chronic HF patients, whether with anemia or without.³⁹ Further studies are needed to unravel the reasons why correction of iron deficiency results in symptomatic improvement even in the absence of a change in hemoglobin.

_ Miscellaneous
Finally, use of analgesics and benzodiazepines is advisable to relieve anxiety, distress, dyspnea, and arrhythmia.<40 Conversely, several drugs should be avoided or withdrawn whenever possible. Nonsteroidal anti-inflammatory drugs, most antiarrhythmic drugs, and most calcium channel blokcers are known to adversely affect the clinical status of patients with current or prior symptoms of HF and reduced LVEF.⁹ Also, the combined use of an ACE inhibitor, an ARB, and an aldosterone receptor blocker is not recommended in patients with current or prior symptoms of HF and reduced LVEF. Infusion of a positive inotropic drug may be harmful in the long-term and is not recommended, except as a palliative treatment for patients with end-stage disease who cannot be stabilized on standard medical treatment.⁹

Device therapy: cardiac resynchronization and implantable cardioverter-defibrillators

As an adjunct to optimal medical therapy, cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillators (ICD) should be used in all eligible patients. As recommended by the recent European guidelines on device therapy in HF,⁴¹ CRT and ICD should be used in patients with severe HF (New York Heart Association [NYHA] class III-IV) who remain symptomatic and with QRS prolongation despite optimal medical therapy. As summarized in a recent review,⁴² clinical trials have shown that HF patients implanted with a device had a remarkably low mortality rate. CRT and ICD have also been found to reduce morbidity and mortality in patients with mildly symptomatic HF (NYHA class I-II).⁴¹

CRT has resulted in substantial improvement in symptoms and a large reduction in mortality by reducing both sudden death and death due to HF.⁴² In HF patients, dyssynchronous contraction can be addressed by electrically activating the right and left ventricles in a synchronized manner with a biventricular pacemaker device.9 CRT improves left ventricular geometry, papillary muscle dyssynchrony, and mitral regurgitation.⁶ Short-term use of CRT has been associated with improvement in cardiac function and hemodynamics, significant improvement in quality of life, functional class, exercise capacity, and LVEF, as well as with reduction in hospitalizations and all-cause mortality.^43,44

ICD implantation is indicated in HF patients with a history of previous cardiac arrest or documented sustained ventricular arrhythmia, to reduce the risk of recurrent events.⁹ In particular, it is indicated for the secondary prevention of death from ventricular tachyarrhythmia in patients with otherwise good clinical function and prognosis, or in those with chronic HF and low LVEF presenting with syncope of unclear origin.

In conclusion, CRT, or a combination of CRT and ICD, is recommended in most HF patients.

How can management of heart failure patients be improved?

The past decades have seen major advances in the management of patients with HF thanks to an extensive body of evidence from RCTs, meta-analyses, and large observational studies, and the resulting revision of the guidelines. This has changed the natural course of this clinical syndrome and improved patient outcomes. However, implementation of optimal HF management is still limited in routine daily practice, and many patients remain symptomatic, with an adverse impact on quality of life,⁴⁵ and frequently receive substandard care.⁴⁶ Different reasons may explain this phenomenon.

First, patient characteristics in clinical practice may differ substantially from those in clinical trials. There appears to be a selection bias in RCTs, which results in underrepresentation of the elderly, women, minorities, patients with concomitant comorbidities, such as renal insufficiency, chronic lung disease, obesity, depression, and neurocognitive disorders, and, generally speaking, of patients in less good health. Conversely, patients who are more likely to adhere to the prescribed treatment and follow-up are overrepresented in RCTs.⁴⁷

Second, as aforementioned, β-blockers are underused, especially in outpatients with HF, as opposed to hospitalized patients. The EuroHeart Failure II survey showed that β-blockers were underprescribed in elderly patients in comparison with younger patients, though there is a substantial increase in the rate of prescription of recommended medications at discharge when compared with the first European Survey.⁴⁸

In addition, discharge planning and follow-up after hospitalization are frequently insufficient, leading to poor self-care behavior, inadequate support for the patients, and suboptimal treatment. Notably, poor compliance is a main factor of poor prognosis.⁴⁹ Nonadherence to medication, diet, or symptom recognition is common and may be responsible for over one third of hospital readmissions.⁶ In contrast, good adherence has been shown to decrease morbidity and mortality and improve well-being.⁴⁹

There is thus room for further improvement and implementation of appropriate HF management. Current European guidelines recommend management programs to improve outcomes based on a multidisciplinary care approach that follows the HF patient along the course of the disease and calls on various services within the health care system.⁶

Such multidisciplinary management care ensures structured follow-up to enhance patient education, optimization of medical treatment, psychosocial support, and access to care. Self-care management strategies are now recognized as an integral part of successful HF treatment,⁵⁰ and promise to exert a significant impact on the symptoms, functional capacity, well-being, morbidity, and prognosis of heart failure patients.⁵¹ _

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36. Gao D, Ning N, Niu X, Hao G, Meng Z. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011;97:278-286.
37. Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ. Evaluation of the efficacy and safety of rly5016, a polymeric potassium binder, in a double- blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J. 2011;32:820-828.
38. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer- blinded trial. J Am Coll Cardiol. 2008;51:103-112.
39. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436-2448.
40. Bekelman DB, Havranek EP, Becker DM, et al. Symptoms, depression, and quality of life in patients with heart failure. J Card Fail. 2007;13:643-648.
41. Dickstein K, Vardas PE, Auricchio A, et al. 2010 focused update of esc guidelines on device therapy in heart failure: An update of the 2008 esc guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 esc guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Eur Heart J. 2010;31:2677-2687.
42. Cleland JG, Buga L, Ghosh J, Nasir M. Applying evidence-based device care in cardiovascular patients: which patient with heart failure and what device? J R Coll Physicians Edinb. 2010;40:229-239.
43. McAlister FA, Ezekowitz JA, Wiebe N, et al. Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med. 2004; 141:381-390.
44. McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol. 2004;44:810-819.
45. Ghali JK, Massie BM, Mann DL, Rich MW. Heart failure guidelines, performance measures, and the practice of medicine: mind the gap. J Am Coll Cardiol. 2010; 56:2077-2080.
46. Stafford RS, Radley DC. The underutilization of cardiac medications of proven benefit, 1990 to 2002. J Am Coll Cardiol. 2003;41:56-61.
47. Peterson ED, Lytle BL, Alexander KP, Coombs LP. The willingness of underrepresented groups to participate in clinical trials. J Am Coll Cardiol. 2005;39: 435A.
48. Komajda M, Hanon O, Hochadel M, et al. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. Eur Heart J. 2009;30:478-486.
49. Hauptman PJ. Medication adherence in heart failure. Heart Fail Rev. 2008;13: 99-106.
50. Lainscak M, Blue L, Clark AL, et al. Self-care management of heart failure: practical recommendations from the patient care committee of the heart failure association of the European Society of Cardiology. Eur J Heart Fail. 2011;13: 115-126.
51. Clark AM, Davidson P, Currie K, Karimi M, Duncan AS, Thompson DR. Understanding and promoting effective self-care during heart failure. Curr Treat Options Cardiovasc Med. 2011;12:1-9.

Keywords: angiotensin-converting enzyme inhibitor; β-blocker; cardioverter-defibrillator; compliance; diuretic; heart failure; ivabradine; management; resynchronization therapy; self-care

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John G. F. CLELAND, MD
Anita TROTMAN-BEASTY, RGN
Paul ATKIN, RGN
Amanda CRUNDALL, RGN
Teresa CASTIELLO, MD
Renjith ANTONY, MD
Department of Cardiology
Castle Hill Hospital
Hull York Medical School
University of Hull
Kingston-upon-Hull
East Riding of Yorkshire
UNITED KINGDOM

Education is a vital component of care to improve the outcomes of patients with heart failure. Patients who are not knowledgeable about their disease and their medications are at a severe disadvantage, as reflected by higher rates of hospitalization and mortality. Patients should play an active role in the management of their health. Effective education of patients and their carers requires a multidisciplinary team approach and should emphasize adherence to treatment, lifestyle recommendations, and help the patient to recognize the symptoms and signs that indicate progression of the disease. This review discusses the approach to patient education, the possible obstacles to patient learning, and some strategies to help patients overcome these obstacles. It is likely that home telemonitoring systems will play a vital role in the management of heart failure and most other long-term medical conditions.

Rationale for patient education

If patients all had a personal nurse or physician to supervise them throughout each and every day then patient education would be unnecessary. Clearly this is not the case and, using conventional methods of delivering care, never can be for the vast majority of patients and interventions. In fact, one of the attractive aspects of implantable defibrillators, cardiac resynchronization, and potentially other devices for treating patients with heart failure is that once they have been successfully implanted the treatment is beyond the patients’ control.¹ Implanted devices work 24 hours a day, 7 days per week, but can be largely forgotten by the patient. Indeed, it is probably good if patients do mostly forget that they have had a device implanted as this indicates good psychological adjustment and a lack of anxiety. However, for many aspects of heart failure management, patients need to be active participants in managing their disease to improve their quality of life, reduce the risk of hospitalization and to increase longevity. Clearly, if the medicine stays in the bottle it can’t do any good; even compliance with placebo is associated with improved outcomes—probably because it indicates that patients are taking their other medications and paying more attention to advice on lifestyle.²

In order for changes in diet, exercise, and pharmacological therapy to deliver benefits, patients have to know what they should do, be willing to do it, and then take action on their intentions. Appropriate advice and effective communication is required for the first task. The patient has to be persuaded that the advice is good and that any inconvenience, discomfort, loss of pleasure or perceived side effects are worth the potential gain. This implies either that patients know what is at stake, the size and nature of the expected benefit, and the rate and severity of potential risks, or that they trust the advice they receive and don’t question it. Clearly this is complex even for those who feel well, have full cognitive function, and are motivated, educated, and intelligent. Patients may receive advice, but remain skeptical about it. Alternatively, patients may make a choice not to give up “bad” habits, such as cigarettes or excess alcohol, in order to live a little longer, but prefer to live the remainder of their life as they wish. Health professionals are there to offer advice and support, but should not apply excessive coercion if the patient doesn’t want to take the advice proffered. If the patients do decide to follow advice, then they must have a plan to implement what they intend to do. There are many distractions, and daily routines are easily disrupted or forgotten. It is to the immense credit of patients, and those who care for them, that so many patients regularly take their medication. The extent to which they are aware of and comply with lifestyle advice is less clear.³ Once patients become knowledgeable and confident about the management of their heart failure, the sense of mastery may contribute to greater well-being and better outcomes.⁴

The educational strategy

The most important aspects of education are timing, hierarchy, content, repetition, consistency, motivation, implementation, and, finally, audit.

Timing is critical. It is important that patients are given a basic understanding as soon as possible that there is a problem with the heart and that the consequences of this can be reduced or prevented by adhering to advice and therapy. However, it is important that patients receive information at a rate they can absorb and cope with. This will vary considerably among patients. Too much education too quickly can be a bad thing. Denial of disease is an important coping mechanism for many patients. Ill-judged attempts at getting patients to understand the enormity of their problems can cause depression and despair. Unless the health professional has the skills (most don’t) to deal with the consequences of full disclosure, then considerable caution is appropriate when informing patients with heart failure about their prognosis.^5-7 However, not making patients aware of the gravity of their disease can have serious consequences if it leads them to decide to stop treatment because of a minor side effect or not to follow advice on changes in lifestyle.

There should be a hierarchy of information with three important considerations in mind. The first consideration is context. Patients who have had a recent episode of worsening heart failure because they forgot their diuretics first need advice about diuretic compliance and investigation of the reasons for noncompliance, which might include lack of planning leading to them running out of tablets, denial of disease, cognitive dysfunction, or avoidance because of the social inconvenience of diuresis. The second consideration is about the size of impact the intervention will have on medical aspects of disease. In this sense, advice about angiotensin-converting enzyme (ACE) inhibitors and β-blockers, which have proven, substantial, and consistent benefits on symptoms and prognosis, is much more important than information about dietary sodium, adjustment of which has not been shown to be of benefit and could even be harmful,⁸ and exercise, which may improve psychological outlook, but has little or no effect in reducing either hospitalization or death.^9,10 The third consideration is the patients’ mastery of their disease, in other words being confident in knowing what to do.^11,12 Building confidence can mean supporting patients in doing things that they believe to be beneficial, as long as they are not harmful, in order to give a greater sense of control over their own life. This might include eating a well-balanced diet and regular exercise, neither of which is really known to have any direct benefit on the rate of hospitalization or longevity in patients with heart failure. In this sense, advice on diet and exercise may be as important as taking medication. Patients should not only be told which of their medications are known to be effective, but also those where doubt and controversy exist as they may wish to rationalize their regimen. The doctor or nurse can then add their personal opinion, but then leave the final decision with the patient.

The content is vital and should be based on professional guidelines adapted for patients’ needs. For most patients education will be delivered by a variety of media. An initial dialogue with a health professional, reinforced periodically, is the expected contemporary standard of care. However, patients often get confused by the volume of information, and therefore reinforcement with paper and electronic educational as well as practical aids such as weekly pill dispensers may make valuable additions to conventional care. The huge advantage of paper and electronic media is that patients can access it as often as they wish and discuss it with friends and family providing that vital component of education: repetition.

Paper and electronic media should also ensure consistency that should be reinforced by advice from health professionals. Patient information material and health professionals should be consistent in making clear what is evidence and what is opinion. There is no doubt that most patients with heart failure and a low left ventricular ejection fraction should receive an ACE inhibitor, a β-blocker, and an aldosterone antagonist. These are facts, not opinions, and the patient should receive a consistent message. On the other hand, there is no evidence that aspirin^13-15 or statins^16,17 are beneficial in patients with heart failure and coronary disease, but there are widely held opinions that such patients should take these medications. Thus, patients should be advised that aspirin and statins have not been shown to be effective and that the balance of harm and benefit is uncertain. Health professionals may then give their opinion on the balance of evidence without introducing dogma. If patients know what is fact and what is opinion then they are less likely to be confused by conflicting advice and can decide which advice to follow.

Table I. Key points a doctor needs to monitor in a patient with heart failure.

Ensuring that patients not only know what to do, but are motivated to do it is critical. Education of patients has improved greatly in the last few decades, but it is unclear whether motivation to act on education has. This has proved difficult to measure. Patients have a surprising number of ways of misunderstanding advice and should be encouraged to discuss any concerns. Implementation is best assessed by audit. It is also good practice to evaluate what patients have understood. Standard questionnaires have been developed to assess patients’ educational attainment about heart failure management.¹⁸ It should be routine at each clinic visit to go through a patient’s medication.

Telemonitoring and education

Education alone does not help patients nor will monitoring of their disease. It is the benefits of changes in mood, lifestyle, medication, and device therapy that education and monitoring help deliver that improve outcome.¹⁹ However, lack of sufficient sophistication in either education or monitoring puts the patient at risk. These activities go hand in hand and should reinforce each other. There are a relatively small number of key things, probably about ten, that a doctor or nurse needs to monitor in order to advise patients about the requirement for further intervention or adjustments to their medications (Table I). Frequent monitoring of these symptoms and signs by conventional clinical follow-up is expensive and sufficient health care resources do not exist. However, home telemonitoring is already able to do most of what is required, efficiently and cost-effectively.^20-22 The last elements required, such as measurement of serum potassium, renal function, and hematocrit should soon be available. Once these are in place, the care of heart failure and many other long-term conditions will be transformed. Expert systems will be able to work with patients to monitor their condition and provide education, motivation, advice, and audit without the frequent intercession of a health-professional.²³ This will start slowly at first, probably just providing advice and motivation on diet, exercise, and diuretic dosing, but within a few years this will extend to other aspects of therapy. Doubtless, these new technologies will reveal some Luddite tendencies in the profession since such systems will be perceived to usurp some of the role of doctors and nurses.⁴ Health professionals will still be needed to provide backup and support. Indeed, it is quite likely that telemonitoring will not reduce staffing levels, but rather make existing staff more effective. Think of telemonitoring as a form of radar that can be used to maintain order and to prevent or detect health crises. In fact, telemonitoring is far better used to maintain patients in a safe “envelope” using a health maintenance strategy than as a means of spotting deterioration that might lead to hospitalization requiring special intervention (a crisis detection strategy) due to the problems of false alerts.¹⁹ Despite some recent negative publicity based around remote monitoring using voice-interactive systems,^24,25 there is compelling evidence that telemonitoring reduces mortality substantially.²² Telemonitoring might also reduce the rate of hospitalization, but this is less certain.²³ Telemonitoring may increase the rate of appropriate and timely hospitalization that could be life-saving.

Table II. Selected, larger randomized controlled heart failure trials of disease management or intervention.

Figure 1. An example of an integrated nurse-based service for the support of patients
with heart failure.

Figure 2. Telemonitoring has the potential to support patient self-management and
enable greater autonomy of patients from nursing and medical supervision (19, 23).

Evidence for education

Clearly, some level of education is required for patients with heart failure to survive at all. Robust evidence that enhanced levels of education improve outcomes is lacking, but this may reflect the failure of the educational programs rather than a failure of the concept (Table II, and Table III page 414 & 415).^9,10,26-50 Indeed, the major problem in studies of patient education may be the effectiveness of education in the control group that will often be higher than in usual clinical practice.

There is good evidence that patients who take treatment as advised do better, even when that treatment is a placebo.² This may reflect the fact that if patients comply with placebo they also comply with other aspects of care. It is also possible that sicker patients with greater comorbidity are less likely to comply and therefore poor outcome and poor compliance are associated, but not cause and effect. Another possibility is that patients who comply are more optimistic and less depressed and that these psychological profiles are themselves associated with a better outcome. Patients rely on doctors and nurses to communicate advice effectively. However, patients are individuals and will have very different personal needs not only in terms of what they need to do and what is going to happen to them, but also how much they want to understand the reasons for the advice. Moreover, patients will differ in how they want to receive advice. Although health professionals often think they provide sufficient advice to patients, it is clear that patients often don’t recall what they have been told. For some patients, understanding the reasons for the advice will help, but for other patients it will just be more things to remember. Ultimately, flexible, easily accessible educational systems that create a dialogue with patients, preferably linked to a telemonitoring system that can help identify the patients’ educational needs and ensure that professional support is available when needed are likely to be the most successful strategy.

Practical implementation

The main problems with implementing patient education are in identifying the patients, identifying their needs, and repeatedly delivering a consistent educational message with limited specialized resources. The strategy being developed in Kingston-upon-Hull is as follows (Figures 1 and 2):

_ Family physicians are encouraged to measure plasma Nterminal pro–brain natriuretic peptide (NT-proBNP) as a routine part of the annual follow-up of patients with ischemic heart disease or diabetes mellitus and for any patient taking a loop diuretic or any other patient thought to have or be at high risk of heart failure or major cardiac dysfunction. Patients with values <200 ng/L are reassured, patients with values between 200-400 ng/L are kept under review, and patients with values >400 ng/L are referred to a heart failure specialist clinic for evaluation or, if serum creatinine is grossly elevated, to a renal clinic.

Table III. Systematic reviews of heart failure management interventions and programs.

_ Patients admitted to hospital with heart failure (about 800 patients per year) or prescribed a loop diuretic (about 2500 per year) for any reason other than renal failure have plasma concentrations of NT-proBNP checked. Most of these patients are managed on upwards of 40 different general medical or surgical wards, which renders coordinated care difficult. Those with elevated values are reviewed by one of a small team of heart failure specialist “discharge-liaison” nurses that ensure that appropriate investigations are done and that those with confirmed heart failure receive specialist input.
_ All patients with confirmed heart failure are considered for home telemonitoring, with priority given to those considered unstable and at high risk of hospitalization or death. A new generation of systems is being developed through the Heart- Cycle Program (FP7-216695; European Union 7th Framework Program).^19,23 Home telemonitoring systems link the patient’s television with equipment to monitor weight, blood pressure, and heart rate and rhythm. Patients are asked to complete questions on their television screens about symptoms and get questions to check that they know how to contribute to their personal management. They are then advised which educational videos they should watch, but can select from a whole variety. The system paces the patient’s education, but patients can choose to go faster and can repeat educational sessions as often as they wish and with friends and relatives. Patients are encouraged to get into a regular 15-minutemorning habit of telemonitoring activities. Patients are remarkably compliant and successful once they know what to do. The provision of feedback in terms of trend charts for weight and blood pressure gets patients much more engaged with their care. New motivational programs and sensors will make the technology more and more efficient and effective. The development of therapeutic algorithms allows patients to make many decisions about the need for repeat measurements of weight or blood pressure, changes in medication, and the timing of blood tests. The system and the patient can deal with up to 70% of the issues generated by conventional telemonitoring systems, relieving health professionals from a substantial workload, which greatly improves work efficiency and effectiveness.
_ A telemonitoring nurse, supported by the “discharge-liaison” nurses, provides daily support for up to 250 telemonitored patients. The system deals with about 70% of issues such as out-of-range measurements and need to adjust dietary sodium, diuretic dosage, and titration of ACE inhibitors and β-blockers. It also provides advice and support to health professionals. The aim is to maintain the patient in an ideal symptomatic and hemodynamic range that, compared with a strategy of crisis detection and management, is much more likely to modify the natural history of disease favorably. The system also sifts the data received to identify patients that are running into trouble and that require intervention from a health professional. Stable patients may only require a health professional to review telemonitoring data once every 6 to 8 weeks.
_ A small team of heart failure specialist community nurses can be directed by the telemonitoring nurse to patients that are running into trouble and require additional support.
_ Community volunteers provide an extra layer of support. Older patients sometimes require more coaching with the equipment and some even require help to make measurements. With a modest amount of training, the voluntary sector can assist some of the most frail and vulnerable patients to benefit from telemonitoring.
_ Currently, patients are offered 4 months of telemonitoring. At that time they are reevaluated. Patients who are considered still unstable or at high risk of events are offered a further 4-month cycle. Patients who are stable are offered the choice of whether to continue or not. About 10% of patients have poor compliance with tests, and telemonitoring is usually withdrawn from these patients after discussion with a specialist nurse who has identified no obvious remediable action that could improve engagement.

In conclusion, patients themselves are a huge potential health care resource that has not been tapped into as yet. The future is home telemonitoring and electronic patient records for those who have chronic disease who wish to have the best chance of improving their quality and quantity of life. Clearly, some will disagree—mainly those who don’t have a severe chronic illness and perceive technology to be intrusive and impersonal. From patients with serious illnesses, who often feel lonely and frightened, the recurrent theme is that they feel like these technologies are their “guardian angel” and their “lifeline.” Rather than isolating patients, they draw them back into society. Patient education and support need to be maintained throughout the patient’s life as withdrawal of support appears associated with adverse outcomes.^51,52 _

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50. McAlister FA, Stewart S, Ferrua S, McMurray JJV. Multidisciplinary strategies for the management of heart failure patients at high risk for readmission: a systematic review of randomized trials. J Am Coll Cardiol. 2004;44:810-819.
51. Ojeda S, Anguita M, Delgado M, et al. Short- and long-term results of a programme for the prevention of readmissions and mortality in patients with heart failure: are effects maintained after stopping the programme? Eur J Heart Fail. 2005;7(5):921-926.
52. Goldberg LR, Piette JD, Wals MN, et al; WHARF Investigators. Randomized trial of a daily electronic home monitoring system in patients with adavanced heart failure: the Weight Monitoring in Heart Failure (WHARF) trial. Am Heart J. 2003; 146(4):705-712.

Keywords: heart failure; patient education; systematic review

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Kateryna AMOSOVA, MD, PhD
Professor and Chief of Internal Medicine
Department No. 2
National Medical University named
after O. O. Bogomolet
13, Shevchenko Boulevard
Kyiv 01004, UKRAINE

Numerous observational studies have demonstrated that “real life” heart failure (HF) patients receive lower medication doses than the targets recommended in guidelines. The problem is more widespread for β-blockers than for angiotensin-converting enzyme inhibitors because of their many contraindications and side effects. Even in outpatients treated by cardiologists, only 18% to 21% actually receive target doses of β-blockers.¹

In the meantime, it seems reasonable to consider that the target dose of β-blocker in HF is not a fixed dose, but the maximal tolerated dose or dose needed to lower sinus rhythm to 60-70 bpm at rest. The latter is probably a pathophysiologically sound target. If this target isn’t reached at the maximal tolerated β-blocker dose, which is what happens in the majority of real life patients, the evidence-based treatment strategy should be the addition of ivabradine. _

Edimar Alcides BOCCHI, MD
Heart Institute of the São Paulo
University Medical School
Rua Dr Melo Alves 690, 4o andar
São Paulo, CEP 01417-010
BRAZIL

Every day, clinicians face difficult decisions on how best to manage heart failure (HF) patients. Ideally, these decisions are guided by the best medical evidence. Clinical practice guidelines are designed to translate medical research and expert opinion into recommendations for everyday practice, but in the case of HF, doctors are reticent or slow to incorporate these recommendations.¹ Clinical practice guidelines are ultimately a consensus developed to help patients, but what many people say collectively, no one believes individually.²

In summary, the prescription of target doses is very important in the treatment of HF. However, in the real world, the association of new effective drugs and treatment strategies should form an additional therapeutic approach. _

Muzaffer DEGERTEKIN, MD, PhD, FESC
Professor of Cardiology
Department of Cardiology
Yeditepe University Hospital
Istanbul, TURKEY

Chronic heart failure (CHF) is a condition characterized by unpleasant symptoms, high mortality, and recurrent and lengthy hospitalizations. It is a major public health concern of growing prevalence. The short-term goals of CHF management are directed toward relieving symptoms and improving functional capacity and quality of life. Long-term goals include reducing mortality and slowing or reversing the underlying cardiac structural abnormalities associated with CHF. Two decades of controlled clinical trials have led to significant developments in the treatment of heart failure. The results of these large placebo-controlled randomized trials have been integrated into European and US treatment guidelines. These guidelines emphasize in particular the beneficial effects on mortality and morbidity of angiotensinconverting enzyme (ACE) inhibitors, β-blockers, angiotensin II receptor blockers (ARBs), and aldosterone antagonists. However, several national and international surveys consistently suggest there is suboptimal utilization of recommended medications in outpatients, as well as in hospital situations.1,2 One reason for this could be that CHF remains underdiagnosed and undertreated. Undertreatment may mean either underuse of modern recommended treatments, or prescription of low doses of these drugs.3

In conclusion, guideline-recommended doses of drugs remain the scientifically validated basis for treatment in all patients with CHF. The additive therapeutic effects of β-blockers and ACE inhibitors can improve prognosis regardless of age and comorbid conditions. However, instead of dogmatic enforcement of high target doses, the dose should be adapted individually, taking into consideration particular characteristics of certain patient subpopulations. Low initial doses and slower uptitration will improve the acceptance of heart failure drugs, thus enabling a more accurate application of the guidelines. _

Stavros V. KONSTANTINIDES,
MD, PhD, FESC
Professor and Chairman
Department of Cardiology
Democritus University of Thrace
University General Hospital
68100 Alexandroupolis
GREECE

Beta-blockers form an essential part of the standard care of patients with systolic chronic heart failure, and current guidelines recommend uptitration to the target dose in order to maximize therapeutic benefit.¹ This recommendation is based on high-quality clinical data supporting a dosedependent beneficial effect of these agents on patient prognosis.^2-5 However, β-blocker target doses are often difficult to achieve in clinical routine; in fact, they have even proven difficult to achieve in the clinical trial setting. In the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), the mean daily dose of study drug in the metoprolol group was 159 mg once daily, with (only) 64% of patients receiving the target dose of 200 mg once daily. Similar or lower target-dose rates were achieved in further landmark trials such as Effect of Carvedilol on Survival in Severe Chronic Heart Failure (COPERNICUS), Cardiac Insufficiency BIsoprolol Study II (CIBIS II), and Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS).^2-5 Of note, reasons for not reaching target doses, or even discontinuing β-blockers in heart failure patients, often remained obscure. For example, in SENIORS, the main reason for discontinuation of nebivolol was reportedly “patient’s decision” (10% patients).⁵ As expected, β-blocker target-dose rates are even lower in the “real world.” A national cohort study in the UK revealed that less than 40% of heart failure patients were treated with a β-blocker, and less than 20% treated with a guideline-recommended agent achieved target dose. As in clinical trials, the reasons for not being treated with a β-blocker or achieving target dose remained obscure for a large proportion (>50%) of patients.⁵

In conclusion, registries, national surveys, and even randomized controlled clinical trials suggest that achieving what has been defined as β-blocker target doses is a utopia in the clinical practice of heart failure management. Targeting heart rate reduction by a dual-drug regimen that respects the patient’s tolerance and (perceived) well-being appears, based on the results of SHIFT, to be the best strategy to achieve better compliance and outcome in terms of mortality and morbidity. _

Henry KRUM, MBBS, PhD, FRACP,
FESC, FCSANZ
Professor Director, CCRE in Therapeutics
School of Public Health, Monash University
Department of Medicine, Alfred Hospital
Melbourne, Victoria
AUSTRALIA

Guideline authorities mandate lifesaving drugs for the treatment of heart failure (HF), to be given at target doses used in definitive outcome trials establishing their benefit.^1,2 However, it is clear that in everyday clinical practice, physicians and patients are unwilling or unable to achieve target doses. This has been well established from epidemiological datasets, and also evaluation of background therapy in randomized clinical trials of new therapies.^3,4 These observations raise two key questions: (i) can optimal dosing actually be achieved in routine clinical practice?; and (ii) does it really matter whether it can be achieved?

All of that is for the future. For the present, we are left with a situation in which patients cannot reach target doses despite strong guideline recommendations. Clearly education is still required among prescribers to optimize achievable doses of HF drugs. Nevertheless, there would still be a significant percentage of patients who cannot reach target dose. This matters at the population level, but does it matter for the individual? We are at present unfortunately unable to definitively answer that question. _

Lip Ping LOW,MBBS, FRACP,
FAMS, FACC, BBM
Consultant Cardiologist
Low Cardiology Clinic
3 Mt Elizabeth #1105
Mt Elizabeth Medical Centre
228510
SINGAPORE

Chronic heart failure is a major public health problem, and is associated with high morbidity and mortality. A number of large double-blind controlled trials in the last three decades have provided evidence for the efficacy and safety of a number of pharmacological treatments for heart failure. The cornerstone of pharmacological treatment is the use of β-blockers and angiotensin-converting enzyme inhibitors. Based on the drug dosages used in the aforementioned large trials, major guidelines on heart failure—including the updated guidelines from the European Society of Cardiology and the American College of Cardiology/American Heart Association—recommend titration of the doses of these agents to the target dose used in the clinical trials. A number of studies have revealed, however, that a significant number of patients receive doses of these medications that are lower than the target doses. The EuroHeart Failure Survey reported that on average, the daily dosage of β-blocker was far below target doses. In the Impact-Reco II Program, 23% of patients received the target dose, and 54% received 50% or more of the target dose. In the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), 56% of patients on β- blockers were treated with at least 50% of the target dose, and 26% reached the target dose.

The recent SHIFT, which showed that heart rate reduction with ivabradine reduced clinical events in heart failure in relation to the heart rate achieved, confirms that heart rate is a risk factor in heart failure, and suggests that guidelines on heart failure may now need to consider heart rate reduction as a target for treatment. _

Viacheslav MAREEV,MD, PhD
M. V. Lomonosov Moscow State University
Moscow, RUSSIA

This is not only a medical question, but a philosophical one. What does “target dose” mean for clinical practitioners? Taking into account themagnitude of the problem and the space for discussion, I will discuss this using the example of β-blocker dosing in chronic heart failure (CHF) patients. Recommendations for optimal doses usually come from randomized clinical trials. But optimal doses often differ in clinical trials, so it is not easy to interpret data.
Officially, target doses of bisoprolol 10 mg/day, metoprolol 200 mg/day, and carvedilol 25 mg twice daily are recommended for CHF patients. These are based on results from Cardiac Insufficiency BIsoprolol Study II (CIBIS II), Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF), and Effect of Carvedilol on Survival in Severe Chronic Heart Failure (COPERNICUS). However, practitioners are often afraid of β-blocker side effects and use substantially lower doses due to concerns for patient safety. Race, sex, age, body weight, liver and renal function, disease severity, and metabolism are all important when considering the abstract “target dose.”

So we can conclude that normally practicing doctors use about half the target dose of β-blocker in CHF treatment, and administration of ivabradine doesn’t change this practice. Although we must try to uptitrate, there is no real possibility of reaching recommended target β-blocker doses in the near future in clinical routine. In a Russian registry, 46% of patients receiving β-blockers didn’t reach the recommended HR of <80 beats per minute. Thus, administration of medications that reduce HR and are not contraindicated with β-blockers could be useful for the successful treatment of CHF. _

Ken McDONALD,MD, FRCPI
Heart Failure Unit
St Vincent’s University Hospital
Dublin, IRELAND

Over the last two decades, there have been significant advances in the pharmacological management of heart failure. Large international clinical trials have demonstrated the impressive impact of β-blockade and therapies modulating the renin-angiotensin-aldosterone system in improving the outlook for patients with reduced ejection fraction heart failure. Beyond clinical trials, the remaining challenge is to apply these advances in the most effective manner to the general heart failure population. This critical last step in the process poses some questions and challenges.

Therefore, to encourage optimal application of guidelines to the community population, we need to encourage widespread use of disease management programs, and within this structure, assess the relative merit of proven therapies in each individual case. In doing so, it may emerge that in certain situations, striving for clinical trial dosing may be inappropriate, but at least this will be decided within a structure of care that attempts to bring best-possible therapy to the wider heart failure population. _

Jeyamalar RAJADURAI,FRCP,
FACC, FESC
Consultant Cardiologist
Sime Darby Medical Center
Kuala Lumpur
MALAYSIA

Globally, the prevalence of heart failure is increasing with aging of the population. Heart failure due to depressed systolic function is an important cause of morbidity and mortality. For many years, treatment consisted only of medications such as digitalis and diuretics. Since the late 1980s however, several landmark clinical trials have revolutionized the management of systolic heart failure with the introduction of neurohormonal blockade, and have clearly established the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers, and aldosterone antagonists as standards of care. These agents have been shown to significantly reduce all-cause mortality, reduce hospitalizations, and improve quality of life.

The challenge of the future is to find ways to address the “treatment gap” that exists in a majority of our patients. _

Karen SLIWA,MD, PhD, FESC, FACC
Hatter Institute for Cardiovascular
Research in Africa
Department of Medicine and IIDMM
Faculty of Health Sciences
Cape Town
SOUTH AFRICA

Current guidelines for the management of heart failure recommend uptitrating the doses of drugs to target doses defined in a number of morbidity and mortality trials. Long-term adherence to the recommendations in “real life” is disappointing, and the average dose of the majority of pharmacological treatments remains below the recommended dose. There are a number of factors responsible for this; ie, health systems, patients, physicians, and treatment factors (Table), with different levels of significance in certain patient subpopulations.

One of the most important issues in clinical practice is the lack of communication between physician and patient. Health systems worldwide are under increasing pressure to be time efficient and cost effective, resulting in patients not being allowed to admit that they cannot tolerate their medication and that they are simply not taking it. This denies the patient the opportunity to explore other better-tolerated treatment avenues with their physician. Treating the hypotensive stable patient with poor left ventricular contractility, but tachycardia remains a challenge. We are still miles away from patient-tailored therapy based on genetic profiling, and therefore dogmatic enforcement of guideline-based recommendations is controversial. Apart from mortality, even the end points for successful short-term and long-term outcomes are under debate. Heart rate is one of the most informative and simple parameters that can be measured in cardiovascular disease. However, it is often not taken in a standardized fashion; ie, body posture, duration of measurements, and environmental temperature are not taken into account. _

B. Daan WESTENBRINK,MD, PhD
Department of Cardiology, Thoraxcenter
University Medical Center Groningen
Hanzeplein 1, P. O. Box 30001
9700 RB Groningen
NETHERLANDS

Pharmacological therapy has dramatically improved heart failure (HF) morbidity and mortality, and remains the cornerstone in disease management. The efficacy of the expanding list of HF drugs has been established in meticulously controlled trials employing careful drug titration protocols aiming for the same target dose in all patients. Clinical practice guidelines therefore recommend titrating all HF patients to the target doses that were used in the original trial protocols. A recent European survey showed that most HF patients received appropriate drugs, yet only 25% were prescribed the recommended target dose.¹ This prompts the question of whether 75% of HF patients are undertreated, or whether the target doses are unrealistic.

Thus, instead of dogmatically enforcing unrealistic targets and chastising physicians who fail to reach these goals, we should encourage titration of medication to the maximal tolerated dose in all HF patients. More may be better, but a little is better than too much. _