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1. Management of HFrEF Brook A. June/2016 Braunwald 10th ed. ESC 2016 guideline

2. Definition HF is a clinical syndrome characterized by typical symptoms ( e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema ) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress

3. Definition The current definition of HF restricts itself to stages at which clinical symptoms are apparent. Before clinical symptoms become apparent , patients canpresentwithasymptomatic structuralorfunctional cardiac abnormalities [systolic or diastolic left ventricular (LV) dysfunction ], which are precursors ofHF

4. Terminologies The main terminology used to describe HF is historical and is based on measurement of the LVEF. HF comprises a wide range of patients , from those with normal LVEF [typically considered asv ≥ 50%; HF with preserved EF ( HFpEF )] to those with reduced LVEF [typically considered as <40 %; HF with reduced EF ( HFrEF )] Patients with an LVEF in the range of 40–49% represent a ‘grey area’, which we now define as HFmrEF

5. Terminologies Differentiation of patients with HF based on LVEF is important due to different underlying aetiologies , demographics, co-morbidities and response to therapies. Most clinical trials published after 1990 selected patients based on LVEF [usually measured using echocardiography, a radionuclide technique or cardiac magnetic resonance (CMR)], and it is only in patients with HFrEF that therapies have been shown to reduce both morbidity and mortality.

6. Terminologies The diagnosis of HFpEF is more challenging than the diagnosis of HFrEF . Patients with HFpEF generally do not have a dilated LV, but instead often have an increase in LV wall thickness and/or increased left atrial (LA) size as a sign of increased filling pressures . Most have additional ‘evidence’ of impaired LV filling or suction capacity, also classified as diastolic dysfunction, which is generally accepted as the likely cause of HF in these patients (hence the term ‘ diastolic HF’).

7. Terminologies However, most patients with HFrEF (previously referred to as ‘systolic HF’) also have diastolic dysfunction, and subtle abnormalities of systolic function have been shown in patients with HFpEF . Hence the preference for stating preserved or reduced LVEF over preserved or reduced ‘systolic function ’.

8. Terminologies In previous guidelines it was acknowledged that a grey area exists between HFrEF and HFpEF . These patients have an LVEF that ranges from 40 to 49%, hence the term HFmrEF . Identifying HFmrEF as a separate group will stimulate research into the underlying characteristics, pathophysiology and treatment of this group of patients. Patients with HFmrEF most probably have primarily mild systolic dysfunction , but with features of diastolic dysfunction

9. Terminologies HF: describes the symptomatic syndrome , graded according to the New York Heart Association ( NYHA) functional classification However, a patient can be rendered asymptomatic by treatment . Asymptomatic LV systolic dysfunction: a patient who has never exhibited the typical symptoms and/or signs of HF and with a reduced LVEF Chronic HF: Patients who have had HF for some time Stable HF: A treated patient with symptoms and signs that have remained generally unchanged for at least 1 month If chronic stable HF deteriorates, the patient may be described as ‘decompensated ’ and this may happen suddenly or slowly, often leading to hospital admission , an event of considerable prognostic importance .

10. Terminologies New-onset (‘de novo’) HF may also present acutely, for example , as a consequence of acute myocardial infarction (AMI), or in a subacute ( gradual) fashion, for example, in patients with a dilated cardiomyopathy ( DCM), who often have symptoms for weeks or months before the diagnosis becomes clear. Although symptoms and signs of HF may resolve, the underlying cardiac dysfunction may not, and patients remain at the risk of recurrent ‘ decompensation ’.

11. Terminologies Occasionally, however, a patient may have HF due to a problem that resolves completely (e.g. acute viral myocarditis, takotsubo cardiomyopathy or tachycardiomyopathy ). Other patients, particularly those with ‘idiopathic’ DCM, may also show substantial or even complete recovery of LV systolic function with modern disease modifying therapy [including ACEIs, beta-blocker, mineralocorticoid receptor antagonist (MRA), ivabradine and/or CRT].

12. Terminologies ‘Congestive HF’ is a term that is sometimes used, and may describe acute or chronic HF with evidence of volume overload. Many or all of these terms may be accurately applied to the same patient at different times, depending upon their stage of illness .

13. Terminologies The NYHA functional classification has been used to describe the severity of symptoms and exercise intolerance. However, symptom severity correlates poorly with many measures of LV function Although there is a clear relationship between the severity of symptoms and survival, patients with mild symptoms may still have an increased risk of hospitalization and death. Sometimes the term ‘advanced HF’ is used to characterize patients with severe symptoms, recurrent decompensation and severe cardiac dysfunction

14. Terminologies Func’l Capacity Objective Assessment Class I Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, dyspnea , or anginal pain. Class II Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea , or anginal pain. Class III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea , or anginal pain. Class IV Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.

15. Terminologies The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) classification describes stages of HF development based on structural changes and symptoms The Killip classification may be used to describe the severity of the patient’s condition in the acute setting after myocardial infarction

16. Epidemiology, Etiology & Prognosis

17. Epidemiology The prevalence of HF depends on the definition applied, but is approximately1–2 % of the adult population in developed countries , rising to ≥10% among people >70 years of age . Among people >65 years of age presenting to primary care with breathlessness on exertion, one in six will have unrecognized HF ( mainly HFpEF ) The lifetime risk of HF at age 55 years is 33% for men and 28% for women. The proportion of patients with HFpEF ranges from 22 to 73%, depending on the definition applied, the clinical setting (primary care, hospital clinic, hospital admission), age and sex of the studied population, previous myocardial infarction and the year of publication

18. Epidemiology Data on temporal trends based on hospitalized patients suggest that the incidence of HF may be decreasing, more for HFrEF than for HFpEF . HFpEF and HFrEF seem to have different epidemiological and aetiological profiles. Compared with HFrEF , patients with HFpEF are Older, More often women and More commonly have a history of hypertension and atrial fibrillation (AF), W hile a history of myocardial infarction is less common. The characteristics of patients with HFmrEF are between those with HFrEF and HFpEF , but further studies are needed to better characterize this population.

19. Epidemiology The aetiology of HF is diverse within and among world regions . There is no agreed single classification system for the causes of HF , with much overlap between potential categories. Many patients will have several different pathologies—cardiovascular and non-cardiovascular—that conspire to cause HF. Identification of these diverse pathologies should be part of the diagnostic workup , as they may offer specific therapeutic opportunities. Many patients with HF and ischaemic heart disease (IHD) have a history of myocardial infarction or revascularization. However , a normal coronary angiogram does not exclude myocardial scar ( e.g. by CMR imaging) or impaired coronary microcirculation as alternative evidence for IHD

20. Epidemiology

21. Epidemiology In 20% to 30% of the cases of HFrEF , the exact etiologic basis is not known . These patients are referred to as having nonischemic , dilated , or idiopathic cardiomyopathy if the cause is unknown Previous viral infection or toxin exposure (e.g ., with excess alcohol consumption or use of chemotherapeutic agents also may lead to a dilated cardiomyopathy .

22. Epidemiology Although excessive alcohol consumption can promote cardiomyopathy, alcohol consumption per se is not associated with increased risk for HF and may protect against the development of HF when consumed in moderation

23. Epidemiology It also is becoming increasingly clear that a large number of cases of dilated cardiomyopathy are secondary to specific genetic defects, most notably those in the cytoskeleton Most of the forms of familial dilated cardiomyopathy are inherited in autosomal dominant fashion . Mutations of genes encoding cytoskeletal proteins ( desmin , cardiac myosin , vinculin ) and nuclear membrane proteins ( lamin ) have been identified thus far.

24. Epidemiology Dilated cardiomyopathy also is associated with Duchenne’s , Becker’s, and limb-girdle muscular dystrophies

25. Epidemiology In clinical practice, a clear distinction between acquired and inherited cardiomyopathies remains challenging. In most patients with a definite clinical diagnosis of HF, there is no confirmatory role for routine genetic testing, But genetic counselling is recommended in patients with hypertrophic cardiomyopathy (HCM), ‘idiopathic ’ DCM or arrhythmogenic right ventricular cardiomyopathy ( ARVC ), since the outcomes of these tests may have clinical implications.

26. Epidemiology In patients with HF (both hospitalized and ambulatory), most deaths are due to cardiovascular causes, mainly sudden death and worsening HF. All-cause mortality is generally higher in HFrEF than HFpEF Hospitalizations are often due to non-cardiovascular causes , particularly in patients with HFpEF . Hospitalization for cardiovascular causes did not change from 2000 to 2010, whereas those with non-cardiovascular causes increased.

27. Prognosis Estimation of prognosis for morbidity, disability and death helps patients , their families and clinicians decide on the appropriate type and timing of therapies (in particular, decisions about a rapid transition to advanced therapies) and assists with planning of health and social services and resources. Numerous prognostic markers of death and/or HF hospitalization have been identified in patients with HF However, their clinical applicability is limited and precise risk stratification in HF remains challenging

28. Prognosis Although several recent reports have suggested that the mortality for patients with HF is subsiding, the overall mortality rate remains higher than for many cancers, including those involving the bladder, breast, uterus, and prostate. In the Framingham Heart Study, the median survival was 1.7 years for men and 3.2 years for women, with only 25% of men and 38 % of women surviving 5 years. European studies have confirmed a similar poor longterm prognosis More recent data from the Framingham Heart Study have examined long-term trends in the survival of patients with HF and shown improved survival in both men and women, with an overall decline in mortality of approximately 12 % per decade from 1950 to 1999

29. Prognosis Sex The role of sex in HF prognosis remains a controversial issue with respect to HF outcomes. Nonetheless , the aggregate data suggest that women with HF have a better overall prognosis than do men . However , women appear to have a greater degree of functional incapacity for the same degree of LV dysfunction and also have higher prevalence of HF with a normal EF

30. Prognosis Race Controversy also has arisen regarding the impact of race on outcome, with higher mortality rates being reported in blacks in some but not all studies. Blacks with HF present at an earlier age and have more advanced LV dysfunction and a worse New York Heart Association (NYHA) functional class at the time of diagnosis. Although the reasons for these differences are not known, as noted previously , differences in HF etiology might explain some of these observations . Additional socioeconomic factors also may potentially influence outcomes in black patients, such as geographic location and access to health care. Age is one of the strongest and most consistent predictors of adverse outcome in HF

31. Prognosis Many other factors have been associated with increased mortality in patients with HF* To this end , several multivariate models for predicting the HF prognosis have been developed and validated. One such model is the Seattle Heart Failure Model

32. Prognosis Seattle Heart Failure Model Derived by retrospectively investigating predictors of survival among patients with HF in clinical trials. The Seattle Heart Failure Model provides an accurate estimate of 1-, 2-, and 3-year survival rates with the use of easily obtained clinical, pharmacologic, device, and laboratory characteristics

33. Prognosis Although obesity is a risk factor for the development of HF, obese patients with HF seem to enjoy a more favorable clinical prognosis. The association between obesity, a traditional cardiovascular risk factor , and improved clinical outcomes in patients with HF (i.e ., reverse epidemiology) has been called the “obesity paradox.”

34. Biomarkers and Prognosis Strong inverse correlations have been reported between survival and plasma levels of Norepinephrine , renin, arginine vasopressin (AVP ), aldosterone , atrial and brain natriuretic peptides (ANP and BNP) and N-terminal pro–B-type natriuretic peptide (NT- proBNP ), endothelin-1 , and inflammatory markers such as tumor necrosis factor (TNF ), soluble TNF receptors, C-reactive protein, galactin-3, pentraxin-3, and soluble ST2 Markers of oxidative stress, such as oxidized low-density lipoprotein and serum uric acid, also have been associated with worsening clinical status and impaired survival in patients with chronic HF.

35. Biomarkers and Prognosis Cardiac troponins T and I, sensitive markers of myocyte damage, may be elevated in patients with nonischemic HF and predict adverse cardiac outcomes The association between a low hemoglobin or hematocrit and adverse HF outcomes also has long been recognized And recently has garnered considerable attention after several reports illustrated the independent prognostic value of anemia in patients with HF with either reduced or normal ejection fraction*

36. Biomarkers and Prognosis Anemia Published estimates of the prevalence of anemia (defined as a hemoglobin concentration less than 13 g/ dL in men and less than 12 g/ dL in women) in patients with HF vary widely, ranging from 4% to 50 %, depending on the population studied and the definition of anemia that is used. In general, anemia is associated with more HF symptoms , worse NYHA functional status, greater risk of HF hospitalization, and reduced survival

37. Biomarkers and Prognosis Anemia Unclear, however, is whether anemia is a cause of decreased survival or simply a marker of more advanced disease. The underlying cause for anemia probably is multifactorial, including Reduced sensitivity to erythropoietin receptors, The presence of a hematopoiesis inhibitor, and/or A defective iron supply for erythropoiesis Although a “transfusion threshold” for maintaining the hematocrit above 30% in patients with cardiovascular disease generally has been accepted, this clinical practice has been based more on expert opinion rather than on direct evidence that documents the efficacy of this form of therapy*

38. Renal Insufficiency Renal insufficiency is associated with poorer outcomes in patients with HF; some uncertainty remains, however, regarding whether renal impairment is a simply a marker for worsening HF or whether renal impairment might be causally linked to worsening HF. Although more common in patients hospitalized for HF, at least some degree of renal impairment is still present in approximately one half of stable outpatients with HF. Patients with renal hypoperfusion or intrinsic renal disease show an impaired response to diuretics and angiotensinconverting enzyme (ACE) inhibitors and are at increased risk for adverse effects during treatment with digitalis.

39. Renal Insufficiency In a recent metaanalysis a majority of patients with HF had some degree of renal impairment . These patients represented a high-risk group with an approximately 50% increased relative mortality risk when compared with patients who had normal renal function. Similar findings were observed in the Acute Decompensated Heart Failure National Registry ( ADHERE )

40. Renal Insufficiency In the second prospective Randomized study of Ibopamine on Mortality and Efficacy, impaired renal function was a stronger predictor of mortality than impaired LV function and NYHA functional class in patients with advanced HF Thus renal insufficiency is a strong, independent predictor of adverse outcomes in patients with HF.

41. Diagnosis

42. Symptoms & Signs HF should be viewed as a continuum comprising four interrelated stages

43. Essential Initial Investigations Natriuretic peptides Useful especially in the non-acute setting when echocardiography is not immediately available Elevated NPs help establish an initial working diagnosis, identifying those who require further cardiac investigation; patients with values below the cutpoint for the exclusion of important cardiac dysfunction do not require echocardiography Patients with normal plasma NP concentrations are unlikely to have HF.

44. Essential Initial Investigations Natriuretic peptides Diagnostic values apply similarly to HFrEF and HFpEF ; on average, values are lower for HFpEF than for HFrEF . At the mentioned exclusionary cut-points, the negative predictive values are very similar and high (0.94–0.98) in both the non-acute and acute setting, but the positive predictive values are lower both in the non-acute setting (0.44–0.57) and in the acute setting ( 0.66–0.67 ) Therefore , the use of NPs is recommended for ruling-out HF, but not to establish the diagnosis

45. Essential Initial Investigations Natriuretic peptides There are numerous cardiovascular and non-cardiovascular causes of elevated NPs that may weaken their diagnostic utility in HF. Among them, AF, age and renal failure are the most important factors impeding the interpretation of NP measurements On the other hand, NP levels may be disproportionally low in obese patients

46. Essential Initial Investigations ECG An abnormal ECG increases the likelihood of the diagnosis of HF, but has low specificity Some abnormalities on the ECG provide information on aetiology (e.g. myocardial infarction ), and findings on the ECG might provide indications for therapy (e.g. anticoagulation for AF, pacing for bradycardia , CRT if broadened QRS complex ) HF is unlikely in patients presenting with a completely normal ECG ( sensitivity 89%) Therefore , the routine use of an ECG is mainly recommended to rule out HF.

47. Essential Initial Investigations Echocardiography T he most useful, widely available test in patients with suspected HF to establish the diagnosis. It provides immediate information on chamber volumes, ventricular systolic and diastolic function, wall thickness, valve function and pulmonary hypertension This information is crucial in establishing the diagnosis and in determining appropriate treatment

48. Diagnosis of HFpEF The diagnosis of HFpEF remains challenging. LVEF is normal and signs and symptoms for HF are often non-specific and do not discriminate well between HF and other clinical conditions The diagnosis of chronic HFpEF , especially in the typical elderly patient with co-morbidities and no obvious signs of central fluid overload , is cumbersome and a validated gold standard is missing

49. Diagnosis of HFpEF To improve the specificity of diagnosing HFpEF , the clinical diagnosis needs to be supported by objective measures of cardiac dysfunction at rest or during exercise. The diagnosis of HFpEF requires the following conditions to be fulfilled: The presence of symptoms and/or signs of HF A ‘preserved’ EF (defined as LVEF ≥50% or 40–49% for HFmrEF ) Elevated levels of NPs Objective evidence of other cardiac functional and structural alterations underlying HF

50. Diagnosis of HFpEF In case of uncertainty, a stress test or invasively measured elevated LV filling pressure may be needed to confirm the diagnosis The cut-off of 50% for a diagnosis of HFpEF is arbitrary ; patients with an LVEF between 40 and 49% are often classified as HFpEF in clinical trials

51. Diagnosis of HFpEF The resting ECG may reveal abnormalities such as AF, LV hypertrophy and repolarisation abnormalities . A normal ECG and/or plasma concentrations of BNP <35 pg /mL and/or NT- proBNP <125 pg /mL make a diagnosis of HFpEF , HFmrEF or HFrEF unlikely The next step comprises an advanced workup in case of initial evidence of HFpEF / HFmrEF and consists of objective demonstration of structural and/or functional alterations of the heart as the underlying cause for the clinical presentation.

52. Diagnosis of HFpEF Key structural alterations are A left atrial volume index (LAVI) >34 mL/m2 or A left ventricular mass index (LVMI) ≥115 g/m2 for males and ≥95 g/m2 for females. Key functional alterations are An E/e′ ≥13 and A mean e’ septal and lateral wall < 9 cm/s Other (indirect ) echocardiographically derived measurements are longitudinal strain or tricuspid regurgitation velocity (TRV)

53. Diagnosis of HFpEF A diastolic stress test can be performed with echocardiography , typically using a semi-supine bicycle ergometer exercise protocol with assessment of LV (E/e′) and pulmonary artery pressures ( TRV), systolic dysfunction (longitudinal strain), stroke volume and cardiac output changes with exercise*

54. Diagnosis of HFpEF Alternatively, invasive haemodynamics at rest with assessment of filling pressures [ pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or left ventricular end diastolic pressure (LVEDP) ≥16 mmHg] followed by exercise haemodynamics If below these thresholds, with assessment of changes in filling pressures, pulmonary artery systolic pressure , stroke volume and cardiac output, can be performed

55. Diagnosis of HFpEF The diagnosis of HFpEF in patients with AF is difficult. Since AF is associated with higher NP levels, the use of NT- proBNP or BNP for diagnosing HFpEF probably needs to be stratified by the presence of sinus rhythm (with lower cut-offs) vs. AF (higher cut-offs). LAVI is increased by AF, and functional parameters of diastolic dysfunction are less well established in AF, and other cut-off values probably apply. On the other hand, AF might be a sign of the presence of HFpEF , and patients with AF and HFpEF often have similar patient characteristics. In addition, patients with HFpEF and AF might have more advanced HF compared with patients with HFpEF and sinus rhythm

56. Cardiac Imaging

57. Other Diagnostic Tests

58. Delaying/Preventing HF There is considerable evidence that the onset of HF may be delayed or prevented through interventions aimed at modifying risk factors for HF or treating asymptomatic LV systolic dysfunction

59. Delaying/Preventing HF For patients at high risk for development of HF (stage A), every effort should be made to prevent HF Treat preventable conditions like hypertension, hyperlipidemia, and diabetes In this regard, ACE inhibitors are particularly useful in preventing HF in patients who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with associated cardiovascular risk factors Population Screening

60. Delaying/Preventing HF Hypertension control Many trials show that control of hypertension will delay the onset of HF and some also show that it will prolong life Different antihypertensive drugs [diuretics, ACEIs, angiotensin receptor blockers (ARBs), beta-blockers] have been shown to be effective, especially in older people, both in patients with and without a history of myocardial infarction Along with the ongoing discussion on optimal target blood pressure values in hypertensive non-diabetic subjects, the recent SPRINT study has already demonstrated that treating hypertension to a lower goal [SBP <120 mmHg vs. <140 mmHg] in older hypertensive subjects (≥75 years of age) or high-risk hypertensive patients reduces the risk of cardiovascular disease , death and hospitalization for HF

61. Delaying/Preventing HF Empaglifozin for T2DM Recently, empaglifozin (an inhibitor of sodium-glucose cotransporter 2 ), has been shown to improve outcomes (including the reduction of mortality and HF hospitalizations) in patients with type 2 diabetes. Other hypoglycaemic agents have not been shown convincingly to reduce the risk of cardiovascular events and may increase the risk of HF. Intensification of hypoglycaemic therapy to drive down glycated haemoglobin (HbA1c) with agents other than empagliflozin does not reduce the risk of developing HF

62. Delaying/Preventing HF Smoking & Alcohol Although smoking cessation has not been shown to reduce the risk of developing HF, the epidemiological associations with the development of cardiovascular disease suggest that such advice, if followed , would be beneficial . The association between alcohol intake and the risk of developing de novo HF is U-shaped, with the lowest risk with modest alcohol consumption (up to 7 drinks/week ). Greater alcohol intake may trigger the development of toxic cardiomyopathy, and when present , complete abstention from alcohol is recommended.

63. Delaying/Preventing HF Physical activity An inverse relationship between physical activity and the risk of HF has been reported. A recent meta-analysis found that doses of physical activity in excess of the guideline recommended minimal levels may be required for more substantial reductions in HF risk

64. Delaying/Preventing HF Statins Statins reduce the rate of cardiovascular events and mortality ; there is also reasonable evidence that they prevent or delay the onset of HF . Antiplatelets Neither aspirin nor other antiplatelet agents, nor revascularization , have been shown to reduce the risk of developing HF or mortality in patients with stable CAD. Treatment of Obesity Obesity is also a risk factor for HF, but the impact of treatments of obesity on the development of HF is unknown.

65. Delaying/Preventing HF ACEIs In patients with CAD, without LV systolic dysfunction or HF, ACEIs prevent or delay the onset of HF and reduce cardiovascular and all cause mortality , although the benefit may be small in the contemporary setting, especially in patients receiving aspirin Up-titration of renin–angiotensin system antagonists and beta-blockers to maximum tolerated dosages may improve outcomes, including HF, in patients with increased plasma concentrations of NPs

66. Delaying/Preventing HF ACEIs In asymptomatic patients with chronically reduced LVEF, regardless of its aetiology , an ACEI can reduce the risk of HF requiring hospitalization . This has not yet been shown for beta-blockers or MRAs.

67. Delaying/Preventing HF A primary percutaneous coronary intervention (PCI) at the earliest phase of an ST segment elevation myocardial infarction (STEMI ) to reduce infarct size decreases the risk of developing a substantial reduction in LVEF and subsequent development of HFrEF . Initiation of an ACEI, a beta-blocker and an MRA immediately after a myocardial infarction, especially when it is associated with LV systolic dysfunction, reduces the rate of hospitalization for HF and mortality, as do statins

68. Delaying/Preventing HF ICD In patients with asymptomatic LV systolic dysfunction ( LVEF<30 %) of ischaemic origin who are ≥40 days after an AMI, an implantable cardioverter -defibrillator (ICD) is recommended to prolong life

69. Delaying/Preventing HF Population Screening At present, only limited information is available to support the screening of broad populations to detect undiagnosed HF and/or asymptomatic LV dysfunction NPs are left out due to low positive predictive value* Whom to screen? Patients who are at very high risk of a developing cardiomyopathy ( e.g., those with a strong family history of cardiomyopathy or those receiving cardiotoxic interventions) are appropriate targets for more aggressive screening such as 2D echocardiography to assess LV function. The routine periodic assessment of LV function in other patients is not currently recommended , however .

70. Population Screening How to screen? Several sophisticated clinical scoring systems have been developed to screen for HF in population-based studies, including The Framingham criteria:, which screen for HF on the basis of clinical criteria , and The National Health and Nutrition Survey (NHANES) criteria: which use self-reporting of symptoms to identify patients with HF Additional laboratory tests, however, are often required

71. Transient HF (LV dysfunction) Some conditions result in HF while the LV has normal function/structure Eg . Commonly postoperatively after cardiac surgery or in the setting of severe brain injury, or after a systemic infection. Mechanism Some form of “stunning” of functional myocardium or A ctivation of proinflammatory cytokines that are capable of suppressing LV function

72. Transient HF (LV dysfunction) Emotional stress can also precipitate severe, reversible LV dysfunction that is accompanied by chest pain, pulmonary edema, and cardiogenic shock in patients without coronary disease ( takotsubo syndrome). In this setting, LV dysfunction is thought to be secondary to the deleterious effects of catecholamines after heightened sympathetic stimulation

73. Treatment

74. Objectives The main goals of treatment for HF are to Reduce symptoms, Prolong survival, Improve the quality of life, and Prevent disease progression . Once structural heart disease has developed (stages B to D), the choice of therapy for patients with HFrEF depends on their NYHA functional classification*

75. Objectives For patients who have developed LV systolic dysfunction but remain asymptomatic (NYHA class I), the goal should be to slow disease progression by blocking neurohormonal systems that lead to cardiac remodeling For patients who have developed symptoms (NYHA class II to IV), the primary goal should be to alleviate fluid retention, lessen disability , and reduce the risk of further disease progression and death. These goals generally require a strategy that combines diuretics (to control salt and water retention) with neurohormonal interventions (to minimize cardiac remodeling).

76. General Measures Identify and treat causes of the underlying structural/functional abnormalities Screen for and treat comorbid illnesses hypertension and diabetes that are believed to underlie the structural heart disease. Identify factors that provoke worsening HF in previously stable patients (see table below)

77. Although documented evidence of the effects of immunization in patients with HF is lacking, these patients are at high risk for developing pneumococcal pneumonia and influenza. Accordingly , clinicians should consider recommending influenza and pneumococcal vaccines to their patients with HF , to prevent respiratory infections.

78. General Measures Activity Although heavy physical labor is not recommended in HF, routine modest exercise has been shown to be beneficial in selected patients with NYHA class I to III HF . HF-ACTION trial A Controlled Trial Investigating Outcomes of Exercise Training No significant improvement in all-cause mortality or all-cause hospitalization A trend toward decreased cardiovascular mortality or HF related hospitalizations (HR, 0.87 [95% CI, 0.74 to 0.99]; P = .06 ) Significant improvement in quality of life

79. General Measures Activity For euvolemic patients, regular isotonic exercise such as walking or riding a stationary-bicycle ergometer may be useful as an adjunctive therapy to improve clinical status after exercise testing has determined the safety of such training (i.e., the patient does not develop significant ischemia or arrhythmias). Exercise training is not recommended, however, in patients with HFrEF Who have had a major cardiovascular event or procedure within the past 6 weeks; Receiving cardiac devices that limit the ability to achieve target heart rates; or With significant arrhythmia or ischemia during baseline cardiopulmonary exercise testing .

80. General Measures Diet Sodium restriction Dietary restriction of sodium (to 2 to 3 g daily) is recommended in all patients with the clinical syndrome of HF and either preserved or depressed EF. Further restriction (<2 g daily) may be considered in moderate to severe HF. Fluid restriction G enerally is unnecessary except in the setting of hyponatremia (<130 mEq /liter ) Causes of hyponatremia Activation of the renin-angiotensin system , E xcessive secretion of AVP, or Loss of salt in excess of water from previous diuretic use.

81. General Measures Diet Fluid restriction ctd Fluid restriction (<2 liters/day) should be considered in hyponatremic patients (<130 mEq /liter), or for those patients whose fluid retention is difficult to control despite high doses of diuretics and sodium restriction. Calorie supplementation Recommended for patients with advanced HF and unintentional weight loss or muscle wasting (cardiac cachexia ) However , anabolic steroids are not recommended for these patients because of the potential problems with volume retention

82. General Measures Diet Calorie supplementation ctd The measurement of nitrogen balance , caloric intake, and prealbumin may be useful in determining appropriate nutritional supplementation. The use of dietary supplements (“ nutriceuticals ”) should be avoided in the management of symptomatic HF because of the lack of proven benefit and the potential for significant interactions with proven HF therapeutics

83. Pharmacological treatment of HFrEF

84. Objectives The goals of treatment in patients with HF are to To improve their clinical status, functional capacity and quality of life, Prevent hospital admission and reduce mortality . It is now recognized that preventing HF hospitalization and improving functional capacity are important benefits to be considered if a mortality excess is ruled out

85. Neuro -hormonal antagonists (ACEIs, MRAs and beta-blockers Have been shown to improve survival in patients with HFrEF Recommended for the treatment of every patient with HFrEF , unless contraindicated or not tolerated. ACEIs have been shown to reduce mortality and morbidity in patients with HFrEF and are recommended unless contraindicated or not tolerated in all symptomatic patients.

86. Neuro -hormonal antagonists ctd ACEIs should be up-titrated to the maximum tolerated dose in order to achieve adequate inhibition of the renin–angiotensin–aldosterone system (RAAS ) There is evidence that in clinical practice the majority of patients receive suboptimal doses of ACEI. ACEIs are also recommended in patients with asymptomatic LV systolic dysfunction to reduce the risk of HF development, HF hospitalization and death

87. Neuro -hormonal antagonists ctd A new compound (LCZ696) that combines the moieties of an ARB (valsartan) and a neprilysin (NEP) inhibitor ( sacubitril ) has recently been shown to be superior to an ACEI ( enalapril ) in reducing the risk of death and of hospitalization for HF in a single trial with strict inclusion/exclusion criteria. 162 Sacubitril /valsartan is therefore recommended to replace ACEIs in ambulatory HFrEF patients who remain symptomatic despite optimal therapy and who fit these trial criteria.

88. Neuro -hormonal antagonists ctd ARBs have not been consistently proven to reduce mortality in patients with HFrEF and their use should be restricted to patients intolerant of an ACEI or those who take an ACEI but are unable to tolerate an MRA

89. Ivabradine Ivabradine is a heart rate–lowering agent that acts by selectively blocking the cardiac pacemaker I f (“funny”) current that controls the spontaneous diastolic depolarization of the sinoatrial node. Ivabradine blocks I f channels in a concentration-dependent manner by entering the channel pore from the intracellular side and thus can only block the channel when it is open. The magnitude of I f inhibition is directly related to the frequency of channel opening and would therefore be expected to be most effective at higher heart rates.

90. Ivabradine Initially developed and approved as an antianginal agent in Europe also was shown to improve outcomes in the Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT )

91. Ivabradine SHIFT trial Enrolled symptomatic patients with an LVEF of 35% or less who were in sinus rhythm with heart rate of 70 beats/min or higher and on standard medical therapy for HF (including beta blockers) Ivabradine ( uptitrated to a maximal dosage of 7.5 mg twice daily) reduced the primary composite outcome of cardiovascular death and HF hospitalization by 18% (HR, 0.82 [95% CI 0.75 to 0.90]; P < .0001) The composite endpoint was driven primarily by reducing hospital admissions for worsening HF (HR, 0.74 [95% CI, 0.66 to 0.83]; P < .0001), as indicated by the lack of decrease in cardiovascular deaths (HR, 0.91 [95% CI, 0.80 to 1.03]; P = .13) or all-cause death

92. Ivabradine SHIFT trial The study included patients with HFrEF (NYHA class II-IV, albeit with only a modest representation of NYHA class IV HF) Ivabradine lowered heart rate by approximately 10 beats/min However, only 26% of the patients in the trial were on optimal doses of beta blockers, it is possible that titrating beta blockers to recommended dose may have reduced the HF hospitalizations to a similar degree

93. Ivabradine Additional safety evidence for ivabradine comes from the morbidity-mortality evaluation of the I f inhibitor Ivabradine in patients with coronary disease and LV dysfunction ( BEAUTIFUL) trial BEAUTIFUL Trial More than 10,000 patients with coronary heart disease and an EF below 40 % Ivabradine 7.5 mg twice daily or placebo. Although this trial did not meet its primary endpoint of reducing cardiovascular death , MI, or HF hospitalization, the drug was well tolerated in this patient population.

94. Ivabradine Ivabradin reduces the elevated heart rate often seen in HFrEF and has also been shown to improve outcomes, and should be considered when appropriate The above medications should be used in conjunction with diuretics in patients with symptoms and/or signs of congestion. The use of diuretics should be modulated according to the patient’s clinical status .

95. Beta-Blockers Beta-blockers reduce mortality and morbidity in symptomatic patients with HFrEF , despite treatment with an ACEI and, in most cases, a diuretic, but have not been tested in congested or decompensated patients There is consensus that beta-blockers and ACEIs are complementary, and can be started together as soon as the diagnosis of HFrEF is made. There is no evidence favouring the initiation of treatment with a beta-blocker before an ACEI has been started

96. Beta-blockers Beta-blockers should be initiated in clinically stable patients at a low dose and gradually up-titrated to the maximum tolerated dose. In patients admitted due to acute HF (AHF) beta-blockers should be cautiously initiated in hospital, once the patient is stabilized .

97. Beta-blockers An individual patient data meta-analysis of all the major betablocker trials in HFrEF has shown no benefit on hospital admissions and mortality in the subgroup of patients with HFrEF who are in AF However , since this is a retrospective subgroup analysis , and because beta-blockers did not increase the risk , the guideline committee decided not to make a separate recommendation according to heart rhythm

98. Beta-blockers Beta-blockers should be considered for rate control in patients with HFrEF and AF, especially in those with high heart rate Beta-blockers are recommended in patients with a history of myocardial infarction and asymptomatic LV systolic dysfunction to reduce the risk of death

99. Mineralocorticoid/aldosterone receptor antagonists MRAs (spironolactone and eplerenone ) block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormone (e.g. corticosteroids, androgens) receptors. Spironolactone or eplerenone are recommended in all symptomatic patients (despite treatment with an ACEI and a beta-blocker) with HFrEF and LVEF ≤35%, to reduce mortality and HF hospitalization.

100. Mineralocorticoid/aldosterone receptor antagonists Caution should be exercised when MRAs are used in patients with impaired renal function and in those with serum potassium levels >5.0 mmol /L. Regular checks of serum potassium levels and renal function should be performed according to clinical status .

101. Other Treatment Diuretics Diuretics are recommended to reduce the signs and symptoms of congestion in patients with HFrEF , but their effects on mortality and morbidity have not been studied in RCTs. Loop diuretics produce a more intense and shorter diuresis than thiazides, although they act synergistically and the combination may be used to treat resistant oedema . However , adverse effects are more likely and these combinations should only be used with care .

102. Other Treatment Diuretics The aim of diuretic therapy is to achieve and maintain euvolaemia with the lowest achievable dose. The dose of the diuretic must be adjusted according to the individual needs over time . In selected asymptomatic euvolaemic / hypovolaemic patients , the use of a diuretic drug might be (temporarily) discontinued. Patients can be trained to self-adjust their diuretic dose based on monitoring of symptoms/signs of congestion and daily weight measurements .

103. Other Treatment Angiotensin receptor neprilysin inhibitor A new therapeutic class of agents acting on the RAAS and the neutral endopeptidase system has been developed [angiotensin receptor neprilysin inhibitor (ARNI)]. Neprilysin is an endopeptidase that degrades natriuretic peptides, bradykinin , and adrenomedullin . Thus, neprilysin inhibition would increase the levels of these peptides increase and counteract the neurohormonal activation seen in heart failure

104. Other Treatment Angiotensin receptor neprilysin inhibitor High circulating A-type natriuretic peptide (ANP) and BNP exert physiologic effects through binding to NP receptors and the augmented generation of cGMP , thereby enhancing diuresis, natriuresis and myocardial relaxation and anti- remodelling . ANP and BNP also inhibit renin and aldosterone secretion. Selective AT1-receptor blockade reduces vasoconstriction, sodium and water retention and myocardial hypertrophy

105. Other Treatment Angiotensin receptor neprilysin inhibitor The first in class is LCZ696, which is a molecule that combines the moieties of valsartan and sacubitril ( neprilysin inhibitor) in a single substance.

106. Other Treatment Angiotensin receptor neprilysin inhibitor 2014: PARADIGM-HF Trial Long-term effects of sacubitril /valsartan vs Enalapril on morbidity and mortality* Sacubitril /valsartan ( 97/103 mg b.i.d .) was superior to ACEI ( enalapril 10mg b.i.d .) in reducing hospitalizations for worsening HF, cardiovascular mortality and overall mortality. Sacubitril /valsartan is therefore recommended in patients with HFrEF who fit this profile

107. Other Treatment Angiotensin receptor neprilysin inhibitor Possible safety issues Symptomatic hypotension Angioedema Cerebral amyloid deposition By decreasing degradation of beta amyloid peptide Long term safety needs to be assessed Combined treatment with an ACEI ( or ARB ) and sacubitril /valsartan is contraindicated (due to higher risk of angioedema)

108. Other Treatment Angiotensin II type I receptor blockers ARBs are recommended only as an alternative in patients intolerant of an ACEI Candesartan has been shown to reduce cardiovascular mortality Valsartan showed an effect on hospitalization for HF ( but not on all-cause hospitalizations) in patients with HFrEF receiving background ACEIs. The combination of ACEI/ARB for HFrEF was reviewed by the EMA , which suggested that benefits are thought to outweigh risks only in a select group of patients with HFrEF in whom other treatments are unsuitable.

109. Other Treatment Angiotensin II type I receptor blockers Therefore, ARBs are indicated for the treatment of HFrEF only in patients who cannot tolerate an ACEI because of serious side effects. The combination of ACEI/ARB should be restricted to symptomatic HFrEF patients receiving a beta-blocker who are unable to tolerate an MRA, and must be used under strict supervision

110. Other Treatment hydralazine/ isosorbide dinitrate There is no clear evidence to suggest the use of this fixed-dose combination therapy in all patients with HFrEF . Evidence on the clinical utility of this combination is scanty and comes from one relatively small RCT conducted exclusively in men and before ACEIs or beta-blockers were used to treat HF . A subsequent RCT conducted in self-identified black patients (defined as being of African descent) showed that addition of the combination of hydralazine and isosorbide dinitrate to conventional therapy (ACEI , beta-blocker and MRA) reduced mortality and HF hospitalizations in patients with HFrEF and NYHA Classes III–IV. The results of this study are difficult to translate to patients of other racial or ethnic origins .

111. Other Treatment hydralazine/ isosorbide dinitrate Additionally, a combination of hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who can tolerate neither ACEI nor ARB (or they are contraindicated ) to reduce mortality. However , this recommendation is based on the results of the Veterans Administration Cooperative Study , which recruited symptomatic HFrEF patients who received only digoxin and diuretics

112. Treatments with Less certain Benefit Digoxin Digoxin may be considered in patients in sinus rhythm with symptomatic HFrEF to reduce the risk of hospitalization (both all-cause and HF hospitalizations ), although its effect on top of beta-blockers has never been tested The effects of digoxin in patients with HFrEF and AF have not been studied in RCTs, and recent studies have suggested potentially higher risk of events (mortality and HF hospitalization ) in patients with AF receiving digoxin

113. Treatments with Less certain Benefit Digoxin In patients with symptomatic HF and AF, digoxin may be useful to slow a rapid ventricular rate, but it is only recommended for the treatment of patients with HFrEF and AF with rapid ventricular rate when other therapeutic options cannot be pursued. Of note, the optimal ventricular rate for patients with HF and AF has not been well established, but the prevailing evidence suggests that strict rate control might be deleterious. A resting ventricular rate in the range of 70–90 bpm is recommended based on current opinion, although one trial suggested that a resting ventricular rate of up to 110 bpm might still be acceptable.

114. Treatments with Less certain Benefit Digoxin Given its distribution and clearance, caution should be exerted in females, in the elderly and in patients with reduced renal function. In the latter patients, digitoxin should be preferred .

115. Treatments with Less certain Benefit n-3 polyunsaturated fatty acids A large body of experimental evidence suggests that n-3 polyunsaturated fatty acids (n-3 PUFAs) have favorable effects on inflammation Including a reduction in endothelial activation and production of inflammatory cytokines, platelet aggregation, autonomic tone, blood pressure , heart rate, and LV function. Preparations differ in composition and dose. Only preparations with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters of at least 85% (850 mg/g) have shown an effect on the cumulative endpoint of cardiovascular death and hospitalization .

116. Treatments with Less certain Benefit n-3 polyunsaturated fatty acids GISSI-HF Trial Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca Heart Failure Long-term administration of 1 g/day of omega n-3 PUFAs resulted in a significant reduction in both all-cause mortality (adjusted HR, 0.91 [95.5% CI, 0.83 to 0.99]; P = .041) and all-cause mortality and cardiovascular admissions (adjusted HR, 0.92 [99% CI, 0.849 to 0.999]; P = .009), in all of the predefined subgroups, including patients with HF associated with nonischemic cardiomyopathy However, in view of the small treatment effect of n-3 PUFAs, they are not endorsed by current practice guidelines.

117. Treatments not recommended (unproven benefit) in HFrEF Statins Although statins reduce mortality and morbidity in patients with atherosclerotic disease, statins are not effective in improving the prognosis in patients with HFrEF . Most statin trials excluded patients with HF (because it was uncertain that they would benefit ). The two major trials that studied the effect of statin treatment in patients with chronic HF did not demonstrate any evidence of benefit . Therefore , evidence does not support the initiation of statins in most patients with chronic HF

118. Treatments not recommended (unproven benefit) in HFrEF Oral anticoagulants and antiplatelet therapy Other than in patients with AF (both HFrEF and HFpEF ), there is no evidence that an oral anticoagulant reduces mortality/morbidity compared with placebo or aspirin Patients with HFrEF receiving oral anticoagulation because of concurrent AF or risk of venous thromboembolism should continue anticoagulation. Similarly , there is no evidence on the benefits of antiplatelet drugs (including acetylsalicylic acid) in patients with HF without accompanying CAD , whereas there is a substantial risk of gastrointestinal bleeding , particularly in elderly subjects, related with this treatment.

119. Renin inhibitors Aliskiren is an orally active direct renin inhibitor that appears to suppress the renin-angiotensin system to a similar degree to that effected by ACE inhibitors Although the benefits of ACE inhibitors and ARBs in HF have been clearly established, these agents provoke a compensatory increase in renin and downstream intermediaries of the reninangiotensin - aldosterone system that may attenuate the effects of ACE inhibitors and ARBs (“ RAAS escape ”)

120. Renin inhibitors- Aliskiren ALOFT Trial: Aliskiren significantly ( P < .01 ) decreased NT- proBNP in urinary aldosterone excretion On the basis of these promising early results, several large pivotal outcomes trials were initiated to determine whether adding aliskiren to standard HF therapy would improve clinical outcomes

121. Renin inhibitors- Aliskiren ASTRONAUT Study The Aliskiren Trial on Acute Heart Failure Outcomes Enrolled patients with an LVEF of 40% or less and elevated natriuretic peptide (BNP ) of 400 pg /mL or higher or NT- proBNP of 1600 pg /mL or greater) who were being discharged from the hospital after admission for ADHF Primary endpoint: Cardiovascular death or HF rehospitalization at 6 months. No significant difference in the primary endpoint was observed in the aliskiren ( titrated up to 300 mg/day)-treated group compared with patients treated with standard medical therapy for HF at 6 months (HR, 0.92 [ 95% CI, 0.76 to 1.12]; P = .41) or at 12 months (HR, 0.93 [95% CI, 0.79 to 1.09]; P = .36). Moreover , the rates of hyperkalemia, hypotension , and renal impairment/renal failure were higher in the aliskiren group than in the placebo group .

122. Treatments not recommended (unproven benefit) in HFrEF Renin inhibitors- Aliskiren ATMOSPHERE Trial Efficacy and Safety of Aliskiren and Aliskiren / Enalapril Combination on Morbi -mortality in Patients with Chronic Heart Failure study Currenly ongoing phase III study that will evaluate the efficacy and safety of both aliskiren monotherapy and aliskiren-enalapril combination therapy as compared with enalapril monotherapy to reduce cardiovascular death and HF-related hospitalizations in NYHA class II to IV HF patients

123. Treatments believed to cause harm in HFrEF Calcium-channel blockers Non- dihydropyridine calcium-channel blockers (CCBs) are not indicated for the treatment of patients with HFrEF . Diltiazem and verapamil have been shown to be unsafe in patients with HFrEF. 214 There is a variety of dihydropyridine CCBs; some are known to increase sympathetic tone and they may have a negative safety profile in HFrEF . There is only evidence on safety for amlodipine 215 and felodipine 216 in patients with HFrEF , and they can be used only if there is a compelling indication in patients with HFrEF

124. Device Therapy in HFrEF

125. Implantable cardioverter -defibrillator A high proportion of deaths among patients with HF, especially those with milder symptoms, occur suddenly and unexpectedly. Many of these are due to electrical disturbances , including ventricular arrhythmias , bradycardia and asystole , although some are due to coronary, cerebral or aortic vascular events. Treatments that improve or delay the progression of cardiovascular disease will reduce the annual rate of sudden death, but they may have little effect on lifetime risk and will not treat arrhythmic events when they occur.

126. ICDs ICDs are effective in preventing bradycardia and correcting potentially lethal ventricular arrhythmias. Some antiarrhythmic drugs might reduce the rate of tachyarrhythmias and sudden death, but they do not reduce overall mortality and may increase it.

127. ICDs Secondary prevention of sudden cardiac death Compared with amiodarone treatment, ICDs reduce mortality in survivors of cardiac arrest and in patients who have experienced sustained symptomatic ventricular arrhythmias. An ICD is recommended in such patients when the intent is to increase survival The decision to implant should take into account The patient’s view and their quality of life, The LVEF (survival benefit is uncertain when the LVEF is >35 %) and The absence of other diseases likely to cause death within the following year. 223–225

128. ICDs Primary prevention of sudden cardiac death Although amiodarone may have reduced mortality in older trials of HF, 242,243 contemporary studies conducted since the widespread introduction of beta-blockers suggest that it does not reduce mortality in patients with HFrEF. 227,244,245 Dronedarone and class I antiarrhythmic agents should not be used for prevention of arrhythmias in this population. Some guideline-recommended therapies, including betablockers , MRAs , sacubitril /valsartan and pacemakers with CRT ( CRT-Ps), reduce the risk of sudden death

129. ICDs Primary prevention of sudden cardiac death Patients with a QRS duration ≥130 ms should be considered for a defibrillator with CRT (CRT-D) rather than ICD. Patients with longer QRS durations may also receive greater benefit from an ICD, but these patients should often receive a CRT device

130. ICDs Primary prevention of sudden cardiac death Two RCTs showed no benefit in patients who had an ICD implanted within 40 days after a myocardial infarction. 158,228 Although sudden arrhythmic deaths were reduced, this was balanced by an increase in non-arrhythmic deaths. Accordingly, an ICD is contraindicated in this time period . A wearable defibrillator may be considered if the patient is deemed to be at high risk of ventricular fibrillation, although evidence from randomized trials is lacking. 239–241

131. ICDs Primary prevention of sudden cardiac death ICD implantation is recommended only after a sufficient trial ( minimum 3 months) of optimal medical therapy (OMT) has failed to increase the LVEF to >35 %. However , one of the two landmark papers on which these recommendations are based included patients with an LVEF >30 %. Fewer than 400 patients with an LVEF of 30–35% were included in the landmark studies, and although there was no statistical interaction between treatment effect and LVEF , the evidence of benefit is less robust in this group of patients .

132. ICDs Primary prevention of sudden cardiac death ICD therapy is not recommended in patients in NYHA Class IV with severe symptoms refractory to pharmacological therapy who are not candidates for CRT, a ventricular assist device or cardiac transplantation , because such patients have a very limited life expectancy and are likely to die from pump failure . Patients with serious co-morbidities who are unlikely to survive substantially more than 1 year are unlikely to obtain substantial benefit from an ICD

133. ICDs Primary prevention of sudden cardiac death Patients should be counselled as to The purpose of an ICD, Complications related to implantation and device activation ( predominantly inappropriate shocks) and Under what circumstances it might be deactivated (terminal disease) or explanted (infection, recovery of LV function If HF deteriorates, deactivation of a patient’s ICD may be considered after appropriate discussion with the patient and caregiver(s).

134. ICDs Primary prevention of sudden cardiac death If the ICD generator reaches its end of life or requires explantation , it should not automatically be replaced . Patients should be carefully evaluated by an experienced cardiologist before generator replacement. Treatment goals may have changed and the risk of fatal arrhythmia may be lower or the risk of non-arrhythmic death higher . It is a matter of some controversy whether patients whose LVEF has greatly improved and who have not required device therapy during the lifetime of the ICD should have another device implanted

135. ICDs Primary prevention of sudden cardiac death Subcutaneous defibrillators may be as effective as conventional ICDs with a lower risk from the implantation procedure. They may be the preferred option for patients with difficult access or who require ICD explantation due to infection. Patients must be carefully selected, as they have limited capacity to treat serious bradyarrhythmia and can deliver neither antitachycardia pacing nor CRT. Substantial RCTs with these devices and more data on safety and efficacy are awaited

136. ICDs Primary prevention of sudden cardiac death A wearable ICD An external defibrillator with leads and electrode pads attached to a wearable vest Able to recognize and interrupt VT/ventricular fibrillation may be considered for a limited period of time in selected patients with HF who are at high risk for sudden death but otherwise are not suitable for ICD implantation ( e.g. those with poor LVEF after acute myocardial damage until LV function recovers, patients scheduled for heart transplantation ) However , no prospective RCTs evaluating this device have been reported

137. Cardiac Resynchronization Therapy CRT improves cardiac performance in appropriately selected patients and improves symptoms and well-being and reduces morbidity and mortality Of the improvement in quality-adjusted life-years (QALYs) with CRT among patients with moderate to severe HF, Two-thirds may be attributed to improved quality of life and One-third to increased longevity

138. CRT Only the COMPANION 265 and CARE-HF trials 262,263 compared the effect of CRT to guideline-advised medical therapy. Most other trials have compared CRT-D to ICD, and a few have compared CRT-P to backup pacing. The prevention of lethal bradycardia might be an important mechanism of benefit shared by all pacing devices. In CARE-HF, at baseline, 25% of patients had a resting heart rate of ≤ 60 bpm. 262–264 If prevention of bradycardia is important, the effect of CRT will appear greater in trials where there is no device in the control group.

139. CRT Most studies of CRT have specified that the LVEF should be <35%, but RAFT 267 and MADIT-CRT 268,269 specified an LVEF <30 %, while REVERSE 270–272 specified < 40 % and BLOCK-HF 274 < 50 %. Relatively few patients with an LVEF of 35–40% have been randomized , but an individual participant data (IPD) meta-analysis suggests no diminution of the effect of CRT in this group.

140. CRT Not all patients respond favourably to CRT Several characteristics predict improvement in morbidity and mortality, and the extent of reverse remodelling is one of the most important mechanisms of action of CRT. Patients with ischaemic aetiology will have less improvement in LV function due to myocardial scar tissue , which is less likely to undergo favourable remodelling 288 Conversely, women may be more likely to respond than men, possibly due to smaller body and heart size

141. CRT QRS width predicts CRT response and was the inclusion criterion in all randomized trials . But QRS morphology has also been related to a beneficial response to CRT. Several studies have shown that patients with left bundle branch block (LBBB) morphology are more likely to respond favourably to CRT, whereas there is less certainty about patients with non-LBBB morphology. However , patients with LBBB morphology often have wider QRS duration, and there is a current debate about whether QRS duration or QRS morphology is the main predictor of a beneficial response to CRT

142. CRT Evidence from two IPD meta-analyses indicates that after accounting for QRS duration , there is little evidence to suggest that QRS morphology or aetiology of disease influence the effect of CRT on morbidity or mortality 266,273 In addition, none of the landmark trials selected patients for inclusion according to QRS morphology, sex or ischaemic aetiology , nor were they powered for subgroup analyses .

143. CRT The Echo-CRT 283,284 trial and an IPD meta-analysis 266 suggest possible harm from CRT when QRS duration is <130 ms , thus implantation of CRT is not recommended if QRS duration is <130 ms.

144. CRT If a patient is scheduled to receive an ICD and is in sinus rhythm with a QRS duration ≥130 ms , CRT-D should be considered if QRS is between 130 and 149 ms and is recommended if QRS is ≥ 150 ms . However , if the primary reason for implanting a CRT is for the relief of symptoms, then the clinician should choose CRT-P or CRT-D, whichever they consider appropriate * Clinical practice varies widely among countries. The only randomized trial to compare CRT-P and CRT-D 265 failed to demonstrate a difference in morbidity or mortality between these technologies

145. CRT If the primary reason for implanting CRT is to improve prognosis , then the majority of evidence lies with CRT-D for patients in NYHA Class II and with CRT-P for patients in NYHA Classes III–IV . It is unclear whether CRT Reduces the need for an ICD ( by reducing the arrhythmia burden) or I ncreases the benefit from an ICD (by reducing mortality rates from worsening HF, leading to longer exposure to the risk of arrhythmia )

146. CRT When LVEF is reduced, RV pacing may exacerbate cardiac dyssynchrony . This can be prevented by CRT, which might improve patient outcomes. However , a difference in outcome was not observed between CRT and RV pacing in a subgroup analysis of RAFT or in patients without HFrEF in BioPACE 291 On balance , CRT rather than RV pacing is recommended for patients with HFrEF regardless of NYHA class who have an indication for ventricular pacing in order to reduce morbidity, although no clear effect on mortality was observed.

147. CRT Patients with HFrEF who have received a conventional pacemaker or an ICD and subsequently develop worsening HF with a high proportion of RV pacing, despite OMT, should be considered for upgrading to CRT. Only two small trials have compared pharmacological therapy alone vs. CRT in patients with AF, with conflicting results.

148. CRT Several studies have indicated that CRT is superior to RV pacing in patients undergoing atrio -ventricular (AV) node ablation However, CRT is not an indication to carry out AV node ablation except in rare cases when ventricular rate remains persistently high (>110bpm ) despite attempts at pharmacological rate control. A subgroup analysis of patients with AF from the RAFT study found no benefit from CRT-D compared with ICD, although less than half of patients had >90 % biventricular capture

149. CRT Observational studies report that when biventricular capture is <98 %, the prognosis of patients with CRT declines . Whether this association reflects A loss of resynchronization ( which might be remedied by device programming ), Poor placing of the LV lead (which might be avoided at implantation ) or Greater difficulty in pacing severely diseased myocardium ( which might not be amenable to the above) is uncertain. This observation has not been confirmed in a randomized trial

150. CRT Imaging tests for dyssynchrony have not yet been shown to be of value in selecting patients for CRT. Patients with extensive myocardial scar will have less improvement in LV function with CRT, but this is true of any treatment for HFrEF and does not reliably predict less clinical benefit Pacing thresholds are higher in scarred myocardium and , if possible, lead placement should avoid such regions. Although patients with extensive scarring have an intrinsically worse prognosis, there is little evidence that they obtain less prognostic benefit from CRT

151. Other Devices Currently, the evidence is considered insufficient to support specific guideline recommendations for other therapeutic technologies These include Baroreflex activation therapy Vagal stimulation Diaphragmatic pacing and Cardiac contractility modulation*

152. Management Of Patients Who Remain Symptomatic As noted, an ACE inhibitor (or an ARB) plus a beta blocker should be standard background therapy for patients with HFrEF . Additional pharmacologic therapy ( polypharmacy ) or device therapy should be considered in patients who have persistent symptoms or progressive worsening despite optimized therapy with an ACE inhibitor and beta blocker

153. Management Of Patients Who Remain Symptomatic Agents that may be considered for part of additional therapy include An ARB (NYHA class II to IV), Mineralocorticoid receptor antagonists ( NYHA class II to IV), Combination of hydralazine and isosorbide dinitrate (NYHA class II to IV) or Digitalis Thus the choice of specific agent will be influenced in part by clinical considerations, including renal function, serum potassium concentration, blood pressure, and race

154. Management Of Patients Who Remain Symptomatic Because mineralocorticoid receptor antagonists have a greater impact on morbidity/mortality than ARBs , ARBs are no longer the agents of first choice in patients with HF and an EF of 40% or less who remain symptomatic despite optimal treatment with an ACE inhibitor. The triple combination of an ACE inhibitor , an ARB, and an aldosterone antagonist is not recommended because of the associated risk of hyperkalemia.

155. Management Of Patients Who Remain Symptomatic Digoxin Recommended for patients with symptomatic LV systolic dysfunction who have concomitant atrial fibrillation Should be considered for patients who have signs or symptoms of HF while receiving standard therapy , including ACE inhibitors and beta blockers

156. Stage D HF- Definition Also known as “advanced HF,” “End-stage HF” and “refractory HF.” AHA/ACC: “Patients with truly refractory HF who might be eligible for specialized, advanced treatment strategies, such as MCS, procedures to facilitate fluid removal, continuous inotropic infusions, or cardiac transplantation or other innovative or experimental surgical procedures, or for end-of-life care, such as hospice The European Society of Cardiology has developed a definition of advanced HF with objective criteria that can be useful (See next slide)

157. Stage D HF- Definition

158. Stage D HF- Definition There are clinical clues that may assist clinicians in identifying patients who are progressing toward advanced HF (Table 24). The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) has developed 7 profiles that further stratify patients with advanced HF (Table 13.2)

159. Stage D HF- Imp’t Considerations Thorough evaluation is needed to ascertain that the diagnosis is correct and that there are no remediable etiologies or alternative explanations for advanced symptoms. For example, it is important to determine that HF and not a concomitant pulmonary disorder is the basis of dyspnea. Similarly , in those with presumed cardiac cachexia, other causes of weight loss should be ruled out. Likewise, other reversible factors such as thyroid disorders should be treated.

160. Stage D HF- Imp’t Considerations Severely symptomatic patients presenting with a new diagnosis of HF can often improve substantially if they are initially stabilized. Patients should also be evaluated for nonadherence to medications, sodium restriction, and/or daily weight monitoring. Finally , a careful review of prior medical management should be conducted to verify that all evidence based therapies likely to improve clinical status have been considered.

161. Stage D HF- Treatment Treatment options Advanced therapy Palliative care

162. Stage D HF- Treatment Inotropic Support Despite improving hemodynamic compromise, positive inotropic agents have not demonstrated improved outcomes in patients with HF in either the hospital or outpatient setting Regardless of their mechanism of action (e.g., inhibition of phosphodiesterase , stimulation of adrenergic or dopaminergic receptors , calcium sensitization), chronic oral inotrope treatment increased mortality, mostly related to arrhythmic events .

163. Stage D HF- Treatment Inotropic Support Parenteral inotropes, however, remain as an option to help the subset of patients with HF who are refractory to other therapies and are suffering consequences from end-organ hypoperfusion . Inotropes should be considered only in such patients with systolic dysfunction who have low cardiac index and evidence of systemic hypoperfusion and/or congestion To minimize adverse effects, lower doses are preferred. Similarly, the ongoing need for inotropic support and the possibility of discontinuation should be regularly assessed

164. Stage D HF- Treatment Mechanical Circulatory Support MCS has emerged as a viable therapeutic option for patients with advanced stage D HF r EF refractory to optimal GDMT and cardiac device intervention. Since its initial use 50 years ago for postcardiotomy shock, the implantable VAD continues to evolve. Designed to assist the native heart, VADs are differentiated by the implant location ( intracorporeal versus extracorporeal), approach (percutaneous versus surgical), flow characteristic (pulsatile versus continuous ), pump mechanism (volume displacement, axial, centrifugal), and the ventricle(s) supported (left , right , biventricular).

165. Stage D HF- Treatment Mechanical Circulatory Support VADs are effective in both the short-term (hours to days) management of acute decompensated , hemodynamically unstable HF r EF that is refractory to inotropic support, and the long-term ( months to years) management of stage D chronic HF r EF . Nondurable , or temporary, MCS provides an opportunity for decisions about the appropriateness of transition to definitive management such as cardiac surgery or durable, that is, permanent, MCS or, in the case of improvement and recovery, suitability for device removal . Nondurable MCS thereby may be helpful as either a bridge to decision or a bridge to recovery.

166. Stage D HF- Treatment Mechanical Circulatory Support More common scenarios for MCS, however, are long-term strategies, including Bridge to transplantation , Bridge to candidacy, and Destination therapy. Bridge to transport and destination therapy have the strongest evidence base with respect to survival, functional capacity, and HRQOL benefits

167. Stage D HF- Treatment

168. Stage D HF- Treatment Cardiac Transplantation Cardiac transplantation is considered the gold standard for the treatment of refractory end-stage HF . The greatest survival benefit is seen in those patients who are at highest risk of death from advanced HF

169. Special Population

170. Special Population Women Poorly represented in clinical trials. Women with HF are more likely to be older, have a preserved EF and nonischemic etiology for their HF Although some studies have reported that HF outcomes are worse for women with than for men, the aggregate data suggest that women have a survival advantage when they develop HF.

171. Special Population Women Although the explanation for this observation is unclear it may be related to sex differences in etiology for HF. Nonetheless, although women appear to have a survival advantage after the diagnosis of HF, they experience increased morbidity, with worse quality of life, and have increased depression. Moreover , women are at increased risk of developing HF after acute MI

172. Special Population Women Pooled analysis of several large-scale prospective clinical trials with beta blockers and ACE inhibitors suggests that these agents provide similar survival benefits in women with systolic dysfunction and in men .

173. Special Population Race/Ethnicity Several retrospective analyses have highlighted differences between African American and white populations in response to some standard HF therapies . Unfortunately , data for Hispanic and Asian HF populations are limited. Retrospective analyses from SOLVD and V- HeFT suggested that African Americans do not benefit from ACE inhibitors. By contrast, post hoc analysis of studies with approved beta blockers has shown that African American patients benefit, although the magnitude of the effect appears to be diminished relative to Caucasians.

174. Special Population Race/Ethnicity The African- American Heart Failure Trial (A- HeFT ) Compared the adjunctive use of a proprietary formulation of isosorbide dinitrate and hydralazine against a standard HF regimen of ACE inhibitors, beta blockers, and diuretics in African Americans with NYHA class III or IV HF Primary endpoint: A composite score made up of weighted values for death from any cause, a first hospitalization for HF, and change in the quality of life. The study was terminated early because Significant 43% reduction in the rate of death from any cause and Significant 33% relative reduction in the rate of first hospitalization for HF

175. Special Population Race/Ethnicity The effect of this combination of isosorbide dinitrate and hydralazine in other patients with HF who are being treated with standard therapy is not known, because the population studied in A- HeFT was limited to African Americans. However , there is no reason to believe that this benefit is limited to blacks.

176. Special Population Elderly Persons Elderly patients are more likely than younger patients to present with atypical symptoms such as altered mental status, depression, or poor executive functioning. The therapeutic approach to HFrEF in elderly persons should be, in principle, identical to that in younger patients with respect to the choice of pharmacologic therapy. However, altered pharmacokinetic and pharmacodynamic properties of cardiovascular drugs in the elderly may require that these therapies be applied more cautiously, with reductions in drug dosages when appropriate

177. Special Population Elderly Persons Other complicating factors may include blunting of baroreceptor function and orthostatic dysregulation of blood pressure, which may make it difficult to use target doses of some neurohormonal antagonists . Multidisciplinary HF programs have been successful in decreasing the rate of readmission and associated morbidity in elderly patients

178. Management of AF in HF AF- the commonest arrythmia occurs in 15% to 30% of patients with HF May lead to worsening HF increases risk of thromboembolic events especially stroke AF-CHF Trial*-Roy et al 2008 Rate vs Rhythm control in patients with chronic HF and a history of AF Rhythm control (pharmacologic or electrical cardioversion ) was not shown to be superior to rate control with respect to reducing death from cardiovascular causes (HR rhythm control group, 1.06 [95% CI, 0.86 to 1.30]; P = .59)

179. Management of AF in HF AF-CHF Trial ctd Secondary outcomes also were similar in the rate and rhythm control groups, including death from any cause, stroke, worsening HF, and the composite of death from cardiovascular causes, stroke, and worsening HF.

180. Management of AF in HF Accordingly , a rhythm control strategy is best suited for use in Patients with a reversible secondary cause of AF Patients who cannot tolerate symptoms of AF after optimization of rate control and HF therapy What to use for rate control for AF in HF? BBs preferred to digoxin b/c of their Better impact on morbidity and mortality Provide better rate control during exercise The combination of digoxin and a BB is more effective than a BB alone in controlling the ventricular rate at rest

181. Management of AF in HF What to use for rate control for AF in HF? When BBs cannot be used, amiodarone has been recommended by some clinicians But chronic use has potentially significant risks, including thyroid disease and lung toxicity The short-term intravenous administration of diltiazem or amiodarone has been used for the acute treatment of patients with AF with FVR H owever , the negative inotropic effects of nondihydropyridine CCBs such as diltiazem and verapamil must be considered if these agents are used

182. Management of AF in HF Target ventricular rate The optimum control of ventricular rate in patients with HF and atrial fibrillation is unclear at present. A resting ventricular response of 60 to 80 beats/min and a ventricular response between 90 and 115 beats/min during moderate exercise has been suggested by some experts However, the RACE II (Rate Control vs Electrical cardioversion for AF) study did not show a difference in a composite of clinical outcomes when a strategy of strict rate control (<80 beats/min at rest and <110 beats/min during a 6-minute walk) was compared with lenient rate control.

183. Absolute difference of − 2.0 percentage points ( 90% CI, −7.6 to 3.5)

184. Management of AF in HF With the recognition that sustained tachycardia can lead to a cardiomyopathy, atrioventricular node ablation and cardiac resynchronization therapy (CRT) have been suggested for control of ventricular rate in extreme cases of a rapid ventricular response with atrial fibrillation

185. Antiarrythmic Agents in HF Most antiarrhythmic agents, with the exception of amiodarone and dofetilide , have negative inotropic effects and are proarrhythmic . Amiodarone A class III antiarrhythmic that has little or no negative inotropic and/or proarrhythmic effects Effective against most supraventricular arrhythmias Amiodarone is the preferred drug for treatment to restore and maintain sinus rhythm and may improve the success of electrical cardioversion in patients with HF.

186. Antiarrythmic Agents in HF Amiodarone ctd Amiodarone increases the level of phenytoin and digoxin and will prolong the INR in patients taking warfarin. Therefore it often is necessary to reduce the dose of these drugs by as much as 50% on initiation of therapy with amiodarone . The risk of adverse events, such as hyperthyroidism, hypothyroidism, pulmonary fibrosis, and hepatitis , is relatively low, particularly when lower doses of amiodarone are used ( 100 to 200 mg/day).

187. Antiarrythmic Agents in HF Dronedarone A novel antiarrhythmic drug that reduces the incidence of atrial fibrillation and atrial flutter and has electrophysiologic properties that are similar to those of amiodarone But does not contain iodine, with the attendant risk of iodine-related adverse reactions. Dronedarone was significantly more effective than placebo in maintaining sinus rhythm in several studies However, ANDROMEDA trial terminated prematurely because of a twofold increase in mortality the Dronedarone treated patients

188. Antiarrythmic Agents in HF Dronedarone The excess mortality was predominantly related to worsening of HF . As a result of this study, dronedarone is contraindicated in patients with NYHA class IV HF, or those with NYHA class II or III HF who have had a recent episode of HF-related decompensation .

189. Antiarrythmic Agents in HF Because of the increased likelihood of proarrhythmic effects of antiarrhythmic agents in patients with LV dysfunction, it is preferable to treat ventricular arrhythmias with implantable cardioverter -defibrillators (ICDs), either alone or in combination with amiodarone

190. Sleep Disordered Breathing Patients with HFrEF (EF < 40%) commonly exhibit sleep-disordered breathing: Approximately 40% of patients exhibit central sleep apneas (CSAs), commonly referred to as Cheyne -Stokes breathing, and Another 10% exhibit obstructive sleep apneas (OSA).

191. Sleep Disordered Breathing CSA Associated with Cheyne - Stokes respiration is a form of periodic breathing, in which central apneas and hypopneas alternate with periods of hyperventilation that exhibit a waxing-waning pattern of tidal volume. Risk factors for the development of CSA in patients with HF include Male sex, Age older than 60 years, The presence of atrial fibrillation, and hypocapnia .

192. Fig.- Pathophysiology of CSA and Cheyne -Stokes respiration in HF. HF leads to increased LV filling pressure. The resulting pulmonary congestion activates lung vagal irritant receptors, which stimulate hyperventilation and hypocapnia . Superimposed arousals cause further abrupt increases in ventilation and drive the arterial partial pressure of carbon dioxide (PaCO2) below the threshold for ventilation, triggering central apnea. CSAs are sustained by recurrent arousal resulting from apnea-induced hypoxia and the increased effort to breathe during the ventilatory phase secondary to pulmonary congestion and reduced lung compliance. Increased sympathetic activity causes increases in blood pressure (BP) and heart rate (HR) and increases myocardial O2 demand in the presence of reduced supply.

193. Sleep Disordered Breathing CSA The main clinical significance of CSA in HF is its association with increased mortality. Whether this is simply because Cheyne -Stokes respiration with CSA is a reflection of advanced disease with poor LV function , or whether its presence constitutes a separate and additive adverse influence on outcomes, is not clear. This statement notwithstanding , multivariate analyses suggest that CSA remains an independent risk factor for death or cardiac transplantation, even after controlling for potentially confounding risk factors.

194. Sleep Disordered Breathing CSA The potential mechanism(s ) for adverse outcomes in patients with HF and CSA may be attributed to marked neurohumoral activation (especially norepinephrine). Studies have suggested that Cheyne -Stokes respirations can resolve with proper treatment of HF. However , if the patient continues to have symptoms related to sleep-disordered breathing ( sleep-onset or sleep-maintenance insomnia) despite optimization of HF therapies, a comprehensive overnight sleep studypolysomnography is indicated .

195. Sleep Disordered Breathing Treatment OSA: Current guidelines recommend continuous positive airway pressure (CPAP) therapy to improve functional capacity and quality of life in patients with HF and OSA CSA: No consensus has emerged regarding how CSA should be treated in these patients .

196. Sleep Disordered Breathing Treatment CSA Optimize drug therapy for HF This is because CSA is to some extent a manifestation of advanced HF Like aggressive diuresis ( to relieve cardiac filling pressures ), use of ACE inhibitors/ARBs and beta blockers , which may lessen the severity of CSA. Caution on aggressive diuresis, a resulting metabolic alkalosis can worsen/predispose to CSA*

197. Sleep Disordered Breathing Treatment CSA Use of nocturnal oxygen and devices that provide continuous positive airway pressure (for upto 1 month) has been reported to Alleviate CSA, A bolish apnea-related hypoxia, Decrease nocturnal norepinephrine levels, Produce symptomatic and functional improvement in patients with HF

198. Sleep Disordered Breathing Treatment CSA However , the effects of supplemental oxygen on cardiovascular endpoints over more prolonged periods have not been assessed. Although no direct evidence for prevention of HF by treatment of sleep-disturbed breathing is lacking , treatment with CPAP breathing has been shown to improve LV structure and function in patients with either obstructive or central sleep apnea disturbed-breathing syndrome

199. Sleep Disordered Breathing Treatment CSA Despite these objective measurements of improvement with CPAP , this treatment modality did not lead to prolongation of life in the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial, Discontinued early after concerns about the early divergence of transplantation free survival favoring the control group. No difference in the primary endpoint of death or transplantation ( P = .54), nor was there a significant difference in the frequency of hospitalization between groups (0.56 versus 0.61 hospitalization/patient-year ; P = .45). A post hoc analysis of the CANPAP study , however , suggested that adequate suppression of CSA by CPAP was associated with improved heart transplant–free survival.

200. Sleep Disordered Breathing Treatment CSA Thus the data remain unclear whether elimination of apnea will lead to improved clinical outcomes. The other therapies that have been proposed for sleep-disordered breathing in HF include N octurnal oxygen , CO2 administration (by adding dead space), Theophylline , Acetazolamide and D iaphragmatic pacing T hese interventions have not yet been systematically studied in outcome-based prospective randomized trials

201. Thank You!