Heart Failure

Peter Damman, MD; Ineke Nederend, MD

Introduction

History

In 1628, William Harvey first described circulation. Little understanding of the nature of heart failure could have existed before that time. Almost 200 years later, René Laennec invents the stethoscope. Röntgen's discovery of x-rays in 1895 and Einthoven's development of electrocardiography (ECG) in the 1890s led to improvements in the understanding of heart failure. In former days, the foxglove was used as a medicine to treat heart failure. This was described by William Withering (1). The flower improves contractility of the cardiac muscle and has important parasympathic effects, particularly on the atrioventricular node.

Framingham heart study

In 1984, the Framingham heart study launched. At start, 5209 residents of the town Framingham aged between 30 and 62 were included in the study which is still continued today. This study is considered the most important longitudinal source of data on the epidemiology of heart failure.

Foxglove (digitalis), used as a medicine for heart failure

Definition and diagnosis

Definition of heart failure

The term heart failure (HF) (or decompensatio cordis) basically describes an acute or chronic situation in which the amount of blood pumped through the circulation by the heart, is insufficient to meet the body’s demands. It is a complex syndrome highlighted by several features including haemodynamics, oxygen consumption and exercise capacity. According to the guidelines of the European Society of Cardiology, HF is defined as a syndrome in which the patient should have the following threefold of features: symptoms of typical of HF; signs typical of HF; and objective evidence of a structural or functional abnormality of the heart at rest (table 1).

Table 1 Definition of heart failure Heart failure is a clinical syndrome in which patients have the following features: • Symptoms typical of heart failure (breathlessness at rest or during exercise, fatigue, tiredness, ankle swelling) and • Signs typical of heart failure (tachycardia, tachypnoea, pulmonary rales, pleural effusion, raised jugular venous pressure, peripheral edema, hepatomegaly) and • Objective evidence of a structural or functional abnormality of the heart at rest (cardiomegaly, third heart sound, cardiac murmurs, abnormality on the electrocardiogram, raised natriuretic peptide concentration)

Acute and chronic heart failure

Heart failure generally is a chronic condition. Although the terms acute and chronic HF have traditionally been used to describe the nature of the clinical presentation, the term acute can interchangeably be used to indicate severity or time. Preferably, a distinction can be made between new-onset HF (first presentation, with an acute or slow onset), transient HR, and chronic HF.

Systolic versus diastolic heart failure

Heart failure patients are broadly classified into one of two groups, or a combination of both, depending on the left ventricular (LV) ejection fraction (EF). This LVEF is most often assessed with echocardiography. When the LVEF is less than 35-40 %, it is named systolic HF. If LVEF is preserved (>40-50%), symptoms are attributed to decreased relaxation of the heart during diastole and therefore is labeled as diastolic HF or HF with a preserved LVEF (7). As a result of the impaired relaxation, end diastolic pressure and subsequently left atrial- and pulmonary pressure will rise with subsequent alveolar pulmonary edema as a possibility. LF diastolic dysfunction might be present in asymptomatic patients, and it is considered an important precursor of heart failure (8). Frequently, patients have both systolic and diastolic failure at the same time. The term heart failure usually implies a failing left ventricle. However, prolonged left ventricular failure increases pressures in the ventricle and atrium, which in time potentially leads to a subsequent increased resistance in the pulmonary vascular system and eventually right ventricular failure.

Etiology of heart failure

Basically, HF is caused by a loss of cardiac pump function or a structural abnormality which both can have multiple underlying mechanisms. The most common causes or pathophysiological mechanisms are a loss and/or weakness of myocardial tissue, a (long-lasting) increased vascular resistance and tachyarrhythmias.

Coronary heart disease

The most important cause (65-70% of the cases) of HF in the Western world is ischaemic heart disease including myocardial infarction (vd wall). These patients mainly suffer systolic HF due to wall motion abnormalities of the affected and remodeling of the non-affected parts of the myocardium.

Hypertension

In patients with a high blood pressure (BP), the heart faces an increased afterload (a higher workload pumping the blood against the increased vascular resistance). At longer duration, this will lead to hypertrophy of the cardiac myocardium. This thicker, stiffer myocardium has a decreased pump function compared with non-hypertrophic myocardium. Moreover, (chronic) hypertension is a risk factor for (coronary) atherosclerosis and thereby increases the risk of myocardial infarction and subsequent HF. In as much as 60-70% of patients suffering HF, hypertension is the primary or secondary cause. (vd wall)

Heart rhythm disorders

Atrial fibrillation is a common rhythm disorder in the elderly. With this condition, the atria do not contract in the coordinated fashion unlike when in normal sinus rhythm, and therefore the atria never optimally empty. Normally, this ‘atrial kick’ contributes to around 15% of the LVEF. The absence of the atrial kick during atrial fibrillation can contribute to a reduced LVEF. Less frequently, , blood can stagnate in the atria during fibrillation which is prone to thrombus formation and embolisation to the coronary arteries with myocardial infarction and HF as possible consequences.

Valvular disease

Valvular disease, especially mitral- or aortic, can cause volume overload of the heart. This overload causes dilation of the ventricle which makes the pump function less pristine.

Cardiomyopathies

Dilated cardiomyopathy (DCM) is characterized by diffuse dilatation of one or more of the chambers of the heart, with a general decrease in contractility and consequently a decreased pump function. In about 30% of the cases, DCM is hereditary. (boek vd wall) Hypertrophic cardiomyopathy (see also Hypertension), restrictive cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy and peripartum cardiomyopathy can be malefactors causing HF.

Tamponade

Tamponade can be the cause of diastolic HF when relaxation and filling of the heart is impaired by blood or fluid in the pericardium.

Drugs

β-blockers, calcium antagonist, antiarrhythmics, cytotoxic agents.

Toxins

Alcohol, medication, cocaine, trace elements (mercury, cobalt, arsenic).

Endocrine disorders

Diabetes mellitus, hypo- or hyperthyroidism, Cushing syndrome, adrenal insufficiency, excessive growth hormone, phaeochromocytoma.

Nutrional status

Deficiency of thiamine, selenium, or camitine, obesity, cachexia.

Infiltrative disorders

Sacroidosis, amyloidosis, haemochromatosis, connective tissue disease.

Others

Chaga’s disease, HIV infection, end-stage renal failure.

Prevalence

The prevalence of HF in the western world is estimated as 1 to 2%, and the incidence is around 5 to 10 per 1000 persons per year REF MOSTERD, HEART 2007. Because at young age coronary heart disease is more prevalent in men, prevalence of HF is also higher in this group compared to age matched women. At older age, prevalence of HF is equal between sexes.

Clinical aspects

History

A careful history of the patients is important for the diagnosis and in order to identify the cause of HF. The history (and physical examination) can be used to differentiate between the abovementioned potential causes of HF (refer to Etiology of heart failure). Besides symptoms, family history of HF, smoking status, hyperlipidaemia, and diabetes mellitus are other factors that should be taken into account during the assessment of the patient history in order to draw a risk profile of the patient. Finally, the history should include previous events and the response to therapy.

Symptoms

HF can manifest with a multitude of different symptoms, but shortness of breath and tiredness are the most characteristic. Other symptoms include:  Orthopnoea  Dyspnea at night  Edema in legs or ankles  Trouble with sleeping  Cold hand/feet  Tickling cough (especially when lying down)  Angina  Palpitations  Syncope In general, correlation between the severity of symptoms and the severity of HF is weak (guidelines). The New York Heart Association functional classification is used most frequently to classify the severity of HF (table 2). Table 2 NYHA functional classification Severity based on symptoms and physical activity Class I No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnoea. Class II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnoea. Class III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity results in fatigue, palpitation, or dyspnoea. Class IV Unable to carry on any physical activity without discomfort. Symptoms at rest. If any physical activity is undertaken, discomfort is increased.

Physical examination

There are several key features in the clinical examination of a patient presenting with HF, and these include observation, palpitation and auscultation. The physical examination should focus on the general appearance of the patient, pulse and blood pressure, signs of fluid overload (increased jugular venous pressure, peripheral oedema, ascites and hepatomegaly), the lungs, and the heart (apex, Gallop rhythm, third heart sound, murmurs).

Additional diagnostic test

In order to assist in diagnosing HF and differentiate between causes, the following modalities are available.

Electrocardiogram

In every patient suspected of HF, an electrocardiogram (ECG) should be performed. Several common abnormalities (including possible causes) indicative of HF on the ECG include but are not limited to; sinus tachy- or bradycardia, atrial tachycardia, -flutter, or –fibrillation, ventricular arrhythmias, ischemia (including myocardial infarction), abnormal Q waves, left ventricular hypertrophy, micro voltages, and QRS length >120 ms. Allthough an abnormal ECG (exluding arrhythmias) has a low positive predictive value for HF, a normal ECG is highly indicative of the absence of HF.

Chest X-ray

A chest X-ray is a part of the standard examination in potential HF patients. Importantly, the x-ray is a tool to detect cardiomegaly or other possible cues that indicate HF. Also, it is important to rule out other causes of dyspnoea.

Echocardiography

Echocardiography is the cornerstone in diagnosing HF, and should routinely be performed, because ventricular function can be evaluated accurately with this technique. It can provide objective evidence of a structural or functional abnormality of the heart at rest besides signs and symptoms typical of heart failure. Important parameters that can be assessed include but are not limited to wall motion, valve function, and left ventricular ejection fraction and diastolic function. Diastolic dysfunction might be an important finding in symptomatic patients with a preserved ejection fraction. Please refer to Table 3 for common echocardiographic findings in HF. Transoesophageal echocardiography is indicated in patients with an inadequate thansthoracic echo window, suspected endocarditis, complicated valvular disease or to exclude a LV thrombus. If echocardiography provides inadequate information or in patients with suspected coronary artery disease, additional imaging includes CT scanning, cardiac magnetic resonance imaging or radionuclide imaging.

Laboratory tests

A standard blood assessment covers a complete blood count. Electrolytes, renal function, glucose and liver function. Furthermore, an urinalysis complete and other tests depending on the clinical condition complete the laboratory assessment. For example, cardiac troponins must be sampled if an ACS is in the differential diagnosis. In patients suspected of HF, values of natriuretic peptides atrial natriuretic peptide (ANP), N-terminal ANP (NT-ANP), B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) can provide important information regarding diagnosis, management and prognosis of HF. Natriuretic peptides are enzymes, secreted by the atria or ventricles in response to myocardial wall stress. ANP and NT-ANP are secreted primarily by the atria, BNP and NT-proBNP mainly by the ventricles. These values are used for evaluating prognosis in patients with known HF, for defining medication dose, and for making a diagnosis in patients suffering shortness of breath. Especially for the last mentioned group, peptide counts can help differentiate between pulmonary- or cardiac problems when they present in the emergency room.

Exercise test

This test is usually performed on a treadmill or on an ergo meter. The patient is asked to give maximal effort while the work load gradually increases. During the test, ECG is constantly monitored for ischemia. When possible, oxygen consumption should be measured during the test. Not only is an oxygen consumption test a good tool to discriminate between lung- peripheral- or heart problems, the obtained maximal oxygen uptake (VO2-max) also has an important prognostic value.

Heart catheterization

Heart catheterization is not part of the routine diagnosis and work-up of patients with HF. But in patients suffering angina pectoris despite optimal medical therapy, it should be considered (Class of recommendation IIa, level of evidence C, see table 4). Also, coronary angiography is recommended in patients at high risk of coronary artery disease (Class of recommendation I, level of evidence C) and in HF patients with significant valvular disease (Class of recommendation IIa, level of evidence C).

Table 3 Common echocardiographic abnormalities in heart failure Measurement Abnormality Clinical implications LVEF Reduced (<45 – 50%) Systolic dysfunction LV ejection fraction Akinesis, hypokinesis, dyskinesis Myocardial infarction/ischaemia, cardiomyopathy, myocarditis End-diastolic diameter Increased (>55 – 60 mm) Volume overload HF likely End-systolic diameter Increased (>45 mm) Volume overload HF likely Fractional shortening Reduced (<25%) Systolic dysfunction Left atrial size Increased (>40 mm) Increased filling pressures, mitral valve dysfunction, atrial fibrillation Left ventricular thickness Hypertrophy (>11 – 12 mm) Hypertention, aortic stenosis, hypertrophic cardiomyopathy Valvular structure and function Valvular stenosis or regurgitation (especially aortic stenosis and mitral insufficiency) May be primary cause of HF or complicating factor Asses haemodynamic consequences Consider surgery Mitral diastolic flow profile Abnormalities of the early and late diastolic filling patterns Indicates diastolic dysfunction and suggests mechanism Tricuspid regurgitation peak velocity Increased (>3 m/s) Increased right ventricular systolic pressure Suspect pulmonary hypertention Pericardium Effusion, haemopericardium, thickening Consider tamponade, uraemia, malignancy, systemic disease, acute or chronic pericarditis, contrictive pericarditis Aortic outflow velocity time integral Reduced (<15 cm) Reduced low stroke volume Inferior vena cava Dilated retrograde flow Increased right atrial pressures, right ventricular dysfunction, hepatic congestion

Management

The management of HF involves both pharmacological and non-pharmacological treatment. The emphasis is on the reduction in mortality and morbidity, prevention of the progression of HF, and the treatment of (non-)cardiovascular co-morbidities. Myocardial infarction (MI) is the most important cause of HF. Management of coronary disease is crucial in these patients, as revascularization of the myocardium will increase exercise capacity and survival. Research shows that good adherence to medication is associated with a decrease in risk of death. (5) Nevertheless, the percentage of HF patients adhering to prescribed pharmacological and non-pharmacological treatment is as low as 20-60 % according to the literature (3-4). Treatment of diastolic- and systolic HF does not differ (vd wall). Non-pharmalogical treatment can be applied in every patient.

Non-pharmacological treatment

Although pharmacological treatment is usually emphasized, non-pharmacological management is of great importance for HF patients. It can have a significant impact on symptoms, functional capacity, wellbeing, morbidity, and prognosis. The most important non-pharmacological opinions are described below.

Education

Education of both the patient and their family about HF and its symptoms is important. The patient and/or the caregiver should be able to undertake appropriate actions such as adjusting the diuretic dose or contact the physician. (Class I recommendation, level of evidence C; see table 4) Education on the importance and (side) effects of medication should be provided to the patient in order to increase compliance. (Class I recommendation, level of evidence C)

Fluid and sodium restriction

In patients with severe symptoms of HF, restriction of fluid intake may be considered. (Class IIa recommendation, level of evidence C) Also, patients should be educated on salt content of food and minimize intake in order to prevent fluid retention. (Class I recommendation, level of evidence C)

Body weight

CHF patients should carefully monitor their body weight. A sudden increase in weight is a potential consequence of fluid retention and deterioration of HF. When patients notice a weight gain of >2kg in 3 days they should consult a physician. (Class I recommendation, level of evidence C) In obese patients (body mass index of > 30 kg/m2), weight reduction should be promoted to prevent progression of HF, decrease symptoms and improve the overall wellbeing of the patient. (Class IIa recommendation, level of evidence C) Also, attention should be paid to weight loss due to malnutrition which is frequently observed in severe HF. An altered metabolism, inflammatory mechanisms or a decreased food intake may be important factors in the pathophysiology of cardiac cachexia in HF. (Class I recommendation, level of evidence C)

Alcohol and tobacco

Alcohol intake should be minimized, as it may increase blood pressure and/or have a negative inotropic effect. (Class IIa recommendation, level of evidence C) Smoking cessation should be encouraged. It is recommended that patients with HF receive support and advice on this topic. (Class I recommendation, level of evidence C). A reduction in alcohol and tobacco intake might also improve co-morbidities including sleep disorders.

Exercise

Exercise training is recommended to all chronic stable HF patients. Twenty years ago, exercise was strongly discouraged in patients with HF as the general conception was that it was harmful. Nowadays, numerous studies have shown the opposite. Rehabilitation programmes have shown to increase exercise capacity and health related quality of life and decrease hospitalization rates and symptoms. (Class I recommendation, level of evidence A)

Other

Other non-pharmacological treatment recommendations include immunization of HF patients (pneumococcal- and influenza vaccination should be considered), the consulting of a physician around pregnancy, the screening for depression and sleep disorders which require additional medical attention.

In conlusion, advices on lifestyle in general are very important. Yet, an extensive survey among HF patients showed that recall and adherence of lifestyle advice was disappointing (6). Health professionals should make sure the patient is able the understand and recall the advice given. With the intention to support this, the European Society of Cardiology (ESC) initiated a website (2007) containing practical heart failure information for patients, families, and caregivers: www.heartfailurematters.org

Pharmacological treatment

The treatment algorithm as proposed in the ESC guidelines 2008 are depicted in figure 2. Patients for whom the medication is indicated, mode of action, contraindications of the medication, and possible side effects included in this algorithm are discussed below.

Angiotensin-converting enzyme (ACE) inhibitors ACE inhibitors are indicated for every HF patient with an EF ≤ 40 %, irrespective of symptoms. (Class I recommendation, level of evidence A) Contraindications for the use of ACE inhibitors are:  History of angioedema  Bilateral renal artery stenosis  Serum potassium concentration > 5.0 mmol/L  Serum creatine > 220 µmol/L  Severe aortic stenosis ACE inhibitors relieve the heart by decreasing the preload and afterload. This is achieved through two mechanisms. Firstly, conversion of angiotensin-I to angiotensin– II is inhibited, which reduces vasoconstriction and lowers BP. Secondly, production of aldosterone is decreased, as angiotensin II induces this production. Aldosterone increases blood volume and thus BP by stimulating sodium- and water retention. Possible side effects are symptomatic hypotension (dizziness), hyperkalaemia, worsening renal function and cough.

β-Blockers

β-Blockade is recommended for every symptomatic (NYHA class II-IV) HF patient with a LVEF ≤40% or asymptomatic patients with a LVEF ≤40% after a MI . (Class I recommendation, level of evidence A) Contraindications are:

• Asthma
• Second- or third degree heart block, sick sinus syndrome, sinus bradycardia

β-Blockers mainly exert their effect by lowering the cardiac output, perpherial vascular resistance and by influencing the renin-angiotensinsysteem. In addition, β-Blockers presumably compass the positive effect on mortality by lowering the chronic sympathic overstimulation. Possible side effects include (symptomatic) hypotension, worsening of HF or bradycardia.

Diuretics (Aldosterone antagonists and angiotensin receptor blockers) Diuretics reduce preload by venous vasodilatation and fluid secretion. As a result, filling pressures of the heart and the lung vasculature decreases and symptoms and signs decrease. (Class I recommendation, level of evidence B)

Aldosterone antagonists Adding this drug to therapy is suggested for patients with severe symptomatic (NYHA class III or IV, refer to table 2) HF and an LVEF < 35%. (Class I recommendation, level of evidence B) Contraindications:

• Serum potassium concentration > 5.0 mmol/L
• Serum creatine > 220 µmol/L
• Concomitant potassium sparing diuretic or potassium supplements
• Combination of an ACEI and ARB

By competing with aldosterone, the antagonists lower the blood pressure through reducing water and sodium retention. Possible side effects include hyperkalaemia, worsening renal function, and breast tenderness and/or enlargement.

Angiotensin receptor blockers (ARBs)

In HF patients with a LVEF≤40% who remain symptomatic despite optimal ACEI en β-blocker treatment, use of ARBs is recommended. (Class I recommendation, level of evidence A). Contraindications are:  Combination of an ACE inhibitor and an aldosterone antagonist  Bilateral renal artery stenosis  Serum potassium concentration > 5.0 mmol/L  Serum creatine > 220 µmol/L  Severe aortic stenosis Possible side effects include symptomatic hypotension (dizziness), hyperkalaemia, and a worsening renal function.

Digoxine

For a long time digoxine, together with β-blockers, has been standard treatment in HF. Presumably, digoxine ameliorates contractility of the heart by increasing intracellular calcium and sodium concentrations. Nevertheless, in contradiction to other drugs (β-blockers , ACE inhibititors, ARBs) it has never proven to decrease mortality rates. Because of that reason, digoxine had to render its place in the treatment algorithm. In patients with symptomatic HF and atrial fibrillation (AF) with a ventricular rate at rest of >80 beats per minute, use of digoxine may be considered to slow the ventricular rate. (Class I recommendation, level of evidence C) In mild to severe symptomatic HF patients in sinus rhythm and with an LVEF ≤40% , digoxin (in addition to an ACEI) improves ventricular function and patient well-being, reduces hospital admission, but does not affect survival rates. (Class IIa recommendation, level of evidence B) Contraindications for the use of digoxin are:

• Second- or third degree heart block without a permanent pacemaker, sick sinus syndrome
• Pre-exitation syndromes

Possible side effects include sinoatrial or atrioventricular block, arrhythmias or signs of toxicity.

Hydralazine and isosorbide dinitrate (H-ISDN)

H-ISDN can be used as an alternative treatment when both ACI and ARBs are not tolerated in symptomatic HF patients with a LVEF ≤40%. When patients continue to have symptoms despite optimal treatment with β-blockers, ACEI, ARBs or aldosterone antagonists, adding H-ISDN should be considered as this may decrease the risk of death in these patients. (Class IIa recommendation, level of evidence B) Treatment with H-ISDN has proven to reduce hospital admission for worsening HF (Class IIa recommendation, level of evidence B) and improves ventricular function and exercise tolerance (Class IIa recommendation, level of evidence A). Contraindications for the use of H-ISDN are:

• Symptomatic hypotention
• Lupus syndrome
• Severe renal failure

The H-ISDN work by decreasing peripheral vascular resistance. Possible side effects include symptomatic hypotension or drug-induced lupus-like syndrome.

Other

Anticoagulants, anti platelet agents, statins, anti arrhythmic medication, calcium antagonists.

Management of HF patients with preserved LVEF (HFPEF)

To date, no evidence exists of any treatment reducing morbidity or mortality in this patient group. With the aim to control water and sodium retention and decrease breathlessness and edema, diuretics are prescribed to HFPEF patients.

  References

(1) Withering W., Keys TE, An account of the foxglove and some of its medical uses, with practical remarks on dropsy, and other diseases, Classics of Cardiology. Volume I. New York, NY: Henry Schuman, Dover Publications; 1941: 231–252. (2) Dickstein K. et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008, European Heart Journal (2008) 29, 2388–2442 (3) Evangelista LS, Dracup K. A closer look at compliance research in heart failure patients in the last decade. Prog Cardiovasc Nurs 2000;15:97–103. (4) van derWal MH, Jaarsma T, van Veldhuisen DJ. Non-compliance in patients with heart failure; how can we manage it? Eur J Heart Fail 2005;7:5–17 (5) Granger BB, Swedberg K, Ekman I, Granger CB, Olofsson B, McMurray JJ, Yusuf S, Michelson EL, Pfeffer MA. Adherence to candesartan and placebo and outcomes in chronic heart failure in the CHARM programme: double-blind, randomised, controlled clinical trial. Lancet 2005;366:2005–2011 (6) Lainscak M, Cleland J, Lenzen MJ. Recall of lifestyle advice in patients recently hospitalised with heart failure: a EuroHeart Failure Survey analysis. Eur J Heart Fail 2007;9:1095–1103 (7) McDonagh TA, Morrison CE, Lawrence A, Ford I, Tunstall-Pedoe H, McMurray JJ, Dargie HJ. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet. 1997 Sep 20;350(9081):829-33 (8) Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC, Vasan RS. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation. 2003 Aug 26;108(8):977-82. Epub 2003 Aug 11.

 

Figure 2

 

Table 4 Size of treatment effect

Class I Benefit >>> Risk

Procedure/treatment should be performed/administered Class IIa Benefit >> Risk Additional studies with focused objectives needed

It is reasonable to perform/administer treatment Class IIb Benefit ≥ Risk Additional studies with broad objectives needed; additional registry data would be helpful

Procedure/treatment may be considered Class III Benefit ≥ Risk No additional studies needed

Procedure/treatment should not be performed/administered since it is not helpful and may be harmful Level A

Multiple (3-5) population risk strata evaluated  Recommendation that procedure or treatment is useful/effective  Sufficient evidence from multiple randomized trials or non-randomized trials  Recommendation in favor of treatment or procedure being useful/effective  Some conflicting evidence from multiple randomized trials or meta-analyses  Recommendation’s usefulness/efficacy less well established  Greater conflicting evidence from multiple randomized trials or meta-analyses  Recommendation that procedure or treatment not useful/effective and may be harmful  Sufficient evidence from multiple randomized trials or meta-analyses Level B

Limited (2-3) population risk strata evaluated  Recommendation that procedure or treatment is useful/effective  Limited evidence from single randomized trial or non-randomized studies  Recommendation in favor of treatment or procedure being useful/effective  Some conflicting evidence from single randomized trial or non-randomized studies  Recommendation’s usefulness/efficacy less well established  Greater conflicting evidence from single randomized trial or non-randomized studies  Recommendation that procedure or treatment not useful/effective and may be harmful  Limited evidence from single randomized trial or non-randomized studies Level C

Very limited (1-2) population risk strata evaluated  Recommendation that procedure or treatment is useful/effective Only experts opinion, case studies, or standard-of-care  Recommendation in favor of treatment or procedure being useful/effective  Only diverging expert opinion case studies, or standard-of-care  Recommendation’s usefulness/efficacy less well established  Only diverging expert opinion case studies, or standard-of-care  Recommendation that procedure or treatment not useful/effective and may be harmful  Only expert opinion case studies, or standard-of-care