IIb B-NR In patients with chronic HF, measurement of other clinically available tests, such as biomarkers of myocardial injury or fibrosis, may be considered for additive risk stratification.27,95,98,99,103,114 119 MODIFIED: 2013 recommendations have been combined into prognosis section, resulting in LOE change from A to B-NR. See Online Data Supplements A and B. Biomarkers of myocardial fibrosis (eg, soluble ST2 receptor, galectin-3, high-sensitivity cardiac troponin, and others) are predictive of hospitalization and death in patients with HF and also are additive to natriuretic peptide biomarker levels in their prognostic value.117,119 126 A combination of biomarkers may ultimately prove to be more informative than single biomarkers.127 Biomarkers: Recommendations for Prognosis (Continued) COR LOE Recommendations Comment/Rationale Yancy et al 7. Treatment of Stages A to D 7.3. Stage C 7.3.2. Pharmacological Treatment for Stage C HF With Reduced Ejection Fraction: Recommendations (See Figure 2 and Table 3). 7.3.2.10. Renin-Angiotensin System Inhibition With Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI COR LOE Recommendations Comment/Rationale I ACE-I: A The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors (Level of Evidence: A),128 133 OR ARBs (Level of Evidence: OR ARNI (Level of Evidence: B-R)138 in conjunction with evidence- based beta blockers,9,139,140 and aldosterone antagonists in selected is recommended for patients with chronic HFrEF to reduce morbidity and mortality. NEW: New clinical trial data prompted clarification and important updates. ARB: A ARNI: B-R See Online Data 18-20. Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF).


Angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). Randomized controlled trials (RCTs) clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without coronary artery disease.128 133 ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium. ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough but also may contribute to their beneficial effect through vasodilation. Angiotensin receptor blockers (ARBs) were developed with the rationale that angiotensin II production continues in the presence of ACE inhibition, driven through alternative enzyme pathways. ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema than ACE inhibitors; but like ACE inhibitors, ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium. Long-term therapy with ARBs produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system and have been shown in RCTs134 137 to reduce morbidity and mortality, especially in ACE inhibitor intolerant patients. In ARNI, an ARB is combined with an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. In an RCT that compared the first approved ARNI, valsartan/sacubitril, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization significantly, by 20%.138 The benefit was seen to a similar extent for both death and HF hospitalization and was consistent across subgroups.


In an RCT that compared the first approved ARNI, valsartan/sacubitril, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACE inhibitor or ARB, the ARNI reduced the composite endpoint of cardiovascular death or HF hospitalization significantly, by 20%.138 The benefit was seen to a similar extent for both death and HF hospitalization and was consistent across subgroups. The use of ARNI is associated with the risk of hypotension and renal insufficiency and may lead to angioedema, as well. I ACE-I: A The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality.128 133,143 2013 recommendation repeated for clarity in this section. See Online Data Supplement 18. ACE inhibitors have been shown in large RCTs to reduce morbidity and mortality in patients with HFrEF with mild, moderate, or severe symptoms of HF, with or without coronary artery disease.128 133 Data suggest that there are no differences among available ACE inhibitors in their effects on symptoms or survival.143 ACE inhibitors should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials. ACE inhibitors can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Angioedema occurs in <1% of patients who take an ACE inhibitor, but it occurs more frequently in blacks and women.144 Patients should not be given ACE inhibitors if they are pregnant or plan to become pregnant. ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough in up to 20% of patients but also may contribute to beneficial vasodilation.


ACE inhibitors also inhibit kininase and increase levels of bradykinin, which can induce cough in up to 20% of patients but also may contribute to beneficial vasodilation. If maximal doses are not tolerated, intermediate doses should be tried; abrupt withdrawal of ACE inhibition can lead to clinical deterioration and should be avoided. Although the use of an ARNI in lieu of an ACE inhibitor for HFrEF has been found to be superior, for those patients for whom ARNI is not appropriate, continued use of an ACE inhibitor for all classes of HFrEF remains strongly advised. I ARB: A The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE inhibitors because of cough or angioedema.134 137,145,146 2013 recommendation repeated for clarity in this section. See Online Data Supplements 2 and 19. ARBs have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs.134 137 Long-term therapy with ARBs in patients with HFrEF produces hemodynamic, neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system.145,146 Unlike ACE inhibitors, ARBs do not inhibit kininase and are associated with a much lower incidence of cough and angioedema, although kininase inhibition by ACE inhibitors may produce beneficial vasodilatory effects. Patients intolerant to ACE inhibitors because of cough or angioedema should be started on ARBs; patients already tolerating ARBs for other indications may be continued on ARBs if they subsequently develop HF. ARBs should be started at low doses and titrated upward, with an attempt to use doses shown to reduce the risk of cardiovascular events in clinical trials. ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L).


ARBs should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Although ARBs are alternatives for patients with ACE inhibitor induced angioedema, caution is advised because some patients have also developed angioedema with ARBs. Head-to-head comparisons of an ARB versus ARNI for HF do not exist. For those patients for whom an ACE inhibitor or ARNI is inappropriate, use of an ARB remains advised. 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES I ARNI: B-R In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality.138 NEW: New clinical trial data necessitated this recommendation. See Online Data Supplements 1 and 18. Benefits of ACE inhibitors with regard to decreasing HF progression, hospitalizations, and mortality rate have been shown consistently for patients across the clinical spectrum, from asymptomatic to severely symptomatic HF. Similar benefits have been shown for ARBs in populations with mild-to-moderate HF who are unable to tolerate ACE inhibitors. In patients with mild-to- moderate HF (characterized by either 1) mildly elevated natriuretic peptide levels, BNP [B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N-terminal pro-B-type natriuretic peptide] 600 pg/mL; or 2) BNP 100 pg/mL or NT-proBNP 400 pg/mL with a prior hospitalization in the preceding 12 months) who were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI (valsartan/sacubitril; 200 mg twice daily, with the ARB component equivalent to valsartan 160 mg), hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with enalapril.


In patients with mild-to- moderate HF (characterized by either 1) mildly elevated natriuretic peptide levels, BNP [B-type natriuretic peptide] >150 pg/mL or NT-proBNP [N-terminal pro-B-type natriuretic peptide] 600 pg/mL; or 2) BNP 100 pg/mL or NT-proBNP 400 pg/mL with a prior hospitalization in the preceding 12 months) who were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNI (valsartan/sacubitril; 200 mg twice daily, with the ARB component equivalent to valsartan 160 mg), hospitalizations and mortality were significantly decreased with the valsartan/sacubitril compound compared with enalapril. The target dose of the ACE inhibitor was consistent with that known to improve outcomes in previous landmark clinical trials.129 This ARNI has been approved for patients with symptomatic HFrEF and is intended to be substituted for ACE inhibitors or ARBs. HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme, which has multiple biological targets. Use of an ARNI is associated with hypotension and a low-frequency incidence of angioedema. To facilitate initiation and titration, the approved ARNI is available in 3 doses that include a dose that was not tested in the HF trial; the target dose used in the trial was 97/103 mg twice daily.147 Clinical experience will provide further information about the optimal titration and tolerability of ARNI, particularly with regard to blood pressure, adjustment of concomitant HF medications, and the rare complication of angioedema.14 III: Harm B-R ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor.148,149 NEW: Available evidence demonstrates a potential signal of harm for a concomitant use of ACE inhibitors and ARNI. See Online Data Supplement 3.


To facilitate initiation and titration, the approved ARNI is available in 3 doses that include a dose that was not tested in the HF trial; the target dose used in the trial was 97/103 mg twice daily.147 Clinical experience will provide further information about the optimal titration and tolerability of ARNI, particularly with regard to blood pressure, adjustment of concomitant HF medications, and the rare complication of angioedema.14 III: Harm B-R ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor.148,149 NEW: Available evidence demonstrates a potential signal of harm for a concomitant use of ACE inhibitors and ARNI. See Online Data Supplement 3. Oral neprilysin inhibitors, used in combination with ACE inhibitors can lead to angioedema and concomitant use is contraindicated and should be avoided. A medication that represented both a neprilysin inhibitor and an ACE inhibitor, omapatrilat, was studied in both hypertension and HF, but its development was terminated because of an unacceptable incidence of angioedema148,149 and associated significant morbidity. This adverse effect was thought to occur because both ACE and neprilysin break down bradykinin, which directly or indirectly can cause angioedema.149,150 An ARNI should not be administered within 36 hours of switching from or to an ACE inhibitor. III: Harm C-EO ARNI should not be administered to patients with a history of angioedema. NEW: New clinical trial data. N/A Omapatrilat, a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF.148 In a very large RCT of hypertensive patients, omapatrilat was associated with a 3-fold increased risk of angioedema as compared with enalapril.149 Blacks and smokers were particularly at risk.


N/A Omapatrilat, a neprilysin inhibitor (as well as an ACE inhibitor and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF.148 In a very large RCT of hypertensive patients, omapatrilat was associated with a 3-fold increased risk of angioedema as compared with enalapril.149 Blacks and smokers were particularly at risk. The high incidence of angioedema ultimately led to cessation of the clinical development of In light of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNI therapy in patients with hypertension153 and then in the large trial that demonstrated clinical benefit of ARNI therapy in HFrEF.138 ARNI therapy should not be administered in patients with a history of angioedema because of the concern that it will increase the risk of a recurrence of angioedema. 7.3.2.11. Ivabradine: Recommendation Recommendation for Ivabradine COR LOE Recommendation Comment/Rationale IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDEM*, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest.154 157 NEW: New clinical trial data. See Online Data Supplement 4. Ivabradine is a new therapeutic agent that selectively inhibits the If current in the sinoatrial node, providing heart rate reduction. One RCT demonstrated the efficacy of ivabradine in reducing the composite endpoint of cardiovascular death or HF The benefit of ivabradine was driven by a reduction in HF hospitalization.


One RCT demonstrated the efficacy of ivabradine in reducing the composite endpoint of cardiovascular death or HF The benefit of ivabradine was driven by a reduction in HF hospitalization. The study included patients with HFrEF (NYHA class II-IV, albeit with only a modest representation of NYHA class IV HF) and left ventricular ejection fraction (LVEF) 35%, in sinus rhythm with a resting heart rate of 70 beats per minute. Patients enrolled included a small number with paroxysmal atrial fibrillation (<40% of the time) but otherwise in sinus rhythm and a small number experiencing ventricular pacing but with a predominant sinus rhythm. Those with a myocardial infarction within the preceding 2 months were excluded. Patients enrolled had been hospitalized for HF in the preceding 12 months and were on stable GDEM* for 4 weeks before initiation of ivabradine therapy. The target of ivabradine is heart rate slowing (the presumed benefit of action), but only 25% of patients studied were on optimal doses of beta-blocker therapy.9,139,140,155 Given the well-proven mortality benefits of beta-blocker therapy, it is important to initiate and up titrate these agents to target doses, as tolerated, before assessing the resting heart rate for consideration of Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI (Continued) COR LOE Recommendations Comment/Rationale *In other parts of the document, the term GDMT has been used to denote guideline-directed management and therapy. In this recommendation, however, the term GDEM has been used to denote this same concept in order to reflect the original wording of the recommendation that initially appeared in the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. 10 Yancy et al 7.3.3.


In this recommendation, however, the term GDEM has been used to denote this same concept in order to reflect the original wording of the recommendation that initially appeared in the 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. 10 Yancy et al 7.3.3. Pharmacological Treatment for Stage C HFpEF: Recommendations Recommendations for Stage C HFpEF COR LOE Recommendations Comment/Rationale I B Systolic and diastolic blood pressure should be controlled in patients with HFpEF in accordance with published clinical practice guidelines to 2013 recommendation remains current. I C Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF. 2013 recommendation remains current. IIa C Coronary revascularization is reasonable in patients with CAD in whom symptoms (angina) or demonstrable myocardial ischemia is judged to be having an adverse effect on symptomatic HFpEF despite GDMT. 2013 recommendation remains current. IIa C Management of AF according to published clinical practice guidelines in patients with HFpEF is reasonable to improve symptomatic HF. 2013 recommendation remains current (Section 9.1 in the 2013 HF guideline). IIa C The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control blood pressure in patients with HFpEF. 2013 recommendation remains current. Figure 2. Treatment of HFrEF Stage C and D. Colors correspond to COR in Table 1. For all medical therapies, dosing should be optimized and serial assessment exercised. *See text for important treatment directions. Hydral-Nitrates green box: The combination of ISDN/HYD with ARNI has not been robustly tested. BP response should be carefully monitored. See 2013 HF guideline.9 Participation in investigational studies is also appropriate for stage C, NYHA class II and III HF.


See 2013 HF guideline.9 Participation in investigational studies is also appropriate for stage C, NYHA class II and III HF. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor-blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BP, blood pressure; bpm, beats per minute; C/I, contraindication; COR, Class of Recommendation; CrCl, creatinine clearance; CRT-D, cardiac resynchronization therapy device; Dx, diagnosis; GDMT, guideline-directed management and therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator; ISDN/HYD, isosorbide dinitrate hydral-nitrates; K+, potassium; LBBB, left bundle-branch block; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSR, normal sinus rhythm; and NYHA, New York Heart Association. 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES IIb B-R In appropriately selected patients with HFpEF (with EF 45%, elevated BNP levels or HF admission within 1 year, estimated glomerular filtration rate >30 mL/min, creatinine <2.5 mg/dL, potassium <5.0 mEq/L), aldosterone receptor antagonists might be considered to decrease NEW: Current recommendation reflects new RCT data. See Online Data Supplement C. Mechanistic studies have suggested that mineralocorticoid receptor antagonists can improve measures of diastolic function in patients with HFpEF, possibly by a similar effect on remodeling.83,168 The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial166 investigated the effects of spironolactone on a combined endpoint of death, aborted cardiac death, and HF hospitalization in patients with HFpEF. A small reduction (HR=0.89) in this composite endpoint did not reach statistical significance, although HF hospitalization was reduced (HR=0.83); known side effects of hyperkalemia and rising creatinine were seen more commonly in the treatment group.166 An unusual amount of regional variation was seen in this trial, prompting a post-hoc analysis167 that showed that rates of the primary endpoint were 4-fold lower in Russia/Georgia than in North America and South America (the Americas).


A small reduction (HR=0.89) in this composite endpoint did not reach statistical significance, although HF hospitalization was reduced (HR=0.83); known side effects of hyperkalemia and rising creatinine were seen more commonly in the treatment group.166 An unusual amount of regional variation was seen in this trial, prompting a post-hoc analysis167 that showed that rates of the primary endpoint were 4-fold lower in Russia/Georgia than in North America and South America (the Americas). Rates in the Americas were comparable to those in other HFpEF trials.169,170 The post-hoc analysis showed efficacy in the Americas (HR=0.83) but not in Russia/Georgia (HR=1.10). Moreover, a sample of the Russia/Georgia population, despite having been in the active treatment arm, had nondetectable levels of the metabolite of spironolactone. These post- hoc analyses have significant limitations, but they suggest that in appropriately selected patients with symptomatic HFpEF (with ejection fraction [EF] 45%, elevated BNP level or HF admission within 1 year, estimated glomerular filtration rate >30 mL/min creatinine <2.5 mg/dL, and potassium <5.0 mEq/L), particularly in those with elevated BNP levels, use of spironolactone might be considered with close monitoring of potassium and renal function. Confirmatory studies are required. With regard to the use of mineralocorticoid receptor antagonists, creatinine should be <2.5 mg/dL in men or <2.0 mg/dL in women (or estimated glomerular filtration rate >30 mL/min) and potassium should be <5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing represents best practices at initiation and during follow-up thereafter to minimize risk of hyperkalemia and worsening renal function. IIb B The use of ARBs might be considered to decrease hospitalizations for patients with HFpEF.169 2013 recommendation remains current.


IIb B The use of ARBs might be considered to decrease hospitalizations for patients with HFpEF.169 2013 recommendation remains current. III: No Benefit B-R Routine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or QoL in patients with HFpEF is ineffective.171,172 NEW: Current recommendation reflects new data from RCTs. See Online Data Supplement C. Nitrate therapy can reduce pulmonary congestion and improve exercise tolerance in patients with HFrEF. However, the NEAT-HFpEF (Nitrate s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction) trial171 randomized 110 patients with EF 50% on stable HF therapy, not including nitrates, and with activity limited by dyspnea, fatigue, or chest pain, to either isosorbide mononitrate or placebo and found no beneficial effects on activity levels, QoL, exercise tolerance, or NT-proBNP levels. On the basis of this trial, routine use of nitrates in patients with HFpEF is not recommended. This recommendation does not apply to patients with HFpEF and symptomatic CAD for whom nitrates may provide symptomatic relief. Phosphodiesterase-5 inhibition augments the nitric oxide system by upregulating cGMP activity. The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection randomized 216 patients with EF 50% on stable HF therapy and with reduced exercise tolerance (peak observed Vo2 <60% of predicted) to phosphodiesterase-5 inhibition with sildenafil or placebo. This study did not show improvement in oxygen consumption or exercise tolerance. III: No Benefit C Routine use of nutritional supplements is not recommended for patients with HFpEF. 2013 recommendation remains current. 9. IMPORTANT COMORBIDITIES IN HF 9.2.


2013 recommendation remains current. 9. IMPORTANT COMORBIDITIES IN HF 9.2. Anemia: Recommendations Recommendations for Anemia COR LOE Recommendations Comment/Rationale IIb B-R In patients with NYHA class II and III HF and iron deficiency (ferritin <100 ng/mL or 100 to 300 ng/mL if transferrin saturation is <20%), intravenous iron replacement might be reasonable to improve functional status and QoL.173,174 NEW: New evidence consistent with therapeutic benefit. See Online Data Supplement D. Routine baseline assessment of all patients with HF includes an evaluation for anemia in addition to other baseline laboratory measurements. Anemia is independently associated with HF disease severity, and iron deficiency appears to be uniquely associated with reduced exercise capacity. When iron deficiency is diagnosed and after full evaluation for cause, intravenous repletion of iron, especially in the setting of concomitant hepcidin deficiency in HF, may improve exercise capacity and QoL. Studies examining correction of iron deficiency in HF have demonstrated improvement in surrogate endpoints, such as QoL, NT- proBNP, and LVEF; however, controlled trials have been underpowered to detect reductions in hard clinical endpoints. The FAIR-HF (Ferric Carboxymaltose Assessment in Patients With Iron Deficiency and Chronic Heart Failure) trial173 demonstrated improvements in NYHA class and functional capacity over a short- term exposure. The CONFIRM-HF (Ferric Carboxymaltose Evaluation on Performance in Patients With Iron Deficiency in Combination with Chronic Heart Failure) included a larger cohort of patients (n=304) and demonstrated improvements in 6-minute walk test. A meta-analysis of 5 prospective controlled studies (631 patients) evaluated the effect of intravenous iron on deaths, hospitalizations, and other events in patients with HF and iron deficiency.175 Patients receiving intravenous iron experienced limited but statistically significant improvements in functional capacity and LVEF but no reduction in mortality rate.


A meta-analysis of 5 prospective controlled studies (631 patients) evaluated the effect of intravenous iron on deaths, hospitalizations, and other events in patients with HF and iron deficiency.175 Patients receiving intravenous iron experienced limited but statistically significant improvements in functional capacity and LVEF but no reduction in mortality rate. The FAIR-HF 2 trial is underway to further address the potential benefit of intravenous iron in HF associated with iron deficiency. Therefore, a strong recommendation for intravenous iron repletion must await the results of an appropriately powered trial on morbidity and mortality. There is an uncertain evidence base for oral iron repletion in the setting of anemia associated with HF. Recommendations for Stage C HFpEF (Continued) COR LOE Recommendations Comment/Rationale Yancy et al III: No Benefit B-R In patients with HF and anemia, erythropoietin-stimulating agents should not be used to improve morbidity and mortality.176 NEW: Current recommendation reflects new evidence demonstrating absence of therapeutic benefit. See Online Data Supplement D. Small studies evaluating the treatment of anemia in patients with HF have suggested a trend toward improvement in functional capacity and reduction in hospitalization with the use of erythropoietin-stimulating agents,177 182 but results have varied183 and have been limited because of sample size. Although a meta-analysis of 11 RCTs (n=794) comparing erythropoietin-stimulating agents to control in patients with HF demonstrated significant improvements in 6-minute walk, exercise duration, peak Vo2 , NYHA functional status, EF, BNP, HF-related hospitalizations, and QoL,184 in the STAMINA-HeFT (Study of Anemia in Heart Failure) trial,183 darbepoetin alfa was not associated with significant clinical benefits.


Although a meta-analysis of 11 RCTs (n=794) comparing erythropoietin-stimulating agents to control in patients with HF demonstrated significant improvements in 6-minute walk, exercise duration, peak Vo2 , NYHA functional status, EF, BNP, HF-related hospitalizations, and QoL,184 in the STAMINA-HeFT (Study of Anemia in Heart Failure) trial,183 darbepoetin alfa was not associated with significant clinical benefits. In the largest RCT to date (n=2278), correction of anemia with darbopoetin alfa did not result in benefit and resulted in a significant increase in the risk of thromboembolic events and a nonsignificant increase in fatal and nonfatal strokes, supporting findings from other trials.176,185 188 In summary, the strongest evidence on erythropoietin-stimulating agent therapy in HF suggests lack of benefit and increased adverse events. Therefore, erythropoietin-stimulating agent therapy cannot be recommended in patients with HF and anemia. Table 3.


Therefore, erythropoietin-stimulating agent therapy cannot be recommended in patients with HF and anemia. Table 3. Drugs Commonly Used for HFrEF (Stage C HF) Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials References ACE inhibitors Captopril 6.25 mg TID 50 mg TID 122.7 mg QD 158 Enalapril 2.5 mg BID 10 20 mg BID 16.6 mg QD 129 Fosinopril 5 10 mg QD 40 mg QD N/A Lisinopril 2.5 5 mg QD 20 40 mg QD 32.5 35.0 mg QD 130 Perindopril 2 mg QD 8 16 mg QD N/A Quinapril 5 mg BID 20 mg BID N/A Ramipril 1.25 2.5 mg QD 10 mg QD N/A Trandolapril 1 mg QD 4 mg QD N/A ARBs Candesartan 4 8 mg QD 32 mg QD 24 mg QD 137 Losartan 25 50 mg QD 50 150 mg QD 129 mg QD 136 Valsartan 20 40 mg BID 160 mg BID 254 mg QD 134 ARNI Sacubitril/valsartan 49/51 mg BID (sacubitril/valsartan) (therapy may be initiated at 24/26 mg BID) 97/103 mg BID (sacubitril/valsartan) 375 mg QD; target dose: 24/26 mg, 49/51 mg OR 97/103 mg BID If channel inhibitor Ivabradine 5 mg BID 7.5 mg BID 6.4 mg BID (at 28 d) 6.5 mg BID (at 1 y) Aldosterone antagonists Spironolactone 12.5 25 mg QD 25 mg QD or BID 26 mg QD 142 Eplerenone 25 mg QD 50 mg QD 42.6 mg QD 159 Beta blockers Bisoprolol 1.25 mg QD 10 mg QD 8.6 mg QD 160 Carvedilol 3.125 mg BID 50 mg BID 37 mg QD 161 Carvedilol CR 10 mg QD 80 mg QD N/A Metoprolol succinate extended release (metoprolol CR/XL) 12.5 25 mg QD 200 mg QD 159 mg QD 139 Isosorbide dinitrate and hydralazine Fixed-dose combination 20 mg isosorbide dinitrate/37.5 mg hydralazine TID mg hydralazine TID 90 mg isosorbide dinitrate/ ~175 mg hydralazine QD Isosorbide dinitrate and hydralazine mg hydralazine TID or QD 40 mg isosorbide dinitrate TID with 100 mg hydralazine TID Modified (Table 15) from the 2013 HF guideline.9 ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; BID, twice daily; CR, controlled release; CR/XL, controlled release/extended release; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; N/A, not applicable; QD, once daily; and TID, 3 times daily.


Recommendations for Anemia (Continued) COR LOE Recommendations Comment/Rationale 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES 9.5. Hypertension (New Section) 9.5.1. Treating Hypertension to Reduce the Incidence of HF: Recommendation Recommendation for Prevention COR LOE Recommendations Comment/Rationale I B-R In patients at increased risk, stage A HF, the optimal blood pressure in those with hypertension should be less than 130/80 mm Hg.189 193 NEW: Recommendation reflects new RCT data. See Online Data Supplements E and F. A large RCT demonstrated that in those with increased cardiovascular risk (defined as age >75 years, established vascular disease, chronic renal disease, or a Framingham Risk Score >15%), control of blood pressure to a goal systolic pressure of <120 mm Hg, as determined by blood pressure assessment as per research protocol, was associated with a significant reduction in the incidence of HF191 and an overall decrease in cardiovascular death. Blood pressure measurements as generally taken in the office setting are typically 5 to 10 mm Hg higher than research measurements; thus, the goal of <130/80 mm Hg is an approximation of the target blood pressure in conventional practice. Targeting a significant reduction in systolic blood pressure in those at increased risk for cardiovascular disease is a novel strategy to prevent HF. 9.5.2. Treating Hypertension in Stage C HFrEF: Recommendation Recommendation for Hypertension in Stage C HFrEF COR LOE Recommendation Comment/Rationale I C-EO Patients with HFrEF and hypertension should be prescribed GDMT titrated to attain systolic blood pressure less than 130 mm Hg.191 NEW: Recommendation has been adapted from recent clinical trial data but not specifically tested per se in a randomized trial of patients with HF.


Treating Hypertension in Stage C HFrEF: Recommendation Recommendation for Hypertension in Stage C HFrEF COR LOE Recommendation Comment/Rationale I C-EO Patients with HFrEF and hypertension should be prescribed GDMT titrated to attain systolic blood pressure less than 130 mm Hg.191 NEW: Recommendation has been adapted from recent clinical trial data but not specifically tested per se in a randomized trial of patients with HF. See Online Data Supplements E and F. Clinical trials evaluating goal blood pressure reduction and optimal blood pressure lowering agents in the setting of HFrEF and concomitant hypertension have not been done. However, it is apparent that in those patients at higher risk, blood pressure lowering is associated with fewer adverse cardiovascular events. GDMT for HFrEF with agents known to lower blood pressure should consider a goal blood pressure reduction consistent with a threshold now associated with improved clinical outcomes but not yet proven by RCTs in a population with HF. 9.5.3. Treating Hypertension in Stage C HFpEF: Recommendation Recommendation for Hypertension in Stage C HFpEF COR LOE Recommendation Comment/Rationale I C-LD Patients with HFpEF and persistent hypertension after management of volume overload should be prescribed GDMT titrated to attain systolic blood pressure less than 130 mm Hg.9,167,169,170,195 199 NEW: New target goal blood pressure based on updated interpretation of recent clinical trial data. See Online Data Supplements E and F. The use of nitrates in the setting of HFpEF is associated with a signal of harm and, in most situations, should be avoided. For many common antihypertensive agents, including alpha blockers, beta blockers, and calcium channel blockers, there are limited data to guide the choice of antihypertensive therapy in the setting of HFpEF.172 Nevertheless, RAAS inhibition with ACE inhibitor, ARB (especially mineralocorticoid receptor antagonists), and possibly ARNI would represent the preferred choice.


For many common antihypertensive agents, including alpha blockers, beta blockers, and calcium channel blockers, there are limited data to guide the choice of antihypertensive therapy in the setting of HFpEF.172 Nevertheless, RAAS inhibition with ACE inhibitor, ARB (especially mineralocorticoid receptor antagonists), and possibly ARNI would represent the preferred choice. A shared decision-making discussion with the patient influenced by physician judgment should drive the ultimate choice of antihypertensive agents. 9.6. Sleep-Disordered Breathing: Recommendations (Moved from Section 7.3.1.4, Treatment of Sleep Disorders in the 2013 HF guideline.) Recommendations for Treatment of Sleep Disorders COR LOE Recommendations Comment/Rationale IIa C-LD In patients with NYHA class II IV HF and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment is NEW: Recommendation reflects clinical necessity to distinguish obstructive versus central sleep apnea. See Online Data Supplement G. Sleep disorders are common in patients with HF. A study of adults with chronic HF treated with evidence-based therapies found that 61% had either central or obstructive sleep apnea.202 It is clinically important to distinguish obstructive sleep apnea from central sleep apnea, given the different responses to treatment. Adaptive servo-ventilation for central sleep apnea is associated with harm.203 Continuous positive airway pressure (CPAP) for obstructive sleep apnea improves sleep quality, reduces the apnea-hypopnea index, and improves nocturnal oxygenation.200,201 IIb B-R In patients with cardiovascular disease and obstructive sleep apnea, CPAP may be reasonable to improve sleep quality and daytime NEW: New data demonstrate the limited scope of benefit expected from CPAP for obstructive sleep apnea.


Adaptive servo-ventilation for central sleep apnea is associated with harm.203 Continuous positive airway pressure (CPAP) for obstructive sleep apnea improves sleep quality, reduces the apnea-hypopnea index, and improves nocturnal oxygenation.200,201 IIb B-R In patients with cardiovascular disease and obstructive sleep apnea, CPAP may be reasonable to improve sleep quality and daytime NEW: New data demonstrate the limited scope of benefit expected from CPAP for obstructive sleep apnea. See Online Data Supplement G. In patients with sleep apnea, a trial evaluated the impact of CPAP with usual therapy versus usual therapy alone on subsequent cardiovascular events, including In this RCT of >2700 patients, there was no evidence of benefit on cardiovascular events at a mean follow-up of 3.7 years for CPAP plus usual care compared with usual care alone. Improvements in sleep quality were noteworthy and represented the primary indication for initiating CPAP treatment.204 However, in patients with atrial fibrillation (AF) (a frequent comorbidity noted with HF), the use of CPAP for obstructive sleep apnea was helpful.


Improvements in sleep quality were noteworthy and represented the primary indication for initiating CPAP treatment.204 However, in patients with atrial fibrillation (AF) (a frequent comorbidity noted with HF), the use of CPAP for obstructive sleep apnea was helpful. In a trial of 10132 patients with AF and obstructive sleep apnea, patients on CPAP treatment were less likely to progress to more permanent forms of AF than were patients without CPAP.205 Yancy et al ACC/AHA TASK FORCE MEMBERS Glenn N. Levine, MD, FACC, FAHA, Chair; Patrick T. O Gara, MD, FACC, FAHA, Chair-Elect; Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair*; Sana M. Al-Khatib, MD, MHS, FACC, FAHA; Kim K. Birtcher, PharmD, MS, AACC; Bi- ykem Bozkurt, MD, PhD, FACC, FAHA; Ralph G. Brindis, MD, MPH, MACC*; Joaquin E. Cigarroa, MD, FACC; Lesley H. Cur- tis, PhD, FAHA; Lee A. Fleisher, MD, FACC, FAHA; Federico Gentile, MD, FACC; Samuel Gidding, MD, FAHA; Mark A. Hlatky, MD, FACC; John Ikonomidis, MD, PhD, FAHA; Jos Joglar, MD, FACC, FAHA; Susan J. Pressler, PhD, RN, FAHA; Duminda N. Wijeysundera, MD, PhD PRESIDENTS AND STAFF American College of Cardiology Mary Norine Walsh, MD, FACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, Quality, and Publishing Amelia Scholtz, PhD, Publications Manager, Science, Education, Quality, and Publishing American College of Cardiology/ American Heart Association Katherine Sheehan, PhD, Director of Guideline Strategy and Operations Lisa Bradfield, CAE, Director, Guideline Methodology and Policy Abdul R. Abdullah, MD, Science and Medicine Advisor Morgane Cibotti-Sun, MPH, Project Manager, Clinical Practice Guidelines Sam Shahid, MBBS, MPH, Associate Science and Medicine Advisor American Heart Association Steven R. Houser, PhD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science and Medicine Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice Presi- dent, Office of Science Operations Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations FOOTNOTES This document was approved by the American College of Cardiology Clinical Policy Approval Committee, the American Heart Association Science Advisory and Coordinating Com- mittee, the American Heart Association Executive Committee, and the Heart Failure Society of America Executive Committee in April 2017.


The Comprehensive RWI Data Supplement table is avail- able with this article at http://circ.ahajournals.org/lookup/ suppl/doi:10.1161/CIR.0000000000000509/-/DC1. The Data Supplement is available with this article at CIR.0000000000000509/-/DC2. This article has been copublished in the Journal of the American College of Cardiology and the Journal of Cardiac Failure. Copies:ThisdocumentisavailableontheWorldWideWeb sites of the American College of Cardiology (www.acc.org), the American Heart Association (professional.heart.org), and the Heart Failure Society of America (www.hfsa.org). A copy of the document is available at http://professional. heart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase addi- tional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com. Expert peer review of AHA Scientific Statements is con- ducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http:// professional.heart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. Circulation is available at http://circ.ahajournals.org. *Former Task Force member; current member during the writing effort. III: Harm B-R In patients with NYHA class II IV HFrEF and central sleep apnea, adaptive servo-ventilation causes harm.203 NEW: New data demonstrate a signal of harm when adaptive servo-ventilation is used for central sleep apnea.


III: Harm B-R In patients with NYHA class II IV HFrEF and central sleep apnea, adaptive servo-ventilation causes harm.203 NEW: New data demonstrate a signal of harm when adaptive servo-ventilation is used for central sleep apnea. See Online Data Supplement G. Mortality rate (all cause and cardiovascular) was higher with adaptive servo-ventilation plus GDMT than with GDMT alone in a single RCT to test the addition of adaptive servo-ventilation ( 5 hours/night, 7 days/week) to GDMT in patients with HFrEF and central sleep apnea.203 A similar risk has been seen in another trial, and a third trial of adaptive servo-ventilation in central sleep apnea and HF was aborted because of ethical concerns. The weight of evidence does not support the use of adaptive servo-ventilation for central sleep apnea in HFrEF. Recommendations for Treatment of Sleep Disorders (Continued) COR LOE Recommendations Comment/Rationale 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES REFERENCES 1. Committee on Standards for Developing Trustworthy Clinical Practice Guidelines, Institute of Medicine (US). Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press, 2011. 2. Committee on Standards for Systematic Reviews of Comparative Ef- fectiveness Research, Institute of Medicine (US). Finding What Works in Health Care: Standards for Systematic Reviews. Washington, DC: National Academies Press, 2011. 3. Anderson JL, Heidenreich PA, Barnett PG, et al. ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Prac- tice Guidelines. Circulation. 2014;129:2329 45. 4. ACCF/AHA Task Force on Practice Guidelines. Methodology Manual and Policies From the ACCF/AHA Task Force on Practice Guidelines; 2010. American College of Cardiology and American Heart Association. Available at: http://my.americanheart.org/idc/groups/ahamah-public/@ wcm/@sop/documents/downloadable/ucm_319826.pdf Accessed May 5, 2017. 5.


American College of Cardiology and American Heart Association. Available at: http://my.americanheart.org/idc/groups/ahamah-public/@ wcm/@sop/documents/downloadable/ucm_319826.pdf Accessed May 5, 2017. 5. Halperin JL, Levine GN, Al-Khatib SM, et al. Further evolution of the ACC/AHA clinical practice guideline recommendation classification sys- tem: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2016;133:1426 8. 6. Jacobs AK, Kushner FG, Ettinger SM, et al. ACCF/AHA clinical practice guideline methodology summit report: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Prac- tice Guidelines. Circulation. 2013;127:268 310. 7. Jacobs AK, Anderson JL, Halperin JL. The evolution and future of ACC/ AHA clinical practice guidelines: a 30-year journey: a report of the Ameri- can College of Cardiology/American Heart Association Task Force on Prac- tice Guidelines. Circulation. 2014;130:1208 17. 8. Arnett DK, Goodman RA, Halperin JL, et al. AHA/ACC/HHS strategies to enhance application of clinical practice guidelines in patients with cardio- vascular disease and comorbid conditions: from the American Heart As- sociation, American College of Cardiology, and US Department of Health and Human Services. Circulation. 2014;130:1662 7. 9. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiol- ogy Foundation/American Heart Association Task Force on Practice Guide- lines. Circulation. 2013;128:e240 327. 10. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016;134:e282 93. 11. Ponikowski P, Voors AA, Anker SD, et al.


2016;134:e282 93. 11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special con- tribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129 200. 12. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131:54 61. 13. Zile MR, Claggett BL, Prescott MF, et al. Prognostic Implications of Changes in N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Heart Failure. J Am Coll Cardiol. 2016;68:2425 36. 14. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor nepri- lysin inhibitor LCZ696 in heart failure with preserved ejection frac- tion: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387 95. 15. Richards AM, Doughty R, Nicholls MG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and predic- tion of benefit from carvedilol in chronic ischemic left ventricular dys- function. Australia-New Zealand Heart Failure Group. J Am Coll Cardiol. 2001;37:1781 7. 16. Tang WH, Girod JP, Lee MJ, et al. Plasma B-type natriuretic peptide lev- els in ambulatory patients with established chronic symptomatic systolic heart failure. Circulation. 2003;108:2964 6. 17. Zaphiriou A, Robb S, Murray-Thomas T, et al. The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study. Eur J Heart Fail. 2005;7:537 41. 18. Son CS, Kim YN, Kim HS, et al. Decision-making model for early diagnosis of congestive heart failure using rough set and decision tree approaches. J Biomed Inform.


Decision-making model for early diagnosis of congestive heart failure using rough set and decision tree approaches. J Biomed Inform. 2012;45:999 1008. 19. Kelder JC, Cramer MJ, Van WJ, et al. The diagnostic value of physical ex- amination and additional testing in primary care patients with suspected heart failure. Circulation. 2011;124:2865 73. 20. Balion C, Don-Wauchope A, Hill S, et al. Use of Natriuretic Peptide Mea- surement in the Management of Heart Failure [Internet]. 13(14)-EHC118- EF ed. Rockville, MD: 2013. 21. Booth RA, Hill SA, Don-Wauchope A, et al. Performance of BNP and NT- proBNP for diagnosis of heart failure in primary care patients: a systematic review. Heart Fail Rev. 2014;19:439 51. 22. Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care set- ting. J Am Coll Cardiol. 2001;37:379 85. 23. Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343:440 4. 24. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B- type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347:161 7. 25. Moe GW, Howlett J, Januzzi JL, et al. N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective random- ized multicenter IMPROVE-CHF study. Circulation. 2007;115:3103 10. 26. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic pep- tide in the evaluation and management of acute dyspnea. N Engl J Med. 2004;350:647 54. 27. van Kimmenade RR, Pinto YM, Bayes-Genis A, et al. Usefulness of in- termediate amino-terminal pro-brain natriuretic peptide concentra- tions for diagnosis and prognosis of acute heart failure. Am J Cardiol. 2006;98:386 90. 28.


Usefulness of in- termediate amino-terminal pro-brain natriuretic peptide concentra- tions for diagnosis and prognosis of acute heart failure. Am J Cardiol. 2006;98:386 90. 28. Januzzi JL Jr, Chen-Tournoux AA, Moe G. Amino-terminal pro-B-type na- triuretic peptide testing for the diagnosis or exclusion of heart failure in patients with acute symptoms. Am J Cardiol. 2008;101:29 38. 29. Santaguida PL, Don-Wauchope AC, Ali U, et al. Incremental value of natriuretic peptide measurement in acute decompensated heart failure (ADHF): a systematic review. Heart Fail Rev. 2014;19:507 19. 30. Hill SA, Booth RA, Santaguida PL, et al. Use of BNP and NT-proBNP for the diagnosis of heart failure in the emergency department: a systematic review of the evidence. Heart Fail Rev. 2014;19:421 38. 31. Costello-Boerrigter LC, Boerrigter G, Redfield MM, et al. Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the gener- al community: determinants and detection of left ventricular dysfunction. J Am Coll Cardiol. 2006;47:345 53. 32. de Lemos JA, McGuire DK, Khera A, et al. Screening the population for left ventricular hypertrophy and left ventricular systolic dysfunction us- ing natriuretic peptides: results from the Dallas Heart Study. Am Heart J. 2009;157:746 53. 33. Goetze JP, Mogelvang R, Maage L, et al. Plasma pro-B-type natriuretic peptide in the general population: screening for left ventricular hypertro- phy and systolic dysfunction. Eur Heart J. 2006;27:3004 10. 34. Ng LL, Loke IW, Davies JE, et al. Community screening for left ventricular systolic dysfunction using plasma and urinary natriuretic peptides. J Am Coll Cardiol. 2005;45:1043 50. 35. Ho JE, Liu C, Lyass A, et al. Galectin-3, a marker of cardiac fibrosis, pre- dicts incident heart failure in the community. J Am Coll Cardiol. 2012;60: 1249 56. 36. Wang TJ, Wollert KC, Larson MG, et al.


2012;60: 1249 56. 36. Wang TJ, Wollert KC, Larson MG, et al. Prognostic utility of novel bio- markers of cardiovascular stress: the Framingham Heart Study. Circulation. 2012;126:1596 604. 37. Xanthakis V, Larson MG, Wollert KC, et al. Association of novel biomark- ers of cardiovascular stress with left ventricular hypertrophy and dysfunc- tion: implications for screening. J Am Heart Assoc. 2013;2:e000399. 38. Anwaruddin S, Lloyd-Jones DM, Baggish A, et al. Renal function, con- gestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. J Am Coll Cardiol. 2006;47:91 7. 39. Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002;40:976 82. 40. Wang TJ, Larson MG, Levy D, et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol. 2002;90:254 8. Yancy et al 41. Chang AY, Abdullah SM, Jain T, et al. Associations among androgens, estrogens, and natriuretic peptides in young women: observations from the Dallas Heart Study. J Am Coll Cardiol. 2007;49:109 16. 42. Clerico A, Giannoni A, Vittorini S, et al. The paradox of low BNP levels in obesity. Heart Fail Rev. 2012;17:81 96. 43. De Vecchis R, Esposito C, Di Biase G, et al. B-type natriuretic peptide- guided versus symptom-guided therapy in outpatients with chronic heart failure: a systematic review with meta-analysis. J Cardiovasc Med (Hager- stown). 2014;15:122 34. 44. Felker GM, Hasselblad V, Hernandez AF, et al. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am Heart J. 2009;158:422 30. 45. Li P, Luo Y, Chen YM. B-type natriuretic peptide-guided chronic heart failure therapy: a meta-analysis of 11 randomised controlled trials. Heart Lung Circ. 2013;22:852 60. 46.


B-type natriuretic peptide-guided chronic heart failure therapy: a meta-analysis of 11 randomised controlled trials. Heart Lung Circ. 2013;22:852 60. 46. Porapakkham P, Porapakkham P, Zimmet H, et al. B-type natriuretic peptide-guided heart failure therapy: a meta-analysis. Arch Intern Med. 2010;170:507 14. 47. Savarese G, Trimarco B, Dellegrottaglie S, et al. Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2686 patients in 12 randomized trials. PLoS One. 2013;8:e58287. 48. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mor- tality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35:1559 67. 49. Xin W, Lin Z, Mi S. Does B-type natriuretic peptide-guided therapy im- prove outcomes in patients with chronic heart failure? A systematic re- view and meta-analysis of randomized controlled trials. Heart Fail Rev. 2015;20:69 80. 50. Berger R, Moertl D, Peter S, et al. N-terminal pro-B-type natriuretic pep- tide-guided, intensive patient management in addition to multidisciplinary care in chronic heart failure: a 3-arm, prospective, randomized pilot study. J Am Coll Cardiol. 2010;55:645 53. 51. Eurlings LW, van Pol PE, Kok WE, et al. Management of chronic heart fail- ure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. J Am Coll Cardiol. 2010;56:2090 100. 52. Gaggin HK, Mohammed AA, Bhardwaj A, et al. Heart failure outcomes and benefits of NT-proBNP-guided management in the elderly: results from the prospective, randomized ProBNP outpatient tailored chronic heart failure therapy (PROTECT) study. J Card Fail. 2012;18:626 34. 53. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide- guided therapy to improve outcome in heart failure: the STARS-BNP Mul- ticenter Study. J Am Coll Cardiol. 2007;49:1733 9. 54.


Plasma brain natriuretic peptide- guided therapy to improve outcome in heart failure: the STARS-BNP Mul- ticenter Study. J Am Coll Cardiol. 2007;49:1733 9. 54. Karlstrom P, Alehagen U, Boman K, et al. Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a signifi- cantly better outcome. Eur J Heart Fail. 2011;13:1096 103. 55. Lainchbury JG, Troughton RW, Strangman KM, et al. N-terminal pro-B- type natriuretic peptide-guided treatment for chronic heart failure: results from the BATTLESCARRED (NT-proBNP-Assisted Treatment To Lessen Serial Cardiac Readmissions and Death) trial. J Am Coll Cardiol. 2009;55:53 60. 56. Persson H, Erntell H, Eriksson B, et al. Improved pharmacological therapy of chronic heart failure in primary care: a randomized Study of NT-proBNP Guided Management of Heart Failure SIGNAL-HF (Swedish Intervention study Guidelines and NT-proBNP AnaLysis in Heart Failure). Eur J Heart Fail. 2010;12:1300 8. 57. Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in El- derly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA. 2009;301:383 92. 58. Shah MR, Califf RM, Nohria A, et al. The STARBRITE trial: a randomized, pilot study of B-type natriuretic peptide-guided therapy in patients with advanced heart failure. J Card Fail. 2011;17:613 21. 59. Troughton RW, Frampton CM, Yandle TG, et al. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) con- centrations. Lancet. 2000;355:1126 30. 60. Singer AJ, Birkhahn RH, Guss D, et al. Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT II): a randomized controlled trial of the effect of serial B-type natriuretic peptide testing on patient management. Circ Heart Fail. 2009;2:287 93. 61. Stienen S, Salah K, Moons AH, et al.


2009;2:287 93. 61. Stienen S, Salah K, Moons AH, et al. Rationale and design of PRIMA II: A multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a pre- defined NT-PRoBNP target on the reduction of readmIssion and Mortality rAtes. Am Heart J. 2014;168:30 6. 62. Stienen S. PRIMA II: can NT-pro-brain-natriuretic peptide (NT-proBNP) guided therapy during admission for acute heart failure reduce mortality and readmissions? J Card Fail. 2016;22:939 40. 63. Kociol RD, Pang PS, Gheorghiade M, et al. Troponin elevation in heart fail- ure prevalence, mechanisms, and clinical implications. J Am Coll Cardiol. 2010;56:1071 8. management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344 426. 65. Masson S, Anand I, Favero C, et al. Serial measurement of cardiac tro- ponin T using a highly sensitive assay in patients with chronic heart fail- ure: data from 2 large randomized clinical trials. Circulation. 2012;125: 280 8. 66. Savarese G, Musella F, D'Amore C, et al. Changes of natriuretic peptides predict hospital admissions in patients with chronic heart failure: a meta- analysis. J Am Coll Cardiol HF. 2014;2:148 58. 67. de Lemos JA. Increasingly sensitive assays for cardiac troponins: a review. JAMA. 2013;309:2262 9. 68. de Boer RA, Daniels LB, Maisel AS, et al. State of the Art: Newer biomark- ers in heart failure. Eur J Heart Fail. 2015;17:559 69. 69. Gopal DM, Sam F. New and emerging biomarkers in left ventricular sys- tolic dysfunction insight into dilated cardiomyopathy. J Cardiovasc Transl Res. 2013;6:516 27. 70. O'Meara E, de DS, Rouleau JL, et al. Circulating biomarkers in patients with heart failure and preserved ejection fraction. Curr Heart Fail Rep. 2013;10:350 8. 71.


Circulating biomarkers in patients with heart failure and preserved ejection fraction. Curr Heart Fail Rep. 2013;10:350 8. 71. Karayannis G, Triposkiadis F, Skoularigis J, et al. The emerging role of Ga- lectin-3 and ST2 in heart failure: practical considerations and pitfalls using novel biomarkers. Curr Heart Fail Rep. 2013;10:441 9. 72. Ahmad T, Fiuzat M, Neely B, et al. Biomarkers of myocardial stress and fibrosis as predictors of mode of death in patients with chronic heart fail- ure. J Am Coll Cardiol HF. 2014;2:260 8. 73. Bayes-Genis A, de AM, Vila J, et al. Head-to-head comparison of 2 myo- cardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 versus galectin-3. J Am Coll Cardiol. 2014;63:158 66. 74. Gaggin HK, Szymonifka J, Bhardwaj A, et al. Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure. J Am Coll Cardiol HF. 2014;2:65 72. 75. Ky B, French B, Levy WC, et al. Multiple biomarkers for risk prediction in chronic heart failure. Circ Heart Fail. 2012;5:183 90. 76. Sabatine MS, Morrow DA, de Lemos JA, et al. Evaluation of mul- tiple biomarkers of cardiovascular stress for risk prediction and guiding medical therapy in patients with stable coronary disease. Circulation. 2012;125:233 40. 77. Ahmad T, Fiuzat M, Pencina MJ, et al. Charting a roadmap for heart failure biomarker studies. J Am Coll Cardiol HF. 2014;2:477 88. 78. Miller WL, Hartman KA, Grill DE, et al. Serial measurements of midre- gion proANP and copeptin in ambulatory patients with heart failure: in- cremental prognostic value of novel biomarkers in heart failure. Heart. 2012;98:389 94. 79. Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomark- ers and extracellular communicators in cardiovascular disease? Circ Res. 2012;110:483 95. 80.


Circulating microRNAs: novel biomark- ers and extracellular communicators in cardiovascular disease? Circ Res. 2012;110:483 95. 80. Wong LL, Armugam A, Sepramaniam S, et al. Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction. Eur J Heart Fail. 2015;17:393 404. 81. Ovchinnikova ES, Schmitter D, Vegter EL, et al. Signature of circulat- ing microRNAs in patients with acute heart failure. Eur J Heart Fail. 2016;18:414 23. 82. Shah SH, Kraus WE, Newgard CB. Metabolomic profiling for the identifi- cation of novel biomarkers and mechanisms related to common cardio- vascular diseases: form and function. Circulation. 2012;126:1110 20. 83. Cheng ML, Wang CH, Shiao MS, et al. Metabolic disturbances identified in plasma are associated with outcomes in patients with heart failure: diagnostic and prognostic value of metabolomics. J Am Coll Cardiol. 2015;65:1509 20. 84. Zheng Y, Yu B, Alexander D, et al. Associations between metabolomic compounds and incident heart failure among African Americans: the ARIC Study. Am J Epidemiol. 2013;178:534 42. 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES 85. Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF random- ized trial. JAMA. 2013;310:66 74. 86. Huelsmann M, Neuhold S, Resl M, et al. PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial. J Am Coll Cardiol. 2013;62:1365 72. 87. Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic pep- tide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003;107:1278 83. 88. Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide pre- dicts sudden death in patients with chronic heart failure. Circulation. 2002;105:2392 7. 89.


B-type natriuretic peptide pre- dicts sudden death in patients with chronic heart failure. Circulation. 2002;105:2392 7. 89. Forfia PR, Watkins SP, Rame JE, et al. Relationship between B-type natri- uretic peptides and pulmonary capillary wedge pressure in the intensive care unit. J Am Coll Cardiol. 2005;45:1667 71. 90. Maeda K, Tsutamoto T, Wada A, et al. High levels of plasma brain natri- uretic peptide and interleukin-6 after optimized treatment for heart fail- ure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol. 2000;36:1587 93. 91. Neuhold S, Huelsmann M, Strunk G, et al. Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure: prediction of death at dif- ferent stages of the disease. J Am Coll Cardiol. 2008;52:266 72. 92. Taub PR, Daniels LB, Maisel AS. Usefulness of B-type natriuretic peptide levels in predicting hemodynamic and clinical decompensation. Heart Fail Clin. 2009;5:169 75. 93. Bettencourt P, Azevedo A, Pimenta J, et al. N-terminal-pro-brain natri- uretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110:2168 74. 94. Cheng V, Kazanagra R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decom- pensated heart failure: a pilot study. J Am Coll Cardiol. 2001;37:386 91. 95. Fonarow GC, Peacock WF, Horwich TB, et al. Usefulness of B-type natri- uretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE. Am J Cardiol. 2008;101:231 7. 96. Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol. 2004;43:635 41. 97. Maisel A, Hollander JE, Guss D, et al.


2004;43:635 41. 97. Maisel A, Hollander JE, Guss D, et al. Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT). A multi- center study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath. J Am Coll Cardiol. 2004;44:1328 33. 98. Zairis MN, Tsiaousis GZ, Georgilas AT, et al. Multimarker strategy for the prediction of 31 days cardiac death in patients with acutely decompen- sated chronic heart failure. Int J Cardiol. 2010;141:284 90. 99. Peacock WFI, De Marco T, Fonarow GC, et al. Cardiac troponin and out- come in acute heart failure. N Engl J Med. 2008;358:2117 26. 100. Lee DS, Stitt A, Austin PC, et al. Prediction of heart failure mortality in emergent care: a cohort study. Ann Intern Med. 2012;156:767 75. 101. Santaguida PL, Don-Wauchope AC, Oremus M, et al. BNP and NT-proBNP as prognostic markers in persons with acute decompensated heart fail- ure: a systematic review. Heart Fail Rev. 2014;19:453 70. 102. Horwich TB, Patel J, MacLellan WR, et al. Cardiac troponin I is associ- ated with impaired hemodynamics, progressive left ventricular dysfunc- tion, and increased mortality rates in advanced heart failure. Circulation. 2003;108:833 8. 103. Ilva T, Lassus J, Siirila-Waris K, et al. Clinical significance of cardiac tropo- nins I and T in acute heart failure. Eur J Heart Fail. 2008;10:772 9. 104. Dhaliwal AS, Deswal A, Pritchett A, et al. Reduction in BNP levels with treatment of decompensated heart failure and future clinical events. J Card Fail. 2009;15:293 9. 105. O'Connor CM, Hasselblad V, Mehta RH, et al. Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol. 2010;55:872 8. 106.


Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol. 2010;55:872 8. 106. O'Brien RJ, Squire IB, Demme B, et al. Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF. Eur J Heart Fail. 2003;5:499 506. 107. Cohen-Solal A, Logeart D, Huang B, et al. Lowered B-type natriuretic peptide in response to levosimendan or dobutamine treatment is associ- ated with improved survival in patients with severe acutely decompen- sated heart failure. J Am Coll Cardiol. 2009;53:2343 8. 108. Salah K, Kok WE, Eurlings LW, et al. A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporat- ing N-terminal pro-B-type natriuretic peptide levels: a European coLlabo- ration on Acute decompeNsated Heart Failure: ELAN-HF Score. Heart. 2014;100:115 25. 109. Flint KM, Allen LA, Pham M, et al. B-type natriuretic peptide predicts 30- day readmission for heart failure but not readmission for other causes. J Am Heart Assoc. 2014;3:e000806. 110. Kociol RD, Horton JR, Fonarow GC, et al. Admission, discharge, or change in B-type natriuretic peptide and long-term outcomes: data from Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) linked to Medicare claims. Circ Heart Fail. 2011;4:628 36. 111. Kociol RD, McNulty SE, Hernandez AF, et al. Markers of decongestion, dyspnea relief, and clinical outcomes among patients hospitalized with acute heart failure. Circ Heart Fail. 2013;6:240 5. 112. Verdiani V, Ognibene A, Rutili MS, et al. NT-ProBNP reduction percent- age during hospital stay predicts long-term mortality and readmission in heart failure patients. J Cardiovasc Med (Hagerstown). 2008;9:694 9. 113. Bayes-Genis A, Lopez L, Zapico E, et al.


2008;9:694 9. 113. Bayes-Genis A, Lopez L, Zapico E, et al. NT-ProBNP reduction percentage during admission for acutely decompensated heart failure predicts long- term cardiovascular mortality. J Card Fail. 2005;11:S3 8. 114. Alonso-Martinez JL, Llorente-Diez B, Echegaray-Agara M, et al. C-reactive protein as a predictor of improvement and readmission in heart failure. Eur J Heart Fail. 2002;4:331 6. 115. Dieplinger B, Gegenhuber A, Kaar G, et al. Prognostic value of estab- lished and novel biomarkers in patients with shortness of breath attend- ing an emergency department. Clin Biochem. 2010;43:714 9. 116. Januzzi JL Jr, Peacock WF, Maisel AS, et al. Measurement of the inter- leukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol. 2007;50:607 13. 117. Manzano-Fernandez S, Mueller T, Pascual-Figal D, et al. Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction. Am J Cardiol. 2011;107:259 67. 118. Rehman SU, Mueller T, Januzzi JL Jr. Characteristics of the novel interleu- kin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol. 2008;52:1458 65. 119. Shah RV, Chen-Tournoux AA, Picard MH, et al. Galectin-3, cardiac struc- ture and function, and long-term mortality in patients with acutely de- compensated heart failure. Eur J Heart Fail. 2010;12:826 32. 120. de Boer RA, Lok DJ, Jaarsma T, et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med. 2011;43:60 8. 121. Lok DJ, van der Meer P, de la Porte PW, et al. Prognostic value of galec- tin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study.


Prognostic value of galec- tin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clin Res Cardiol. 2010;99:323 8. 122. Tang WH, Shrestha K, Shao Z, et al. Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. Am J Cardiol. 2011;108:385 90. 123. Tang WH, Wu Y, Grodin JL, et al. Prognostic Value of Baseline and Changes in Circulating Soluble ST2 Levels and the Effects of Nesiritide in Acute Decompensated Heart Failure. J Am Coll Cardiol HF. 2016;4:68 77. 124. Januzzi JL, Mebazaa A, Di SS. ST2 and prognosis in acutely decompen- sated heart failure: the International ST2 Consensus Panel. Am J Cardiol. 2015;115:26B 31B. 125. Mebazaa A, Di SS, Maisel AS, et al. ST2 and multimarker testing in acute decompensated heart failure. Am J Cardiol. 2015;115:38B 43B. 126. Fermann GJ, Lindsell CJ, Storrow AB, et al. Galectin 3 complements BNP in risk stratification in acute heart failure. Biomarkers. 2012;17:706 13. 127. Lassus J, Gayat E, Mueller C, et al. Incremental value of biomarkers to clinical variables for mortality prediction in acutely decompensated heart failure: the Multinational Observational Cohort on Acute Heart Failure (MOCA) study. Int J Cardiol. 2013;168:2186 94. 128. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429 35. 129. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991;325:293 302. 130. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, Yancy et al lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation.


Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, Yancy et al lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;100:2312 8. 131. Pfeffer MA, Braunwald E, Moy LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocar- dial infarction: results of the Survival and Ventricular Enlargement Trial. The SAVE Investigators. N Engl J Med. 1992;327:669 77. 132. Effect of ramipril on mortality and morbidity of survivors of acute myocar- dial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993;342:821 8. 133. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the an- giotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333:1670 6. 134. Cohn JN, Tognoni G, Investigators VHFT. A randomized trial of the angio- tensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667 75. 135. Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893 906. 136. Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose ver- sus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374: 1840 8. 137. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759 66. 138. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibi- tion versus enalapril in heart failure. N Engl J Med. 2014;371:993 1004. 139.


Angiotensin-neprilysin inhibi- tion versus enalapril in heart failure. N Engl J Med. 2014;371:993 1004. 139. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001 7. 140. Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194 9. 141. Eschalier R, McMurray JJV, Swedberg K, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening re- nal function: analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol. 2013;62:1585 93. 142. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709 17. 143. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995;273:1450 6. 144. Woodard-Grice AV, Lucisano AC, Byrd JB, et al. Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenet Genomics. 2010;20:532 6. 145. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547 59. 146. Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intol- erant to angiotensin-converting enzyme inhibitors: a randomised con- trolled trial. Lancet. 2008;372:1174 83. 147. Entresto [package insert]. Hanover, NJ: Novartis Pharmaceuticals Corporation, 2015. 148. Packer M, Califf RM, Konstam MA, et al.


Hanover, NJ: Novartis Pharmaceuticals Corporation, 2015. 148. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106:920 6. 149. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in pa- tients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17:103 11. 150. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin- angiotensin system inhibition for the treatment of heart failure. J Am Coll Cardiol HF. 2014;2:663 70. 151. Messerli FH, Nussberger J. Vasopeptidase inhibition and angio-oedema. Lancet. 2000;356:608 9. 152. Braunwald E. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure. J Am Coll Cardiol. 2015;65:1029 41. 153. Ruilope LM, Dukat A, B hm M, et al. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active com- parator study. Lancet. 2010;375:1255 66. 154. Bohm M, Robertson M, Ford I, et al. Influence of cardiovascular and non- cardiovascular co-morbidities on outcomes and treatment effect of heart rate reduction with ivabradine in stable heart failure (from the SHIFT Trial). Am J Cardiol. 2015;116:1890 7. 155. Swedberg K, Komajda M, B hm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875 85. 156. Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371:1091 9. 157. Fox K, Ford I, Steg PG, et al. Ivabradine for patients with stable coro- nary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372: 807 16. 158. Pitt B, Segal R, Martinez FA, et al.


2008;372: 807 16. 158. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349:747 52. 159. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial in- farction. N Engl J Med. 2003;348:1309 21. 160. Authors CI. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a ran- domised trial. Lancet. 1999;353:9 13. 161. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651 8. 162. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide di- nitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049 57. 163. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314:1547 52. 164. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206 52. 165. Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557 62. 166. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383 92. 167. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131:34 42. 168. Edelmann F, Wachter R, Schmidt AG, et al.


2015;131:34 42. 168. Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA. 2013;309:781 91. 169. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777 81. 170. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456 67. 171. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015;373:2314 24. 172. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiester- ase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268 77. 173. Anker SD, Comin CJ, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436 48. 174. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in pa- tients with symptomatic heart failure and iron deficiency. Eur Heart J. 2015;36:657 68. 175. Kapoor M, Schleinitz MD, Gemignani A, et al. Outcomes of patients with chronic heart failure and iron deficiency treated with intrave- nous iron: a meta-analysis. Cardiovasc Hematol Disord. Drug Targets. 2013;13:35 44. 176. Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbe- poetin alfa in systolic heart failure. N Engl J Med. 2013;368:1210 19. 177. Cleland JG, Sullivan JT, Ball S, et al.


2013;368:1210 19. 177. Cleland JG, Sullivan JT, Ball S, et al. Once-monthly administration of dar- bepoetin alfa for the treatment of patients with chronic heart failure 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES and anemia: a pharmacokinetic and pharmacodynamic investigation. J Cardiovasc Pharmacol. 2005;46:155 61. 178. Klapholz M, Abraham WT, Ghali JK, et al. The safety and tolerability of darbepoetin alfa in patients with anaemia and symptomatic heart failure. Eur J Heart Fail. 2009;11:1071 7. 179. Ponikowski P, Anker SD, Szachniewicz J, et al. Effect of darbepoetin alfa on exercise tolerance in anemic patients with symptomatic chronic heart failure: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2007;49:753 62. 180. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001;37:1775 80. 181. van der Meer P, Groenveld HF, Januzzi JL Jr, et al. Erythropoietin treat- ment in patients with chronic heart failure: a meta-analysis. Heart. 2009;95:1309 14. 182. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J. 2007;28:2208 16. 183. Ghali JK, Anand IS, Abraham WT, et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008;117:526 35. 184. Kotecha D, Ngo K, Walters JA, et al. Erythropoietin as a treatment of anemia in heart failure: systematic review of randomized trials. Am Heart J. 2011;161:822 31. 185. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299:914 24. 186.


Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299:914 24. 186. Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoi- etins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708 14. 187. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoe- tin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019 32. 188. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008;74:791 8. 189. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387:435 43. 190. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 7. Effects of more vs. less inten- sive blood pressure lowering and different achieved blood pressure levels - updated overview and meta-analyses of randomized trials. J Hypertens. 2016;34:613 22. 191. Wright JT Jr, Williamson JD, Whelton PK, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373:2103 16. 192. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs stan- dard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: A randomized clinical trial. JAMA. 2016;315:2673 82. 193. Lv J, Ehteshami P, Sarnak MJ, et al. Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic re- view and meta-analysis. CMAJ. 2013;185:949 57. 194. Deleted in press. 195. Aronow WS, Fleg JL, Pepine CJ, et al.


Deleted in press. 195. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consen- sus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. Circulation. 2011;123:2434 506. 196. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. 197. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no pro- pranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction > or = 40% treated with diuretics plus angiotensin-converting enzyme inhibitors. Am J Cardiol. 1997;80:207 9. 198. van Veldhuisen DJ, Cohen-Solal A, Bohm M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol. 2009;53:2150 58. 199. Piller LB, Baraniuk S, Simpson LM, et al. Long-term follow-up of participants with heart failure in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Circulation. 2011;124:1811 8. 200. Arzt M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115:3173 80. 201.


Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115:3173 80. 201. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive air- way pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353:2025 33. 202. MacDonald M, Fang J, Pittman SD, et al. The current prevalence of sleep disordered breathing in congestive heart failure patients treated with beta-blockers. J Clin Sleep Med. 2008;4:38 42. 203. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. N Engl J Med. 2015;373:1095 105. 204. McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovas- cular events in obstructive sleep apnea. N Engl J Med. 2016;375:919 31. 205. Holmqvist F, Guan N, Zhu Z, et al. Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in pa- tients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J. 2015;169:647 54. Yancy et al Appendix 1.


Am Heart J. 2015;169:647 54. Yancy et al Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure (December 2015) Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals By Section* Clyde W. Yancy, Chair Northwestern University Feinberg School of Medicine, Division of Cardiology Professor of Medicine and Chief; Diversity and Inclusion Vice Dean None None None None None None None Mariell Jessup, Vice Chair Fondation Leducq Chief Scientific Officer None None None None None None None Biykem Bozkurt Baylor College of Medicine, Department of Medicine Professor of Medicine; Cardiology Section, DeBakey VA Medical Center Chief; The Mary and Gordon Cain Chair & W.A. Tex and Deborah Moncrief, Jr. Chair; Winters Center for Heart Failure Research Director; Cardiovascular Research Institute Associate Director None None None Novartis None None 7.3.2.10, 9.5. Javed Butler Stony Brook University Division Chief of Cardiology Bayer Boehringer Ingelheim CardioCell Luitpold Medtronic Merck Novartis Relypsa Takeda Trevena Z Pharma Zensun Novartis None Amgen (DSMB) None None 7.3.2.10, 9.5. Donald E. Casey, Jr Thomas Jefferson College of Population Health Faculty; Alvarez & Marsal Founder None None None None None None None Monica M. Colvin University of Michigan Associate Professor of Medicine, Cardiology None None None None None None None Mark H. Drazner University of Texas Southwestern Medical Center Professor, Internal Medicine None None None None None None None Gerasimos S. Filippatos National and Kapodistrian University of Athens; Attikon University Hospital, Department of Cardiology, Heart Failure Unit Professor of Cardiology None None None Bayer Bayer (DSMB) Novartis Servier Pharmaceuticals Vifor None None 7.3.2.10, and 9.5.


Donald E. Casey, Jr Thomas Jefferson College of Population Health Faculty; Alvarez & Marsal Founder None None None None None None None Monica M. Colvin University of Michigan Associate Professor of Medicine, Cardiology None None None None None None None Mark H. Drazner University of Texas Southwestern Medical Center Professor, Internal Medicine None None None None None None None Gerasimos S. Filippatos National and Kapodistrian University of Athens; Attikon University Hospital, Department of Cardiology, Heart Failure Unit Professor of Cardiology None None None Bayer Bayer (DSMB) Novartis Servier Pharmaceuticals Vifor None None 7.3.2.10, and 9.5. Gregg C. Fonarow Ahmanson-UCLA Cardiomyopathy Center Director; UCLA Division of Cardiology Co-Chief Amgen Janssen Pharmaceuticals Novartis None None Novartis None None 7.3.2.10, 9.5. (Continued) 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES Michael M. Givertz Brigham and Women's Hospital Professor of Medicine Merck Novartis None None None None None 7.3.2.10, 9.5. Steven M. Hollenberg Cooper University Hospital Director, Coronary Care Unit, Professor of Medicine None None None None None None None JoAnn Lindenfeld Vanderbilt Heart and Vascular Institute Director, Advanced Heart Failure and Transplant Section Professor of Medicine Abbott Janssen Pharmaceuticals Novartis Relypsa ResMed None None AstraZeneca Novartis None None 6.3, and 9.6.


Steven M. Hollenberg Cooper University Hospital Director, Coronary Care Unit, Professor of Medicine None None None None None None None JoAnn Lindenfeld Vanderbilt Heart and Vascular Institute Director, Advanced Heart Failure and Transplant Section Professor of Medicine Abbott Janssen Pharmaceuticals Novartis Relypsa ResMed None None AstraZeneca Novartis None None 6.3, and 9.6. Frederick A. Masoudi University of Colorado, Anschutz Medical Campus Professor of Medicine, Division of Cardiology None None None None None None None Patrick E. McBride University of Wisconsin School of Medicine and Public Health Professor of Medicine and Family Medicine; Associate Director, Preventive Cardiology None None None None None None None Pamela N. Peterson University of Colorado, Denver Health Medical Center Associate Professor of Medicine, Division of Cardiology None None None None None None None Lynne Warner Stevenson Brigham and Women s Hospital Cardiovascular Division Director, Cardiomyopathy and Heart Failure Program None None None Novartis PARENT trial (PI) NHLBI INTERMACS (Co PI) None None 7.3.2.10, 9.5. Cheryl Westlake Azusa Pacific University, School of Nursing, Doctoral Programs Professor None None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year.


A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC/AHA, a person has a relevant relationship IF: a) The relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person s household has a reasonable potential for financial, professional, or other personal gain or loss as a result of the issues/content addressed in the document. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Significant relationship. ACC indicates American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; DCRI, Duke Clinical Research Institute; DSMB, data safety monitoring board; HFSA, Heart Failure Society of America; NHLBI, National Heart, Lung, and Blood Institute; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; PARENT, Pulmonary artery pressure reduction with entresto; UCLA, University of California, Los Angeles; and VA, Veterans Affairs. Appendix 1.


ACC indicates American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; DCRI, Duke Clinical Research Institute; DSMB, data safety monitoring board; HFSA, Heart Failure Society of America; NHLBI, National Heart, Lung, and Blood Institute; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; PARENT, Pulmonary artery pressure reduction with entresto; UCLA, University of California, Los Angeles; and VA, Veterans Affairs. Appendix 1. Continued Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals By Section* Yancy et al Appendix 2.