Disclosures. Overview. Goal statement. Advances in Chronic Heart Failure Management 10/12/17

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1 Disclosures Advances in Chronic Heart Failure Management I have nothing to disclose Van N Selby, MD UCSF Advanced Heart Failure Program October 12, 2017 Goal statement To review recently-approved therapies and updates to practice guidelines for chronic heart failure Overview New pharmacologic therapies for heart failure with reduced ejection fraction (HFrEF) New pharmacologic options for heart failure with preserved ejection fraction (HFpEF) Remote hemodynamic monitoring for heart failure Anemia and iron deficiency as a therapeutic target in chronic heart failure 1

2 Medical Therapy for HFrEF: 2013 ACE Inhibitors (Class Ia) o ARB as an alternative (Class Ia) Beta-blockers (Class Ia) Mineralocorticoid receptor antagonists (Class Ia) Hydralazine/Isosorbide for African-Americans (Class Ia) Other: Diuretics, digoxin, etc Yancy CW et al, Circulation 2013 PARADIGM-HF 8442 patients with class II, III, or IV chronic heart failure o EF < 35-40% o SBP 95, GFR 30, K 5.4 o Tolerated enalapril 10 mg daily or equivalent for 4 weeks Randomized to enalapril 20 mg daily vs sacubitril-valsartan 400 mg daily Primary outcome was a composite of cardiovascular death or HF hospitalization McMurray JJV et al, N Engl J Med

3 PARADIGM-HF 2016 Guideline Update Sacubitril-Valsartan also associated with decreases in: o CV Death o HF Hospitalization o All-cause mortality Subgroup analysis showed the benefit was seen in NYHA class I/II, but not III/IV Yancy, CW et al. Circulation Guideline Update Sacubitril/Valsartan (Entresto TM ) III: Harm B-R the rare complication of angioedema (30). ARNI should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor (31, 32). Oral neprilysin inhibitors, used in combination with ACE inhibitors can lead to Starting dose is 49/51 mg BID o Start with a reduced dose of 24/26 mg for those not previously taking ACE/ARB, or those on a low dose 36 hour washout period Double the dose after 2-4 weeks to a target dose of 97/103 mg The rate of hypotension was slightly higher than with enalapril, but did not lead to higher rates of study drug discontinuation $4500/year Yancy, CW et al. Circulation

4 Compared to enalapril, sacubitril/valsartan is: Associated with reduced risk of hyperkalemia when combined with al aldosterone antagonist 1 No more likely to cause severe hypotensive events 2 More cost-effective 3 Ivabradine: The SHIFT Trial Heart rate is an independent predictor of mortality in heart failure Ivabradine is an inhibitor of the I f current in the SA node The SHIFT trial randomized 6558 patients: o Symptomatic HF with LVEF 35% o HR 70 in sinus rhythm o HF hospitalization in the past year o On background HF therapy including BB if tolerated Ivabradine (titrated to a max of 7.5 mg BID) vs placebo 1 Desai AS et al, JAMA Cardiology Vardeny O et al, HFSA Scientific Sessions Gaziano TA et al, JAMA Cardiology 2016 Swedberg K et al, Lancet 2010 SHIFT: HF Death or Hospitalization Patients with primary composite endpoint (%) A 40 Placebo (937 events) Ivabradine (793 events) HR 0 82 (95% CI ), p< Patients with first hospital admission SHIFT Trial: Considerations No patients enrolled from the US Only 23% were on target dose beta-blocker o Average systolic BP was 122 mmhg at enrollment o There was no significant improvement in the primary outcome among patients taking at least 50% target dose beta-blocker at randomization Months Number at risk Placebo group Ivabradine group C Swedberg K et al, Lancet

5 2016 Guideline Update Spironolactone for HFpEF Recommendation for Ivabradine COR LOE Recommendation 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 (37-40). Ivabradine is a new therapeutic agent that selectively inhibits the I current in Approximately 50% of all patients with heart failure have preserved ejection fraction No medical therapy has been proven to improve outcomes for these patients Mineralocorticoid receptor antagonists (MRA) improve outcomes in HFrEF and post-mi with LV dysfunction Small studies suggested MRAs may improve diastolic function Yancy, CW et al. Circulation 2016 TOPCAT: Spironolactone for HFpEF The TOPCAT trial randomized patients with HFpEF to spironolactone vs placebo No significant difference in the primary composite outcome of cardiovascular death, aborted cardiac arrest, or HF hospitalization BUT, there were significant differences in the patient populations depending on country TOPCAT: Americas Sub-Analysis Among patients randomized to placebo, those from the Americas had much higher event rates than those from Russia/Georgia Patients from the Americas appeared to have much higher-risk baseline characteristics in general Pitt B, NEJM 2014 Pfeffer MA et al, Circulation

6 Pfeffer et al Regional Variation in TOPCAT 39 relative to placebo was greater in the Americas (0.26 mmol/l; P<0.001) than in Russia/Georgia (0.08 mmol/l; P<0.001; interaction P<0.001), and the average magnitude of the increase in creatinine associated with spironolactone relative to placebo was greater in the Americas (0.10 mg/dl; P<0.001) than in Russia/ ACCEPTED Georgia (0.02 mmol/l; P=0.002; interaction P<0.001). These 3 differences in magnitude of treatment response similarly peryancy, et. al.using these serial measurements. sisted in adjusted models 2017 ACC/AHA/HFSA Heart Failure Focused Update HR 0.82 Regional Variation in TOPCAT Discussion relative to placebo was greater in the Americas (0.26 mmol/l; P<0.001) than in Russia/Georgia (0.08 mmol/l; P<0.001; interaction P<0.001), and the average magnitude of the increase in creatinine associated with spironolactone relative to placebo was greater in the Americas (0.10 mg/dl; P<0.001) than in Russia/ Georgia (0.02 mmol/l; P=0.002; interaction P<0.001). These 3 differences in magnitude of treatment response similarly persisted in adjusted models using these serial measurements. HR 0.74 Discussion This post hoc analysis was based on the observation of an unusually large difference in the placebo event rates between the sites 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA of Heart Failure 39 conducting TOPCAT in the 4 Guideline countries in the Americas com-management for the pared with those in Russia and Georgia.14 In addition to the marked differences in prognosis, this regional analysis revealed many additional important dissimilarities in patient characteristics; the potassium, creatinine, and American blood pressurecollege responsesof to Cardiology/American Heart Association Task Force A Report of the spironolactone; and reports adherencepractice to study medications. on of Clinical Guidelines and the Heart Failure Society of America Regional differences have complicated the interpretations of other randomized trials in cardiovascular medicine.1 7,20 22 The Developed in Collaboration with the American Academy of Family Physicians, American prior observed pattern of fewer events in patients from Eastern College Chest in Physicians, and Russia International Society for Heart and Lung Transplantation have beenofamplified TOPCAT because Europe2,5,7 may and Georgia contributed 49% of the total enrollment. However, the observed difference between regions in TOPCATWRITING is striking GROUP MEMBERS* in magnitude, exceeding that anticipated by variations in practice Clyde Yancy, MD, MSc, MACC, FAHA, FHFSA, Chair patterns; indeed, it is the marked difference in thew. placebo groups Mariell Jessup, MD, FACC, FAHA, Vice Chair that distinguishes this from many previous reports of regional Biykem Bozkurt, MD, PhD, FACC, FAHA* Steven M. Hollenberg, MD, FACC# variation. This observed difference in population risk profiles Javed MPH, FACC, JoAnn Lindenfeld, MD, FACC, FAHA, FHFSA* obfuscates our Butler, ability tomd, unitemba, the results from these 2FAHA* disparate regions to draw conclusions the results the overall study. Donald E. Casey, about Jr, MD, MPH,ofMBA, FACC Frederick A. Masoudi, MD, MSPH, FACC** The regional almost every important basemonica differences M. Colvin,inMD, FAHA Patrick E. McBride, MD, MPH, FACC line variable that clinical diagnostic criteria werefhfsa not Marksuggest H. Drazner, MD, MSc, FACC, FAHA, Pamela N. Peterson, MD, FACC, FAHA Yancy, CW et MD, al. Circulation uniformly interpreted or applied. Making the assessment that Gerasimos S. Filippatos, MD* Lynne Warner Stevenson, FACC* 2017 the dyspnea andc.fatigue of a patient with a FAHA, preservedfhfsa* ejection Gregg Fonarow, MD, FACC, Cheryl Westlake, PhD, RN, ACNS-BC, FAHA, FHFSA fractionmichael are attributed to heart MD, failurefacc, rather FHFSA* than to the comm. Givertz, monly associated comorbidities is notoriously difficult The additional protocol inclusion criterion in TOPCAT of either a prior hospitalization in which heart failure was a prominent feature or an elevated natriuretic peptide level ACC/AHA was intended TASK FORCE MEMBERS to both improve diagnostic certainty and to augment risk. The Glenn N. have Levine, MD, FACC, FAHA, Chair assumption that those with a prior hospitalization would Patrick T.randomO Gara, MD, FACC, FAHA, Chair-Elect patients higher risk31 35 was confirmed only for the Jonathan L. nonadjudicated Halperin, MD, FACC, FAHA, Immediate Past Chair ized from the Americas, suggesting that the qualifying hospitalization criterion enrolled different patientfaha Sana M. Al-Khatib, MD, MHS, FACC, Federico Gentile, MD, FACC populations. However, event rates also Kim K.multifold Birtcher,lower PharmD, MS, were AACC Samuel Gidding, MD, FAHA observed in thebiykem patientsbozkurt, qualifyingmd, by PhD, natriuretic peptides FACC, FAHA Mark A. Hlatky, MD, FACC from Russia/Georgia. event rates of those from RalphThe G. Brindis, MD, MPH,enrolled MACC John Ikonomidis, MD, PhD, FAHA the Americas were reflective of other clinical populations Joaquin E. Cigarroa, MD, trial FACC José Joglar, MD, FACC, FAHA with symptomatic heart failure and preserved ejection fraclesley H. Curtis, PhD, FAHA Susan J. Pressler, PhD, RN, FAHA tion,36,37 whereas the observed heart failure hospitalization rate Lee A. Fleisher, MD, FACC, FAHA Duminda N. Wijeysundera, MD, PhD of 1 per 100 patient-years in the placebo arm of the Russia/ Georgia cohort is quite consistent with rates reported in hypertension trials such as the Antihypertensive and Lipid Lowering *Writing are required to recuse themselves from voting on sections to which their specific relationships with Treatment to Preventgroup Heartmembers Attack Trial (ALLHAT), Valsartan industry may apply; see Appendix 1 for detailed information. ACC/AHA Task Force on Clinical Practice Guidelines Liaison. Antihypertensive Long-Term Use Evaluation (VALUE), and ACC/AHA Representative. ACP Representative. ISHLT Representative. HFSA Representative. #CHEST Representative. Losartan Intervention fortask Endpoint in Hypertension **ACC/AHA ForceReduction on Performance Measures Representative. AAFP Representative. Former Task Force member; (LIFE), andcurrent it is 5-fold the 2 prior memberlower duringthan the writing effort.heart failure with preserved ejection fraction trials, Candesartan in Heart This document was approved by the American College of Cardiology Clinical Policy Approval Committee, the American Heart Failure: Assessment of Reduction in Mortality and Morbidity RI PT Pfeffer et al SC TOPCAT: Americas Sub-Analysis MANUSCRIPT AC C EP TE D M AN U This post hoc analysis was based on the observation of an unusually large difference in the placebo event rates between the sites conducting TOPCAT in the 4 countries in the Americas compared with those in Russia and Georgia.14 In addition to the marked differences in prognosis, this regional analysis revealed many additional important dissimilarities in patient characteristics; the potassium, creatinine, and blood pressure responses to spironolactone; and reports of adherence to study medications. Regional differences have complicated the interpretations of other randomized trials in cardiovascular medicine.1 7,20 22 The Pfeffer MAofetfewer al, events Circulation prior observed pattern in patients2014 from Eastern Europe2,5,7 may have been amplified in TOPCAT because Russia and Georgia contributed 49% of the total enrollment. However, the observed difference between regions in TOPCAT is striking in magnitude, exceeding that anticipated by variations in practice patterns; indeed, it is the marked difference in the placebo groups that distinguishes this from many previous reports of regional variation. This observed difference in population risk profiles obfuscates our ability to unite the results from these 2 disparate regions to draw conclusions about the results of the overall study. FigureThe 1. Kaplan-Meier plots of primary outcome and important 2 regional differences in almost every basemajor components. A, Time to primary outcome; B, time line variable (CV) suggest that clinical criteria were not to cardiovascular death; and C, timediagnostic to first confirmed hospitalization heart failure. uniformly for interpreted or applied. Making the assessment that the dyspnea and fatigue of a patient with a preserved ejection fraction attributed to heartanalysis failurerestricted rather than to the comamplified in are additional sensitivity to patients monly notoriously reported to associated be on studycomorbidities medication at is that visit (Tabledifficult. VIII in the The additional protocol inclusion in TOPCAT of the either a online-only Data Supplement). Allcriterion values obtained through prior hospitalization in which heart failure was a prominent first year of follow-up are shown in Figure 2. The average magfeature an elevated peptide associated level was with intended nitude of theorsystolic blood natriuretic pressure reduction to both improve diagnostic certainty and to risk. The spironolactone relative to placebo was greater in augment the Americas that those within arussia/georgia prior hospitalization would (4.2assumption mm Hg; P<0.001) than (0.6 mm Hg: have confirmed only for patients randomhigherinteraction risk31 35 was P=0.10; P<0.001). Similarly, the the average magnifrom the Americas, nonadjudicated tudeized of the increase in potassiumsuggesting associated that with the spironolactone qualifying hospitalization criterion enrolled different patient Association Science Advisory and Coordinating Committee, the American Heart Association Executive Committee, and the Downloaded fromevent by guestheart on September 13, 2015 populations. However, multifold lower rates were also Failure Society of America Executive Committee in April observed in the patients qualifying by natriuretic peptides The American College of Cardiology requests that this document be cited as follows: Yancy CW, Jessup M, Bozkurt B, Butler J, from Russia/Georgia. The event rates of those enrolled from Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, the Americas were reflective of other clinical trial populations McBride PE, Peterson PN, Stevenson LW, Westlake C ACC/AHA/HFSA focused update of the 2013 ACCF/AHA with symptomatic heart failure and preserved ejection frac36,37 whereas the observed heart failure hospitalization rate tion, of 1 per 100 patient-years in the placebo arm of the Russia/ Georgia cohort is quite consistent with rates reported in hypertension trials such as the Antihypertensive and Lipid Lowering 1 Treatment to Prevent Heart Attack Trial (ALLHAT), Valsartan Antihypertensive Long-Term Use Evaluation (VALUE), and Losartan Intervention for Endpoint Reduction in Hypertension (LIFE), and it is 5-fold lower than the 2 prior heart failure with preserved ejection fraction trials, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity Figure 1. Kaplan-Meier plots of primary outcome and 2 major components. A, Time to primary outcome; B, time to cardiovascular (CV) death; and C, time to first confirmed hospitalization for heart failure. amplified in additional sensitivity analysis restricted to patients reported to be on study medication at that visit (Table VIII in the online-only Data Supplement). All values obtained through the first year of follow-up are shown in Figure 2. The average magnitude of the systolic blood pressure reduction associated with spironolactone relative to placebo was greater in the Americas (4.2 mm Hg; P<0.001) than in Russia/Georgia (0.6 mm Hg: P=0.10; interaction P<0.001). Similarly, the average magnitude of the increase in potassium associated with spironolactone Remote Hemodynamic Monitoring for HF CardioMEMS Downloaded from by guest on September 13, 2015 Adapted from Adamson PB, et al. Curr Heart Fail Reports,

7 CHAMPION TRIAL NYHA Class III heart failure Previous HF hospitalization No ejection fraction criteria Randomized to a wireless implantable hemodynamic monitoring system vs control At least 6 months follow-up Primary outcome: re-hospitalization Abraham WT et al, Lancet 2011 CHAMPION CardioMEMS Risk reduction: 36% Risk reduction: 29% Inserted via venous catheter, requires selective pulmonary angiogram (10 cc) No batteries or leads FDA approved May 2014 Indication: o Wirelessly measuring and monitoring PA and HR o In patients with functional class III heart failure with at least one hospitalization in the past year o Hemodynamic data are used by physicians with the goal of better HF management and to reduce hospitalization Abraham WT et al, Lancet 2011 Abraham WT et al, Lancet

8 Remote PA Pressure Monitoring: NNT Compared to Other HF Therapies Intervention Trial Mean Duration of Randomized Follow-Up Annualized Reduction in HF Hospitalization Rates NNT per year to Prevent 1 HF Hospitalization Beta-blocker COPERNICUS 10 months 33% 7 Aldosterone antagonist RALES 24 months 36% 7 CRT CARE-HF 29 months 52% 7 Beta-blocker MERIT-HF 12 months 29% 15 ACE inhibitor SOLVD 41 months 30% 15 Aldosterone antagonist EMPHASIS-HF 21 months 38% 16 Digoxin DIG 37 months 24% 17 Angiotensin receptor blocker Angiotensin receptor blocker PA pressure monitoring Val-HeFT 23 months 23% 18 CHARM 40 months 27% 19 CHAMPION 17 months 33% 4 CHAMPION According to LVEF Follow-Up (17.6 Months) Ejection Fraction Randomization Group 40% Treatment group (n=62) Control group (n=57) 50% Treatment group (n=35) Control group (n=31) <40% Treatment group (n=208) Control group (n=222) CI indicates confidence interval. No. of Heart Failure Hospitalizations Annualized Rate of Hospitalization for Heart Failure Incidence Rate Ratio (95% CI; P Value) ( ; <0.0001) ( ; <0.0001) ( ; ) Iron Deficiency: A therapeutic Target in HF Iron Deficiency in Heart Failure Anemia is common in HF Treatment of mild to moderate anemia with Epo agents shows no clear benefit and is associated with increased risk of VTE in HF patients Up to 50% of patients with HF have also have iron deficiency o Defective absorption o Reduced availability of iron recycled in the reticuloendothelial system van Veldhuisen, D. J. et al. Nat. Rev. Cardiol

9 FAIR-HF Trial 459 patients with chronic HF and NYHA Class II or III symptoms LVEF 40% if class II or 45% if class III Hgb between 9.5 and 13.5 g/dl Iron deficiency: o Ferritin < 100 μg/l, or: o Ferritin μg/l if transferrin % sat < 20% Randomized to ferric carboxymaltose vs placebo o 200 mg weekly until iron stores normal, then q 4 weeks Anker SD et al, NEJM P<0.001 P<0.001 P< FCM Placebo P<0.001 P<0.001 P< FCM Placebo No. of patients Mean 274±6 294±7 312±6 313±7 distance (m) No. of patients Mean 269±9 269±10 272±10 277±10 distance (m) 21±6 37±7 35±8 P<0.001 P<0.001 P< FCM Placebo P<0.001 P<0.001 P< FCM Placebo No. of patients Mean 54±1 60±1 62±1 63±1 score No. of patients Mean 54±1 54±2 56±2 57±2 score 6±1 6±2 7±2 CONFIRM-HF 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure IPT A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America AC 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 NEW: New evidence consistent with See Online Data Supplement D. if transferrin saturation is <20%), intravenous iron replacement might be reasonable to improve functional status and QoL(173, 174). therapeutic benefit. Routine baseline assessment of all patients with HF includes an evaluation for anemia in addition to other Yancy, CW et al. Circulation 2017 Ponikowski P et al. Eur Heart J

10 Targeting Iron Deficiency in Heart Failure No significant difference in adverse events among those receiving IV iron vs placebo o No allergic reactions with newer formulations The benefits are seen regardless of serum hemoglobin High dose oral iron has not shown the same benefit in clinical trials FAIR-HF 2, a larger trial of IV iron in HF, is underway Advanced Heart Failure: Know the Signs NYHA Class IIIB/IV symptoms Worsening renal function Systolic BP < 90 mmhg Multiple hospitalizations Inability to tolerate ACE inhibitors or beta-blockers o Need to stop or decrease LV ejection fraction < 25% High diuretic dose (> 100 mg/day of furosemide) Lewis GD et al, JAMA 2017 Left Ventricular Assist Device Therapy Adult Heart Transplant: Survival by Era All pair-wise comparisons were significant at p < Median survival (years): =8.5; =10.4; =11.9; /2014=NA J Heart and Lung Transp

11 Conclusions New therapies continue to improve outcomes for patients with HFrEF o Sacubitril/valsartan improves HFrEF outcomes compared to ACEi o Ivabradine may be useful in selected HFrEF patients Consider aldosterone antagonists for appropriately selected patients with HFpEF Remote hemodynamic monitoring reduces heart failure rehospitalizations in patients at risk Patients with chronic HF should be screened for iron deficiency and those who meet criteria should be treated with IV iron Prompt referral to a HF center for those with signs of advanced disease Thank you van.selby@ucsf.edu 11