What Next? Management of Heart Failure with Reduced Ejection Fraction What Does the Evidence Show Us?

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1 65 yr WM presents for followup of HFrEF. Management of Heart Failure with Reduced Ejection Fraction What Does the Evidence Show Us? NYHA II-III, HFH 6 mo ago. Prior CABG, DM and HTN. LVEF 30%. Meds: lisinopril 10 mg, carvedilol 12.5 mg bid, spironolactone 25 mg, furosemide 40 mg, metformin 500 mg, aspirin, atorvastatin 40 mg. James C. Fang, MD University of Utah Health Sciences Salt Lake City, UT BP 122/75, HR 73, BMI 28, NAD, no JVD, HS normal, sternal scar, lungs clear, no edema. EKG SR anterior Qs, NT-proBNP 1500, Cr 1.2, Hgb A1c 8.2%. What Next? A. No changes B. Ivabradine C. Sacubitril/valsartan D. Empagliflozin Impact of Medical Therapy in Heart Failure w/ Reduced Ejection Fraction Therapy RR Red Mortality (%) NNT (36 mo) RR Red Hosp (%) ACEI or ARB Beta Blocker Aldo antagonist Hydralazine/Isordil Yancy C, et al ACC AHA HF Guidelines 1

2 What Next? A. No changes B. Ivabradine C. Sacubitril/valsartan D. Empagliflozin Heart Rate, Mortality, and HFrEF BEAUTIFUL Trial HR for CV Death HR Fox K, et al. Lancet 2008 Ivabradine Inhibition of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. NYHA II IV Admitted to hospital within 12 months LVEF <35% Normal sinus rhythm Heart rates >70 bpm Psotka and Teerlink Circ

3 SHIFT Outcomes Driven by reduction in HF hosp Beta Blockers Use in SHIFT Ivabradine Placebo HF hosp HF, MI hosp Swedberg K, et al. Lancet 2010 Swedberg K, et al. Lancet 2010 SHIFT and Beta blocker Trials Apples and oranges? Ivabradine 2016 HF guidelines Class IIa Ivabradine can be beneficial to reduce HF hosp for pts w/ NYHA II-III stable chronic HFrEF who are receiving GEM, including a BB at maximum tolerated dose, and who are in SR with a HR of 70 bpm or greater at rest. Cost effective? Wholesale cost 24,920 per QALY <$1.00 per pill Teerlink JR. Lancet 2010 Kansal AR, et al. JAHA

4 What Next? Angiotensin Receptor Neprilysin Inhibitor A. No changes B. Ivabradine C. Sacubitril/valsartan D. Empagliflozin Vardney O et al. JACC-HF 2014 Run-In Trial Design NYHA II IV BNP >150 pg/ml (>100 if 12m HFH) NT-proBNP >600 pg/ml (>400 if 12m HFH) LVEF <35% ACEi or ARB BP >100 mmhg egfr >30 cc/min/1.73m 2 4

5 Off Target Risks? Other ARNI Benefits 21% in worsening HF death, 80% in SCD Eur Heart J 2015;36: Reduction HF hosp apparent in first 30d Circulation 2015;131:54-61 Absolute benefit across spectrum of patient risk JACC 2015;66: Benefit consistent regardless of background Rx CircHF 2016;9:e

6 Angiotensin Receptor Neprilysin Inhibitor 2016 HF guidelines Class I In pts w/ chronic HFrEF NYHA II or III who tolerate an ACEi or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. Inhibition of RAS w/ ACEi, or ARBs, or ARNI in conjunction with evidence-based BBs and AldoAnt in selected pts is recommended for pts w/ chronic HFrEF to reduce morbidity and morbidity. ( but not w/ ACEi, w/in 36h of ACEi or angioedema) Unanswered Questions New onset HFrEF Advanced HF Acute Decompensated HF Chronic Kidney Disease Post-MI HFpEF Cost Effective? Wholesale acquistion cost: $4560 Lisinopril: $32 Enalapril: $480 Valsartan: $628 Cost per QALY = $50,915 Assuming 0.57 QALY gained Greater than $100K/QALY if effect <3y U.S. health system budget impact $3 billion/year To avoid exceeding economic growth, estimated WAC would be $4168 Olendorf DA, Sandhu AT, Pearson SD. JAMA Internal Medicine

7 California s Perspective California Technology Assessment Forum concluded that sacubitril/valsartan had intermediate to high long-term care value. But felt at current price, value was low due to the short-term impact on budget => preferred tier on fomularies. Recommended: Restricting prescribing to cardiologists Younger patients for tolerability Patients with worsening disease What Next? A. No changes B. Ivabradine C. Sacubitril/valsartan D. Empagliflozin Olendorf DA, Sandhu AT, Pearcould D. JAMA Internal Medicine 2015 Drugs for Type II Diabetes Mellitus Sodium Glucose Co-Transporters Glucosuria and Natriuresis Sulfonylureas (glipizide, glyburide) Biguanides (metformin) Meglitinides ( -glinides ) Thiazolidinediones ( -glitazones ) DPP-4 inhibitors ( -gliptins ) SGLT2 inhibitors ( -gliflozin ) Alpha-glucosidase inhibitors (acarbose) Empagliflozin X Bailey and Day Brit J Fam Med

8 EMPA REG OUTCOME Trial Type II DM HgbA1c % Established CVD egfr >30 cc/min/m 2 BMI <40 kg/m 2 Age 63 HgbA1c 8.0% CAD 76% HF 10% egfr 74 cc/min/m 2 Metformin 74% Zinman B, et al. NEJM 2015 SGLT2 decreases HF in DMII The EMPA REG Trial SGLT2 inhibitor and Weight Loss EMPA REG Renal Fitchett D, et al. European Heart Journal 2015 Barnett AH, et al. Lancet Diab Endo

9 Summary Ivabradine decreases HFH but doesn t appear to impact mortality Sacubitril/valsartan represents significant advance to pharmacologic treatment of HF SGLT2 inhibitors may have a significant impact on the intersection of HF and DM Heart Rate, Mortality, and HFrEF Omecamtiv Mecarbil Selective Cardiac Myosin Activator Mechanochemical Cycle of Myosin OM increases the rate of myosin into a slightly-bound, force-producing state with actin ( More hands pulling on the rope ) Increases duration of systole Increases stroke volume No increase in myocyte calcium Force produc1on No change in dp/dtmax No increase in MVO2 Bohm M, et al. Lancet 2010 Malik FI, et al. Science

10 Relaxin Mechanisms of Action Relaxin Receptor LGR7 Vasodilation NO, cgmp effectors Induction of NOS II/III Upregulation of endothelial endothelin type B receptor, which mediate vasodilation Preferential dilation of preconstricted vessels Natriuretic Anti-inflammatory Down-modulation of inflammatory cytokine linked to outcome in HF (TNF-α, TGF-β) Anti-ischemic Anti-apoptotic Anti-fibrotic Cost Effective? Teichman SL, et al. HF Rev 2009; Dschietzig T, et al. Pharm Therap 2006 Gaziano TA, et al. JAMA