65 yr WM presents for followup of HFrEF. Management of Heart Failure with – NYHA II-III, HFH 6 mo ago. Prior CABG, DM and HTN. Reduced Ejection Fraction LVEF 30%. What Does the Evidence Show Us? – 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 – BP 122/75, HR 73, BMI 28, NAD, no JVD, HS normal, University of Utah Health Sciences sternal scar, lungs clear, no edema. Salt Lake City, UT – EKG SR anterior Qs, NT-proBNP 1500, Cr 1.2, Hgb A1c 8.2%. What Next? Impact of Medical Therapy in Heart Failure w/ Reduced Ejection Fraction A. No changes B. Ivabradine Therapy RR Red Mortality NNT (36 mo) RR Red Hosp (%) C. Sacubitril/valsartan (%) ACEI or ARB 17 26 31 D. Empagliflozin Beta Blocker 34 9 41 Aldo antagonist 30 6 35 Hydralazine/Isordil 43 7 33 Yancy C, et al. 2013 ACC AHA HF Guidelines 1
Heart Rate, Mortality, and HFrEF What Next? BEAUTIFUL Trial A. No changes B. Ivabradine HR for CV Death C. Sacubitril/valsartan D. Empagliflozin 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 2016 2
SHIFT Outcomes Beta Blockers Use in SHIFT Driven by reduction in HF hosp Ivabradine Placebo HF hosp HF, MI hosp Swedberg K, et al. Lancet 2010 Swedberg K, et al. Lancet 2010 Ivabradine SHIFT and Beta blocker Trials 2016 HF guidelines – Class IIa Apples and oranges? • 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 2016 3
Angiotensin Receptor – Neprilysin Inhibitor What Next? A. No changes B. Ivabradine C. Sacubitril/valsartan D. Empagliflozin Vardney O et al. JACC-HF 2014 Run-In Trial Design •NYHA II – IV •BP >100 mmHg •BNP >150 pg/ml (>100 if 12m HFH) •eGFR >30 cc/min/1.73m 2 •NT-proBNP >600 pg/ml (>400 if 12m HFH) •LVEF <35% •ACEi or ARB 4
Other ARNI Benefits Off Target Risks? • 21% in worsening HF death, 80% in SCD – Eur Heart J 2015;36:1990-1997 • Reduction HF hosp apparent in first 30d – Circulation 2015;131:54-61 • Absolute benefit across spectrum of patient risk – JACC 2015;66:2059-2071 • Benefit consistent regardless of background Rx – CircHF 2016;9:e003212 5
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) Cost Effective? Unanswered Questions • Wholesale acquistion cost: $4560 • New onset HFrEF – Lisinopril: $32 • Advanced HF – Enalapril: $480 – Valsartan: $628 • Acute Decompensated HF • Cost per QALY = $50,915 • Chronic Kidney Disease – Assuming 0.57 QALY gained • Post-MI – Greater than $100K/QALY if effect <3y • HFpEF • 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 2015 6
California’s Perspective What Next? • California Technology Assessment Forum A. No changes concluded that sacubitril/valsartan had intermediate to high long-term care value. B. Ivabradine • But felt at current price, value was low due to the C. Sacubitril/valsartan short-term impact on budget => ‘preferred’ tier on D. Empagliflozin fomularies. • Recommended: – Restricting prescribing to cardiologists – Younger patients for tolerability – Patients with worsening disease Olendorf DA, Sandhu AT, Pearcould D. JAMA Internal Medicine 2015 Sodium Glucose Co-Transporters Drugs for Type II Diabetes Mellitus Glucosuria and Natriuresis • Sulfonylureas (glipizide, glyburide) • Biguanides (metformin) • Meglitinides (‘-glinides’) • Thiazolidinediones (‘-glitazones’) Empagliflozin • DPP-4 inhibitors (‘-gliptins’) X • SGLT2 inhibitors (‘-gliflozin’) • Alpha-glucosidase inhibitors (acarbose) Bailey and Day Brit J Fam Med 2014 7
EMPA REG OUTCOME Trial •Type II DM •Age 63 •HgbA1c 7.0 – 10.0% •HgbA1c 8.0% •Established CVD •CAD 76% •eGFR >30 cc/min/m 2 •HF 10% •BMI <40 kg/m 2 •eGFR 74 cc/min/m 2 •Metformin 74% Zinman B, et al. NEJM 2015 SGLT2 inhibitor and Weight Loss SGLT2 decreases HF in DMII EMPA REG Renal The EMPA REG Trial Barnett AH, et al. Lancet Diab Endo 2014 Fitchett D, et al. European Heart Journal 2015 8
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 Omecamtiv Mecarbil Heart Rate, Mortality, and HFrEF Selective Cardiac Myosin Activator OM increases the rate of myosin into a Mechanochemical Cycle of Myosin 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 No change in dP/dt max Force produc1on No increase in MVO 2 Bohm M, et al. Lancet 2010 Malik FI, et al. Science 2011 9
Relaxin Cost Effective? 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 pre- constricted vessels • Natriuretic • Anti-inflammatory • Down-modulation of inflammatory cytokines linked to outcome in HF (TNF-α, TGF-β) • Anti-ischemic • Anti-apoptotic • Anti-fibrotic Teichman SL, et al. HF Rev 2009; Dschietzig T, et al. Pharm Therap 2006 Gaziano TA, et al. JAMA 2016 10
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