Heart Failure 6/29/2018 #FSHP2018 #FSHP2018 #FSHP2018 #FSHP2018 #FSHP2018 #FSHP2018

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1 Ht Papers & Guidelines in Cardilgy Christine Price, Pharm.D. Clinical Crdinatr PGY1 Residency Directr Disclsure I d nt have a vested interest in r affiliatin with any crprate rganizatin ffering financial supprt r grant mnies fr this cntinuing educatin activity, r any affiliatin with an rganizatin whse philsphy culd ptentially bias my presentatin Objectives Evaluate new and emerging clinical practice guidelines and primary literature related t heart failure and STEMI Describe the limitatins and/r cntrversies assciated with this data Outline current treatment gaps in guidelines related t unique patient ppulatins Determine ptimal treatment regimens fr a patient case applying the evidence reviewed Heart Failure 2016 ACC/AHA/HFSA Fcused Update f the 2013 ACCF/AHA Guideline n New Pharmaclgical Therapy fr Heart Failure 2017 ACC/AHA/HFSA Fcused Update f the 2013 ACCF/AHA Guideline fr the Management f Heart Failure Yancy et al. Circulatin 2016;134:e282 Yancy et al. JACC 2017;70(6): Intrductin 2016 Fcused Update n New Pharmaclgical Therapy ACC/AHA/HFSA cllabratin with ESC 2016 guideline New therapies fr stage C HF with reduced ejectin fractin (HFrEF) Angitensin receptr-neprilysin inhibitr (ARNI): Valsartan/sacubitril Sinatrial nde mdulatr: Ivabradine Intrductin 2017 Fcused Update Guidance n Management New therapies fr stage C HFrEF Was riginally discussed in 2016 Updated 2017 Update n treatment f HFpEF Bimarkers Cmrbidities: Sleep apnea, anemia, hypertensin Insights t preventin 1

2 2016 & 2017 Fcused Update The clinical strategy f inhibitin f the renin-angitensin system with ACEIs (Level f Evidence A) OR ARBs (Level f Evidence A) OR ARNI (Level f Evidence B-R) in cnjunctin with evidence based B- blckers and aldsterne antagnists in selected patients, is recmmended fr chrnic HFrEF t reduce mrbidity and mrtality New: New clinical trial data prmpted clarificatin and imprtant updates 2016 & 2017 Fcused Update 2013 ACC/AHA HF guidelines repeated Reduce M&M in mild, mderate, severe HFrEF with and withut CAD All ACEIs have same effects n symptms and survival New: The use f ACEIs is beneficial fr patients with prir r cncurrent symptms f HFrEF t reduce mrbidity and mrtality (M&M) Althugh the use f an ARNI in lieu f an ACEI fr HFrEF has been shwn t be superir, fr thse patients fr whm ARNI is nt apprpriate, cntinue use f ACEI fr all classes f HFrEF 2016 & 2017 Fcused Update The use f ARBs t reduce M&M is recmmended in patients with prir r current symptms f chrnic HFrEF wh are intlerant t ACEIs because f cugh r angiedema 2013 ACC/AHA HF guidelines repeated: ARBs if intlerant t ACEIs On ARBs fr ther indicatins: if they develp HF may cntinue taking ARBs Only candesartan, lsartan and valsartan NEW: Head-t-head cmparisns f an ARB vs ARNI fr HF dn t exist. Fr thse patients fr whm an ACEI r ARNI is inapprpriate, use f an ARB remains advised & 2017 Fcused Update Decreased hspitalizatins and mrtality cmpared t enalapril NEW: In patients with chrnic symptmatic HFrEF NYHA class II r III wh tlerate an ACEI r ARB, replacement by an ARNI is recmmended t further reduce M&M Patients with mild t mderate HF characterized by: Mildly elevated natriuretic peptide levels BNP >150 pg/ml r NT-prBNP 600 pg/ml BNP 100 pg/ml r NT-prBNP 400 pg/ml with prir hspitalizatin within the past 12 mnths Tlerated ACEI r ARB 2016 & 2017 Fcused Update NEW: ARNI shuld nt be administered cncmitantly with ACEIs r within 36 hurs f the last dse f an ACEI NEW: ARNI shuld nt be administered t patients with a histry f angiedema Can lead t angiedema; use tgether is cntraindicated Prir agent, mapatrilat (neprilysin, ACEI), had a 3-fld increased risk f angiedema and significant mrbidity Bth ACEI and ARNI (neprilysin) break dwn bradykinin African Americans and smkers at increased risk 2

3 2016 & 2017 Update: ARNI Neprilysin Endgenus vasactive peptides (natriuretic peptides, adrenmedullin, bradykinin, substance P, calcitnin gene-related peptide) Inactive metablites Neprilysin inhibitin Cunters neurhrmnal activatin Vasdilatin Decrease sdium retentin Decrease remdeling ARNI Landmark Trial fr 2016 & 2017 Update: PARADIGM-HF 10,521 patients screened at 1043 centers in 47 cuntries Duble-blind 8399 patients randmized fr ITT analysis LCZ696 (n=4187) 200 mg bid Swedberg et al. Lancet 2010;376(9744): :1 median 27 mnths f fllw-up Enalapril (n=4212) 10 mg bid Methds: Study Ppulatin ARNI Landmark Trial: PARADIGM-HF Inclusin Criteria At least 18 yrs NYHA class II, III, IV Ejectin Fractin 40% ( 35%- changed 12/10) NT-prBNP 600 pg/ml ( 400 if recently hspitalized) BNP 150 pg/ml ( 100 if recently hspitalized) ACE r ARB/BB use equivalent t enalapril 10mg 4 wks prir Exclusin Criteria Symptmatic hyptensin SBP 100 mmhg egfr <30 ml/min Serum K 5.2 mml Hx f angiedema r side effect frm ACEI r ARB use Acute decmpensated HF CVA, ACS, Vent arrhythmia r CRT within previus 3 mnths ARNI Landmark Trial: PARADIGM-HF 2016 & 2017 Fcused Update NEW: Ivabradine can be beneficial t reduce HF hspitalizatin fr patients with symptmatic (NYHA class II-III) stable chrnic HFrEF (LVEF 35%) n GDEM, including a beta blcker at max tlerated dse, in sinus rhythm with HR f 70 bpm r greater at rest Sinatrial nde mdulatr Selectively inhibits the If current in the sinatrial nde Prvides heart rate reductin SHIFT trial: Ivabradine and utcmes in chrnic heart failure (Lancet 2010;376:875-85) 3

4 2016 & 2017 Update: Sinatrial nde mdulatr 2016 & 2017 Update: Landmark Trial SHIFT Study Lancet 2010;376: STUDY DESIGN 7411 screened 6558 randmized 3268 t ivabradine 3290 t placeb 5mg BID Excluded: 27 Excluded: analyzed 2 lst t fllw-up 3264 analyzed 1 lst t fllw-up Median study duratin: 22.9 mnths; maximum: 41.7 mnths 2016 & 2017 Update: Landmark Trial SHIFT Study 2016 & 2017 Update: Landmark Trial SHIFT Study Inclusin Criteria Exclusin Criteria 18 yrs Class II t IV NYHA heart failure Ischemic/nn-ischemic etilgy LV systlic dysfunctin (EF 35%) Heart rate 70 bpm Sinus rhythm Dcumented hspital admissin fr wrsening heart failure 12 mnths On nndihydrpyridine calcium channel blckers On Class I antiarrhythmics On strng inhibitrs f CYP3A4 On medicatins that can prlng the QT interval Recent MI (<2 mnths) Atrial fibrillatin r flutter Symptmatic hyptensin Swedberg et al. Lancet 2010;376(9744): & 2017 Update: T SHIFT r Nt T SHIFT Lack f US patients N African-Americans Primarily white (89%) and Male (76%) Lw elderly ppulatin Average BMI f 28 Class IV HF 2% Duratin f HF 3.5 (4.2) yrs egfr 74 (22) 2016 & 2017 Update: T SHIFT r Nt T SHIFT Can benefits be achieved with aggressive use f B-blckers 89% f patients were n ß-blckers Only 26% f patients were at target dses f ß-blcker Only 56% at a 50% target dse f ß-blckers Cncerning results frm ther studies: BEAUTIFUL: N significant effects in stable CAD with LVEF <40%, hwever decreased risk f crnary events SIGNIFY: N imprvements in stable CAD with HR > 70 BEAUTIFUL Lancet 2008;372: SIGNIFY NEJM 2014;371(12):

5 2017 Fcused Update: Stage C HFpEF 2017 Fcused Update: Stage C HFpEF 2017 Fcused Update: TOPCAT Trial Spirnlactne vs, placeb, >50 yrs, HFpEF Cmpsite f CV mrtality, HF hspitalizatin, r abrted cardiac arrest N difference vs. placeb HF hspitalizatins were reduced with spirnlactne (p=0.04) Increased hyperkalemia with spirnlactne Decreased hypkalemia with placeb Mre dubling f creatinine with spirnlactne Pitt et al. NEJM 2014;370: Fcused Update: TOPCAT Reginal Analysis Pst hc analysis t capture differences in gegraphy Primary utcme events 522 (29.5%) patients in the Americas 149 (8.9%) in Russia/Gergia HR spirnlactne vs. placeb 0.82; 95% CI: ; p=0.026 in the Americas % CI: ; p=0.12 in Russia/Gergia Pfeffer et al. Circulatin 2015;131: Fcused Update: Cmrbidities Anemia 2017 Fcused Update: Cmrbidities Hypertensin 5

6 2016 &2017 Fcused Update Patient with Chrnic HFrEF Therapy with ACEI and B-blcker (titrated t evidence based dse) ARB if intlerant t ACEI LVEF <35%? ADD MRA Able t tlerate ACEI r ARB Sinus Rhythm, QRS 150 msec Sinus Rhythm HR 70 bpm Hydralazine/issrbide dinitrate in AA with NYHA class III-IV r thse wh can t tlerate ACEI r ARB ARNI t replace ACEI/ARB Cnsider CRT Ivabradine STEMI O Gara et al. Circulatin 2013;127:e370 Antman EM et al. Circulatin. 2004;110: ACC/AATS/ASE/ASNC/SCAI/SCCT/STS Apprpriate Use Criteria in ACS O Gara et al. Circulatin 2013;127:e370 Patel et al. JACC

7 O Gara et al. Circulatin 2013;127:e STEMI Guidelines Clinical Relevance: Antiplatelets TRITON-TIMI 38 (prasugrel) and PLATO (ticagrelr) Mre ptent P2Y12 platelet receptr inhibitrs Cmpared t clpidgrel, significant imprvement in utcmes cmpsite f CV death, MI r Strke The increase in bleeding is reasnable and smetimes negligible, hwever, with the exceptin f prasugrel in sme high-risk subgrups PRAGUE-18 Study Prasugrel vs. ticagrelr in 1,230 AMI prir t PCI N sign difference in: primary end pint f death, reinfarctin, urgent target vessel revascularizatin, strke r serius bleeding at 30 days Stpped early fr futility (50% enrllment) Lancet 2009;373: Circulatin 2011;124(5): Circulatin 2016;134:1603 Clinical Relevance: Antiplatelets Patients treated with primary PCI, ASA plus Ticagrelr Als apprved 60mg fr cntinuatin f DAPT beynd 1 year Ticagrelr is suitable fr use amng a brader ACS ppulatin, irrespective f histry, use f PCI r pre-treatment with clpidgrel Prasugrel If n cntraindicatins: Strke, TIA If n relative cntraindicatins: Age >75 years, weight less than 60kg ACCOAST: Pretreatment study terminated fr lack f efficacy and excess bleeding TRILOGY-ACS: nt superir in ACS withut PCI in reducing the rate f CV death, MI r strke Clpidgrel Patients at high risk f bleeding Prasugrel r ticagrelr can nt be used PRAGUE-8: N benefit fr pretreatment ACCOAST NEJM 2013;369: TRILOGY-ACS NEJM 2012;367(14): PRAGUE-8 Eur Heart J 2008;29(12): Clinical Relevance: Antiplatelets Cangrelr Intravenus P2Y12 receptr blcker FDA apprved June 2015 as an adjunct t PCI in patients nt being treated with a P2Y12 inhibitr and wh are nt being given GP IIb/IIIa inhibitrs Fast nset, ptent, reversible with a half-life f 3 t 6 hurs Studied in >25,000 patients in three trials CHAMPION PHOENIX CHAMPION PLATFORM CHAMPION PCI Harringtn RA, et al. CHAMPION PCI. NEJM 2009 Bhatt DL, et al. CHAMPION PLATFORM. NEJM 2009 Bhatt DL, et al. CHAMPION PHOENIX. NEJM 2013 White HD, et al. Meta-Analysis f CHAMPION PCI and PLATFORM. AHJ 2012 CHAMPION Trials Study Designs Randmized, Duble Blind, Cntrlled Trials f patients underging PCI CHAMPION PHOENIX n=10,942 mitt SA / NSTE-ACS / STEMI P2Y 12 naïve Placeb r clpidgrel befre r after PCI CHAMPION PCI n=8667 mitt SA / NSTE-ACS / STEMI Placeb r clpidgrel befre PCI CHAMPION PLATFORM n=5301 mitt SA / NSTE-ACS P2Y 12 naïve Placeb r clpidgrel after PCI 0 Cangrelr 30 g/kg then 4 g/kg/min OR Clpidgrel 600 mg r 300 mg ral Cangrelr 30 g/kg then 4 g/kg/min Clpidgrel 600 mg ral Cangrelr 30 g/kg then 4 g/kg/min Clpidgrel 600 mg ral PCI ~ hurs Clpidgrel 600 mg ral Clpidgrel 600 mg ral Clpidgrel 600 mg ral 7

8 Primary Efficacy Outcmes at 48 Hurs, mitt Clinical Relevance: Antiplatelets Cangrelr (N=12,475) Clpidgrel (N=12,435) OR (95% CI) P-value CHAMPION Limitatins: Death/MI/IDR/ST 473/12,459 (3.8%) 579/12,422 (4.7%) 0.81 ( ) The definitin f MI differed, but was standardized fr CHAMPION PHOENIX Secndary Efficacy Outcmes at 48 Hurs, mitt Stent thrmbsis Death/MI/IDR MI Q-wave MI IDR Death 62/12,459 (0.5%) 446/12,459 (3.6%) 387/12,459 (3.1%) 19/12,459 (0.2%) 66/12,459 (0.5%) 33/12,459 (0.3%) 105/12,422 (0.8%) 543/12,422 (4.4%) 453/12,422 (3.6%) 36/12,422 (0.3%) 92/12,422 (0.7%) 45/12,422 (0.4%) 0.59 ( ) ( ) ( ) ( ) ( ) ( ) MI, mycardial infarctin; IDR, ischemia-driven revascularizatin; ST, stent thrmbsis Fllw-up limited t 30 days: nly data available fr CHAMPION PHOENIX The cmparatr arm differed amng the three trials Different timing f administratin f clpidgrel befre vs. after PCI Different lading dses f clpidgrel - 300mg vs. 600mg Different clpidgrel status - clpidgrel naïve vs. pretreated 2013 STEMI Guidelines New Update: May 2018 The TREAT Trial Mving STEMI Care Frward, With Mre t D Ticagrelr vs. Clpidgrel After Fibrinlytic Therapy in Patients with STEMI Address the questins f safety and efficacy f ticagrelr use fr STEMI Patients n fibrinlytics were randmized t delayed ticagrelr (median 11.4hrs) after fibrinlysis vs. clpidgrel, duratin f fllw up 30 days 90% were pretreated with clpidgrel Age <75 yrs Results: Delayed administratin f ticagrelr was nn-inferir t clpidgrel TIMI majr bleeding 0.73% with ticagrelr vs. 0.69% with clpidgrel (p<0.001) Secndary: N difference in fatal bleeding, ICH, MACE Nt pwered fr primary utcme, trial will likely reprt efficacy thrugh ne year TREAT Trial JAMA 2018;3(5): ACC/AHA duratin f DAPT guidelines. Levine et al. Circulatin 2016;134:e-123-e155 Levine et al. Circulatin 2016;134:e-123-e155 8

9 Levine et al. Circulatin 2016;134:e-123-e STEMI Guidelines 2016 Meta-Analysis cmparing GPI, heparin, bivalirudin Lipinski, Cardivasc Revasc Med 2016;17: Meta-Analysis cmparing GPI, heparin, bivalirudin Clinical Relevance: GPIIb/IIIa (GPI) Things changed in the era f DES and P2Y12 Mst GPI trials that shwed benefit was prir t P2Y12 HORIZONs & EUROMAX: P2Y12 lading Bivalirudin was superir t heparin plus GPIs BRIGHT: trial adding GPI t heparin and all clpidgrel pre-pci Decrease in Net adverse events N benefit in majr adverse cardiac r cerebral events HORIZON-AMI Lancet 2009;374(9696): EUROMAX NEJM 2013;369: BRIGHT JAMA 2015;313(13): Rutine Medical Care Aspirin 81mg p 1xdaily indefinitely Prevent re-thrmbsis, prevent acute stent thrmbsis Beta Blckers Initiated within 24 hurs t prevent recurrent ischemia, ventricular arrhythmias Shuld be cntinued during and after hspitalizatin fr all patients with STEMI ACEIs r ARBs if intlerant t ACEI Fr patients with anterir infarctin, pst-mi LV systlic dysfunctin (EF 40%) r HF May be given t all patients withut cntraindicatin t prevent LV remdeling Aldsterne antagnist EPHESUS trial with eplerenne, lw LVEF with HF and/r diabetes Dahal et al. (May 2018) patients withut HF Statins: All patients and shuld be high intensity dse Nitrglycerin sublinqual NEJM 2003;348(14): JAMA di: /jamainternmed

10 References References 1. Writing Cmmittee Members: Yancy CW, Jessup M, et al ACC/AHA/HFSA Fcused Update f the 2013 ACCF/AHA Guideline fr the Management f Heart Failure. A Reprt f the American Cllege f Cardilgy/American Heart Assciatin Task Frce n Clinical Practice Guidelines and the Heart Failure Sciety f America. JACC 2017;70(6): Writing Cmmittee Members: Yancy CW, Jessup M, et al ACC/AHA/HFSA Fcused Update n New Pharmaclgical Therapy fr Heart Failure: An Update f the 2013 ACCF/AHA Guideline fr the Management f Heart Failure. A Reprt f the American Cllege f Cardilgy/American Heart Assciatin Task Frce n Clinical Practice Guidelines and the Heart Failure Sciety f America. Circulatin 2016;134:e Yancy CW, Jessup M, et al. ACCF/AHA Practice Guideline: 2013 ACCF/AHA Guideline fr the Management f Heart Failure: A Reprt f the American Cllege f Cardilgy Fundatin/American Heart Assciatin Task Frce n Practice Guidelines Circulatin. 2013;128:e240-e327, published nline befre print June , di: /cir.0b013e31829e McMurray J, Packer M, Desai AS, et. al. PARADIGM-HF: Angitensin Neprilysin Inhibitin versus Enalapril in Heart Failure. NEJM 2014;371(11): Swedberg K, Kmajda M, Bhm M, et al. Ivabradine and utcmes in chrnic heart failure (SHIFT): a radmized placeb-cntrlled study. Lancet 2010;376(9744): Fx K, Frd I, Steg PG, et al. Ivabradine fr patients with stable CAD and left-ventricular systlic dysfunctin (BEAUTIFUL): a randmized, duble-blind, placeb-cntrlled trial. Fx K, Frd I, Steg PG, et al. Ivabradine in stable crnary artery disease withut clinical heart failure. NEJM 2014;371(12): Fx K, Frd I, Steg PG, et al. Ivabradine in stable crnary artery disease withut clinical heart failure. NEJM 2014;371(12): Pitt B, Pfeffer MA, Assmann SF, et al. Spirnlactne fr heart failure with preserved ejectin fractin. N. Engl. J Med. 2014; 370: Pfeffer MA, Claggett B, Assmann SF, et al. Reginal variatin in patients and utcmes in the Treatment f Preserved Cardiac Functin Heart Failure With an Aldsterne Antagnist (TOPCAT) trial. Circulatin. 2015; 131: Writing Cmmittee Members: O Gara PT, Kusher FG, Ascheim DD, et al ACCF/AHA Guideline fr the Management f ST-Elevatin Mycardial Infarctin A Reprt f the American Cllege f Cardilgy Fundatin/American Heart Assciatin Task Frce n Practice Guidelines. Circulatin 2013; Patel MR, Calhn JH, Dehmer GJ et al. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2016 Apprpriate Use Criteria fr Crnary Revascularizatin in Patients with Acute Crnary Syndrmes. JACC 2016; Schiele F, Gale CP, Bnnefy E et al. Editr s Chice-Quality Indicatrs fr Acute Mycardial Infarctin: A psitin paper f the Acute Cardivascular Care Assciatin. Eurpean Heart Jurnal. 2017;6(1): Mntalesct G, Wivitt SD, Braunwald E, et al. Prasugrel cmpared with clpidgrel in patients underging percutaneus crnary interventin fr ST-elevatin mycardial infarctin (TRITON-TIMI 38): Duble-blind, randmized cntrlled trial. Lancet 2009; 373: Mahaffey KW, Wjdyla DM, Wallentin L, et al; PLATO Investigatrs. Ticagrelr cmpared with clpidgrel by gegraphic regin in the Platelet Inhibitin and Patient Outcmes (PLATO) trial. Circulatin Aug 2;124(5): Mtvska Z, Hlinmaz O, Miklik R et al. Prasugrel versus Ticagrelr in Patients with Acute Mycardial Infarctin Treated with Primary Percutaneus Crnary Interventin: Multicentered Randmized PRAGUE-18 Study. Circulatin 2016;134: Widimsky P, Mtvska Z, Simek S, et al. Clpidgrel pre-treatment in stable angina: fr all patients >6hr befre elective crnary angigrapy r nly fr angigraphically selected patients a few minutes befre PCI? A randmized multicenter trial PRAGUE-8. Eur Heart J 2008;29(12): Mntalesct G, Blgnese L, Dudek D, et al. Pretreatment with prasugrel in NSTEMI ACS. ACCOAST NEJM 2013;369: Re MT, Armstrng PW, Fx KA, et al. Prasugrel versus clpidgrel fr acute crnary syndrms withut revascularizatin. NEJM 2012;367: Lipinski MJ, Gaglia MA, Trgusn R, et al. Cmparisn f heparin, bivalirudin, and different GP Iib/IIIa inhibitr regimens fr anticagulatin during PCI: a netwrk meta-analysis. Cardivasc Revasc Med 2016;17: Gabriel P, van t Hf, A, Hamm CW, et al. Bivalirudin started during emergency transprt fr primary PCI. NEJM 2013;369: Thiele H, Whrle J, Hambrecht R et al. Intracrnary vs intravenus blus abciximab during PCI in STEMI. AIDA STEMI. Lancet 2012;379: Yancy CW, Harringtn RA. The TREAT Trial-Mving STEMI Care Frward, With Mre t D. JAMA 2018;3(5) Pitt B, Remme W, Zannad F, et al; Eplerenne Pst-Acute Mycardial Infarctin Heart Failure Efficacy and Survival Study Investigatrs. Eplerenne, a selective aldsterne blcker, in patients with left ventricular dysfunctin after mycardial infarctin. N Engl J Med. 2003;348(14): QUESTIONS? Christine Price, Pharm.D. Clinical Crdinatr PGY1 Residency Directr Christine.Price@baycare.rg 10