Behandeling van Hartfalen: over 5 jaar

Transcription

1 Behandeling van Hartfalen: over 5 jaar Adriaan Voors, cardioloog UMCG

2 Over 5 jaar

3 Heart Failure Treatment in 5 Years HFrEF: best evidence, biggest pipeline Entresto Omcamtiv LVAD: destination therapy HFrEF: no evidence, smallest pipeline Entresto Septostomy Acute Heart Failure: minimal evidence, biggest problem Ularitide, Serelaxin Preventing early hospital readmission

4 Treatment of HFrEF: getting better!

5 HFrEF: Unmet Needs?

6 % Decrease in Mortality WCN : Drugs Reducing Mortality in HFrEF 0% Angiotensin receptor blocker ACE inhibitor Beta blocker Mineralocorticoid receptor antagonist 10% 20% 30% Drugs that inhibit the renin-angiotensin system have modest effects on survival 40% Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

7 ARNI have the potential to restore the appropriate balance of the RAAS and natriuretic peptides in HF Damage Beneficial physiological response Pathophysiological response NPs NP system RAAS Ang II NEP X Vasodilation blood pressure sympathetic tone aldosterone level fibrosis hypertrophy Natriuresis/Diuresis Inactive fragments NEP/RAAS inhibition (LCZ696) HF symptoms/ progression X AT 1 receptor Vasodilation blood pressure sympathetic tone aldosterone fibrosis hypertrophy Neurohormonal balance

8 Aim of the PARADIGM-HF Trial Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) LCZ mg daily Enalapril 20 mg daily Specifically Designed To Replace Current Use Of Ace Inhibitors And Angiotensin Receptor Blockers As The Cornerstone Of The Treatment Of Heart Failure

9 Effect of LCZ696 vs Enalapril on Primary Endpoint Components LCZ696 (n=4187) Enalapril (n=4212) Hazard Ratio (95% CI) P Value Primary endpoint 914 (21.8%) 1117 (26.5%) 0.80 ( ) Cardiovascular death 558 (13.3%) 693 (16.5%) 0.80 ( ) Hospitalization for heart failure 537 (12.8%) 658 (15.6%) 0.79 ( ) NEJM 2014

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11 Entresto approved by EMA and FDA "Entresto is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.

12 Hasenfuss and Teerlink; Eur Heart J 2011;32:

13 COSMIC-HF Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure Primary objectives To select an oral modified release formulation and dose for chronic twice daily dosing in patients with symptomatic HFrEF (NYHA II/III, LVEF 40%, NT-proBNP 200 pg/ml/ 1200 pg/ml if AF) Secondary objectives Safety and tolerability Changes in SET, SV, LVESD, LVEDD, heart rate and NT-pro BNP levels University JR Teerlink, Medical Late-Breaking Center Groningen Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015

14 Efficacy of Omecamtiv Mecarbil JR Teerlink, Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015

15 Efficacy of Omecamtiv Mecarbil, Cardiac troponin I levels JR Teerlink, Late-Breaking Clinical Trial Session at the American Heart Association (AHA) Scientific Sessions 2015

16 Left Ventricular Assist Device

17 HFrEF versus HFpEF HFrEF: LVEF <40% HFpEF: LVEF >50% Between 40-50%: grey-area ESC Heart Failure Guidelines 2012

18 Treatment of Diastolic Heart Failure No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFPEF. Diuretics are used to control sodium and water retention and relieve breathlessness and oedema. Adequate treatment of hypertension and myocardial ischaemia is also considered to be important, as is control of the ventricular rate in patients with AF. ESC Heart Failure Guidelines EJHF

19 HFpEF: Unmet Needs?

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21 PARAMOUNT: main results 301 HFpEF patients; LVEF 45%; NT-proBNP>400 pg/ml LCZ696 2 dd 200 mg or Valsartan 2 dd 160 mg Solomon et al. Lancet 2012

22 PARAGON-HFPEF: study design Target patient population: 4,300 patients with symptomatic HF (NYHA Class II IV) and LVEF 45% Randomization 1:1 Screening Active run-in period Valsartan 80 mg BID* LCZ mg BID Double-blind treatment period LCZ mg BID Valsartan 160 mg BID up to 2 weeks 3 8 weeks On top of optimal background medications for co-morbidities (excluding ACEIs and ARBs) ~240 weeks Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events) *Valsartan 40 mg BID (up to 2 weeks) followed by valsartan 80 mg BID as an optional starting run-in dose for those patients being treated with less than the minimum University dose of Medical ACEI or Center ARB at Groningen Visit 1 Solomon SD, et al. Poster presentation at ESC-HF Congress, 25 May 2013; Clinicaltrials.gov NCT ;accessed March 2014

23 Interatrial Shunt Device: Novel therapy for HFpEF?

24 Prospective, nonrandomized, open-label trial A minimum of 60 patients: LVEF>40% and NYHA III-IV PCWP >15 mm Hg at rest or >25 mm Hg during exercise All patients receive IASD System II Primary outcome measures for safety are periprocedural and 6-month major adverse cardiac and cerebrovascular events (MACCE) and systemic embolic events (excluding pulmonary thromboembolism).

25 Acute Heart Failure: Recommendations and levels of evidence Group Medication Class recommendation, Level of evidence Diuretics Indication I, B Vasodilators Nitrates IIa, B Sodium Nitroprusside IIb, B Morphine Indication IIa, C Inotropics Dopamine IIb, C Dobutamine IIa, C McMurray et al. Eur J Heart Fail 2012; 33:

26 Several Drugs in AHF Not Successful PDE inhibitors: milrinone: OPTIME-CHF Endothelin antagonists: tezosentan: VERITAS Calcium sensitizers: levosimendan; SURVIVE/REVIVE AVP antagonists: tolvaptan; EVEREST Adenosine A1-receptor antagonist: rolofylline; PROTECT Natriuretic peptides: nesiritide: ASCEND-HF Wrong drugs? AVP = arginine vasopressin; PDE = phosphodiesterase Wrong study design? Wrong concept?

27 Ularitide: Sirius II Mitrovic V, et al. Eur Heart J. 2006;27(23):

28 Ularitide: TRUE-AHF A phase 3, double-blind, randomized, placebo-controlled, multicenter study 48-hour IV infusion with ularitide, 15 ng/kg body weight/min 2152 patients hospitalized for acute heart failure Study treatment within 12 hours after ED admission Co-Primary endpoint: hierarchical clinical composite including dyspnea relief, worsening of heart failure, and all-cause mortality CV-mortality ClinicalTrials.gov NCT

29 Relaxin Naturally occurring hormone, discovered in 1929 Elevated in circulation in first trimester of pregnancy and throughout 9 months Relaxin receptors, identified in 2002, localized in blood vessels Mechanism of action involves activation of the endothelial endothelin type B receptor Relaxin Contributes to maternal hemodynamic adjustments to pregnancy Hsu et al. Science 2002;295: ; Jeyabalan et al. Adv Exp Med Biol 2007;612:65 87; Dschietzig et al. Circ Res 2003;92:32 40

30 Serelaxin Is NOT Just Another Vasodilator Relaxin Relaxin receptor TNF- TGF- MMP ET-1 ET 1-32 NOS VEGF Collagen deposition Endothelial ET B receptor NO Inflammation Fibrosis Vasodilation Renal effects Angiogenesis ET B receptor = endothelin receptor type B; ET-1= endothelin-1; MMP = matrix metalloproteinase; NO = nitric oxide; NOS = nitric oxide synthase; TGF = transforming growth factor; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor Teichman SL, et al. Curr Heart Fail Rep. 2010;7(2):75-82.

31 Change From Baseline (mm) WCN 2015 RELAX-AHF Randomized, Double-Blind, Placebo-Controlled Trial in 1161 ADHF Patients First primary endpoint: change in dyspnea with VAS Placebo: mean AUC (SD) = 2308 (3082) mm/h Serelaxin: mean AUC (SD) = 2756 (2588) mm/h P =.007 Serelaxin (n=581) Placebo (n=580) 0 0 6h 12h Day 1 Day 2 Day 3 Day 4 Day 5 Follow-up but no significant effects on second primary endpoint and secondary endpoints AUC = area under the curve; SD = standard deviation; VAS = visual analogue scale Teerlink JR, et al. Lancet. 2013;381(9860):29-39.

32 Patients (%) WCN 2015 Signs and Symptoms at Day DOE P =.02 Orthopnea P =.002 Edema P =.01 Rales P =.008 JVP P =.06 None Mild None None None <6 cm 40 1 Pillow 20 Moderate 2 Pillows <1/ cm 0 Severe > /3 2/3 >2/3 >10 cm DOE = dyspnea on exertion; JVP = jugular venous pressure Teerlink JR, et al. Lancet. 2013;381(9860):29-39.

33 CV Death (%) WCN 2015 RELAX-AHF: CV Mortality Placebo: 55 CV deaths (9.6%) Serelaxin: 35 CV deaths (6.1%) HR, 0.63 (95% CI, ) P =.028 n= n= Time Since Randomization (days) CI = confidence interval; HR = hazard ratio Teerlink JR, et al. Lancet. 2013;381(9860):29-39.

34 RELAX-AHF-2: study design Please note that the study design information for RELAX-AHF-2 is subject to change Target patient population: 6,375 patients hospitalized with AHF, presenting with dyspnea, normal to elevated SBP ( 125 mmhg) and mild-to-moderate renal impairment Randomization 1:1 Double-blind randomized treatment period Placebo i.v. Screening Screening occurred after 40 mg i.v. furosemide Serelaxin 30 µg/kg/d i.v.* In addition to standard HF therapy Presentation <16 h h d 48 h study drug infusion (i.v.) period Discharge # Primary outcome: time to CV death *Same weight range-adjusted dosing as in RELAX-AHF; Standard HF therapy permitted at physician s discretion; # If discharge visit coincides with a scheduled visit, only the discharge visit will be performed. AHF=acute heart failure; CV=cardiovascular; d=day; h=hour; i.v.=intravenous; SBP=systolic blood pressure Clinicaltrials.gov: NCT ; Novartis, data on file 2013

35 General unmet needs Better understanding of the disease Prevention Personalized medicine

36 Acute Heart Failure AHF early post-discharge vulnerable phase periods of highest risk for readmission unavoidable readmissions Desai AS and Stevenson LW.Circulation. 2012;126:

37 How to prevent early re-admission? Appropriate discharge therapy Training and education before discharge Length of hospital stay Adequate decongestion during hospital admission Discharge planning and disease management programs

38 Valente, et al. EHJ 2014

39 % re-admission WCN 2015 Diuretic response in AHF related to re-hospital admission up to day 60 PROTECT: 2033 AHF patients; Diuretic response = kg weight loss/40 mg furosemide Valente, et al. EHJ 2014

40 Diuretic response: death or HF/RF readmission through day 60 RELAX-AHF: 1161 AHF patients; Diuretic response = kg weight loss/40 mg furosemide P< Voors et al. Eur J Heart Fail 2014

41 General unmet needs Better understanding of the disease Prevention Personalized medicine

42 Differential response to therapy

43 Over 5 jaar HFrEF: best evidence, biggest pipeline Better drugs in severe HFrEF? HFrEF: no evidence, smallest pipeline Better understanding, better therapies Acute Heart Failure: minimal evidence, biggest problem First proven thersapies upcoming? Preventing early hospital readmission General aims: prevention and personalized medicine