Hjärtsvikt. Introduktion - Krister Lindmark 15 min. Sköterskebaserad sviktmottagning Katarina Ekenstedt 20 min

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1 Hjärtsvikt Krister Lindmark Docent, Överläkare Kardiologen Umeå Introduktion - Krister Lindmark 15 min Sköterskebaserad sviktmottagning Katarina Ekenstedt 20 min Fysisk aktivitet och träning vid hjärtsvikt Camilla Sandberg 20 min Entresto vid hjärtsvikt Krister Lindmark 30 min Ca människor dog i Sverige 2012, av dem dog av hjärt/kärlsjukdom 1

2 Livstidsrisk för hjärtsjukdom Livstidsrisk för hjärtsjukdom Frisk 45-åring Man 60.3 % Kvinna 55.6 % Detta gäller kranskärlssjukdom, stroke, hjsvikt och kardiovaskulär död (JAMA Nov 7;308(17): ) 2

3 WOSCOPS primärpreventionsstudie med pravastatin 40 mg i 5 års tid 6595 män ålder år Efter 5 år fick alla aktiv behandling Hjärtsvikt Slutstadiet av alla andra hjärtsjukdomar Förbättrad behandling av andra hjärtsjukdomar leder till senare insjuknande Förbättrad behandling av hjärtsvikt leder till fler sviktpatienter som är i livet Sviktpatienterna blir fler, äldre och sjukare 3

4 Lindmark et al, abstract 2017 Lindmark et al, abstract 2017 Lindmark et al, abstract

5 Basbehandling hjärtsvikt Ace-hämmare Betablockad 5

6 Spironolactone Survival Annual Mortality Aldactone 18%; Placebo 23% Aldactone N = 1663 NYHA III-IV EF<40% Mean follow-up 2 y p < RALES Placebo months NEJM 1999;341: Sviktpace och ICD Drugs don't work in patients who don't take them. C. Everett Koop, M.D. 6

7 Survival Curves for Adherence With Statins in 3 Cohorts Jackevicius, C. A. et al. JAMA 2002;288: Copyright restrictions may apply. Entresto 7

8 A Comparison of Angiotensin Receptor- Neprilysin Inhibition (ARNI) With ACE Inhibition in the Long-Term Treatment of Chronic Heart Failure With a Reduced Ejection Fraction Milton Packer, John J.V. McMurray, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg and Michael R. Zile for the PARADIGM-HF Investigators and Committees Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter Maladaptive Mechanisms in Heart Failure Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin Neprilysin inhibition Inactive metabolites LCZ696: Angiotensin Receptor Neprilysin Inhibition LCZ696 Angiotensin receptor blocker Inhibition of neprilysin 8

9 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 PARADIGM-HF: Entry Criteria NYHA class II-IV heart failure LV ejection fraction 40% 35% BNP 150 (or NT-proBNP 600), but one-third lower if hospitalized for heart failure within 12 months Any use of ACE inhibitor or ARB, but able to tolerate stable dose equivalent to at least enalapril 10 mg daily for at least 4 weeks Guideline-recommended use of beta-blockers and mineralocorticoid receptor antagonists Systolic BP 95 mm Hg, egfr 30 ml/min/1.73 m 2 and serum K 5.4 meq/l at randomization PARADIGM-HF: Patient Disposition 10,521 patients screened at 1043 centers in 47 countries Did not fulfill criteria for randomization (n=2079) Randomized erroneously or at sites closed due to GCP violations (n=43) 8399 patients randomized for ITT analysis LCZ696 (n=4187) At last visit 375 mg daily 11 lost to follow-up median 27 months of follow-up Enalapril (n=4212) At last visit 18.9 mg daily 9 lost to follow-up 9

10 Kaplan-Meier Estimate of Cumulative Rates (%) Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: Baseline Characteristics LCZ696 (n=4187) Enalapril (n=4212) Age (years) 63.8 ± ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± ± 6.3 NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9% Systolic blood pressure (mm Hg) 122 ± ± 15 Heart rate (beats/min) 72 ± ± 12 N-terminal pro-bnp (pg/ml) 1631 ( ) 1594 ( ) B-type natriuretic peptide (pg/ml) 255 ( ) 251 ( ) History of diabetes 35% 35% Digitalis 29.3% 31.2% Beta-adrenergic blockers 93.1% 92.9% Mineralocorticoid antagonists 54.2% 57.0% ICD and/or CRT 16.5% 16.3% PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Enalapril (n=4212) LCZ696 (n=4187) HR = 0.80 ( ) P = Number needed to treat = 21 Patients at Risk Days After Randomization LCZ Enalapril PARADIGM-HF: All-Cause Mortality HR = 0.84 ( ) P< Enalapril (n=4212) LCZ696 (n=4187) Days After Randomization Patients at Risk LCZ Enalapril

11 % Decrease in Mortality % Decrease in Mortality PARADIGM-HF: Adverse Events Prospectively identified adverse events LCZ696 (n=4187) Enalapril (n=4212) P Value Symptomatic hypotension < Serum potassium > 6.0 mmol/l Serum creatinine 2.5 mg/dl Cough < Discontinuation for adverse event Discontinuation for hypotension NS Discontinuation for hyperkalemia NS Discontinuation for renal impairment Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction 0% Angiotensin receptor blocker ACE inhibitor Beta blocker Mineralocorticoid receptor antagonist 10% 20% 30% 40% Drugs that inhibit the renin-angiotensin system have modest effects on survival Based on results of SOLVD-Treatment, CHARM-Alternative, COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System 0% Angiotensin receptor blocker ACE inhibitor Angiotensin neprilysin inhibition 10% 15% 18% 20% 30% 20% 40% Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial 11

12 Riktlinjer ESC Hur skall vi göra Dyrt preparat - ca 50 kr/dag Enbart till de patienter som har nedsatt ejektionsfraktion trots full annan behandling = studiepopulationen Sätt inte in det på nya sviktpatienter utan avvakta svar på basbehandling Specialistpreparat till en början!! Hjärn och Järtsvikt 12

13 Traditional view of iron a critical element in erythropoiesis About 3 4 days Iron dependence Erythropoietin Iron About days About 21 days Erythropoietin dependence About 1 2 days Pluripotent stem cell Erythroblasts Burst-forming Colony-forming Proerythroblasts unit-erythroid cells unit-erythroid cells Reticulocytes Red blood cells Adapted from Besarab et al. Oncologist 2009 Iron is essential for growth and survival IRON CELLS TISSUES ORGANS BODY POPULATION Mitochondrial dysfunction Deranged enzyme activity Abnormal transport and structural proteins Apoptosis Tissue remodelling Impaired organ efficacy Impaired exercise capacity Reduced work efficiency Impaired cognitive performance and behaviour Increased morbidity and mortality Iron is particularly important for cells of high mitogenic potential and high energy demand (e.g. skeletal myocytes and cardiomyocytes) Andrews N Engl J Med 1999 Cairo et al. Genes Nutr 2006 Zimmermann, Hurrell. Lancet 2007 Dual effects of iron deficiency: defective oxygen delivery and utilization Iron deficiency Hb Aerobic enzymes Mitochondrion ATP synthesis O 2 ATP O 2 delivery O 2 utilisation pvo 2 Anker et al. Eur J Heart Fail 2009 Haas, Brownlie J Nutr 2001 Dallman J Intern Med

14 Peak VO 2 (ml/min/kg) VE-VCO 2 slope Causes of iron deficiency in heart failure Malnutrition Loss of appetite: <50% intake Malabsorption: GI oedema PPI, PO 4 binders GI blood losses Anti-platelets Anti-coagulants NSAIDs Mucosal integrity Reduced Iron storage: Absolute iron deficiency Inflammation Cytokines, IL-6, IL-1, TNF-α Blunted responses to EPO Apoptosis of erythroid progenitors Hepcidin-mediated malabsorption and RES pooling Reduced iron mobilization: Functional iron deficiency Modified from Jankowska et al. Eur. Heart J 2013 Prevalence Anaemic Non-Anaemic Whole population Iron deficiency definition used: Serum ferritin <100 µg/l or Serum ferritin <299 µg/l if TSAT <20% ID/Anaemia ID/No-Anaemia No-ID/Anaemia No-ID/No-Anaemia N= 1506 Adapted from Klip et al. Am Heart J 2013 Iron deficiency but not anaemia is associated with reduced exercise capacity in CHF patients Peak oxygen consumption 17 Iron deficiency p<0.001 Anaemia p=0.15 Interactions p= Ventilatory response to exercise 58 Iron deficiency p< Anaemia p=0.102 Interactions p= ( ) anaemia (+) anaemia ( ) anaemia (+) anaemia ( ) anaemia (+) anaemia ( ) anaemia (+) anaemia ( ) ID ( ) ID (+) ID (+) ID ( ) ID ( ) ID (+) ID (+) ID Iron deficiency defined as serum ferritin <100μg/L, or serum ferritin μg/L with TSAT <20% Anaemia defined as haemoglobin level <12g/dL in women and <13g/dL in men Jankowska et al. J Cardiac Fail

15 N Engl J Med 2009; 361: Design Main inclusion criteria: NYHA class II / III, LVEF 40% (NYHA II) or 45% (NYHA III) Hb: g/dL Iron deficiency: serum ferritin <100 µg/l or <300 µg/l, if TSAT <20% Treatment adjustment algorithm: Interruption: Hb>16.0g/dL or ferritin>800µg/l or ferritin>500µg/l, if TSAT>50% Restart: Hb <16.0g/dL and serum ferritin <400µg/L and TSAT<45% Blinding: Clinical staff: unblinded and blinded personnel Patients: usage of curtains and black syringes for injections *total dose required for repletion calculated using the Ganzoni formula Anker et al. Eur J Heart Fail 2009 Improvement of all primary and secondary endpoints with i.v. ferric carboxymaltose Patient Global Assessment NYHA functional class 6-minute walk test KCCQ overall score EQ-5D VAS score Anker et al. N Eng J Med

16 Förbättring av PGA & NYHA hos CHF patienter with och utan anemi *Mean treatment effect, adjusted for the baseline value Anker SD, et al. N Eng J Med 2009;361: CONFIRM-HF Longer-term sustainability of beneficial effects and safety Potential impact on the outcomes CONFIRM-HF Study design Design: Multicentre, randomised (1:1), double-blind, placebo-controlled Main inclusion criteria: NYHA class II / III, LVEF 45% BNP > 100 pg/ml or NT-proBNP > 400 pg/ml Iron deficiency: serum ferritin <100 ng/ml or ng/ml if TSAT <20% Hb < 15 g/dl Blinding: Clinical staff: unblinded and blinded personnel Patients: usage of curtains and black syringes for injections Correction phase FCM up to 2000mg (2 x mg i.v.) Maintenance phase FCM treatment continues if ID is not corrected (500mg i.v.) Screening R FCM Placebo 1 EP: 6MWT D0 W6 W12 W24 W36 W52 Ponikowski P et al. ESC Heart Fail J

17 LSM change in 6MWT distance from baseline (m) Primary endpoint: 6-minutes walking distance at week 24 FCM improved 6MWT at week 24: FCM vs placebo: 33 m P= FCM (n=150) Placebo (n=151) Week 24 Secondary end-point: Outcome events FCM (N=150) Placebo (N=151) End-point or event Total events (n) Incidence/ (100 patient risk-year) Total events (n) Incidence/ (100 patient risk-year Time to first event Hazard ratio 95% CI P- value Death (8.9) (9.9) Death for any CV reason (8.1) (8.5) 0.89 ( ) 0.96 ( ) Hospitalisation (26.3) (37.0) 0.71 ( ) 0.14 Hospitalisation for any CV reason (16.6) (26.3) 0.63 ( ) Hospitalisation due to worsening HF (7.6) (19.4) 0.39 ( ) FCM reduced the risk of recurrent hospitalisations due to worsening HF (post-hoc): Incidence Rate Ratio (95% CI) 0.30 ( ), p= Primary end-point: Subgroup analyses Subgroup No. of patients FCM/placebo P-value for interaction Subgroup No. of patients FCM/placebo P-value for interaction Median age * Estimated GFR Age high ( 71 years) 65/55 Age low (<71 years) 65/ egfr 60 ml/min/ /72 egfr <60 ml/min/ / Median BNP BNP high ( 425 pg/ml) 66/ Gender Male 73/ BNP low (<425 pg/ml) 64/70 Female 57/67 NYHA function class Class III 60/ Median ferritin * Ferritin high ( 46 ng/ml) 65/ Class II 70/79 Heart failure aetiology Ferritin low (<46 ng/ml) 65/68 Diabetes Non-ischaemic 20/21 No 98/96 Ischaemic 110/ Yes 32/ Median LVEF (%) Haemoglobin LVEF high ( 40) 75/64 Haemoglobin 12 g/dl 86/83 LVEF (<40) 54/67 Haemoglobin <12 g/dl 44/ Difference FCM-placebo in 6MWT distance in m LSM (95% CI) Difference FCM-placebo in 6MWT distance in m LSM (95% CI) * Defined post-hoc 17

18 ESC Socialstyrelsen Prio 6 Hur gör vi? Hur borde vi göra? Behövs större studier? (Fair-HF 459 pat, CONFIRM-HF 304 pat) Mer robust primär endpoint? 18

19 Lite pragmatism Symptomvinst Kolla järnstatus på de patienter som har tydliga sviktsymptom Gör det enkelt 1000 mg ferinject som engångsdos 19