Tài liệu Suy tim mạn: Góc nhìn từ ACC 2017 - Châu Ngọc Hoa

PGS TS Chõu Ngọc Hoa Bộ mụn Nội ĐHYD Tp HCM Suy tim mạn: GểC NHèN TỪ ACC 2017 ACC Focused update on HF, 2017 Two New Pharmacological Therapies Approved by FDA for Heart Failure • Ivabradine (April 15, 2015) • Sacubitril/Valsartan (July 7, 2015) WHO, WHEN AND ON IVABRADINE WHY ADD Ivabradine approval timeline • 2005 approved in EU for angina • 2012 approved in EU for heart failure • 2015 approved in US for heart failure to reduce the risk for hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with LVEF ≤35%, who are in sinus rhythm with a resting heart rate of ≥70 beats per minute (bpm) and are taking maximally tolerated doses of beta-blockers or have a contraindication to beta-blockers. Ivabradine Blocks If channel Slows heart rate Few if any other CV effects SHIFT Trial > 6500 HF patients (NYHA II-IV) LVEF < 35% Resting HR > 70 BPM Primary endpoint: composite of CV death/HF hospitalization On maximally tolerated beta-blocker SHIFT: primary outcome CV death 40 or hospitalization for HF (%) HR= 0.82 p<0.0001 Placebo 30 20 10 Months 12 18 24 6 lvabradine Swedberg K., et al. Lancet.2010;376:875-885 SHIFT: HF hospitalization Hospitalization for HF (%) 30 HR= 0.74 Placebo 20 10 Months 6 12 18 24 30 Swedberg K, et al. Lancet. 2010;376:875-885. Ivabradine in HF Up-titrate beta blocker dose as much as possible Add on therapy to beta blocker; not replacement Does not lower blood pressure Contraindicated in atrial fibrillation Benefit greater in patients with higher baseline heart rate Startingdose(mg) Targetdose(mg) ACEI Enalapril 2.5b.i.d 10-20b.i.d Lisinopril 2.5-5.0o.d 20-35o.d Ramipril 2.5o.d 5b.i.d Beta-blocker Bisoprolol 1.25o.d 10o.d Carvedilol 3.125b.i.d 25-50b.i.d Metoprololsuccinate 12.5/25o.d 200o.d MRA Eplerenone 25o.d 50o.d Spironolactone 25o.d 25-50o.d IfInhibitor Ivabradine 5b.i.d 7.5b.i.d Target doses as defined in the ESC guidelines Can we reach and maintain „target” dose in „real-life” elderly HF patients with comorbidities ? CIBIS-ELD – 883 elderly HF patients; The primary endpoint: tolerability, defined as reaching and maintaining guideline- recommended target doses after 12 weeks treatment. Dungen HD, et al. Eur J Heart Fail. 2011:13:670–680. Trials Targetdose (mg) Time to reach target/max tolerated dose ACEI Enalapril SOLVD 10b.i.d Notspecified Lisinopril ATLAS 35o.d 4weeks Beta-blocker Bisoprolol CIBISII 10o.d 11weeks Carvedilol COPERNICUS 25b.i.d 6weeks Metoprololsuccinate MERITHF 200o.d 6weeks Nebivolol SENIORS 10o.d 6weeks MRA Eplerenone EMPHASIS-HF 50o.d 4weeks IfInhibitor Ivabradine SHIFT 7.5b.i.d 2weeks 1- The SOLVD Investigators. N Engl J Med.1991;325:293-302. 2- Packer M, et al. Circulation. 1999;100:2312-2318. 3- CIBIS-II study group. Lancet.1999;353:9-13. 4- Packer M, et al. Circ. 2002;106:2194-2199. 5- Merit-HF study group. Lancet.1999;353:2001- 2007. 6- Zannad F, et al. N Engl J Med. 2011:364:11-21. 7- Swedberg K, et al. . Lancet 2010;376: 875-885. Up-titration period as defined in the landmark trials Uptitration target in stable HF patients . Dose Beta-blockers 6 weeks ACEIs 4 weeks MRAs 4 weeks Ivabradine 2 weeks Reasons for non-reaching target dose CIBIS-ELD: RCT aimed to reach guideline-recommended target doses 883 HF patients, NYHA II-IV, >65 y, no contraindication or intolerance to BB Dungen HD, et al. Eur J Heart Fail. 2011:13:670–680. Yes but My Patient - is too old - has low blood pressure - has COPD - has renal impairment - is too sick Treatment Effect of Ivabradine According to Blood Pressure Komajda M, et al. Eur Heart J. 2013;34 (Abst. Suppl), 610. N at risk COPD (pl) COPD (iva) NCOPD (pl) NCOPD (iva) 372 358 2892 2883 298 312 2570 2616 250 266 2239 2334 209 216 1852 1957 110 124 979 1067 0 6 12 18 24 Patients (%) 50 45 40 35 30 25 20 15 10 5 0 Time (months) Effect of ivabradine on composite of CV death or HF hospitalization COPD (placebo) COPD (ivabradine) Non-COPD (placebo) Non-COPD (ivabradine) Tavazzi L, et al. Eur Heart J. 2013;34 (Abst. Suppl), 652. 0 6 12 18 24 30 Patients (%) 50 40 30 20 10 0 Time (months) Effect of ivabradine on composite of CV death or HF hospitalization Placebo, renal dysfunction Ivabradine,renal dysfunction Placebo, no renal dysfunction Ivabradine, no renal dysfunction Voors A, et al. Eur Heart J. 2013;34 (Abst. Suppl). N at risk RD (pl) RD (iva) NRD (pl) NRD (iva) 799 780 2293 2288 706 720 2119 2166 612 612 1847 1963 488 489 1551 1662 261 273 820 906 95 104 343 339 Effect of early treatment of Ivabradine with BBs vs BB alone in patients hospitalized for WHF: randomized ETHIC study LV EF , % Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11 n=71 patients hospitalized for WHF P=0.039 Greater improvement in LVEF 29.8 32.9 44.8 29.9 31.9 38.1 10. 19. 28. 37. 46. 55. Admission Dicharge 4 months FU Ivabradine + BB BB alone P=0.039 Effect of early treatment of Ivabradine with BBs vs BB alone in patients hospitalized for WHF: randomized ETHIC study n=71 patients hospitalized for WHF 1469 463 259 1061 671 554 100 475 850 1225 1600 Admission Dicharge 4 months FU Ivabradine + BB BB alone Better reduction in BNP P=0.02 B N P , p g/ m l Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11 Effect of early treatment of Ivabradine with BBs vs BB alone in patients hospitalized for WHF: randomized ETHIC study n=71 patients hospitalized for WHF Better HR control 87.3 70.1 60.6 88.4 73.9 67.8 50. 60. 70. 80. 90. 100. Admission Dicharge 4 months FU Ivabradine + BB BB alone H R , b p m Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11 Background Romans used a non-Digoxin cardiac glycoside derived from sea onion Used sporadically in Middle Ages but popularized in 18th century Used for dropsy and recognized to decrease edema and slow HR Withering in 1785 published an account of 156 patients successfully treated including Erasmus Darwin “That it has a power over the motion of the heart, to a degree yet unobserved in any other medicine, and this power may be converted to salutary ends” Withering, 1775 Background Inhibits Cardiac isoform of Na/K ATPase which indirectly increases intracellular Ca concentration • Increased cardiac output in low output states without increased oxygen consumption • Decreases PCWP • Improves baroreceptor sensitivity in the carotid which may decrease RAAS activation • Increases AV node refractory period by increasing vagal tone tea++ \ tTN-C --- t1notropy Ca" binding All-cause death HF hospitalization Composite outcome 23780 pts with HFrEF, 4194 (18%) receiving Digoxin All-cause death Composite outcome HF hospitalization HF hospitalization All-cause death Composite outcome Conclusions • Digoxin was associated with decreased risk of HF hospitalization in HFrEF with permanent AF • Digoxin was associated with increased risk of death in HFrEF with sinus rhythm or concomitant paroxysmal AF • Digoxin was neutral for other patient categories and outcomes The human face of heart failure Hypertension Angina Diabetes Atrial fibrillation Prostatic disease Depression Cognitive impairment Arthritis Cachexia Renal impairment Parkinson’s disease Two New Pharmacological Therapies Approved by FDA for Heart Failure • Ivabradine (April 15, 2015) • Sacubitril/Valsartan (July 7, 2015) Over 1 million hospitalizations for HF annually in US and in Europe 33 Mor ta l i t y i n HF rE F rema ins h i gh desp i t e new the rap ies t ha t imp rove su rv i va l ▪ Survival rates in chronic HF have improved with the introduction of new therapies1 ▪ However, significant mortality remains – ~50% of patients die within 5 years of diagnosis6–8 16% (4.5% ARR; mean follow up of 41.4 months) SOLVD1,2 34% (5.5% ARR; mean follow up of 1.3 years) CIBIS-II3 R e d u c ti o n i n r e la ti v e r is k o f m o rt a lit y v s p la c e b o 30% (11.0% ARR; mean follow up of 24 months) RALES4 17% (3.0% ARR; median follow up of 33.7 months) CHARM- Alternative5 ACEI* β-blocker* MRA* ARB* • Quality of life for patients with HF is:1 – Worse than those with diabetes – Similar to those with Parkinson’s disease or motor neuron disease • Patients may require assistance with daily activities such as taking their medication2,3 – Caregiver burden can be substantial3,4 Quality of life is worse in patients with HF than in those suffering from other chronic conditions 1. Calvert et al. Eur J Heart Fail 2005;7:243–51; 2. Boyd et al. Eur J Heart Fail 2004;6:585–591; 3. Clark et al. J Adv. Nurs. 2008;61:373–83; 4. Saunders. West J Nurs Res 2008;30:943–59. HF=heart failure; NYHA=New York Heart Association Mean EQ-5D in patients with NYHA class III/IV HF compared with general population & other chronic diseases1 0. 0.23 0.45 0.68 0.9 1.13 EQ-5D Index score General population General population age 65–74 HF patients NYHA III/IV Type 2 diabetes Mild motor neuron disease Moderate motor neuron disease Parkinson’s disease Hospitalized after ischemic stroke 3-month assessment post-stroke Non–small cell lung cancer HFrEF SYMPTOMS & PROGRESSION Overactivation of RAAS & SNS is detrimental in HFrEF and underpins the basis of therapy 1. McMurray et al. Eur Heart J 2012;33:1787–847; Figure References: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–71; Schrier & Abraham. N Engl J Med 2009;341:577–85 ACEI: angiotensin-converting-enzyme inhibitor; Ang: angiotensin; ARB: angiotensin receptor blocker; AT1R: angiotensin II type 1 receptor; MRA: mineralocorticoid receptor antagonist; NPs: natriuretic peptides; NPRs: natriuretic peptide receptors; RAAS: renin-angiotensin-aldosterone system; SNS: sympathetic nervous system Epinephrine Norepinephrine α1, β1, β2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility Sympathetic nervous system Ang II AT1R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis Renin-angiotensin- aldosterone-system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy Natriuretic peptide system1 • The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1 • Benefits of β-blockers indicate that the SNS also plays a key role1 ▪ Wall stress as a result of volume expansion or pressure overload induces the synthesis of precursors of NPs2 ▪ The NP system consists mainly of three peptides: ANP, BNP and CNP7 • ANP is produced primarily in the atrial myocardium • BNP is produced primarily in the ventricular myocardium • CNP predominates in brain, kidney, vascular endothelial cells and plasma The NP system6 NT-proBNP (aa1-aa76) BNP1–32 (aa77-aa108) BNP3–32 BNP7–32 DPP-IV Meprin A proBNP (aa1-aa108) Cleavage Pre-proBNP Natriuretic peptides are cleared by NPR-C and neprilysin ANP: atrial natriuretic peptide; Ang: angiotensin; AT1: angiotensin II type 1; BNP: B-type natriuretic peptide; cGMP: cyclic guanosine monophosphate; CNP: C-type natriuretic peptide; GTP: guanosine triphosphate; HF: heart failure; NP: natriuretic peptide; NPR: natriuretic peptide receptor; RAAS: renin-angiotensin-aldosterone system Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26; Molkentin. J Clin Invest 2003;111:1275–77; Nishikimi et al. Cardiovasc Res 2006;69:318–28; Guo et al. Cell Res 2001;11:165–80; Von Lueder et al. Circ Heart Fail 2013;6:594–605; Yin et al. Int J Biochem Cell 2003;35:780–3; Mehta & Griendling. Am J Physiol Cell Physiol 2007;292:C82–97 Signaling cascades GTP GTP cGMP Inactive peptides ANP/CNP ANP BNP NPR-A CNP NPR-B Inactive NP fragments ANP/CNP/BNP NPR-C Ang II AT1 receptor Internalization Receptor recycling Neprilysin Vasodilation Cardiac fibrosis/hypertrophy Natriuresis/diuresis Vasoconstriction Cardiac fibrosis/hypertrophy Sodium/water retention NP signaling and effects RAAS over-activation in HF NP degradation and clearance Neprilysin has many substrates that are metabolized with differing levels of affinity Metabolism of natriuretic and other vasoactive peptides* by NEP1–9 1. Erdos, Skidgel. FASEB J 1989;3:145–51; 2. Levin et al. N Engl J Med 1998;339;321–8; 3. Stephenson et al. Biochem J 1987;243:183–7; 4. Lang et al. Clin Sci 1992;82:619–23; 5. Kenny et al. Biochem J 1993;291:83–8; 6. Skidgel et al. Peptides 1984;5:769–76; 7. Abassi et al. Metabolism 1992;41:683–5; 8. Murphy et al. Br J Pharmacol 1994;113:137–42; 9. Jiang et al. Hypertens Res 2004;27:109–17; 10. Langenickel & Dole. Drug Discovery Today: Ther Strateg 2012;9:e131–9; 11. Richards et al. J Hypertens 1993;11:407–16; 12. Ferro et al. Circulation 1998;97:2323–30 Relative affinity for NEP ANP and CNP Endothelin Substance P Bradykinin Ang II Adrenomedullin Ang I NEP Inactive fragments or metabolites Implications for NEP inhibition ▪ NEP substrates can have opposing biological actions10 ▪ Overall effect is dependent upon the net effect on NEP metabolism of individual substrates10 ▪ Benefits in enhancing NP system may be offset by increased Ang II11 ▪ Needs to be complemented by simultaneous RAAS suppression2,11,12 *Not an exhaustive list of all neprilysin substrates; the most relevant substrates for cardiovascular physiology are listed BNP Ang=angiotensin; ANP=atrial natriuretic peptide; BNP=B-type natriuretic peptide; CNP=C-type natriuretic peptide; NEP=neprilysin; NP=natriuretic peptide; RAAS=renin angiotensin aldosterone system ▪ NEP inhibitors: natriuretic and other vasoactive peptides enhancement Evolution of pharmacologic approaches in HF: Neprilysin inhibition as a new therapeutic strategy in patients with HF1 SNS RAAS Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis Ang II AT1R HF SYMPTOMS & PROGRESSION INACTIVE FRAGMENTS NP system Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy NPRs NPs Epinephrine Norepinephrine α1, β1, β2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility Neprilysin inhibitors RAAS inhibitors (ACEI, ARB, MRA) β-blockers 1. McMurray et al. Eur J Heart Fail. 2013;15:1062–73; Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier & Abraham N Engl J Med 2009;341:577–85 ACEI=angiotensin-converting-enzyme inhibitor; Ang=angiotensin; ARB=angiotensin receptor blocker; AT1 = angiotensin II type 1; HF=heart failure; MRA=mineralocorticoid receptor antagonist; NEP=neprilysin; NP=natriuretic peptide; NPRs=natriuretic peptide receptors; RAAS=renin- angiotensin-aldosterone system; SNS=sympathetic nervous system 40 Primary endpoint: death from CV causes or first hospitalization for HF CI: confidence interval; CV: cardiovascular; HF: heart failure McMurray et al. N Engl Med 2014;371:993–1004. C u m u la ti v e p ro b a b il it y 0.4 0 1.0 0.6 0.2 0 180 360 540 720 900 1,080 1,260 4,187 3,922 3,663 3,018 2,257 1,544 896 249 4,212 3,883 3,579 2,922 2,123 1,488 853 236 LCZ696 Enalapril No. at risk Hazard ratio = 0.80 (95% CI: 0.73–0.87) p<0.001 Enalapril LCZ696 Days since randomization Who, When, and How to Transition to Sacubitril/Valsartan 1) 2) 3) 4) 5) Sacubitril/Valsartan was studied in mild-moderate HF. Do not wait for patients to deteriorate! Data is lacking for inpatients and the ACE/ARB naùve. Stop ACE 36 hours prior to starting sacubitril/valsartan. Go low and slow with dose titration. Dose Selection and Titration High Dose ACE/ARB 49-51 mg BID Consider Low Dose ACE/ARB 24-26 mg BID ACE/ARB_ Start ,_Cons_ider v l No ACE/ARB J Monitor for Adverse Effects High Risk: Older, lower SBP, higher Cr, higher NT-proBNP, worse NYHA class, diabetes (from Vardeny EJHF 2016) Wait at least 2-4 weeks before doubling the dose. Hypotension Check BP and for symptoms of hypotension. Hyperkalemia Check serum K+ before dose change. Renal Dysfunction Check serum Cr before dose change. Biomarkers BNP falsely elevated. Follow NT-proBNP. Populations, trials and guidelines All patients Clinical trial inclusion/ exclusion criteria Clinical trial – actual patients randomized Guidelines 47