Terapia Farmacologica della Insufficienza Cardiaca Cronica: è in arrivo una rivoluzione? Gennaro Cice Cattedra di Cardiologia Seconda Università di Napoli 60 CONGRESSO NAZIONALE SIGG NAPOLI, 25-28 NOVEMBRE 2015
HEMODINAMYC HYPOTHESY OF HEART FAILURE CHRONICAL ARTERO-VENOUS CONSTRICTION REDUCED RENAL PERFUSION SKELETAL MUSCLE REDUCED PERFUSION INCREASED PRELOAD AND AFTERLOAD INCREASED SODIUM AND WATER RETENCTION LEFT VENTRICULAR HYPERTROPHY-DILATATION OEDEMA PULMONARY CONGESTION REDUCED TOLERANCE TO PHISICAL STRESS G. Cice
NEURO-ENDOCRINE HYPOTHESY OF HEART FAILURE LEFT VENTRICULAR REMODELLING/DYSFUNCTION HYPERTROPHY FIBROSIS APOPTOSIS MYOCARDIAL DAMAGE CARDIAC OUTPUT CONTRACTILE DISFUNTION PERPHERAL AND PULMONARY CONGESTION CARDIAC WORK BLOOD PRESSURE BLOOD FLOW LEFT VENTRICULAR FILLING PRESSURE INOTROPIC AND CHRONOTROPIC ACTION ARTERO-CONSTRICTION AFTERLOAD NEURO-HORMONAL ACTIVATION VENOCONSTRICTION PRELOAD TISSUTAL IPOPERFUSION RENAL ISCHAEMIA CIRCULATING VOLUME IDRO-SALINE RETENTION G. Cice
Event-free survival Probabiility of Death RAAS INHIBITORS 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 CONSENSUS N Engl J Med 1987 Placebo p< 0.001 Enalapril % 50 40 30 20 10 CHARM-Alternative Placebo 406 (40.0%) 334 (33.0%) Candesartan HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001 0 0 1 2 3 4 5 6 7 Months 8 9 10 11 12 0 0 1 2 3 3.5 years Mortality % 30 20 AIRE Lancet 1993 10 0 0 6 Placebo Ramipril p = 0.002 12 18 24 30 1.000 0.914 0.829 0.743 0.657 0.571 0.486 0.400 Val-HeFT Risk reduction: 33,1% p= 0.0002 Valsartan Placebo 0 3 6 9 12 15 18 21 24 27 Months Time since randomization (months) G. Cice
Cumulative Incidence (%) Pitt et al.. N Engl J Med 1999 B.Pitt et al.:nejm 2003;348:1309-21 Zannad F- N Engl J Med 2011;364:11-21. % Survival DeathfromAnyCause(%) ARA: ALL-CAUSE MORTALITY 1.00 0.90 0.80 0.70 RALES N=1663 EF<35% F.U. 24 m Spironolactone 100 60 30 EMPHASIS-HF Hazard ratio, 0.76 (95% CI, 0.62 0.93) P=0.008 PLACEBO 0.60 Placebo 0.50 RR=30% p< 0.001 0.40 0 6 12 18 24 30 36 Months EPLERENONE 0 0 1 2 3 Years since randomization 40 35 30 25 20 15 10 5 0 death from any cause EPHESUS Placebo Eplerenone P = 0.008 RR= 0.85 (95% CI, 0.75-0.96) 0 3 6 9 12 15 18 21 24 27 30 33 36 Months since randomization
Survival Mortality (%) Survival 1.0 0.9 0.8 0.7 0.6 0.5 Risk reduction 65% p<0.001 Carvedilol Placebo US Carvedilol NEJM 1996 0 50 100 150 200 250 300 350 400 Days -BLOCKERS ALL-CAUSE MORTALITY 1.0 Bisoprolol 20 MERIT-HF Lancet 1999 Placebo 0.8 0.6 p<0.0001 Placebo Risk reduction 34% CIBIS-II Lancet 1999 15 10 5 Risk reduction 34% p=0.0062 Metoprolol CR/XL 0 0 200 400 600 800 Time after inclusion (days) 0 0 3 6 9 12 15 18 21 Months of follow-up G. Cice
HF CLASSIFICATION ACC/AHA NYHA STAGE A Asymptomatic with no heart damage but have risk factors for heart failure NYHA I No symptoms and no limitation in ordinary physical activity STAGE B STAGE C STAGE D Asymptomatic left ventricular dysfunction Have symptoms and heart damage End-stage disease NYHA II Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity NYHA III Marked limitation in activity due to symptoms, even during less-than-ordinary activity. Comfortable only at rest. NYHA IV Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. ACC/AHA guidelines, 2005
SUMMARY OF DRUG TREATMENT FOR CHF Asymptomatic LV Dysfunction ACE inhibitor Beta blocker Mild to Moderate CHF ACE inhibitor and/or ARB Beta blocker+ivabradine Diuretics Digoxin (?) Moderate to Severe CHF ACE inhibitor and/or ARB Beta blocker+ivabradine Diuretics Digoxin Spironolactone ESC - CHF guidelines - update 2012
All cause mortality (%) PROGNOSIC VALUE OF LVEF<35% 12 10 8 6 4 2 0 <35% >35% 0 2 4 6 8 10 12 months SOLD REGISTRY DATA
Fraction of patients Fraction of patients LV EF RESPONSE IMPACTS ON MORTALITY AND HOSPITALISATIONS Freedom from cardiac death Freedom from cardiac death or hospitalisation 1.00 LV EF > 15 95% 1.00 LV EF > 15 0.80 LV EF < 15 77% 0.80 79% 0.60 0.60 LV EF < 15 59% 0.40 0.40 0.20 P < 0.001 0.20 P < 0.001 0 0 6 12 18 24 Time (months) 0.00 0 6 12 18 24 Time (months) Metra M et al. Am Heart J 2003
End-diastolic Volume (cc) End-systolic Volume (cc) Ejection Fraction ACE Inhibition Prevents Remodelling: SOLVD Echocardiographic Substudy 220 P = 0.025 160 P = 0.019 0.40 210 200 155 150 145 0.30 0.20 190 140 0.10 0 0 4 12 0 4 12 0 4 12 Month Month Month Placebo n = 130 130 142 Enalapril n = 128 127 137 Greenberg B et al. Circulation 1995
LVESVI (biplane) [ml/m 2 ] Primary Endpoint: LVESVI Comparison Between Treatments 0 Baseline Month 6 Month 12 Month 18-1 -2-3 NS P < 0.002-4 P < 0.05-5 -6-7 P values for BL to M6, M12, M18 Carvedilol & Enalapril Carvedilol Enalapril Poole-Wilson PA et al. Lancet 2003;362:7-13
LVEF (%) LVEF: Change From Baseline Within Treatment-arm Comparison 5 4 3 Carvedilol & Enalapril *** *** *** Carvedilol *** *** ** Enalapril 2 * 1 0-1 M6 M12 M18 M6 M12 M18 M6 M12 M18 * P < 0.05; ** P < 0.01; *** P < 0.001 Poole-Wilson PA et al. Lancet 2003;362:7-13
Survival (%) SURVIVAL RATES IN CHF PATIENTS SOLVD-PREVENTION 100 ACE-i+BB BB ENALAPRIL NOTHING 90 80 0 365 730 1095 1460 days of follow-up J Am Coll Cardiol, 1999; 33:916-23
Survival (%) SURVIVAL RATES IN CHF PATIENTS SOLVD-TREATMENT 100 90 ACE-i+BB BB ENALAPRIL NOTHING 80 70 60 0 365 730 1095 1460 days of follow-up J Am Coll Cardiol, 1999; 33:916-23
LANDMARK TRIALS IN CHF AIRE, TRACE SOLVD V-HeFT II SAVE, ISIS-4 Hy-C CONSENSUS CIBIS III SENIORS COMET COPERNICUS captopril propranolol Potential benefit: vasodilatation Beta-blockers contra-indicated Recognition of neurohormonal activation USCP MERIT-HF CIBIS II CHARM US-CARVEDILOL Val-HeFT ELITE II CIBIS MDC VALIANT OPTIMAAL Heart Rate therapeutic target in HF SHIFT EMPHASIS - HF losartan EPHESUS spironolactone RALES 1960 1970 1980 1990 2000 2011 courtesy of P.Ponikowski
RENEWAL ETANERCEPT anti TNF-a 2002 ENABLE BOSENTAN endothelin-blk 2002 MILRINONE EARTH DARUSENTAN Endothelin-i 2004 PROTECT ROLOFILLIN Adenosine-ago 2011 DIG-TRIAL DIGITALIS Inotrope 1997 FUSION NESIRITIDE 2006 PRIME II IBOPAMINE Ino-dilator 1997 SURVIVE LEVOSIMWENDAN 2007 FLOSEQUINAN vasodilator 2000 MONOXIDINE COMPOSE CINACIGUAT Guanliat cyclase act 2012 NECTAR-HF VAGAL-STIM 2014 OVERTURE OMAPATRILAT vasopeptidase-i 2002 G. Cice
G. Cice
LCZ696 Valsartan/Sacubitril Combination drug of valsartan and sacubitril, in a 1:1 mixture Dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) although the two effects are achieved by two different molecules Valsartan blocks the angiotensin II receptor type 1 (AT 1 ) Sacubitril is a progrug activated to LBQ657 by de-ethylation via esterases LBQ657 inhibits the enzyme neprilysin,which is responsible for the degradation of atrial and brain natriuretic peptide G. Cice
OPPOSITE FORCES IN HEART FAILURE Renin-Angiotensin-Aldosterone Endothelin Catecholamines Vasodilation natriuresis/diuresis Cardiac stress Remodelling Vasoconstriction Sodium/fluid retention Chronic cardiac stress Tissue remodelling/fibrosis Natriuretic Peptides G. Cice
G. Cice NP system HEART FAILURE RAS NPs Ang II AT 1 receptor Vasodilation BP Sympathetic tone Aldosterone Fibrosis Hypertrophy Natriuresis/diuresis HF symptoms progression Vasoconstriction BP Sympathetic tone Aldosterone Fibrosis Hypertrophy Ferro Circulation 1998;97:2323 30; Levin N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier Kidney Int 2000;57:1418 25; Schrier & Abraham. N Engl J Med 1999;341:577 85; Stephenson Biochem J. 1987;241:237 47; Langenickel, Dole. Drug Discov Today: Ther Strategies 2014
G. Cice NP system HEART FAILURE LCZ696 RAS NPs Neprilysin Ang II Inactive fragments AT 1 receptor Vasodilation BP Sympathetic tone Aldosterone Fibrosis Hypertrophy Natriuresis/diuresis HF symptoms progression Vasoconstriction BP Sympathetic tone Aldosterone Fibrosis Hypertrophy Ferro Circulation 1998;97:2323 30; Levin N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier Kidney Int 2000;57:1418 25; Schrier & Abraham. N Engl J Med 1999;341:577 85; Stephenson Biochem J. 1987;241:237 47; Langenickel, Dole. Drug Discov Today: Ther Strategies 2014
PARADIGM-HF: Study Design NYHA class II-IV heart failure with LV ejection fraction 40% BNP 150 (or NT-proBNP 600), or 400 if hospitalized for heart failure within 12 months Beta-blockers and mineralocorticoid receptor antagonists and use of ACE inhibitor or ARB able to tolerate dose equivalent to enalapril 10 mg daily for at least 4 weeks Systolic BP 95 mm Hg, egfr 30 ml/min/1.73 m 2 and serum K 5.4 meq/l Primary endpoint was cardiovascular death or hospitalization for heart failure, but sample-size of the PARADIGM-HF was defined on the basis of cardiovascular mortality alone G. Cice
PARADIGM-HF: Study Design Randomization Single-blind run-in period Double-blind period LCZ696 200 mg BID Enalapril LCZ696 (1:1 randomization) 10 mg BID 100 mg BID 200 mg BID Enalapril 10 mg BID 2 weeks 1-2 weeks 2-4 weeks G. Cice
PARADIGM-HF: Study Population 8399 patients randomized for ITT analysis LCZ696 (n=4187) Enalapril (n=4212) Age (years) 63.8 ± 11.5 63.8 ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3 NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9% Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15 Heart rate (beats/min) 72 ± 12 73 ± 12 N-terminal pro-bnp (pg/ml) 1631 (885-3154) 1594 (886-3305) B-type natriuretic peptide (pg/ml) 255 (155-474) 251 (153-465) 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% G. Cice
Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: PRIMARY ENDPOINT CARDIOVASCULAR DEATH OR HF HOSPITALIZATION 40 32 HR = 0.80 (0.73-0.87) P = 0.0000002 Enalapril (n=4212) 1117 914 24 LCZ696 (n=4187) 16 8 NNT=21 Patients at Risk 0 0 180 360 540 720 900 1080 1260 Days After Randomization LCZ696 Enalapril 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236 McMurray, et al. N Engl J Med 2014
Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: CARDIOVASCULAR DEATH 32 24 HR = 0.80 (0.71-0.89) P = 0.00004 Enalapril (n=4212) 693 558 16 8 NNT=32 LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril 0 0 180 360 540 720 900 1080 1260 4187 4212 4056 4051 3891 3860 Days After Randomization 3282 3231 2478 2410 1716 1726 1005 994 280 279 McMurray, et al. N Engl J Med 2014
Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: ALL-CAUSE MORTALITY 32 HR = 0.84 (0.76-0.93) P<0.0001 Enalapril (n=4212) 835 24 711 16 LCZ696 (n=4187) 8 Patients at Risk 0 0 180 360 540 720 900 1080 1260 Days After Randomization LCZ696 Enalapril 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 McMurray, et al. N Engl J Med 2014
Patients No PARADIGM-HF: ADVERSE EVENTS 700 600 500 400 300 200 100 0 Symptomatic hypotension Serum potassium >6.0 mmol/l Serum creatinine 2.5 mg/dl Cough Angioedema LCZ-696 ENALAPRIL McMurray, et al. N Engl J Med 2014
Patients No PARADIGM-HF: PROGRESSION, SEVERITY AND QUALITY OF LIFE 1200 1000 800 600 400 200 0-0,5-1 -1,5-2 -2,5-3 -3,5-4 -4,5 0 intensification of medical treatment hospitalizations for worsening heart failure intensive care needs -5 *KCCQ LCZ-696 Enalapril Mod. *McMurray, et al. N Engl J Med 2014 Packer M, et al. Circulation 2015
PARADIGM-HF: PRIMARY OUTCOME BY AGE p for interaction=0.94 for treatment by age Hazard ratio (95% CI) All patients (n=8,399) 0.80 (0.73 0.87) Age category (year) <55 (n=1,624) 0.78 (0.64 0.96) 55 64 (n=2,655) 0.76 (0.65 0.90) 65 74 (n=2,557) 0.80 (0.68 0.93) 75 84 (n=1,442) 0.84 (0.69 1.03) >85 (n=121) 0.96 (0.54 1.70) Favors LCZ696 0.80 1.00 Hazard ratio Favors enalapril McMurray et al. Eur J Heart Fail 2015;17(Suppl 1):143 (Abstract 689)
McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: 10.1056/NEJMoa1409077.
EVOLUTION OF PHARMACOLOGIC THERAPY IN HF Sympathetic nervous system Epinephrine Norepinephrine α 1, β 1, β 2 receptors Natriuretic Peptide System β-blockers NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy Neprilysin inhibitors LCZ696 Renin angiotensin aldosterone system Ang II AT 1 R RAAS inhibitors (ACEI, ARB, MRA)
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Patients who discontinued study drug for hypotension (%) PARADIGM-HF: DISCONTINUATION FOR HYPOTENSION 2 1.5 During run-in 1 * 1.4 % 1.7 % Following randomization 1,2 p=0.38 1 0.5 0.7 % 0.9 % 0 n=10,513 n=9,419 n=4,212 n=4,187 Enalapril period 2 weeks 10 mg b.i.d. LCZ696 period 1 2 weeks 100 mg b.i.d.; 2 4 weeks 200 mg b.i.d. Median 27 months follow-up LCZ696 Enalapril 1. Bohm et al. Eur J Heart Fail 2015;17(Suppl 1):393 (Abstract P1794); 2. McMurray et al. N Engl J Med 2014;371:993 1004; 3. McMurray et al. Eur J Heart Fail 2013;15:1062 73
PARADIGM-HF: TAKE HOME MESSAGES CONCLUSIONS FROM PUBLICATION angiotensin receptor neprilysin inhibition with LCZ696 was superior to ACE inhibition alone in reducing the risks of death and of hospitalization for HF The magnitude of the beneficial effect of LCZ696, as compared with enalapril, on CV mortality was at least as large as that of long-term treatment with enalapril, as compared with placebo. This robust finding provides strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the RAS alone in patients with chronic HF. results are applicable to a broad spectrum of patients with HF, including those who are currently taking an ACE inhibitor or ARB or who are likely to be able to take such an agent without having unacceptable side effects. McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: 10.1056/NEJMoa1409077. G. Cice
% Decrease in Mortality DRUGS THAT IMPROVE PROGNOSYS IN HF 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% Ivabradine Based on results of SOLVD-Treatment, CHARM-Alternative, OPERNICUS, MERIT-HF, CIBIS II, RALES EMPHASIS-HF SHIFT
PARADIGM-HF: TAKE HOME MESSAGES In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril on top of B-Blocker and ARA: LCZ696 was more effective than enalapril in Reducing the risk of CV death and HF hospitalization Reducing the risk of CV death by incremental 20% Reducing the risk of HF hospitalization by incremental 21% Reducing all-cause mortality by incremental 16% Incrementally improving symptoms and physical limitations LCZ696 was better tolerated than enalapril Less likely to cause cough, hyperkalemia or renal impairment Less likely to be discontinued due to an adverse event More hypotension, but no increase in discontinuations Not more likely to cause serious angioedema G. Cice
Mortality Increase in Life Expectancy by Enalapril in Combined SOLVD Trials 0.8 p=0.004 0.7 0.6 0.5 0.4 0.3 0.2 Median Life Expectancy Difference of 9.4 months 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 http://www.phri.ca/x-solvd/ Years after Randomization Enalapril (n=472)* Placebo (n=448)* * Number of patients alive at 12 years
PARADIGM-HF may well represent a new threshold of hope for patients with HF Now, a novel drug, LCZ696, a dual inhibitor of angiotensin II receptor and neprilysin, may prove to be the first disruptive agent to the heart-failure treatment algorithm, which has remained essentially unchanged for a decade The beneficial results seen in PARADIGM-HF may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy Jessup. N Engl J Med 2014; epub ahead of print: DOI: 10.1056/NEJMe1409898 G. Cice
NEURO-ENDOCRINE EFFECTS OF HF Sympathetic nervous system Epinephrine Norepinephrine α 1, β 1, β 2 receptors Natriuretic Peptide System NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy Vasoconstriction RAAS activity Vasopressin Heart rate Contractility Renin angiotensin aldosterone system Ang II AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis
PARADIGM-HF: ADVERSE EVENTS LCZ696 (n=4187) Enalapril (n=4212) P Value Prospectively identified adverse events Symptomatic hypotension 588 388 < 0.001 Serum potassium > 6.0 mmol/l 181 236 0.007 Serum creatinine 2.5 mg/dl 139 188 0.007 Cough 474 601 < 0.001 Discontinuation for adverse event 449 516 0.02 Discontinuation for hypotension 36 29 NS Discontinuation for hyperkalemia 11 15 NS Discontinuation for renal impairment 29 59 0.001 Angioedema (adjudicated) Medications, no hospitalization 16 9 NS Hospitalized; no airway compromise 3 1 NS Airway compromise 0 0 ---- McMurray, et al. N Engl J Med 2014