Terapia Farmacologica della Insufficienza Cardiaca Cronica: è in arrivo una rivoluzione? Gennaro Cice

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1 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, NOVEMBRE 2015

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3 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

4 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

5 Event-free survival Probabiility of Death RAAS INHIBITORS CONSENSUS N Engl J Med 1987 Placebo p< Enalapril % CHARM-Alternative Placebo 406 (40.0%) 334 (33.0%) Candesartan HR 0.77 (95% CI ), p= Adjusted HR 0.70, p< Months years Mortality % AIRE Lancet Placebo Ramipril p = Val-HeFT Risk reduction: 33,1% p= Valsartan Placebo Months Time since randomization (months) G. Cice

6 Cumulative Incidence (%) Pitt et al.. N Engl J Med 1999 B.Pitt et al.:nejm 2003;348: Zannad F- N Engl J Med 2011;364: % Survival DeathfromAnyCause(%) ARA: ALL-CAUSE MORTALITY RALES N=1663 EF<35% F.U. 24 m Spironolactone EMPHASIS-HF Hazard ratio, 0.76 (95% CI, ) P=0.008 PLACEBO 0.60 Placebo 0.50 RR=30% p< Months EPLERENONE Years since randomization death from any cause EPHESUS Placebo Eplerenone P = RR= 0.85 (95% CI, ) Months since randomization

7 Survival Mortality (%) Survival Risk reduction 65% p<0.001 Carvedilol Placebo US Carvedilol NEJM Days -BLOCKERS ALL-CAUSE MORTALITY 1.0 Bisoprolol 20 MERIT-HF Lancet 1999 Placebo p< Placebo Risk reduction 34% CIBIS-II Lancet Risk reduction 34% p= Metoprolol CR/XL Time after inclusion (days) Months of follow-up G. Cice

8 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

9 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

10 All cause mortality (%) PROGNOSIC VALUE OF LVEF<35% <35% >35% months SOLD REGISTRY DATA

11 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 > LV EF < 15 77% % LV EF < 15 59% P < P < Time (months) Time (months) Metra M et al. Am Heart J 2003

12 End-diastolic Volume (cc) End-systolic Volume (cc) Ejection Fraction ACE Inhibition Prevents Remodelling: SOLVD Echocardiographic Substudy 220 P = P = Month Month Month Placebo n = Enalapril n = Greenberg B et al. Circulation 1995

13 LVESVI (biplane) [ml/m 2 ] Primary Endpoint: LVESVI Comparison Between Treatments 0 Baseline Month 6 Month 12 Month NS P < P < P values for BL to M6, M12, M18 Carvedilol & Enalapril Carvedilol Enalapril Poole-Wilson PA et al. Lancet 2003;362:7-13

14 LVEF (%) LVEF: Change From Baseline Within Treatment-arm Comparison Carvedilol & Enalapril *** *** *** Carvedilol *** *** ** Enalapril 2 * M6 M12 M18 M6 M12 M18 M6 M12 M18 * P < 0.05; ** P < 0.01; *** P < Poole-Wilson PA et al. Lancet 2003;362:7-13

15 Survival (%) SURVIVAL RATES IN CHF PATIENTS SOLVD-PREVENTION 100 ACE-i+BB BB ENALAPRIL NOTHING days of follow-up J Am Coll Cardiol, 1999; 33:916-23

16 Survival (%) SURVIVAL RATES IN CHF PATIENTS SOLVD-TREATMENT ACE-i+BB BB ENALAPRIL NOTHING days of follow-up J Am Coll Cardiol, 1999; 33:916-23

17 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 courtesy of P.Ponikowski

18 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

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20 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

21 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

22 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: ; Levin N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier Kidney Int 2000;57: ; 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

23 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: ; Levin N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier Kidney Int 2000;57: ; 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

24 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

25 PARADIGM-HF: Study Design Randomization Single-blind run-in period Double-blind period LCZ 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

26 PARADIGM-HF: Study Population 8399 patients randomized for ITT analysis 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% G. Cice

27 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: PRIMARY ENDPOINT CARDIOVASCULAR DEATH OR HF HOSPITALIZATION HR = 0.80 ( ) P = Enalapril (n=4212) LCZ696 (n=4187) 16 8 NNT=21 Patients at Risk Days After Randomization LCZ696 Enalapril McMurray, et al. N Engl J Med 2014

28 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: CARDIOVASCULAR DEATH HR = 0.80 ( ) P = Enalapril (n=4212) NNT=32 LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril Days After Randomization McMurray, et al. N Engl J Med 2014

29 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: ALL-CAUSE MORTALITY 32 HR = 0.84 ( ) P< Enalapril (n=4212) LCZ696 (n=4187) 8 Patients at Risk Days After Randomization LCZ696 Enalapril McMurray, et al. N Engl J Med 2014

30 Patients No PARADIGM-HF: ADVERSE EVENTS 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

31 Patients No PARADIGM-HF: PROGRESSION, SEVERITY AND QUALITY OF LIFE ,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

32 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 ( ) Age category (year) <55 (n=1,624) 0.78 ( ) (n=2,655) 0.76 ( ) (n=2,557) 0.80 ( ) (n=1,442) 0.84 ( ) >85 (n=121) 0.96 ( ) Favors LCZ Hazard ratio Favors enalapril McMurray et al. Eur J Heart Fail 2015;17(Suppl 1):143 (Abstract 689)

33 McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

34 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)

35 Thanks for not having left the conference hall!

36 Patients who discontinued study drug for hypotension (%) PARADIGM-HF: DISCONTINUATION FOR HYPOTENSION During run-in 1 * 1.4 % 1.7 % Following randomization 1,2 p= % 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: ; 3. McMurray et al. Eur J Heart Fail 2013;15:

37 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: /NEJMoa G. Cice

38 % 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

39 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

40 Mortality Increase in Life Expectancy by Enalapril in Combined SOLVD Trials 0.8 p= Median Life Expectancy Difference of 9.4 months Years after Randomization Enalapril (n=472)* Placebo (n=448)* * Number of patients alive at 12 years

41 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: /NEJMe G. Cice

42 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

43 PARADIGM-HF: ADVERSE EVENTS LCZ696 (n=4187) Enalapril (n=4212) P Value Prospectively identified adverse events 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 McMurray, et al. N Engl J Med 2014