Recent and Future Advances in the treatment of Chronic Systolic Heart Failure

Transcription

1 Recent and Future Advances in the treatment of Chronic Systolic Heart Failure

2 2016

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4 Mechanisms of Progression in Heart Failure Myocardial or vascular stress or injury Increased activity or response to maladaptive mechanisms Decreased activity or response to adaptive mechanisms Evolution and progression of heart failure

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17 % Decrease in Mortality 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

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21 Mechanisms of Progression in Heart Failure Myocardial or vascular stress or injury Increased activity or response to maladaptive mechanisms Angiotensin receptor blocker Decreased activity or response to adaptive mechanisms Inhibition of neprilysin Evolution and progression of heart failure

22 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

23 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

24 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

25 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) Kaplan-Meier Estimate of Cumulative Rates (%) Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk LCZ696 Enalapril Days After Randomization HR = 0.80 ( ) P = Number needed to treat =

26 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: Cardiovascular Death HR = 0.80 ( ) P = Number need to treat = 32 Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril

27 PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its 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 ( )

28 Kaplan-Meier Estimate of Cumulative Rates (%) PARADIGM-HF: All-Cause Mortality HR = 0.84 ( ) P< Enalapril (n=4212) LCZ696 (n=4187) Patients at Risk Days After Randomization LCZ696 Enalapril

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31 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

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47 Contraindications: Corlanor - Ivabradine Clinical Application Acute decompensated heart failure Blood pressure less than 90/50 mmhg Sick sinus syndrome, sinoatrial block or 3 rd degree AV block, unless a functioning demand pacemaker is present Resting heart rate less than 60 bpm prior to treatment Severe hepatic impairment Pacemaker dependence (heart rate maintained exclusively by the pacemaker)

48 Corlanor - Ivabradine Adverse Effects Common Adverse Effects: Ivabradine (N=3,260) Placebo (N=3,278) Bradycardia 10% 2.2% Atrial Fibrillation 8.3% 6.6% Phosphenes, visual brightness Hypertension, blood pressure increase 2.8% 0.5% 8.9% 7.8%

49 Corlanor - Ivabradine Prescription Information Recommended starting dose 5mg tablet by mouth twice daily with meals or 2.5mg tablet by mouth twice daily for patients in whom bradycardia could lead to hemodynamic compromise or with a history of conduction defects >60 bpm After 2 weeks, check resting heart rate Increase dose by 2.5mg twice daily up to max of 7.5mg twice daily bpm (target range) Maintain dose <50 bpm Decrease dose by 2.5mg twice daily *Discontinue therapy if current dose is 2.5mg twice daily

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54 Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator Mechanochemical Cycle of Myosin Omecamtiv mecarbil increases the entry rate of myosin into the tightly-bound, force-producing state with actin More hands pulling on the rope Increases duration of systole Increases stroke volume No increase in myocyte calcium Force production No change in dp/dt max No increase in MVO 2 Malik FI, et al. Science 2011; 331:

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58 Table 1. Characteristics at Baseline in the Modified Intent-to-treat Population* Characteristic Placebo (n = 122) AAV1/SERCA2a (n = 121) All Patients (N = 243) Age-yr 58.4± ± ±11.11 Female sex no. (%) 24 (19.7) 21 (17.4) 45 (18.5) Race no. (%) White Black/African American American Indian/Alaskan Native Native Hawaiian/Pacific Islander Other 98 (81.1) 22 (18.0) 0 (0.0) 0 (0.0) 1 (0.8) 99 (81.8) 18 (14.9) 1 (0.8) 1 (0.8) 2 (1.7) 198 (81.5) 40 (16.5) 1 (0.4) 1 (0.4) 3 (1.2) Ethnicity no. (%) Not Hispanic Hispanic 118 (96.7) 4 (3.3) 114 (94.2) 7 (5.8) 232 (95.5) 11 (4.5) Country no. (%) United States Non-United States 79 (64.8) 43 (35.2) 79 (65.3) 42 (34.7) 158 (65.0) 85 (35.0) Coronary artery disease no. (%) 67 (54.9) 68 (56.2) 135 (55.6) Six-minute walk test meters 336.6± ± ±82.23 Left ventricular ejection fraction % 24.0± ± ±6.37 NYHA functional class no. (%) II III IV 21 ( (82.0) 1 (0.8) 22 (18.2) 96 (79.3) 3 (2.5) 43 (17.7) 196 (80.7) 4 (1.6) KCCQ overall score 59.2± ± ±21.02 NT-proBNP (IQR) pg/ml 1504 ( ) 1754 ( ) 1679 ( )

59 Continued - Table 1. Characteristics at Baseline in the Modified Intent-to-treat Population* Characteristic Placebo (n = 122) AAV1/SERCA2a (n = 121) All Patients (N = 243) Heart failure etiology no. (%) Ischemic Idiopathic Hypertensive Familial Peripartum Other 63 (51.6) 50 (41.0) 5 (4.1) 1 (0.8) 2 (1.6) 1 (0.8) 62 (51.2) 48 (39.7) 5 (4.1) 2 (1.7) 0 (0.0) 7 (5.8) 125 (51.4) 98 (40.3) 10 (4.1) 3 (1.2) 2 (0.8) 8 (3.3) Heart failure regimen no. (%) ACE inhibitor/arb Aldosterone antagonist Beta blocker Diuretic Digoxin OAC/NOAC 110 (90.2) 74 (60.7) 117 (95.9) 109 (89.3) 48 (39.3) 81 (66.4) 111 (91.7) 83 (68.6) 117 (96.7) 111 (91.7) 45 (37.2) 76 (62.8) 221 (90.9) 157 (64.6) 234 (96.3) 220 (90.5) 93 (38.3) 157 (64.6) Cardiac resynchronization therapy no. (%) 39 (32.0) 53 (43.8) 92 (37.9) Implantable cardioverter-defibrillator no. (%) 89 (73.0) 98 (81.0) 187 (77.0) Other medical history no. (%) Chronic renal insufficiency Type 2 diabetes Atrial fibrillation COPD 37 (30.3) 49 (40.2) 49 (40.2) 18 (14.8) 36 (30.0) 59 (48.8) 44 (36.4) 15 (12.5) 73 (30.2) 108 (44.4) 93 (38.3) 33 (13.6) Plus-minus values are means ± SD.

60 Figure 1. Key study outcomes by study group in the modified intent-to-treat population. Panel A. Primary efficacy end point, cumulative number of recurrent events per patient at the primary analysis data cutoff

61 Panel C. Probability of death from any cause

62 Stem Cells for the treatment of Heart Failure

63 Mechanisms of Progression in Heart Failure Myocardial or vascular stress or injury Increased activity or response to maladaptive mechanisms Decreased activity or response to adaptive mechanisms Evolution and progression of heart failure

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68 , DREAM-HF)

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73 , DREAM-HF)

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80 DREAM-HF

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84 The Future, DREAM-HF)

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