Paradigm hf-trial-ppt-pptx - copia
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The document discusses a new angiotensin-neprilysin inhibitor (lcz696) for chronic heart failure (HF), highlighting its efficacy compared to traditional treatments like enalapril. It cites the prevalence of HF worldwide, the mechanisms of disease progression, and the significant results from the PARADIGM-HF trial, which demonstrated lcz696's superior mortality reduction and better tolerability. The study indicates that lcz696 not only reduces cardiovascular death and HF hospitalization but also minimizes adverse events compared to standard treatments.
Paradigm hf-trial-ppt-pptx - copia
- 1. New Angiotensin - Neprolysin inhibitor in Chronic HF
- 2. Heart Failure Incidence and Prevalence ♥ Prevalence Worldwide – 22 million United States – 5 million ♥ Incidence Worldwide – 2 million new cases year United States – 500,000 new cases year ♥ Afflicts 10 out of every 1,000 people over age 65 in the United States (Stats from American Heart association - 2002)
- 3. Beta blocker Mineralocorticoid receptor antagonist Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction ACE inhibitor Angiotensin receptor blocker 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 10% 20% 30% 40% 0% %DecreaseinMortality
- 4. HF medical treatment: Lives saved/1000/year TRIAL Lives saved/1000/year SOLVD-P 7 SOLVD-R 17 MERIT 38 CIBIS 42 RALES 52 COPERNICUS 70
- 5. Myocardial or vascular stress or injury Evolution and progression of heart failure Mechanisms of Progression in Heart Failure Increased activity or response to maladaptive mechanisms Decreased activity or response to adaptive mechanisms
- 6. One Enzyme — Neprilysin — Degrades Many Endogenous Vasoactive Peptides Endogenous vasoactive peptides (natriuretic peptides, adrenomedullin, bradykinin, substance P, calcitonin gene-related peptide) Inactive metabolites Neprilysin
- 7. 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) Inactive metabolites Neurohormonal activation Vascular tone Cardiac fibrosis, hypertrophy Sodium retention Neprilysin Neprilysin inhibition
- 8. Myocardial or vascular stress or injury Evolution and progression of heart failure Mechanisms of Progression in Heart Failure Angiotensin receptor blocker Inhibition of neprilysin Increased activity or response to maladaptive mechanisms Decreased activity or response to adaptive mechanisms
- 9. LCZ696 LCZ696: Angiotensin Receptor Neprilysin Inhibition Angiotensin receptor blocker Inhibition of neprilysin LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that comprises the molecular moieties of a neprilysin inhibitor and the angiotensin receptor blocker (ARB) valsartan as a single compound. •
- 10. Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter Maladaptive Mechanisms in Heart Failure Effect of oral administration of LCZ696: change from baseline in plasma atrial natriuretic peptide immunoreactivity (ANPir) in Sprague-Dawley rats (n = 4) infused with ANP (450 ng/kg/min); Effect of LCZ696 200 mg twice daily versus valsartan 160 mg twice daily (dose equivalent) in patients with chronic HF with preserved ejection fraction (NYHA class II–III, LVEF =45%, NT-proBNP >400 pg/mL). PARAGON Study Drug Discovery Today: Therapeutic Strategies Volume 9, Issue 4, Winter 2012, Pages e131–e139
- 11. Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) SPECIFICALLY DESIGNED TO REPLACE CURRENT USE OF ACE INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS AS THE CORNERSTONE OF THE TREATMENT OF HEART FAILURE Aim of the PARADIGM-HF Trial LCZ696 400 mg daily Enalapril 20 mg daily
- 12. • NYHA class II-IV heart failure • LV ejection fraction ≤ 40% 35% (amendment Dec/2010) • BNP ≥ 150 (or NT-proBNP ≥ 600), or BNP ≥ 100 (or NT- proBNP ≥ 400), if hospitalized for HF 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 m2 and serum K ≤ 5.4 mEq/L at randomization PARADIGM-HF: Entry Criteria
- 13. 2 weeks 1-2 weeks 2-4 weeks Single-blind run-in period Double-blind period (1:1 randomization) Enalapril 10 mg BID 100 mg BID 200 mg BID Enalapril 10 mg BID LCZ696 200 mg BID PARADIGM-HF: Study Design Randomization LCZ696
- 14. PARADIGM-HF Was Designed to Show Incremental Effect on Cardiovascular Death The sample size of the trial was determined by effect on cardiovascular mortality, not the primary endpoint The Data Monitoring Committee was allowed to stop the trial only for a compelling effect on cardiovascular mortality (in addition to the primary endpoint) Difference in cardiovascular mortality of 15% (relative reduction) N= 1229 between LCZ696 and enalapril was prospectively identified as being clinically important (n=8000 yielded 80% power) Primary endpoint was a composite: cardiovascular death or hospitalization for heart failure, but PARADIGM-HF was designed as a cardiovascular mortality trial
- 15. All-cause mortality(time to death from any cause) • Change from baseline in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire at 8 months • Time to new onset of atrial fibrillation • Time to first occurrence of a protocol-defined decline in renal function PARADIGM-HF: Secondary Endpoints
- 16. 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 Enalapril (n=4212) At last visit 18.9 mg daily 9 lost to follow-up median 27 months of follow-up PARADIGM-HF: Patient Disposition
- 17. 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% PARADIGM-HF: Baseline Characteristics
- 18. 0 16 32 40 24 8 Enalapril (n=4212) 360 720 10800 180 540 900 1260 Days After Randomization PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint) 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236 LCZ696 Enalapril Patients at Risk 1117 Kaplan-MeierEstimateof CumulativeRates(%)
- 19. 0 16 32 40 24 8 Enalapril (n=4212) 360 720 10800 180 540 900 1260 Days After Randomization 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236 LCZ696 Enalapril Patients at Risk 1117- 26,5% Kaplan-MeierEstimateof CumulativeRates(%) 914- 21,8% LCZ696 (n=4187) PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
- 20. 0 16 32 40 24 8 Enalapril (n=4212) 360 720 10800 180 540 900 1260 Days After Randomization 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 249 236 LCZ696 Enalapril Patients at Risk 1117 Kaplan-MeierEstimateof CumulativeRates(%) 914 LCZ696 (n=4187) HR = 0.80 (0.73-0.87) P = 0.0000002 Number needed to treat = 21 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
- 21. Enalapril (n=4212) Kaplan-MeierEstimateof CumulativeRates(%) Days After Randomization PARADIGM-HF: Cardiovascular Death 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 LCZ696 Enalapril Patients at Risk 360 720 10800 180 540 900 1260 0 16 32 24 8 693
- 22. Enalapril (n=4212) LCZ696 (n=4187) Kaplan-MeierEstimateof CumulativeRates(%) Days After Randomization 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 LCZ696 Enalapril Patients at Risk 360 720 10800 180 540 900 1260 0 16 32 24 8 693 558 PARADIGM-HF: Cardiovascular Death
- 23. Enalapril (n=4212) LCZ696 (n=4187) HR = 0.80 (0.71-0.89) P = 0.00004 Number need to treat = 32 Kaplan-MeierEstimateof CumulativeRates(%) Days After Randomization 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 LCZ696 Enalapril Patients at Risk 360 720 10800 180 540 900 1260 0 16 32 24 8 693 558 PARADIGM-HF: Cardiovascular Death
- 24. PARADIGM-HF: All-Cause Mortality 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 LCZ696 Enalapril Enalapril (n=4212) LCZ696 (n=4187) HR = 0.84 (0.76-0.93) P<0.0001 Kaplan-MeierEstimateof CumulativeRates(%) Days After Randomization Patients at Risk 360 720 10800 180 540 900 1260 0 16 32 24 8 835 711
- 27. In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril: 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 PARADIGM-HF: Summary of Findings
- 28. 10% Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin-Angiotensin System 20% 30% 40% ACE inhibitor Angiotensin receptor blocker 0% %DecreaseinMortality 18% 20% 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 Angiotensin neprilysin inhibition 15%