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HEART FAILURE & Co. Ninth International Symposium Milano, 17 – 18 aprile 2009

HEART FAILURE & Co. Ninth International Symposium Milano, 17 – 18 aprile 2009. IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM CARDIOVASCOLARE DOPO TRENT’ANNI DI ESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORI I sartani non sono inferiori ed insieme possono fare meglio Pasquale Perrone Filardi

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HEART FAILURE & Co. Ninth International Symposium Milano, 17 – 18 aprile 2009

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  1. HEART FAILURE & Co. Ninth International Symposium Milano, 17 – 18 aprile 2009 IL BLOCCO DEL SISTEMA RAAS NEL CONTINUUM CARDIOVASCOLARE DOPO TRENT’ANNI DI ESPERIENZATERAPEUTICA: NON SOLO ROSE E FIORI I sartani non sono inferiori ed insieme possono fare meglio Pasquale Perrone Filardi Università Federico II di Napoli

  2. ARBs, morbidity and mortality along the cardiovascular continuum OPTIMAAL VALIANT ELITE II Val-HeFT CHARM LIFE ONTARGET TRANSCEND Ventricular dilation Remodeling DIRECT Congestive heart failure Myocardial infarction End-stage micro-vascular and heart disease Atherosclerosis and LVH NAVIGATOR RENAAL IDNT IRMA-2 MARVAL Risk factors Diabetes Hypertension Death VALUE SCOPE Adapted from Dzau V, Braunwald E. Am Heart J 1991; 121: 1244–1263

  3. BIOLOGICAL EFFECTS OF RAS  Bradykinin Angiotensin I ACE Inhibitors Angiotensin II Escape (Chymase, Cathepsin G, CAGE) Kininase II ( - ) Inactive Fragments Angiotensin II NO, PGI2, HPF t-PA B2 Receptor AT-II AT-I Natriuresis, Vasodilation & Anti-Inflammatory Effects Dephosphorylation Anti-Proliferative Effects Phosphorylation CNS Stimulation Endothelin release Vasoconstriction NADPH Oxidase Inflammation Aldosteron Proliferative Effects

  4. QUESTIONS • ROLE OF ARBs IN CARDIOVASCUAR PROTECTION • ROLE OF DUAL RAS BLOCKADE IN CARDIOVASCULAR PROTECTION TARGET ORGANS • HEART • Patients at high cardiovascular risk without LV dysfunction • Post-MI ischemic dysfunction • Patients with chronic LV systolic dysfunction • Patients with chronic LV diastolic dysfunction • KIDNEY • EYE • BRAIN

  5. The ONTARGET Trial ProgrammeOutcome:Primario: mortalità CV , IMA, Ictus, ospedalizzazione per scompenso cardiacoSecondario: mortalità CV , IMA, Ictus (outcome HOPE) ONTARGET TRANSCEND NO PLACEBO YES PLACEBO Screening Randomisation (n= 6,000) † Randomisation (n=23,400) * Because of an extraordinary effort by investigators in 40 countries, it was possible to complete recruitment for the ONTARGET study in May 2003, seven months ahead of the scheduled timeline. The ONTARGET trial currently recruited 25,621 patients. n = 7,800Telmisartan80 mg/day +placebo n = 7,800Ramipril10 mg/day +placebo n = 7,800Telmisartan80 mg/day + Ramipril10mg/day n = 3,000Telmisartan80 mg/day n = 3,000Placebo 5.5 Years Follow-up at 6 weeks Follow-up at 6 weeks Follow-up at 6 months for 5.5 years Follow-up at 6 months for 5.5 years *planned. Actual = 25,620 †planned. Actual = 5,926 Teo K., et al. Am Heart J 2004;148:52–61

  6. Tempo al Primary Outcome ONTARGET # at Risk Yr 1 Yr 2 Yr 3 Yr 4 T 8542 8176 7778 7420 7051 0.25 R 8576 8214 7832 7473 7095 0.20 IS RAS INHIBITION STILL USEFUL IN CONTEMPORARY PATIENTS AT HIGH CARDIOVASCULAR RISK? 0.15 Telmisartan Cumulative Hazard Rates Ramipril 0.10 0.05 0.0 0 1 2 3 4 Years of Follow-up

  7. TRANSCEND patients on “2008 standard care, so called placebo arm”, were almost as protected as with ramipril in HOPE -17% absolute risk reduction 17,8% 14,8% 14% 13% The Lancet, published on line Aug 31, 2008 N Engl J Med 2000;342:145-53

  8. TRANSCENDPrimary and Key Secondary Outcomes

  9. Cumulative Hazard Rates Years of Follow-up Tempo al Primary Outcome ONTARGET # at Risk Yr 1 Yr 2 Yr 3 Yr 4 0.25 8576 8214 7832 7473 7095 R 8502 8134 7740 7377 7023 T&R 0.20 0.15 Ramipril 0.10 Telmi & Ram 0.05 0.0 0 1 2 3 4

  10. Modifiche della PA (mmHg)ONTARGET e HOPE

  11. Dogma Disputed: Can Agressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Messerli et al Ann Intern Med 2006

  12. ARBs AND DUAL RAS BLOCKADE IN LEFT VENTRICULAR SYSTOLIC DYSFUNCTION • Post-ischemic (OPTIMA; VALIANT) • Chronic (VAL-HeFT; CHARM)

  13. VALSARTAN, CAPTOPRIL, OR BOTH IN MYOCARDIAL INFARCTION COMPLICATED BY HEART FAILURE, LV DYSFUNCTION OR BOTH Pfeffer et al for the VALIANT Investigators. N Engl J Med 2003 0.4 Valsartan Valsartan and Captopril Captopril n=14808 f.u. 24.7 m 0.3 0.2 Probability of Event 0.1 p = n.s. for all comparisons 0.0 0 6 12 18 24 30 36 No.at Risk Months Valsartan 4909 4464 4272 4007 2648 1437 357 Valsartan and Captopril 4885 4414 4265 3994 2648 1435 382 Captopril 4909 4428 4241 4018 2635 1432 364

  14. CHARM-Overall All-cause death % 35 30 945 (24.9%) Placebo 25 886 (23.3%) 20 Candesartan 15 -9%( p=0,055) 10 HR 0.91 (95% CI 0.83-1.00), p=0.055 Adjusted HR 0.90, p=0.032 5 0 0 1 2 3 3.5 years ANNUAL MORTALITY: 8.8 % (PL) VS 8.1 % (CANDESARTAN)

  15. CHARM-Overall: CV Death and non-CV Death CV death HR 0.88 (95% CI 0.79-0.97), p=0.012Adjusted HR 0.87, p=0.006 30 25 Placebo 20 Candesartan % 15 10 Non-CV death p=0.45 Candesartan 5 Placebo 0 0 1 2 3 3.5 years Number at risk Candesartan 3803 Placebo 3796 Lancet. September 6, 2003

  16. CHARM: EFFECTS ON MORTALITY IN PTS WITH REDUCED EF(Alternative + Added) 40 35 30 25 All-cause death (%) 20 15 10 5 0 0 1 2 3 3.5 anni Placebo 708 (31.0%) Candesartan 642 (28.0%) HR 0.88 (95% CI 0.79 – 0.98) p=0.018 Young et al Circulation 2004; 110: 2618-26

  17. CHARM-Alternative: Primary outcome CV death or CHF hospitalisation % 50 406 (40.0%) Placebo 40 334 (33.0%) 30 Candesartan 20 -23%( p=0,0004) 10 HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001 0 0 1 2 3 3.5 years

  18. MOST RECENT AND UPCOMING RANDOMIZED CLINICAL TRIALS IN HEART FAILURE • TRIAL INTERVENTION RESULTS YEAR • PEP-CHF perindopril NEUTRAL 2006 • EVEREST tolvaptan NEUTRAL 2007 • CORONA rosuvastatin NEUTRAL 2008 • ACCLAIM immunomodulation NEUTRAL 2008 • Anemia darbopoetin NEUTRAL 2008 • AFCHF rhytm vs rate control NEUTRAL 2008 • DSG dronaderone NEUTRAL 2008 • BEAUTIFUL ivabradine NEUTRAL 2008 • GISSI-HF rosuvastatin, omega-3 NEUTRAL 2008 • I-PRESERVE irbesartan NEUTRAL 2008 • EMPHASIS eplerenone ongoing • TOPCAT anti-aldosterone ongoing • RED-HF darbopoetin ongoing

  19. ACE-Is, ARBs AND DUAL RAS BLOCKADE IN LEFVT VENTRICULAR DIASTOLIC DYSFUNCTION • ACE-Is (PEP-CHF) • ARBs (I-PRESERVE; CHARM PRESERVED) • Dual blockade (no studies)

  20. Left ventricular morphology and function in patients with heart failure with reduced or normal ejection fraction Maeder et al. Journal of the American College of Cardiology 2009;53: 905-918

  21. EFFECTS OF PERINDOPRIL IN ELDERLY PEOPLE WITH DIASTOLIC HEART FAILURE Cleland et al for the PEP-CHF Investigators Eur Heart J 2006; 27: 2338–2345

  22. Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction I-PRESERVE N Engl J Med 2008;359:2456-67 Death or hospitalization for cardiovascular causes

  23. Angiotensin Receptor Antagonists Trials Across The Whole Spectrum Of Type 2 Diabetic Renal Disease Progression Prevention Protection Microalbuminuria Proteinuria ESRD Cardiovascular morbidity and mortality Early Stage Late Stage End Stage IRMA 2 MARVAL IDNT RENAAL IRMA 2: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria MARVAL: Microalbuminuria Reduction with Valsartan IDNT: Irbesartan Diabetic Nephropathy Trial RENAAL: Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan ESRD: End-stage renal disease

  24. Effects of ramipril, telmisartan or both on renal outcomes (dialysis, doubling of serum creatinine, and death) in theONTARGETtrial Mann et al. The Lancet 2008; 372: 547-553

  25. DIRECT-Protect 2: Retinopathy regression 0.4 Placebo Candesartan 0.3 0.2 Cumulative proportion 0.1 p=0.009 0.0 0 1 2 3 4 5 6 Time from randomisation (years) No at risk Placebo 954 812 760 713 510 93 1 Candesartan 951 811 755 692 492 100 0

  26. CONCLUSIONS • ARBs (telmisartan) have demonstrated to be as efficacious as ACE-Is in patients at high cardiovascular risk without LV dysfunction, and in patients with post-ischemic (valsartan) and chronic LV systolic dysfunction (valsartan, candesartan) • ARBs (candesartan, irbesartan) have not demonstrated to be efficacious in patients with LV diastolic dysfunction, similarly to ACE-Is • ARBs (losartan, valsartan, irbesartan) have demonstrated to provide renal protection in patients with pre-clinical and clinical diabetic nephropathy • ARBs (candesartan) have demonstrated to induce retinopathy regression in type II diabetics (but needs confirmation) • Dual RAS blockade was ineffective and potentially harmful in patients without LV dysfunction and this association should be used with caution and strict surveillance of renal function • Dual RAS blockade (valsartan, candesartan) reduces mortality/morbidity in patients with chronic LV systolic dysfunction

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