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Zofenopril

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Zofenopril

  1. 1. Dr. Gustavo Ruiz Deza Jefe Unidad Coronaria HIGA Pte. Perón Avellaneda Jefe Servicio de Cardiología Sanatorio Bernal Bernal- Pcia. Buenos Aires
  2. 2. Hipertensión:Visión general y distintosenfoques de tratamiento
  3. 3. Enfermedad Cardiovascular: PandemiaThe Atlas of Heart Disease and Stroke; http://www.who.int
  4. 4. Tratamiento de la hipertensión: Reducción estimativa de la mortalidad Antes del Después del tratamiento tratamiento Reducción de la TA Reduction in SBP % Reduction in mortality mmHg Stroke CHD Total 2 -6 -4 -3 3 -8 -5 -4 5 -14 -9 -7JNC7 Guidelines, 2003*
  5. 5. Objetivos del tratamiento JNC 7 ESH/ESC 2007 • Reducción de la mortalidad • Reducción máxima a largo plazo de cardiovascular y renal. la morbilidad y mortalidad • SBP/DBP < 140/90 mmHg. cardiovascular. • SBP/DBP < 130/80 mmHg en • SBP/DBP < 140/90 mmHg. pacientes con diabetes y • SBP/DBP < 130/80 mmHg en enfermedad renal pacientes diabéticos y de lato riesgo cardiovascularESH/ESC Guidelines, 2007*JNC7 Guidelines, 2003**
  6. 6. Iniciación del tratamiento - JNC7 Guidelines 2007 Modificación del estilo de vida Logró objetivo No lo logro continúa (< 140/90 mmHg or < 130/80 mmHg for those with diabetes or chronic kidney disease) Iniciar drogas HTA sin daño de organo blanco HTA con daño de organo blanco HTA estadio 1 HTA estadío 2 (systolic BP 140-159 mmHg or diastolic BP 90-99 mmHg) (systolic BP > 160 mmHg or diastolic BP > 100 Combinación de drogas según sea mmHg) necesario Tiazida, IECA, BB, BC, ARA II. Combinación de II drogas (Usualmente IECA + tiazida / ARA II + tiazida / IECA + BC No logró objetivo Optimización de las distintas drogas, buscar causa secundaria o eventualmente realizar otra consulta BP, Blood Pressure; ACE, Angiotensin-Converting Enzyme; JNC7 Guidelines, 2003 ARB, Angiotensin-Receptor Blocker; CCB, Calcium Channel Blocker.
  7. 7. Iniciación del Tratamiento- ESH/ESC Guidelines 2007 Ligera elevación de la TA Evaluar entre Marcada elevación de la TA Bajo a moderado riesgo Alto riesgo Una sola droga a Combinación de baja dosis dos drogas a bajas dosis No se llega al objetivo Previa droga a Cambio por diferentes Combinación previa a Agregar una dosis plena drogas a dosis bajas dosis plena tercera droga No se llega al objetivo Dos o tres drogas a Monoterapia Dos o tres drogas a dosis dosis plena dosis plena plenaESH/ESC Guidelines, 2007
  8. 8. Papel de los IECA en HTA • Los IECA juegan un papel principal en el tratamiento de la HTA , tanto en monoterapia como combinado con: • Diureticos • Calcio antagonistas • Los IECA son la única clase de antihipertensivos que cumplen con todas las directivas de la JNC7 • Las indicaciones de peso de los IECA incluyen: JNC7 ESH/ESC Insuficiencia cardíaca Insuficiencia cardíaca Post. IAM Disfunción del VI Alto riesgo de enfermedad coronaria Post- IAM Diabetes Nefropatía diabética Enfermedad renal crónica Nefropatía no diabética Prevensión del Stroke recurrente Hipertrofia del VI Arterioesclerosis carotídea Proteinuria/Microalbuminuria Fibrilación auricular Sindrome metabólicoESH/ESC Guidelines, 2007JNC7 Guidelines, 2003
  9. 9. Química
  10. 10. Structural formula of zofenopril calcium and its active metabolite Zofenopril calcium ZofenoprilatSubissi A. et al.; Cardiovasc Drug Rev. 1999; 17: 115-133
  11. 11. Un IECA con elevado indice lipofílico Comparación de los coeficientes de distribución de los inhibidores de la ECA determinado a pH 7 ACE inhibitor Distribution coefficient (High value = high lipophilicity) Captopril 0.004 Zofenopril 3.5 Enalapril 0.07 Ramipril 1.12 Lisinopril < 0.001 Fosinopril ∼ 500 FREE INHIBITOR Distribution coefficient Zofenoprilat 0.22 Enalaprilat < 0.001 Ramiprilat 0.011 Fosinoprilat 0.33Subissi A. et al.; Cardiovasc Drug Rev. 1999; 17: 115-133
  12. 12. Propiedadesfarmacocinéticas
  13. 13. Propiedades farmacocinéticas • Biodisponibilidad oral: 70% • Tmax: 1.5 hours • Vida medias: 5.5 horas (zofenoprilat) • Excreción: 60% en orina, 40% en heces • No actua a nivel del citocromo P-450Sleight; 1999Zofenopril – Summary of product characteristics
  14. 14. Distribución del IECA en plasma y tejidos 0.5 h 4h 24 h Zofenoprilat (µg/g or ml tissue)Subissi A. et al.; Cardiovasc Drug Rev. 1999; 17: 115-133
  15. 15. Metabolism o n ati xid lf o SuSubissi A. et al.; Cardiovasc Drug Rev. 1999; 17: 155-133
  16. 16. Propiedadesfarmacocinéticas
  17. 17. High in vitro cardiac ACE inhibition 100 Zofenoprilat 90 Enalaprilat % inhibition of cardiac ACE activity 80 Ramiprilat 70 Fosinoprilat 60 Lisinopril 50 Captopril 40 30 20 10 0 0.01 0.1 1 10 100 1000 Concentration (µM)Grover G.J. et al.; J Pharmacol Exp Ther. 1991; 257: 919-929
  18. 18. Efectiva y duradera inhibición a nivel cardíaco 1h 8h 24 h % cardiac ACE inhibition Zofenopril Captopril Fosinopril Ramipril Lisinopril EnalaprilIn ex vivo dose-response and time-course studies, the inhibitory effects on tissue ACEs and their relative tissue distributions of sevendrugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta,brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) following oral administration.Cushman D.W. Et al; Br. J. Clin. Pharmacol. 1989; 28: 115S-131S
  19. 19. Actividad antioxidante LDL oxidisability 30 * MDA (nmol/mg of proteins) 25 20 ** 15 10 5 0 Healthy subjects Hypertens. subjects Hypertens. subjects Hypertens. subjects (n = 46) before treatment +12 weeks enalapril +12 weeks Zofenopril (n = 96) (n = 48) (n = 48) Two-period study in 96 untreated patients with moderate essential hypertension without clinically evident target organ damage. 48 patients were treated with Zofenopril 15-30 mg/day and 48 with enalapril 20 mg/day for 12 weeks. *p < 0.05 vs. healthy controls; **p < 0.05 vs. hypertensive patients at baselineNapoli C. et al.; Am Heart J. 2004; 148 (1): e5.
  20. 20. Efectos cardioprotectoras Prevention of cardiac tissue necrosis 40 TTC-negative tissue (%) 30 20 * 10 0 Control Enalaprilat Lisinopril Zofenoprilat 100 µM *p < 0.05 vs. controlThe study investigated the effects of different ACE-inhibitor (Zofenoprilat, enalaprilat, lisinopril and irbesartan) on tissue injury on isolatedrat hearts subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion.Frascarelli S. et al.; J Cardiovasc Pharmacol. 2004; 43: 294-299.
  21. 21. Efecto cardioprotector Restauración de la función cardíaca Ischemia Reperfusion Ischemia Reperfusion Ischemia Reperfusion pressure (mmHg) Left ventricular 100 80 60 40 20 0 dp/dt (mmHg/sec) Left ventricular +3,500 0 -3,500 -30 0 30 60 90 -30 0 30 60 90 -30 0 30 60 90 Minutes Control Captopril 10-6 M Zofenopril 10-6 MThe study investigated the effects of zofenopril (10-6 M) and captopril (10-6 M) on the mechanical function, cellularredox state, and norepinephrine (NE) content of isolated and aerobically perfused rabbit hearts.Ferrari R. et al.; J Cardiovasc Pharmacol. 1992; 20: 694-704
  22. 22. Efecto vasculoprotector Estimulación y liberación de NO por celulas endoteliales Captopril 1,000 Enalapril NO inconditioned media * Zofenopril 800 (% of control) 600 400 * 200 0 0 10 30 60 *p < 0.001 Concentration (µM)Experimental study that assessed the comparative effects of three angiotensin-converting-enzyme inhibitors on endothelial nitric oxideproduction and action, and on endothelial oxidative stress using bovine aortic endothelial cells. Captopril, Enalapril and Zofenopril wereadministered at concentration of 1, 10, 30 and 60 µM.Scribner A. W. et al.; Eur J Pharmacol. 2003; 482: 95-99
  23. 23. Efecto vasculoprotector Incremento del efecto del NO Mejoría en la respuesta vasodilatadora Lisinopril + 18% Zofenopril + 100%This study evaluated the role of SH-groups in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure.The study compared the vasoprotective effets of 11-week treatment with zofenopril and lisinopril in myocardial infarcted heart failure rats.Buikema H. et al.; Br J Pharmacol. 2000; 130: 1999-2007
  24. 24. Efecto vasculoprotector Normalización de la vía del NO Pacientes Hipertensos Hipertensos Personas hipertensos después de 12 después de 12 sanas antes del semanas con semanas con tratamiento enalapril zofenopril Plasma NO2 33.5 53.8* 44.9‡ 40.8† (µmol/L)* p < 0.001 vs. healthy subjects; †p < 0.01 vs. hypertensive subjects before treatment;‡ p < 0.05 vs. hypertensive subjects before treatment; § p < 0.05 vs. hypertensive subjects + 12 weeks enalapril Napoli C. et al.; Am Heart J. 2004; 148 (1): e5
  25. 25. Efecto vasculoprotector Reducción del indice intima – media carotídeo 0.82 0.79 0.78 0.78 0.78 0.74 0.74 0.74MT (mm) 0.74 0.74 0.74 0.73 0.72 0.72 0.72 ° ° ° Right 0.72 0.72 0.72 * * * 0.72 0.72 0.72 0.70 0.70 0.70 0.70 0.70 Left 0.70 0.69 Right + Left 0.66 0.62 il ril il ril il ril ril il pr pr pr pr op op op op ala al a ala ala f en f en f en f en En En En En Zo Zo Zo Zo Baseline Years 1 Years 3 Years 5 *p <0.05 or °p <0.01 vs. enalapril.Prospective randomized clinical trial on 48 newly diagnosed mildly hypertensive patients with no additional risk factors foratherosclerosis. Patients were randomly assigned either to enalapril (20 mg/d, n = 24) or zofenopril (30 mg/d, n = 24);the planned duration of the trial was 5 years.Napoli C. et al.; Am Heart J. 2008; 156 (6): 1154.e1-8
  26. 26. Eficacia clínica
  27. 27. Reducción de la TA dosis dependiente Zofenopril Placebo 7.5 mg/day 15 mg/day 30 mg/day 60 mg/day 0 -2 DBP decrease (mmHg) -4 -6 -8 -10 * -12 n = 211 *p = 0.0018 *DBP: Diastolic Blood PressureRandomised, double-blind, placebo-controlled, multicentre study comprising a 2-week placebo lead-in and a 6-week treatmentphase with placebo (n = 43) or zofenopril 7.5 mg (n = 43), 15 mg (n = 39), 30 mg (n = 44) or 60 mg (n = 42) once daily.Malacco E. et al.; Clin Drug Invest. 2002; 22 (1): 9-15
  28. 28. Redduccion de la TA por 24 Hs. Basal After 6 weeks of treatment T/P ratio: DBP (mmHg) 73% Hours post-doseRandomized, double-blind, parallel-group, placebo-controlled multicenter trial conducted on 211 patients with mild to moderatehypertension. Patients were randomized to receive zofenopril at the doses od 7.5, 15, 30 and 60 mg or placebo once daily for 6 weeks.Malacco E. et al.; Am J Hypertens. 1998; 11 (4): D007
  29. 29. Eficacia clínica versus otros IECA
  30. 30. Zofenopril vs. enalapril Sitting DBP Blood pressure reductions after 2 and 4 weeks DBP SBP 2 weeks 4 weeks 2 weeks 4 weeks 0 (n = 308) -5 -10 Enalapril 20 mg (n = 156) mmHg Zofenopril 30 mg (n = 152) -15 -20 p = 0.005 p = 0.038 p = 0.006 p = 0.030 -25Comparative parallel-group, double-blind, randomized, multicentre study on 308 patients with mild to moderate hypertension. Patientswere treated with zofenopril 30 mg od (with an up-titration to 60 mg od after 4 weeks in nonresponder patients) or with enalapril 20 mgod (with an up-titration to 40 mg od after 4 weeks in nonresponders) for 12 weeks.Mallion J.M. et al.; Blood Press. 2007; 16 (Suppl. 2): 13-18
  31. 31. Zofenopril vs. enalapril Response to treatment 80% 69% 71% 70% 64% 59% 60% 50% 40% 30% 20% 10% 0% 4 weeks 12 weeks 4 weeks 12 weeks Enalapril 20-40 mg Zofenopril 30-60 mgComparative parallel-group, double-blind, randomized, multicentre study on 308 patients with mild to moderate hypertension. Patientswere treated with zofenopril 30 mg od (with an up-titration to 60 mg od after 4 weeks in nonresponder patients) or with enalapril 20 mgod (with an up-titration to 40 mg od after 4 weeks in nonresponders) for 12 weeks.Mallion J.M. et al.; Blood Press. 2007; 16 (Suppl. 2): 13-18
  32. 32. Eficacia clínica versus losartan
  33. 33. Zofenopril vs. losartan Office BP reduction at 4 weeks DBP SBP 0 -2 Losartan 50-100 mg -4 Zofenopril 30-60 mg/day -6 -8 mmHg -10 (n = 327) -12 - 10.5 -14 - 12.8 - 13.2 -16 p < 0.003 -18 - 16.6 p < 0.01 -20Parallel double-blind multicentre study on 327 patients treated for 12 weeks with zofenopril 30 mg o.d. (titration 60mg o.d., n = 165) or losartan 50 mg o.d. (titration 100 mg o.d., n = 162).Narkiewicz K.; Blood Press. 2007; 16 (Suppl. 2): 7-12
  34. 34. Zofenopril vs. losartan Pacientes que requieren ajustes de la dosis 45 42.1% 40 35 33.1% Patients (%) 30 25 (n = 327) 20 15 10 5 0 Losartan 50-100 mg Zofenopril 30-60 mg Parallel double-blind multicentre study on 327 patients treated for 12 weeks with zofenopril 30 mg o.d. (titration 60 mg o.d., n = 165) or losartan 50 mg o.d. (titration 100 mg o.d., n = 162).Narkiewicz K.; Blood Press. 2007; 16 (Suppl. 2): 7-12
  35. 35. Eficacia Clínica versus amlodipine
  36. 36. Zofenopril vs. amlodipine SBP/DBP reduction through 12 weeks All p < 0.001 vs baseline; p = NS between groups 160 SBP 150 140 BP (mmHg) 130 Zofenopril – SBP 120 Zofenopril – DBP Amlodipine – SBP 110 Amlodipine – DBP 100 DBP 90 80 Baseline Week 2 Week 4 Week 6 Week 8 Week 12Parallel-group double-blind, randomized, multi-centre, 12-weeks study in 303 patients with mild to moderatehypertension, randomized to zofenopril 30-60 mg o.d. (n = 151) or amlodipine 5-10 mg o.d. (n = 152).Farsang C.; Blood Press. 2007; 16 (Suppl. 2): 19-24
  37. 37. Zofenopril vs. amlodipine BP control at 12 weeks 65 62.2% 61.4% 60 55 P = NS 50 Patients (%) 45 40 35 30 25 20 15 10 5 0 (n = 303) Amlodipine 5-10 mg Zofenopril 30-60 mgParallel-group double-blind, randomized, multi-centre, 12-weeks study in 303 patients with mild to moderate hypertension, randomizedto zofenopril 30-60 mg o.d. (n = 151) or amlodipine 5-10 mg o.d. (n = 152).Farsang C.; Blood Press. 2007; 16 (Suppl. 2): 19-24
  38. 38. Efectos adversos y seguridad
  39. 39. Safety: Zofenopril vs. enalapril Adverse events Enalapril 20-40 mg/day Zofenopril 30-60 mg/day (n = 303)Review of the efficacy and tolerability of zofenopril in the treatment of essential hypertension that evaluated the results of four studies(overall n = 1130) in which zofenopril was administered at doses of 7.5-60 mg/day (dose-finding study) or 30-60 mg/day (comparativestudy) and was compared with atenolol 50-100 mg/day, amlodipine 5-10 mg/day and enalapril 20-40 mg/day.Borghi C. et al.; Clin Drug Invest. 2000; 20 (5): 371-384
  40. 40. Safety: Zofenopril vs. enalapril Incidence and severity of adverse events Incidence of adverse events (%) 20 18.45 Enalapril (n = 168) Zofenopril (n = 155) 15 11.61 (n = 323) p = 0.008 for moderate AEs 10 8.39 7.74 5 2.98 0.65 0 Mild Moderate Severe Severity of adverse eventsComparative parallel-group, double-blind, randomized, multicentre study on 308 patients with mild to moderate hypertension.Patients were treated with zofenopril 30 mg od (with an up-titration to 60 mg od after 4 weeks in nonresponder patients) orwith enalapril 20 mg od (with an up-titration to 40 mg od after 4 weeks in nonresponders) for 12 weeks.Mallion J.M. et al.; Blood Press. 2007; 16 (Suppl. 2): 13-18
  41. 41. Safety: Zofenopril vs. amlodipine Most frequent adverse events 20 19 18 16 Number of AE 14 Amlodipine 5-10 mg 12 Zofenopril 30-60 mg 10 8 8 6 5 4 3 2 2 0 0 (n = 303) Headache Cough OedemaParallel-group double-blind, randomized, multi-centre, 12-weeks study in 303 patients with mild to moderatehypertension, randomized to zofenopril 30-60 mg o.d. (n = 151) or amlodipine 5-10 mg o.d. (n = 152).Farsang C.; Blood Press. 2007; 16 (Suppl. 2): 19-24
  42. 42. The SMILE project
  43. 43. Overview and future implications of the SMILE projectSMILE Pilot Study 204 thrombolyzed patientsAmerican Journal of Cardiology 1991 Zofenopril vs standard treatment Safety assessment 1556 non thrombolyzed patientsSMILE Study Zofenopril vs placeboNew England Journal of Medicine 1995Am J Cardiol, 1996 6-week mortality and severe CHFAm J Hypertens, 1999 1-year mortality rateSMILE-2 Study 1024 thrombolyzed patientsAm Heart J, 2002 Zofenopril vs lisinopril 6-week rate of severe hypotension 6-week safety profileSMILE-3 Ischemia Study 349 thrombolyzed patients normal LVF Zofenopril vs placeboAm Heart J, 2007 6-months ischemic events rateSMILE-4 Study 871 thrombolyzed patients with systolic LV disfunction (EF < 45%)Clin Cardiol 2012 Zofenopril + ASA vs ramipril + ASA 1-year cardiovascular event rate
  44. 44. The SMILE StudyThe effect of the angiotensin-converting enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-term Evaluation (SMILE) Study. Outlines of the study Study Design: randomised, double-blind, placebo-controlled Population: 1556 non thrombolysed patients with acute anterior M.I. Treatment: zofenopril calcium 7.5-30 mg b.i.d. (n = 772) or placebo (n = 784) + conventional therapy Duration of treatment: 6 weeks Follow-up: 1 yearAmbrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  45. 45. Objectives of the SMILE study Primary • 6-week combined occurrence of death or severe CHF Secondary • 6-week occurrence of angina • 6-week rate of non-fatal recurrent MI • 6-week incidence of mild-to moderate CHF • 1-year mortalityAmbrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  46. 46. The SMILE study Inclusion criteria - Anterior MI (Q- and non-Q wave) - No thrombolytic treatment - Age 18-80 years - Killip class on entry < 3 - Systolic blood pressure > 100 mmHg - No history of CHF - No current treatment with ACE-IAmbrosioni E. et al.; Controlled Clinical Trials 1994; 15: 201-210
  47. 47. The SMILE study Baseline patient characteristics PLACEBO ZOFENOPRIL CHARACTERISTICS (n = 784) (n = 772) Mean age (yr) 64.3 63.9 Age > 70 yrs (%) 31 29 Sex ratio M/F (%) 73/27 72/28 Clinical history (%) Hypertension 40 39 Diabetes 21 20 Previous MI 13 13 Current smoker 41 41 Angina 33 32Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  48. 48. The SMILE study Drug titration 1 7.5 mg b.i.d. HYPOTENSION 2 7.5 mg b.i.d. 7.5 mg o.d. HYPOTENSION DISCONTINUATION 15 mg b.i.d. DAYS 3 HYPOTENSION OF TREATMENT 4 15 mg b.i.d. 5 30 mg b.i.d. HYPOTENSION 6 30 mg b.i.d. CHRONIC DOSE 30 mg b.i.d. 15 mg b.i.d. 7.5 mg b.i.d.Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  49. 49. The SMILE study Primary end-point Placebo Zofenopril (n = 784) (n = 772) Mortality or severe CHF Events 83 55 Percentage 10.6% 7.1% Risk reduction (95% CI) 34% (8-54) p = 0.018Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  50. 50. The SMILE study 6-week occurrence of death and severe CHF 16 14 Risk reduction: Placebo 12 Incidence (%) 10 Zofenopril -34.0% 8 6 4 P = 0.018 2 0 0 7 14 21 28 35 42 DayThe SMILE study was a randomized, double-blind, placebo-controlled trial involving 1556 patients with acute anterior myocardialinfarctions who were not eligible for thrombolytic therapy. Patients were randomized to received Zofenopril 7.5-30 mg (n = 772) orplacebo (n = 784) twice daily.Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  51. 51. The SMILE study 6-week mortality Placebo Zofenopril (n = 784) (n = 772) Mortality Events 65 50 Percentage 8.3% 6.5% Risk reduction (95% CI) 22% (-12/48) p = 0.17Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  52. 52. The SMILE study 6-week occurrence of severe CHF Placebo Zofenopril (n = 784) (n = 772) Severe CHF Events 34 17 Percentage 4.1% 2.2% Risk reduction (95% CI) 46% (11/71) p = 0.018Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  53. 53. The SMILE study 6-week occurrence of severe CHF 0.04 Placebo 0.035 Zofenopril Events rate (%) 0.03 Risk reduction = 56% 0.025 2p = 0.032 0.02 0.015 0.01 0.005 0 0 7 14 21 28 35 42 Time after randomisation (days)Sub-study of the SMILE study on patients with anterior wall AMI, randomized to receive zofenopril 7.5-30 mg(n = 560) or placebo (n = 586) twice daily for a cumulative period of 6 weeks.Borghi C. et al.; Am J Cardiol. 1996; 78: 317-322
  54. 54. The SMILE study Early mortality (day 2) -56% p=0.03 Mortality (%)Review of the efficacy and tolerability of zofenopril in the treatment of essential hypertension that evaluated the results of four studies(overall n = 1130) in which zofenopril was administered at doses of 7.5-60 mg/day (dose-finding study) or 30-60 mg/day (comparativestudy) and was compared with atenolol 50-100 mg/day, amlodipine 5-10 mg/day and enalapril 20-40 mg/day.Borghi C. et al.; Clin Drug Invest. 2000; 20 (5): 371-384
  55. 55. The SMILE study 1-year mortality Placebo Zofenopril (n = 784) (n = 772) Mortality Events 111 77 Percentage 14.1% 10.0% Risk reduction (95% CI) 29.0% (6/51) p = 0.011Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  56. 56. The SMILE study 1-year mortality 16 Placebo Risk reduction: 14 Zofenopril 29.0% p = 0.011 Incidence (%) 12 10 8 6 4 P = 0.018 2 0 0 7 14 21 28 35 42 DayThe SMILE study was a randomized, double-blind, placebo-controlled trial involving 1556 patients with acute anterior myocardialinfarctions who were not eligible for thrombolytic therapy. Patients were randomized to received Zofenopril 7.5-30 mg (n = 772) orplacebo (n = 784) twice daily.Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85
  57. 57. The SMILE study 1-year mortality in hypertensive patients 1 1 Placebo n = 290 Placebo n = 432 Placebo Zofenopril n = 275 Zofenopril n = 444 Zofenopril 0.95 0.95 Survival rate Survival rate 0.9 0.9 0.85 0.85 RR = 39.3% RR = 23.4% p < 0.05 p < 0.22 0.8 0.8 0 15 30 45 100 160 220 280 360 . 0 15 30 45 100 160 220 280 360 . Time (days) Time (days) History of hypertension No history of hypertensionPost-hoc analysis of SMILE study in patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy.The SMILE study was a randomized, double-blind, placebo-controlled trial involving 1556 patients with acute anterior myocardialinfarctions who were not eligible for thrombolytic therapy. Patients received zofenopril 7.5-30 mg or placebo twice daily for 6 weeks andmortality rate was calculated at 1 year. Borghi C. et al.; Am J Hypertens. 1999; 12 (7): 665-672
  58. 58. The SMILE study Primary endpoint in diabetic patients 30 RR = 53% 25 Death + severe CHF (%) 20 18.3 15 10 8.6 5 0 Placebo Zofenopril (n = 164) (n = 139) p = 0.019Cohort of diabetic patients of the SMILE study. The SMILE study was a randomized, double-blind, placebo-controlled trial involving1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. 303 diabetic patients wererandomized to receive placebo (n = 164) or zofenopril 7.5-30 mg (n = 139) twice daily.Borghi C. et al.; Diabetes Care 2003; 26 (6): 1862-1868
  59. 59. The SMILE study 1-year mortality in diabetic and non-diabetic patients 25 p = 0.52 Placebo p = 0.01 Zofenopril 20 16.5 Event rate (%) 15 13.7 13.8 10 9.1 5 0 Diabetes (n.303) No diabetes (n.1209) n = 164 n = 139 n = 602 n = 607Cohort of diabetic patients of the SMILE study. The SMILE study was a randomized, double-blind, placebo-controlled trial involving1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. 303 diabetic patients wererandomized to receive placebo (n = 164) or zofenopril 7.5-30 mg (n = 139) twice daily.Borghi C. et al.; Diabetes Care 2003; 26 (6): 1862-1868
  60. 60. The SMILE study1-year mortality in patients with and without the metabolic syndrome MS+ MS- RRR -29% RRR -19% (95% CI: 4-51) (95% CI: 6-34) 20 2p = 0.048 2p = 0.025 18 16 Event rate (%) 14 12 10 MS = Metabolic Syndrome 8 6 4 2 0 Placebo Zofenopril Placebo Zofenopril (n = 324) (n = 362) (n = 375) (n = 357)Post-hoc analysis of the SMILE study stratifing patients by presence or absence of the metabolic syndrome. 1418 were randomized toreceive zofenopril 7.5-60 mg (n = 719) or placebo (n = 699) twice daily for 6 weeks.Borghi C. et al.; Vascular Health Risk Manag. 2008; 4 (3): 665-671
  61. 61. The SMILE study Primary endpoint in patients with previous MI - 80% p = 0.0006 25 Death and severe CHF (%) 19.6 20 15 10 5 4 0 Placebo ZofenoprilSub-group of the SMILE study on elderly patients. The SMILE study was a randomized, double-blind, placebo-controlled trialinvolving 1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. Patients receivedzofenopril 7.5-30 mg or placebo twice daily for 6 weeks.Borghi C et al.; “Efficacy of myocardial infarction therapy”;. Dekker Inc.; 1999
  62. 62. The SMILE study Primary endpoint in patients with angina -55% p = 0.003Sub-group of the SMILE study on elderly patients. The SMILE study was a randomized, double-blind, placebo-controlled trialinvolving 1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. Patients receivedzofenopril 7.5-30 mg or placebo twice daily for 6 weeks.Borghi C et al.; “Efficacy of myocardial infarction therapy”;. Dekker Inc.; 1999
  63. 63. The SMILE study 1-year mortality by the Q-wave Q-wave MI Non-Q-wave MI Placebo 20 20 Zofenopril 15 15 Mortality rate (%) Mortality rate (%) N = 519 N = 107 10 10 N = 512 N = 99 5 5 Risk reduction: 39.5% Risk reduction: -1.0% p = 0.003 p = 0.99 0 0 0 1 2 3 4 5 6 7 8 9 10 1112 0 1 2 3 4 5 6 7 8 9 10 11 12 Time after randomisation (months) Time after randomisation (months)Sub-group of the SMILE study on elderly patients. The SMILE study was a randomized, double-blind, placebo-controlled trial involving1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. Patients received zofenopril7.5-30 mg or placebo twice daily for 6 weeks.Borghi C et al.; “Efficacy of myocardial infarction therapy”;. Dekker Inc.; 1999
  64. 64. The SMILE study Conclusiones The SMILE Study demostro que la administracion temprana de zofenopril en pacientes con IAM anterior : • Con 6 semanas de TTO. •Reduce la aparición de end points combinado de muerte de causa cardiovascular e Insuficiencia cardíaca grave Reduce la progresión a ICC grave Reduce la mortalidad a 1 año • Se asocia con una excelente tolerancia y bajo indice de complicaciones.Ambrosioni E. et al.; N Engl J Med.1995; 332 (2): 80-85; Borghi C. et al.; Am J Cardiol. 1996; 78: 317-322; Borghi C. et al.;“Efficacy of myocardial infarction therapy”.; Dekker Inc.; 1999; Borghi C. et al.; Am J Hypertens. 1999; 12 (7): 665-672.
  65. 65. The SMILE 2 study “Double-blind comparison between early administration of zofenopril and lisinopril in patients with acutemyocardial infarction: results of the Survival of Myocardial Infarction Long-term Evaluation 2 (SMILE-2) Study. Outlines of the study Study design: Randomised, double-blind, placebo-controlled Population: 1024 patients with acute myocardial infarction undergoing thrombolysis Treatment: Within 24 hours of the onset of symptoms: zofenopril 7.5-30 mg b.i.d. (n = 504) or lisinopril 2.5-10 mg o.d. + placebo (n = 520) Duration of treatment: 6 weeks Borghi C. et al.; Am Heart J. 2003; 145 (1): 80-87
  66. 66. The SMILE 2 study Endpoints • Primary • 6 week occurrence of drug-related severe hypotension (SBP < 90 mmHg). • Secondary • 6-week cumulative mortality • incidence of severe CHF • deterioration in renal function • 6-week LV function (EF%) • need for PTCA or CABG • incidence of angina • incidence of reinfarctionBorghi C. et al. Am Heart J. 2003; 145 (1): 80-87
  67. 67. The SMILE 2 study 6-week incidence of drug-related severe hypotension p = 0.048 % (n = 520) (n = 504)SMILE-2 study. Phase III, double-blind, parallel-group, multicenter study conducted in 1024 thrombolyzed patients with acutemyocardial infarction. Patients were randomized to receive zofenopril 30-60 mg/day (n = 504) or lisinopril 5-10 mg/day (n = 520) for 6weeks.Borghi C. et al. Am Heart J. 2003; 145 (1): 80-87
  68. 68. The SMILE 2 study Early incidence of drug-related hypotension p = 0.017 p = 0.031 % Lisinopril Zofenopril Lisinopril Zofenopril (n = 520) (n = 504) (n = 520) (n =504) 0-48 hours After 5 days of treatmentSMILE-2 study. Phase III, double-blind, parallel-group, multicenter study conducted in 1024 thrombolyzed patients with acute myocardialinfarction. Patients were randomized to receive zofenopril 30-60 mg/day (n = 504) or lisinopril 5-10 mg/day (n = 520) for 6 weeks.Borghi C. et al.; Am Heart J. 2003; 145 (1): 80-87
  69. 69. The SMILE 2 study Secondary endpoints Lisinopril Zofenopril Parameter (n = 520) (n = 504) p Death (%) 4.0 3.2 NS Severe heart failure (Killip classification) day 1 to 7 (%) 0.6 0.8 NS Severe heart failure (NYHA classification) 3.5 4.2 NS at the end of treatment period (%) Acute revascularisation (%) 3.3 3.4 NS Mean LVEF (%) 52.0 51.9 NS Myocardial reinfarction (%) 3.8 4.2 NS Renal function deterioration (%) 2.7 2.6 NS Angina pectoris (%) 20.6 20.6 NS NYHA, New York Heart Association; LVEF, Left Ventricular Ejection Fraction, NS, Not Significant.Borghi C. et al. Am Heart J. 2003; 145 (1): 80-87
  70. 70. The SMILE 2 study Conclusions • Zofenopril es bien tolerado cuando se inicia dentro de 24 horas de inicio de los síntomas • El tratamiento con zofenopril se asocia con una disminución ligera pero estadísticamente significativo en la incidencia de grave hipotensión relacionada con drogas en comparación con lisinopril, particularmente durante la fase aguda tras la hospitalización •Borghi C. et al. Am Heart J. 2003; 145 (1): 80-87
  71. 71. The SMILE-ISCHEMIA study Outlines of the studyStudy design: Multicentre, randomized, double-blind, placebo-controlledPopulation: 349 AMI patients with preserved LV function (LVEF > 40%)Treatment: zofenopril calcium 7.5 - 30 mg b.i.d. (n = 177) or placebo (n = 172) + standard therapyDuration of treatment: 6 months Borghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14
  72. 72. The SMILE-ISCHEMIA study Endpoints • Primary: Global ischemic burden • Combined 6-month occurence of: • onset of ST-T abnormalities at 24-hour ambulatory ECG monitoring • onset of ECG abnormalities or angina symptoms at treadmill test • onset of angina symptoms at treadmill test • recurrent MI • need for revascularisation because of angina Secondary • Capacity of zofenopril to reduce the occurrence of any single event of the primary endpoint or any other major CV event, including deathBorghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14
  73. 73. The SMILE-ISCHEMIA study Primary endpoint – global ischemic burden p = 0.001 35.9 20.3 %SMILE-ISCHEMIA study. Randomized, double-blind, multicenter, placebo-controlled study conducted in 349 post-myocardial infarctionpatients with preserved left ventricular ejection fraction treated for 6 months with zofenopril 30 to 60 mg (n = 177) or placebo (n = 172).Borghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14
  74. 74. The SMILE-ISCHEMIA study Single components of the primary endpoint 30 Placebo p = 0.017 Zofenopril 25 p = 0.027 20 % of patients p = 0.024 p = 0.048 15 10 5 0 ST depression ST depression in Angina in Re-infarction CABG/PTCA ambulatory ECG response to TT response to TTSMILE-ISCHEMIA study. Randomized, double-blind, multicenter, placebo-controlled study conducted in 349 post-myocardial infarctionpatients with preserved left ventricular ejection fraction treated for 6 months with zofenopril 30 to 60 mg (n = 177) or placebo (n =172).Borghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14
  75. 75. The SMILE-ISCHEMIA study Major cardiovascular events at 6 months -64,6% p = 0.001 % incidenceSMILE-ISCHEMIA study. Randomized, double-blind, multicenter, placebo-controlled study conducted in 349 post-myocardial infarctionpatients with preserved left ventricular ejection fraction treated for 6 months with zofenopril 30 to 60 mg (n = 177) or placebo (n = 172).Borghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14
  76. 76. The SMILE-ISCHEMIA study Conclusions Los resultados del estudio SMILE-isquemia extienden el uso de Zofenopril en términos de cardioprotección y prevención de eventos coronarios desde el inicio hasta la fase tardía del infarto de miocardio. De acuerdo a estos resultados, zofenopril puede ser recomendado como un tratamiento de prevención secundaria en pacientes con infarto de miocardio con enfermedad arterialBorghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14
  77. 77. The SMILE 4 study“Comparison between zofenopril and ramipril in combination with acetyl salicylic acid in patients with leftventricular systolic dysfunction after acute myocardial infarction: results of a randomized, double-blind, parallel-group, multicenter, European study (SMILE 4)”. Outlines of the study Study design: Phase IIIb, randomized, double-blind, parallel-group, multicentre Population: 771 post-MI LVD patients with clinical sign of heart failure or a left ventricular ejection fraction or LVEF < 45% Treatment: zofenopril 60 mg/day (n = 389) + ASA 100 mg/day or ramipril 10 mg/day (n = 382) + ASA 100 mg/day Duration of treatment: 12 monthsBorghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  78. 78. The SMILE 4 study Primary endpoint The 1-year combined occurrence of: • cardiovascular mortality • hospitalization for CV causesBorghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  79. 79. The SMILE 4 study Secondary endpoints • Hospitalization for CV causes • Changes in LVEF • Changes in left ventricular end-diastolic and end-systolic volumes • Changes in plasma NT-proBNP levels • BP changes • Overall incidence of non-CV adverse events • Occurrence of severe hypotension • Deterioration of renal functionBorghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  80. 80. The SMILE 4 study Significant reduction in the primary outcome at 1 year -30% -36% p = 0.028 p = 0.006 1 1 1 Ramipril 0,9 10 mg/day zofenopril vs. ramipril 0,8 0.7 Zofenopril 0.64 Odds ratio (OR) 0,7 0,6 60 mg/day 0,5 0,4 0,3 0,2 0,1 0 Primary endpoint Hospitalization for CV causes An RR < 1 means the event is less likely to occur in the experimental group than in the control groupSMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treatedwith zofenopril 30-60 mg/day (n = 389) or ramipril 5-10 mg/day (n = 382) in combination with ASA 100 mg/day for 12 months.Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  81. 81. The SMILE 4 study Significant reduction in the incidence of CV death and hospitalization at 1 year 0.5 A p = 0.044 0.4 Log rank test Cumulative hazard of 1-year combined endpoint 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) Number at risk Zofenopril 365 317 298 287 281 276 267 262 261 260 258 255 247 Ramipril 361 305 276 269 263 260 247 243 238 236 233 228 215SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated withzofenopril 30-60 mg/day (n = 389) or ramipril 5-10 mg/day (n = 382) in combination with ASA 100 mg/day for 12 months.Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  82. 82. The SMILE 4 study Lower frequency of major CV events requiring hospitalization vs. ramipril at 1 year 35% 33.3 Frequency of major CV events requiring hospitalization (%) 30% 24.1 25% 20% 15% 10% 8.0 9.1 6.3 5.5 6.8 4.6 3.6 4.1 5% 3.4 3 2.0 1.1 0% Congestive heart Acute myocardial Angina pectoris Decline in LVEF Revascularization Other causes All causes failure infarction > 15% Ramipril 10 mg/day (n = 351) Zofenopril 60 mg/day (n = 365)SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated withzofenopril 30-60 mg/day (n = 389) or ramipril 5-10 mg/day (n = 382) in combination with ASA 100 mg/day for 12 months.Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  83. 83. The SMILE 4 study Significant reduction in the primary endpoint in patients without previous coronaropathies Patients without Effect of zofenopril vs. ramipril on the risk of CV Patients without previous angina previous MI (n = 577) mortality or hospitalization for CV causes pectoris (n = 450) -0% -5% -10% -15% -20% -25% -30% -35% -40% -45% -39% OR: 0.61 -42% -50% OR: 0.58 p = 0.007 p = 0.008 MI: Myocardial Infarction; OR: Odds RatioSMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treatedwith zofenopril 30-60 mg/day (n = 389) or ramipril 5-10 mg/day (n = 382) in combination with ASA 100 mg/day for 12 months.Borghi C. et al.; Poster SMILE IV; AHA 2011
  84. 84. The SMILE 4 study Significant reduction in the primary endpoint in patients without previous coronaropathies Effect of zofenopril vs. ramipril on the risk of CV Patients without Patients with baseline SBP ≥ Patients with baseline LVEF > 40% (n = 448) Mortality or hospitalization for CV causes hypercholesterolemia (n = 375) 140 mmHg (n = 367) 0% -10% -20% -30% -40% -39% -40% -50% OR: 0.61 OR: 0.6 p = 0.026 -48% p = 0.016 OR: 0.52 -60% p = 0.003 SBP: Systolic Blood Pressure; LVEF: Left Ventricular Ejection Fraction, OR: Odds RatioSMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated withzofenopril 30-60 mg/day (n = 389) or ramipril 5-10 mg/day (n = 382) in combination with ASA 100 mg/day for 12 months.Borghi C. et al.; Poster SMILE IV; AHA 2011
  85. 85. The SMILE 4 study Significant reduction in the incidence of CV hospitalization at 1 year 0.5 Cumulative hazard of 1-year CV 0.4 p = 0.013 Log rank test hospitalization 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) Number at risk Zofenopril 365 317 298 287 281 276 267 262 261 260 258 255 247 Ramipril 351 305 276 269 263 260 247 243 238 236 233 228 215SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treatedwith zofenopril 30-60 mg/day (n = 389) or ramipril 5-10 mg/day (n = 382) in combination with ASA 100 mg/day for 12 months.Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  86. 86. The SMILE 4 study Significant reduction in concomitant CV drugs use 30% 26% Patients treated with multiple (≥ 8) 25% p < 0.001 20% CV drugs (%) 15% 12% 10% 5% 0% Ramipril 5-10 mg/day Zofenopril 30-60 mg/daySMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treatedwith zofenopril 30-60 mg/day (n = 389) or ramipril 5-10 mg/day (n = 382) in combination with ASA 100 mg/day for 12 months.Borghi C. et al.; Poster SMILE IV; AHA 2011
  87. 87. The SMILE 4 study Safety analysis • No statistically significant differences were observed between treatment groups in the distribution of non-cardiovascular adverse events • Most of events were of a mild or moderate intensity • The most common drug-related adverse events were cough, hypotension, asthenia or vertigo.Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  88. 88. The SMILE 4 study Conclusiones • En pacientes con fallla de VI asociado a IAM la asociación de Zofenopril + AAS fue mas eficiente que Ramipril + AAS • Zofenopril tiene un impacto mas favorable que el Ramipril en eventos cardiovasculares relacionados al IAM en el seguimiento a 1 año. • Zofenopril y ramipril presentaron la misma incidencia de efectos adversos siendo bien tolerados • Estos resultados tienen mucha importancia para el tratamiento de la falla cardiaca relacionada al IAM en el futuro. (concepto de cardiomioprotección).Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423
  89. 89. Preguntas mas frecuentes
  90. 90. Es necesaria la aparición de un nuevo IECA?• 1) De acuerdo a los resultados de los estudios presentados, el Zofenopril, es seguro, eficaz, con elevada liposulubilidad, sencilla posología, y elevada distribución miocárdica.• 2) Aparición del concepto de cardiomioprotección, con disminución significativa de la mortalidad (independientemente de la TA) en el IAM con falla del VI
  91. 91. GRACIAS

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