This document discusses hypertension and cardiovascular disease, and compares guidelines for treating hypertension from JNC7 and ESH/ESC. It provides the following key points: 1) Treatment of hypertension can significantly reduce mortality from stroke and coronary heart disease. Reductions in blood pressure of just 2-5 mmHg can lower mortality risks. 2) Guidelines recommend treating hypertension to target blood pressures of less than 140/90 mmHg, and less than 130/80 mmHg for those with diabetes or chronic kidney disease. 3) Angiotensin converting enzyme (ACE) inhibitors play a major role in hypertension treatment, both as monotherapy and in combination with other drugs like diuretics and calcium channel block

1. Dr. Gustavo Ruiz Deza
Jefe Unidad Coronaria
HIGA Pte. Perón
Avellaneda
Jefe Servicio de Cardiología
Sanatorio Bernal
Bernal- Pcia. Buenos Aires

2. Hipertensión:
Visión general y distintos
enfoques de tratamiento

3. Enfermedad Cardiovascular: Pandemia
The Atlas of Heart Disease and Stroke; http://www.who.int

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 -7
JNC7 Guidelines, 2003*

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
cardiovascular
ESH/ESC Guidelines, 2007*
JNC7 Guidelines, 2003**

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. 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 plena
ESH/ESC Guidelines, 2007

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 metabólico
ESH/ESC Guidelines, 2007
JNC7 Guidelines, 2003

10. Química

11. Structural formula of zofenopril calcium
and its active metabolite
Zofenopril calcium Zofenoprilat
Subissi A. et al.; Cardiovasc Drug Rev. 1999; 17: 115-133

12. 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 0.33
Subissi A. et al.; Cardiovasc Drug Rev. 1999; 17: 115-133

13. Propiedades
farmacocinéticas

14. 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-450
Sleight; 1999
Zofenopril – Summary of product characteristics

15. 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

16. Metabolism
o n
ati
xid
lf o
Su
Subissi A. et al.; Cardiovasc Drug Rev. 1999; 17: 155-133

17. Propiedades
farmacocinéticas

18. 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

19. Efectiva y duradera inhibición a nivel cardíaco
1h
8h
24 h
% cardiac ACE inhibition
Zofenopril Captopril Fosinopril Ramipril Lisinopril Enalapril
In ex vivo dose-response and time-course studies, the inhibitory effects on tissue ACEs and their relative tissue distributions of seven
drugs (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

20. 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 baseline
Napoli C. et al.; Am Heart J. 2004; 148 (1): e5.

21. 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. control
The study investigated the effects of different ACE-inhibitor (Zofenoprilat, enalaprilat, lisinopril and irbesartan) on tissue injury on isolated
rat hearts subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion.
Frascarelli S. et al.; J Cardiovasc Pharmacol. 2004; 43: 294-299.

22. 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 M
The study investigated the effects of zofenopril (10-6 M) and captopril (10-6 M) on the mechanical function, cellular
redox state, and norepinephrine (NE) content of isolated and aerobically perfused rabbit hearts.
Ferrari R. et al.; J Cardiovasc Pharmacol. 1992; 20: 694-704

23. 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 oxide
production and action, and on endothelial oxidative stress using bovine aortic endothelial cells. Captopril, Enalapril and Zofenopril were
administered at concentration of 1, 10, 30 and 60 µM.
Scribner A. W. et al.; Eur J Pharmacol. 2003; 482: 95-99

24. 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

25. 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

26. Efecto vasculoprotector
Reducción del indice intima – media carotídeo
0.82
0.79
0.78 0.78
0.78
0.74 0.74 0.74
MT (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 for
atherosclerosis. 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

27. Eficacia clínica

28. 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 Pressure
Randomised, double-blind, placebo-controlled, multicentre study comprising a 2-week placebo lead-in and a 6-week treatment
phase 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

29. Redduccion de la TA por 24 Hs.
Basal After 6 weeks of treatment
T/P ratio:
DBP (mmHg)
73%
Hours post-dose
Randomized, double-blind, parallel-group, placebo-controlled multicenter trial conducted on 211 patients with mild to moderate
hypertension. 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

30. Eficacia clínica
versus otros IECA

31. 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
-25
Comparative 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) or with 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

32. 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 mg
Comparative 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) or with 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

33. Eficacia clínica
versus losartan

34. 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
-20
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. 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

36. Eficacia Clínica
versus amlodipine

37. 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 12
Parallel-group double-blind, randomized, multi-centre, 12-weeks study in 303 patients with mild to moderate
hypertension, 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

38. 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 mg
Parallel-group double-blind, randomized, multi-centre, 12-weeks study in 303 patients with mild to moderate hypertension, 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

39. Efectos adversos y
seguridad

40. 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 (comparative
study) 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

41. 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
events
Comparative 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) or
with 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

42. 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 Oedema
Parallel-group double-blind, randomized, multi-centre, 12-weeks study in 303 patients with mild to moderate
hypertension, 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

43. The SMILE project

44. Overview and future implications
of the SMILE project
SMILE Pilot Study 204 thrombolyzed patients
American Journal of Cardiology 1991 Zofenopril vs standard treatment
Safety assessment
1556 non thrombolyzed patients
SMILE Study Zofenopril vs placebo
New England Journal of Medicine 1995
Am J Cardiol, 1996 6-week mortality and severe CHF
Am J Hypertens, 1999 1-year mortality rate
SMILE-2 Study 1024 thrombolyzed patients
Am Heart J, 2002 Zofenopril vs lisinopril
6-week rate of severe hypotension
6-week safety profile
SMILE-3 Ischemia Study 349 thrombolyzed patients normal LVF
Zofenopril vs placebo
Am Heart J, 2007
6-months ischemic events rate
SMILE-4 Study 871 thrombolyzed patients with systolic
LV disfunction (EF < 45%)
Clin Cardiol 2012
Zofenopril + ASA vs ramipril + ASA
1-year cardiovascular event rate

45. The SMILE Study
The 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 year
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

46. 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 mortality
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

47. 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-I
Ambrosioni E. et al.; Controlled Clinical Trials 1994; 15: 201-210

48. 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 32
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

49. 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

50. 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 = 0.018
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

51. 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
Day
The SMILE study was a randomized, double-blind, placebo-controlled trial involving 1556 patients with acute anterior myocardial
infarctions who were not eligible for thrombolytic therapy. Patients were randomized to received Zofenopril 7.5-30 mg (n = 772) or
placebo (n = 784) twice daily.
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

52. 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 = 0.17
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

53. 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 = 0.018
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

54. 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

55. 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 (comparative
study) 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

56. 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 = 0.011
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

57. 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
Day
The SMILE study was a randomized, double-blind, placebo-controlled trial involving 1556 patients with acute anterior myocardial
infarctions who were not eligible for thrombolytic therapy. Patients were randomized to received Zofenopril 7.5-30 mg (n = 772) or
placebo (n = 784) twice daily.
Ambrosioni E. et al.; N Engl J Med. 1995; 332 (2): 80-85

58. 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 hypertension
Post-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 myocardial
infarctions who were not eligible for thrombolytic therapy. Patients received zofenopril 7.5-30 mg or placebo twice daily for 6 weeks and
mortality rate was calculated at 1 year.
Borghi C. et al.; Am J Hypertens. 1999; 12 (7): 665-672

59. 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 = 0.019
Cohort of diabetic patients of the SMILE study. The SMILE study was a randomized, double-blind, placebo-controlled trial involving
1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. 303 diabetic patients were
randomized 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. 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 = 607
Cohort of diabetic patients of the SMILE study. The SMILE study was a randomized, double-blind, placebo-controlled trial involving
1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. 303 diabetic patients were
randomized 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

61. The SMILE study
1-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 to
receive 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

62. 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 Zofenopril
Sub-group of the SMILE study on elderly patients. The SMILE study was a randomized, double-blind, placebo-controlled trial
involving 1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. Patients received
zofenopril 7.5-30 mg or placebo twice daily for 6 weeks.
Borghi C et al.; “Efficacy of myocardial infarction therapy”;. Dekker Inc.; 1999

63. The SMILE study
Primary endpoint in patients with angina
-55%
p = 0.003
Sub-group of the SMILE study on elderly patients. The SMILE study was a randomized, double-blind, placebo-controlled trial
involving 1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. Patients received
zofenopril 7.5-30 mg or placebo twice daily for 6 weeks.
Borghi C et al.; “Efficacy of myocardial infarction therapy”;. Dekker Inc.; 1999

64. 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 involving
1556 patients with acute anterior myocardial infarctions who were not eligible for thrombolytic therapy. Patients received zofenopril
7.5-30 mg or placebo twice daily for 6 weeks.
Borghi C et al.; “Efficacy of myocardial infarction therapy”;. Dekker Inc.; 1999

65. 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.

66. The SMILE 2 study
“Double-blind comparison between early administration of zofenopril and lisinopril in patients with acute
myocardial 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

67. 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 reinfarction
Borghi C. et al. Am Heart J. 2003; 145 (1): 80-87

68. 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 acute
myocardial infarction. 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. 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 treatment
SMILE-2 study. Phase III, double-blind, parallel-group, multicenter study conducted in 1024 thrombolyzed patients with acute myocardial
infarction. 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

70. 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

71. 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

72. The SMILE-ISCHEMIA study
Outlines of the study
Study design: Multicentre, randomized, double-blind, placebo-controlled
Population: 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 therapy
Duration of treatment: 6 months
Borghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14

73. 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 death
Borghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14

74. 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 infarction
patients 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. 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 TT
SMILE-ISCHEMIA study. Randomized, double-blind, multicenter, placebo-controlled study conducted in 349 post-myocardial infarction
patients 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. The SMILE-ISCHEMIA study
Major cardiovascular events at 6 months
-64,6%
p = 0.001
% incidence
SMILE-ISCHEMIA study. Randomized, double-blind, multicenter, placebo-controlled study conducted in 349 post-myocardial infarction
patients 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

77. 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 arterial
Borghi C. et al.; Am Heart J. 2007; 153: 445.e7-445.e14

78. The SMILE 4 study
“Comparison between zofenopril and ramipril in combination with acetyl salicylic acid in patients with left
ventricular 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 months
Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423

79. The SMILE 4 study
Primary endpoint
The 1-year combined occurrence of:
• cardiovascular mortality
• hospitalization for CV causes
Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423

80. 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 function
Borghi C. et al.; Clin Cardiol. 2012; 35 (7): 416-423

81. 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
group
SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated
with 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

82. 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 361 305 276 269 263 260 247 243 238 236 233 228 215
SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated with
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

83. 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 with
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

84. 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 Ratio
SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated
with 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

85. 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 Ratio
SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated with
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

86. 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 351 305 276 269 263 260 247 243 238 236 233 228 215
SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated
with 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

87. 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/day
SMILE IV study. Double-blind, randomized study in 771 patients with post-myocardial infarction left ventricular dysfunction treated
with 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

88. 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

89. 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

90. Preguntas mas
frecuentes

91. 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

92. GRACIAS