PROTECCION CARDIOVASCULAR DADA POR BLOQUEADORES DEL RECEPTOR AT1 DEL SRAA

1. BRAS ‘ Y PROTECCIÓN
CARDIOVASCULAR
•Cuando se usan de primera línea?
•Cuales son sus mejores beneficios ?
•Donde no?
DR. MARTÍN VELARDE 2014
CARDIÓLOGO CLÍNICO. MASVH.
MASVC.MAAVA.MACDP
2014

4. Tratamiento de la hipertension,no complicada, sin
factores de riesgo adicionales con cifras de
PA<160/100mmHg

5. Guías de la Sociedad Argentina de
Hipertensión Arterial
 Diuréticos
 Betabloqueantes
 Inhibidores de la enzima convertidora
 Antagonistas de los receptores AT1 de la angiotensina II
 Antagonistas cálcicos
Sugerencias de Drogas
Drogas de 1ª línea
Otras drogas
• Antialdosterónicos
• Antirreninas
• Alfabloqueantes
2011

6. ValsartánLosartán
OlmesartCandesartán
Exp3174
N
N
N NH
N
N
Cl
N
O
N
N
N
NH
N
N
N NH
N
N
Me
N
N
N NH
N
N
OMe
OH
COOH COOH
COOH
COOH
Miura S, et al. Curr Hypertens Rev. 2005
Imidazol
Bifenil
Tetrazol
i
N
N
N NH
N
N
Cl
CH OH2
Estructura Química de los ARA II

8. El receptor AT1 en el continuo
cardiovascular
Hipertensión
Diabetes
Dislipidemia
Obesidad
Arteriosclerosis
Remodelado vascular
HVI
> Grosor IM
Infartos lacunares
Microalbuminuria
IAM, Angina
Ictus
Insuficiencia cardiaca
Insuficiencia Renal
Arteriopatía Periférica Episodios
reincidentes
no mortales
IR terminal
Diálisis
Demencia
Genes
Estilo de vida
Muerte
HTA
HTA
HTA
HTA
HTA
Bloqueo del receptor
AT1

9. Systolic Blood Pressure (SBP) Reduction with Valsartan is Superior
to Losartan and Comparable to Other ARBs
Drug and dose
Candesartan 8 mg
Candesartan 16 mg
Candesartan 32mg
Irbesartan 150 mg
Irbesartan 300 mg
Losartan 50 mg
Losartan 100 mg
Olmesartan 20 mg
Olmesartan 40 mg
Telmisartan 40 mg
Telmisartan 80 mg
Valsartan 80 mg
Valsartan 160 mg
Valsartan 320 mg
n
142
329
821
531
261
369
1733
145
199
275
233
321
3661
3091
Estimate and 95% CI
–10.04 (–13.89, –6.19)
–12.70 (–15.32, –10.07)
–15.28 (–17.75, –12.80)
–11.75 (–13.91, –9.54)
–15.98 (–18.89, –13.10)
–9.93 (–12.69. –7.14)
–12.01 (–13.78, –10.25)
–10.88 (–15.63, –6.05)
–13.98 (–18.53, –9.44)
–13.98 (–16.64, –11.23)
–16.50 (–19.26, –13.76)
–11.52 (–14.39, –8.70)
–15.32 (–17.09, –13.63)
–15.85 (–17.60, –14.12)
–18 –14 –10 –6
Changes in SBP (mmHg)
Nixon et al. Int J Clin Pract 2009;63:766–75
Meta-regression analysis of 31 randomized controlled trials (n=13,110 patients) with at least one
angiotensin receptor blocker (ARB) arm. The meta-analysis adjusted for the influence of
different baseline BP between studies. Studies ranged in duration from 6–12 weeks.
Data are from baseline to follow-up

10. La Terapia Combinada es Más Efectiva que la Monoterapia
∆PAS(mmHg)
Valsartan 80 mg o.d.†
Valsartan 160 mg o.d.†
Valsartan-HCTZ 160/12.5 mg o.d.†
*
*
*‡
*‡
*‡
#PAS/PAD >150/90 mmHg; *p<0.05 vs.. Valsartan 80 mg; ‡p<0.05 vs.. Valsartan 160 mg; †indica dosis de inicio; Valsartan
80 titulado hasta Valsartan-HCTZ 160/12.5, Valsartan 160 y Valsartan-HCTZ 160/12.5 titulado hasta Valsartan-HCTZ
160/25 mg o.d. a la semana 4 y 2 respectivamente; en prensa
-30
-25
-20
-15
-10
-5
0
0 1 2 3 4 5 6
semanas
Resultado de 1 año de estudio en 648 pacientes con hipertensión#
(Estudio VELOCITY)

11. AMLODIPINA/VALSARTAN: reducción de la PAS
en pacientes con HTA st 2 Estudio EX-EFFeCTS
Destro et al. J.AmSocHypertens 2008:2;294-302
BRA+BCC: Eficacia

12. 24
1. VALUE
2. VALIANT
3. NAVIGATOR
4. Val-HeFT
5. JIKEI HEART
6. KYOTO HEART
7. VART
27. HIJ-CREATE
28. E-COST
29. HOPE-3*
30. 4C*
31. I-PRESERVE
32. IDNT
33. ACTIVE-I*
34. NID-2
35. SUPPORT*
36. COLM*
37. OSCAR*
38. ORIENT
39. MOSES
8. VALISH*
9. NAGOYA-HEART*
10. V-CARD*
11. ONTARGET
12. PRoFESS
13. TRANSCEND
14. HALT-PKD*
*Expected enrolment‡Ongoing and completed
randomized controlled
trials with death or hard
CV events as or part of
the primary endpoint
¶Valid as of December 2009
15. NCT00490958*
16. LIFE
17. OPTIMAAL
18. ELITE II
19. RENAAL
20. NCT00090259*
21. VA NEPHRON-D*
22. CHARM
23. SCOPE
24. SCAST*
25. CASE-J
26. ACCOST
Numberofpatients
Valsartan Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan
57,046
53,247
25,019
36,940
6,777
1,405
15,693
1
2
5
4
3
7
8
6
11
12
14
13
20
21
18
16
17
25
26
28
22
23
39
36
35
37
38
34
33
32
31
27
1Julius et al. 2004; 2Pfeffer et al. 2003; 3Califf et al 2008; 4Cohn et al. 2001; 5Mochizuki et al. 2007; 6Sawada et al 2009
7Narumi et al. 2009 [abstract at ESC]; 8http://clinicaltrials.gov (NCT00151229); 9http://clinicaltrials.gov (NCT00129233)
10http://clinicaltrials.gov (NCT00140790); 11ONTARGET Investigators 2008; 12Yusuf et al 2008; 13TRANSCEND Investigators 2008
14http://clinicaltrials.gov (NCT00283686); 15http://clinicaltrials.gov (NCT00490958); 16Dahlöf et al. 2002; 17Dickstein et al. 2002
18Pitt et al. 2000; 19Brenner et al. 2001; 20http://clinicaltrials.gov (NCT00090259); 21Fried et al 2009; 22Pfeffer et al 2003
23Papademetriou et al. 2004; 24http://clinicaltrials.gov (NCT00120003); 25Ogihara et al. 2008
26http://clinicaltrials.gov (NCT00108706); 27Laufs et al. 2008; 28Suzuki et al. 2005; 29http://clinicaltrials.gov (NCT00468923)
30http://clinicaltrials.gov (NCT00139386); 31Massie et al 2008; 32Lewis et al. 2001; 33http://clinicaltrials.gov (NCT00249795)
34http://clinicaltrials.gov (NCT00535925); 35http://clinicaltrials.gov (NCT00417222); 36Ogihara et al 2009; 37Ogawa et al 2009
38Imai et al. 2009 (Abstract F-FC313 at ASN 2009); 39Schrader et al. 2005
15
19
29
30
9
10
60,000
50,000
40,000
30,000
20,000
10,000
0
EL CONTINUO CARDIOVASCULAR
# ESTUDIOS CON ARA2

13. HIPERTENSOS NO CONTROLADOS,
Impacto sobre Órgano Blanco y Conductas Terapéuticas en
HTA
En el cerebro:
La HTA multiplica por 6 el riesgo
de sufrir un ictus, de forma que se
estima que el 50 % de los infartos
isquémicos o hemorrágicos tienen
como base la HTA:
1. Además, la segunda clase en frecuencia de demencia,
la vascular, tiene una estrecha correlación con la
HTA.

15. Stroke
Losartan
Atenolol
Adjusted Risk Reduction 24.9%, p=0.001
Unadjusted Risk Reduction 25.8%, p=0.0006
Study
Month
0 6 12 18 24 30 36 42 48 54 60 66
0
1
2
3
4
5
6
7
8
Dahlöf B et al Lancet 2002;359:995-1003.
Losartan 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925
Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897
Fatal and nonfatal stroke
Proportionofpatientswithfirstevent(%)
Number
at Risk

16. Systolic BP, mm Hg
Diastolic BP, mm Hg
Pulse rate, bpm
BMI, kg/cm2
Smokers, %
174.3
97.9
73.9
28.0
15.8
174.5
97.7
73.7
28.0
16.8
LIFE: Baseline Characteristics (II)
Losartan
(N=4605)
Atenolol
(N=4588)

17. Lithell H et al. J hypertens 2003;21:875-886 17
A Favor Candesartan A Favor Control

18. ARB and CARDIOVASCULAR MORTALITY
VALUE
Valsartan vs Amlodipine
15,245 pts, >50 yrs
+hypertension and high
risk of cardiac events
The main outcome of
cardiac disease did not
differ between the
treatment groups
TA : 158/88

20. Thiazides v any other -1,4 0,2 15 4229
Β blockes v any other 1,4 0,6 10 2182
Enzyme inhibitors v any other
Angiotensin converting 0,9 0,4 21 6026
BRA -0,4 0,1 10 2744
Blockers v any other
Blockers v any other
Calcium channel -0,4 -0,9 21 6288
Law and Wald . BMJ 2009
Blood pressure
Difference (mmHg)
Systolic Diastolic
No of No of
Trials events
No of No of
Trials events
Relative risk
(95%CI)
StrokesCoronary heart disease events
Relative risk
(95%CI)
Relative risk
(95%CI)
Relative risk
(95%CI)
099 (0,91 to 1,08) 15 2255
1,04 (0,92 to 1,17) 13 2004
1,00 (0,91 to 1,10) 25 4981
0,94(0,82 to 1,09)
0,97 (0,90 to 1,03) 17 2951
1,04 (0,94 to 1,16) 7 1643
1,18(1,03 to 1,36)
0,91(0,84 to 0,98)
0,90(0,71 to 1,13)
1,06(0,94 to 1,20)
0,7 0,7 1 1,41,41
Specified
Drug better
Specified
Drug worse
Specified
Drug better
Specified
Drug worse

21. ACV
EAC
INSUF. CARDIACA
EVENTOS CV MAYORES
MUERTE CV
MORTALIDAD TOTAL
0,5 1,0 2,0
FAVORECE
ARA 2
RR ( 95 % IC )
0,79 ( 0,69 – 0,90 )
0,96 ( 0,85 – 1,09 )
0,84 ( 0,72 – 0,97 )
0,90 ( 0,83 – 0,96 )
0,96 ( 0,85 – 1,08 )
0,94 ( 0,86 – 1,02 )
FAVORECE
0TROS
Clase terapéutica y eventos

22. 22

23. Incidence of new-onset atrial fibrillation: The VALUE trial
Cumulativeprobability
Time since randomization ( years )
0
3.0 3.5 4.0 4.5 5.02.52.01.51.00.5
0.20
4.0
0.15
0.05
0
0.25
Amlodipine
Valsartan
Hazard ratio: 0.683(95% CI 0.525, 0.889;P=0.005)
Patients at risk (n)
Year 0 1 2 3 4 5
Amlodipine 6888 6882 6634 6317 5848 1681
Valsartan 6872 6862 6644 6324 5876 1660

24. Presiones arteriales en estudio con IECAS
CAMELOT 127-77mmHg
HOPE 138-76 mmHg
SAVE 113-70 mmHg
EUROPA 136-80 mmHg
TREND 127-73 mmHg

26. Tratamiento en pacientes Hipertensos y
nefroprotección .
Steno 2
MARVAL
IRMA-2
RENAAL
IDNT
AMADEOBENEDICT
Ruggenenti P, et al. N Egl J Med 2009; 351: 1941-51.
ADA. Diabetes Care 2009; 27(Suppl. 1): S79-S83.
IRCNormoalbuminuria MacroalbuminuriaMicroalbuminuria
20-199 200UAE (µg/min) <20 >_
DROP
SMARTROADMAP ORIENT
AVOID
Detail
Nefropatía
incipiente
Nefropatía
Establecida
GLOMERULAAR *
COOPERATE *
* ERC no diabetica

27. MARVAL: MicroAlbuminuria
Reduction With Valsartan
Weeks
UAER
%
change
from
baseline
Amlodipine
Valsartan
0 4 8 12 18 24
-60
-40
-20
0
20
P < 0.001
-8%
-44%
Viberti et al, Circulation. 2002;106;672-678

28. Hermida et al. Hypertens 2007;25:1921-1926

29. RENAAL: endpoints

30. Captopril
4909
4871 (99.2%)
Vital status
unknown:
38 (0.8%)
Valiant : diseño
Median follow-up: 24.7 months
Valsartan
4909
4856 (98.9%)
Vital status
unknown:
53 (1.1%)
14,808 Patients Randomized
4837 (99.0%)
Vital status
unknown:
48 (1.0%)
Combination
4885
Informed consent
not ensured: 105 patients
Vital status ascertained in 14,564 patients (99.05%)
Vital status not ascertained in 139 patients (0.95%)
(lost to follow-up at 1 year: 0.4%; 2 years: 0.7%)
14,703 Patients
13

31. Non-inferiority
Val Superior to Cap Cap Superior to Val
Non-inferiority not
Demonstrated
Cardiovascular Mortality and Morbidity
Valsartan vs. Captopril(POST INFARTO)
0.8 1 1.2
Hazard Ratio
(97.5% CI)
1.13
P-value
(non-inferiority)
non-
inferiority
margin
CV Death
(1657 events)
0.001
CV Death or HF
(2661 events)
0.0001
CV Death or MI
(2234 events)
0.00001
CV Death,
MI, or HF
(3096 events)
0.000001
23

32. BRAS VS IECAS
NO EVIDENCIA EN DIABETES TIPO 1
NO EVIDENCIA EN NEFROPATIA NO
DIABETICA

33. Copyleft Clinical Trial Results. You Must Redistribute Slides
HFSA 2010 Practice Guideline
ARBs
Y EN INSUFICIENCIA CARDIACA?
ARBs are recommended for routine
administration to symptomatic and
asymptomatic patients with an
LVEF ≤ 40% who are intolerant to ACE
inhibitors for reasons other than
hyperkalemia or renal insufficiency.
Strength of Evidence = A
Lindenfeld J,et al. HFSA 2010 Comprehensive
Heart Failure Guideline. J Card Fail 2010;16:e1-e194

34. VALSARTAN HEART FAILURE TRIAL
alHeFT

36. Copyleft Clinical Trial Results. You Must Redistribute Slides
HFSA 2010 Practice Guideline
ARBs
Lindenfeld J,et al. HFSA 2010 Comprehensive
Heart Failure Guideline. J Card Fail 2010;16:e1-e194
Generic Name Trade Name Initial Daily
Dose
Target Dose Mean Dose in
Clinical Trials
Candesartan Atacand 4-8 mg qd 32 mg qd 24 mg/day
Losartan Cozaar 12.5-25 mg qd 150 mg qd 129 mg/day
Valsartan Diovan 40 mg bid 160 mg bid 254 mg/day

37. Riesgo de desarrollar DM de nuevo inicio con diversas
terapias antihipertensivas
Dtsch Med Wochenschr 2007; 132: 689-695
Familia Odds 95% CI “p”
Ratio
BRAs 0.57 0.46-0.72 p<0.0001
IECAs 0.67 0.56-0.80 p<0.0001
BCC 0.75 0.62-0.90 p<0.002
Placebo 0.77 0.63-0.94 p<0.009
β-Bloq 0.90 0.75-1.09 p<0.30
Diuréticos 1.0 Referencia
1,00,5 0,6 0,7 0,8 0,9 1,1 1,20,4
Metaanálisis de 22 estudios
N = 143.153 pacientes
Mayor RiesgoMenor Riesgo

38. McMurray JJ et al, N Engl J Med, 2010
Incidence of Diabetes(NAVIGATOR)
Placebo1722 events (36.8%)
Valsartan1532 events (33.1%)

39. DREAM: Ramipril demonstrates neutral effect on
new-onset diabetes or death
DREAM Trial Investigators. N Engl J Med. 2006.
Placebo
Ramipril
No. at risk
Placebo
Ramipril
Follow-up (years)
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 1 2 3 4
2646
2623
2510
2498
2277
2287
1240
1218
200
194
9% RRR
HR 0.91 (0.81–1.03)
P = 0.15
Cumulative
hazard rate

40. ARBs are Associated with Higher Adherence Rates Compared with Other
Antihypertensive Drug Classes
TOS CON IECAS : 5-39%.
Adapted from Höer A et al.
J Hum Hypertens 2007;21:744–6
Adherence(medication
possessionratio)
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker;
CCB = calcium channel blocker; MPR = medication possession ratio
Mean (95% CI) MPR: ARBs 0.697 (95%CI:0.686–0.707); ACEIs 0.556 (0.550–0.562); beta-blockers
0.385 (0.382–0.388); CCBs 0.540 (0.531–0.548); diuretics 0.533 (0.525–0.541)
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
ARB ACEI CCB Diuretic Beta blocker

41. GRACIAS….