bra intercontinental
TRANSCRIPT
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BRAS ‘ Y PROTECCIÓNCARDIOVASCULAR
• Cuando se usan de primera línea?
• Cuales son sus mejores beneficios ?
• Donde no?
DR. MARTÍN VELARDE 2014CARDIÓLOGO CLÍNICO. MASVH.
MASVC.MAAVA.MACDP2014
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14 %
9 %
60 %
40 %
15%30%
25 %
12%
9 %
17%20%
22%
14 %
Control de la hipertensión arterial
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Tratamiento de la hipertension,no complicada, sin factores de riesgo adicionales con cifras de
PA<160/100mmHg
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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
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ValsartánLosartán
OlmesartCandesartán
Exp3174
NN
N NH
N
N
Cl
N
O
N
NN
NH
NN
N NH
N
N
Me
NN
N NH
N
N
OMe
OH
COOH COOH
COOHCOOH
Miura S, et al. Curr Hypertens Rev. 2005
Imidazol
Bifenil
Tetrazol
i
NN
N NH
N
N
Cl
CH OH2
Estructura Química de los ARA II
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El receptor AT1 en el continuo cardiovascular
HipertensiónDiabetes
DislipidemiaObesidad
ArteriosclerosisRemodelado vascular
HVI> Grosor IM
Infartos lacunaresMicroalbuminuria
IAM, AnginaIctus
Insuficiencia cardiacaInsuficiencia Renal
Arteriopatía Periférica Episodiosreincidentesno mortales
IR terminalDiálisis
Demencia
GenesEstilo de vida Muerte
HTA
HTA
HTA
HTA
HTA
Bloqueo del receptor AT1
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Systolic Blood Pressure (SBP) Reduction with Valsartan is Superior to Losartan and Comparable to Other ARBs
Drug and doseCandesartan 8 mgCandesartan 16 mgCandesartan 32mgIrbesartan 150 mgIrbesartan 300 mgLosartan 50 mgLosartan 100 mgOlmesartan 20 mgOlmesartan 40 mgTelmisartan 40 mgTelmisartan 80 mgValsartan 80 mgValsartan 160 mgValsartan 320 mg
n 142 329 821 531 261 3691733 145 199 275 233 32136613091
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 –6Changes 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
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La Terapia Combinada es Más Efectiva que la Monoterapia∆
PAS
(mm
Hg)
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 6semanas
Resultado de 1 año de estudio en 648 pacientes con hipertensión#
(Estudio VELOCITY)
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AMLODIPINA/VALSARTAN: reducción de la PASen pacientes con HTA st 2 Estudio EX-EFFeCTS
Destro et al. J.AmSocHypertens 2008:2;294-302
BRA+BCC: Eficacia
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24
1. VALUE2. VALIANT3. NAVIGATOR4. Val-HeFT5. JIKEI HEART6. KYOTO HEART7. VART
27. HIJ-CREATE28. E-COST29. HOPE-3*30. 4C*31. I-PRESERVE32. IDNT 33. ACTIVE-I* 34. NID-235. SUPPORT*36. COLM*37. OSCAR*38. ORIENT39. MOSES
8. VALISH*9. NAGOYA-HEART* 10. V-CARD*11. ONTARGET12. PRoFESS 13. TRANSCEND14. 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. LIFE17. OPTIMAAL 18. ELITE II19. RENAAL20. NCT00090259*21. VA NEPHRON-D*22. CHARM23. SCOPE24. SCAST*25. CASE-J26. ACCOST
Num
ber o
f pat
ient
s
Valsartan Telmisartan Losartan Candesartan Irbesartan Olmesartan Eprosartan
57,04653,247
25,019
36,940
6,777
1,405
15,693
1
2
5
4
3
78
6
11
12
1413
2021
18
16
17
2526
28
22
23
3936
35
37
38
34
33
3231
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
910
60,000
50,000
40,000
30,000
20,000
10,000
0
EL CONTINUO CARDIOVASCULAR# ESTUDIOS CON ARA2
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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.
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Stroke
Losartan
Atenolol
Adjusted Risk Reduction 24.9%, p=0.001Unadjusted Risk Reduction 25.8%, p=0.0006
Study Month
0 6 12 18 24 30 36 42 48 54 60 660
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 925Atenolol 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897
Fatal and nonfatal stroke
Pro
porti
on o
f pat
ient
s w
ith fi
rst e
vent
(%)
Number at Risk
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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)
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Lithell H et al. J hypertens 2003;21:875-886 17
A Favor Candesartan A Favor Control
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ARB and CARDIOVASCULAR MORTALITY
VALUEValsartan vs Amlodipine15,245 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
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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 pressureDifference (mmHg)
Systolic Diastolic No of No ofTrials events
No of No ofTrials events
Relative risk(95%CI)
Strokes Coronary 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 1,4 1,4 1
SpecifiedDrug better
SpecifiedDrug worse
SpecifiedDrug better
SpecifiedDrug worse
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ACV
EAC
INSUF. CARDIACA
EVENTOS CV MAYORES
MUERTE CV
MORTALIDAD TOTAL
0,5 1,0 2,0
FAVORECEARA 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 )
FAVORECE0TROS
Clase terapéutica y eventos
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22
Research article
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Incidence of new-onset atrial fibrillation: The VALUE trialC
umul
ativ
e pr
obab
ility
Time since randomization ( years )
0 3.0 3.5 4.0 4.5 5.0 2.52.0 1.5 1.0 0.5
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 5Amlodipine 6888 6882 6634 6317 5848 1681Valsartan 6872 6862 6644 6324 5876 1660
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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
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Tratamiento en pacientes Hipertensos y nefroprotección .
Steno 2MARVALIRMA-2
RENAALIDNT
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 >_
DROPSMART ROADMAP ORIENT
AVOID
Detail
Nefropatía incipiente
Nefropatía Establecida
GLOMERULAAR *COOPERATE *
* ERC no diabetica
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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
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Hermida et al. Hypertens 2007;25:1921-1926
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RENAAL: endpoints
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Captopril4909
4871 (99.2%)
Vital status unknown:38 (0.8%)
Valiant : diseño
Median follow-up: 24.7 months
Valsartan4909
4856 (98.9%)
Vital status unknown:53 (1.1%)
14,808 Patients Randomized
4837 (99.0%)
Vital status unknown:48 (1.0%)
Combination4885
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
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Non-inferiority
Val Superior to Cap Cap Superior to Val
Non-inferiority not Demonstrated
Cardiovascular Mortality and MorbidityValsartan 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
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BRAS VS IECAS
NO EVIDENCIA EN DIABETES TIPO 1NO EVIDENCIA EN NEFROPATIA NO DIABETICA
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Copyleft Clinical Trial Results. You Must Redistribute Slides
HFSA 2010 Practice GuidelineARBs
Y EN INSUFICIENCIA CARDIACA?
ARBs are recommended for routineadministration to symptomatic andasymptomatic 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 ComprehensiveHeart Failure Guideline. J Card Fail 2010;16:e1-e194
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VALSARTAN HEART FAILURE TRIAL
VALSARTAN IN HEART FAILURE
alHeFT
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Copyleft Clinical Trial Results. You Must Redistribute Slides
HFSA 2010 Practice GuidelineARBs
Lindenfeld J,et al. HFSA 2010 ComprehensiveHeart 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
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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 1,20,4Metaanálisis de 22 estudiosN = 143.153 pacientes
Mayor RiesgoMenor Riesgo
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McMurray JJ et al, N Engl J Med, 2010
Incidence of Diabetes(NAVIGATOR)
Placebo1722 events (36.8%)Valsartan1532 events (33.1%)
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DREAM: Ramipril demonstrates neutral effect on new-onset diabetes or death
DREAM Trial Investigators. N Engl J Med. 2006.
Placebo
Ramipril
No. at riskPlaceboRamipril
Follow-up (years)
0.6
0.5
0.4
0.3
0.2
0.1
0.00 1 2 3 4
26462623
25102498
22772287
12401218
200194
9% RRRHR 0.91 (0.81–1.03)
P = 0.15Cumulative hazard rate
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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
Adh
eren
ce (m
edic
atio
n po
sses
sion
ratio
)
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; MPR = medication possession ratioMean (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
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GRACIAS….