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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

14 %

9 %

60 %

40 %

15%30%

25 %

12%

9 %

17%20%

22%

14 %

Control de la hipertensión arterial

Tratamiento de la hipertension,no complicada, sin factores de riesgo adicionales con cifras de

PA<160/100mmHg

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

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

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

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

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)

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

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

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.

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

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)

Lithell H et al. J hypertens 2003;21:875-886 17

A Favor Candesartan A Favor Control

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

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




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

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

22

Research article

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

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

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

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

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

RENAAL: endpoints

Captopril4909

4871 (99.2%)

Vital status unknown:38 (0.8%)

Valiant : diseño

Median follow-up: 24.7 months

Valsartan4909

4856 (98.9%)


14,808 Patients Randomized

4837 (99.0%)


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

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

BRAS VS IECAS

NO EVIDENCIA EN DIABETES TIPO 1NO EVIDENCIA EN NEFROPATIA NO DIABETICA

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

VALSARTAN HEART FAILURE TRIAL

VALSARTAN IN HEART FAILURE

alHeFT

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

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

McMurray JJ et al, N Engl J Med, 2010

Incidence of Diabetes(NAVIGATOR)

Placebo1722 events (36.8%)Valsartan1532 events (33.1%)

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

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

GRACIAS….

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