prevenciÓn de...

VBM

PREVENCIÓN DE MICROALBUMINURIA

Dr. Vicente Bertomeu MartínezServicio de CardiologíaHospital Universitario de San Juan. Alicante

• Reunión Anual de la Sección de HTA de la SEC

• Sevilla. 5 Febrero 2010

Reunión anual HTA 2010-Sevilla

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CKD predicts CV diseaseA large Community study population (1,120,295 adults) mean follow-up 2.8

years

01234567

45 to 59 30 to 44 15 to 29 <15GFR ml/min

Adju

sted

haz

ard

ratio

Death all causes CV events

The risk are independent:Prior CV diseaseHypertensionDiabetesDyslipemiaProteinuria

Outcomes:Deaths: 51,424CV events: 138,291RRT : 3,500

AS Go : NEJM 351;13: 1296, 2004


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MA: Marcador Pronóstico en Diabéticos

1.0

0.5

0

Supervivencia

Años tras diagnóstico0 10

El riesgo de muerte CV prematura en DM con MA es 4 veces mayor

Marshall SM eta Al Diab Med 1999

Schmitz A et al 1988

EUA (mg/ml)a <1516-40>40

Mortalidad por CI (OR)

10

8

6

4

2

0

MA Tabaco TAD Col

Estman RC et al 1997Gimeno Orna et al. 2003;

16

0

NA MA PA

N 4633.7 años

Episodios CV


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Patogenia de la lesión glomerular y la proteinuria

Ang II

Presión glomerularaumentada

Ang II

AlbuminuriaGlucosa

AGEs

glicación

Vasoconstricción de la arteriola

eferente

= Receptor AT1 de la

angiotensina


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140

160

100

120

60

80

20

40

0

4

1

3

2GFR

(ml/min)

Protein excretion(g/day)

Pre-clinical diabetic renal disease Overt proteinuriaMAU

Proteinuria

PersistentMAU

Adapted from Mogensen CE. Kidney Int 1982;21:673. and Friedman EA. Kidney Int 1982;21:780.

Time (yrs 10)0 20

Course of diabetic renal diseaseReunión anual HTA 2010-Sevilla

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RENAALPrimary Composite Endpoint

Doubling of Serum Creatinine/ESRD/Death

Months

% w

ith e

vent

p=0.024Risk Reduction: 16%

P

L

Months0 12 24 36 48

0

10

20

30

40

50

0 12 24 36 480

10

20

30

40

50p=0.008Risk Reduction: 22%

751 692 583 329 52762 689 554 295 36P (+ CT)

L (+ CT) 746 612 479 263 36760 584 431 214 24

P

L

Intention-to-treat analysis Per-protocol analysis

Brenner BM et al. N Engl J Med. 2001;345:861-69.


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PRIME

IRMA 2IRMA 2 IDNTIDNTPrevention Protection

ESRD ESRD

Early Stage Late Stage End Stage

Microalbuminuria Microalbuminuria ProteinuriaProteinuria

PRIME: Program for Irbesartan Mortality and Morbidity EvaluationsIRMA 2: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria IDNT: Irbesartan Diabetic Nephropathy TrialESRD: End-stage renal disease

Cardiovascular morbidity and mortalityCardiovascular morbidity and mortalityCardiovascular morbidity and mortalityCardiovascular morbidity and mortality

PRIMETime course of type 2 diabetic renal disease


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14

18

16

12

10

86

4

2

0

Pacientes(%)

Control (n=201)

150 mg(n=195)

300 mg(n=194)

Irbesartán

9,7

5,2

14,9

RRR=39%P=0,085

RRR=70%P=0,0004

IRMA II. Objetivo primario:Desarrollo de proteinuria franca

Parving HParving H--H, et al. N Engl J Med 2001; 345: 870H, et al. N Engl J Med 2001; 345: 870--878.878.


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Subjects (%)

0 6 12 18 24 30 36 42 48 54Follow-up (months)

60

0

10

20

30

40

50

60

70Irbesartan

Amlodipine

Control

IDNT primary endpoint: Time to doubling of serum creatinine, ESRD, or death

RRR = 23%p = 0.006

p = NS

RRR = 20%p = 0.02

Lewis EJ et al. N Engl J Med 2001;345(12):851–60.

RRR: Relative Risk Reduction


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E. Detail. Cambio en la TFG en relación al valor de referencia

-25

-20

-15

-10

-5

0

5

10

0 1 2 3 4 5

Tasa

de

filt

raci

ón g

lom

eru

lar

(ml/

min

/1,7

3 m

2 )

Año

EnalaprilTelmisartan

Número de Enalaprilpacientes Telmisartanevaluados(carried forward)

113 (39)103 (41)

103(0)86 (0)

110(22)99 (23)

113 (23)102 (21)

113 (30)102 (31)

Barnett et al. N Engl J Med 2004;351:1952-61


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70

80

90

100

110

120

130

140

150

160

0 3 6 12 15 18 21 24 27 30 33 36 39 42 45 48Nos de RiesgoTrandolapril 301 270 262 249 239 231 225 218 212 204 201 196 190 167 145 115 90Verapamilo 303 256 241 223 216 205 203 197 196 189 183 177 172 153 136 112 89Verapamilo + trandolapril 300 266 255 243 234 226 223 216 214 208 203 197 194 175 161 133 102Placebo 300 258 235 224 218 208 206 200 194 183 180 172 167 151 130 113 84

Prevención de la Microalbuminuria en la Diabetes Tipo2. Estudio BENEDICT

Ruggenenti P et al, N Engl J Med 2004;351:1941-51

PA

(m

mH

g)

Seguimiento (meses)

PlaceboVerapamilo + trandolapril

TrandolaprilVerapamilo

Sistólica

Diastólica


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0

5

10

15

0 12 18 24 30 36 42 48

Prevención de la Microalbuminuria en la Diabetes Tipo2. Estudio BENEDICT


Verapamilo + trandolapril 300 249 232 217 210 201 192 162 115Placebo 300 229 214 203 187 176 164 136 89

Suje

tos

con

Mic

roal

bum

inu

ria

(%)

Seguimiento (meses)

Placebo

Verapamilo +

trandolapril


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Prevención de la Microalbuminuria en la Diabetes Tipo2.Estudio BENEDICT

0

5

10

15

20

0 12 18 24 30 36 42 48

188220

270311

338380

357399

376417

405441

424469

463503

603No IECA601

IECA

Seguimiento (meses)

No IECA

IECA

Nosde Riesgo

0

5

10

15

20

0 12 18 24 30 36 42 48

194214

285296

352366

374382

394399

27419

451422

483483

601No Calcioantagonistas

603Calcioantagonistas

Seguimiento (meses)

Calcioantagonistas

Nos de Riesgo

No calcioantagonistas



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Condiciones alto riesgo con indicaciones obligatorias

Diuréticos -bloqueantes IECA ARA

II BCCAntagonistas

aldosterona

IC Post IM Alto riesgo enfermedad coronaria

Diabetes Enfermedad Renal crónica Prevención ictus recurrente

Elección del Tratamiento en HTA Complicada. JNC-VII

Chobanian, et al JAMA, 2003;289-19:2560-2572


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Objetivo

120 / 75

DM-2 con macroalbuminuria, IRC


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RamN=8576

TelN=8542

Tel vs. RamRR P

Hipotensión 149 224 1.51 0.0001

Síncope 15 18 1.20 0.593

Tos 359 93 0.26 <0.0001

Diarrea 12 19 1.59 0.20

Angioedema 25 10 0.40 0.0115

Deterioro F Renal 59 68 1.16 0.41

Cualquier causa 2098 1962 0.94 0.02

ONTARGET: Discontinuación de medicación de estudio

N Engl J Med 2008;358:1547-59


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ONTARGET: Discontinuación de medicación de estudio

RamN=8576

Ram + TelN=8502

Ram + Tel vs. RamRR P

Hipotensión 149 406 2.75 <0.0001

Síncope 15 29 1.95 0.032

Tos 360 392 1.10 0.1885

Diarrea 12 39 3.28 0.0001

Angioedema 25 18 0.73 0.30

Deterioro F Renal 60 94 1.58 0.0050

Discontinuación por cualquier causa

2099 2495 1.20 <0.0001

N Engl J Med 2008;358:1547-59


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ONTARGET: Changes in urinary albumin excretion

0

0,5

1

1,5

2

2,5

UAE initial(mg/mmol)

Second yearRatio to initial

FinalRatio to initial

Ramipril Telmisartan Ram+Telm

<0.0001 0.0009

Occurrenceproteinuria

0.019

Mann J et al. Lancet 2008


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ONTARGET: Acute and chronic necesity of dialysis

0

10

20

30

40

50

60

70

Ramipril Telmisartan Ram+Telm

Num

ber o

f pat

ient

s

Chronic Acutea


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Study DesignRandomization to Double-blind treatment

End of study

MI, stroke orCrCl <30ml/min

Open-labelOlmesartan

40 mg od

4-weekpre-randomization

Study stop at 326 confirmed MAU cases

MI, stroke orCrCl <30ml/min

Olmesartan 40 mg od (n=2200*)

Placebo od (n=2200*)

Haller H, et al. J Hypertens. 2006;24:403–8.

MAU confirmed

Observationonly

Observationonly

MAU confirmed

*2200 pts planned per treatment arm to detect a 30% risk reduction in the incidence of MAU (hazard ratio of 1.433); power of 90% at 5% significance level

20


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ROADMAP:Primary and Secondary Parameters

• Primary endpoint– Time to first onset of microalbuminuria by morning spot

urine measurements*

• Secondary endpoints– Cardiovascular events

• Morbidity: ACS, CHF, silent MI, coronary revascularization (PTCA/CABG), stroke, PVD, new-onset AF, TIA

• Mortality: Sudden cardiac death, fatal MI, fatal stroke, CHF death, death post PTCA or CABG, recent MI on autopsy

– Renal function• End stage renal disease (ESRD), doubling serum creatinine, eGFR

– Microvascular morbidity• Retinopathy, MAU


* ≥2 positive out of 3 valid tests21


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• 18–75 years old male or female• T2DM patients (FPG ≥7.0 mmol/L, HbA1c ≥6.5% or treatment for diabetes)

• Normoalbuminuria (≤25 mg/g for men, ≤35 mg/g for women)

• At least one additional CV risk factor: hypercholesterolemia, low HDL, high triglycerides, obesity, large waist circumference, hypertension, smoker

Roadmap: Inclusion Criteria

Exclusion Criteria• Documented renal and/or renal-vascular disease• A recent history (≤6 months prior to study) of MI, stroke, TIA,

myocardial revascularization or reperfusion• Use or recent use (≤6 months prior to study) of ARBs or ACEIs• Presence of severe hypertension (SBP>200 and/or DBP>110 mmHg)

22


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Roadmap: Baseline CharacteristicsOlmesartan

(n=2232)Placebo (n=2215)

Overall (n=4447)

Male gender, n (%) 1049 (47) 1003 (45) 2052 (46)

Age [years], median (min–max) 58 (28–75) 58 (29–75) 58 (28–75)

BMI [kg/m2], median (min–max) 30.6(18.1–53.9)

30.4(17.2–64.8)

30.5(17.2–64.8)

Duration of diabetes [months], mean (SD) 73.9 (72.3) 72.7 (72.5) 73.3 (72.4)

HbA1c [%], mean (SD) 7.65 (1.62) 7.66 (1.62) 7.65 (1.62)

Metabolic syndrome*, n (%) 1834 (82) 1797 (81) 3631 (82)

Albumin/creatinine ratio (MAU) [mg/g], mean (SD) 6.27 (7.58) 5.88 (6.71) 6.08 (7.16)

eGFR [mL/min/1,73m2], mean (SD) 84.99 (17.01) 84.72 (17.30) 84.86 (17.15)

Serum creatinine [mmol/L], mean (SD) 77.44 (15.20) 77.47 (17.06) 77.45 (16.15)

Triglycerides [mmol/L], mean (SD) 2.13 (1.70) 2.03 (1.28) 2.08 (1.51)

Mean sitting systolic BP [mmHg], mean (SD) 137 (16) 136 (15) 136 (15)

Mean sitting diastolic BP [mmHg], mean (SD) 81 (10) 80 (9) 81 (10)

Daiichi-Sankyo. Data on file.*ATP III

FAS-DB 23


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Percentage of Patients Reaching BP Goal*

20

30

40

50

60

70

80

0 12 6 12 18 24 30 36 42

Pa

tien

ts (%

)

OlmesartanPlacebo

Weeks Months

*<130/80 mmHg ; at physician’s discretion, CCBs, diuretics, BBs were allowed to be used to reach target BP goal

FAS-DB 24


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Mean Sitting Blood Pressure*

Weeks Months22322214

21252112

20542038

19601930

18701832

17571707

16511612

12351215

698640

Olmesartan:Placebo:no. of pts.

FAS-DB

*ANCOVA on absolute change from baseline, BL-BP as covariate; p <0.001 any visit

25


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Primary Endpoint:Time to First Occurrence of MAU

Patie

nts w

ith m

icro

albu

min

uria

(%)

20

15

10

5

0

Olmesartan:Placebo:no.of pts.

1218171779

6 mo18921875

1817251685

2416291595

3015361510

3612571260

42717680

486546

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

OlmesartanPlacebo

Days

Risk Reduction: 23% (p=0.0104)

RFAS-DB 26


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-25

-20

-15

-10

-5

0

TreatmentDBP

CorrectedSBP

Corrected

Risk

redu

ctio

n (%

)

Time to First Occurrence of MAU:Hazard Ratios and Risk Reduction with

Blood Pressure Correction

Analysis HR RR p value

Treatment 0.770 23% p=0.0104

DBP corrected* 0.823 18% p=0.0596

SBP corrected* 0.834 17% p=0.0789

-23%

BP-independent Olmesartan effect:

-18% -17%

* Area under the curve (SBP/DBP) from baseline to last assessment in DB period

RFAS-DB 27


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Renal Function: Mean eGFR

60

65

70

75

80

85

90

0 12 6 12 18 24 30 36 42

eGFR

(mL/

min

/1.7

3 m

2 )

OlmesartanPlacebo

Olmesartan:Placebo:

no. of pts.

19601930

17571707

22322214

4.76 (p<0.0001)*

Weeks Months

Difference between groups

FAS-DB

*ANCOVA on absolute change from baseline

12361216

28


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Renal Morbidity Events

ESRD=end-stage renal disease; sCr=serum creatinine

(1%) (1%)

(0%) (0%)

FAS-DB 29


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CV events & Total Mortality N

umbe

r of p

atie

nts

DB=double blind period; OL=open labelperiod; OBS=observation period;ALL=all periods combined; n.s.=not significant

FAS-DB 30


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Cardiovascular Events N

umbe

r of p

atie

nts

FAS-DB 31


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Cardiovascular Events

0

10

20

30

40

Num

ber o

f pat

ient

s

OlmesartanPlacebo

ACS=acute coronary syndrome; AF=atrial fibrillation; CABG=coronary artery bypass graft;CHF=congestive heart failure; MI=myocardial infarction; PTCA= percutaneous transluminalcoronary angioplasty; PVD=peripheral vascular disease; TIA=transient ischemic attack

FAS-DB 32


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Varón 60 años.FRCV: HTA .DMID. HIPERCOLESTEROLEMIA. OBESIDAD.Historia cardiológica: IAM inferior en 1996. (A los 47 años).Otros AP: SAOS

Enfermedad actual: desde 1996 clínica de angor muy ocasional de moderados-grandes esfuerzos. Ingreso actual por angor de reposo sin objetivarse alteraciones de ECG (dolor no presenciado) ni elevación enzimática. TA: 120/65 mmHgTalla/Peso: 165 cm/85 KgErgometría con descenso de ST de 3mm en I y aVL y ascenso en II, III y aVF (estadio 2). No angina.Ecocardiograma: aquinesia inferoposterior. FEVI 60%


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ECG:


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Enfermedad coronaria extensa y difusa de 3 vasos

DA


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Quartiles of initial SBP and risk of primary outcome, CV death, MI and stroke

Sleight, et al . J. Hypertens 2009;27:1360-69


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Adjusted risk of outcome events by achieved SBP divided into deciles

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 161

0

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 143 149 1600

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 1610

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 1600

2

4

6

8

10

Adj

uste

d 4.

5-ris

k of

eve

nts

Hazard R

atio, 95% C

onfidence Intervals

Primary Study Outcome Cardiovascular Mortality

Myocardial Infarction Stroke

In-treatment Systolic Blood Pressure, Deciles (mmHg)

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 161

0

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 143 149 1600

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 1610

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 1600

2

4

6

8

10

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 161

0

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 143 149 1600

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 1610

0.5

1

1.5

2

2.5

3

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 1600

2

4

6

8

10

0

5

10

15

20

25

30

112 121 126 130 133 136 140 144 149 1600

2

4

6

8

10

Adj

uste

d 4.

5-ris

k of

eve

nts

Hazard R

atio, 95% C

onfidence Intervals

Primary Study Outcome Cardiovascular Mortality

Myocardial Infarction Stroke

In-treatment Systolic Blood Pressure, Deciles (mmHg)



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Adjusted relationship between tertiles of changes in SBP within each quartile of baseline SBP on the primary outcome


11.04 (0.89-1.22) 0.5991.19 (1.01-1.40) 0.042

10.81 (0.69-0.95) 0.0100.94 (0.80-1.10) 0.415

10.76 (0.65-0.88) 0.00030.74 (0.63-0.87) 0.0002

10.80 (0.69-0.92) 0.0020.73 (0.63-0.86) <0.001

Reduced Risk

IncreasedRisk

HR (96% CI) p value

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

P fortrend

0.050

0.364

0.0001

0.0001

Quartile 1 : Baseline SBP <130 mmHgTertile 1: Increase by 10 mmHgTertile 2: Increase by 0 -10 mmHgTertile 3: Decrease in BP

Tertile 1: No change or increase in BPTertile 2: Decrease by 1 9 mmHgTertile 3: Decrease > 9 mmHg

Tertile 1: Decrease ? 6 mmHgTertile 2: Decrease 6Tertile 3: Decrease > 15 mmHg

Tertile 1: Decrease Tertile 2: Decrease 13Tertile 3: Decrease > 24 mmHg

Quartile 2 : Baseline SBP 131 -

Quartile 3 : Baseline SBP 143-154 mmHg

Quartile 4 : Baseline SBP > 154 mmHg

11.04 (0.89-1.22) 0.5991.19 (1.01-1.40) 0.042

10.81 (0.69-0.95) 0.0100.94 (0.80-1.10) 0.415

10.76 (0.65-0.88) 0.00030.74 (0.63-0.87) 0.0002

10.80 (0.69-0.92) 0.0020.73 (0.63-0.86) <0.001

Reduced Risk

IncreasedRisk

HR (96% CI) p value

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

P fortrend

0.050

0.364

0.0001

0.0001

Quartile 1 : Baseline SBP Tertile 1: Increase by 10 mmHgTertile 2: Increase by 0 -10 mmHgTertile 3: Decrease in BP

Tertile 1: No change or increase in BPTertile 2: Decrease by 1Tertile 3: Decrease > 9 mmHg

Tertile 1: Decrease ? 6 mmHgTertile 2: Decrease 6Tertile 3: Decrease > 15 mmHg

Tertile 1: Decrease Tertile 2: Decrease 13Tertile 3: Decrease > 24 mmHg

Quartile 2 : Baseline SBP 131 -142 mmHg



Quartile 1 : Baseline SBP Tertile 1: Increase by 10 mmHgTertile 2: Increase by 0 -10 mmHgTertile 3: Decrease in BP

Tertile 1: No change or increase in BPTertile 2: Decrease by 1-Tertile 3: Decrease > 9 mmHg

Tertile 1: Decrease ? 6 mmHgTertile 2: Decrease 6- 15 mmHgTertile 3: Decrease > 15 mmHg

Tertile 1: Decrease <13 mmHgTertile 2: Decrease 13-24 mmHgTertile 3: Decrease > 24 mmHg

Quartile 2 : Baseline SBP 131 -




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OBJETIVOS DE TRATAMIENTO• Objetivo TA < 140/90 tiene evidencia en todo el espectro de pacientes salvo los

ancianos, en ellos el beneficio de TAS < 140 no está demostrado.

• Objetivo TAS < 130 en diabéticos y pacientes de alto riesgo cardiovascular, aunque

parece razonable no está sustentada por evidencia científica.

• Reducción progresiva hasta 120/75 parece aportar beneficio progresivo, salvo en

pacientes con enfermedad aterosclerótica avanzada.

• Recomendación actual: objetivo TA 130-139/80-85 mmHg,

probablemente en el límite inferior del rango, en todos los pacientes.

Reappraisal of HT guidelines. Task Force Document. In press


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CONCLUSIONES

• La MA es un potente marcador pronóstico y debe de ser valorada rutinariamente en los hipertensos.

• El BSRA ha demostrado reducir la MA.• Olmesartán ha demostrado prevenir la aparición

de MA, la mayor parte de su efecto es independiente de la PA.

• Debe evitarse la hipotensión.


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Summary• Olmesartan significantly delayed the occurrence of

microalbuminuria Risk Reduction 23% Majority of this effect is blood pressure independent

• No adverse effects of olmesartan on hard renal outcomes• Olmesartan exhibited powerful BP control in the

ROADMAP study (~80% target BP at 42 months)• Incidence of CV morbidity and mortality was low• CV events to be further investigated (Follow-up study)• Olmesartan’s adverse event profile was similar to that of

placebo

41


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Conclusiones

• ROADMAP is the first and only primary prevention study with an ARB (olmesartan) to demonstrate reduced occurrence of microalbuminuria

• The study yielded unprecedented BP control for this population of type 2 diabetes mellitus patients

• Olmesartan had no detrimental effect on hard renal outcomes in the ROADMAP study

42


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IDNT y RENAAL: ResultadosComparación de objetivos principales

Losartán vs. control

Irbesartán vs. control

Irbesartán vs. amlodipino

Amlodipino vs. control

RRR (%)

RENAAL IDNT

Lewis EJ et al. N Engl J Med 2001; 345: 851Lewis EJ et al. N Engl J Med 2001; 345: 851--860.860.Brenner B et al. N Engl J Med 2001; 345: 861Brenner B et al. N Engl J Med 2001; 345: 861--869.869.

Duplic. Creat. , 16 (P=0,02) 20 (P=0,02) 23 (P=0,006) -4 (P=0,69) ERT o muerte

Duplic. Creat. 25 (P=0,006) 33 (P=0,003) 37 (P<0,001) -6 (P=0,60)

ERT 28 (P=0,002) 23 (P=0,07) 23 (P=0,07) 0 (P=0,99)

Muerte -2 (P=0,88) 8 (P=0,57) -4 (P=0,8) 12 (P=0,4)

Morbi- 10 (P=0,26) 9 (P=0,4) -3 (P=0,79) 12 (P=0,29) mortalidad CV


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95 98 101 104 107 110 113 116 119

r = 0.69; P < 0.05

MAP (mmHg)

GFR

(mL/

min

/yea

r)

130/85 140/90

HTA no tratada

0

-2

-4

-6

-8

-10

-12

-14

A menor TAS, menor deterioro del filtrado glomerular

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.


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Stages of Chronic Kidney Disease

STAGE DESCRIPTION GFR(ml/min/1.73 m2)

1 Kidney damage with normal or GFR

≥ 90

2 Kidney damage with mild GFR

60 – 89

3 Moderate GFR 30 - 59

4 Severe GFR 15 - 29

5 Kidney failure < 15 (or dialysis)


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ROADMAP: A Multinational Study Steering Committee

• Chairman: H Haller ( Germany)• S Ito (Japan)• JL Izzo Jr (USA)• A Januszewicz (Poland)• S Katayama (Japan)• A Mimran (France)• AJ Rabelink ( The Netherlands)• E Ritz (Germany)• LM Ruilope ( Spain)• LC Rump (Germany)• GC Viberti (UK)

Data Safety Monitoring Board• Chairman: J Staessen (Belgium)• R Clarke (UK)• BT Hedner (Sweden)• T Kuznetsova (Belgium)• K Narkiewicz (Poland)

Endpoint Monitoring Committee• Chairman: A Heagerty (UK)• R Cifkova (Czech Republic)• J Petrie (UK)

SK 285

EE91

n=4449randomized

AT30

NL180

BG391

CZ342

DE255

ES110

FR118

UK80

HU299

IT28

LV 94

PL530

PT8

RO168

UA781

RU537BE

120

46


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All presented results refer to the Double-blind period

Patient DispositionRandomization to Double-blind treatment

Olmesartan 40 mg n=2233

Placebo n=2216

Withdrawalstotal n=519(S)AE = 104LTFU = 57

WOC = 332+other

Withdrawalstotal: n=506(S)AE = 111LTFU = 51

WOC = 319+other

Open-label periodOlmesartan 40 mg

n=350

Olmesartan 40 mgn=1534

Placebon=1477

Observation MI, Stroke, CrCl<30:

n=69

n=178 n=210

n=29 n=34n=6

MAU confirmed

MAU confirmed

n=186n=164

47


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Baseline CV Risk Factors

0

5

10

15

20

25

30

0 1 2 3 4 5 6 7

Number of CV risk factors

Olmesartan

Placebo

0

20

40

60

80

100

Pati

ents

(%

)

FAS-DB48


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Time to First Occurrence of MAU: Incidences and Hazard Ratio

0.5 1 2 Olmesartan < -- -- > Placebo

Incidence of MAU MAU Hazard Ratio

RFAS-DB

Hazard Ratio(95%-CI)

RiskReduction

p value

0.770(0.630–0.941)

23% p=0.0104

49


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Causas de Insuficiencia Renal Terminal (pacientes que inician diálisis 1996-1998)

12% 12%

32% 41%

3% 26%

14% 18%

23%8%

11%

EEUU España

.Diabetes.HTA (EVR) .GN .NIC.EPQ .Otras


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Respuesta en la PA sistólica, media y diastólica

PA(mmHg)

Visita de seguimiento (meses)

IrbesartanAmlodipinoControl

0 6 12 18 24 30 36 42 48 54

80

100

120

140

160

PAS

Media

PAD

Lewis EJ et al. N Engl J Med 2001; 345: 851-860.


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ONTARGET: Necesidad de dialisis

Mann J et al. Lancet 2008

0.005

0.004

0.003

0.002

0.001

00 1 2 4

Años de seguimiento

Cu

mu

lati

ve in

cid

ence

T vs R p=0.747R+T vs R p=0.133

3 5

R+TTR


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Decrease in eGFR during the trial, from baseline to study end (ONTARGET)

Mann et al. Lancet 2008


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