PREVENCIÓN DE MICROALBUMINURIA

Transcripción

1 PREVENCIÓN DE MICROALBUMINURIA Reunión Anual de la Sección de HTA de la SEC Sevilla. 5 Febrero 21 Dr. Vicente Bertomeu Martínez Servicio de Cardiología Hospital Universitario de San Juan. Alicante VBM

2 VBM CKD predicts CV disease A large Community study population (1,12,295 adults) mean follow-up 2.8 years Adjusted hazard ratio Outcomes: Deaths: 51,424 CV events: 138,291 RRT : 3,5 The risk are independent: Prior CV disease Hypertension Diabetes Dyslipemia Proteinuria 45 to 59 3 to to 29 <15 GFR ml/min Death all causes CV events AS Go : NEJM 351;13: 1296, 24

3 1..5 VBM MA: Marcador Pronóstico en Diabéticos Supervivencia EUA (mg/ml)a < >4 Schmitz A et al 1988 Años tras diagnóstico 1 16 Episodios CV Gimeno Orna et al. 23; N años NA MA PA Mortalidad por CI (OR) El riesgo de muerte CV prematura en DM con MA es 4 veces mayor Estman RC et al 1997 MA Tabaco TAD Marshall SM eta Al Diab Med 1999 Col

4 Reunión anual HTA 21-Sevilla ec ht a. or g Patogenia de la lesión glomerular y la proteinuria Glucosa Albuminuria glicación = Receptor AT1 de la angiotensina AGEs Vasoconstricción de la arteriola eferente w w w.s Presión glomerular aumentada Ang II Ang II VBM

5 VBM GFR (ml/mi n) Course of diabetic renal disease Pre-clinical diabetic renal disease Persistent MAU MAU Proteinuria Overt proteinuria 2 Time (yrs 1) Protein excretion (g/day) Adapted from Mogensen CE. Kidney Int 1982;21:673. and Friedman EA. Kidney Int 1982;21:78.

6 VBM % with event RENAAL Primary Composite Endpoint Doubling of Serum Creatinine/ESRD/Death Risk Reduction: 16% p=.24 P Reunión anual HTA 21-Sevilla Intention-to-treat analysis Months L Per-protocol analysis Risk Reduction: 22% p=.8 P Months P (+ CT) L (+ CT) Brenner BM et al. N Engl J Med. 21;345: L

7 VBM Prevention IRMA 2 Microalbuminuria Reunión anual HTA 21-Sevilla PRIME Time course of type 2 diabetic renal disease PRIME Proteinuria Protection IDNT Cardiovascular morbidity and mortality ESRD Early Stage Late Stage End Stage PRIME: Program for Irbesartan Mortality and Morbidity Evaluations IRMA 2: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria IDNT: Irbesartan Diabetic Nephropathy Trial ESRD: End-stage renal disease

8 Pacientes (%) VBM IRMA II. Objetivo primario: Desarrollo de proteinuria franca RRR=7% P=,4 RRR=39% P=,85 14,9 Control (n=21) 9,7 15 mg (n=195) Irbesartán 5,2 3 mg (n=194) Parving H-H, H, et al. N Engl J Med 21; 345:

9 4 Subjects (%) 3 VBM Irbesartan Amlodipine Control Reunión anual HTA 21-Sevilla IDNT primary endpoint: Time to doubling of serum creatinine, ESRD, or death RRR = 23% p =.6 p = NS RRR = 2% p = Follow-up (months) RRR: Relative Risk Reduction 6 Lewis EJ et al. N Engl J Med 21;345(12):851 6.

10 VBM Tasa de filtración glomerular (ml/min/1,73 m 2 ) Número de pacientes evaluados (carried forward) E. Detail. Cambio en la TFG en relación al valor de referencia Enalapril Telmisartan 13() 86 () 11(22) 99 (23) Año 113 (23) 12 (21) Enalapril Telmisartan 113 (3) 12 (31) 113 (39) 13 (41) Barnett et al. N Engl J Med 24;351:

11 PA (mmhg) Prevención de la Microalbuminuria en la Diabetes Tipo2. Estudio BENEDICT Sistólica Diastólica Seguimiento (meses) Trandolapril Verapamilo Verapamilo + trandolapril Placebo N os de Riesgo Trandolapril Verapamilo Verapamilo + trandolapril Placebo VBM Ruggenenti P et al, N Engl J Med 24;351:1941-5

12 Prevención de la Microalbuminuria en la Diabetes Tipo2. Estudio BENEDICT Sujetos con Microalbuminuria (%) Placebo Verapamilo + trandolapril Seguimiento (meses) Verapamilo + trandolapril Placebo VBM Ruggenenti P et al, N Engl J Med 24;351:

13 VBM Prevención de la Microalbuminuria en la Diabetes Tipo2.Estudio BENEDICT N os de Riesgo IECA No IECA Seguimiento (meses) No IECA IECA Calcioantagonistas No calcioantagonistas Seguimiento (meses) N os de Riesgo Calcioantagonistas No Calcioantagonistas Ruggenenti P et al, N Engl J Med 24;351:

14 Condiciones alto riesgo con indicaciones obligatorias VBM Diuréticos - bloqueantes IECA ARA II BCC Antago nistas aldoste rona IC Post IM Alto riesgo enfermedad coronaria Reunión anual HTA 21-Sevilla Elección del Tratamiento en HTA Complicada. JNC-VII Diabetes Enfermedad Renal crónica Prevención ictus recurrente Chobanian, et al JAMA, 23;289-19:

15 Objetivo 12 / 75 DM-2 con macroalbuminuria, IRC VBM

16 Ram N=8576 Reunión anual HTA 21-Sevilla ONTARGET: Discontinuación de medicación de estudio Tel N=8542 Tel vs. Ram Hipotensión Síncope Tos <.1 Diarrea Angioedema Deterioro F Renal Cualquier causa RR P N Engl J Med 28;358:

17 ONTARGET: Discontinuación de medicación de estudio Ram N=8576 Ram + Tel N=852 Ram + Tel vs. Ram Hipotensión <.1 Síncope Tos Diarrea Angioedema Deterioro F Renal Discontinuación por cualquier causa Reunión anual HTA 21-Sevilla RR <.1 P N Engl J Med 28;358:

18 VBM ONTARGET: Changes in urinary albumin excretion 2,5 2 1,5 1,5 UAE initial (mg/mmol) <.1.9 Second year Ratio to initial Final Ratio to initial Ramipril Telmisartan Ram+Telm.19 Occurrence proteinuria Mann J et al. Lancet 28

19 Number of patients ONTARGET: Acute and chronic necesity of dialysis VBM Ramipril Telmisartan Ram+Telm Chronic Acutea

20 Olmesartan 4 mg od (n=22*) Study Design Randomization to Double-blind treatment MAU confirmed MI, stroke or CrCl <3ml/min Observation only Open-label Olmesartan 4 mg od End of study MAU confirmed MI, stroke or CrCl <3ml/min Observation only *22 pts planned per treatment arm to detect a 3% risk reduction in the incidence of MAU (hazard ratio of 1.433); power of 9% at 5% significance level Haller H, et al. J Hypertens. 26;24: Placebo od (n=22*) 4-week pre-randomization Study stop at 326 confirmed MAU cases

21 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 tests Haller H, et al. J Hypertens. 26;24:

22 Roadmap: Inclusion Criteria years old male or female T2DM patients (FPG 7. mmol/l, HbA 1c 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 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>2 and/or DBP>11 mmhg) Haller H, et al. J Hypertens. 26;24:

23 Roadmap: Baseline Characteristics Olmesartan (n=2232) Placebo (n=2215) Overall (n=4447) Male gender, n (%) 149 (47) 13 (45) 252 (46) Age [years], median (min max) 58 (28 75) 58 (29 75) 58 (28 75) BMI [kg/m 2 ], median (min max) 3.6 ( ) 3.4 ( ) 3.5 ( ) 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) 6.8 (7.16) egfr [ml/min/1,73m 2 ], mean (SD) (17.1) (17.3) (17.15) Serum creatinine [mmol/l], mean (SD) (15.2) (17.6) (16.15) Triglycerides [mmol/l], mean (SD) 2.13 (1.7) 2.3 (1.28) 2.8 (1.51) Mean sitting systolic BP [mmhg], mean (SD) 137 (16) 136 (15) 136 (15) Mean sitting diastolic BP [mmhg], mean (SD) 81 (1) 8 (9) 81 (1) *ATP III Daiichi-Sankyo. Data on file. FAS-DB 23

24 Patients (%) Percentage of Patients Reaching BP Goal* 8 7 Olmesartan 6 Placebo Weeks Months *<13/8 mmhg ; at physician s discretion, CCBs, diuretics, BBs were allowed to be used to reach target BP goal FAS-DB 24

25 Olmesartan: Placebo: no. of pts. Mean Sitting Blood Pressure* Weeks Months *ANCOVA on absolute change from baseline, BL-BP as covariate; p <.1 any visit FAS-DB 25

26 Patients with microalbuminuria (%) Primary Endpoint: Time to First Occurrence of MAU Olmesartan: Placebo: no.of pts. Risk Reduction: 23% (p=.14) 6 mo Olmesartan Placebo Days RFAS-DB 26

27 Risk reduction (%) Time to First Occurrence of MAU: Hazard Ratios and Risk Reduction with Blood Pressure Correction Treatment -23% BP-independent Olmesartan effect: DBP Corrected SBP Corrected -18% -17% * Area under the curve (SBP/DBP) from baseline to last assessment in DB period RFAS-DB 27 Analysis HR RR p value Treatment.77 23% p=.14 DBP corrected* % p=.596 SBP corrected* % p=.789

28 egfr (ml/min/1.73 m 2 ) Olmesartan: Placebo: no. of pts. Renal Function: Mean egfr Olmesartan Placebo Weeks *ANCOVA on absolute change from baseline FAS-DB Difference between groups Months (p<.1)*

29 Renal Morbidity Events (1%) (1%) ESRD=end-stage renal disease; scr=serum creatinine FAS-DB 29 (%) (%)

30 Number of patients CV events & Total Mortality DB=double blind period; OL=open label period; OBS=observation period; ALL=all periods combined; n.s.=not significant FAS-DB 3

31 Number of patients Cardiovascular Events FAS-DB 31

32 Number of patients Cardiovascular Events ACS=acute coronary syndrome; AF=atrial fibrillation; CABG=coronary artery bypass graft; CHF=congestive heart failure; MI=myocardial infarction; PTCA= percutaneous transluminal coronary angioplasty; PVD=peripheral vascular disease; TIA=transient ischemic attack FAS-DB 32 Olmesartan Placebo

33 Varón 6 años. FRCV: HTA.DMID. HIPERCOLESTEROLEMIA. OBESIDAD. Historia cardiológica: IAM inferior en (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: 12/65 mmhg Talla/Peso: 165 cm/85 Kg Ergometría 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 6%

34 ec ht a. or g Reunión anual HTA 21-Sevilla w w w.s ECG:

35 Enfermedad coronaria extensa y difusa de 3 vasos DA

36 Quartiles of initial SBP and risk of primary outcome, CV death, MI and stroke Sleight, et al. J. Hypertens 29;27:136-69

37 Adjusted risk of outcome events by achieved SBP divided into deciles Adjusted 4.5-risk of events Primary Study Outcome Myocardial Infarction Stroke In-treatment Systolic Blood Pressure, Deciles (mmhg) 1 5 Cardiovascular Mortality Hazard Ratio, 95% Confidence Intervals Sleight, et al. J. Hypertens 29;27:136-69

38 Adjusted relationship between tertiles of changes in SBP within each quartile of baseline SBP on the primary outcome Quartile 1 : Baseline SBP <13 mmhg Tertile 1: Increase by 1 mmhg Tertile 2: Increase by -1 mmhg Tertile 3: Decrease in BP Quartile 2 : Baseline SBP mmhg Tertile 1: No change or increase in BP Tertile 2: Decrease by 1-9 mmhg Tertile 3: Decrease > 9 mmhg Quartile 3 : Baseline SBP mmhg Tertile 1: Decrease? 6 mmhg Tertile 2: Decrease 6-15 mmhg Tertile 3: Decrease > 15 mmhg Quartile 4 : Baseline SBP > 154 mmhg Tertile 1: Decrease <13 mmhg Tertile 2: Decrease mmhg Tertile 3: Decrease > 24 mmhg Reunión anual HTA 21-Sevilla HR (96% CI) ( ) ( ) ( ).1.94 (.8-1.1) ( ).3.74 ( ).2 1 p value.8 ( ).2.73 ( ) <.1 Reduced Risk Increased Risk P for trend Sleight, et al. J. Hypertens 29;27:136-69

39 OBJETIVOS DE TRATAMIENTO Objetivo TA < 14/9 tiene evidencia en todo el espectro de pacientes salvo los ancianos, en ellos el beneficio de TAS < 14 no está demostrado. Objetivo TAS < 13 en diabéticos y pacientes de alto riesgo cardiovascular, aunque parece razonable no está sustentada por evidencia científica. Reducción progresiva hasta 12/75 parece aportar beneficio progresivo, salvo en pacientes con enfermedad aterosclerótica avanzada. Recomendación actual: objetivo TA /8-85 mmhg, probablemente en el límite inferior del rango, en todos los pacientes. Reappraisal of HT guidelines. Task Force Document. In press

40 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.

41 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 ( ~ 8% 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

42 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

43 VBM IDNT y RENAAL: Resultados Comparación de objetivos principales RENAAL Losartán vs. control Irbesartán vs. control RRR (%) IDNT Irbesartán vs. amlodipino Amlodipino vs. control Duplic. Creat., 16 (P=,2) 2 (P=,2) 23 (P=,6) -4 (P=,69) ERT o muerte Duplic. Creat. 25 (P=,6) 33 (P=,3) 37 (P<,1) -6 (P=,6) ERT 28 (P=,2) 23 (P=,7) 23 (P=,7) (P=,99) Muerte -2 (P=,88) 8 (P=,57) -4 (P=,8) 12 (P=,4) Morbi- 1 (P=,26) 9 (P=,4) -3 (P=,79) 12 (P=,29) mortalidad CV Lewis EJ et al. N Engl J Med 21; 345: Brenner B et al. N Engl J Med 21; 345:

44 GFR (ml/min/year) A menor TAS, menor deterioro del filtrado glomerular MAP (mmhg) /85 14/9 r =.69; P <.5 HTA no tratada VBM Bakris GL, et al. Am J Kidney Dis. 2;36(3):

45 Stages of Chronic Kidney Disease STAGE DESCRIPTION GFR (ml/min/1.73 m 2 ) 1 Kidney damage with 9 normal or GFR 2 Kidney damage with mild 6 89 GFR 3 Moderate GFR Severe GFR Kidney failure < 15 (or dialysis) VBM

46 ROADMAP: PT 8 A Multinational Study ES 11 UK 8 BE 12 FR 118 NL 18 DE 255 IT 28 CZ 342 AT 3 PL 53 SK 285 HU 299 EE 91 LV 94 RO 168 BG 391 UA RU 537 n=4449 randomized 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)

47 Withdrawals total: n=56 (S)AE = 111 LTFU = 51 WOC = 319 +other Olmesartan 4 mg n=2233 Olmesartan 4 mg n=1534 Patient Disposition Randomization to Double-blind treatment MAU confirmed n=178 n=21 n=164 Open-label period Olmesartan 4 mg n=35 n=29 n=6 n=34 Observation MI, Stroke, CrCl<3: n=69 All presented results refer to the Double-blind period MAU confirmed n=186 Placebo n=2216 Placebo n= Withdrawals total n=519 (S)AE = 14 LTFU = 57 WOC = 332 +other

48 Patients (%) Baseline CV Risk Factors FAS-DB Olmesartan Placebo Number of CV risk factors

49 Time to First Occurrence of MAU: Incidences and Hazard Ratio Incidence of MAU Hazard Ratio (95%-CI).77 ( ) Risk Reduction Olmesartan < > Placebo MAU Hazard Ratio p value 23% p=.14 RFAS-DB 49

50 Causas de Insuficiencia Renal Terminal (pacientes que inician diálisis ) EEUU 12% 3% 12% 32% 41% 11% 8% 26% 14% 18% España.Diabetes.HTA (EVR).GN.NIC.EPQ.Otras 23% VBM

51 PA (mmhg) VBM Respuesta en la PA sistólica, media y diastólica PAS Medi a PAD Visita de seguimiento (meses) Irbesartan Amlodipino Control Lewis EJ et al. N Engl J Med 21; 345:

52 VBM Cumulative incidence ONTARGET: Necesidad de dialisis R+T T R Años de seguimiento T vs R p=.747 R+T vs R p=.133 Mann J et al. Lancet 28

53 VBM Decrease in egfr during the trial, from baseline to study end (ONTARGET) Mann et al. Lancet 28