Dr. Gabriel Waisman Profesor Asociado del Departamento de Clínica Médica, Instituto Universitario del Hospital Italiano de...
Gabriel D. Waisman <ul><li>Profesor Asociado de Clínica Médica - Instituto Universitario Escuela de Medicina del Hospital ...
La ECV: Principal Causa de Muerte 0 100 200 300 400 500 A  ECV* B  Cancer D  Enfermedades respiratorias crónicas  C  Accid...
El Riesgo de EC Aumenta Agudamente Luego de la Quinta Década de la Vida 0.0 1.4 3.0 11.6 11.5 16.8 0.3 0.2 1.6 3.6 6.3 10....
Obesidad y Diabetes Entre los Adultos: Prevalencia Creciente Obesidad (BMI ≥30 kg/m 2 ) Población (%) 30 25 2000 2001 2002...
El daño de órgano blanco precede en décadas a los eventos clínicos Vasoconstricción Hipertrofia vascular Disfunción endote...
El daño de órgano blanco incrementa el riesgo cardiovascular Kannel.  Eur Heart J  1992;13 (Suppl D):82–88 Hipertrofia ven...
El daño de órgano blanco incrementa el riesgo cardiovascular Gimeno Orna et al.  Rev Clin Esp  2003;203:526–531 * *P<0.05 ...
Inibición de la ECA Circulación sistémica Angiotensinógeno Riñon Renina Ang-I ECA Pulmones Sistema Adrenal Aldosterona Sis...
Adaptado de Kaplan NM,  Clinical Hypertension  1994 Angiotensina II Adrenal  Riñón  SNC  SN Periférico  Músculo Liso Vascu...
Sistema Renina Angiotensina Nuevos componentes Warner FJ.  Clinical Science , 2007;113:109-18
Función y Estructura Cardiovascular Papel de los Receptores AT 1   Receptor AT1 Angiotensina  II Vasoconstricción Estrés O...
SRA – Conceptos Emergentes ANGIOTENSINÓGENO ANGIOTENSINA I ANGIOTENSINA II RECEPTOR  AT1 ANGIOTENSINÓGENO ANGIOTENSINA I A...
Santos R &Ferreira A.  Curr Opin Nephrol Hypertens.  2007;16:122-8 Angiotensina I Angiotensina  II Angiotensina- (1-7) Rec...
SRAA: Sitios de intervención con  IECA-ARAII-IDR Angiotensinógeno Angiotensina I Renina IECA ECA Angiotensina II Receptor ...
SRAA: Otros sitios potenciales de intervención Struthers AD, MacDonald TM.  Cardiovasc Res.  2004;61:663-70. Jacoby DS, Ra...
The 1998 National Medal of Technology , Scientific American, March 1999 Teprotide – Bradychinin Potentiating Factor (Ferre...
AII y los mecanismos de ateroesclerosis Alteración de la  ON  sintasa Jacoby DS, Rader DJ.  Arch Intern Med.  2003;163:115...
PERTINENT  PERindopril–Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial  IECA    NO v...
El bloqueo del receptor AT 1  mejora la vasodilatación mediada por flujo 122 pacientes hipertensos tratados durante 2 mese...
AII y los mecanismos de ateroesclerosis Alteración de la  ON  sintasa Jacoby DS, Rader DJ.  Arch Intern Med.  2003;163:115...
La inhibición de la ECA reduce el stress oxidativo y la inflamación 20 Pacientes con diabetes tipo 2 Marketou ME et al.  J...
AII y los mecanismos de ateroesclerosis Alteración de la  ON  sintasa Jacoby DS, Rader DJ.  Arch Intern Med.  2003;163:115...
AT 1  y el receptor LOX-1 promueve la expresión de moléculas de adhesión: Interacción entre SRAA y dislipidemia Mehta JL, ...
La AII regula la expresión de LOX-1 * P <  0.0001 vs control †  P < 0.0001 vs A II ‡  P < 0.05 vs A II Bai = baicaleina (i...
AII y los mecanismos de ateroesclerosis Alteración de la  ON  sintasa Jacoby DS, Rader DJ.  Arch Intern Med.  2003;163:115...
HOPE: Efectos dosis-dependientes de  ramipril sobre la masa y función del VI 5.31 2.9 – 1.9 – 3 0 2 4 6 8.21 7.86 – 3.53 –...
LIFE: Mayor reducción de la masa del VI con el bloqueante del receptor AT1 vs BB Devereux RB et al.  Circulation.  2004;11...
AII y los mecanismos de ateroesclerosis Alteración de la  ON  sintasa Jacoby DS, Rader DJ.  Arch Intern Med.  2003;163:115...
Liberación de TPA: Diferentes efectos de los IECA y los Bloqueantes AT1 Matsumoto T et al.  J Am Coll Cardiol.  2003;41:13...
Los bloqueantes AT1 impiden la expresión en placas carotideas humanas de metaloproteinasas de la matriz: Papel potencial e...
Tratamiento de la HTA en el Paciente Diabético
UKPDS, BMJ 1998, 317: 703 Control estricto    Control “habitual” 144/82 mmHg   154/87 mmHg PA inicial = 160/94 mmHg Difere...
Reducción del riesgo relativo original y en el seguimiento alejado con el “intenso” descenso de la presión arterial Holman...
Modulación del SRAA en  Pacientes con Diabetes
Glomérulo Matriz mesangial Arteriola renal eferente Células mesangiales Nervios simpáticos renales  Cápsula de Bowman  Túb...
Arteriola eferente Constricción Glomérulo Incremento en la albuminuria Arteriola Aferente Dilatación Incremento  en la pre...
1.0 0.9 0.8 0.7 0.6 0.5 0 1 2 3 4 5 6 Años Sobrevida (todas las causas de mortalidad) Normoalbuminuria (n=191) Microalbumi...
HTA, Microalbuminuria, y Riesgo de Cardiopatía Isquémica Jensen J et al. Hypertension 2000;35:898-903
-P-H -P+H +P-H +P+H Tasa de mortalidad estandarizada Estado de Proteinuria (P) e  Hipertensión (H) en Diabéticos tipo 2 -P...
<ul><li>Funcionales </li></ul><ul><ul><li>Disminución TFG </li></ul></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><li>Es...
Factor de crecimiento renal y activación de citocinas Fibrogénesis Hipertensión sistémica Pérdida progresiva de superficie...
Adaptado de Breyer JA et al.  Am J Kid Dis  1992; 20(6): 535. Tiempo (años) 0 5 20 30 Inicio de Diabetes Inicio de Protein...
Diagnóstico de albuminuria Recolección  de orina sin tiempo controlado         MODIFICADA POR CONCENTRA-  DIAGNOSTICO     ...
Factores que pueden afectar la excreción urinaria de albúmina AUMENTO   DISMINUCION INSUFICIENCIA CARDIACA CONGESTIVA EXCE...
Go A et al. N Engl J Med 2004;351:1296-305 Enfermedad Renal Crónica y Riesgo de Muerte, Eventos Cardiovasculares y Hospita...
Beneficios de disminuir la PA en forma intensiva Zanchetti et al.  J Hypertens  2003;21:797–804 * P≤0.05 vs tratamiento me...
IECA Y  A RA II Beneficios en diabéticos <ul><li>Descenso de la vasoconstricción  </li></ul><ul><li>Disminución de la prol...
MICRO-HOPE:  Los IECA mejoran los puntos finales renales y cardiovasculares en diabéticos tipo 2 HOPE Study Investigators....
LIFE: Efectos del tratamiento en la población total vs los pacientes con diabetes Pacientes con hipertensión e HVI Dahlöf ...
Nefroprotección en diabetes tipo I MUERTE DIALISIS O TRANSPLANTE (%)  0 10 20 30 40 50 6 12 18 24 30 36 42 48 SEGUIMIENTO ...
Estudios clínicos en pacientes hipertensos con diabetes tipo 2 <ul><li>SHEP (Diabetes), JAMA 1996  </li></ul><ul><li>FACET...
Metanálisis (100 estudios; n= 2.494 DM tipos 1 y 2); Kasiske, 1993 0 0,2 -0,2 -0,4 -0,6 Proteinuria Albuminuria IECA   ACA...
ARA II en Diabetes Tipo 2 con Nefopatía Progresión de la microalbuminuria † A Tasa de excreción de albúmina de 20 a 200  ...
ARA II en Diabetes Tipo 2 con Nefropatía Progresión de la Insuficiencia Renal *En combinación con tratamiento hipotensor c...
Efectos de los ARAII en diabetes tipo 2:  Puntos finales renales y CV Lewis EJ et al.  N Engl J Med.  2001;345:851-60. Bre...
IECA y Bloqueantes de los canales del calcio: Una asociación nefroprotectora en diabeticos tipo 2 con microalbuminuria Fog...
Combinación de IECA con Antagonistas de Receptores AT1 Puede Ser Necesario en Algunas Situaciones? Es Util la Asociación e...
Razones para el tratamiento combinado con IECA y ARA II Mooser V.,  et al.   J Cardiovasc Pharmacol 1990;15:276 – 282; Gai...
Consecuencias bioquímicas y hormonales del bloqueo combinado del SRA Menard J. & Azizi M., Circulation 2004;109:2492–2499 ...
Evaluación de la Terapéutica Combinada IECA/ARAII <ul><li>Reducción de la Presión Arterial </li></ul><ul><ul><li>Hay algun...
Aliskiren in the eValuation of proteinuria In Diabetes (AVOID – Evaluación de la proteinuria en diabetes) Visión general d...
<ul><li>Evaluación de los efectos nefroprotectores del bloqueo dual del SRAA </li></ul><ul><li>a través de la adición de a...
La PA permaneció similar en los grupos de Aliskiren y placebo a lo largo del estudio 60 140 PA (mmHg) 130 120 110 20 16 12...
Aliskiren produce una disminución significativamente mayor en albuminuria comparado con placebo Tratamiento óptimo  + Alis...
Intervención Multifactorial y Enfermedad Cardiovascular en Pacientes Diabéticos Tipo 2 con Microalbuminuria Gaede P et al....
Intervención Multifactorial y Enfermedad Cardiovascular en Pacientes Diabéticos Tipo 2 con Microalbuminuria Gaede P. et al...
Riesgo relativo (95% CI) 0. 0 1.0 2.0 Tratamiento intensivo vs convencional Enf. cardiovascular 0.47 (0. 24 - 0.73 ) 0. 66...
Paradigma futuro Progresión Lenta con Neuroprotección, Cardioprotección, Protección Renal y Vascular Enfermedad Precoz <ul...
CAMPUS VIRTUAL Puesta al día intensiva en Medicina Interna y Ambulatoria 2011 www.hospitalitaliano.org.ar/campus [email_ad...
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Puesta al día intensiva en medicina interna y ambulatoria

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Puesta al día intensiva en medicina interna y ambulatoria: Al finalizar el curso los participantes serán capaces de:
* Actualizar temas relevantes y frecuentes de la práctica clínica ambulatoria y de la internación

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  • First of all, we can take a look at BP and all the necessary components for an optimal control With Coveram, your hypertensive patients benefit from a STRONGer blood pressure reduction; other fixed combinations can’t claim to do the same.
  • Total cardiovascular (CV) disease, including diseases of the heart, cerebrovascular disease, and arterial disorders, remains the leading cause of death in the United States. 1 Data compiled from death certificates by the National Center for Health Statistics for 2002 indicate that CV disease claimed 927,448 American lives in 2002, including 433,825 men and 493,623 women. 1 Overall, CV disease claims about as many Americans each year as the next 5 leading causes of death combined. 1. CDC/NCHS and NHLBI. In: Heart Disease and Stroke Statistics–2005 Update . Dallas, Tex: American Heart Association; 2005.
  • As shown by NHANES data covering 1999 – 2002, the prevalence of coronary heart disease (CHD) rises sharply after age 55 years in both men and women. 1 This finding implies that most high-risk patients seen in clinical practice will fall in this age group. 1. American Heart Association. Heart Disease and Stroke Statistics— 2005 Update. Dallas, Tex: American Heart Association; 2005.
  • The slide summarizes unadjusted estimated prevalence data from the January – September 2004 National Health Interview Survey. 1 As shown, the prevalences of obesity and diabetes appear to have grown at comparable rates over the past 5 years. 1. National Center for Health Statistics. Early release of selected estimates based on data from the January-September 2004 National Health Interview Survey: 3/23/2005. Available at: www.cdc.gov/nchs/nhis.htm.
  • The concept of a cardiovascular continuum was first published in 1991. 1 Factors such as hypertension can left ventricular hypertrophy (LVH), which increase the risk of cardio- and cerebrovascular events. 1 Ventricular wall remodelling, if untreated, may ultimately result in congestive heart failure, end-stage heart disease and death. These can be accompanied by cognitive dysfunction and, as the disease progresses, dementia. 2 Vascular remodelling, atherosclerosis and cardiac embolism can result in stroke. Hypertension and diabetes are also among the risk factors that lead to endothelial dysfunction. This can result in damage to the glomeruli, microalbuminuria and macroproteinuria, leading to progressive nephrosis and the development of renal failure. 3–5 Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 1991;121:1244–1263. Hofman A, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam study. Lancet 1997;349:151–154. Cooper ME. Pathogenesis, prevention and treatment of diabetic nephropathy. Lancet 1998;352:213–219. Taylor AA. Pathophysiology of hypertension and endothelial dysfunction in patients with diabetes mellitus. Endocrinol Metabol Clin North Am 2001;30:983–997. Erhardt LR. Endothelial dysfunction and cardiovascular disease: the promise of blocking the renin-angiotensin system. Int J Clin Pract 2003;57:211–218.
  • Patients with hypertension have an elevated risk of cardiovascular events compared with normotensive individuals. However, if hypertension is associated with LVH, the overall risk of cardiovascular morbidity and mortality increases even more. Data from the 32-year Framingham Heart Study follow-up of men aged 32–64 years show that the presence of LVH in patients with established hypertension nearly triples the incidence of coronary heart disease and stroke, and increases the incidence of heart failure by about 7-fold. 1 Kannel WB. Left ventricular hypertrophy as a risk factor in arterial hypertension. Eur Heart J 1992;13 (Suppl D):82–88.
  • 463 patients with type 2 diabetes and normoalbuminuria (n=330), microalbuminuria (n=106) or macroproteinuria (n=27) were followed for an average of 4.64 years. 1 The overall cardiovascular morbidity and mortality rate was 3.7%/year. 1 After multiple adjustment for co-existing risk factors, microalbuminuria was associated with a 1.9-fold increase in relative risk, and macroproteinuria with a 4.1-fold increase. 1 Gimeno Orna JA, et al. [Microalbuminuria and clinical proteinuria as the main predictive factors of cardiovascular morbidity and mortality in patients with type 2 diabetes]. Rev Clin Esp 2003;203:526–531.
  • 1. Nickenig G. Should angiotensin II receptor blockers and statins be combined? Circulation. 2004;110:1013-1020.
  • 1. Struthers AD, MacDonald TM. Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc Res. 2004;61:663-670. 2. Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: From genes to treatment. Arch Intern Med. 2003;163:1155-1164. 3. Zisman LS. ACE and ACE2: A tale of two enzymes. Eur Heart J. 2005; 26:322-324. Ang II stimulates release of aldosterone. 1 Aldosterone interacts with mineralocorticoid receptors to promote endothelial dysfunction, facilitate thrombosis, reduce vascular compliance, impair baroreceptor function, and cause myocardial and vascular fibrosis. Enzymes other than angiotensin-converting enzyme (ACE) also generate Ang II. 2 These include cathepsin G, a chymostatin-sensitive Ang II-generating system, and chymase. ACE2 is a novel ACE homologue that converts Ang I to Ang (1–9) and Ang (1–7). 2,3
  • Major proatherogenic effects of Ang II are listed on the slide. 1 Subsequent slides in this section will address each topic as it is highlighted. First, recent data on the effect of Ang II on endothelial function will be presented. 1. Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: From genes to treatment. Arch Intern Med. 2003;163:1155-1164.
  • The PERindopril–Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial (PERTINENT) 1 was a substudy of the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) study. 2 EUROPA randomized 12,218 patients with stable CAD to placebo or the ACE inhibitor perindopril 8 mg. PERTINENT was designed to test the hypothesis that the ACE inhibitor would have possible vascular and antiatherosclerotic effects (the effects of perindopril on clinical outcomes in EUROPA is discussed later in this slide kit). Human umbilical vein endothelial cells (HUVEC) were isolated and incubated for 72 hours with serum from 45 healthy volunteers and 87 EUROPA participants (44 in placebo and 43 in perindopril groups). The slide shows activity of endothelial nitric oxide (NO) synthase (eNOS), the main source of NO in endothelial cells. As shown, eNOS activity was depressed at baseline in EUROPA patients compared with controls, illustrating the endothelial dysfunction characteristic of CAD. At 1 year, eNOS activity in the placebo group remained depressed, while eNOS activity in the ACE inhibitor group was similar to the controls. Thus, 1 year of perindopril treatment in CAD patients had a beneficial effect on endothelial function by increasing eNOS activity. 1. Ferrari R, Remme WJ, Simoons M, Bertrand M, Fox K, for EUROPA investigators. PERTINENT: A substudy of EUROPA. Available at: www.europa-trial.org. 2. Fox KM, EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.
  • Koh et al administered placebo, losartan 100 mg, irbesartan 300 mg, and candesartan 16 mg for 2 months to 122 patients with mild to moderate hypertension. 1 The slide shows flow-mediated vasodilation (expressed as percent change from baseline) in each group. Each AT 1 receptor blocker significantly improved flow-mediated vasodilation (P = 0.005 vs placebo). 1. Koh KK, Han SH, Chung W-J, Ahn JY, Jin DK, Kim HS, et al. Comparison of effects of losartan, irbesartan, and candesartan on flow-mediated brachial artery dilation and on inflammatory and thrombolytic markers in patients with systemic hypertension. Am J Cardiol. 2004;93:1432-1435.
  • Major proatherogenic effects of Ang II are listed on the slide. 1 Subsequent slides in this section will address each topic as it is highlighted. First, recent data on the effect of Ang II on endothelial function will be presented. 1. Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: From genes to treatment. Arch Intern Med. 2003;163:1155-1164.
  • Marketou et al randomized 40 patients with type 2 diabetes to placebo (n = 20) or perindopril 4 mg (n = 20). 1 All patients had relatively well-controlled baseline BP (124 mm Hg systolic) and glucose (HbA 1c &lt;7.5%). As shown, after 6 months significant reductions in lipid peroxides, tumor necrosis factor-  (TNF-  ), and interleukin-6 (IL-6), compared with baseline, were observed in the ACE inhibitor group. 1. Marketou ME, Zacharis EA, Nikitovic D, Kochiadakis GE, Karalis IK, Simantirakis ES, et al. Beneficial modification of oxidative stress and systemic inflammation in normotensive patients with diabetes type 2 after angiotensin-converting enzyme inhibition treatment. J Am Coll Cardiol. 2005;45(suppl A):396A. Abstract 808-6.
  • Major proatherogenic effects of Ang II are listed on the slide. 1 Subsequent slides in this section will address each topic as it is highlighted. First, recent data on the effect of Ang II on endothelial function will be presented. 1. Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: From genes to treatment. Arch Intern Med. 2003;163:1155-1164.
  • Formation of oxidized LDL (oxLDL) is a key step in the pathogenesis of atherosclerosis. The oxLDL receptor (LOX-1) is present mostly on the surface of endothelial cells, although small amounts have also been detected in vascular smooth muscle cells, macrophages, and platelets. 1 LOX-1 – mediated ingestion of oxLDL activates mitogen-activated protein kinases (MAPKs) in the cell, which in turn activate nuclear factor-  B (NF-  B), a transcriptional factor involved in expression of monocyte chemoattractant protein-1 (MCP-1). In turn, MCP-1 leads to adhesion molecule expression. As shown, LOX-1 expression is upregulated by a number of factors. In particular, Ang II, via the AT 1 receptor, increases LOX-1 expression. Conversely, oxLDL, via LOX-1, upregulates the AT 1 receptor. 1. Mehta JL, Li D. Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor. J Am Coll Cardiol. 2002;39:1429-1435.
  • Limor et al studied Ang II-mediated upregulation of LOX-1 expression in human vascular smooth muscle cells. 1 At a concentration of 10 -7 mol/L, Ang II increases expression of LOX-1 approximately 2.5-fold. In the presence of losartan or baicalein (a specific blocker of 12-lipoxygenase), this effect was almost completely abolished. The investigators concluded that, at least in vascular smooth muscle cells, the 12-lipoxygenase pathway may be important for Ang II-dependent signal transduction. 1. Limor R, Kaplan M, Sawamura T, Sharon O, Keidar S, Weisinger G, et al. Angiotensin II increases the expression of lectin-like oxidized low-density lipoprotein receptor-1 in human vascular smooth muscle cells via a lipoxygenase-dependent pathway. Am J Hypertens. 2005;18:299-307.
  • Major proatherogenic effects of Ang II are listed on the slide. 1 Subsequent slides in this section will address each topic as it is highlighted. First, recent data on the effect of Ang II on endothelial function will be presented. 1. Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: From genes to treatment. Arch Intern Med. 2003;163:1155-1164.
  • A Heart Outcomes Prevention Evaluation (HOPE) substudy compared the effects of two doses of ramipril (10 mg and 2.5 mg/day) on LV mass and function in 446 evaluable patients. The results demonstrated a significant dose-dependent effect. 1 After 4 years, LV mass increased in both the placebo and ramipril 2.5-mg groups. In contrast, LV mass decreased by 3.53 g in the ramipril 10-mg group (P = 0.03 for trend). LV end-systolic volume increased with placebo and ramipril 2.5 mg, in contrast with a reduction of 1.90 mL with ramipril 10 mg (P = 0.001 for trend). 1. Lonn E, Shaikholeslami R, Yi Q, Bosch J, Sullivan B, Tanser P, et al. Effects of ramipril on left ventricular mass and function in cardiovascular patients with controlled blood pressure and with preserved left ventricular ejection fraction: A substudy of the Heart Outcomes Prevention Evaluation (HOPE) Trial. J Am Coll Cardiol . 2004;43:2200-2206.
  • The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial randomized 9193 patients with hypertension and left ventricular hypertrophy (LVH) to losartan-based or atenolol-based antihypertensive therapy. The slide summarizes results of an echocardiographic substudy in 457 losartan-treated and 459 atenolol-treated patients with  1 follow-up measurement. 1 After 1 year, a greater decrease in mean LV mass was noted in the losartan group compared with the atenolol group and this difference persisted to the final echocardiogram (P = 0.009). 1. Devereux RB, Dahlöf B, Gerdts E, Boman K, Nieminen MS, Papademetriou V, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation. 2004;110:1456-1462.
  • Major proatherogenic effects of Ang II are listed on the slide. 1 Subsequent slides in this section will address each topic as it is highlighted. First, recent data on the effect of Ang II on endothelial function will be presented. 1. Jacoby DS, Rader DJ. Renin-angiotensin system and atherothrombotic disease: From genes to treatment. Arch Intern Med. 2003;163:1155-1164.
  • Ang II induces PAI-1 release. In contrast, bradykinin induces tissue plasminogen activator (tPA) release. Matsumoto et al randomized 45 hypertensive patients with atypical chest pain to a 4-week treatment with perindopril 4 mg, losartan 50 mg, or no treatment (control). 1 Immediately after the final dose, graded doses of bradykinin were administered into the left coronary artery. In a dose-dependent manner, bradykinin increased coronary blood flow, coronary vasomotor responses, and tPA in all 3 groups. Perindopril and losartan augmented bradykinin-mediated vasodilation to similar extents (data not shown). However, as shown, tPA levels in the perindopril group were significantly higher than in the losartan and control groups (P &lt; 0.05 for both comparisons). 1. Matsumoto T, Minai K, Horie H, Ohira N, Takashima H, Tarutani Y, et al. Angiotensin-converting enzyme inhibition but not angiotensin II type-1 receptor antagonism augments coronary release of tissue plasminogen activator in hypertensive patients. J Am Coll Cardiol. 2003;41:1373-1379.
  • Cipollone et al randomized 70 patients with symptomatic carotid artery stenosis to irbesartan 300 mg or chlorthalidone 50 mg for 4 months prior to scheduled endarterectomy. 1 Following the procedure, carotid plaque samples were analyzed for matrix metalloproteinases (MMP-2 and MMP-9), inducible cyclooxygenase-2 (COX-2), and prostaglandin E 2 -dependent synthase (PGES-1). As shown, the AT 1 receptor blocker, but not the diuretic, significantly blunted expression of all four proteins. A previous study from the same group had shown that activation of MMP-2 and MMP-9 is controlled by a COX-2/PGES-1 pathway. The new data extend this finding by showing that this pathway is modulated by the AT 1 receptor. 1. Cipollone F, Fazia M, Iezzi A, Pini B, Cuccurullo C, Zuchelli M, et al. Blockade of the angiotensin II type-1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E 2 -dependent matrix metalloproteinase activity. Circulation. 2004;109:1482-1488.
  • Proteinuria as a Risk Factor for Mortality in Type 2 Diabetes In this study, the impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 non-insulin-dependent diabetic patients followed for 5 years. During follow-up, 51 patients died (16%). A total of 18 out of 51 patients with macroalbuminuria died (35%) compared to 17 out of 86 with microalbuminuria (20%), and 16 out of 191 with normoalbuminuria (8%). Reference: Gall MA, Borch-Johnsen K, Hougaard P, Nielsen FS, Parving HH. Albuminuria and poor glycemic control predict mortality in NIDDM. Diabetes. 1995;44(11):1303-1309.
  • Proteinuria and Hypertension in Type 2 Diabetes In this stratified random sample of 4,714 diabetic patients in the World Health Organization Multinational Study of Vascular Disease in Diabetes (WHO MSVDD), the relationship between excess mortality and proteinuria/hypertension was examined. Standardized mortality ratios (SMRs) for type 2 diabetic patients (n=3,448) were similar for men and women. Compared with the background population, type 2 diabetic patients with both hypertension and proteinuria experienced high excess mortality: 5-fold for men and 8-fold for women. Patients with only proteinuria tended to have higher SMRs than those with only hypertension. SMRs were in general higher for patients with type 1 diabetes. Reference: Wang SL, Head J, Stevens L, Fuller JH. Excess mortality and its relation to hypertension and proteinuria in diabetic patients. The world health organization multinational study of vascular disease in diabetes. Diabetes Care. 1996 Apr;19(4):305-312.
  • Intensive antihypertensive treatment (i.e. with a target DBP ≤85 mmHg) can significantly reduce the risk of a major cardiovascular event compared with less intensive treatment (target DBP ≤90 mmHg). The data shown in this slide are from the Hypertension Optimal Treatment (HOT) study of 18,790 hypertensives treated for an average 3.8 years. 1 Benefits were greatest in diabetics (relative risk = 0.53 for cardiovascular events). 1 In non-smokers, there was reduced risk in many important patient groups, including those with a global risk considered to be high or very high. 1 In smokers, more intensive DBP lowering was associated with increased risk of all types of cardiovascular event. 1 Zanchetti A, et al. Benefits and risks of more intensive blood pressure lowering in hypertensive patients of the HOT study with different risk profiles: does a J-shaped curve exist in smokers? J Hypertens 2003;21:797–804.
  • The results of MICRO-HOPE demonstrate that ACE inhibition (ramipril 10 mg) has vasculoprotective as well as renoprotective effects in individuals with type 2 diabetes. 1 The risk for overt nephropathy was reduced by 24% after 4.5 years. At baseline, 32% of patients in MICRO-HOPE had microalbuminuria. Treatment lowered the risk of nephropathy in those who did and did not have baseline microalbuminuria. The CV benefits included significant reductions in MI, stroke, and CV death. Ramipril 10 mg also was associated with a significant reduction in the albumin-creatinine ratio at both 1 year (P = 0.001) and end of study (P = 0.02). 1. HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259.
  • In the overall population enrolled in the LIFE trial, the effects of losartan on the primary outcome were driven by a significant 35% relative risk reduction in stroke. 1 Stroke reduction in the losartan group may have been related in part to the large BP reduction achieved (30.2/16.6 mm Hg). Relative to atenolol, there were trends toward an increase in risk of MI and a decrease in risk of CV death. Results in the diabetic cohort showed a different pattern. 2 There was a 37% relative risk reduction in CV death (P = 0.028) and trends toward reduced risk of stroke (21% risk reduction, P = 0.204) and MI (17% risk reduction, P = 0.073). 1. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002;359:995-1003. 2. Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, de Faire U, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomized trial against atenolol. Lancet. 2002;359:1004-1010.
  • The IRMA II trial addressed the question of whether an angiotensin II receptor antagonist, irbesartan, would delay or prevent the development of clinical proteinuria in patients with type 2 diabetes mellitus, normal serum creatinine and microalbuminuria. Type 2 diabetic patients with normal serum creatinine (1.3 mg/dl for men and 1.1 mg/dl for women) whose overnight urinary albumin excretion rate was 20 to 200  g per minute on 2 of 3 consecutive samples were randomized to receive irbesartan 150 mg QD, irbesartan 300 mg QD, or placebo. Goal blood pressure was &lt;135/85 mmHg 3 months after randomization and additional antihypertensive agents, except ACE inhibitors and dihydropyridine calcium channel blockers, were allowed to achieve that goal. The primary endpoint of the study was defined as the occurrence of a urinary albumin excretion rate &gt;200  g per minute and at least 30% higher than baseline on at least 2 consecutive measurements. Patients were followed for an average of 2 years. Average blood pressure values were slightly lower in the two groups treated with irbesartan than with placebo during the first 6 months of the study, but were comparable among the three groups during the last 12 months of the study. There was a 39% reduction in the development of clinical proteinuria in the group treated with 150 mg irbesartan daily vs placebo (p=0.08, not significant) and a 70% reduction in the primary endpoint in patients treated with irbesartan 300 mg daily (p&lt;0.001). Restoration of normoalbuminuria, defined as a urinary albumin excretion rate &lt;20  g/minute, was 34% more frequent among patients treated with irbesartan 300 mg QD than among patients in the placebo group (p=0.006). The results of this study demonstrate that the angiotensin II receptor antagonist, irbesartan, at a dose of 300 mg QD can delay the progression of microalbuminuria to clinical proteinuria in patients with type 2 diabetes. Reference: Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-878. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_ui ds=11565519&amp;dopt=Abstract
  • Two randomized, blinded clinical trials that examine the impact of treatment with an angiotensin II receptor antagonist on the progression of nephropathy among type 2 diabetics have recently been completed and the primary findings published. The primary endpoint (a composite of doubling of serum creatinine, the occurrence of end stage renal disease, as defined by the need for renal dialysis, or death) was the same for both RENAAL ( R eduction of E ndpoints in N IDDM with the A ngiotensin II A ntagonist L osartan) and IDNT ( I rbesartan D iabetic N ephropathy T rial). Each trial was designed to have sufficient statistical power to detect an approximately 25% difference in the primary outcome measure between the specific intervention (losartan in RENAAL and irbesartan in IDNT) and the placebo group. IDNT patients randomized to the placebo group were treated with antihypertensive agents as needed (primarily diuretics and beta-blockers) to a goal systolic BP of &lt; 135 mmHg (or 10 mmHg lower than the value at screening if it was more than 145 mmHg) and diastolic BP of &lt; 85. RENAAL patients randomized to the placebo group were treated with antihypertensive agents as needed (primarily diuretics and beta-blockers) to a goal blood pressure of &lt;140/&lt;90. Each study was designed to maintain comparable blood pressure values among treatment arms; the study results demonstrate that indeed comparable average blood pressure values were achieved in the treatment and placebo arms of each trial. Despite comparable reductions in blood pressure, there was a 16% reduction in the number of patients who reached the primary endpoint in losartan-treated patients in RENAAL vs those randomized to the placebo group, and a 20% reduction in patients reaching the primary endpoint in irbesartan treatment vs placebo arms of the IDNT trial. Although patients in the IDNT trial randomized to receive amlodipine as initial therapy achieved reductions in blood pressure comparable to those in the irbesartan and placebo groups, the % of patients reaching the primary endpoint in this arm (41%) was slightly greater than the % of patients in the placebo arm (39%). In each clinical trial a secondary composite cardiovascular endpoint was specified. In RENAAL this composite endpoint was specified as mortality and morbidity from cardiovascular causes that included myocardial infarction, stroke, first hospitalization for heart failure or unstable angina, coronary or peripheral vascular revascularization, or death from cardiovascular causes. A slightly different composite cardiovascular endpoint was specified in IDNT and included death from cardiovascular causes, nonfatal myocardial infarction, heart failure resulting in hospitalization, stroke causing permanent neurologic deficit, or lower limb amputation above the ankle. Although there were not differences in ARB-treated vs placebo-treated patients in the composite cardiovascular endpoint in either trial, there was a reduction in hospitalizations for heart failure of 32% when losartan was compared to placebo in the RENAAL trial and 23% when irbesartan was compared to placebo in the IDNT trial. References: Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-869. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=11565518&amp;dopt=Abstract Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=11565517&amp;dopt=Abstract
  • The Irbesartan Diabetic Nephropathy Trial (IDNT) randomized 1715 patients with type 2 diabetes, hypertension, and nephropathy to irbesartan 300 mg, amlodipine 10 mg, or placebo. 1 After a mean of 2.6 years, irbesartan reduced the primary outcome (composite of doubling of baseline serum creatinine, end-stage renal disease, or all-cause mortality) by 20% vs placebo (P = 0.02) and by 23% vs amlodipine (P = 0.006). There were no significant differences between treatments in CV outcomes. The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL) randomized 1514 patients with type 2 diabetes and nephropathy to losartan 100 mg or placebo. 2 After a mean of 3.4 years, losartan reduced the primary outcome (composite of doubling of baseline serum creatinine, end-stage renal disease, or all-cause mortality) by 16% (P = 0.02). There were no differences between groups with regard to CV outcomes. The Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients Study (IRMA-2) assessed the effect of irbesartan 150 mg or 300 mg daily vs placebo in 590 patients with type 2 diabetes, hypertension, and microalbuminuria. 3 Compared with placebo, irbesartan was associated with risk reductions in the primary outcome (time to onset of nephropathy) of 39% (150-mg group, P = 0.08) and 70% (300-mg group, P &lt; 0.001). This study did not assess the impact of treatment on CV outcomes. 1. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860. 2. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. 3. Parving H-H, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. N Engl J Med. 2001;345:870-878.
  • Rationale for dual blockade of the RAS This rationale is based, as we saw earlier, on providing the most efficient blockade of the deleterious effects of angiotensin II while maintaining the positive benefits, such as increased bradykinin production and possibly decreased aldosterone secretion. By adding an ARB to an ACE inhibitor, the effects of continuous angiotensin production should be blocked at the AT 1 receptor level but still active at the AT 2 receptor. Clinical studies that have looked at combined therapy have noticed additional clinical benefits over and above changes in blood pressure, which can be interpreted as tissue-protective effects as a result of a more complete blockade of RAS. Improvements in insulin sensitivity by various different mechanisms have been seen. In diabetic nephropathy, dual blockade leads to a decrease in protienuria and there is evidence that this occurs in non-diabetic renal disease. Additive effects have also been noted in trials of patients with heart failure. References 1. Mooser, V., et al. Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition. J Cardiovasc Pharmacol 1990;15:276 – 282 2. Gainer J.V., et al. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998;339:1285 – 1292 3. Sandmann S. &amp; Unger T., Pathophysiological and clinical implications of AT(1)/AT(2) angiotensin II receptors in heart failure and coronary and renal failure Drugs 2002;62(Spec No 1):43 – 52 4. Cao Z., et al . Angiotensin type 2 receptor antagonism confers renal protection in a rat model of progressive renal injury. J Am Soc Nephrol 2002;13:1773 – 1787
  • Biochemical Consequences of Combined Blockade of the RAS by an ACE Inhibitor and an AT 1 Receptor Antagonist (ARB) Dual blockade of the RAS combines the biochemical consequences of ACE inhibition and AT 1 receptor antagonism on the RAS cascade, as shown in the slide. Although the combination of an AT 1 receptor antagonist and an ACE inhibitor allows essentially for a more complete and sustained blockade of both circulating and tissue RAS, alternative mechanisms involving bradykinin and Ang(1-7) accumulation and angiotensin II type 2 (AT 2 ) receptor stimulation, and consequently NO release, may participate in its overall pharmacodynamic effect. Indeed, as with ACE inhibitors, the combination induces accumulation of vasodilatory and natriuretic peptides, such as bradykinin and Ang(1-7,) and of the haematological peptide AcSDKP. The reduced breakdown of bradykinin by ACE inhibitors activates the B2 receptor and consequently the release of NO, prostacyclin, and other potent endothelium-derived local vasodilator substances, which in turn may participate in their short-term haemodynamic effect. During chronic ACE inhibition and dual RAS blockade, elevation of Ang(1-7) levels may serve to potentiate the vasodilator actions of bradykinin by stimulating NO release. The combination should also stimulate potentially functioning AT 2 receptors, although less strongly than does an AT 1 R antagonist given alone, because of the ACE inhibitor. Stimulation of AT 2 receptors per se could trigger a vasodilator and natriuretic cascade involving bradykinin, NO and cGMP. Finally, no major additive effect of the combined RAS blockade has been detected on the decrease in plasma aldosterone, especially in the long-term, in clinical settings other than CHF, probably because of the multiplicity of factors regulating aldosterone secretion, particularly plasma potassium. References Azizi M. &amp; Menard J., Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation 2004;109:2492 – 2499
  • Evaluation of combined ACE inhibitor/angiotensin receptor blocker therapy We can therefore summarise the extent of the published findings on the dual role of ACE and ARBs in blocking the RAS. In blood pressure reduction: There is some evidence for additive BP-lowering effects For renal protection: There is some evidence from small trials for the additive beneficial effects on renal protection and proteinuria reduction For cardiac effects: There is substantial evidence for additive benefits in heart failure and LVH Fatal and non-fatal cardiovascular outcomes need further investigation (ONTARGET) Valiant and Val-HeFT have failed to show reductions in CV mortality with valsartan in addition to ACE inhibitors (in fact, have highlighted a potentially dangerous combination In the Val-Heft trial benefits come mainly from reduction in hospitalisations for heart failure CHARM-added showed reductions in CV mortality with candesartan in addition to ACE inhibitors
  • Aliskireno External Slide Kit Item code: 2008.253 Release date: August 2008 The Aliskireno in the eValuation of prOteinuria In Diabetes (AVOID) study was a 6-meses, doble ciego, randomized, placebo-controlled study in 599 pacientes with mild-to-moderate hipertensión, type 2 diabetes and nephropathy (urinary albumin-to-creatinine ratio [UACR] 200–3500 mg/g). Patients enrolled in the AVOID study received 3 meses of losartan 100 mg una vez al día monoterapia, with optional addition of other antihypertensive agents as necessary, with the aim of achieving blood pressure (PA) &lt;130/80 mmHg. After the 3 meses open-label period, pacientes were randomized to receive Aliskireno 150 mg or placebo una vez al día, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 3 meses, the dosage of Aliskireno was force-titrated from 150 to 300 mg for a further 3 meses. Abbreviations AVOID = Aliskireno in the eValuation of prOteinuria In Diabetes PA = blood pressure UACR = urinary albumin-to-creatinine ratio Reference Parving H-H, Persson F, Lewis JB, et al . The Combinación of Aliskireno, a direct renina inhibitor, and losartan in pacientes with type 2 diabetes and nephropathy. New Engl J Med 2008;358:2433–2446. .
  • Aliskireno External Slide Kit Item code: 2008.253 Release date: August 2008 The Aliskireno in the eValuation of prOteinuria In Diabetes (AVOID) study was a 6-meses, doble ciego, randomized, placebo-controlled study in 599 pacientes with mild-to-moderate hipertensión, type 2 diabetes and nephropathy (urinary albumin-to-creatinine ratio [UACR] 200–3500 mg/g). Patients enrolled in the AVOID study received 3 meses of losartan 100 mg una vez al día monoterapia, with optional addition of other antihypertensive agents as necessary, with the aim of achieving blood pressure (PA) &lt;130/80 mmHg. After the 3 meses open-label period, pacientes were randomized to receive Aliskireno 150 mg or placebo una vez al día, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 3 meses, the dosage of Aliskireno was force-titrated from 150 to 300 mg for a further 3 meses. In pacientes already receiving losartan 100 mg once-daily and optimal antihypertensive therapy, mean sitting PA remained similar in the Aliskireno and placebo groups throughout the course of the AVOID study. At línea de base mean sitting PA was 135/78 mmHg in the Aliskireno grupo and 134/77 mmHg in the placebo grupo. After 6-meses’ tratamiento, mean sitting PA was reduced from línea de base by 2/1 mmHg in the Aliskireno grupo (p=0.08 vs placebo). These results demonstrate that there were no clinically relevant changes from línea de base in PA in either grupo at the study endpoint. Abbreviations AVOID = Aliskireno in the eValuation of prOteinuria In Diabetes PA = blood pressure UACR = urinary albumin-to-creatinine ratio Reference Parving H-H, Persson F, Lewis JB, et al . The Combinación of Aliskireno, a direct renina inhibitor, and losartan in pacientes with type 2 diabetes and nephropathy. New Engl J Med 2008;358:2433–2446.
  • Aliskireno External Slide Kit Item code: 2008.253 Release date: August 2008 The Aliskireno in the eValuation of prOteinuria In Diabetes (AVOID) study was a 6-meses, doble ciego, randomized, placebo-controlled study in 599 pacientes with mild-to-moderate hipertensión, type 2 diabetes and nephropathy (urinary albumin-to-creatinine ratio [UACR] 200–3500 mg/g). 1 Patients enrolled in the AVOID study received 3 meses of losartan 100 mg una vez al día monoterapia, with optional addition of other antihypertensive agents as necessary, with the aim of achieving blood pressure (PA) &lt;130/80 mmHg. After the 3 meses open-label period, pacientes were randomized to receive Aliskireno 150 mg or placebo una vez al día, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 3 meses, the dosage of Aliskireno was force-titrated from 150 to 300 mg for a further 3 meses. 1 In pacientes receiving losartan 100 mg once-daily and optimal antihypertensive therapy, addition of Aliskireno 300 mg provided significantly greater reductions in UACR from línea de base compared with placebo after 6 meses of tratamiento (p&lt;0.001). 1,2 The cambio medio from línea de base in UACR in pacientes who received Aliskireno 300 mg was −18% compared with an increase of 2% in pacientes who received placebo. 2 As PA was similar in the Aliskireno and placebo groups throughout the study, the effect of Aliskireno on UACR is likely to be independent of the level of PA control. 1,2 Abbreviations AVOID = Aliskireno in the eValuation of prOteinuria In Diabetes PA = blood pressure UACR = urinary albumin-to-creatinine ratio References 1. Parving H-H, Persson F, Lewis JB, et al . The Combinación of Aliskireno, a direct renina inhibitor, and losartan in pacientes with type 2 diabetes and nephropathy. New Engl J Med 2008;358:2433–2446. 2. Parving H-H, Lewis JB, Lewis EJ, Hollenberg NK. Aliskireno in the Evaluation of Proteinuria in Diabetes (AVOID). Abstract and poster #SA-PO1051 presented at American Society of Nephrology Renal Semana, San Francisco, USA. 3 November 2007.
  • It is also important to know that thanks to the increased flexibility afforded by the 4 dosages along with the reduced rate of side effects, COVER AM gives you MORE compliance. Note: Bangalore published that an antihypertensive fixed-dose combination reduces the risk of noncompliance by -26% compared to the individual components. We recalculated this percentage according the increase in the compliance rate, which gives a 21% increase.
  • It is also important to know that thanks to the increased flexibility afforded by the 4 dosages along with the reduced rate of side effects, COVER AM gives you MORE compliance. Note: Bangalore published that an antihypertensive fixed-dose combination reduces the risk of noncompliance by -26% compared to the individual components. We recalculated this percentage according the increase in the compliance rate, which gives a 21% increase.
  • Puesta al día intensiva en medicina interna y ambulatoria

    1. 1. Dr. Gabriel Waisman Profesor Asociado del Departamento de Clínica Médica, Instituto Universitario del Hospital Italiano de Buenos Aires Jefe de Servicio de Clínica Médica y Jefe de Sección Hipertensión Arterial-Hospital Italiano de Buenos Aires Ex Presidente de la Sociedad Argentina de Hipertensión Arterial (SAHA) “ Hipertensión Arterial y Nefropatía Diabética” CAMPUS VIRTUAL Hospital Italiano de Buenos Aires www.hospitalitaliano.org.ar/campus [email_address] Tel. 4959- 0200 Int. 4518 / 4519 Fax. 4959- 0335
    2. 2. Gabriel D. Waisman <ul><li>Profesor Asociado de Clínica Médica - Instituto Universitario Escuela de Medicina del Hospital Italiano de Buenos Aires. </li></ul><ul><li>Jefe de Servicio de Clínica Médica y Jefe de Sección Hipertensión Arterial, Hospital Italiano de Buenos Aires. </li></ul><ul><li>Director de la Carrera de Especialistas Universitarios en Medicina Interna (UBA). </li></ul><ul><li>Presidente de la Sociedad Argentina de Hipertensión Arterial (SAHA), período 2005-2007. </li></ul>“ Hipertensión Arterial y Nefropatía Diabética”
    3. 3. La ECV: Principal Causa de Muerte 0 100 200 300 400 500 A ECV* B Cancer D Enfermedades respiratorias crónicas C Accidentes 433,825 288,768 69,257 60,713 34,301 493,623 268,503 64,103 38,948 41,877 Muertes (Miles) *EC, ACV, IC, HTA, EVP Hombres Mujeres F Enf de Alzheimer E Diabetes CDC/NCHS and NHLBI A B C D E A B C E F
    4. 4. El Riesgo de EC Aumenta Agudamente Luego de la Quinta Década de la Vida 0.0 1.4 3.0 11.6 11.5 16.8 0.3 0.2 1.6 3.6 6.3 10.3 0 5 10 15 20 Hombres Mujeres AHA. Heart Disease and Stroke Statistics—2005 Update . NHANES 1999–2002 % de la Población 20–34 35–44 45–54 55–64 65–74 ≥ 75 Edad
    5. 5. Obesidad y Diabetes Entre los Adultos: Prevalencia Creciente Obesidad (BMI ≥30 kg/m 2 ) Población (%) 30 25 2000 2001 2002 2003 20 15 0 2004 8 6 4 2 0 2000 2001 2002 2003 2004 Diabetes Mellitus tipo 2 Diagnosticada CDC. 2004 NHIS; www.cdc.gov/nchs/nhis.htm. 21.8 23.0 23.9 23.7 24.3 5.9 6.4 6.5 6.6 6.6 +11.9% +11.5%
    6. 6. El daño de órgano blanco precede en décadas a los eventos clínicos Vasoconstricción Hipertrofia vascular Disfunción endotelial Aterosclerosis Muerte Disminución de FG Proteinuria/albuminuria Glomerulosclerosis Insuficiencia renal Apoptosis HVI Fibrosis ACV Trastornos Cognitivos Arritmia I.Cardíaca IAM Factores de riesgo : diabetes, obesidad, tabaquismo, edad Enfermedad Vascular Estado Protrombótico HTA
    7. 7. El daño de órgano blanco incrementa el riesgo cardiovascular Kannel. Eur Heart J 1992;13 (Suppl D):82–88 Hipertrofia ventricular izquierda
    8. 8. El daño de órgano blanco incrementa el riesgo cardiovascular Gimeno Orna et al. Rev Clin Esp 2003;203:526–531 * *P<0.05 versus normoalbuminuria después de ajustar por otros marcadores de riesgo * Albuminuria (en Diabetes tipo 2)
    9. 9. Inibición de la ECA Circulación sistémica Angiotensinógeno Riñon Renina Ang-I ECA Pulmones Sistema Adrenal Aldosterona Sistema Vascular  Retención de Na/H 2 O Vasoconstricción Elevación de la PA Adaptado de Laragh. Em: New Frontiers in Cardiovascular Therapy . 1989;83-116 Ang-II Via Hepática Comprensión Clásica del SRA
    10. 10. Adaptado de Kaplan NM, Clinical Hypertension 1994 Angiotensina II Adrenal Riñón SNC SN Periférico Músculo Liso Vascular Aldosterona Reabsorción Sodio y Agua Sed y Apetito por Na Descarga Simpática Vasoconstricción Resistencia Periférica Total Mantener o incrementar líquido en la sangre Angiotensina II Acciones Fisiológicas
    11. 11. Sistema Renina Angiotensina Nuevos componentes Warner FJ. Clinical Science , 2007;113:109-18
    12. 12. Función y Estructura Cardiovascular Papel de los Receptores AT 1 Receptor AT1 Angiotensina II Vasoconstricción Estrés Oxidativo Proliferación celular Hipertrofia Vascular Hipertrofia VI Proteinuria
    13. 13. SRA – Conceptos Emergentes ANGIOTENSINÓGENO ANGIOTENSINA I ANGIOTENSINA II RECEPTOR AT1 ANGIOTENSINÓGENO ANGIOTENSINA I ANGIOTENSINA-(1-7) RECEPTOR MÁS Vasoconstrictor Proliferativo Vasodilatador Anti-proliferativo ECA2 Agata J. Hypertens. Res , 2006; 29: 865-74 . Raizada MK. J Cardiovasc Pharmacol , 2007; 50: 112-9. RENINA ECA RENINA NEP, PEP, ECA2
    14. 14. Santos R &Ferreira A. Curr Opin Nephrol Hypertens. 2007;16:122-8 Angiotensina I Angiotensina II Angiotensina- (1-7) Receptor AT1 Más Vasoconstricción Disfunción endotelial Proliferación/Hipertrofia Fibrosis Aterosclerosis Arritmogénico Trombosis Vasodilatación Función endotelial Proliferación Hipertrofia Fibrosis Trombosis Anti- arritmogénico Dos caminos del SRA Contribución para el control de la PA
    15. 15. SRAA: Sitios de intervención con IECA-ARAII-IDR Angiotensinógeno Angiotensina I Renina IECA ECA Angiotensina II Receptor AT 1 ARAII Receptor AT 2 Protección Vascular? Adaptado de Nickenig G. Circulation. 2004;110:1013-20. IDR Ateroesclerosis, Hipertensión
    16. 16. SRAA: Otros sitios potenciales de intervención Struthers AD, MacDonald TM. Cardiovasc Res. 2004;61:663-70. Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. Zisman LS. Eur Heart J . 2005;26:322-4. Efectos Aldosterona  Función endotelial  Trombosis  Distensibildad vascular  Función de los barorreceptores  Fibrosis Catepsina G Angiotensinógeno  AII Quimasa AI  AII ECA2 AI  A(1–9), A(1–7)
    17. 17. The 1998 National Medal of Technology , Scientific American, March 1999 Teprotide – Bradychinin Potentiating Factor (Ferreira)
    18. 18. AII y los mecanismos de ateroesclerosis Alteración de la ON sintasa Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. IL-6 MCP-1 PDGF NF-kB RANTES LOX-1 PAI-1 TF TGF-  CTGF VEGF VCAM ICAM Angiotensina II Oxidación de Lípidos Trombosis Inflamación Proliferación y fibrosis Adhesión Disfunción endotelial Disfunción Endotelial
    19. 19. PERTINENT PERindopril–Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial IECA  NO via  de la actividad de la eNOS en células endoteliales (vena umbilical humana) Ceconi C et al. Atherosclerosis. 2009;204:273-5. 0 1 2 3 4 2.5 3.5 2.4 2.9 3.3 Controles n = 45 Placebo n = 44 Placebo n = 44 Perindopril n = 43 Perindopril n = 43 P < 0.01* P < 0.05 † Basal 1 año Actividad de eNOS (pmol/min/ mg proteinas) Controles Pacientes con EC * vs basal †  perindopril vs  placebo PER indopril – T hrombosis, I nflammatio N , E ndothelial dysfunction and N eurohormonal activation T rial (substudy of EUROPA)
    20. 20. El bloqueo del receptor AT 1 mejora la vasodilatación mediada por flujo 122 pacientes hipertensos tratados durante 2 meses *P < 0.05 vs basal y vs placebo Koh KK et al. Am J Cardiol. 2004;93:1432-5. 0.15 1.14 1.66 1.32 0.0 0.5 1.0 1.5 2.0 Placebo (n = 30) Irbesartan 300 mg (n = 30) Losartan 100 mg (n = 31) Candesartan 16 mg (n = 31)  flujo en arteria humeral (%) 2.5 * * *
    21. 21. AII y los mecanismos de ateroesclerosis Alteración de la ON sintasa Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. IL-6 MCP-1PDGF LOX-1 PAI-1 TF TGF-  VCAM ICAM Angiotensina II Oxidación de Lípidos Trombosis Inflamación Proliferación y fibrosis Adhesión Disfunción endotelial TGF-  CTGF VEGF IL-6 MCP-1 PDGF NF-kB RANTES Inflamación
    22. 22. La inhibición de la ECA reduce el stress oxidativo y la inflamación 20 Pacientes con diabetes tipo 2 Marketou ME et al. J Am Coll Cardiol. 2005;45 (suppl A):396A. Basai Perindopril 4 mg x 6 meses * P < 0.05 vs basal TNF-  IL-6 Peroxidos Lipidos 3.3 2.0 0 1 2 3 4 2.9 1.8  mol/L pg/mL * * * 370 264 0 100 200 300 400
    23. 23. AII y los mecanismos de ateroesclerosis Alteración de la ON sintasa Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. L-6 MCP-1 PDGF LOX-1 PAI-1 TF TGF-  VCAM ICAM Angiotensina II Oxidación de Lípidos Trombosis Inflamación Proliferación y fibrosis Adhesión Disfunción endotelial TGF-  CTGF VEGF IL-6 MCP-1 PDGF NF-kB RANTES Oxidación de Lípidos Adhesión
    24. 24. AT 1 y el receptor LOX-1 promueve la expresión de moléculas de adhesión: Interacción entre SRAA y dislipidemia Mehta JL, Li D. J Am Coll Cardiol. 2002;39:1429-35. OxLDL Célula Endotelial LOX-1 Endotelina Shear stress TNF-  AII AT 1 Scavenger receptors?? ROS MCP-1 eNOS Bad Fas Activación de Monocitos Ateroesclerosis Disfunción Apoptosis Injuria PKs MAPKs NF-  B Expresión de moléculas de adhesión
    25. 25. La AII regula la expresión de LOX-1 * P < 0.0001 vs control † P < 0.0001 vs A II ‡ P < 0.05 vs A II Bai = baicaleina (inhibidor de la -lipoxigenasa) Células de músculo liso vascular humano Limor R et al. Am J Hypertens . 2005;18:299-307. A II 10 -7 mol/L+ losartan 10 -5 mol/L 0 100 200 300 Control A II 10 -7 mol/L A II 10 -7 mol/L+ Bai 10 -5 mol/L LOX-1 mRNA * † ‡ 400
    26. 26. AII y los mecanismos de ateroesclerosis Alteración de la ON sintasa Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. IL-6 MCP-1 PDGF LOX-1 PAI-1 TF TGF-  VCAM ICAM Angiotensina II Oxidación de Lípidos Trombosis Inflamación Proliferación y fibrosis Adhesión Disfunción endotelial TGF-  CTGF VEGF IL-6 MCP-1 PDGF NF-kB RANTES Proliferación y fibrosis
    27. 27. HOPE: Efectos dosis-dependientes de ramipril sobre la masa y función del VI 5.31 2.9 – 1.9 – 3 0 2 4 6 8.21 7.86 – 3.53 – 4 0 5 10 Volúmen de fin de sístole VI Masa VI Lonn E et al. J Am Coll Cardiol. 2004;43:2200-6. Media basal VFSVI 58%, todos los grupos  (mL)  (g) P Trend = 0.001 P Trend = 0.03 N = 446 pacientes seguidos, 4 años Placebo Ramipril 2.5 mg Ramipril 10 mg
    28. 28. LIFE: Mayor reducción de la masa del VI con el bloqueante del receptor AT1 vs BB Devereux RB et al. Circulation. 2004;110:1456-62. Pacientes con HTA e HVI Cambios en la masa del VI (g) – 50 – 20 Año – 10 0 Losartan 50–100 mg (n = 457) Atenolol 50–100 mg (n = 459) – 30 – 40 1 2 3 4 5 Última visita P = 0.009 para todos los puntos
    29. 29. AII y los mecanismos de ateroesclerosis Alteración de la ON sintasa Jacoby DS, Rader DJ. Arch Intern Med. 2003;163:1155-64. IL-6 MCP-1 PDGF LOX-1 PAI-1 TF TGF-  VCAM ICAM Angiotensina II Oxidación de Lípidos Trombosis Inflamación Proliferación y fibrosis Adhesión Disfunción endotelial TGF-  CTGF VEGF IL-6 MCP-1 PDGF NF-kB RANTES Trombosis
    30. 30. Liberación de TPA: Diferentes efectos de los IECA y los Bloqueantes AT1 Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9. *P < 0.05 vs basal 20 10 15 5 0.2 0 0 0.6 2.0 Antígeno tPA en seno coronario (ng/mL) Bradikinina (  g/min) Perindopril 4 mg (n = 16) Losartan 50 mg (n = 15) Control (n = 14) P < 0.05 * * * * * * * 25
    31. 31. Los bloqueantes AT1 impiden la expresión en placas carotideas humanas de metaloproteinasas de la matriz: Papel potencial en la estabilización de placas 25.8 28.2 25.1 22.4 5.8 6.2 7.2 5.6 0 10 20 30 MMP-2 MMP-9 COX-2 mPGES-1 P < 0.0001 todas las comparaciones % Tinciones Positivas Clortalidona Irbesartan Cipollone F et al. Circulation . 2004;109:1482-8 . Muestras de endarterectomía carotídea
    32. 32. Tratamiento de la HTA en el Paciente Diabético
    33. 33. UKPDS, BMJ 1998, 317: 703 Control estricto Control “habitual” 144/82 mmHg 154/87 mmHg PA inicial = 160/94 mmHg Diferencia = 10/5 mmHg Tratamiento antihipertensivo en Diabetes Mellitus IAM Mortalidad ACV Microvasc. Albuminuria  24%  32%  44%  37%  29% Captopril/Atenolol
    34. 34. Reducción del riesgo relativo original y en el seguimiento alejado con el “intenso” descenso de la presión arterial Holman RR et al. N Engl J Med 2008; 359 :1 565-76 1997: Reducción de riesgo relativo (%) p 2007: Reducción de riesgo relativo (%) p Cualquier punto final relacionado a diabetes 24 0.0046 7 0.35 Enfermedad microvascular 37 0.0092 16 0.20 IAM 21 0.13 10 0.35 Mortalidad total 18 0.17 11 0.18
    35. 35. Modulación del SRAA en Pacientes con Diabetes
    36. 36. Glomérulo Matriz mesangial Arteriola renal eferente Células mesangiales Nervios simpáticos renales Cápsula de Bowman Túbulo contorneado distal Túbulo contorneado proximal Mastocito de la adventicia/Macrófago Células musculares lisas vasculares Células yuxtaglomerulares Mácula densa Componentes de la Nefrona Normal
    37. 37. Arteriola eferente Constricción Glomérulo Incremento en la albuminuria Arteriola Aferente Dilatación Incremento en la presión glomerular Angiotensina II Flujo Sanguíneo Flujo Sanguíneo Rol Hemodinámico de la Angiotensina II en la injuria glomerular diabética
    38. 38. 1.0 0.9 0.8 0.7 0.6 0.5 0 1 2 3 4 5 6 Años Sobrevida (todas las causas de mortalidad) Normoalbuminuria (n=191) Microalbuminuria (n=86) Macroalbuminuria (n=51) P<0.01 normoalbuminuria vs microalbuminuria P<0.001 normoalbuminuria vs macroalbuminuria P<0.05 microalbuminuria vs macroalbuminuria Gall MA, et al. Diabetes. 1995;44:1303-1309. Proteinuria como factor de riesgo para mortalidad en Diabetes tipo 2
    39. 39. HTA, Microalbuminuria, y Riesgo de Cardiopatía Isquémica Jensen J et al. Hypertension 2000;35:898-903
    40. 40. -P-H -P+H +P-H +P+H Tasa de mortalidad estandarizada Estado de Proteinuria (P) e Hipertensión (H) en Diabéticos tipo 2 -P-H Hombres -P+H +P-H +P+H Mujeres Wang SL, et al. Diabetes Care. 1996;19:305-312. Proteinuria e Hipertensión Arterial en Diabetes tipo 2
    41. 41. <ul><li>Funcionales </li></ul><ul><ul><li>Disminución TFG </li></ul></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><li>Estructurales </li></ul><ul><ul><li>Alteraciones en la membrana basal glomerular </li></ul></ul><ul><ul><li>Expansión de la matriz mesangial </li></ul></ul><ul><ul><li>Glomeruloesclerosis </li></ul></ul><ul><ul><li>Fibrosis túbulo-intersticial </li></ul></ul>Presión Arterial Consecuencias Insuficiencia Renal Campese VM Kidney Int 2000;57(Suppl 75):S2-S6. Klahr S, Morrissey JJ Kidney Int 2000;57(Suppl 75):S7-S14. Leehey DJ et al Kidney Int 2000;58(Suppl 77):S93-S98. Consecuencias de la Lesión Renal en la Hipertensión
    42. 42. Factor de crecimiento renal y activación de citocinas Fibrogénesis Hipertensión sistémica Pérdida progresiva de superficie de filtración TFG Lesión renal Masa de nefronas Hipertensión Glomerular Cicatrización renal Hiperlipidemia  Filtración de proteinas (proteinuria) <ul><li>Recaptación de proteínas </li></ul><ul><li>en el túbulo proximal </li></ul>Daño micorvascular renal Afluencia de monocitos y macrófagos Transdiferenciación de las células renales al fenotipo fibroblástico Brenner BM, Keane WF. 2001. Vías que Conducen a la Insuficiencia Renal Progresiva
    43. 43. Adaptado de Breyer JA et al. Am J Kid Dis 1992; 20(6): 535. Tiempo (años) 0 5 20 30 Inicio de Diabetes Inicio de Proteinuria Insufic. Renal Terminal CAMBIOS ESTRUCTURALES (Engrosamiento de la MBG y expansión del mesangio) Hipertensión Historia Natural de la Nefropatía Diabética NEFROPATIA FRANCA Aumento Cr sérica, Disminución FG NEFROPATIA INCIPIENTE Hiperfiltración, microalbuminuria, aumento de la tensión arterial NEFROPATIA PRECLINICA
    44. 44. Diagnóstico de albuminuria Recolección de orina sin tiempo controlado MODIFICADA POR CONCENTRA- DIAGNOSTICO SIN MODIFICAR CION DE CREATININA EN LA ORINA Normoalbuminuria <20ug / ml <30 mg / g Microalbuminuria 20 a 200 ug / ml 30 a 300 mg / g Macroalbuminuria >200 ug / ml >300 mg / g DIAGNOSTICO DURANTE LA NOCHE LAS 24 HORAS RECOLECCION DE ORINA EN TIEMPO CONTROLADO Normoalbuminuria < 20 ug / min < 30 mg / 24 h Microalbuminuria 20 a 200 ug / min 30 a 300 mg / 24 h Macroalbuminuria >200 ug / ml > 300 mg / 24 h
    45. 45. Factores que pueden afectar la excreción urinaria de albúmina AUMENTO DISMINUCION INSUFICIENCIA CARDIACA CONGESTIVA EXCESO DE INGESTION DE PROTEINAS EJERCICIO HEMATURIA HIPERTENSION NO CONTROLADA DIABETES NO CONTROLADA INFECCION TRACTO URINARIO CONTAMINACION DEL FLUIDO VAGINAL DESNUTRICION TRATAMIENTO CON IECA TRATAMIENTO CON AINES
    46. 46. Go A et al. N Engl J Med 2004;351:1296-305 Enfermedad Renal Crónica y Riesgo de Muerte, Eventos Cardiovasculares y Hospitalización
    47. 47. Beneficios de disminuir la PA en forma intensiva Zanchetti et al. J Hypertens 2003;21:797–804 * P≤0.05 vs tratamiento menos intensivo ** P≤0.01 vs tratamiento menos intensivo † Intensivo = PAD ≤85 mmHg; menos intensivo= PAD <90 mmHg La reducción intensiva de la PA reduce el riesgo † (no-fumadores) ** ** ** * * *
    48. 48. IECA Y A RA II Beneficios en diabéticos <ul><li>Descenso de la vasoconstricción </li></ul><ul><li>Disminución de la proliferación en el músculo liso de la pared vascular </li></ul><ul><li>IECA aumentan bradikinina promoviendo vasodilatación y aumento de la sensibilidad a la insulina. </li></ul><ul><li>ARA II Disminuyen PAI1 y reducen la agregación plaquetaria </li></ul>
    49. 49. MICRO-HOPE: Los IECA mejoran los puntos finales renales y cardiovasculares en diabéticos tipo 2 HOPE Study Investigators. Lancet . 2000;355:253-9. 3.0 2.5 2.0 1.5 1.0 0.5 0 1 2 3 4.5 Placebo Ramipril 10 mg Media cociente albumina- creatinina Años P = 0.001 P = 0.02 0 10 20 30 40 Nefropatía Muerte CV ACV IAM Reducción de Riesgo (%) P = 0.027 P = 0.0001 P = 0.007 P = 0.01 22 33 37 24 N = 3577 (32% con microalbuminuria)
    50. 50. LIFE: Efectos del tratamiento en la población total vs los pacientes con diabetes Pacientes con hipertensión e HVI Dahlöf B et al. Lancet . 2002;359:995-1003. Lindholm LH et al. Lancet . 2002;359:1004-10. 0.5 1.0 1.5 Todos (n = 9193) Diabetes (n = 1195) 0.206 0.028 0.001 0.204 0.491 0.373 A favor losartan 50–100 mg A favor atenolol 50–100 mg P Muerte CV ACV IAM Hazard ratio
    51. 51. Nefroprotección en diabetes tipo I MUERTE DIALISIS O TRANSPLANTE (%) 0 10 20 30 40 50 6 12 18 24 30 36 42 48 SEGUIMIENTO (MESES) Placebo Captopril p = 0.006 Placebo 202 198 192 186 171 121 100 59 26 Captopril 207 207 204 201 195 140 103 64 37 Lewis EJ et al. N Engl J Med 1993;329:1456-1462
    52. 52. Estudios clínicos en pacientes hipertensos con diabetes tipo 2 <ul><li>SHEP (Diabetes), JAMA 1996 </li></ul><ul><li>FACET, Diabetes Care 1998 </li></ul><ul><li>ABCD, NEJM 1998 </li></ul><ul><li>Diabetes Care 2000 </li></ul><ul><li>UKPDS, BMJ 1998 </li></ul><ul><li>HOT, Lancet 1998 </li></ul><ul><li>CAPPP, Lancet 1999 </li></ul><ul><li>Syst Eur, NEJM 1999 </li></ul><ul><li>STOP-2 (Diabetes), J Hypertens 2000 </li></ul><ul><li>Nordil, Lancet 2001 </li></ul><ul><li>Insight, Lancet 2001 </li></ul><ul><li>MICRO-HOPE (solamente 50% hipertensos) </li></ul><ul><li>LIFE, 2002 </li></ul><ul><li>ALLHAT, 2002 </li></ul><ul><li>Value 2004 </li></ul>
    53. 53. Metanálisis (100 estudios; n= 2.494 DM tipos 1 y 2); Kasiske, 1993 0 0,2 -0,2 -0,4 -0,6 Proteinuria Albuminuria IECA ACA  -B Control Proteinuria: prevención
    54. 54. ARA II en Diabetes Tipo 2 con Nefopatía Progresión de la microalbuminuria † A Tasa de excreción de albúmina de 20 a 200  g por minuto en 2 de 3 muestras de orina consecutivas. ‡ Tasa de excreción urinaria de albúmina >200  g por minuto y por lo menos 30% mayor que la basal en al menos 2 mediciones consecutivas *En combinacón con terapéutica antihipertensiva convencional (excluyendo IECA) Parving HH, et al. N Engl J Med. 2001;345(12):870-878. IRMA II=The Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients Study 2 años Irbesartan 300mg vs placebo* Irbesartan 150mg vs placebo* Duración Objetivo Primario: Desarrollo de proteinuria clinica‡  39% (P=0.080) IRMA II (n=590)  70% (P<0.001)
    55. 55. ARA II en Diabetes Tipo 2 con Nefropatía Progresión de la Insuficiencia Renal *En combinación con tratamiento hipotensor convencional (excluyendo IECA) RENAAL=The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study IDNT=The Irbesartan in Diabetic Nephropathy Trial Brenner BM, et al. N Engl J Med. 2001;345(12):861-869. Lewis EJ, et al. N Engl J Med. 2001;345(12):851-860. Irbesartan 150-300 mg vs Amlodipina* Irbesartan 150-300mg vs placebo* Losartan 50-100 mg vs placebo* 3.4 años RENAAL (n=1,514)  23% (p=0.006) 2.6 años  20% (p=0.02) IDNT (n=1,715)  16% (p=0.02) Duración promedio Objetivo Primario: Compuesto de doble de la creatininemia, enfermedad renal terminal, o muerte
    56. 56. Efectos de los ARAII en diabetes tipo 2: Puntos finales renales y CV Lewis EJ et al. N Engl J Med. 2001;345:851-60. Brenner BM et al. N Engl J Med. 2001;345:861-9. Parving HH et al. N Engl J Med. 2001;345:870-8. *Doble de creatinina sérica basal, prograsión a ERCT (IDNT, RENAAL): progresión a nefropatía diabética (IRMA-2) Estudio (N) ARAII Punto final primario: Progresión de enf. renal* Puntos finales secundarios (CV) Duración promedio (años) IDNT (N = 1715) Irbesartan 300 mg/d vs amlodipina 10 mg  20% vs placebo, (P = 0.02) y  23% vs amlodipina (P = 0.006) Puntos finales Combinados CV: NS 2.6 RENAAL (N = 1514) Losartan 100 mg/d vs placebo †  16% (P = 0.02) Morbilidad y mortalidad CV: NS Hospitalización por IC  32% 3.4 IRMA-2 (N = 590) Irbesartan 150–300 mg vs placebo  39% with 150 mg (P = 0.08)  70% with 300 mg (P < 0.001) Eventos CV no fatales: NS 2
    57. 57. IECA y Bloqueantes de los canales del calcio: Una asociación nefroprotectora en diabeticos tipo 2 con microalbuminuria Fogari R. Am J Hypertens 2002;15:1042-1049 Hipertensos diabéticos con microalbuminuria aleatorizados a tres grupos: Amlodipina (5-15 mg/dia), fosinopril (10-30 mg/dia) o la combinación de ambos fármacos durante 3 meses. A los respondedores (309) seguimiento de 4 años. La disminución de la albuminuria fue mas pronunciada y mas precoz en los tratados con fosinopril y el efecto antiproteinúrico fue mayor aún en los que recibieron tratamiento combinado.
    58. 58. Combinación de IECA con Antagonistas de Receptores AT1 Puede Ser Necesario en Algunas Situaciones? Es Util la Asociación en Alguna Circunstancia? Russo D. et al. Am J Kid Dis 1999 , 33 :851-856 Taal MW et al. Curr Opin Nephrol Hypertens 2002;11:377-381 <ul><li>Efectos antiproteinúricos adicionales beneficiosos en pacientes con: </li></ul><ul><ul><li>Glomerulonefritis y macroproteinuria </li></ul></ul><ul><ul><li>Nefropatía por IgA </li></ul></ul><ul><li>También podría ser de utilidad la asociación cuando con monoterapia no logra reducirse la proteinuria </li></ul>
    59. 59. Razones para el tratamiento combinado con IECA y ARA II Mooser V., et al. J Cardiovasc Pharmacol 1990;15:276 – 282; Gainer J.V., et al. N Engl J Med 1998;339:1285 – 1292; Sandmann S., et al . Drugs 2002;62(Spec No 1):43 – 52; Cao Z.., et al . J Am Soc Nephrol 2002;13:1773 – 1787 <ul><li>El bloqueo dual se basa en en principio de obtener el mas amplio y eficiente bloqueo de los efectos de la AII utilizando una ARAII y un IECA. </li></ul><ul><li>Se incrementa la producción de kininas, y posiblemente disminuye la secreción de aldosterona. </li></ul><ul><li>El escape de AII con los IECA puede llevar a una mayor estimulación del receptor AT 2 durante la terapéutica combinada . </li></ul><ul><li>Se mejora la sensibilidad a la insulina por mecanismos diferentes. </li></ul><ul><li>Efectos aditivos en la nefropatía diabética y en la insuficiencia cardíaca. </li></ul>
    60. 60. Consecuencias bioquímicas y hormonales del bloqueo combinado del SRA Menard J. & Azizi M., Circulation 2004;109:2492–2499 * Debido al fenómeno de escape IECA ARAII IECA & ARAII Enzimas ECA plasmática + tisular Inhibida No inhibida Inhibida Sustrato Bradikinina Incrementada Sin cambios Incrementada Receptor AT 1 AT 2 Bradikinina (B2) No estimulado No estimulado Estimulado Bloqueado Estimulado Estimulado No estimulado & bloqueado Normal o estimulado Efecto aditivo Productos finales de Aldosterona Angiotensina II Disminución/no cambio* Disminución/no cambio* Disminución/no cambio* Incremento Posible disminución sostenida Incremento o normal Misceláneas SRA tisular Oxido Nítrico Inhibido Incrementado Bloqueado Incrementado Efecto aditivo* Efecto aditivo*
    61. 61. Evaluación de la Terapéutica Combinada IECA/ARAII <ul><li>Reducción de la Presión Arterial </li></ul><ul><ul><li>Hay alguna evidencia de efectos adiitivos sobre la reducción de la presión arterial </li></ul></ul><ul><li>Protección Renal </li></ul><ul><ul><li>Alguna evidencia en pequeños estudios para los efectos beneficiosos aditivos sobre la protección renal y la reducción de la proteinuria </li></ul></ul><ul><li>Efectos Cardíacos </li></ul><ul><ul><li>Alguna evidencia de beneficio adicional en insuficiencia cardíaca e HVI </li></ul></ul><ul><li>Estudios con Puntos Finales Duros (Eventos CV fatales y no fatales) </li></ul><ul><ul><li>El estudio Valiant y el Val-HeFT fracasaron en demostrar reducciones en la mortalidad CV con valsartan combinado con ICEA </li></ul></ul><ul><ul><li>En el estudio Val-HeFT los pacientes se beneficiaron por reducción en la tasa de hospitalizaciones por insuficiencia cardíaca </li></ul></ul><ul><ul><li>El estudio CHARM-adicionado mostró reducciones en la mortalidad CV con la combinación candesartan en adición a los IECA </li></ul></ul>
    62. 62. Aliskiren in the eValuation of proteinuria In Diabetes (AVOID – Evaluación de la proteinuria en diabetes) Visión general del diseño del estudio <ul><li>Todos los pacientes continuaron recibiendo losartan 100mg en forma abierta junto con un tratamiento antihipertensivo óptimo durante el período doble ciego </li></ul><ul><li>Titulación obligada después de 3 meses </li></ul><ul><li>Todos los tratamientos se administraron una vez al día </li></ul>3 meses Placebo Aliskiren 150 mg + 3 meses 3 meses Placebo Aliskiren 300 mg Aleatorización Abierto Doble ciego Losartan 100 mg + tratamiento antihipertensivo óptimo
    63. 63. <ul><li>Evaluación de los efectos nefroprotectores del bloqueo dual del SRAA </li></ul><ul><li>a través de la adición de aliskiren (inhibidor directo de la renina por via oral), </li></ul><ul><li>al tratamiento con la dosis máxima recomendada de losartan (100 mg/dia) </li></ul><ul><li>y un tratamiento antihipertensivo óptimo en hipertensos y diabetes tipo 2 con </li></ul><ul><li>nefropatía </li></ul><ul><li>599 pacientes (18-85 años), estudio multinacional, randomizado y doble ciego. Diabéticos tipo 2 con nefropatía ( relación urinaria albúmina/creatinina de >300 mg/g, o >200 mg/gr en pacientes que reciben tratamiento que bloquea el SRAA) </li></ul><ul><li>Objetivo de PA <130/80 mmHg Aleatorizados a recibir 6 meses de tratamiento con aliskiren (150 mg/día durante 3 meses, seguidos por 300 mg/día durante 3 meses mas) o placebo, adicionándolo al losartan. </li></ul><ul><li>Objetivo primario: Reducción en la relación alb/creat en una muestra de orina a la mañana temprano a los 6 meses. </li></ul>Estudio Avoid
    64. 64. La PA permaneció similar en los grupos de Aliskiren y placebo a lo largo del estudio 60 140 PA (mmHg) 130 120 110 20 16 12 8 4 – 2 Semana 24 Sistólica Diastólica 100 90 80 70 22 18 14 10 6 2 0 Aliskiren Placebo Tratamiento antihipertensivo óptimo +
    65. 65. Aliskiren produce una disminución significativamente mayor en albuminuria comparado con placebo Tratamiento óptimo + Aliskiren 300 mg Cambio promedio basal/mes 6 (%) 0 − 15 − 20 − 10 − 5 n=289 n=287 − 18 5 2 * Tratamiento óptimo + placebo *p<0.001 vs placebo
    66. 66. Intervención Multifactorial y Enfermedad Cardiovascular en Pacientes Diabéticos Tipo 2 con Microalbuminuria Gaede P et al., N Engl J Med 2003;348:383-93 . STENO 2 160 pac. diabéticos tipo 2 con microalbuminuria randomizados a cuidados convencionales vs tto. Intensivo Seguimiento 7.8 años Una estrategia multifactorial reduce el riesgo de enfermedad cardiovascular entre los pacientes con diabetes tipo 2.
    67. 67. Intervención Multifactorial y Enfermedad Cardiovascular en Pacientes Diabéticos Tipo 2 con Microalbuminuria Gaede P. et al., N Engl J Med 2003;348:383-93 . STENO 2 Niveles a alcanzar de FRC en Diabéticos PA < 130/80 mmHg LDL colesterol < 100 mg/dl Trigliceridos < 150 mg/dl HDL colesterol > 40 mg/dl Hemoglobina glicosilada < 7%
    68. 68. Riesgo relativo (95% CI) 0. 0 1.0 2.0 Tratamiento intensivo vs convencional Enf. cardiovascular 0.47 (0. 24 - 0.73 ) 0. 66 Nefropatía 0. 3 9 (0. 17-0.87 ) 0. 003 Retinopatía 0.42 ( 0.21-0.86 ) 0. 02 Neuropat. autonómica 0. 37 (0. 18 - 0.79 ) 0. 002 p 0. 5 1.5 2.0 N Eng J of Med 2003; 348: 383-393 STENO 2 Trat. intensivo Trat. convencional mejor mejor
    69. 69. Paradigma futuro Progresión Lenta con Neuroprotección, Cardioprotección, Protección Renal y Vascular Enfermedad Precoz <ul><li>Estatinas </li></ul><ul><li>Bloqueo del SRAA </li></ul><ul><li>Antihipertensivos </li></ul><ul><li>Donantes/amplificadores de ON </li></ul><ul><li>Terapéutica innovadora </li></ul>
    70. 70. CAMPUS VIRTUAL Puesta al día intensiva en Medicina Interna y Ambulatoria 2011 www.hospitalitaliano.org.ar/campus [email_address] Tel. 4959- 0200 Int. 4518 / 4519 Fax. 4959- 0335 Servicio de Clínica Médica Curso PIMA (Puesta al día Intensiva en Medicina Interna y Ambulatoria) 6 y 7 de Octubre de 2011
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