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Advantages of renin-angiotensin system blockade in the treatment of cardiovascular disease V. Gerc Clinic for Heart Disease and Rheumatism Sarajevo The cardiovascular continua in cardiovascular disease The pathophysiological continua in cardiovascular disease Angiotensin II is central to atherosclerotic mechanisms Oxidative Stress Inflammation NAD(P)H oxidase activity ↑ Vascular permeability ↑ Leucocyte infiltration ↑ Reactive oxygen species ↑ Activation of signalling pathways LDL peroxidation ↑ LDL peroxidation ↓ Production of inflammatory mediators Angiotensin II Nitric oxide ↓ Proliferation of VSMCs Vasoconstriction PAI-1 activation Platelet aggregation Endothelial dysfunction Matrix deposition MMP activation Tissue remodelling Schmieder et al. Lancet 2007;369:1208−1219 Vascular Risk Factors and Endothelial Dysfunction Role of oxidative stress: Angiotensin II Smoking Hypertension Homocysteine oxLDL Diabetes Bradykinin/NO - oxidative stress - Endothelial Dysfunction mod. from Gibbons GH, Clin Cardiol 20 (1997) Antioxidants (?) Long-term cardiovascular effects of angiotensin II Metabolism of the Renin-Angiotensin System Component Half-life in circulation Degrading enzyme(s) Renin 15–20 min — Angiotensinogen 4–16 h Renin Angiotensin I 1–2 min Angiotensinconverting enzyme Angiotensin II Seconds Aminopeptidase A, endopeptidase, Prolylcarboxypeptidase Mechanism of action of angiotensinconverting enzyme inhibitors EFFECTS OF ANGITENSIN II vasoconstriction (”afterload” ) reabsorption of Na+ and water (“preload” ) coronary constriction syntesis of cellular proteins (HLV) fibroblastic hyperplasia (myocardial fibrosis) apoptosis of myocites diastolic dysfunction of the heart EFFECTS OF ANGIOTENSIN II sympathetic, vagal activity adrenocortex ( catecholamine, aldosterone) endothelial dysfunction PAI-1 ( fibrinolysis) tissue factor proliferation and migration of smooth muscles Potential pathogenic properties of Angiotensin II • Heart • Myocardial hypertrophy • Interstitial fibrosis Potential pathogenic properties of Angiotensin II • Coronary Arteries • Endothelial dysfunction with decreased release of nitric oxide • Coronary constriction via release of noradrelanine • Increased oxidative stress; oxygen derived free radicals formed via NADH • Promotion of inflamatory response and atheroma Potential pathogenic properties of Angiotensin II • • • • • Kidneys Increased intraglomerular pressure Increased protein leak Glomerular growth and fibrosis Increased sodium reabsorption Potential pathogenic properties of Angiotensin II • Adrenals • Increased formation of aldosterone Potential pathogenic properties of Angiotensin II • Coagulation system • Increased fibrinogen • Increased PAI-1 Inhibition of the RAS • Inhibition of the RAS is established for the treatment and now prevention of a wide range of cardiovascular disease. The basic concept hinges on the adverse effects of excess angiotensin II and increase protective bradykinin. Renin – Angiotensin - Aldosterone system: where inhibitors act Dual role of ACE inhibitors, both preventing and treating cardiovascular disease Pharmacodynamic effects of ACEI Hemodynamic: vasodilation (AII, BK, PGI, NO) Sympatholytic: Ach NA Endothel: PGI, NO, AII, endothelin Antiproliferative: AII, aldo, c-fos, c-myc Antithrombotic: PAI-1 Antiatherogenic: the above + antioxidants Indications for ACEI, based on trial data • • • • 1.Heart failure, all stages 2. Hypertension 3.AMI, postinfarct LV dysfunction 4.Nephropathy, nondiabetic and diabetic • 5. Diabetes type 2, lessens new microalbuminuria and LV hypertrophy Antiatherosclerotic effect of LISINOPRIL Blood pressure Inflammation Endothelian dysf. ACE Nitric oxide Growth of the plaque Fibrinolysis tPA PAI-1 Reduction of cardiovascular events Oxidative stress Pleiotropic effects of renin-angiotensin system blockers Pleiotropic effects Statins ACEI Early effects (hours, days) LDL,TG;HDL NOS, O- AII, BK, PG O- Intermediary effects (weeks) Viscosity Tr aggregation PAI-1 Fibrinolysis Tr activation BMP-2 Late effects (months) Cell migration, proliferation; stabilisation of the plaque Cell migration, proliferation; stabilisation of the plaque Angiotensin-converting enzyme inhibitors in hypertensive patients at high cardiovascular risk ACEI ACE inhibitors in hypertension • ACEI are effective as monotherapy in BP reduction in most patients. There are few side effects and contraindication ACE inhibitors in hypertension • A particulary attractive combination is that with diuretics, because diuretics increase circulating renin activity and angiotensin II levels, wich ACEI counterregulate by inhibiting the conversion of angiotensin I to angiotensin II. RAAS, ACEIs, and ARBs: Summary • RAAS is a major regulator of CV and renal function • RAAS blockade – Reduces BP – Exerts antiatherosclerotic effects – Delays or avoids onset of T2DM • ACEIs and ARBs are the major RAAS blockers in use • ACEIs do not inhibit Ang II formation by non-ACE pathways • ACEIs block AT1 and AT2 receptors, whereas ARBs inhibit AT1 receptors and leave AT2 receptors open for stimulation Schmieder RE et al. Lancet. 2007;369:1208-19. Role of ARB in the treatment of cardiovascular diseases, with a special reference to LOSARTAN Arguments favoring development of ARBs • ACE inhibitors are not specific • ACE inhibitors do not provide complete blockade of RAS • Alternative pathways for angiotensin II formation • Significant incidence of cough Arguments favoring development of ARBs • ACE inhibitors are not specific • ACE inhibitors do not provide complete blockade of RAS • Alternative pathways for angiotensin II formation • Significant incidence of cough Angiotensin II formation in the heart mediated by chymase v.s. formation mediated by angiotensin converting enzyme ACE mediated Chymase mediated A II formation, % 100 80 60 40 20 0 Mouse Rabbit Rat Balcells E, et al. Am J Physiol. 1997;273:H1769–H1774. Dog Human “Escape” of angiotensin II despite ACE inhibition 100 80 Plasma ACE 60 (nmoL/mL/min)40 20 0 * * * * * * * 24 h 1 2 3 4 5 6 * 30 20 Plasma Ang II (pg/mL) 10 * 0 Placebo Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4(6):966-972. 4h Hospital Months *P <.001 vs placebo Inhibition of the RAS • ARBs directly block the angiotensin II receptor (AT1), thereby largely avoiding the side effects of excess bradykinin such as cough and angioedema. Mechanism of action of angiotensin receptor blockers Effects of Angiotensin II upon AT1 i AT2 receptors AT1 Vasoconstriction Aldosteron release Oxidative stress Vasopresin release Activation of SNS Inhibition of renin release Renal reabsorption of Na+ i H2O Cell growth and proliferation Siragy H. Am J Cardiol. 1999;84:3S-8S. AT2 Vasodilation Antiproliferative effect Apoptosis Antidiuresis/antinatriuresis Bradykinin formation Release of NO ARBs currently available for clinical use Generic name Trade name Drug company Losartan Losartan H Tenlop Tenlop H Bosnalijek Valsartan Diovan, Tareg, Nisis Novartis Irbesartan Aprovel, Avapro, Karvea Bristol-Myers, Squibb, Sanofi Candesartan Atacand, Kenzen, Blopress AstraZeneca/ Takeda Telmisartan Micardis, Pritor Glaxo Smith Kline Eprosartan Teveten Glaxo Smith Kline Olmesartan Benycar, Daiichi Sankyo Pharmacology of Angiotensin Receptor Blockers Half-life, h Bio availabilit y% Volume of distributio n Renal/ hepatic clearance, % Candesartan 9 15 0.13 L/kg 60/40 Eprosartan 5 13 13 L 30/70 Irbesartan 11–15 60–80 53–93 L 1/99 2 33 34 L 10/90 6–9 − 12 L 50/50 Olmesartan 10–15 28 17 L 45/55 Telmisartan 24 42–58 500 L 1/99 6 ∼25 17 L 30/70 Drug Losartan E-3174 Valsartan ARBs currently available for clinical use Drug Recommended initial dosage Dosage range Tablet/capsule Losartan, Tenlop 50 mg once daily 25-50 mg, once daily, or 100 mg once daily tablet 12,5, 50, 100 mg Valsartan 80 mg once daily 80-320 mg once or twice daily capsule 80,160 mg . Irbesartan 150 mg once daily 150-300mg once daily tablet 75,150, 300 mg Candesartan 8 mg once daily 8-16 mg once or twice daily;32 mg once daily tablet 4,8,16,32 mg Eprosartan 400 mg once daily 400-800 mg once daily tablet 200, 400 mg Telmisartan 40 mg once daily 40-80 mg once daily tablet 40,80 mg Olmesartan 20 mg once daily 20-40 mg once daily tablet 20,40 mg ARBs Indications • Hypertension • Heart failure • Secondary prevention following myocardial infarction • Diabetic nephropathy • Proteinuria/microalbuminuria • Left ventricle hypertrophy • Atrial fibrilation • Cough caused by ACEI Losartan and hypertension Studies with Losartan The Losartan Heart Failure Study (ELITE) n=722 The Losartan Hypertension Survival Study (LIFE) n=9194 The Losartan Heart Failure Survival Study (ELITE II) n=3152 The Losartan Post-MI Survival Study (OPTIMAAL) n=5000 The Losartan Renal Protection Study (RENAAL) n=1520 19,588 Comparison of efficacy of candesartan and losartan in the treatment of hypertension : results at trough Andersson, 1998 DP mmHg Plac 4 Los 50 CC 8 CC 16 SP mmHg 4 0 0 -4 -4 -8 * -12 *# -16 -12 -16 -20 -20 85 Los 50 CC 8 CC 16 -8 * n Plac 83 82 84 * * * * p<0.001 vs plac ; # p>0.05 vs Los Comparison of efficacy of candesartan and losartan in the treatment of hypertension : results at peak DP mmHg Andersson, 1998 SP mmHg Plac 4 Los 50 CC 8 CC 16 4 0 0 -4 -4 -8 -8 * -12 -16 -16 -20 -20 n 85 83 82 Los 50 CC 8 CC 16 -12 * * Plac 84 * * * p<0.001 vs * plac Comparison of efficacy of ARBs and amlodipine in the treatment of mild and moderate hypertension Los 50 Amlo 10 Vals 80 0 0 -4 -4 mmHg -8 -8 -12 -12 Amlo 5 SP DP -16 -16 Irbe 75 - 300 CC 8 Amlo 10 Plac Amlo 2.5 - 10 0 0 -4 -4 mmHg -8 -8 -12 -12 -16 -16 Comparison of efficacy of ARBs and enalapril in the treatment of mild and moderate hypertension 0 Los 50 Enal 20 0 -4 -4 mmHg -8 -8 -12 -12 -16 -16 0 mmHg Vals 80 Enal 20 SP Irbe 75-300 Enal 10- 40 0 -4 -4 -8 -8 -12 -12 -16 -16 DP CC 4- 8 Enal 10-20 Comparison of efficacy of ARBs and hydrochlorothiazide in the treatment of hypertension Los 50 HCTZ 12.5 Vals 80 0 0 -4 -4 mmHg -8 -8 -12 -12 -16 -16 CC 8 HCTZ 25 0 -4 mmHg -8 -12 -16 SP DP HCTZ 25 Comparison of efficacy of ARBs and atenolol in the treatment of mild and moderate hypertension Los 50 Atenolol 50 0 0 -2 -2 -4 -4 mmHg -6 -6 Irbes Atenolol 75-150 50-100 -8 -8 -10 -10 -12 -12 -14 -14 SP DP Dijastolni P. Angiotensin receptor blockers and hypertension: meta-analysis Meta-analysis of CV events with ARBs vs comparators Blood Pressure Lowering Treatment Trialists’ Collaboration 4 trials; N = 16,791 1.2 1.0 Relative risk of event with ARB vs comparator 0.8 0.6 Stroke CHD Heart failure Major CV event BPLTTC. Lancet. 2003;362:1527-35. Efficacy vs. Tolerability AT1- Receptor Antagonists excellent Tolerability 50 % low Therapeutic Window DOSE Compliance With Antihypertensive Treatment at 1 Year * 64 Compliance at 1 Year (%) 65 60 58 55 50 50 45 40 35 0 43 38 Thiazide Diuretics Beta Blockers CCBs ACE Inhibitors ARBs ARBs: Evolution of protective benefits ARBs: Evolution of protective benefits s↓BP tifeneb ↓BP evitcetorp fo noitulovE :sBRA ↓Stroke ↓Stroke PB↓ ↓Heart failure ↓Heart failure ekortS↓ ↓Renal eruldysfunction iaf tdysfunction raeH↓ ↓Renal ↑Glycemic control noitcnufsyd lan eR↓↑Glycemic control lortnoc cimecylG↑ )?( DHC↓ ↓CHD (?) (?) ↓CHD Combination antihypertensive therapy and cardiovascular event rate: amlodipine and renin-angiotensin system blockade ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy 90 Control rate (%) 80 78.5 81.7 70 60 50 40 30 37.2 37.9 ACEI / HCTZ CCB / ACEI N=5733 N=5713 20 10 P<0.001 at 30 months follow-up Control defined as <140/90 mmHg Baseline Control Rates Kaplan Meier for Primary Endpoint Cumulative event rate ACEI / HCTZ 20% Risk Reduction 650 CCB / ACEI 526 p = 0 .0002 Time to 1st CV morbidity/mortality (days) HR (95% CI): 0.80 (0.72, 0.90) I Primary Endpoint and Components Risk Ratio (95%) Composite CV mortality/morbidity 0.80 (0.72–0.90) Cardiovascular mortality 0.81 (0.62-1.06) Non-fatal MI 0.81 (0.63-1.05) Non-fatal stroke 0.87 (0.67-1.13) Hospitalization for unstable angina 0.74 (0.49-1.11) Coronary revascularization procedure 0.85 (0.74-0.99) Resuscitated sudden death 1.75 (0.73-4.17) 0.5 Favors CCB / ACEI 1.0 2.0 Favors ACEI / HCTZ Clinical trials of RAAS manipulation with ARBs Diabetes and/or renal disease CAD/MI VALIANT OPTIMAAL Val-PREST RENAAL IDNT IRMA-2 ABCD-2V AMADEO DETAIL MARVAL Stroke SCOPE MOSES Hypertension VALUE SCOPE TROPHY LIFE CHF ELITE 1 and 2 Val-HEFT CHARM Dzau V. J Hypertens. 2005. Dahlof B. Am J Cardiol. 2007. Barnett AH et al. N Engl J Med. 2004. Bakris G et al. ASH 2007 Scientific Sessions. LIFE study • The Losartan Intervention For Endpoint reduction in hypertension study • Prospective, multinational, double-blind, controlled, random study, intention-to-treat study • 9.193 patients with hypertension and ecg signes of LVH • Losartan compared to atenololom Dahlöf B. et al, Lancet 2002.; 359:995-1003. LIFE: Losartan and atenolol reduced comparably blood pressure 180 Atenolol Losartan 160 Systolic mmHg 140 120 Mean arterial pressure 100 Diastolic 80 60 40 0 6 12 18 24 30 36 Duration (months) Dahlöf B et al Lancet 2002;359:995–1003. 42 48 54 LIFE: LVH Regression and Primary Endpoint 16 -2 14 -4 -6 12 4.4% 10 -8 9.0% -10 -12 -14 -16 -18 Composite of CV Death, Stroke and MI Sokolow-Lyon Voltage Proportion of Patients with First Event (%) Change from Baseline (%) Cornell Voltage-Duration Product 0 10.2% P < 0.0001 15.3% P < 0.0001 8 6 4 Adjusted Risk Reduction: 13.0%, P = 0.021 2 0 0 6 12 18 24 30 3642 48 5460 66 Months Atenolol Dahlöf B et al. Lancet. 2002;359:995-1003. Losartan LIFE – significant regression of LVH in comparison to baseline values Cornell Product Sokolow-Lyon Mean changes in the baseline values (%) 0 -2 -4 losartan 4.4 % -6 atenolol -8 -10 -12 -14 -16 -18 9.0 % 10.2 % p<0.0001 15.3 % p<0.0001 Reduction of left ventricular mass stratified according to various antihypertensive regimens reduction in left ventricular mass LV (%) 20 * 15 * ** 10 5 0 *p<0.05; **p<0.001 vs beta-blocker Diuretics Betablockers Calcium antagonist ACE inhibitors ARBs Klingbeil et al Am J Med 2003 Losartan reduces CV complications with equal antihypertensive efficacy % of patients with the first signes of hypertensive complications 16 14 Cardiovascula death, stroke and myocardial infarction miokarda Atenolol 13% 12 10 Losartan 8 6 4 2 Adjusted risk reduction Non-adjusted risk reduction 13.0%, p=0.021 14.6%, p=0.009 0 Months 0 No. of patients Losartan (n) 4605 with risk Atenolol (n) 4588 6 12 18 24 30 36 42 48 54 60 66 4524 4494 4460 4414 4392 4349 4312 4289 4247 4205 4189 4135 4112 4066 4047 3992 3897 3821 1889 1854 901 876 Dahlöf B i sur. Lancet 2002;359:995-1003. Losartan reduces more efectively stroke with equal antihypertensive efficacy Stroke with and without death % of patients with the first stroke 8 7 Atenolol 6 5 Losartan 4 3 2 1 Months Losartan Atenolol 25% Adjusted risk reduction 24.9%, p=0.001 Non-adjusted risk reduction 25.8%, p=0.0006 0 0 4605 4588 6 12 18 24 30 36 42 48 54 60 66 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897 Dahlöf B i sur. Lancet 2002;359:995-1003. Angiotensin receptor blockers and stroke risk MOSES: ARB surpasses CCB for secondary stroke prevention N = 1405 with HTN and prior cerebral event Primary composite outcome* Fatal/nonfatal CV events Fatal/nonfatal stroke -25 -25 P = 0.061 P = 0.026 0 -5 -10 RRR Eprosartan vs nitrendipine† (%) -15 -20 -25 -21 P = 0.014 -30 *Cerebrovascular, CV events, and all-cause death †Events per 100 person-years, including recurrent events Schrader J et al. Stroke. 2005;36:1218-26. Meta-analysis of CV events with ARBs vs comparators Blood Pressure Lowering Treatment Trialists’ Collaboration 4 trials; N = 16,791 1.2 1.0 Relative risk of event with ARB vs comparator 0.8 0.6 Stroke CHD Heart failure Major CV event BPLTTC. Lancet. 2003;362:1527-35. LIFE: New Onset Diabetes Intention-to-Treat 0.10 0.09 Atenolol Endpoint Rate 0.08 0.07 0.06 Losartan 0.05 0.04 0.03 0.02 Adjusted Risk Reduction 25%, p<0.001 Unadjusted Risk Reduction 25%, p<0.001 0.01 0.00 Study Day 0 180 360 540 B Dahlof et al. Lancet 2002;359:995-1003 720 900 1080 1260 1440 1620 1800 1980 Cardiovascular death, stroke and myocardial infarction in diabetics 24 Atenolol % of patients with the first onset of complications n= 139 (23%) 25% 20 16 Losartan n= 103 (18%) 12 8 4 Adjusted risk reduction = 24,5%; p=0,031 Non- adjusted risk reduction = 26,7%; p=0,017 0 Months 0 6 Losartan (n) 586 569 Atenolol (n) 609 588 12 558 562 18 548 552 24 532 540 30 520 527 LH Lindholm, et al Lancet 2002; 359:1004-1010 36 513 507 42 501 486 48 484 472 54 459 434 60 237 204 66 127 99 LIFE: Diabetes Subgroup (n = 1195) Total Mortality Proportion of patients, % (secondary endpoint) 24 (from Lindholm LH et al., Lancet 359: 1004-1010, 2002) 20 Atenolol RRR 16 39% 12 p = 0.002 Losartan 8 4 0 0 6 12 18 24 30 36 42 Study Month 48 54 60 66 The role and importance of Losartan in the treatment of diabetic nephropathy with proteinuria Effect of ACE Inhibition on Nephropathy in Patients with Type 1 Diabetes 40 Captopril Placebo Progression to death, dialysis or transplant (%) 30 20 * 10 0 0 Collaborative Study Group * p = 0.006 vs placebo. 1 2 Follow-up (y) 3 4 Lewis EJ et al. N Engl J Med 1993;329:1456-1462. Effect of BP Reduction vs ACE Inhibition on Proteinuria and Renal Function in Patients with Diabetes Meta-regression analysis of 100 studies totaling 2,494 patients with type 1 and type 2 diabetes. * p < 0.05 vs calcium channel blockers. † p < 0.05 vs control. Kasiske BL et al. Ann Intern Med 1993;118:129-138. Renal protection beyond RR ? DHP- Ca Antag. Other drugs Risk ESRF ACEI or ARB RR DHP- Ca Antag ACEI or ARB Dilation of efferent artheriole RR Dilation of afferent arteriole RR Ang II Intraglomerular pressure may stay unchanged Ang II Reduction of intraglomerular pressure Studies with ARBs in diabetics RENAAL (Reduction in Endpoints in NIDDM with Angiotensin II Antagonist Losartan) IDNT (Irbesartan in Diabetic Nephropathy Trial) IRMA2 (Irbesartan Micro-Albuminuria type 2 diabetes mellitus in hypertensive patients RENAAL study The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study Brenner BM et al. N Engl J Med 2001; 345(12):861-869. Brenner BM et al J Renin-Angio-Aldo System 2000;1(4):328-335. RENAAL Progression of renal disease p=0.01 18% reduction dl/mg/year -.08 -.06 -0.069 -0.056 -.04 -.02 0 Losartan Brenner BM et al New Engl J Med 2001 ;345(12):861-869. Placebo RENALL – Results Patients in the losartan group had a reduction in proteinuria of 35%, while the patients in the placebo group had an increase in proteinuria (P=<0.001) Brenner et al. NEJM. 2001. RENALL – Conclusions • Losartan has renoprotective effects by reducing risk of doubling creatinine AND by reducing progression to ESRD • Losartan reduces episodes of CHF • Effects reported as independent of blood pressure ARBs decrease renal complications in T2DM T2DM (N) Treatment IRMA-2 Microalbuminuria (590) Time to nephropathy: Irbesartan 150/300 mg vs 39% (150 mg, P = 0.08) placebo 70% (300 mg, P < 0.001) IDNT Nephropathy (1715) Irbesartan/ amlodipine/ placebo ESRD/ Cr 2/mortality: 20% vs placebo (P = 0.02) 23% vs amlodipine (P = 0.006) MARVAL Microalbuminuria (332) Valsartan/ amlodipine UAER at 24 weeks: 44% valsartan vs 8% amlodipine (P < 0.001) RENAAL Nephropathy (1513) Losartan/ placebo ESRD/Cr 2 /all deaths: 16% vs placebo (P = 0.02) Cr = creatinine UAER = urinary albumin excretion rate Primary outcome Adapted from Sharma AM. Hypertension. 2004;44:12-19. Combination treatment • ACEI+ARB: different mechanisms of action make combination treatment useful owing to complete RAS blockade, CALM (Candesartan And Lisinopril Microalbuminuria study) Objectives: To assess and compare the effects of candesartan or lisinopril, or both, on blood pressure and urinary albumin excretion in patients with microalbuminuria, hypertension, and type 2 diabetes Design: 12 weeks' monotherapy with candesartan or lisinopril followed by 12 weeks' monotherapy or combination treatment 199 patients aged 30-75 years Candesartan 16 mg od or lisinopril 20 mg Outcome: Blood pressure and urinary albumin:creatinine ratio CALM Mean difference at week 24 Candesartan Lisinopril Sitting DBP (mm Hg) 10.4 Combination 10.7 16.3 p=0.005 p=0.003 Sitting SBP (mm Hg) 14.1 16.7 p=0.02 25.3 39 p>0.20 50 p=0.002 Urinary albumin/ creatinine ratio (%) Mogensen et al. BMJ 321; 1440 24 p=0.04 CALM • Conclusions – Candesartan 16 mg od has similar effect to lisinopril on BP and microalbuminuria in hypertensive patients with type 2 diabetes – Combination treatment ACEI+ARB is more effective than either monotherapy at reducing BP and urinary albumin/creatinine ratio Mogensen et al. BMJ 321; 1440 Pharmacokinetic differences between angiotensinconverting enzyme inhibitors and angiotensin receptor blockers in renal failure Parameter ACE inhibitors Angiotensin receptor antagonists Proteinuria ↓↓ ↓↓ Uric acid ↓ ↓↓ Glomerular filtration rate ↓↓ ↓↓ Hyperkalemia ↑↑ ↑ Blood pressure reduction ↓↓ ↓↓ Systemic accumulation Yes No AT2-receptor stimulation Possibly ↑↑ Renal and Pharmacokinetic Aspects of ACE Inhibitor and Angiotensin Receptor Antagonist Therapy in End-stage Renal Disease Parameter ACE inhibitors Angiotensin receptor antagonists Angioneurotic edema Yes Yes, but much less frequently Dialyzer reactions Yes No Residual renal function ↓↓ ↓↓ Dialyzability Yes No Hyperkalemia ↑↑ ↑↑ Blood pressure reduction ↓↓ ↓↓ Systemic accumulation Yes No AT2-receptor stimulation Possibly ↑↑ Landmark studies with ACEI and ARBs and clinical significance of RAAS blockade in hypertension, coronary disease, MI and heart failure ACEI in post-MI > 100 000 patients ! Reduction of mortality (%) 35 29 30 27 22 25 19 20 12 15 10 7 5 0 ISIS-4 GISSI-3 SMILE SAVE TRACE AIRE ACEI in early phase AMI • ACE inhibitors achieve a modest but statistically significant reduction in mortality ( 6% to 11%). Best results are obtained in higher risk patients treated long term, such as those with large infarcts, in whom ACEI give a striking reduction of 26% in mortality ACE Inhibitors • ACEI in patients with heart failure reduce – morbidity – mortality • ACEI in sedondary prevention of MI reduce – – morbidity – mortality - development of HF Studies: CONSENSUS, SOLVD, SAVE, AIRE, ISSIS-4 ARBs and chronic heart failure ® Studies of ARBs in chronic heart failure ELITE ELITE II Val-HeFT CHARM ELITE study • Application of 50 mg losartan, in comparison with captopril, in patients with heart failure reduced mortality by 46% and sudden cardiac death by 64% ARBs and heart failure • ARBs have been tested in an era when ACE inhibitors were already the established therapy of choise for heart failure. Had the ARBs come earlier, they would probably have been first choise. Combination therapy with ACE inhibitors and ARB • Adding the ARB to the ACEI gave better results in more severe heart failure with the mean ejection fraction about 25% (ValHeFT and CHARM trials). In diabetes and diabetic renal disease, the combination is advised when monotherapy fails to reduce proteinuria sufficiently. Indication and evidence for combining ACEI and ARB Indication Indication for dual RAS inhibition Hypertension Not standard, possibly in LVH, microalbuminuria, DM Systolic heart failure Yes, when symptoms persist despite diuretic, beta blocker, and ACEI Post myocardial infarction No Nephroprotection (diabetics) Yes Nephroprotection (non -diabetics) Da ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial The telmisartan trial in cardiovascular protection Sponsored by Boehringer Ingelheim Indication and evidence for combining ACEI and ARB Indication Indication for dual RAS inhibition Hypertension Not standard, possibly in LVH, microalbuminuria, DM Systolic heart failure Yes, when symptoms persist despite diuretic, beta blocker, and ACEI Post myocardial infarction No Nephroprotection (diabetics) Yes Nephroprotection (non -diabetics) Yes Less new diabetes • An important finding with ACE inhibitors and ARBs, especially when compared with beta blockers or diuretics, is the decreased developement of new diabetes. Effect of ACEIs and ARBs on new-onset diabetes Meta-analysis: 12 randomized controlled trials; N = 72,333 patients without T2DM at baseline Less likely to develop T2DM More likely to develop T2DM CAPPP STOP-2 HOPE LIFE ALLHAT ANBP2 SCOPE ALPINE CHARM SOLVD VALUE PEACE All pooled ACEI pooled ARB pooled 0.125 0.25 0.5 Relative risk (95% CI) 1 2 Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6. New-onset diabetes rate reduced by reninangiotensin-aldosterone system modulation Risk of new-onset diabetes in hypertension: comparison of antihypertensive drug classes Drug related new diabetes Inhibitors of renin-angiotensinaldosterone system • Several analyses of retrospective clinical trials suggest benefit of ACE inhibitors or AT1 blockers in prevention of atrial fibrillation, especially in patients with left ventricular hypertrophy or dysfunction. Atrial Fibrillation (AF) - Primary Prevention • In 2007 ESH / ESC guidelines recommendation to preferentially use ARBs / ACEIs • Evidence mainly from post-hoc analyses Atrial Fibrillation • In a meta-analysis on almost 12.000 patients with systolic HF BBs were found to reduce (-27%) AF • In patients with an AF history and systolic HF BBs are a specific indication Angiotensin receptor blockers in atrial fibrillation: losartan versus atenolol Pleiotropic effects of renin-angiotensin system blockers Inhibitors of renin-angiotensinaldosterone system • Plasma aldosterone concentracions increase in patients with atrial fibrillation and atrial expression of the aldosterone receptor is higher in these patients than in those without the disorder. Inhibitors of renin-angiotensinaldosterone system • Patients with primary hyperaldosteronism have a 12-fold greater risk of atrial fibrillation than do controls matched for blood pressure. Inhibitors of renin-angiotensinaldosterone system • Hence blockade of aldosterone receptors could be a therapeutic option for patients with atrial fibrillation, but data from trials are not available.