• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
UPDATES OF RENIN ANGIOTENSIN SYTEM INTERVENTION
 

UPDATES OF RENIN ANGIOTENSIN SYTEM INTERVENTION

on

  • 1,227 views

RENIN ANGIOTENSIN SYSTEM

RENIN ANGIOTENSIN SYSTEM

Statistics

Views

Total Views
1,227
Views on SlideShare
1,227
Embed Views
0

Actions

Likes
0
Downloads
91
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Available from: URL:http://www.endocrinetoday.com/view.aspx?rid=50284. Accessed on 25 th march, 2010
  • The CHARM and VALIANT studies have substantially increased our knowledge on the role of ARBs in patients with HF and post-MI LV dysfunction. 1 Results from both studies support previous findings that ARBs are a good alternative to ACE inhibitors in the minority of patients who cannot tolerate ACE inhibitors, both after acute MI and in HF. ARBs consistently reduced HF hospitalizations in CHARM and VALIANT, as was also shown in Val-HeFT. Whereas no effect on all-cause mortality was demonstrated in either Val-HeFT or VALIANT, a reduction in CV mortality was shown in CHARM. 1 1. Voors AA, van Veldhuisen DJ. Role of angiotensin receptor blockers in patients with left ventricular dysfunction: Lessons from CHARM and VALIANT. Int J Cardiol. 2004;97:345-348.
  • This slide summarizes questions and answers before and after the CHARM and VALIANT studies about the role of ARBs in patients with LV dysfunction. 1 ARBs superior to ACE inhibitors? There is no evidence that ARBs are superior to ACE inhibitors, either in acute MI or HF; however when adequately dosed, ARBs may be equivalent to ACE inhibitors. ARBs non-inferior to ACE inhibitors? It is now well established that an ARB is a good alternative for the ACE inhibitor, both in CHF and in acute MI with signs of HF or LV dysfunction. ARBs additive on top of ACE inhibitors? VALIANT showed that in patients with acute MI, adding an ARB to an adequate-dose ACE inhibitor has no benefit. In contrast, CHARM showed that in patients with chronic HF, adding an ARB to an ACE inhibitor (and a beta-blocker) might reduce CV mortality. Moreover, a reduction in HF hospitalizations can be anticipated in both HF and after acute MI. Is the combination of ARB, ACE inhibitor, and beta-blocker dangerous? No, it is not. However, the benefits of triple therapy might be less pronounced following adequate and high doses of both the ACE inhibitor and beta-blocker. 1. Voors AA, van Veldhuisen DJ. Role of angiotensin receptor blockers in patients with left ventricular dysfunction: Lessons from CHARM and VALIANT. Int J Cardiol. 2004;97:345-348.
  • Clinical Overview of Benicar and Benicar HCT
  • There is strong evidence from outcomes studies that ARBs slow the progression of kidney disease in type 2 diabetes. Studies of patients with type 2 diabetes treated for various treatment periods with losartan, ibesartan ,or valsartan show risk reduction in CVS or renal endpoints. References Kopyt NP. Slowing progression along the renal disease continuum. JAOA. 2005;105(4):207–15. RENAAL: Brenner BM, et al, for the RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9. IDNT: Lewis EJ, et al, for the 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;345:851–60. IRMA-2: Parving HH, et al, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8. MARVAL: Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672 – 8. LIFE: Dahlöf B, 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. DIRECT: Sjolie AK, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet. 2008;372:1361–3.

UPDATES OF RENIN ANGIOTENSIN SYTEM INTERVENTION UPDATES OF RENIN ANGIOTENSIN SYTEM INTERVENTION Presentation Transcript

  • RAAS INHIBITIONNEWER MOLECULES AND TRIALS
  • POINTS FOR DISCUSSION• NEWER UNDERSTANDING IN THE RAAS• RECENT LAND MARK TRIALS• NEWER MOLECULES• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION
  • ANGIOTENSIN II – CENTRAL ROLE High CV Risk Post MI RemodellingHypertension Ventricular dilation/ cognitive dysfunction Myocardial infarction & Congestive heart failure/ stroke secondary stroke Heart Failure Micro- Macro- albuminuria proteinuria Atherosclerosis End-stage and LVH heart disease, Endothelial Nephrotic brain damage dysfunction proteinuria and dementia End-stage Cardio/ Hypertension risk factors renal cerebrovascular diabetes, obesity, elderly disease death Adapted from Dzau V. and Braunwald E., Am Heart J 1991;121:1244–1263
  • CURRENT VIEW
  • NEW CONCEPTS• PRO-RENIN• LOCAL RENINS• EXTRA RENAL RAS• INTRA CELLULAR RAS• ACE 2• AT 2 RECEPTORS• CHYMASE PATHWAYS• MAS RECEPTOR AXIS
  • POINTS FOR DISCUSSION• NEWER UNDERSTANDING IN THE RAAS• SOME LAND MARK TRIALS• NEWER MOLECULES• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION
  • AT1-Receptor Blocker (ARB) Clinical Outcome Studies HBP VASCULAR MI HF LIFE (ONTARGET) OPTIMAAL ELITE II SCOPE (TRANSCEND) VALIANT Val-Heft VALUE JIKEI CHARM (I-PRESERVE)PRE-DIABETES DIABETES DIABETES RENAL(NAVIGATOR) OPTHAL (DIRECT) RENAAL ATRIAL FIB IDNT (ACTIVE)
  • Current Trial Programmes Cover the Largest Population of CV High Risk Patients High CV Risk HOPE, EUROPA, Post MI PEACE, QUIET SAVE AIRE; TRACE ONTARGET OPTIMAL, TRANSCEND VALIANT PROfESS Remodelling Heart Failure Ventricular dilation/ CHARM, ValHeFT cognitive dysfunction EPHESUS MyocardialHypertension infarction & Congestive heart failure/ LIFE etc stroke secondary stroke Micro- Macro-73 million* albuminuria proteinuria Atherosclerosis End-stage and LVH heart disease, Endothelial Nephrotic brain damage dysfunction proteinuria and dementia End-stage Cardio/ Hypertension risk factors renal cerebrovascular diabetes, obesity, elderly disease death Summary: Reduction of Neuroendocrine Activation by Target Doses
  • Major Studies in RAS-Inhibition0.25 (HOPE Composite) Global Protection0.20 HOPE Placebo ONTARGET Ramipril Telmisartan0.15 Placebo Telmisartan/Ramipril Ramipril Telmisartan0.10 TRANSCEND0.050.00 0 360 720 1080 1440 1800 2160 Days of follow-up AS-as7-0908
  • Major Studies in RAS-Inhibition0.25 (HOPE Composite)0.20 HOPE Placebo ONTARGET Ramipril Telmisartan0.15 Placebo Telmisartan/Ramipril Ramipril Telmisartan0.10 TRANSCEND0.05 Unmet medical need0.00 0 360 720 1080 1440 1800 2160 Days of follow-up AS-as7-0908
  • RECENT Studies of Olmesartan in Diabetes
  • ROADMAP(RANDOMISED OLMESARTAN AND DIABETES MICROALBUMINURIA PREVENTION STUDY)
  • Benefit of ARB + ACE inhibitor in HF HF hospitalization All-cause mortality ARB+ ACEI ARB+ ACEI ACEI better alone better ACEI better alone better CHARM (HF) VALIANT (post MI + HF/LV dysfunction) Val-HeFT (HF)0.6 0.8 1.0 1.2 1.4 0.6 0.8 1.0 1.2 1.4 Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.
  • ARBs in LV dysfunction: Before/after CHARM and VALIANT Before After CHARM, VALIANT CHARM, VALIANTARBs superior to ACEI? No (ELITE II, OPTIMAAL) NoARBs non-inferior to ACEI? ? (ELITE II, OPTIMAAL) YesARBs additive on top Yes, HFof ACEI? ? (Val-HeFT) No, post-MICombination ARB, ACEI, and β-blocker dangerous? ? (ELITE II, Val-HeFT) No Voors AA, van Veldhuisen DJ. Int J Cardiol. 2004;97:345-8.
  • POINTS FOR DISCUSSION• NEWER UNDERSTANDING IN THE RAAS• SOME LAND MARK TRIALS• NEWER MOLECULES• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION
  • NEW THERAPEUTIC APPROACHES 1. RENIN INHIBITION 2. ACE INHIBITION 3. AT1R BLOCKADE 4. AT2R STIMULATION 5. (P)RR BLOCKADE – ANGIOTENSIN-INDEPENDENT SIGNALING 6. NEP INHIBITION – COMBINED VASOPEPTIDASE (NEP PLUS ACE) INHIBITION 7. ALDOSTERONE-RECEPTOR BLOCKADE OR ALDOSTERONE-SYNTHASE INHIBITION 8. NO–CGMP STIMULATION Nat. Rev. Cardiol. 7, 431–441 (2010)
  • NEWER RAS INHIBITORS ON THE WALL Nat. Rev. Cardiol. 7, 431–441 (2010);
  • DIRECT RENIN INHIBITORS 1980 -INTRODUCED PEPSTATIN - THE FIRST SYNTHETIC RENIN INHIBITOR BUT REQUIRED PARENTERAL ADMINISTRATION. ORAL AGENTS : ENALKIREN, REMIKIREN, AND ZANKIREN HAD LIMITED CLINICAL USE POOR BIOAVAILABILITY (<2%) SHORT HALFLIVES WEAK ANTIHYPERTENSIVE ACTIVITY .
  • ALISKIREN OCTANAMIDE, NEW CLASS NONPEPTIDE, LOW MOLECULAR WEIGHT, ORALLY EFFECTIVE AT A DOSE OF 300 MG DECREASES PRA BY 50–80% THE PLASMA HALF-LIFE OF 23–70 HOURS
  • ALISKIREN METABOLISM BY CYTOCHROME P450 (CYP3A4) NO CHANGE OF DOSE IN HEPATIC AND RENAL INSUFFICIENCY ADVERSE EVENTS : DIARRHEA, HEADACHE, NASOPHARYNGITIS, DIZZINESS, FATIGUE, BACK PAIN, GASTROINTESTINAL DISORDERS, RASH, AND RENAL STONE ,COUGH AND ANGIOEDEMA
  • ALSKIREN -TRAILS
  • ALSKIREN -TRAILSATMOSPHERE- ACUTE & CHRONIC CCF
  • VASOPEPTIDASE INHIBITORS• KNOWN DRUGS OMAPATRILAT, SAMPATRILAT – TRIALS: OVERTURE AND OCTAVE – EFFECTIVE IN THE TREATMENT OF HYPERTENSION AND HEART FAILURE – ?ANGIOEDEMA Nat. Rev. Cardiol. 7, 431–441 (2010);
  • ALDOSTERONE ANTAGONISM
  • ALDOSTERONE-SYNTHASE INHIBITORS• NONINFERIOR TO AND BETTER TOLERATED• EFFICACY IN CONDITIONS WITH LOW ALDOSTERONE LEVELS ?• FAD286 (NOVARTIS; BASEL, SWITZERLAND), – AN ENANTIOMERE OF FADRAZOL(CYP11B2) – LOWERED BLOOD PRESSURE IN RATS OVER EXPRESSING RENIN AND ANGIOTENSINOGEN – AMELIORATED CARDIAC AND RENAL TARGET-ORGAN DAMAGE• SPP2745 (SPEEDEL PHARMACEUTICALS; BASEL, SWITZERLAND) – GOOD SPECIFICITY, – PROTECTION TO THE CARDIAC, RENAL, AND VASCULAR SYSTEMS – COMPATIBLE WITH CONVENTIONAL RX
  • CALCIUM CHANNELBLOCKERS AS RASINHIBITORS
  • CALCIUM CHANNEL BLOCKERS
  • RECENT EVOLUTION OF DUAL AND TRIPLE COMBINATIONS.
  • In 2009, the US Food and Drug Administrationapproved the fixed combination ofaliskiren/valsartan at the dosages of 150/160mg and 300/320 mg for the treatment ofhypertension in patients not adequatelycontrolled on aliskiren or ARB monotherapyand as initial therapy in patients likely to needmultiple drugs to achieve their BP goals
  • POINTS FOR DISCUSSION• NEWER UNDERSTANDING IN THE RAAS• RECENT LAND MARK TRIALS• NEWER MOLECULES• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION
  • SECONDARY END POINT QUALITATIVE DATA OF BLINDED ONE-YEAR BLOOD PRESSURE REDUCTIONKey Message:OLMESARTAN CONFERRED VASCULAR PROTECTION BY DELAYING THEOCCURRENCE OF MICROALBUMINURIA (RISK REDUCTION OF 23%) ANDCONTROLLING BLOOD PRESSURE IN PATIENTS WITH TYPE 2 DIABETES American Society of Nephrology Oct, 30th 2009
  • Impact of OLmesarten onOLIVUS progression ofTRIAL coronary atherosclerosis: evaluation by IntraVascularOlivus study provides confirmation that UltraSoundOlmesartan can retard progression ofcoronary atherosclerosis, theunderlying cause of heart diseaseJ Am Coll Cardiol 2010;55:976–82
  • OLIVUS TRIAL : IVUS ANALYSISRepresentative Serial Volumetric IVUS Analysis in the Control Group(A) Baseline intravascular ultrasound (IVUS); (B) 14-month follow-up. J Am Coll Cardiol 2010;55:976–82
  • OLAS• The OLAS study was performed to assess whether combination therapy with OLM/AML was beneficial for markers of metabolic dysfunction J Hypertension 2008; 26 Suppl. 1: 331.
  • OLAS-RESULTS OLM/AM 20/5 L OLM/AM 20/5 or 40/10 LChange from baseline BP (mmHg) Week 13 Week 26 0 -2 -4 -6 -8 -7.9 -10 * -12 -11.2 -14 -12.6 ** ** -16 -18 -20 -19.3 *** * P<0.01, ** P<0.005, *** P<0.001, vs baseline. Martinez-Martin ICTHD 2008.
  • OLAS-CHANGE IN INFLAMMATORY MARKERS T Fα N hsCRP ICAM-1 VCAM-1 IL6 IL8 0 Change from baseline (%) -5 -10 -9.4 * -12.3 -15 * -15.7 -15.5 -16.9 * * -20 * -25 -24.4 † *P<0.05 vs baseline †P<0.01 vs baseline. Martinez-Martin ICTHD 2008.Change in inflammatory markers after 26 weeks’ treatment witholmesartan/amlodipine.
  • ARBS SLOW PROGRESSION OF KIDNEY DISEASE IN TYPE 2 DIABETESTrial Patients (n) Treatment Duration Endpoint Risk reduction (all p≤0.05)RENAAL DM, Losartan vs 3.4 y Composite: 2x serum cr 15% risk ↓ in comp nephropathy PBO conc, ESRD, death endpoint (1513)IDNT HTN, DM, Irbesartan vs 2.6 y Composite: 2x serum cr 24% risk ↓ comp nephropathy amlodipine vs conc, ESRD, death endpoint (1715) PBOIRMA-2 HTN, DM, MA Irbesartan vs 2y Time to new-onset 39–70% risk ↓ (590) PBO diabetic nephropathyMARVAL DM, MA (332) Valsartan vs 24 wk % Δ urinary baseline 44% risk ↓ with PBO albumin excretion rate valsartanLIFE ≥55 y + HTN, Losartan vs 4.8 y CVS death, MI or stroke, Up to 25% risk ↓ of LVH (9193) atenolol DM CVS endpoints, 25% risk ↓ of DMDIRECT DM, Candestan vs 4.7 y Progression of 13% risk ↓in retinopathy PBO retinopathy progression (ns), (1905) ↑ regressionAll studies reviewed by Kopyt NP. JAOA. 2005;105(4):207–15. exceptDIRECT, Sjolie AK, et al. Lancet. 2008;372:1361–3.
  • NEWER HF TRIALS • EMPHASIS HF TRIAL • ATMOSPHERE TRIAL
  • PARADIUM-HF • PARADIGM-HF – SAFETY AND EFfiCACY OF LCZ696 COMPARED TO ENALAPRIL. – NEUTRAL ENDOPEPTIDASE INHIBITOR ADDED TO AN ARB – AVOID THE SHORTCOMINGS OF OVERTURE STUDY • LONGER HALF-LIFE • TWICE A DAY • ARB INSTEAD OF AN ACEI • LITTLE RISK OF ANGIOEDEMA
  • POINTS FOR DISCUSSION• NEWER UNDERSTANDING IN THE RAAS• RECENT LAND MARK TRIALS• NEWER MOLECULES• NEWER TRIALS• FUTURE ADVANCES• CONCLUSION
  • AT2R AGONISTS: STIMULATING THE RAAS • MORE PRONOUNCED IN PATHOLOGICAL CONDITIONS WHERE AT2R DENSITY IS INCREASED. COMPOUND 21 – SELECTIVE AT2R AGONIST – ORAL BIOAVAILABILITY OF 20–30% – ↑ SYSTOLIC AND DIASTOLIC FUNCTION AFTER MI IN RATS – ANTI-INFLAMMATORY AND ANTIAPOPTOTIC ACTION – ACUTE INFUSION OF ↓ BLOOD PRESSURE – INHIBITS NUCLEAR FACTOR KAPPA B, ACTIVATES PROTEIN PHOSPHATASES, AND REDUCES THE EXPRESSION OF THE INFLAMMATORY CYTOKINES – POSSIBLE BENEFITS in MYOCARDIAL FIBROSIS, ATHEROSCLEROSIS, MYOCARDIAL INFARCTION, OR MYOCARDITIS
  • PRO-RENIN Preprorenin >>>prorenin >>> renin sequential cleavage of the N-terminal 20 and 46 amino acids of preprorenin kidney also releases unprocessed pro-renin via a constitutive pathway prorenin accounts for about 70% to 90% of the immunoreactive renin
  • (PRO)RENIN RECEPTOR: NEW POSSIBILITIES• ANGIOTENSIN- INDEPENDENT EFFECTS, CONTROLLED THROUGH THE BINDING OF RENIN TO THE NEWLY DISCOVERED (P)RR• REDUCED NEPHROPATHY IN DIABETIC RATS, AND CARDIAC FIBROSIS IN HYPERTENSIVE RATS• A NONPEPTIDE INHIBITOR OF (P)RR  RAAS INHIBITION WITH SIMULTANEOUS BLOCKADE OF ANGIOTENSIN-INDEPENDENT PRORENIN EFFECTS• PARTICULARLY BENEFICIAL IN HIGH-RISK PATIENTS
  • ACE 2 ACTIVATORS XNT
  • Ang-(1-7) FORMULATIONS• UNFAVOURABLE PHARMACOKINETICS• SYNTHETIC MAS RECEPTOR AGONISTS- AVE 0991
  • CHYMASES INHIBITORS
  • • THIS STUDY SHOWED - CHYMASE INHIBITION (TEI-F00806) MAY PROTECT AGAINST ELEVATED INTRARENAL ANGIOTENSIN II LEVELS, OXIDATIVE STRESS, AND RENAL DYSFUNCTION IN DIABETES.• CHYMASE OFFERS A NEW THERAPEUTIC TARGET FOR DIABETIC NEPHROPATHY
  • ANTIANGIOTENSIN VACCINES• ANTI-ANGIOTENSIN I VACCINE---- PMD3117 – SOME EVIDENCE FOR RAAS BLOCKADADE• CYT006, – ANTI-ANGIOTENSIN II ANTIGENIC PEPTIDE CONJUGATED TO A VIRUS-LIKE PARTICLE – LOWERED SBP BY UP TO 21 MMHG IN SPONTANEOUSLY HYPER TENSIVE RATS AND – WAS WELL TOLERATED IN A PHASE I STUDY – MODEST BLOOD PRESSURE REDUCTION (9/4 MMHG) IN A PHASE IIA STUDY Tissot, A. C. et al. effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet 371, 821–827 (2008).
  • GENE-BASED THERAPIES OVEREXPRESSION OF ACE2 AND AT2R DELIVERED IN VIRAL VECTORS REDUCED CARDIAC REMODELLING. ? SAFETY AND RELIABILITY
  • CONCLUSIONS• THE SCIENCE AND ART OF OPTIMAL,EFFECTIVE AND PATIENT FRIENDLY “RASS INHIBITION” STRATEGIES ARE STILL EVOLVING• WE SHOULD HOPE FOR BETTER AND SAFER MOLECULES THAN THE EXISTING ONES IN NEAR FUTURE