Σσνδσαζμός ανηι-σπερηαζικών θαρμάκων ποσ δροσν ζηο ζύζηημα ρενίνης-αγγειοηενζίνης-αλδοζηερόνης.
Ρήγαο Καιαϊηδίδεο Νευρολόγος - Επιμελητής A΄ Νευρολογική Κλινική Πανεπιστημιακού Νοσοκομείοσ Ιωαννίνων
5o θερινό σεμινάριο αθηροσκλήρωσης, Ιούλιος 2012
Δνκή παξνπζίαζεο • Σν ζύζηεκα ξελίλεο -αγγεηνηελζίλεο-αιδνζηεξόλεο • πλδπαζκόο αληηππεξηαζηθώλ θαξκάθωλ πνπ δξνπλ ζην ζύζηεκα ξελίλεο-αγγεηνηελζίλεο-αιδνζηεξόλεο. • Κιηληθέο κειέηεο κε πξωηεύνληεο θαξδηαθνύο ζηόρνπο
• Κιηληθέο κειέηεο κε πξωηεύνληεο λεθξηθνύο ζηόρνπο • πκπεξάζκαηα
Renin generates Ang I which is converted to Ang II by ACE Arteries Ang I
Ang II
Angiotensinogen Adrenal gland
Renin
Na+
Na+
Na+ retention
Aldosterone
Na+
Na+
Kidney
Chronic activation of the renin system contributes to end-organ damage Atherosclerosis Vasoconstriction Vascular hypertrophy Endothelial dysfunction
Stroke
Hypertension
↑Ang II
Ang, angiotensin MI, myocardial infarction
Hypertrophy Fibrosis Remodelling Cell death
Heart failure MI
↓Glomerular filtration rate Proteinuria ↑Aldosterone release Glomerular sclerosis
Renal failure
Death
Adapted from Anderson, Goodfriend, and Phillips In: Hypertension Primer, 2003.
Local tissue Renin-Angiotensin Systems (RAS) are activated in a numbers of diseases Brain 1, 2
Pituitary Gland 1, 2
Eye 9 ↑ in diabetes Aorta 10 ↑ in atherosclerosis
Adipose Tissue 3, 4 ↑ in obesity, hypertension Adrenal Glands
Kidney 5-7 ↑ in diabetes, membranous nephropathy
Heart 11-13 ↑ in diabetes, post-MI, failing ventricle Pancreas 14 ↑ in diabetic nephropathy Reproductive system 1, 2
Vasculature 8 ↑ in atherosclerosis
Carey and Siragy. 2003; 2 Lavoie and Sigmund. 2003; 3 Faloia et al. 2002; 4 Vega. 2004; 5 Hollenberg et al. 2003; 6 Mezzano et al. 2003a; 7 Mezzano et al. 2003b; 8 Dzau. 2001; 9 Strain and Chaturvedi. 2002; 10 Arakawa and Urata. 2000; 11 Frustaci et al. 2000; 12 Danser et al. 1997; 13 Hokimoto et al. 1996; 14 Leung and Chappell. 2003. 1
Circulating and local tissue renin systems have different effects on the CV system Circulating RS Short-term effects
Circulating +Tissue RS ACE
Non ACE pathways
Long-term effects
Intraglomerular hypertension
Na+/H2O reabsorption via aldosterone secretion
Ang II
Vascular hypertrophy
Vasoconstriction Myocardial hypertrophy
Modified from: Dzau VJ. 1993
The Renin-angiotensin-aldosterone System (RAAS) is Involved Throughout the Cardiovascular Continuum
Ventricular Remodelling
Ventricular Dilation
Myocardial Infarction Heart Failure Atherosclerosis and LVH
Risk factors Diabetes Hypertension
End-stage Heart Disease
RAAS activation Angiotensin II
Death
LVH = left ventricular hypertrophy Adapted from Dzau V. J Hypertens Suppl 2005;23:S9–17
H αλαζηνιή ηνπ ζπζηήκαηνο RAS •
•
ACE Inhibitors • ARBs Renin inhibitors • b-blockers
2008
Renin Inhibitors
Αλαζηνιείο ηεο ξελίλεο
ACEIs Αλαζηνιείο ηεο Αιδνζηεξόλεο ARBs
πλδπαζκνί θαξκάθωλ γηα ηελ αλαζηνιή ηνπ RAAS
Summary of Guidelines/Position Papers for Goal Blood Pressure in People with Kidney Disease or Diabetes from Various Consensus Committees around the World
Κhosla N, Kalaitzidis R et al Med Clin North Am 2009
ACE Inhibitors & ARBs
The additive effect of the dual blockade on BP control has been shown to be less than that attained by either drug combined with a diuretic or a calcium channel blocker Expert Opin. Pharmacother. (2010) 11(16)
Κιηληθέο Μειέηεο κε πξωηεύνληεο θαξδηαθνύο ζηόρνπο κε ζπλδπαζκό θαξκάθωλ πνπ αλαζηέιινπλ ηνλ άμνλα
Additive Effect of ACE Inhibition and Angiotensin II Receptor Blockade in Type I Diabetic Patients with Diabetic Nephropathy
20 patients, 8 weeks Benazepril 20 mg Valsartan 80 mg Dual
SBP: -6, -7 mmHg DBP: -7 mmHg
-65%
-65%
Additional -43% -80%
Jacobsen P et al. J Am Soc Nephrol 2003; 14: 992-9
Hypertension. 2005;45:880-886;
Hypertension. 2005;45:880-886;
•
The results of this meta-analysis suggest that the combination of an ACEI and ARB reduces BP by 4/3 mm Hg when compared with an ACEI or ARB administered as monotherapy. Hypertension. 2005;45:880-886
CHARM study :An ARB may provide added benefit, at acceptable risk, in HF patients already taking spironolactone as well as an ACE-I and beta blocker.
Weir et al. European Journal of Heart Failure 10 (2008) 157–163
The effect of combination of the 2 drugs on LVH is similar to that of ramipril alone.
Circulation. 2009; 120:1380-1389.
•
•
•
Rate of co-prescribing of ACEIs and ARBs per 1000 GMS population (A) from January 2000 to April 2009, (B) according to gender from January 2000 to April 2009 and (C) according to different age groups from January 2000 to April 2009,with intersections representing four major trials. (B) Rate/1000 Males GMS (—); Rate/1000 Females GMS (– –); Rate/1000 aged 16–44 years GMS (—); (C) Rate/1000 aged 45–64 years GMS (– –); Rate/1000 aged >65 years GMS .
Wan et al BJCP:71:3:458-466, 2010
Atherosclerosis 221 (2012) 18– 33
Journal of Cardiovascular Pharmacology and Therapeutics 2012, 00(0) 1-7
Effect of single or dual blockade of renin-angiotensin system in acute myocardial infarction patients according to renal function
窶｢
The incidence of composite of MACEs was significantly higher in the combination group and the control group than in the ACEI group (17.3% vs. 11.7%, pb0.001, 16.9% vs. 11.7%, pb0.001, respectively.
International Journal of Cardiology xxx (2012) xxx窶度xx
ONTARGET: Study design
25620 αζζελείο-38% δηαβεηηθνί
Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial N = 25,620 ≥55 Years with coronary, cerebrovascular, or peripheral vascular disease or diabetes + end-organ damage
Ramipril 10 mg
Telmisartan 80 mg
Ramipril 10 mg + telmisartan 80 mg
Primary outcome: CV death, MI, stroke, hosp for HF Secondary outcomes: Newly diagnosed HF, T2DM, or AF; revascularization procedures; development of dementia/cognitive decline, nephropathy
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
Kaplan–Meier Curves for the Primary Outcome in the three Study Groups: The composite primary outcome was death from cardiovascular causes,myocardial infarction, stroke, or hospitalization for heart failure .
The combination-therapy (telmisartan plus ramipril) group and the ramipril group The risk score from the Heart Outcomes Prevention Evaluation (HOPE) trial ranges from 2.350 to 5.928, with higher scores indicating higher risk. The sizes of the squares are proportioned to the numbers of events.
ONTARGET
Λόγνη δηαθνπήο ηωλ θαξκάθωλ ππό κειέηε Ram
Ram + Tel
N=8576
N=8502
Hypotension
149
406
2.75
<0.0001
Syncope
15
29
1.95
0.032
Cough
360
392
1.10
0.1885
Diarrhea
12
39
3.28
0.0001
Angioedema
25
18
0.73
0.30
Renal Impairment
60
94
1.58
0.0050
2099
2495
1.20
<0.0001
Any Discontinuation
Ram + Tel vs. Ram
RR
P
Adjusted survival curves in patients in whom treatment was initiated with an ACEI þ other antihypertensive (antiHTN) medications (ACEI þ Rx), an angiotensin receptor blocker (ARB) þ antiHTN (ARB þ Rx), or an ACEI þ ARB. ACEI, angiotensin converting enzyme inhibitor.
increased mortality with ACEi and ARBs in hemodialysis patients, supporting emerging evidence that such dual therapy may be detrimental
Κιηληθέο Μειέηεο κε πξωηεύνληεο λεθξηθνύο ζηόρνπο κε ζπλδπαζκό θαξκάθωλ πνπ αλαζηέιινπλ ηνλ άμνλα
CALM Study • Combo Rx with candesartan & lisinopril reduced BP • Lisinopril reduced proteinuria • Candesartan reduction of proteinuria was NS either alone or in combination with lisinopril
COOPERATE: Primary Endpoint Proportion Reaching Endpoint, %
Doubling of Serum Creatinine or Progression to ESRD 30
Trandolapril
25
Losartan
Combination 20 15 10 5
P = 0.02
0 Number at Risk Losartan Trandolapril Combination
0
5
89 86 88
88 85 87
12 18 24 Months After Randomization 84 83 86
79 75 83
65 72 76
Reprinted with permission from Nakao N et al. Lancet. 2003;361:117â&#x20AC;&#x201C;124.
30
36
59 63 73
47 58 67
ACEI/ARB vs combination
O ζπλδπαζκόο ππεξέρεη ηεο κνλνζεξαπείαο ωο πξνο ηε κείωζε ηεο ιεπθωκαηνπξίαο
Kunz et al, 2008
The study showed that combination therapy leads to a further reduction in albuminuria despite minimal changes in the mean BP. Singapore Med J 2010;51(2) : 151
ύγθξηζε ηνπ ΑΜΕΑ vs ARB θαη ΑΜΕΑ vs ζπλδπαζκνύ ζηελ πξωηεϊλνπξία
•Mεγαιύηεξε αληηπξωηεϊλνπξηθή δξάζε κε ηνζπλδπαζκό •Ο ΑRB ππεξέρεη ηνπ AMEA όζνλ αθνξά ζηελ πξωηεϊλνπξία
Μann et al, Lancet 2008
ONTARGET: Effects of telmisartan, ramipril, and combination on primary renal outcome 0.20 0.15 Cumulative incidence of primary renal 0.10 outcome*
0.968 T vs R; P = 0.068 T+R vs R; P = 0.037
0.05 0
0
Telmisartan (T) + ramipril (R)
*Dialysis, doubling of serum creatinine, death
1
2 3 Follow-up (years) Telmisartan
4
5
Ramipril JFE et al. Lancet. Î&#x153;ann etMann al, 2008;372:547-53. Lancet 2008
ONTARGET: Decline in eGFR with ramipril, telmisartan, and combination -6.11ml/min
-6 -5
-4.12ml/min
-4 Decrease in eGFR from run-in
-2.82ml/min
-3 -2
p<0.05
-1 0 Run-in
Week 6
Year 2
Time period Telmisartan + ramipril
Telmisartan
Study end Ramipril
Î&#x153;ann et al, Lancet 2008
Mann JFE et al. Lancet. 2008;372:547-53.
Bakris G, KI
2010;78:546-549
Relationship between glycemia & renal injury
Bakris G, KI
2010;78:546-549
Juxtaglomerular apparatus hyperplasia under dual angiotensin blockade. A footprint of adequate RAS inhibition or a concern for renal fibrosis?
Beatriz Fernandez-Fernandez,BMC Nephrology 2012, 13:21 doi:10.1186/1471-2369-13-21
RAAS blocker and aliskeren
Assessing the renal protection potential of aliskiren
Published in NEJM 2008
Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) study – Study design overview Randomization
Aliskiren 150 mg
Aliskiren 300 mg
Placebo
Placebo
+ Losartan 100 mg + optimal antihypertensive therapy
Open-label 3 months •
Double-blind 3 months
All patients continue to receive openlabel losartan 100 mg and optimal antihypertensive therapy during the double-blind period
3 months •
•
Patients force-titrated after 3 months All treatments administered once daily Parving H-H, et al. 2008 (AVOID)
BP remained similar in the aliskiren and placebo groups throughout the course of the study Mean sitting BP (mmHg) 140
Systolic
130 120 110 100 90 80
Diastolic
70 60 â&#x20AC;&#x201C;2
0
2
4
6
8
10
12
14
16
18
20
22
24
Week Optimal antihypertensive therapy + Aliskiren Placebo Parving H-H, et al. 2008 (AVOID)
Aliskiren provides significantly greater reductions in UACR compared with placebo Mean change from baseline§ in UACR at Month 6 (%) 5 2 0
n=289
n=287
−5 −10 −15 −20
§Baseline
−18
*
Optimal treatment + aliskiren 300 mg
UACR values – aliskiren 513 pg/mL, placebo 553 pg/mL; baseline was Week −2 value; data are shown as percentage change in geometric mean *p<0.001 vs placebo
Optimal treatment + placebo Parving H-H, et al. 2007 (AVOID) Parving H-H, et al. 2008 (AVOID)
Drug combination in hypertension
Hopkins, Curr Opin Nephrol Hypertens
2010;19:450
Mειέηεο πνπ ζα δώζνπλ απάληεζε γηα ην αλ ν δηπιόο απνθιεηζκόο ηνπ άμνλα RAS κπνξεί λα κεηώζεη ηα θαξδηαγγεηαθά ζπκβάκαηα
ALTITUDE • NEPHRON-D • HALT-PKD •
Cardio-renal outcomes in diabetic patients
Study design published in Nephrol Dialysis Transplant 2009
ALTITUDE — Overview
• Aζζελείο κε Δ ηύπνπ ΙΙ θαη κε έλα από ηα παξαθάηω: – πξωηεϊλνπξία – κηθξναιβνπκηλνπξία + eGFR 30–60 mL/min – Πξνεγνύκελν ηζηνξηθό ΚΑ λόζνπ + eGFR 30–60 mL/min • Η κειέηε ζα δηαξθέζεη 5 ρξόληα • Πξωηεύνλ θαηαιεθηηθό ζεκείν: Scr x 2, ESRD, ζάλαηνο πνπ ζρεηίδεηαη κε ΚΑ λόζν, έκθξαγκα κπνθαξδίνπ, ΑΕΕ
ALTITUDE – Design overview Randomization (n=~8600 patients) Aliskiren 150 mg
Aliskiren 300 mg once daily
Placebo
Conventional treatment (according to national guidelines; must include an ACEI or ARB, but not both) 4–12 weeks
4 weeks
*ALTITUDE is an event driven study eGFR – estimated glomerular filtration rate
~4 years*
Parving H-H, et al. 2009 (ALTITUDE)
Assessing the effect of aliskiren on LVH
Published in Circulation
ALLAY â&#x20AC;&#x201C; Design overview Randomization (n=465)
Prior ACEI/ARB treatment: 12 weeks
Aliskiren 150 mg
Aliskiren 300 mg once daily
No prior ACEI/ARB treatment: 2 weeks
Losartan 50 mg
Losartan 100 mg once daily
Aliskiren/losartan 150/50 mg
Aliskiren/losartan 300/100 mg once daily
+
Addition of diuretics, and CCBs, ď Ą-blockers and/or vasodilators as necessary*
Screening & washout phase 2 or 12 weeks
Double-blind
2 weeks
*To achieve BP <140/90 mmHg (<130/80 mmHg for patients with diabetes)
34 weeks Solomon SD, et al. 2008 (ALLAY)
Aliskiren/losartan combination provides an ~20% greater numerical reduction in LVMI from baseline compared with losartan monotherapy Aliskiren/losartan Aliskiren 300 mg
Losartan 100 mg
300/100 mg
n=132
n=123
n=136
0 –1 –2
–3 –4 –5
– 4.7 – 5.4
–6 –7
*
§
*
– 6.4
* ‡ Mean percentage change from baseline§ in LVMI after 36 weeks’ treatment (%) §Baseline
LVMI values – aliskiren 78 g/m2, losartan 79 g/m2, aliskiren/losartan 78 g/m2 Between-treatment analyses based on least-squares mean data: *p<0.0001 vs baseline §p<0.0001 for non-inferiority vs losartan 100 mg; ‡p=0.52 vs losartan 100 mg Solomon SD, et al. 2008 (ALLAY)
Influence of diabetes on efficacy of aliskiren, losartan or both on left ventricular mass regression
Journal of the Renin-Angiotensin-Aldosterone System0(0)2012
RAAS blocker and aldosterone antagonists
Transplantation Proceedings, 42, 2899â&#x20AC;&#x201C;2901 (2010)
Khosla, Kalaitzidis et al Am J Nephrol 2009; 30:418
Renal outcomes not favored with RAAS blockade: ACE inhibitors & ARBs vs other antihypertensives
Kalaitzidis R & Bakris G. et al. Curr Cardiol Rep 2009; 11:436-5442
Macaulay Onuigbo,Nephron Clin Pract 2009;113:c63-c70
Number of antihypertensive medications required to achieve BP goals in major clinical trials over the past decade
Î&#x161;hosla N, Kalaitzidis R et al Med Clin North Am 2009
πκπέξαζκα •
Σν RAAS παίδεη έλαλ ξόιν «θιεηδί» ζηελ παζνθπζηνινγία ηεο ππέξηαζεο
•
Οη αλαζηνιείο ηνπ RAAS (ACEIs,ΑRBs, Renin Inhibitors είλαη απνηειεζκαηηθά θάξκαθα γηα ηελ αληηκεηώπηζε ηνπ ππεξηαζηθνύ αζζελή
• •
Combined therapy should not be considered in the treatment of hypertension or other disorders unless there is compelling evidence of benefit
πκπεξάζκαηα Ο ζπλδπαζκόο ACEI/ARB
κάιινλ αλαζηέιιεη ηελ εμέιημε ηεο
λόζνπ ζε αζζελείο κε ΧΝΝ θαη πξωηεϊλνπξία, …αιιά απμάλνπλ ηνλ θίλδπλν ΟΝΑ ζε αζζελείο κε
ΧΝΝ ρωξίο
πξωηεϊλνπξία.
εβαζκόο ζηνπο θαλόλεο ρνξήγεζεο απνθιεηζηώλ ηνπ RAAS
κεηώλεη ηνλ θίλδπλν επηπινθώλ.