5 Kalaitzidis

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.