Ace-ccb Pit Palembang

Dr.Dr. dr. dr. H. Zulkhair Ali, SpPD-KGH H. Zulkhair Ali, SpPD-KGH

Tempat/tanggal Lahir:Tempat/tanggal Lahir: Air Molek/ 21 April 1961Air Molek/ 21 April 1961

Pendidikan:Pendidikan: FK Unsri 1987FK Unsri 1987

Peny.Dalam FK Unsri 1996Peny.Dalam FK Unsri 1996Pend.Ginjal Hipertensi FKUI 2000Pend.Ginjal Hipertensi FKUI 2000

PG Course of Nephrology Australia 2001,2003PG Course of Nephrology Australia 2001,2003Konsultan Ginjal Hipertensi, 2004Konsultan Ginjal Hipertensi, 2004

S3S3 Unair 200 Unair 20088Jabatan:Jabatan:

Staf PDL RSMH/FK UnsriStaf PDL RSMH/FK UnsriOrganisasi:Organisasi:

Sekretaris PAPDI CabSekretaris PAPDI Cab Sumbagsel Sumbagsel Ketua IKetua IKA FK Unsri KA FK Unsri

Publikasi:Publikasi: 446 makalah Nasional6 makalah Nasional

66 makalah Internasional makalah InternasionalContact:Contact:

[email protected]@yahoo.com Medan, 2001

Zulkhair AliZulkhair Ali

DivDiv. of . of Nephrology & HypertensionNephrology & HypertensionDept. of Internal Medicine Dept. of Internal Medicine

RSMH/ FK UnsriRSMH/ FK UnsriPalembangPalembang

Antihypertensive Drugs Antihypertensive Drugs and Renal Protection: and Renal Protection: The Role of The Role of ACEIACEI & & CCBCCB

Can be modified Cannot be modified

Hypertension AgeAlbuminuria/Proteinuria Ethnicity

Dyslipidemia GenderHemoglobin A1C

SmokingAnemiaCa•P04

Proteinuria (albuminuria) results from injury to glomerular circulation Increased proteinuria (albuminuria) is

associated with progressive kidney disease

In diabetes and hypertension, proteinuria (albuminuria) is also an indicator of injury in the systemic circulation Proteinuria (albuminuria) is associated with

increased cardiovascular risk

Hypertension and proteinuria (albuminuria) are both independent variables that predict long-term decline in renal function Renal disease is both a cause and

consequence of hypertension Reduction of blood pressure reduces

cardiovascular risk and renal risk Reduction of proteinuria (albuminuria) may

lower both cardiovascular risk and renal risk

Excess Mortality with Hypertension Excess Mortality with Hypertension and Proteinuria in Type 2 Diabetesand Proteinuria in Type 2 Diabetes

Status of hypertension (H) and proteinuria (P) in Type 2 Status of hypertension (H) and proteinuria (P) in Type 2 diabetesdiabetes

Standardized Standardized Mortality RatioMortality Ratio

1,001,0000

500500

00P- P- H-H-

P- P- H+H+

P+ P+ H-H-

P+ P+ H+H+

P- P- H-H-

P- P- H+H+

P+ P+ H-H-

P+ P+ H+H+

MenMen WomenWomen

Wang SL Wang SL et al.et al., , Diabetes CareDiabetes Care 1996;19:305- 1996;19:305-312.312.

With

ESR

D E

nd P

oint

(%)

With

ESR

D E

nd P

oint

(%) 8080

100100

4040

6060

2020

004848363624241212

Month

3.0 g/g3.0 g/g

1.5<3.0 g/g1.5<3.0 g/g

<1.5 g/g<1.5 g/g

HRHR

8.108.10

3.233.23

1.01.0

00

Baseline AlbuminuriaBaseline Albuminuria

de Zeeuw et al. de Zeeuw et al. Kidney Int.Kidney Int. 2004;65:2309-2320. 2004;65:2309-2320.

ProteinuriaProteinuria ProteinuriaProteinuria

OtherOther OtheOtherr

DamageDamage KidneyKidneyFailureFailureGFRGFRHypertensionHypertension HypertensionHypertension

National Kidney Foundation. Am J Kidney Dis. 2004;43(suppl 1):S1-S290.

Modified from Bakris et al. Modified from Bakris et al. Am J Kidney DisAm J Kidney Dis. 2000;36:646-661.. 2000;36:646-661.

Systolic Blood Pressure (mm Hg)Systolic Blood Pressure (mm Hg)

Trials included: MDRD, RENAAL, IDNT, AIPRI, Captopril Trial, REIN, AASK.Trials included: MDRD, RENAAL, IDNT, AIPRI, Captopril Trial, REIN, AASK.

130130 134134 138138 142142 146146 150150 154154 170170 180180

r=0.52; r=0.52; PP<.01<.01

Dec

line

in G

FR F

rom

Bas

elin

eD

eclin

e in

GFR

Fro

m B

asel

ine

(mL/

min

/yea

r)

(mL/

min

/yea

r) UntreatedUntreated

HTNHTN

00

-2-2

-4-4

-6-6

-8-8

-10-10

-12-12

-14-14

14

Adhesion molecules Chemotactic factors Cell growth Apoptosis TGF-, CTGF PAI-1

Glomerular capillarypressure

Single nephron GFR

Macrophageinfiltration

Angiotensin II

Mechanical stressMesangial changesOxidative stressProteinuriaNF-B activation

Glomerulosclerosis

Tubulo-interstitial

fibrosis

Renaldisease

Nephronloss

www.hypertensiononline.org

Angiotensin I

ACEACE

Inhibitor

Ang II

Increasedglomerularpressure

Ang II

Urinary proteinGlucose

AGEsGlycoxidation (glycation)

Efferent arteriolarconstriction

=angiotensin AT1 receptor


TGF-

TGF- plays a key role in extracellular matrix formation in mesangiumand interstitium that leadsto fibrosis and loss of nephron units


bFGF PDGF

Ang II

TSP1

TGF-

O2•


O2•


TIMP

bFGF PDGF

Ang II

Proteases

(-)

(-)

(+)

(+)

(+)

TSP1

ET-1

PAI-1

O2•

TGF-


O2•


Study Drug Dosing Survival Benefit

Study Duration

AIPRI Benazepril 10-20mg qd P<0.001 ~3.0 years

REIN Ramipril 5-10 mg qd P=0.03 ~ 3.5 years

AIPRI = ACE Inhibition in Progressive Renal Insufficiency StudyREIN = Ramipril Efficacy In Nephropathy Study

Maschio G, et al. N Engl J Med. 1996;334(15):939-945.The GISEN Group. Lancet. 1997;349:1857-1863.

Study Drug N Dosing Study years Endpoint P-value

Lewis Captopril 409 25 mg tid ~ 3

Doubling of serum

creatinineP=0.007

Lebovitz Enalapril 165 5-40 mg qd ~ 3

Correlation of MAP w/ rate of change in GFR

P=0.026

ABCD Trial Enalapril 470 5-40

mg qd 5 24-hr creatinine clearance NS

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462. Lebovitz HE, et al. Kidney Int. 1994;45(suppl45):S150-S155.Estacio RO, et al. Diabetes Care. 2000;23(suppl2):B54-B64.

ABCD = Appropriate Blood Pressure Control in Diabetes Trial

Trial Year Endpoint significance

Achieved BP

Captopril 1993 P=0.007 141/82

AIPRI 1996 P<0.001 139/82

REIN 1997 P=0.03 142/84

RENAAL 2001 P=0.01 142/77

IDNT 2001 P=0.02

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462. Maschio G, et al. N Engl J Med. 1996;334(15):939-945. The GISEN Group. Lancet. 1997;349:1857–1863.

Baseline SBP ∆ SBP Baseline DBP ∆ DBPRamipril 149.8 -5.8 mmHg 92.4 -4.2 mmHgPlacebo 148.0 -3.4 mmHg 91.3 -3.4 mmHg

0 6 12 18 24 30 36

10080604020

0

Ramipril

Placebo

P=0.02

Reprinted from The GISEN Group. Lancet. 1997;349:1857–1863 with permission from Elsevier.

% o

f pat

ient

s with

out

com

bine

d en

dpoi

nt*

*Combined endpoint = doubling of baseline serum creatinine concentration or end stage renal failure

Intraglomerular pressure descent caused by Intraglomerular pressure descent caused by efferent arteriole dilationefferent arteriole dilation

Supervised by S Katayama, Professor of Internal Medicine 4, Saitama Medical School

Diabetic nephropathyAfferentarteriole

Efferentarteriole

Bowman’scapsule

Glomerulus

Intraglomerularpressure

Imidapril dosage

Normalizedintraglomerularpressure

Afferentarteriole Efferent arteriole

Glomerulus

Bowman’scapsule

Coordinating Investigator Shigehiro Katayama, MD Saitama Medical School

Study Coordinators Ryuichi Kikkawa, MD Shiga Univ. of Med. Sci.

Syo Isogai, MD Toho Univ., Sch. Of Med.

Nozomu Sasaki, MD Saitama Medical School

Nobuo Matsuura, MD Kitasato Univ., Sch. Of Med.

Naoko Tajima, MD Jikei Univ., Sch. Of Med.

Tatsuhiko Uragami, MD Nihon Univ., Surugadai Hosp.

Yasuko Uchigata, MD Tokyo Women’s Med Univ. Sch. Of Med.

Contoroller Yasuo Ohashi, PhD Univ. of Tokyo, Sch. of Health Sci & Nursing

Supported by a grant-in-aid for orphan drug development from

MHW and Research on Health Sciences focusing on Drug Innovation, Japan Health Sciences

●Subjects79 IDDM patients aged 20 to 50 years old associated with

Urinary Albumin Excretion (UAE) ≧ 30mg/daySerum creatinine level ≦ 2.0mg/dL

●MethodCaptopril 12.5mg x 3/day, imidapril 5mg/day or their placebos, originally planned to include 100pts each into three groups for 3 years (mean 1.48 years) in a double-blind manner.

JAPAN-IDDMJapanese trial of ACE inhibitors on renal protection against nephropathy in IDDMs

Katayama S. et al. ： Diabetes Research and Clinical Practice, 2002 　

Profile of a Randomized Controlled TrialProfile of a Randomized Controlled TrialRegistered Patientsn = 81

Randomizationn = 79

Received Placebon= 27

Received Captopriln = 26

Withdrawn (n = 8)Withdrawal of informed consent (n = 3)Doubling of serum creatinine (n = 2)Others (n = 3)

Completed Trial

Not Eligible Patientsn = 2

n = 18

Received Imidapriln = 26

Completed Trial Completed Trial n = 22 n = 17

Withdrawn (n = 4)Doubling of serum creatinine (n = 1)Others (n = 3)

Withdrawn (n = 10)Withdrawal of informed consent (n = 2)Doubling of serum creatinine (n = 2)Others (n = 6)

Twenty-two patients were withdrawn from the study.

10 in the placebo, 8 in the captopril and 4 in the imidapril group

placebo Captopril Imidapril

withdrawal of informed consent 2 3 -

doubling of serum creatinine 2 1 1

adverse events 1 2 -

BP elevation 1 - -

intercurrent illness or condition 2 1 2

other reasons 2 1 1

Change in Urinary Albumin ExcretionChange in Urinary Albumin Excretion95% confidence : p<0.05 （ vs placebo ） : p<0.001 （ vs placebo ）

placebo（ n=26 ）

imidapril（ n=26 ）

captopril（ n=25 ）

2.5

2.0

1.5

1.0

0.5

0

1.72

0.59

0.94

Chan

ge in

UAE　

（fin

al／

basa

l ra

tio）

41%

Change in Urinary Albumin ExcretionChange in Urinary Albumin Excretionー subgroup analysis by basal UAE ー

95% confidence : p<0.05 （ vs placebo ） : p<0.01 （ vs placebo ）

3.5

3.0

2.0

1.0

0.5

0（ n=12 ）（ n=13 ）（ n=13 ）

2.5

1.5

（ n=14 ）（ n=13 ）（ n=12 ）

30 ～ 300mg/day ＞ 300mg/day

placeboimidaprilcaptopril

1.86

0.680.78

1.61

0.52

1.14

Chan

ge in

UAE 　

（fin

al／

basa

l ra

tio）

Analysis of variance

32%48%

Change in Serum Creatinine LevelChange in Serum Creatinine LevelmeanSD

placebo（ n=26 ）

imidapril（ n=25 ）

captopril（ n=25 ）

0.20

0.15

0.10

0.05

0Chan

ge in

Ser

um C

reat

inin

e Le

vel

（ mg/dL ）

0.130

0.051

0.147

（fin

al -

basa

l）Analysis of variance

ー subgroup analysis by basal serum creatinine level ー

Change in Serum Creatinine LevelChange in Serum Creatinine Level

meanSD : p<0.05 （ vs placebo ）

0.90.8

0.4

0.10

（ n=23 ）（ n=22 ）（ n=21 ）

0.6

0.2

（ n=3 ）（ n=3 ）（ n=4 ）

＜ 1.0mg/dL ≧1.0mg/dL placeboimidaprilcaptopril

0.5

0.7

0.3

（ mg/dL ）

0.05 0.040.12

0.77

0.17

0.31

Chan

ge in

Ser

um C

reat

inin

e Le

vel

（fin

al -

basa

l）

The study ended on January 31st, 2,000 on the recommendation of the independent data safety and monitoring board (Kazuo Kaizu, Shoji Kawazu, Yoshitada Yajima, Chikuma Hamada), since a significant difference between the treated and placebo group (p=0.007) was obtained. Fifty-nine patients completed the study. The average follow-up for these patients was 1.48 years.

SENSOR

The role in decreasing proteinuria is still controversial

Spesific vasodilator for afferent arteriole RBF GFR proteinuria

glomerulosclerosis.

Calcium Antagonist / CCBs

Franz H. Messerli :

“ Not all calcium antagonists are created equal; therefore, one cannot assume that all calcium antagonists are equally dangerous or equally beneficial. “

The Calcium antagonists controversy. Am J Cardiol 1998;82:35R-39R

• Dihydropyridine ( DHP ) Nifedipine, Amlodipine, Felodipine

• Non-Dihydropyridine ( NDHP ) Diltiazem, Verapamil

OPIE, DRUGS FOR THE HEART, 2001

Calcium Channel Blockers ( CCBs )

Proteinuria < 500 mg/day : DHP CCB and Verapamil ACEI

Proteinuria > 500 mg/day : DHP CCB couldn’t reduce proteinuria Non-DHP CCB ACEI

Kaplan NM, 2004Kaplan NM, 2004

With similar reductions of blood pressure… Dihydropyridine calcium channel blockers

(DHPCCB) increase proteinuria− Ref: Mimran A, et al. Diabetes Care. 1988;11:850-853.− Ref: Demarie BK, Bakris GL. Ann Intern Med. 1990;113:987-

988.− Ref: Agodoa L, et al. JAMA. 2001;285(21):2719-2728.

Non-DHPCCB reduces proteinuria when a DHPCCB produces no change or increase in proteinuria Ref: Smith AC, et al. Kidney Int. 1998;54:889-896. Ref: Kloke H, et al. Kidney Int. 1998; 53:1559-1573.

N=173 N=121 N=111 N=723

NifedipineOtherDihydropyridineCCBs

Diltiazem &VerapamilCCBs

AllACE Inhibitors

Kloke H, et al. Kidney Int. 1998;53:1559-1573.

DHP vs NDHPRenal EffectsCapillary Glomerular PressureProteinuria

Cardiac EffectsReflex Sympathetic ActivityRisk-Ratio of Ischemia

Cerebral EffectsIntracranial Pressure

Ca-Antagonists Differs in Clinical Practice

Epstein M, 1991, Bakris GL, 1993, Mancia G, 1996, Messerly FH, 1996

The general consensus is that the Non-Dihydropyridine CCBs Diltiazem and Verapamil decrease proteinuria, whereas dihydropyridine CCBs agents has a minimal or minor effects on proteinuria

The Role of Hypertension on the Progression of Chronic Kidney Diseases

• CARDIO PROTECTION EFFECTINTERCEPT STUDY : Diltiazem reduced cardiac events : non-fatal re-infarction or refractory ischemia, and the need for PTCA / CABG in acute myocardial infarction ( AMI ).

William E. Boden, et al;, Lancet, 2000, 355: 1751-1756

• RENAL PROTECTION EFFECTKidney International. 1998 ; 54 : 889-896 : Diltiazem show lower urinary protein excretion compared to Nifedipine

• CEREBRAL PROTECTION EFFECTNORDIL STUDY : showed Diltiazem group had a 20% lower rate of all stroke than Diuretics and -Blockers

The Lancet, Vol 356, July 29, 2000

“ “ DILTIAZEMDILTIAZEM “ More Than Just Anti-hypertensive “ More Than Just Anti-hypertensive Agent : Organ Protection Effect “ Agent : Organ Protection Effect “

EAR

FilteredProteins

Bowman’sCapsule

GlomerulusDiltiazem reduce Afferentvasoconstriction

BP

GCP

Diltiazem reduce Efferentvasoconstriction

Renal Protection Effect of DiltiazemRenal Protection Effect of Diltiazem

Randomized trial in 21 patients type-2 DM with hypertensionDiltiazem O.D. ( mean dose 436 + 43 mg ) and Nifedipine O.D. ( mean dose 78 + 12 mg )

Kidney International. 1998 ; 54: 889-896

Effect of Diltiazem & Nifedipine Effect of Diltiazem & Nifedipine on Urinary Protein Excretion on Urinary Protein Excretion

mg / day

Nifedipine

600P < 0.05

Baseline

Diltiazem

200

1000

21 months

Perbandingan efektivitas Diltiazem HCl dan Perbandingan efektivitas Diltiazem HCl dan Imidapril HCl dalam menurunkan Imidapril HCl dalam menurunkan

mikroalbuminuria penderita hipertensimikroalbuminuria penderita hipertensi

Ferry Usnizar, Zulkhair Ali, Ian Effendi, Ali Ghanie

Bagian Ilmu Penyakit Dalam Fakultas Kedokteran Universitas Sriwijaya

2005

Cross-over study Usia 18-65 tahun 30 pasien hipertensi derajat I dengan

mikroalbuminuria : kelompok diltiazem HCl kerja panjang kelompok imidapril HCl

Selama 2 x 4 minggu

Alur penelitianAlur penelitian

N = N = 1515

Hipertensi stage I Hipertensi stage I dengandenganmimikkroalbuminuriaroalbuminuria

N=N=1515

Diltiazem

Imidapril

Diltiazem

Imidapril4 mingggu 4 mingggu

CCB non dihidropiridin (Diltiazem HCl) sama efektif dengan ACE inhibitor (Imidapril) dalam menurunkan proteinuria pada pasien hipertensi.

Trandolapril (5.5 mg/d)

Verapamil (315 mg/d)

Trandolapril (2.9 mg/d) + Verapamil (219 mg/d)

*

Bakris GL, et al. Kidney Int. 1998;54:1283-1289. Reprinted by permission, Blackwell Science, Inc.

-33%-27%

-62%

*p <0.001 combination vs either monotherapy

Perc

ent

redu

ctio

n

n=12 n=11 n=14

Diltiazem & ACE-I CombinationType 2 Diabetics –Microalbuminuria

Pèrez-Maraver M, et al. (EASD) Meeting 2001; Abstract: 1056.

0

50

100

150

200

250

300

Captopril (n=17) Captopril + Diltiazem (n=11)

UAE

(mg/

24 h

rs)

Initial 2 Year Follow-Up

p < 0.05

T Tsuge1, A Kurusu1, I Ohsawa1, W Prodjosudjadi2, Suhardjono2, Dharmeizar2, G Nainggolan2, A Lidya2, RM

Yogiantoro3, Pranawa3, CI Mohani3, D Santoso3, G. Rizaniansyah3, Y Tomino1

1Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan2Nephrology Division, Department of Internal Medicine, Indonesia University, Jakarta, Indonesia3Nephrology Division, Department of Internal Medicine, Airlangga University, Surabaya, Indonesia

Thirty-seven patients were divided into imidapril monotherapy group and combination group and were treated for 12 months.

Monotherapy group (n=12): Imidapril

Combination group (n=25): Imidapril + Diltiazem

Therapy groupTreatment period SBP DBP UAE SCr

(No of patients) (mmHg) (mmHg) (g/gCr) (mg/dL)

　 Baseline140±23 84±14 1.13±1.29 1.13±0.53

　 (n=12)

Imidapril 6 month129±20* 80±8 1.67±2.77 1.12±0.56

monotherapy (n=12)

　 12 month134±14* 83±14 0.99±1.43 1.16±0.71

　 (n=10)

　 Baseline143±16 85±11 0.68±1.13 1.00±0.34

　 (n=25)

Imidapril + CCB 6 month133±14* 79±8* 0.29±0.46 1.02±0.32

combination (n=25)

　 12 month132±16* 80±9* 0.14±0.26 1.04±0.35

　 (n=22)

Total

Baseline142±18 85±11 0.83±1.19 1.04±0.40

(n=37)

6 month131±16* 79±8* 0.69±1.61 1.05±0.40

(n=37)

12 month133±15* 81±11* 0.40±0.89* 1.08±0.48

(n=32)

t-test, *: p<0.05 (vs baseline)

SStudy Conclusionstudy ConclusionsIn monotherapy group:

• imidapril significantly reduced SBP at 6 and 12 month,

• marginally decreased UAE at 12 month, • did not increase SCr during the study period

In combination group: • imidapril and CCB significantly reduced SBP/DBP at

6 and 12 months compared with that of baseline, • decreased UAE at 6 and 12 month, • did not increase SCr during this period.

.

Hypertension and proteinuria (albuminuria) are both independent variables that predict long-term decline in renal function Renal disease is both a cause and consequence of

hypertension Reduction of blood pressure reduces cardiovascular and

renal risk Reduction of proteinuria (albuminuria) may lower both

cardiovascular and renal risk Imidapril is a unique ACE-inhibitor which has potent BP

lowering, and reno-vascular protection The use of Non DHP CCBs (diltiazem, verapamil) may be

considered to reduce urinary albumin excretion in proteinuric hypertensive patients, alone or together with ACEI.

Mandi telanjang di tempat terbuka

Ace-ccb Pit Palembang

Documents