PENYAKIT JANTUNG KATUP

B. Rudy Utantio
Rully Roesli Indonesian Society of Hypertension (InaSH)
12-Jan-14
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CARDIO VASCULAR SYSTEM

# HEART # CIRCULATORY SYSTEM ----- PULMONARY SYSTEMIC # BLOOD VESSELLS ARTERY VEIN

HEART CHAMBERS
**RIGHT ATRIAL <---- SUPERIO/INFERIOR CAVAL VEIN --- RIGHT VENTR. --- PULMONANARY ARTERY --- PULMONAR CIRCULATION

**LEFT ATRIUM ----LEFT PULMONARY VEIN ---- LEFT VENTRICEL ---- AORTA ---- SYSTEMIC CIRCULATION

Penyakit Jantung Katup

Disfungsi jantung akibat abnormalitas struktur atau abnormalitas fungsi katup jantung Disfungsi katup jantung dapat menyebabkan pressure overload akibat keterbatasan pembukaan katup (stenosis gangguan pembukaan) atau volume overload akibat penutupan katup yang tidak adekuat (regurgitasi gangguan penutupan) PJ Katup dapat diklasifikasikan berdasarkan lesi patologis yaitu obstruktif (stenosis) atau nonobstruktif (regurgitasi) atau berdasarkan patofisiologi sebagai pressure overload atau volume overload
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PENYAKIT JANTUNG KATUP

Lesi katup penyebab pressure overload Aorta Stenosis (AS) Mitral Stenosis (MS) Lesi katup penyebab volume overload Aorta Regurgitasi (AR) Mitral Regurgitasi (MR)

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AORTA STENOSIS (AS)

BATASAN AS adalah obstruksi pada katup Ao yang menyebabkan aliran darah dari ventrikel kiri ke aorta terganggu. Lokasi obstruksi dapat terjadi di valvular, supravalvular atau subvalvular PERJALANAN PENYAKIT AS berat dapat asimptomatik selama beberapa tahun walaupun terdapat obstruksi yang berat cenderung bebas dari gejala sampai akhir perjalanan penyakit dengan mortalitas dan morbiditas cukup rendah

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Aorta Stenosis
Angka harapan hidup hampir mendekati angka normal sampai timbul gejala klasik seperti angina, sinkop dan sesak nafas. ETIOLOGI 1. Kongenital (unikuspid, bikuspid, trikuspid) 2. Rematik 3. Degeneratif

PATOFISIOLOGI
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Patofisiologi AS
Obstruksi dari aliran keluar ventrikel kiri akan meningkatkan tekanan sistolik ventrikel kiri, waktu ejeksi, tekanan diastolik dan menurunkan tekanan aortik Peningkatan tekanan sistolik ventrikel kiri bersama dengan beban volume meningkatkan massa ventrikel kiri, yang dapat menyebabkan disfungsi dan gagal jantung kiri
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MEMBUAT DIAGNOSIS PENYAKIT JANTUNG

I. Anamnesa & Pemeriksaan Fisik * Inspeksi * Palpasi * Perkusi * Auskultasi II. Foto Thorax ( Chest X-Ray ) III.Rekaman EKG IV. Plan of Dx lain: Laboratorium, Treadmill, Echocardiography, Nuclear Cardiology, Cardiac CT Scan, MRI, Catheterisation
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DIAGNOSIS PENYAKIT JANTUNG

1. DIAGNOSIS ETIOLOGI 2. DIAGNOSIS ANATOMI 3. DIAGNOSIS FISIOLOGI
Contoh : - RHD, Mitral Stenosis, Dekompensata - SKA, IMA inferior, Kompensata - HT st II, H V kiri, Decompensata-, R

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PEMERIKSAAN KLINIK PENYAKIT JANTUNG

1. ANAMNESA 2. PEMERIKSAAN FISIK : - Inspeksi - Palpasi - Perkusi - Auskultasi

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Auscultation

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AREA AUSKULTASI
Apeks : Mitral RAI II KI : Pulmonal RAI II KA : Ao RAI IV-V KI : Trikuspid Bising Organik : Turbulensi Bising fungsional : aliran darah melalui katub Normal 1. Fase 2. Lokasi dan Penjalaran 3. Intensitas I VI, IV Thrill + 4. Nada : Rendah tinggi 5. Lama dan kualitas :

Crescendo Decrescendo
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Blowing

Rumbling
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Ada 4 area yang harus mendapat perhatian khusus pada auskultasi

RAI II kanan RAI II kiri RAI IV V kanan Apeks kordis : auskultasi katup Ao : auskultasi katup Pu : auskultasi katup Tr : auskultasi katup Mi

Perubahan posisi tubuh untuk mendengar lebih jelas : * Terlentang miring ke kiri : katup mitral * Duduk membungkuk ke depan : katup Ao

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Murmurs (Bising)
Grading of Murmurs: Grade 1 - only a staff man can hear Grade 2 - audible to a resident Grade 3 - audible to a medical student Grade 4 - associated with a thrill or palpable heart sound Grade 5 - audible with the stethoscope partially off the chest Grade 6 - audible at the bed-side
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Functional Murmur: short and soft Normal S1 and S2 Normal cardiac impulse No evidence for hemodynamic abnormality

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Bising sistolik : AS, PS, VSD, MI Bising diastolik : AI Bising menerus (continous Murmur) : PDA Bising Late Systolic : ( Prolaps katup mitral) Bising Early Diastolic : ( AI, PI ) Bising Late Diastolic : ( MS ) Bising Sea Gull : Rumbling, Musical, High Pitched, Blowing

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Common Murmurs and Timing

Systolic Murmurs Aortic stenosis Mitral insufficiency Mitral valve prolapse Tricuspid insufficiency Diastolic Murmurs Aortic insufficiency Mitral stenosis
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S1

S2

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S1

Aortic Stenosis: Physical Findings

S1

S2

S1
Severe

S2

Mild-Moderate

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Low rate of hypertension awareness in Asia

Awareness of hypertension is low despite the clear relationship between high BP and CVD13 Low rates of awareness usually corresponded with suboptimal treatment rates, particularly in low-income Asian countries4

1. Sharma AK, et al. Indian Heart J 2006;58:21-7. 2. Sison J, et al. Philipp J Cardiol 2007;35:1-9. 3. Rampal L, et al. Public Health 2008;122:11-18. 4. Perkovic V, et al. Hypertension 2007;50:991-7.
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Asia: Prevalence, awareness and treatment of hypertension

Country China1 India2 Korea3 (>40 years, rural areas) Korea4 (30 years) Malaysia5 (>18 years) Philippines6 Singapore7 Indonesia (>18 years)8 Patients (n) 13,364 4,711 6,388 8,485 33,976 3,415 5,022 9,348 Prevalence (%) 43.8 36.0 43.8 24.9 32.2 21.0 41.5 31.7 Awareness (%) 26.2 22.1 60.1 63.5 35.8 16.0 51.8 _ Treated (%) 22.2 36.7 91.7 54.8 31.4 65.0 84.4 _ Controlled (%) 3.9 _ 27.2 38 26.3 20.0 27.1 _

1. Li H, et al. J Hypertens 2010;28:432-8. 2. Sharma AK, et al. Indian Heart J 2006;58:21-7. 3. Lee HS, et al. Clin Exp Hypertens 2010;32:166-78. 4. Korean National Health and Nutrition Examination Survey (KNHANES) 2008 [Korean]. Available at: http7. Basic Health Researches, 2008. Indonesian Health Department (c/o Dr Arieska Ann Soenarta).
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Data riskesdas 2007 : 1. Satu diantara 3 tiga orang (31,7 %) dewasa di Indonesia menderita HIPERTENSI 2. 76 % kasus hipertensi belum terdeksi

3 STROKE dan HIPERTENSI adalah penyebab kematian pertama dan kedua

4. Indonesia adalah negara ke 4 yang mempunyai penderita DM terbanyak didunia 5. 70 % penderita DM menderita hipertensi
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PATHOPHYSIOLOGY of HTN

C.O X Peripheral Resistance

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PATHOPHYSIOLOGY of HTN

WHY HIGH BP ??

MECHANISM Non specific explanation Essensial HTN : Dynamic interaction about : - genetic factor - environment factor - others C.O X Peripheral Resistance BP formula =

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CARDIAC OUTPUT = CO = Curah Jantung = pumped blood by heart per minute = HR x SV

BP = HR x SV x Peripheral resistance

HR = frequency per minute SV = one stroke of the hearts volume

Peripheral Resistance
Depend on lumen arteriole diameter
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OTHERS CONTRIBUTING FACTORS FOR ESSENTIAL HTN

Excess sodium intake Decreased Renal Filtration Increased sympathetic nervous system activity Increased RAA activity Vascular smooth muscle cell membrane alteration Obesity - Hyperinsulinemia Endothelial dysfunction
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Single-pills combination therapy Block Renin Angiotensin II Activity (ARB Telmisartan) & vascular smooth muscle membrane (CCB Amlodipin)
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PATHOPHYSIOLOGY OF HYPERTENSION
Blood pressure = Cardiac output (CO) x Peripheral resistance (PR)
Hypertension = Increased CO and/or Increased PR
Vasoconstriction

Preload Fluid volume Renal sodium Retention / Decreased Renal Filtraion Excess sodium intake

Contractility Fluid volume

Sympathetic nervous system Genetic factors

ReninAngiotensinAldosterone system

(Adapted from Kaplan, 1994)

RAAS

Renin-Angiotensin Cascade
Angiotensinogen
Non-renin (e.g. tPA)

Renin Bradykinin

Angiotensin I
Non-ACE (e.g. chymase)

ACE
Inactive peptides

Angiotensin II
AT1 AT2

ATn

PHYSIOLOGIC EFFECTS OF RAAS: AT1 RECEPTOR INHIBITION

Angiotensinogen
Renin

Bradykinin/Kinins Angiotensin I
ACE

Degradation

AT1-Antag

Angiotensin II
B1/B2-Receptor

AT1 Receptor

AT2 Receptor

Vasoconstriction Reactive oxygen species Cellular growth Apoptosis Neurohumoral activation

Nitric Oxide
Vasodilation Growth inhibition Apoptosis

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Recommendations for Multiple-mechanism Therapy: What the Treatment Guidelines Say

JNC VII1 Most patients with hypertension will require two or more

antihypertensive agents to achieve their BP goals

When BP is more than

20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be given to
initiate therapy with 2 drugs, either as separate prescriptions or in fixeddose combinations

ESHESC2 To reach target blood pressures, it is likely that a large proportion of

patients will require therapy with more than one agent

1Chobanian 2ESHESC

the recommendation
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et al. JAMA 2003;289:256072 Guidelines. J Hypertens 2003;21:101153

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Single-pills combination therapy ARB Telmisartan & CCB Amlodipin

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Hypertension management guidelines recommend CCBs and ARBs as preferred combination therapy partners
2007 ESH/ESC Guidelines1
Diuretics

2009 ESH/ESC Reappraisal2

Diuretics

-blockers

ARBs

ARBs

1-blockers

CCBs

CCBs

ACE inhibitors

ACE inhibitors

The begining
12-Jan-14 B. Rudy Utantio

The latest
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Calcium Channel Blockers (CCB)

Direct vasodilators Avoid in patients with CHF Most common side effects
Constipation Peripheral edema Headache

CCB Important :
Calcium channel blockers are especially effective in isolated systolic hypertension, a common condition in the elderly that is characterized by increased large arterial stiffening manifest as a wide peripheral pulse pressure

Classification Calcium Antagonists

Generation: First Second

Third

Latest

Nifedipine Verapamil Diltiazem

Felodipine Isradipine Nicardipine Nimodipine Nisoldipine Nitrendipine

Amlodipine Lercanidipine (hydrophilic) (lipophilic)

Prototype

Tissue selectivity Tissue selectivity Tissue selectivity gradual onset gradual onset Plasma controlled membrane-controlled
J Clin Basic Cardiol 1999;2:155

Classes of Calcium Channel Blocker

Dihydropiridines Non - dihydropiridines
Phenylalkylamines Benzothiazepines

Examples

Nifedipines Amlodipines Lercanidipine Increase

Verapamil

Diltiazem

Effect on heart rate

decrease

Decrease

Site of action
Side effects

Vasculature
Headache Ankle swelling (less with lercanidipine)

Vasculature and Vasculature heart and heart

Constipation Heart failure Heart block Heart failure Heart block constipation

SELECTIVITY CARDIAC vs VASCULAR

NONDHPs
Verapamil and diltiazem Verapamil and diltiazem Verapamil and diltiazem DHPs to varying extent (offset by reflex adrenergic activation Arterioles
SA node AV node Contractility

DHPs
Nifedipine and amlodipine (10 : 1)

Highly selective DHPs (100 : 1 or more) (felodipine, isradipine, nicardipine, nisoldipine)

Evolution of Calcium Antagonist

First generation: conventional
Verapamil, Diltiazem Nifedipine, Felodipine, Isradipine, Nicardepine, Nitrendipine

Second generation: modified release

Verapamil SR, Nifedipine XL/GITS, Felodipine ER Diltizem CD, Isradipine CR

Third generation: intrinsically long-acting

1. Long plasma half-life
Amlodipine

2. Long receptor half-life

Lercanidipine (Zanidip) Lacidipine Manidipine

Messerli, AJH 2002; 15:94s-97s

MECHANISM OF ACTION OF AMLODIPINE

Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle
Inhibition is selective, with a greater effect on vascular smooth muscle cells

It binds to both dihydropyridine and non-dihydropyridine binding sites Amlodipine is also a peripheral arterial vasodilator
Acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and a reduction in BP

http://www.pfizer.com/pfizer/download/uspi_norvasc.pdf

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PERIPHERAL OEDEMA ASSOCIATED WITH CCBS

Fluid leakage

Arterial dilation

No venous dilation

Fluid leakage Capillary bed

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273 White et al. Clin Pharmacol Ther 1986;39:438 48 Gustaffson. J Cardiovasc Pharmacol 1987;10(Suppl 1):S12131

COMPLEMENTARY EFFECTS OF A CCB/ARB: REDUCTION OF CCB-ASSOCIATED OEDEMA

Arterial dilation (CCB and ARB)

Venous dilation (ARB)

Capillary bed
Opie. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273 White et al. Clin Pharmacol Ther 1986;39:438; Gustaffson. J Cardiovasc Pharmacol 49 1987;10(Suppl. 1):S12131; Messerli et al. Am J Cardiol 2000;86:11827

CONCLUSION

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Algorithm for Treatment of Hypertension

Lifestyle Modifications
Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Stage 2 Hypertension
Without Compelling With Compelling (SBP >160 or DBP >100 mmHg) Indications Indications 2-drug combination for most (usually Drug(s) for the compelling Stage 2 Hypertension Stage 1 Hypertension indications Stage 2 Hypertension thiazide-type diuretic and (SBP >160 or DBP >100 mmHg) 2-drug combination for most ACEI, or ARB, or BB, or CCB) (usually thiazide-type diuretic and
(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Initial Drug Choices

(SBP 140159 or DBP 9099 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

ACEI, or ARB, or BB, or CCB)

Not at Goal Blood Pressure

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Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

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Hypertension management guidelines recommend CCBs and ARBs as preferred combination therapy partners
2007 ESH/ESC Guidelines1
Diuretics

2009 ESH/ESC Reappraisal2

Diuretics

-blockers

ARBs

ARBs

1-blockers

CCBs

CCBs

ACE inhibitors

ACE inhibitors

The begining
12-Jan-14 B. Rudy Utantio

The latest
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TWYNSTA?

----- L O V E N O X

YESSSS !!

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Hypertension Is Prevalent Among Diabetic Adults

Diabetes alone

29%
hipertensi

71%
Diabetes + HTN*
NHANES III = Third US National Health and Nutrition Examination Survey (19881994).
* Hypertension defined according to JNC-6: BP 130/85 mm Hg
12-Jan-14 Analisis dan Interprestasi Cepat 54 Geiss LS et al. Am J Prev Med. 2002;22:42-8. Membaca EKG

Hypertension: A Significant Risk Factor for Type 2 Diabetes

6 Year Follow-up of the Atherosclerosis Risk in Communities (ARIC-Study) Incidence of Diabetes
(Cases per 1000 Person Years)

30

* 29,1

*RR for Development of Type 2 Diabetes in Hypertension: 2.43

20 16,6 10 12,0

All Subjects (n=12.550)

Hypertension (n=3.804)

No Hypertension (n=8.746)

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Rully Roesli , 2008

Analisis dan Interprestasi Cepat Gress et al .N.Engl.J.Med. 2000;342: 905 55 Membaca EKG

DATA WHO

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Rully Roesli , 2008

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Type 2 Diabetes Mellitus (T2DM) Is the Tip of the Iceberg

40

30

(%)
20

Impaired glucose tolerance (IGT)

Undiagnosed diabetes

10

diabetes Diagnosed
0 20-44 45-54 55-64 65-74

Age (years)
Adapted from: Harris, MI et al. Diabetes Care. 1993;16:642-652.
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Coexistence of Hypertension in Metabolic Syndrome (Diabetes)

The DEADLY CONSPIRATION...
HYPERTENSION IN DIABETICS associated with a doubling of the presence of

Diabetic Kidney Disease

LVH

ECG signs of MI and a prior history of overt CV events

LVH, left ventricle hypertrophy; ECG, electrocardiogram; MI, myocardial ischemia, CV, cardiovascular.
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HIGH MORTALITY
Kaplan NM. In Ellenberg and Rifkins Diabetes Mellitus: Theory and Practice, 5th ed. 1997. Analisis dan Interprestasi Cepat
Membaca EKG

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Global cardiometabolic risk*

METABOLIC SYNDROME

DEATH

* working definition

Gelfand EV et al, 2006; Vasudevan AR et al, 2005

Hypertension Highlights

New US National Hypertension Guidelines -JNC 8 -- To Be Announced? Linda Brookes, MSc

Medscape Cardiology. 2008; 2008 Medscape Posted 02/19/2008

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Insulin Resistance and Angiotensin II

Glucose Intolerance Insulin Resistance Hyperinsulinemia Angiotensin II

DM
Hypertension Increase in RAS in Blood Vessel Contraction VSMC Proliferation Na Retension Sympathetic Nervous System
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Cardiovascular Events

REACHING GOAL OF TREATMENT What the guidelines says

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Blood pressure reduction of 2 mmHg reduces the risk of cardiovascular events by 710% Meta-analysis of 61 prospective, observational studies 1 million adults 7% reduction in 12.7 million person-years
2 mmHg decrease in mean SBP
risk of ischaemic heart disease mortality

10% reduction in risk of stroke mortality

Lewington et al. Lancet 2002;360:190313 Analisis dan Interprestasi Cepat 63 Membaca EKG

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Goals of Therapy Blood pressure target values for treatment of hypertension

Condition
Isolated systolic hypertension Systolic/Diastolic Hypertension Systolic BP Diastolic BP
Diabetes or Chronic Kidney Disease Systolic Diastolic

Target
SBP and DBP mmHg <140
<140 <90 <130 <80

CHEP 2011
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Hypertension and Antihypertensive Agents in Diabetic Kidney Disease

Clinical Assessment Target Blood Pressure Preferred Agents for CKD Other Agent to Reduce CVD Risk and Reach Target Blood Pressure Diuretic preferred, then betablocker or calciumchannel blocker A

Blood pressure > 130/80 mmHg

< 130/80 mm Hg

ACE Inhibitor or ARB

Blood pressure < 130/80 mm Hg

ACE inhibitor or ARB

Letters in shaded areas denote strength of recommendations

AJKD, Vol 43 No. 5, Suppl 1 (May), 2004, S142

Canadian Hypertension Education Program

2011
Part 2: Recommendations for Hypertension Treatment

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Treatment of Hypertension in association with Diabetic Nephropathy

THRESHOLD equal or over 130/80 mmHg and TARGET below 130/80 mmHg

DIABETES
with Nephropathy

ACE Inhibitor or ARB

IF ACEI and ARB are contraindicated or not tolerated, SUBSTITUTE Long-acting CCB or Thiazide diuretic

Addition of one or more of Long-acting CCB or Thiazide diuretic 3 - 4 drugs combination may be needed

If Creatinine over 150 mol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired

Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB

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Treatment of Hypertension in association with Diabetes Mellitus: Summary

Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg
with Nephropathy

ACE Inhibitor or ARB

Diabetes
1. ACE Inhibitor or ARB

A combination of 2 first line drugs may be considered as initial therapy if the blood pressure is >20 mmHg systolic or >10 mmHg diastolic above target. Combining an ACEi and a DHP-CCB is recommended.

without Nephropathy

or 2. DHP-CCB or Thiazide diuretic

> 2-drug combinations

Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB

Combinations of an ACEI with an ARB are specifically not recommended in the absence of proteinuria
More than 3 drugs may be needed to reach target values for diabetic patients
If Creatinine over 150 mol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired 12-Jan-14 Analisis dan Interprestasi Cepat Membaca EKG 69

WHICH IS BETTER ARB (SARTAN) OR ACE-I ?

Telmisartan

ACE of the ARB

Composite Endpoint*

Ramipril

ACE of the ACE-I

Secondary composite: HOPE Primary endpoint

p< 0.01 vs. non-inferiority margin (1.13)

0.8

0.9

1.0

1.1

1.2

Telmisartan better

Ramipril better

* ONTARGET primary composite endpoint = CV death + MI + stroke+ hospitalisation for CHF HOPE primary endpoint = CV death + MI + stroke Analisis dan Interprestasi Cepat 12-Jan-14 The ONTARGET Investigators. N Engl J Med 2008;358:1547 1559 Membaca EKG

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ACEIs in diabetic renal disease

ACEIs have proven to be effective in type 1 diabetes and nondiabetic kidney disease Micro-HOPE study confirmed that ACEIs reduce the risk of overt proteinuria and CV events in diabetic patients Before 2001, when DETAIL was designed, ACEIs were considered first line therapy for diabetic patients with nephropathy Today, ACEI is still the most commonly used antihypertensive class used to treat hypertensive diabetics, with usage ranging from Lewis EJ, N Engl J Med 1993;329:14561462 GISEN group. Lancet 1997;349:18571863 49% of patients in Japan Remuzzi et al. Ann.Intern.Med 2002:136:604-615 73% of patients in Germany HOPE Study Investigators. Lancet 2000;355:253259
Vivian et al. Ann Pharmacother 2001;35:452463 Treatment Algorithms: Hypertension 3rd Edition. Datamonitor 2002. London UK
71 12-Jan-14 Analisis dan Interprestasi Cepat Membaca EKG

ARBs in diabetic renal disease

In major clinical trials, ARBs have demonstrated effective renoprotection in type 2 diabetic nephropathy RENAAL IRMA 2 IDNT ARBs are a first line therapy for compelling indications in hypertension treatment guidelines Both ACEIs and ARBS are recommended for diabetic hypertension and for the treatment of renal disease in the medical literature and guidelines
Parving et al. N Engl J Med 2001;345:870878; Brenner et al. N Engl J Med 2001;345:861869 Lewis et al. N Engl J Med 2001;345:851860; ESH/ESC Guidelines. J Hypertens 2003;21:10111053 JNC 7. JAMA 2003;289:2560257; Johnson. Intern Med J 2004;34:5057 American Diabetes Association. Diabetes Care 2004;27(Suppl 1):S65S67 National Kidney Foundation. Am J Kidney Dis 2002; 39(2 Suppl 1):S1-266 Analisis dan Interprestasi Cepat National Kidney Foundation. Am J Kidney Dis 2004; 43(5 Suppl 1):S1 S268 12-Jan-14 72
Membaca EKG

ARBs vs ACE inhibitors in patients with CHF or MI

Outcome Trial
ARB Events/n ACE inhibitor Relative risk (95% CI) 1.63 ( 0.773.44) 1.06 ( 0.841.33) 0.95 ( 0.761.17) 1.02 ( 0.871.19) 1.24 ( 1.001.55) 1.08 ( 0.971.20) 0.97 ( 0.891.05) 1.06 ( 0.941.19) 0.87 ( 0.591.28) 1.14 ( 0.991.31) 1.01 ( 0.931.11) 1.05 ( 0.951.15) 1.0 2.0
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Stroke

ELITE II 18/1578 11/1574 OPTIMAAL 140/2744 132/2733 VALIANT 157/4909 166/4909 Overall ELITE II 161/1578 129/1574 OPTIMAAL 576/2744 533/2733 VALIANT 868/4909 896/4909 Overall ELITE II 46/1578 53/1574 OPTIMAAL 363/2744 318/2733 VALIANT 813/4909 801/4909 Overall Relative risk 0.5

Major CHD

Heart failure

12-Jan-14 Turnbull F. Lancet 2003;362:152735.

Favours ACE Favours ARB Analisis dan Interprestasi Cepat inhibitor Membaca EKG

From

Medscape Cardiology Angiotensin II Receptor Blockade Expert Column

Angiotensin Receptor Blockers: What Is Their Current Status?

Norman K. Hollenberg, MD, PhD

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Study
CONSENSUS I (1987) CONSENSUS II (1992) SOLVD I (1991) SOLVD II (1992) SAVE (1992) AIRE (1993) TRACE (1995) ATLAS (1999) ELITE (1997) ELITE II (2000)

Drug Class
ACEI ACEI ACEI ACEI ACEI ACEI ACEI ACEI ARB ARB CHF Post-MI

Clinical Condition

Primary Outcome
Favorable Neutral Favorable Favorable Favorable Favorable Favorable Favorable Favorable Neutral vs ACEI

Ventricular dysfunction Post-MI Post-MI Post-MI Post-MI CHF CHF CHF

HOPE (2000)
PROGRESS (2001) IDNT (2001) IRMA 2 (2001) RENAAL (2001) Val-HeFT (2001) ALLHAT (2002)

ACEI
ARB ARB ARB ARB ARB ACEI

High-risk profile
Stroke ESRD ESRD DM, microalbuminuria, HF CHF High-risk profile

Favorable
Favorable Favorable Favorable Favorable Favorable Neutral

LIFE (2002)
OPTIMAAL (2002) EUROPA (2003) ANBP2 (2003) VALIANT (2003) ONTARGET (2003) CHARM (2003)

ARB
ARB ACEI ARB ARB ARB ARB

Hypertension
High-risk profile Chronic stable CAD Elderly High-risk profile High-risk profile CHF

Favorable
-Favorable Favorable Neutral vs ACEI -Favorable

VALUE (2004)
BENEDICT (2004) DETAIL (2004) PEACE (2004)

ARB
ACEI ARB ACEI

Hypertension
DM, microalbuminuria DM, microalbuminuria

Neutral
Favorable Neutral vs ACEI

12-Jan-14

Neutral AnalisisPost-MI dan Interprestasi Cepat 75 Membaca EKG Medscape Cardiology. 2005;9(2) 2005 Medscape

Outcome trials completing the picture

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

76

Antihypertensive therapy: unanswered questions

What effects do the newer drug classes (ACE inhibitors, ARBs, CCBs) have on major CV events? Do these newer classes produce greater reductions in CHD? Does more intensive BP-lowering produce greater benefits? Are there special benefits associated with inhibition of the RAAS?

No single study is likely to answer all these questions

12-Jan-14 Analisis dan Interprestasi Cepat Membaca EKG 77

BPLTTC analyses: conclusions of second analysis

ACE inhibitors

Reduce risk of stroke Reduce risk of CHD Reduce risk of heart failure
ARBs

Reduce risk of stroke Reduce risk of heart failure Have no clear effect on CHD, but confidence limits are wide (15% to +9%)
12-Jan-14 BPLTTC, Blood Pressure Lowering Treatment Trialists Collaboration. Turnbull F. Lancet 2003;362:152735. Analisis dan Interprestasi Cepat Membaca EKG 78

Question:
Are the metabolic effects of all ARBs the same ?

Answer:
No
Some ARBs may have special metabolic benefits that go beyond angiotensin receptor blockade
12-Jan-14 Analisis dan Interprestasi Cepat Membaca EKG 79

valsartan

losartan

candesartan

olmesartan

irbesartan

telmisartan

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

80

Telmisartan is the Most Studied in Mortality and Morbidity Endpoint Trials Amongst ARBs
60.000
Number of patients
51,878

50.000 40.000 30.000 20.000

12,565 19,335

44,264

10.000
1,405

4,449 Olmesartan
ROADMAP2

6,405
Irbesartan
IRMA II3 IDNT4 I-Preserve5

Eprosartan
MOSES1

Candesartan
SCOPE6 CHARM7

Losartan
RENAAL8 ELITE II9 OPTIMAAL10 LIFE11

Valsartan
Val-HeFT12 NAVIGATOR13 VALIANT14 VALUE15

Telmisartan
TRANSCEND16 PRoFESS16 ONTARGET16

1. Schrader et al. Stroke. 2005;36:12181226; 2. http://www.roadmapstudy.org/resident.aspx; 3. Parving et al. NEJM. 2001;345:870878; 4. Lewis et al. NEJM. 2001;345:851860; 5. Carson et al. J Card Fail. 2005;11:576585; 6. Papademetriou et al. J Am Coll Cardiol. 2004;44:1175 1180; 7. www.atacand.com; 8. Brenner et al. NEJM. 2001;345:861869; Analisis dan Interprestasi Cepat 12-Jan-14 9. Pitt et al. Lancet. 2000;355:15821587; 10. Dickstein et al. Lancet. 2002;360:752760; 11. Dahlof et al. Lancet. 2002;359:9551003; 12. Cohn et al. NEJM. 2001;345:16671675; Membaca EKG 13. www.novartis.com; 14. Pfeffer et al. NEJM. 2003;349:18931906; 15. Julius et al. Lancet. 2004;363:20222031; 15. www.ontarget-micardis.com.

81

Volume of Distribution of Different ARBs

(Index of the Ability of a Drug to Enter Tissues Throughout the Body)

500
450 400 350
Liters

Telmisartan unique structure

1. Highly lipophilic molecule 2. Longest half life of all ARBs - Good 24 hour control of BP 3. Very high tissue penetrating ability - ability to access PPAR inside cells 4. Ability to interact more effectively with PPAR than other ARBs

300

250
200 150 100 50

Candesartan Valsartan
12-Jan-14

Olmesartan Losartan

Losartan Metabolite

Irbesartan

Telmisartan
82

Analisis dan Interprestasi Cepat Membaca EKG

Ability of Different ARBs To Activate PPAR

Fold activation

30

20

10

Candesartan Olmesartan Eprosartan

Valsartan

Irbesartan Losartan Metabolite

Telmisartan

10 micromolar
12-Jan-14 Analisis dan Interprestasi Cepat Membaca EKG Benson SC et al. Hypertension

2004;43:993-1002

83

Telmisartan: favourable pharmacokinetic and antihypertensive properties

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

84

Comparative pharmacokinetics of ARBs

Candesartan Cilexetil
Candesartan 15%

Telmisartan
Active metabolite Oral bioavailability Volume of distribution Terminal halflife Hepatic:renal elimination Protein binding No 4060%

Losartan
EXP3174 ~30%

Irbesartan
No 6080%

Valsartan
No 25%

500L

12L

1593L

10L

17L

~24 hours

69 hours

1115 hours

59 hours

69 hours

98:2 no CYP450 >99.5%

65:35 CYP450 99.8%

80:20 CYP450 9092%

60:40 CYP450 >99%

69:31 no CYP450 9497%

Unique properties of telmisartan beyond RAAS inhibition

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

86

Table 2. Antidiabetic mechanisms of ACE inhibitors and particular ARBs that may go beyond their effects on the renin-angiotensin system
ACE inhibitors may enhance glucose metabolism by : Activating bradykinin / nitric oxide pathways

Particular ARBs (e.g. telmisartan) may improve glucose and lipid metabolism by : Activating PPAR
ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; PPAR, peroxisome proliferator activated receptor gamma

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

Journal of Hypertension 2004, 22:2253-2261

87

Table 3. Potential anti-atherosclerotic mechanisms of PPAR activators

Increase insulin sensitivity Decrease fatty acid and triglyceride levels Increase reverse cholesterol transport and HDL levels Increase buoyancy of LDL particles Decrease inflammantion Decrease oxidative stress Decrease blood pressure Decrease vascular smooth muscle cell proliferation and migration
PPAR, peroxisome proliferator activated receptor gamma; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol Journal of Analisis dan Interprestasi Cepat Membaca EKG Hypertension 2004, 22:2253-2261 88

12-Jan-14

Telmisartan
Activates Blocks

PPAR pathways

Angiotensin pathways

Insulin resistance

Dyslipidemia

Cell inflammation

Cell proliferation

Hypertension

Oxidative stress

Potential influence of telmisartan on pathways that are likely primarily to mediate the anti-atherosclerotic effects of peroxisome proliferator activated receptor gamma (PPAR) activation and angiotensin II receptor blockade
12-Jan-14

Atherosclerosis Analisis dan Interprestasi Cepat

Membaca EKG

Journal of Hypertension 2004, 22:2253-2261

89

Dual ARB / PPAR Ligand

NF-B TNF- PAI-1 Fibrinogen CRP IL-6 VCAM NO

AT1-R Blockade AT2-R Activation

PPARModulation

Dyslipidemia Adiponectin Insulinemia Insulin sensitivity Leptin ACC2 Weight gain

Blood pressure Tissue fibrosis Tissue inflammation Cell proliferation Oxidative stress Endothelial dysfunction SNS activity

Ang - II

Steatohepatitis Atherosclerosis Atherogenesis

Cardiac function Cardiomyopathy

Glomerulosclerosis Islet function

90

12-Jan-14

Analisis dan Interprestasi Cepat Neuroregulation Membaca EKG

Two Classes of PPAR Activators

Non-Selective PPAR Activators Rosiglitazone, Pioglitazone Selective PPAR Modulators Telmisartan, nTZDpa Yes No No

Improve glucose & lipid metabolism

Adipocyte Hypertrophy Fluid retention Weight gain
12-Jan-14

Yes Yes Yes

Yes
Analisis dan Interprestasi Cepat Membaca EKG

No
91

AT1 receptor antagonism and PPAR-

Angiotensin II
ARB Cell membrane

AT1

AT2
Nuclear membrane

Antihypertensive Anti-inflammatory Anti-atherosclerotic Antidiabetic

L PPARs

p300
RXR

RA

PPRE

Gene

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

92

ARBs induce PPAR- activity

PPAR- target gene regulation
600

PPAR- binding domain activation

500

aP2-mRNA expression

400

Binding

Pioglitazone Eprosartan Losartan Irbesartan Telmisartan

25 20 15 10 5 0 0,1 1 10

Pioglitazone Telmisartan Irbesartan Losartan

300

200

EC50 Pioglitazone
100

0.2mmol/L 5.02mmol/L 26.97mmol/L

100

EC50 Telmisartan EC50 Irbesartan

EC50 Losartan
10

>50mmol/L

0.1 100 0.1 100 0.1 100 0.1 100 Analisis dan Interprestasi Cepat 12-Jan-14 Schupp M, et al. Circulation 2004;109:20547. Membaca EKG

93

Effects on Adiponectin and hs-CRP Levels of Replacing Valsartan or Candesartan by Telmisartan

(Miura Y et al., Diabetes Care 2005 Mar; 28, 757-758)

(mg/dl)

Adiponectin
**

(mg/dl)

hs-CRP
*

10

0.2

9
8 7 6 5 4 3 2 1 0
12-Jan-14

P<0.01

0.15

0.1

P<0.05

0.05

Candesartan/ Telmisartan Valsartan

Analisis dan Interprestasi Cepat Membaca EKG

Candesartan/ Telmisartan Valsartan

94

Telmisartan reduces triglyceride levels in patients with type 2 diabetes

Double-blind, placebo-controlled, 12-month trial in patients with type 2 diabetes and mild hypertension (DBP 91104mmHg)

140 Triglycerides (mg(dL) 120 100 80 60 40 20 0

p<0.05

n.s.

n.s.

Before treatment

After treatment

Telmisartan

Eprosartan

Placebo
95

Analisis dan Interprestasi Cepat 12-Jan-14 Derosa G, et al. Hypertens Res 2004;27:45764. Membaca EKG

PPAR--activating ARB reduces fasting insulin levels in hypertensive type 2 diabetics

Valsartan 80mg/day, n=11 Candesartan 8mg/day, n=7 All patients Telmisartan 40mg/day 12 weeks Fasting insulin Fasting glucose HbA1c Total cholesterol HDL cholesterol Adiponectin CRP

Fasting insulin level

12 10 8 g/mL mU/L 6 4 2 0 p<0.01 8 7 6 5 4 3 2 1 0

Adiponectin level
p<0.01

Baseline

After 12 weeks

Baseline

After 12 weeks
96

HDL, high-density lipoprotein; CRP, C-reactive protein. Analisis dan Interprestasi Cepat 12-Jan-14 Miura Y, et al. Diabetes Care 2005;28:7578. Membaca EKG

Telmisartan improves insulin sensitivity

40 patients recently diagnosed with hypertension and metabolic syndrome received 12 weeks telmisartan 80mg or losartan 50mg

8
Change from baseline 0 8 16 24 32 Fasting glycaemia

Losartan

Telmisartan

Fasting insulinaemia

HOMA index

HbA1c

HbA1c, glycosylated haemoglobin; HOMA, homeostasis model assessment. Vitale C, et al. Cardiovasc Diabetol 2005;4:18. Analisis dan Interprestasi Cepat 12-Jan-14 Membaca EKG

97

Telmisartan: from

to

Remodelling

Ventricular dilation/ cognitive dysfunction Congestive heart failure/ secondary stroke End-stage heart disease/ brain damage and dementia

MI and stroke Microalbuminuria Atherosclerosis Endothelial dysfunction Macroproteinuria

Nephrotic Proteinuria

Risk factors, e.g. hypertension, diabetes, obesity

End-stage renal disease

Cardio/ cerebrovascular death

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

98

The

programme

Programme of Research tO show Telmisartan End-organ proteCTION

Early morning BP surge Telmisartan vs ramipril Early morning BP surge Telmisartan+HCTZ vs Losartan+HCTZ Renal endothelial dysfunction Telmisartan vs ramipril Diabetic nephropathy Telmisartan vs placebo

Elderly/systolic hypertension Telmisartan+HCTZ vs Amlodipine+HCTZ

Diabetic nephropathy Telmisartan vs enalapril

Diabetic nephropathy Telmisartan vs losartan Diabetic nephropathy Telmisartan vs valsartan

Analisis dan Interprestasi Cepat Membaca EKG 99

Diabetic obese Telmisartan + HCTZ vs valsartan + HCTZ

12-Jan-14

COMBINATION OF ARB and/or ACE-I and CCB A FIRST LINE TREATMENT

ARB & CCB ??

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

100

Recommendations for Multiple-mechanism Therapy: What the Treatment Guidelines Say

JNC VII1 Most patients with hypertension will require two or more

antihypertensive agents to achieve their BP goals

When BP is more than

20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be
given to initiate therapy with 2 drugs, either as separate prescriptions or in fixed-dose combinations

ESHESC2 To reach target blood pressures, it is likely that a large proportion of

patients will require therapy with more than one agent

the recommendation
12-Jan-14

1Chobanian 2ESHESC

et al. JAMA 2003;289:256072 Guidelines. J Hypertens 2003;21:101153

101

Analisis dan Interprestasi Cepat Membaca EKG

Hypertension management guidelines recommend CCBs and ARBs as preferred combination therapy partners
2007 ESH/ESC Guidelines1
Diuretics

2009 ESH/ESC Reappraisal2

Diuretics

-blockers

ARBs

ARBs

1-blockers

CCBs

CCBs

ACE inhibitors

ACE inhibitors

The begining
12-Jan-14 Analisis dan Interprestasi Cepat Membaca EKG

The latest
102
102

Practical Guideline for Hypertension Management In Asian Popolation (cough with ACE-I = 30%)

ARB diuretics
FIXED COMBINATION

ACE-I CCB
FREE COMBINATION
Analisis dan Interprestasi Cepat Membaca EKG

12-Jan-14

103

Venous Fluid Leakage Induced by CCBs

Analisis dan Interprestasi Cepat Ther. Opie et12-Jan-14 al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42 73; White et al. Clin Pharmacol Membaca EKG 1986;39:4348; Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121S131.

104

 Gets Reduced by Co-administration of ARBs

Analisis dan Interprestasi Cepat Ther. 1986;39:4348; Opie et12-Jan-14 al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:42 73; White et al. Clin Pharmacol Membaca EKG 2000;86:11821187. Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121S131; Messerli et al. Am J Cardiol.

105

Renal Hyperfiltration Induced by Amlodipine is reduced by Telmisartan

Amlodipine
L-type Ca channels

Amlodipine + Telmisartan
L-type Ca channels

Increased
Glomerular pressure and filtration

Decreased
Glomerular pressure and filtration

12-Jan-14 Peti-Peterdi; Abstract ESC 2010 (submitted).

Analisis dan Interprestasi Cepat Membaca EKG

106

WHY AMLODIPINE ?

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

107

Amlodipine The longest half-life in class

35

Plasma elimination half-life (h)

> 30
30 25 20 16 15 10 5 0
Lercanidipine Nifedipine Nimodipine Nisoldipine Nicardipine Felodipine Lacidipine

19 14 12 9 7

Amlodipine
108

Based on available online product information.

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

Changes in Visceral Fat

(Shimabukuro et al, Japanese Circulation Society, 2006)

Amlodipine
300 300 250

Telmisartan

250

VFA cm2

200

VFA cm2

P< .05

200

150

150

P< .01

100

100

50

50

Before Treatment

After 6 months

Before Treatment

After 6 months

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

109

Benefits of single-pills combination therapy

Rationale for fixed-dose combinations (FDCs): efficacy; tolerability; compliance and persistence Beneficial impact of FDCs on compliance and persistence, and costs

12-Jan-14

Analisis dan Interprestasi Cepat Membaca EKG

110

CONCLUSION
There is NO such a BEST drug While there are GOOD DOCTOR s

who know which drug is BEST for their PATIENTS

Analisis dan Interprestasi Cepat Membaca EKG

12-Jan-14

111

Hatur Nuhun Matur Sushme

SALAM TWYNSTA
12-Jan-14 Analisis dan Interprestasi Cepat Membaca EKG 112

ESHESC RECOMMENDATIONS FOR COMBINING BP-LOWERING DRUGS AND AVAILABILITY AS FIXED-DOSE COMBINATIONS
Diuretics

b-blockers

Angiotensin receptor blockers (ARBs)

?
-blockers Calcium channel blockers (CCBs) Angiotensin-converting enzyme (ACE) inhibitors
Most rational combinations Combinations used as necessary 113 Available as FDC Adapted from ESHESC Guidelines. J Hypertens 2003;21:101153