the important antihypertension (april 2004)

The Important Antihypertensive Agent in Preventing the Progression of Cardiovascular DemagesDjanggan SargowoBatu, 2004

HYPERTENSIONWorldwide 1 billion peopleUSA 50 million peoplePrevalence will be higher if there are no effective preventions

In INDONESIA complex problems:EtiologyPreventionEarly detectionManagementMonitoringSocio economicEducationIncome Etc. HYPERTENSION

ETIOLOGY OF HYPERTENSION Rudnie,Danilson & Sinclair (5.448 P. Hy)

Essential hypertension: 92,1 95,3 % Renal disease: 3,4 6,3 %Coarctasion of Aorta: 0 0,2 %Primary Aldosteronism: 0 0,3 %Cushings syndrome: 0,1 0,2 %Prehormacytoma: 0 0,2 %Oral Contraceptive induced: 0,2 1 %

NATURAL HISTORY OF HYPERTENSION

HEREDITY - ENVIRONMENTPRE - HYPERTENSIONEARLY HYPERTENSIONESTABLISHED HYPERTENSIONUNCOMPLICATEDCOMPLICATEDAccelerated Malignant courseCARDIAC Hypertrophy Failure InfarctionLARGE VESSEL Aneurysm DissectionCEREBRAL Ischemia Thrombosis HemorrhageRENAL Nephrosclerosis FailureNormotension Age0 - 3020 4030 5040

CVD Risk FactorsHypertension*Cigarette smokingObesity* (BMI >30 kg/m2)Physical inactivityDyslipidemia*Diabetes mellitus*Microalbuminuria or estimated GFR

WHO-ISH (1999)

Klasifikasi Derajat Tekanan Darah menurut WHO-ISH 1999 yang diadaptasi dari JNC VI 1997Kategori SistolikDiastolik (mmHg)(mmHg)1Optimal 120 802Normal 130 853Normal Tinggi130 - 13985 - 894Hipertensi derajat 1 (ringan) 140 - 15990 - 99Subgrup : perbatasan140 - 14990 - 945Hipertensi derajat 2 (sedang)160 - 179100 - 1096Hipertensi derajat 3 (berat) 180 1107Hipertensi Sistolik 140 90(Isolated Systolic Hypertension)

The hypertension to heart failure continuum

HypertensionLV hypertrophyMyocardial infarction RemodellingSystolicDiastolicSymptomsDecreased tissue perfusionIncreased hospitalisationsCoronary risk factorsDeathCoronary artery diseaseLV dysfunctionHeart failureLV dilationLV damage

Hemodynamic overload

HypertensionMyocardial InfarctionMyocardial RemodelingMyocardial FailureHemodynamic Overload

Myocardial Remodeling

Systolic OverloadHypertensionAortic StenosisDiastolic OverloadMyocardial InfarctionValvular RegurgitationConcentric HypertrophyEccentricHypertrophy

Factors Controlling LVH in Hypertension

LVHBLOOD PRESSUREAGEGENDERWEIGHTINSULIN, GROWTH, THYROID HORMONRENIN-ANGIOTENSIN SYSTEMADRENERGICSYSTEMCOEXISTENTCARDIAC DISORDERSEXERCISE

LVHMyocardialIschemiaInfarction

ArrhythmiaSudden deathImpairedLV fillingImpairedcontractilityHeart failure

Adapted with permission from Dzau V, Braunwald E. Am Heart J. 1991;121:1244-1263.MIThe Cardiovascular ContinuumNeurohormonalactivationLoss ofmuscleLV RemodelingRisk factorsHyperlipidemiaHTNDiabetesSmokingInsulin resistance

Atherosclerosis&LVHEndothelial dysfunctionMicrovascular DiseaseCADVentricular dilationHFDeathEnd-stage Microvascular & Heart Disease

Heart failure is the final common endpoint of a variety of CV insults.Initially, risk factors such as hypertension, hyperlipidemia, diabetes, and insulin resistance elicit progressive changes in the vasculature and heart resulting in atherosclerosis and LVH.These pathophysiologic changes can lead to myocardial ischemia and MI.The renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system, and other neurohormonal systems are activated in response to these CV insults initially to compensate for hemodynamic dysfunction, but ultimately their stimulation leads to further cardiac impairment.

Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J. 1991;121:1244-1263.

THE LATEST GUIDELINES:

HYPERTENSION

The Seventh Report of the JOINT NATIONAL COMMITTEE on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) (May, 2003)

2003 Guidelines for the management of hypertension from European Society of Hypertension European Society of Cardiology (ESH ESC 2003)(June, 2003)

JNC VIINEW GUIDELINES IN JNC VII:1. Classification and Management of Blood Pressure for Aduls2. Patient Evaluation3. Treatment

1. Classification and Management of Blood Pressure for Adults

JNC V (1988)Isolated systolic Hypertension> 160Borderline isolated systolic H.140 159Normal BP< 140

DBP < 90 mmHg

SBP, whenSevere Hypertension > 115Moderate hypertension105 114Mild Hypertension90 104High normal BP85 89Normal BP< 85

BDPCategoryBP Range, mmHgClassification of HypertensionJoint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Presure (JNC)

JNC VI (1997)> 110> 180Stage 3100 109160 179Stage 290 99140 159Stafe 185 89130 139Normal high< 85< 130NormalDiastolic( mmHg )Systolic ( mmHg )Blood Presure

JNC VII> 100or> 160Stage 2 H.90 99or140 159Stage 1 H.80 89or120 139Prehypertension< 80and< 120NormalDBP

SBPBlood Presure(mmHg)

The Aims of Hypertension ManagementDecrease mortality and morbidityRestore blood pressure to normal levels1Maintain blood pressure at TD < 140/90 mmHg21. 1999 World Health Organisation-International Society of Hypertension Guidelines for the Management of Hypertension.2. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Seperti yang diketahui, tujuan akhir manajemen hipertensi adalah menurunkan angka morbiditas dan mortalitas, dimana diantaranya dicapai den gan mengembalikan/mempertahankan TD ke tingkat normal/optimal.

The Ideal of Antihypertension DrugDecrease cardiac outputDecrease systemic peripheral resistenseMaintain the normal cardiac outputMaintain organ perfussion

Cardioprotective Effect of Antihypertension DrugsPrevents atherosclerosis progression Prevents hearth attacksPrevent and regression of LVHDoes not increase risk factors

2.a. Management of treatment :

- Based on Risk Stratification - We start with antihypertensive drugs: Very High Risk High Risk Moderate Risk ( if BP didnt after 3 months non-pharmocology treatment) Low Risk (if BP didnt after 3 - 12 months non-pharmocology treatment)

Risk Stratification and Treatment (JNC-VI)Risk Group BRisk Group C(At Least 1 Risk(TOD/CCD and/orRisk Group AFactor, Not IncludingDiabetes, With orBlood Pressure Stages(No Risk FactorsDiabetes; NoWithout Other Risk(mmHg)No TOD/CCD)TOD/CCD)Factors)

High-normalLifestyleLifestyleDrug therapy(130-139/89-89)modificationmodification

Stage 1LifestyleLifestyleDrug therapy(140-159/90-99)modificationmodification(up to 12 months)(up to 6 months)

Stages 2 and 3 Drug therapyDrug therapyDrug therapy(> 160/> 100)For example, a patient with diabetes and a blood pressure of 142/94 mmHg plus left ventricular hypertrophy should be classified as having stage 1 hypertension with target organ disease (left ventricular hypertrophy) and with another major risk factor (diabetes). This patient would be categorized as Stage 1, Risk Group C, and recommended for immediate initiation of pharmacologic treatment.

2. PATIENT EVALUATION

2. PATIENT EVALUATION:

2.1. To asses lifestyle and identify other cardiovascular risk factors or concomitant disorders that may effect prognosis and guide treatment

2. PATIENT EVALUATION

2.2. To reveal identifiable causes of high Blood Pressure2.3. To assess the presence or absence of target organ damage and CVD

3. TREATMENT

ESH ESC 2003NEW GUIDELINES IN ESH-ESC 2003:1. Classification and Risk Stratification2. Treatment 2.1. Management of treatment 2.2. Indication & contra-indication of 6 antihypertensive drugs

1999 WHO-ISH Guidelines for Initiationof Anti-Hypertensive Treatment The six classes of antihypertensive agents listed in the new WHO/ISH guidelines:

DiureticsBeta-blockersACE Inhibitors

Calcium antagonistsAlpha-blockersAngiotensin II Receptor Blockers

Guidelines Subcommitte 1999 WHO-Intl Society of Hypertension. Guidelines for Management of Hypertension. J Hypertens 1999;17:151-83

Classification and Management of BP for adults

JNC VII 2003JAMA.2003;289

Compelling indicationsHeart FailurePost Myocardial InfarctionHigh Coronary Art. Disease RiskDiabetesChronic Kidney DiseaseRecurrent Stroke Prevention

JNC VII 2003JAMA.2003;289

Lifestyle Modifications to Prevent and Manage HypertensionAvoid tobacco

(JNC VI. Arch Intern Med. 1997)Reduce weight

Moderate consumption of:alcohol sodiumsaturated fatcholesterol

Increase physical activity

Maintain adequate intake of dietary:potassiumcalcium magnesium

1950196019701980DiureticsBeta blockersCCBs1-blockersACE-inhibitors19902000AT1-antagonists?Reserpin (1949)HCT (1958)Verapamil (1963)Furosemide (1964)Propanolol (1965)Nifedipin (1975)Prazosin (1977)Captopril (1981)Losartan (1995)ValsartanDevelopment of Antihypertensive Drugs

INDICATIONS FOR INDIVIDUAL DRUG CLASSES

Stroke prevention

Chronic kidney diseaseDiabetes

High coronary disease risk

Post-MI

Heart failureCCBARBACE inhibitor-blockerDiureticCompelling indicationsThe JNC VII Report. JAMA 2003;289:2560-2572

HypertensionWithoutCompelling indicationStage 1 HypertensionSyst. 140 159 ORDiast. 80 90 mmHg

Thiazide type diuretics for mostMay consider ACE inh,ARB, CCB, BetablockerOr Combination

Stage 2 HypertensionSyst. > 160 mmHg ORDiast > 100 mmHg

2 Drug Combination for mostUsualy thiazide type withACE inh. or ARB or BetaBlocker or CCBJNC VII 2003JAMA.2003;289

Treatment Algorithm for Adults with Systolic-Diastolic Hypertension without another compelling indication

TARGET

HypertensionWithCompelling IndicationDrugs for the compelling indications.

PRICEMETABOLIC ( ec : DM )/ COPDHEARTFAILURE /LV DYS-FUNCTIONDiureticACE inh / ARB. Ec: Tanapress ( Tanabe )BetablockerEc : Maintate ( Tanabe )CCB* Ec : Herbesser CD( Tanabe )JNC VII 2003CCB* : CalciumChannel BlockerC.H.D /ANGINAJAMA.2003;289

Renin inhibitors AII receptor blockersAngiotensin IIReninConverting enzymeAngiotensinreceptorsAngiotensinogenACE inhibitorAngiotensin ILiverTissueCirculatingLocalNon Renin pathways - t-PA - Cathepsin G - ToninNon-ACE pathways - Chymase - CAGE - Cathepsin GThe Renin-Angiotensin SystemAlternate Pathway

Indikasi Spesifik dari ACEIHipertensi ringan, sedang, beratHipertensi disertai hipertropi ventrikel kiriGagal jantung kiriMiokard infark disertai remodelingDiabetes disertai mikroalbuminuriaHipertensi disertaiPenyakit vaskuler periferPenyakit jalan nafas obstruktif menahunDepresi

ACE INHIBITOR (ACEI)

TANAPRESS Selectively Inhibit RAA System

Kubo M et al. Jpn J Pharmacol 57(4): 517-26 (1991)Inhibitory effects on tissue ACE activitySubjects : Young male SHRs (n = 7 8)Method: Inhibition of ACE activity was measured 9 days after stopping administration of ACEIs for 10 weeks.108642012ACE Activity in the Thoracic Aorta(nmol/min/mg protein)ControlCaptopril(5 mg/kg/day)Enalapril(5 mg/kg/day)Imidapril(5 mg/kg/day)P < 0.05

Change in Exercise Durationafter 12 weeks treatment with IMIDAPRILChange in Physical Working Capacity (PWC) after 12 weeks treatment with IMIDAPRILChange in Exercise Durationafter 12 weeks treatment with IMIDAPRILChange in Physical Working Capacity (PWC) after 12 weeks treatment with IMIDAPRIL

TANAPRESS Optimally Control Blood Pressure With Once Daily Regimen

TANAPRESS Reduce Urinary Albumin Excretion at Similar Degress Compared to Captopril in Diabetic Patients with Hypertension

AT1-receptor blockers: improving heart function Reducing hypertension [1] Reducing LV hypertrophy/improving LV relaxation Antagonising adverse effects of elevated neurohormones Reducing aldosterone levels Maintaining renal function 1Goodfriend et al. N Engl J Med 1996; 334: 1649542.Swedberg et al. J Card Failure 1999; 5: 27682

AT1-receptor blockers have been widely used in the treatment of systemic hypertension and are generally considered effective agents for lowering blood pressure with a favourable tolerability profile [1].Theoretically, an AT1-receptor blocker could improve heart function and prognosis by several mechanisms. These could include reducing LV hypertrophy and improving LV relaxation, thus reducing diastolic dysfunction; antagonising the adverse effects of elevated neurohormones; reducing aldosterone levels that could lead to less myocardial fibrosis; and maintaining renal function which may, in turn, reduce fluid retention and sodium overload. In addition, the risk of a development of a systolic dysfunction over time might be decreased by lowering blood pressure, improving ventricular coupling and reducing ischaemia [2].

References Goodfriend TL, Elliot ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996; 334:164954. Swedberg K, Pfeffer M, Granger C et al. Candesartan in Heart Failure Assessment of Mortality and Morbidity (CHARM): rationale and design. J Card Failure 1999; 5(3): 27682.

Risk factors Hyperlipidemia Hipertensi Diabetes Smoking Insulin resistance

Atherosclerosis&LVHEndothelial dysfunctionMicrovascular DiseaseCADMIRole of ARBs inThe Cardiovascular ContinuumLoss ofmuscleVentricular dilationHFDeathLV RemodelingOPTIMAALVALIANTEnd-stage Microvascular & Heart DiseaseRENAALIDNTIRMA-2MARVALElite II Val-HeFTCHARMNAVIGATORVALUESCOPEONTARGETTRANSCENDLIFE



Compelling Indications for Individual Drug Classes

THE CARDIOVASCULAR CONTINUUMMyocardialinfarctionArrhythmia &loss of muscleRemodellingVentriculardilatationCongestiveheart failureDeathCoronarythrombosisMyocardialischaemiaCADAtherosclerosisLVHRisk factorssmoking,hypertensioncholesterol, diabetes

Adrenergicblockade

Hypertrophy, apoptosis, ischemia,arrhythmia, remodelling, fibrosisACTIVATION AND BLOCKADE OF NEUROHUMORAL SYSTEM IN CHFRAA System SNS SystemAngiotensin IINoradrenalinACE-I-Blocker

WHERE -BLOCKERS WORKHypertensionDiabetesHyperlipidemiaHypertrophiccardiomyopathyCoronaryarterydiseaseAnginaMyocardialinfarctionLVdysfunctionHeartfailurePumpfailureVentriculararrhythmias

SuddendeathMechanical death

Atrialfibrillation

Cardiacrupture

-blocking agentsAntihypertensiveAnti-ischemicAntiarrythmicTreatment for heart failure

Not all -BLOCKERS are the same !ISA -ISA +NadololPindolol PropanololPenbutololTimololAlprenololSotalolOxprenololNON SELECTIVEISA -ISA +AtenololAcebutololEsmololCeliporlolMetoprololBisoprololBetaxololSELECTIVEBisoprololNon-selective withalfa-blocking activityLabetololBucindololCarvedilol

Modified from:CIBIS II,Lancet,Vol.353,1999*no data

Treatment Algorithm for Adults with Systolic-Diastolic Hypertension without another compelling indication

TARGET

10050AtenololBisoprololBetaxololMetoprololBalanced clearanceMetabolitesUnchanged substanceMETABOLISM OF VARIOUS -BLOCKERLeopold G.J.Cardiovasc. Pharmacol. 1986; 8(Suppl. 11): 16-20%

Survival Rate of BisoprololCIBIS-II, Lancet, Vol. 353, 1999Bisoprololp0,0001placebo200 400 600 800Time after inclusion (days)Survival34% reduction in all-cause mortality with bisoprolol

87654321Start1 Year2 Years3 Years4 Years5 YearsTotal cholestrolTriglycerides

HDL-cholesterolLDL-cholesterolMmol/lBISOPROLOL : NEUTRAL EFFECT ON LIPID METABOLISMFrithz G.5th Internat Symposium on Cardiovascular Pharmacotherapy,Minneapolis,Abstract 1993

170160150140130120110 A B C A B C678910Glucose (mg/dl)HbA1 (%)A: Initial ValueB: after 2 weeks of BisoprololC: after 2 weeks of placebo

BISOPROLOL : Neutral Effect on Glucose MetabolismJanka HU etal.J Cardiovasc Pharmacol 1986; 8 (Suppl.11):96-99

60801001201401601801 3 5 7 9 11 13 15 17 19 21 23 h SBPDBPLast day of placeboAfter 4 weeks of Bisoprolol(mmHg)BISOPROLOL : Circadian rhythm

Chart2

88.670

84.565.5

8867.5

82.569.5

75.373

84.574.4

10480.7

109.890.7

114.690

10686.2

96.877

10382

103.682

100.983

97.586.6

10777

105.284.5

104.481.8

10284

102.884

10281.8

10083

98.977.7

94.177.7

9170.9

87.370.2

placebo

bisoprolol

Sheet1

placebobisoprolol

88.670

84.565.5

8867.5

82.569.5

75.373

84.574.4

10480.7

109.890.7

114.690

10686.2

96.877

10382

103.682

100.983

97.586.6

10777

105.284.5

104.481.8

10284

102.884

10281.8

10083

98.977.7

94.177.7

9170.9

87.370.2

Sheet1

placebo

bisoprolol

Sheet2

placebo

bisoprolol

Sheet3

Bisoprolol : Dose-dependent blood pressure reduction in hypertensives0-10-20-30-400-10-20-30-40SBPDBP285684285684DaysDays5 mg10 mg20 mgBisoprololmmHgmmHgKirsten,R.,et al.;J. Cardiovasc. Pharmacol. 8(Suppl.11)(1986):S 11

RECENT STUDIES REPORTING INCREASEDRISK WITH ANTIHYPERTENSIVE DRUGSShort acting Calcium Antagonist-particulary at high doses-increase MI risk in Hypertensive patients (Psaty et. Al. JAMA 1995; 274 : 629-625)

Short acting Nifedipine increase mortality risk in patients with CHD(Furberg et al. Circulation 1995; 92:1326-1331)

Short - acting nifedipine has not approved by the Food and Drug Administration of USA for the treatment of hypertension.(Bassett et al. Journal of Hypertension 1997; 15:915-923)

PREVENT: Hospitalization for Unstable Angina

and Major Vascular Procedures by Treatment

Pitt et al. Circulation. 2000;102:1503-1510.

Months of Follow-up

Any Revascularization

Placebo

Amlodipine besylate

43%

P=.001

30.0

25.0

20.0

15.0

10.0

5.0

0.0

0

6

12

18

24

30

36

Cumulative Event/

Procedure Rate (%)

Months of Follow-up

Documented Unstable Angina/

Congestive Heart Failure

Placebo (n=408)

Amlodipine besylate (n=417)

35%

P=.01

30.0

25.0

20.0

15.0

10.0

5.0

0.0

0

6

12

18

24

30

36

Pitt B, Byington RP, Furberg CD, et al, for the PREVENT Investigators. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;102:1503-1510.

In PREVENT, treatment with amlodipine besylate was associated with significant reductions in clinical outcomes at 3 years for patients with documented heart disease. Long-term treatment with amlodipine besylate resulted in a 35% reduction in hospitalizations for unstable angina and CHF (P=.01) compared with placebo. Major vascular procedures, including CABG and percutaneous coronary intervention (PCI), were reduced by 43% in amlodipine besylatetreated patients compared with placebo controls (P=.001). The curves separated early, and the treatment effect continued with time.

SLIDE 92

Pitt B, Byington RP, Furberg CD, et al, for the PREVENT Investigators. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000;102:1503-1510.

In PREVENT, treatment with amlodipine besylate was associated with significant reductions in clinical outcomes at 3 years for patients with documented heart disease. Long-term treatment with amlodipine besylate resulted in a 35% reduction in hospitalizations for unstable angina and CHF (P=.01) compared with placebo. Major vascular procedures, including CABG and percutaneous coronary intervention (PCI), were reduced by 43% in amlodipine besylatetreated patients compared with placebo controls (P=.001). The curves separated early, and the treatment effect continued with time.

SLIDE 92

MENURUNKAN KEBUTUHAN OKSIGEN MIOKARDIUM Menurunkan Tekanan Darah Menurunkan Denyut Jantung

MENEKAN KERUSAKAN SEL MIOKARDIUM AKIBATINFLIKS ION CA++ YANG BERLEBIHAN KE DALAM SEL Menekan peningkatan ion Ca++ di dalam sel miokardium Menekan penurunan ATP & CP di dalam sel miokardium

MENINGKATKAN PENYEDIAAN OKSIGEN MIOKARDIUM Menghilangkan spasme koroner Meningkatkan aliran darah sub-endokardium Menurunkan denyut jantung (memperpanjang periode diastolik) Menekan sklerosis koroner

EFEK : Anti AritmiaEFFEK KARDIOPROTEKTIF CALSIUM ANTAGONIST

CAPARES : Amlodipine Treatment

Reduced Need for Repeat PTCA

No. of Events

40

Composite Endpoint

(Death, MI, CABG,

Repeat PTCA)

Repeat

PTCA

20

23

9

P=.011

P=.007

Jrgensen et al. J Am Coll Cardiol. 2000;35:592-599.

N=635

No change in primary endpoint: loss in minimal lumen diameter

Significant reduction in composite clinical endpoint and repeat PTCA

SLIDE *

Jrgensen B, Simonsen S, Endresen K, et al. Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the Coronary AngioPlasty Amlodipine REStenosis Study (CAPARES). J Am Coll Cardiol. 2000;35:592-599.

The need for repeat PTCA and the rate of composite major clinical endpoints were reduced by amlodipine therapy, despite an apparent absence of effect on restenosis as measured by QCA.

Slide 49

SLIDE *

Jrgensen B, Simonsen S, Endresen K, et al. Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the Coronary AngioPlasty Amlodipine REStenosis Study (CAPARES). J Am Coll Cardiol. 2000;35:592-599.

The need for repeat PTCA and the rate of composite major clinical endpoints were reduced by amlodipine therapy, despite an apparent absence of effect on restenosis as measured by QCA.

Slide 49

Diltiazem in the management of acute myocardial infarction treated with trombolythic agents ; a randomized controlled trialWilliam E Boden et al for the INTERCEPTstudy groupTHE LANCET Vol 355 May 20 2000 1751-1756 Articel

INTERCEPT : PurposeBACKGROUNDDiltiazem reducesNon-fatal reinfarction,Refractory ischaemia after non-Q-wave myocardial infarction (acute coronary syndrome).

PURPOSETo evaluate whether diltiazem would reduce cardiac events in patients after acute MI treated initially with thrombolytic agents.

BODEN WE et al . LANCET 2000; 355: 1751-1756

INTERCEPT : RESULTS (1)Primary endpoint BODEN WE et al . LANCET 2000 ; 355 : 1751-1756

21%P= 0.0719%P= 0.0729%P= 0.0524%P= 0.0520%P= 0.0533%P= 0.0339%P= 0.03Cardiac death + Non-fatal reinfarction + Refractory ischemiaCardiac death + Non-fatal reinfarction + All recurrent ischemiaCardiac death + Non-fatal reinfarction + PTCA/CABGNon-fatal reinfarction + Refractory ischemiaNon-fatal reinfarction + All recurrent ischemiaNon-fatal reinfarction + PTCA/CABGPTCA/CABGDiltiazem reduced non-fatal cardiac death, non-fatal reinfarction or refractory ischemia, and the need for PTCA / CABG in Acute Myocardial Infarction (AMI). INTERCEPT : RESULTS (2) BODEN WE et al . LANCET 2000; 355 : 1751-1756

INTERCEPT : CONCLUSION BODEN WE et al . LANCET 2000 ; 355 : 1751-1756The INTERCEPT showed that diltiazem reduce all composite endpoints of non-fatal cardiac events:reinfarction (21%),refractory ischemia (24%),recurrent ischemia (20%),the need for PTCA/CABG (39%).

The implications of the INTERCEPT findings are important to cardiovacular therapeutics of Heart rate lowering Calcium Antagonists - Diltiazem in the management of ACS.

As Evidenced based Medicine( Lancet 2000 )

NORDIL : The NORdic DILtiazem StudyA Prospective Intervention Trial of Ca-Antagonist Therapy in Hypertension

Heart failure is a condition in which the diastolic and/or systolic function is impaired resulting in characteristic signs and symptoms. Coronary artery disease accounts for the vast majority of cases of heart failure. For most patients this will begin with an acute myocardial infarction. The size of the initial myocardial injury is probably the main determinant of progression to overt heart failure. Patients with larger infarcts, causing more extensive damage to the myocardium, are most likely to develop heart failure. Hypertension is another important risk factor in the development of heart failure. Other causes are idiopathic, perhaps of viral origin in some cases, or valvular defects. There are also a number of non-cardiac causes of heart failure.Chronic heart failure usually presents with breathlessness ( dyspnoea ) and fatigue. In the early phases this is often due to diastolic dysfunction. In the later stages the reduction in cardiac output causes fatigue and lethargy, and fluid retention can lead to peripheral and pulmonary oedema ( swollen ankles and breathlessness and wheezing ).In the USA there are 59 million people with cardiovascular disease of which 50 million have hypertension, 3 million have congestive heart failure and 1.5 million have acute myocardial infarction. Thus congestive heart failure is a major public health problem and represents the leading cause of hospitalisation in patients over the age of 65 years. Prognosis is poor, with one year mortality ranging from 15% among relatively unselected patients to 50% among those with severe disease.

NORDIL Relative risk

Myocardial infarction(fatal and non-fatal)Stroke(fatal and non-fatal)Primary endpointRelative risk(95%CI)1.16(0.94-1.14)0.80(0.65-0.99)1.00(0.87-1.15)p0.170.040.97Diltiazem/D

0.51.02.0Adjusted for age, sex, diabetes, blood pressure and smokingTHE LANCET Vol 356 July 29 2000 359-365

1.020%

Stroke4510012345Years%Patients with eventConventionalDiltiazem23

Myocardial infarction4510012345Years%Patients with eventConventionalDiltiazem23

The NORDIL Study- Stroke and MI in subgroups -% 615434Percentage of patients with stroke (above) and MI (below)DBP 105StrokePatients at risk-blockers/diureticsDiltiazem2022% 6

29742905288928201971

24932501243324451509MIPatients at risk-blockers/diureticsDiltiazemDiltiazem5321042002% 653210297429052868282319780p = 0.0304321543210n.s.5% 60453211545DBP < 105 24932501242724501516543210n.s.45321043210n.s.5-bl/diur

ConclusionNORDIL study showed:( 10.881 patients 50 74 years old , follow up 4.5 years )

Diltiazem was as effective as the beta-blocker and/or diuretics in preventing CV mortality and morbidity.

Diltiazem ( Herbesser ) reduced fatal and non-fatal stroke 20% more than conventional therapy.

Combination Drugs of Hypertension

DiureticsACE Inhibitor (ARB) - blockerC.C. Blocker

PERCENTAGE OF PATIENTS WHO NEEDED COMBINATION THERAPY0102030405060708090100Syst-EurSTOP1NORDILMRC1INSIGHTCOOPEAverage% OF PATIENTS

DIURETICSBETHA BLOCKERSALFA BLOCKERSACE INHIBITORSCALCIUM ANTAGONISTSAT1- RECEPTOR BLOCKERSPOSSIBLE COMBINATIONS OF DIFFERENT CLASSES OF ANTIHYPERTENSIVE AGENTS

Efective drug combinationsDiuretic and -blockerDiuretic and ACE Inhibitor or AIIRACalcium antagonist (dihydropyridine) and -blocker.Calcium antagonist and ACE inhibitor.-Blocker and -blocker

Thank You



Seperti yang diketahui, tujuan akhir manajemen hipertensi adalah menurunkan angka morbiditas dan mortalitas, dimana diantaranya dicapai den gan mengembalikan/mempertahankan TD ke tingkat normal/optimal.

AT1-receptor blockers have been widely used in the treatment of systemic hypertension and are generally considered effective agents for lowering blood pressure with a favourable tolerability profile [1].Theoretically, an AT1-receptor blocker could improve heart function and prognosis by several mechanisms. These could include reducing LV hypertrophy and improving LV relaxation, thus reducing diastolic dysfunction; antagonising the adverse effects of elevated neurohormones; reducing aldosterone levels that could lead to less myocardial fibrosis; and maintaining renal function which may, in turn, reduce fluid retention and sodium overload. In addition, the risk of a development of a systolic dysfunction over time might be decreased by lowering blood pressure, improving ventricular coupling and reducing ischaemia [2].

References Goodfriend TL, Elliot ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996; 334:164954. Swedberg K, Pfeffer M, Granger C et al. Candesartan in Heart Failure Assessment of Mortality and Morbidity (CHARM): rationale and design. J Card Failure 1999; 5(3): 27682.



Heart failure is a condition in which the diastolic and/or systolic function is impaired resulting in characteristic signs and symptoms. Coronary artery disease accounts for the vast majority of cases of heart failure. For most patients this will begin with an acute myocardial infarction. The size of the initial myocardial injury is probably the main determinant of progression to overt heart failure. Patients with larger infarcts, causing more extensive damage to the myocardium, are most likely to develop heart failure. Hypertension is another important risk factor in the development of heart failure. Other causes are idiopathic, perhaps of viral origin in some cases, or valvular defects. There are also a number of non-cardiac causes of heart failure.Chronic heart failure usually presents with breathlessness ( dyspnoea ) and fatigue. In the early phases this is often due to diastolic dysfunction. In the later stages the reduction in cardiac output causes fatigue and lethargy, and fluid retention can lead to peripheral and pulmonary oedema ( swollen ankles and breathlessness and wheezing ).In the USA there are 59 million people with cardiovascular disease of which 50 million have hypertension, 3 million have congestive heart failure and 1.5 million have acute myocardial infarction. Thus congestive heart failure is a major public health problem and represents the leading cause of hospitalisation in patients over the age of 65 years. Prognosis is poor, with one year mortality ranging from 15% among relatively unselected patients to 50% among those with severe disease. 1.020%

the important antihypertension (april 2004)

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