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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
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
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.
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
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.
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 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.
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%