Summary of general pharmacotherapeutic approaches in cardiology Jan Bultas, Debora Karetová 2013.
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Transcript of Summary of general pharmacotherapeutic approaches in cardiology Jan Bultas, Debora Karetová 2013.
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Summary of general pharmacotherapeutic
approaches in cardiology
Jan Bultas, Debora Karetová 2013
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Topics
• heart rate and conduction intervention
• blood pressure intervention
• myocardial ischemia intervention
• myocardial contractility intervention
• fluid retention intervention
• hyperactivated hemostasis intervention
• dyslipidemia intervention
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Heart rate and conduction
chronotropy
dromotropy
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Heart rate interventionheart rate acceleration •sinus node: muscarine rec. inhibition (atropine) or β1 adrenergic receptor activation (xamoterol or isoprenaline)•cardiostimulation
heart rate slowdown•β1 adrenergic receptor inhibition (betablockers)•sinus node specific iont channels inhibition (slowdown of sinus node pacemacker cells spontanneous depolarisation)
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Importance of heart rate slowdown
• coronary flow rate improvement due to diastolic phase prolongation
• metabolic myocardial demand reduction
• correlation of heart rate and prognosis
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calciumL channel
potassium channel Ik
natrio-potassium channel If
Sinus rhythm - rate control
parasympatheticmuscarine rec.
adrenergic 1 receptor
calciumT channel
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calciumL channel
potassium channel Ik
natrio-potassium channel If
Sinus rhythm - rate control
parasysympath.muscarine rec.
adrenergic 1 receptor
calciumT channel
atropine -blockers
CCB /verapamil/bradins – If channel inhib.
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.
Benetos A et al. Hypertension 1999;33:44-52
Relation of heart rate and total and cardiovascular mortality in males and females in the course of 20 yrs of follow-up
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Pharmacology of heart rate slowdown
• β1 adrenergic stimulation inhib. (β blockers)
- heart rate reduction by 10-20 beats/min
• Na/K channel If inhibition (bradins, ivabradine)
- heart rate reduction by 10-20 beats/min• calcium L type channel inhib. (verapamil)
- heart rate reduction by only ≈5 beats/min
Better is β blocker and bradin combination than β blocker and verapamil (due to negative AV
conduction effect)
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Relation of mortality reduction and heart rate slowdown with -blocker therapy in secondary prevention
pindolol
oxprenolol
practolol
mo
rtal
ity
re
du
ctio
n (
%)
heart rate slowdown (beats/min)
timolol
metoprolol
propanololpropanolol
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0
50
100
150
200
250
70 až <72 72 až <75 75 až <80 80 až <87 ≥87
SHIFT, Bohm M et al. Lancet 2010
115%133%
180%
234%
100%
heart rate CV
mo
rtal
ity
and
ho
spit
alis
atio
n d
ue
to h
eart
fai
lure
(%)
%
ns
P=0,027
P<0,001
P<0,001
Relation of CV mortality to heart rate (in quintiles of heart rate) – chronic HF
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Atrio-ventricular conduction deceleration
• slowdown of ventricular rate in atrial fibrilation
• tachyarrhytmia treatment
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Atrio-ventricular conduction deceleration strategy - β1 adrenerg. activity inhibition (β1 -blockers)
- parasympatic activity stimulation (digoxin)
- ion channel inhibition- Ca2+ (verapamil) - Na+ (propafenone,..) - K+ (amiodarone,…)
I. cl. IV. cl.
III. cl.I. cl.
digoxin
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Antiarrhythmics in atrial fibrillation - sinus node rhythm restauration
propafenone flecainide sotalol
amiodarone
contraindic.in left ventricle failure
failure of other antiarhythmics orheart failure
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Antiarrhythmics in atrial fibrillation - reduction of ventricle rate by atrio-ventricular conduction deceleration
• betablockers• verapamil, diltiazem • digoxin (vagus activation)
combination of antiarrhytmics to reach the ventricle rate <90/min
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Antihypertensive therapy
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Blood pressure
- arterial hypertension – common status (≈ 1/3 population), important risk factor of CV diseases (stroke, CHD,…) with negative prognostic effect
- habitual arterial hypotension – rare status deteriorating life quality with no prognostic impact
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Hypertension prevalence according to age
Kearney et al. Lancet 2005;365:21723
14,421,2
32,6
44,8
60,3
71,2
6,29,9
23,3
42,0
61,3
80,3
0
20
40
60
80
100males females
hyp
erte
nsi
on
pre
vale
nce
(%
)
2029 703039 4049 5059 6069 age
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CV
mo
rtal
ity
0
2
4
8
115/75 135/85 155/95 175/105
6
syst. BP/diast. BP (mmHg)
*Individuals aged 40–69 years
4x risk
CV mortality doubles with BP increase by 20/10 mmHg
Lewington et al. Lancet 2002;360:1903–13
1x risk
2x risk
8x risk
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Strategy for the treatment of hypertension
• blockade of hyperactivated regulatory mechanisms
– ACE-I, ARBs, aldosterone rec. blockers,
– - or α+-blockers
• peripheral resistance decrease
– calcium channel blockers, central + peripheral
vazodilatators, ACE-I, ARBs, α-blockers
• reduction of circulating fluid volum
– diuretics
• reduction of hyperkinetic circulation
– - or α+-blockers
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BP normalisation / optimalisation
- vascular wall damage risk reduction
- bleeding risk reduction
- endothelial dysfunction improvement
- hypertrophy and remodelation of left
ventricle and resistence arterial
prevention
- plaque destabilisation risk reduction
- metabolic myocardial demand reduction
- nephropathy risk reduction
- retinopathy risk reduction
resist. art.
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Adjustment of the hyperactivated regulatory mechanisms
hyperactivation of RAAS, SA,…XX- atherogenesis acceleration- trombogenic effect- hypertension developement- apoptosis activation- arrhythmogenic effect- vasoconstriction- fluid retention- ischaemia of live saving organs
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-12
-8
-4
0
diuretics beta-block. ACE-I ARBs CCB
Comparison of the decline of BP with different antihypertensives monotherapy
(analysis of > 40 thousand hypertensives)
B
P r
ed
uc
tio
n in
mm
Hg
No significant difference of antihypertensives on BP reduction
Health Technology Assessment, 2003, 7, 31
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Stroke incidence reduction in primary and secondary prevention
(analysis >200 st, >40 thousand hypertensives)
sfr
oke
inc
iden
ce
re
du
ctio
n (
%)
-35
-25
-15
-5
ACE-I ARBs CCB diuret. BB
25% 22%31% 26% 18%
Health Technology Assessment, 2007
ACE-I are the most effective in stroke prevention
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-35
-25
-15
-5
ACE-I sartans CCB diuret. BB
21% 21%27% 23% 26%
Health Technology Assessment, 2007
CHD incidence reduction in primary and secondary prevention
(analysis >200 st, >40 thousand hypertensives)
CH
D in
cid
en
ce r
ed
uc
tio
n (
%)
ACE-I and BB are the most effective in CHD prevention
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Appropriate and inappropriate combination of antihypertensives
diuretics -block.
sartansAT1R inhib.
ACE-I
CCBdihydropyridines
CCBnon-dihydrop.
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Pulmonary hypertension therapy
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Pulmonary artery resistance control
nitric oxide prostaglandins endothelins
cGMP rec. I2 a E2 rec. ETA , ETB
dilatation dilatation constriction
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Pulmonary hypertension pharmacotherapy
• endotheline receptors antagonists
- nonselective A + B rec. – bosentan,
- selective rec. A – ambrisentan
• prostaglandine rec. agonists - PGI2, PGE2 and
analogs - iloprost (inhal.)
- epoprostenol (iv.)
• increase of cGMP availability - cGMP degradation inhibition by phosphodiesterase 5 blockers – sildenafil, tadalafil
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Treatment of Hypotension
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Hypotension treatment
• asymptomatic habitual hypotension - does not require treatment, only life mode modification
• symptomatic hypotension – after exclusion of secondary ethiology (drugs, bleeding,…), the circul. volume substitution, vasoconstrictive drug application is problematic
• hypotension in critical circulation deterioration
- specific therapy according to the mode of failure
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Myocardial ischaemiatreatment / prevention
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organic stenosis stable angina
vasospasmus vasospastic angina
thrombusunstable angina, MI
Myocardial ischemia ethiology
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Coronary circulation curiosity
• left ventricle myocardial perfusion (in contrast to other organs) only in diastola
• maximal arteriovenose difference – no reserve for oxygen coronary circulation extraction
• minimal myocardial functional reserve – contractility failure even in mild ischemia
• enormous perfusion difference at rest and during the effort
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Heart rate reduction importance• diastole prolongation → coronary perfusion
improvement + metabolic demand reduction
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Vasodilatation in prevention of ischemia – perfusion improvement
( 70% of coronary stenoses are excentric)
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Dynamic coronary obstruction in coronary organic stenosis – CCB and nitrate effect
intact coronary artery stenotic coronary artery
CCB+ CCB+
CCB-
CCB-
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MYOCARDIAL ISCHEMIA – IMBALANCE OF DELIVERY AND COMSUMPTION
coronary organic stenosis,
spasm or thrombosis
↑ heart rate
↓ perfusion pressure (↓dTK)
↓ transport oxygen capacity
↑ heart rate
↑ contractility (catecholamines,…)
↑ left ventricle end-
diastolic tension
DELIVERY CONSUMPTION
O2
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Myocardial ischaemiatreatment / prevention strategy
↑ coronary perfusion - revascularisation
- relaxation of the site of stenosis
- diastole prolongation
- optimal diastolic BP maintaining
myocardial demand - optimal heart rate
- optimal systolic BP (avoid ↑ BP)
- heavy physical burden reduction
metabolism optim. - preferential metabolism - glycolysis
(shifting from fatty acid β-oxidation)
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Coronary perfusion improvement
- relaxation at the site of stenosis
• CCB (amlodipine, verapamil,…) • nitrates (molsidomine, ISMN, ISDN, GTN)
CAVE – steal phenomenon – rapid arteriolodilatation → ↓ BP → ↑ catecholamine → heart rate and oxygen consumption ↑
- diastole prolongation (heart rate ↓) • -blockers (opt. cardioselect., long-acting – bisoprolol,
…)
• non dihydropyridine CCB (verapamil)
• bradins (ivabradine)
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Myocardial demand reduction
- heart rate slowdown
-blockers or non-dihydropyridine CCB (verapamil)
CAVE – substantial contractility reduction – leads to LV dilatation, BP drop-out, catecholamine wash out and metabolic demand increases
-blockers (opt. cardioselective and prolonged )CCB (verapamil)bradins (ivabradin)
- contractility reduction ???
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CCB or nitrates ?
CCB
long acting (>24h)
- no tolerance developement
- positive prognostic effect
- more reliable effect
- antihypertensive effect
- arteriolodilatation (steal phenomenon induction)
NITRATES
- rapid onset of action
- effect concentrated to
epicardial part of
coronary bed (no steal ef.)
- short acting effect
- tolerance developement
- neutral prognostic effect
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Ischemic myocardium metabolism optimalisation
• in mild ischemia, the glycolysis is used for ATP synthesis in the myocardium
• in severe ischemia (with pH drop-out due to lactate tissue accumulation), the glycolysis is inhibited and less effective fatty acid ß-oxidation is preferably used for ATP production
• conversion of FA ß-oxidation to glycolysis is possible to obtain ≈15% makroergic phosphate (ATP) in addition (trimetazidine effect)
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0
25
50
75
100
125
150
175
200
225
Improvement of effort tolerance with drugs combination
no therapy CCB nitrates CCB + trimetazidine + -blocker (triple therapy)
%
+57%+44%
+41%+18%
Boden WE et al., 2007
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Complex care - IHD patient
• thrombotic occlussion prevention
• plaque destabilisation and atherogenesis progression prevention • myocardial ischemia prophylaxis
• left ventricle remodelation and heart failure prevention
• arrhythmia occurence prevention
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0
5
10
15
Effect of complex strategy in chronic CHD – serious vascular events and mortality
reduction
mo
rtal
ity
per
yea
r i
n %
life mode modification
+ aspirin or clopidogrel -25%
+ -block. -27%
+ statin -31%
+ ACE-I -23%
life mode modification
+ aspirin
life mode modification
+ aspirin+β-blocker
life mode modification
+ aspirin+β-blocker
+statin
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Heart failure treatment
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Pharmacotherapy od heart failure
contractility (cardiotonics, sympatomimetics):
quality of life improvement, no prognostic effect
fluid and electrolytes retention (diuretics): important quality of life improvement no data on prognostic effect
• sympaticus activation (-block., +-block.):
LV function, life quality and important
prognosis improvement
RAAS activity (ACE-I, aldosterone rec. inhib.):
LV function, life quality and prognosis improv.
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Mechanism of beta-blockade in heart failure
1) antiischemic effect (myocardial perfussion improvement)
2) antiarrhythmic effect (fibrilation threshold increase, ventricle arrhythmia reduction)
3) hyperactivated regulatory mechanism inhib. - sympatoadrenal inhibition - renin-angiotensin-aldosterone syst. inhib.
4) apoptosis inhibition (cardiomyocyte number and contractility decrease prevention)
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Mortality reduction in heart failure studies
-80
-70
-60
-50
-40
-30
-20
-10
0
carvedilol bisoprolol metoprolol
total mortality
pump failure
sudden death
US Carvedilol St. CIBIS II MERIT HF
65%
34%34%
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Mechanism of ACE-I in heart failure
1)peripheral vascular resistence reduction (direct and due to bradykinine stimul.) - life important organs perfusion improvement and LV metabol. demand reduction
2) diuretic and natriuretic effect (direct and indirect - ADH + aldosterone release inhibition - fluid retention
3) noradrenaline release - sympathetic activity
4) fibrinolysis – thrombosis risk 5) apoptosis inhibition – contractility improvement
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ACE-I effect on mortality reduction in heart failure(compared to placebo)
SAVEkaptopril
TRACEtrandolapril
AIREramipril
MORTALITY INCREASE MORTALITY DECREASE
N: 2 000
N: 2 000
N: 2 000
19%
22%
27%
100% 100%
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ARBs effect in heart failure
• in comparison to ACE-I significantly less effective - on mortality/morbidity
• ARBs in heart failure indicated only in ACE-I intolerance (or in combination with ACE-I)
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SAVE(kaptopril)
TRACE (trandolapril)
AIRE(ramipril)
19%
22%
27%
9%
100% 100%
CHARM (candesartan)
ACE-I
ARBs17%
VAL-HEFT (valsartan) 1%
CV mortality
ACE-I and ARBs effect on mortality in heart failure (compared to placebo)
MORTALITY INCREASE MORTALITY DECREASE
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RALESspironolactoneserious chronic heart failure
EPHESUSeplerenone acute LV insuf.
REMINDEReplerenonepost MI with preserved LV function
EMPHASIS-HFeplerenonemild chronic heart failure
Aldosterone rec. inhibitors - in different heart failure types
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RALESspironolactoneserious chronic heart failure
EPHESUSeplerenone acute LV insuf.
REMINDEReplerenonepost MI with preserved LV function
EMPHASIS-HFeplerenonemild chronic heart failure
Mortality (total and CV) reduction with aldosterone rec. inhibitors
↓ 27%
↓ 24%
↓ 15%
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SAVE(kaptopril)
TRACE (trandolapril)
AIRE(ramipril)
19%
22%
27%
9%
100% 100%
CHARM(cardesartan) added
RALES(sprironolactone)27%
EPHESUS (eplerenone)15%
CIBIS II (bisoprolol)
MERIT HF (metoprolol)
34%
34%
US CARVEDILOL (carvedilol)65%
ACE-I
ARBs
aldost.antag.
-block.
17%
VAL-HEFT (valsartan) 1%
24%EMPHASIS HF (eplerenone)
Mortality reduction in heart failure (comparison with placebo)
MORTALITY INCREASE MORTALITY DECREASE
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• beta-blockers – carvedilol (no bronchial obstruction, no hypotension) or bisoprolol, metoprolol, nebivolol
– titration to target dose in stabilised patient
• ACE-I – preferention of perindopril or ramipril – dose titration only in seniors or in hypotension
• aldosterone rec. inhib.– spironolactone (cheaper), eplerenone (better tolerated) in low (subdiuretic) dose
CAVE – real risk of hyperkalemia in combination of ACE-I with aldosterone rec. inhibitors (periodical K+ control)
Beta-blocker, ACE-I and aldosterone rec. inhibitors combination in heart failure
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Mortality/morbidity reduction in chronic heart failure (analysis > 40 st., 36 000. pts.)
vasu
lar
even
ts r
edu
ctio
n
(%)
-35
-25
-15
-5
ACE-I ARBs ald.inh. CCB diuret. BB
3% 4%26% 23% 34%
Health Technology Assessment, 2007
Optimal combination: ACE-I + BB + aldosterone rec. inhib., no prognostic data for diuretic therapy
?21%
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Diuretics in heart failure treatmentmanitol
acetazolamid manitol thiazidediuretics
loopdiuretics
potassium sparing
diuret.
metylxantiny
aquaretic
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Diuretics in heart failure treatment• indication – fluid retention (pulmonary congest.,
oedema, ascites, hydrothorax) or hypertension
• fluid and electrolyte retention (diuretics) or pure water retention (aquaretics – tolvaptam)
• important quality of life improvement in heart failure, but no prognostic studiy available
• preference of most potent loop diuretic (furosemide or torasemide) or loop and thiazide diuretic combination
• in hypoosmolar fluid retention – aquaretics (rarely)
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Positive inotropic drugs in heart failure treatment
a) contractility increase due to increase of calcium sarkoplasm concentration
• cardiotonics (digoxin) -sympatomimetics (dopamine, dobutamine,
denopamine) – only in acute failure
• PDE III inhibitors (amrinone, milrinone) - obsolent
b) contractility stimulation without sarkoplasmatic calcium concentration increase
• kalcium sensitisers (levosimendan,…) – in acute failure, increase affinity of Ca2+ to troponine C
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CARDIOTONICS (cardioglykosides)
pharmacodynamic effect:
- myocardium – contractility improvement• autonomic nerve system – vagal activation
(negat. chrono- and dromotropic ef.)
• important interindividual plasma level variation – blood level monitoring initially
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Increased mortality in elevated digoxine plasma level
(above the therapeutic range)
0
5
10
15
20
25
30
35
40
45
total mortality heart failure mortality
placebo
digoxine<0,9 ng/ml
digoxine≥0,9 ng/ml
mo
rtal
ity
(%
)
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Heart failure therapy:
• ACE-I opt. perindopril or ramipril (all)
• -blocker carvedilol or selective -bl. (all)
• aldosterone rec. inhib. (spironolactone
or eplerenone - NYHA II-IV)
• ARBs (only in ACE-I intolerant)
• diuretics (in fluid retention)
• digoxin (in symptomatic pts or AFib )
• anticoagulants (in AFib, …)
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0
20
40
Decrease of mortality in chronic heart failure – - combination therapyan
nu
al m
ort
alit
y i
n H
F p
ts -
%
digoxindiuretics
digoxindiureticsinhib. ACE
digoxindiureticsinhib. ACEspironolactone
digoxindiureticsinhib. ACEspironolactone-blocker
+ ACE-I -28%
+ spironolactone -27%
+ -blok. -34%
+ resyn- chron. -36%
study with ACE-I
study RALES
study-blok.
study CARE-HF
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Thank you