1. Prim. Mr. Sc. Dr. Nediljko Pivac Interna klinika, KBC Split
KARDIOVASKULARNE BOLESTI
Prim. Mr. Sc. Dr. Nediljko Pivac
Interna klinika, KBC Split

2. Ukupna smrtnost u svijetu 2002
Smrtnost (milijuni)
Kardiovaskularne bolesti
Maligne bolesti
Povrede
Respiracijske infekcije
KOPB i astma
HIV/AIDS
Perinatalne bolesti
Bolesti probavnog sustava
Crijevne bolesti
Tuberkuloza
Dječje bolesti
Malarija
Dijabetes
According to 2002 mortality figures compiled for the World Health Organization’s (WHO) World Health Report 2003: Shaping the Future, cardiovascular diseases (CVD) (mainly ischaemic heart disease and stroke) were the leading global causes of death, accounting for approximately 16.6 million deaths, followed by cancer (7.1 million deaths), intentional and unintentional injuries (5.2 million), upper and lower respiratory infections (3.8 million), chronic obstructive pulmonary disease (COPD) and asthma (2.9 million), and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (2.8 million).
WHO. The World Health Report 2003: Shaping the Future
Reference
1. World Health Organization. The World Health Report 2003: Shaping the Future. Geneva, Switzerland: World Health Organization; 2003.

3. Uzroci smrtnosti u SAD 959.2 544.7 93.8 32.7 Smrtnost (tisuće) KB
Malignomi
Nesreće
HIV/AIDS
959.2
544.7
93.8
32.7
American Heart Association. Heart and Stroke Statistical Update 2007.

4. Uzroci smrti u Hrvatskoj 2001. godine
Izvor podataka: Državni zavod za statistiku, Hrvatski zavod za javno zdravstvo

5. Kardiovaskularna smrtnost 1980-2004
Data recently published by American Heart Association shows almost similar trends with a much higher reduction in CHD related mortality in men all the way from 70 to 2004, whereas in women the trend has been stable and only shown a decline after around 2000.
American Heart Association 2007 5

6. Bolesti kardiovaskularnog sustava
Angina pektoris
Infarkt miokarda
Zatajenje srca
Nagla smrt
TIA
Ishemijski udar
Hemoragijski udar
Renovaskularna bolest
Zatajenje bubrega
Klaudikacije
Aneurizma aorte

7. Primarni čimbenici rizika za razvoj KVB
Nepromjenjivi
Hipertenzija
Dob
Promjenjivi
KVB
Šećerna bolest
Obiteljska povijest KVB
/ genetika
Pušenje
Dislipidemija
NCEP. Circulation 1994;89:1329–1445. Eur Heart J 1994;15:1300–1331.
Wood D i sur. Eur Heart J 1998;19:1434–1503.

8. INTERHEART: utjecaj životnih navika na nastanak infarkta miokarda
Čimbenik
Pušenje
Dijabetes
INTERHEART is a large international study of MI risk factors with 15,152 cases (patients) and 14,820 controls. It was conducted in 52 countries and includes every inhabited continent.1
The study objective was to determine the relation of smoking, history of hypertension or diabetes, waist/hip ratio, dietary patterns, physical activity, consumption of alcohol, blood apolipoproteins (Apo), and psychosocial factors (stress, depression) to MI. Participants were followed for 4 years. Collectively, these nine risk factors accounted for 90% of the risk for a first MI in both sexes and at all ages throughout the world.
As shown, INTERHEART recorded similar odds ratios in men and women for the association of acute MI with smoking, elevated lipid levels, abdominal obesity, composite of psychosocial variables, and vegetable and fruit consumption. However, the increased risk associated with hypertension and diabetes was greater in women than in men.
Women seemed to benefit more than men from the protective effects of exercise and alcohol.
These findings support the importance of lifestyle modification in CV risk reduction.
Hipertenzija
Žene
Pretilost
Muškarci
Psihosocijalni č.
Voće/povrće
Tjelovježba
Alkohol
0.25
0.5
1.0 2 4 8 16
Odds ratio (99% CI)
Yusuf S et al. Lancet. 2004;364:
1. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet. 2004;364:

9. Kumulativni učinak čimbenika rizika u nastanku KV bolesti2 4 6 8 10 12 14
HTN DM
Pušenje
BMI >27
Kol >5,7
Pojedinačni čimbenici
Multipli čimbenici
Odds ratios
Pušenje + BMI
+ kol>5,7 3
+ kol >5,7
+ DM
+ DM + HTN 5
This slide illustrates the cumulative effect of risk factors and illustrates that risk factors are more than additive; the total risk is higher than just the sum of the individual risk factors.
Monitoring of a USA population cohort in the town of Framingham, Massachusetts, USA, for the period of 12 years led to the identification of the major CVD risk factors, including high blood pressure, high total blood cholesterol, smoking, obesity and diabetes. Odds ratio for each of these risk factors alone ranges from around 1.2 to 2.2. When more than one factor is present, odds ratios are increased by more than an additive rate, so that all five (BMI>27, smoking, high total cholesterol, diabetes and hypertension) led to an approximate 7-fold increased risk compared to any one risk factor alone.
1. Wilson PWF, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. May 1998;97:1837–1847
Wilson PWF et al. Circulation. 1998;97:1837–1847. 9

10. Hipertenzija združena s ostalim KV čimbenicima rizika povećava rizik nastanka IM
Odds Ratio (95% CI)
512
256
128 64 32 16 8 4 2 1 PŠ
(1) ŠB
(2)
HTN (3)
ApoB/A1 (4)
1+2+3 (1)
svi 4
+deblj
+PS
Svi ČR
2.9 ( )
2.4 ( )
1.9 ( )
3.3 ( )
13.0 ( )
42.3 ( )
68.5 ( )
182.9 ( )
333.7 ( )
INTERHEART was a case-control study of acute myocardial infarction (MI) in 52 countries of 15,152 cases and 14,820 controls. The INTERHEART data show the association of risk factors with acute MI in men and women after adjustment for age, sex, and geographic region.
Each of the major risk factors individually, eg, current smoking, diabetes, hypertension, and dyslipidaemia (ApoB/A1), was associated with an odds ratio of having an acute MI event of approximately 2. The effects of these risk factors are consistent across both sexes.
The concomitant presence of 3 of the major risk factors increased the odds ratio to 13.1, and accounted for 53% of the attributable risk for MI. The presence of all 4 major risk factors increased the odds ratio to 42.3 and accounted for 75.8% of the attributable risk. If, in addition to the major risk factors, abdominal obesity, psychosocial factors, lack of daily consumption of fruits and vegetables, regular alcohol consumption, and lack of regular activity are considered, altogether these accounted for 90% of the attributable risk in men and 94% of the attributable risk in women.
PŠ=pušenje; ŠB=šećerna bolest, deblj=abdominalna debljina;
PS=psichosocijalni čimbenici, ČR=čimbenici rizika IM=srčani udar.
Yusuf. Lancet. 2004; 364:
Reference
1. Yusuf S, Hawken S, Ôunpuu S, et al, on behalf of the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:

11. Kardiovaskularni niz Koronarna bolest Ruptura plaka Ateroskleroza
Infarkt miokarda
Disfunkcija endotela
Dilatacija/
Remodeliranje
The many pathophysiologic effects of angiotensin II, mediated by stimulation of the AT1 and AT2 receptors, have diverse consequences. It is reasonable to suggest that most of these pathophysiologic effects of angiotensin II (through the stimulation of AT1 receptors) will result in pivotal, and potentially deleterious effects throughout the cardiovascular continuum.
Čimbenici rizika
Zatajenje srca
Hipertenzija
Hiperlipidemija
Dijabetes
Krajnji stadij/
smrt 11

12. Ishemijska bolest srca

13. Ishemijska bolest srca
Iznenadna smrt
Infarkt miokarda
Nestabilna angina pektoris
Stabilna angina pektoris
Zatajenje srca

14. Infarkt miokarda ili iznenadna smrt: prvi znak koronarne bolesti
Muškarci
Žene 10 20 30 40 50 60 70 42 62
Bolesnici sa KB (%)
Murabito et al, Circulation 1993 14

15. ishemija (stanični “Ca overload”) pritisak na nutritivne krvne žile
Patofiziologija koronarne bolesti- neravnoteža između potrošnje i opskrbe kisikom!
ishemija (stanični “Ca overload”)
↑ potrošnja O2
frekvencija
arterijski tlak
vol. opterećenje
kontraktilnost
↓ opskrba O2
ateroskleroza-ishemija
posljedice ishemije
električna nestabilnost
disfunkcija miokarda (↓ sist. funkcija/ ↑ dijastolička “krutost”)
pritisak na nutritivne krvne žile
(Stone, 2004)

17. Suzbijanje čimbenika rizika
pušenje
arterijska hipertenzija
hiperkolesterolemija
šećerna bolest
tjelovježba
pretilost

18. Mediteranska dijeta u bolesnika sa koronarnom bolesti
1989
Diet and Reinfarction Trial (N = 2000)
 29% ukupna smrtnost
 27% IM
1997
Indian Experiment of Infarct Survival Trial (N = 360)
 50% kardijalna smrt
 48% IM
1999
GISSI-Prevenzione (N = 11,324)
 20% ukupna smrtnost
 30% KV smrtnost
The Lyon Diet Heart Study randomized 605 post-MI subjects to prudent Western-style diet or to diet rich in fruits, vegetables, and fish, and incorporating an alpha-linoleic acid (ALA)-based margarine.1 After 46 months, there was 68% risk reduction in cardiac death and nonfatal MI (P = ).
The GISSI-Prevenzione study randomized 11,324 post-MI patients to placebo or 1 g/d omega-3 fatty acid fish-oil supplements.1 After 3.5 years, there was a 20% risk reduction in all-cause mortality (95% CI, 6%–33%) and 30% risk reduction in CV death (95% CI, 13%–44%).
The Indian Experiment of Infarct Survival Trial randomized 360 post-MI patients to placebo, eicosapentaenoic acid (EPA) supplement, or ALA supplement.1 After 1 year, the EPA supplement was associated with 50% risk reduction in cardiac death (P < 0.05) and 48% risk reduction in nonfatal MI (P < 0.05). The ALA supplement was associated with 40% risk reduction in cardiac events (P < 0.05) (data not shown).
The Indo-Mediterranean Diet Heart Study randomized 1000 patients with angina, MI, or multiple risk factors to a National Cholesterol Education Program Step 1 diet or to a diet rich in whole grains, fruits, vegetables, walnuts, mustard seed, and soybean oil.1 After 2 years, the Mediterranean-style diet was associated with a 33% risk reduction in MI (P < 0.001).
The Diet and Reinfarction Trial randomized 2000 post-MI men to their usual diet or to a diet with fish consumption twice weekly (300 g total).1 After 2 years, there was 29% risk reduction in all-cause mortality and 27% risk reduction in fatal MI.
1999
Lyon Diet Heart Study (N = 605)
 68% kardijalna smrt, IM
2002
Indo-Mediterranean Diet Heart Study (N = 1000)
 33% smrtni IM
Parikh P et al. J Am Coll Cardiol. 2005;45:
1. Parikh P, McDaniel MC, Ashen D, Miller JI, Sorrentino M, Chan V, et al. Diets and cardiovascular disease: An evidence-based assessment. J Am Coll Cardiol. 2005;45:

19. Medikamentno liječenje koronarne bolesti
antitrombocitni lijekovi (ASK, klopidogrel)
 blokatori (selektivni, neselektivni, vazodilatacijski)
nitrati
kalcijski antagonisti (DHP, verapamil, diltiazem)
ACEI, ARB
hipolipemici (statini, fibrati, ezetimib)
novi lijekovi (ivabradin, trimetazidin, ranolazin, omega 3- nezasićene masne kiseline)

20. Koronarna bolest- mjesta dijelovanja lijekova
posljedice ishemije
električna nestabilnost
disfunkcija miokarda (↓ sist. funkcija/ ↑ dijastolička “krutost”)
ishemija (stan.“Ca overload”)
↑ potrošnja O2
frekvencija
arterijski tlak
vol. opterećenje
kontraktilnost
↓ opskrba O2
ateroskleroza-ishemija
hemodinamski
lijekovi (+ASK):
ß blokatori
nitrati
Ca++ blokatori
ACEI
metabolički lijekovi (trimetazidin, ranolazin, omega -3)
pritisak na nutritivne krvne žile
(Stone, 2004)

21. Učinak ASK-e u visokorizičnih bolesnika
Patrono C et al. N Engl J Med. 2005;22:

22. Učinak različitih doza ASK-e na KV događanja u visokorizičnih bolesnika
doza ASK-e # studije RR(%)
relativni rizik
500–1500 mg
160–325 mg
75–150 mg
<75 mg
sve doze
The Antithrombotic Trialists’ Collaboration compared data from 65 aspirin trials to examine the effects of aspirin dose on vascular events in high-risk patients (in some trials, the doses of aspirin used were in more than one of the comparisons).[1] Serious vascular events (the primary measure of outcome) included nonfatal MI, nonfatal stroke, death from vascular causes, and death from unknown causes. They found that all doses of aspirin studied reduced the risk for vascular events. The greatest number of trials (34) examined high aspirin doses (500 mg to 1500 mg) and revealed a proportional reduction in vascular events of 19%. Aspirin doses of 160 mg to 325 mg were associated with a 26% proportional reduction in vascular events, whereas 75 mg to 150 mg and <75 mg were associated with reductions of 32% and 13%, respectively.
Antithrombotic Trialists’ collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.
0,5
1,0
1,5
2,0
ASK-bolje
ASK-gore
Antithrombotic Trialists’ Collaboration. Brit Med J. 2002;324:71-86.
*smanjenje rizika učinak - p < 0,0001.

23. Učinak klopidogrela u bolesnika nakon PCI-e
PCI – CURE*
CREDO 15 15
12.6%
Placebo‡
Klopidogrel‡
Placebo*
Klopidogrel*
31%
RRR
11.5%
27%
RRR 10
8.8% 10
KV smrt ili IM (%)
8.5%
IM, CVI ili smrt (%) 5 5
P=0.02
P = N = 2658
100
200
300
400 3 6 9 12
Dani
Mjeseci
Slide source:
Lipids online
†do12 mjeseci
‡plus ASK i ostali lijekovi
Mehta et al. Lancet 2001;358:
Steinhubl S et al. JAMA. 2002; 288:

24. Nitrati: upozorenja
čuvanje: hladna i tamna prostorija, suha i tamna posuda
uzimanje: NTG u sjedećem stavu, peckanje
nuspojave: glavobolja, crvenilo, halitoza, sinkopa, hipotenzija, tahikardija, methemoglobinemija
interakcije: beta blokatori (+); etanol, sildenafil (-)
kontraindikacije: IHSS, hipotenzija!
tolerancija (nejasni, složeni mehanizmi)
ustezanje (“monday morning angina”)

25. Utjecaj  blokade na ishemijsko srce
MVO2
opterećenja

26. Efekt  blokade na smrtnost nakon infarkta
Kumulativna smrtnost (%)
25-30%

27. Učinci kalcijskih antagonista
nedihidropiridini: jednako učinkoviti na miokard, provodni sustav i arterije -uravnoteženi hemodinamski učinak
dihidropiridini:
selektivni vazodilatatori
usporavaju ritam
ubrzavaju ritam i povećavaju potrošnju kisika
periferni i koronarni dilatatori SA
periferni i koronarni dilatatori SA AV AV
SA=sino-atrijski čvor
AV= atrio-ventrikulski čvor
slabe inotropiju
Ferrari R i sur., Cardiovasc Dugs Ther 1994; 8 (Suppl 3):

28. Kalcijski antagonisti u koronarnoj bolesti
kao lijek prvog izbora (DHP) u Prinzmetalovoj angini,
u stabilnoj AP nakon  blokatora (DHP) te
u sekundarnoj prevenciji koronarne bolesti u bolesnika u kojih su  blokatori kontraindicirani!

29. CAMELOT: Smanjenje primarnih ishoda uz enalapril i amlodipin
0.25
HR (95% CI)
A vs P: 0.69 (0.54–0.88)
E vs P: 0.85 (0.67–1.07)
A vs E: 0.81 (0.63–1.04)
P = 0.16
0.20
P = 0.003
P = 0.1
The primary outcome occurred in 23.1% of placebo-treated patients, 16.6% of amlodipine-treated patients HR, 0.69; 95% CI, 0.54–0.88; P = vs placebo), and 20.2% of enalapril-treated patients (HR, 0.85; 95% CI, 0.67–1.07; P = 0.16 vs placebo).1 The difference in primary outcome for amlodipine versus enalapril was not significant (HR, 0.81; 95% CI, 0.63–1.04; P = 0.10).
0.15
Kumulativni
KV događaji
0.10
Placebo
Enalapril
0.05
Amlodipin
Mjeseci 6 12 18 24
Br. bolesnika
Placebo
655
588
558
525
488
Enalapril
673
608
572
553
529
Amlodipin
663
623
599
574
535
Primarni ishod= učestalost KV događaja
Nissen et al. JAMA. 2004;292:
1. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, et al, for the CAMELOT Investigators. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: The CAMELOT Study: A randomized controlled trial. JAMA. 2004;292:

30. Vjerojatnost događaja
SAVE
AIRE
TRACE
0.05
0.1
0.15
0.2
0.25
0.3 1 2 3
0.35
0.4 4
Ukupna smrtnost
Placebo
ACE-I
Vjerojatnost događaja
Placebo: 866/2971 (29.1%)
SAVE, AIRE and TRACE represent the 3 placebo-controlled trials that tested an ACE inhibitor in higher risk MI patients and maintained the therapy beyond 6 months. The survival advantage occurred early and increased to approximately 60 lives saved per thousand treated with long-term therapy. In this meta-analysis, ACE inhibitor use reduced the odds ratio for death by approximately 26%. With over 1500 deaths, the confidence intervals were narrow and the results considered sufficiently robust so that no further placebo-controlled trials are warranted
Flather MD, et al. Lancet:2000;355:
ACE-I: 702/2995 (23.4%)
OR: 0.74 (0.66–0.83)
God
ACE-I
Placebo
Flather MD, et al. Lancet. 2000;355:1575–1581

31. Smrtnost i veliki KV događaji
SAVE
AIRE
TRACE
Smrtnost i veliki KV događaji
(0.67 – 0.83)
0.75*
Događaji (%) 10 20 30 40
Placebo (n = 2971)
ACE-I (n = 2995)
Hospitalizacija zbog
zatajenja srca
n = 460
n = 355
(0.63 – 0.85)
0.73*
Reinfarkt
n = 324
n = 391
(0.69 – 0.95)
0.80*
In addition to the survival benefit shown in the three post-infarction trials with ACEIs, rates of readmission for heart failure were lower than with placebo, as were rates of reinfarction or the composite of these events. The benefits were observed early after the start of therapy and persisted long term. The benefits of treatment on all outcomes were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers.
The use of ACE inhibitors in these patients was also associated with important reductions in the risk of major nonfatal CV events, such as hospital admission for the management of heart failure and experiencing a recurrent myocardial infarction. Indeed, in the meta-analysis with over 2200 events, there was a 25% reduction in the risk of death, non-fatal MI or heart failure in those randomized to an ACE inhibitor as compared to placebo plus conventional medical therapies.
Flather MD, et al. Lancet:2000;355:
1. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000;355:1575–1581.
n = 1049
n = 1244
Smrt/IM ili hospitalizacija
zbog zatajenja srca
Flather MD, et al. Lancet. 2000;355:1575–1581

32. In the HOPE study, relative risk of the composite outcome of MI, stroke, or death from CV causes in the ramipril group as compared with the placebo group was 0.78 at five years.
In EUROPA the relative risk reduction of CV death, MI, or cardiac arrest was 20%.

33. LDL-C i koronarna bolest30
4S-Rx
4S-PI 25
2° prevencija 20
% sa KB
događajem 15
LIPID-Rx
LIPID-PI
CARE-Rx
CARE-PI
1° prevencija
HPS-Pl 10
HPS-Rx
AFCAPS-Rx
AFCAPS-PI
WOSCOPS-PI
WOSCOPS-Rx 5
1,8
2,3
2,8
3,4
3,9
4,4
4,9
5,4
PI=placebo Rx=liječenje
LDL-C (mmol/l))
HPS. Lancet. 2002;360:7. Downs. JAMA. 1998;279:1615.
LIPID. N Engl J Med. 1998;339:1349. Sacks. N Engl J Med ;335: S. Lancet. 1995;345:1274. Shepherd. N Engl J Med. 1995;333:1301.

34. LDL kolesterol i KV bolesti
smrtnost KB % † ‡ * *
*Confidence interval (CI) not reported.
†95% CI, 14%-41%.
‡95% CI, 16%-37%.
§95% CI, 12%-31%.
Hebert PR et al. JAMA. 1997;278:

35. Kardiovaskularni učinci lijekova koji usporavaju učestalost bila
verapamil
diltiazem
β-blokatori
ivabradin®
srčana frekvencija     
kontraktilnost   Ø
provodljivost
Da zaključimo ovaj dio o farmakološkim svojstvima Corlentora: za razliku od drugih lijekova koji usporavaju srčanu frekvenciju Corlentor pruža isključivo usporavanje srčane frekvencije. Osim što ovo isključivo usporavanje srčane frekvencije nudi anti-ishemični učinak, ono je zaslužno i za očuvanje ostalih kardiovaskularnih parametara kao što su kontraktilnost, provodljivost, podražljivost i krvni tlak.
Sve je ovo potrđeno kliničkim programom Corlentora.   Ø
podražljivost  Ø Ø
arterijski tlak   Ø

36. Sekundarna prevencija nakon AIM: GISSI-Prevenzione Trial
GISSI = Gruppo Italiano per lo Studio della Sopravvivenza nell´Infarto miocardico
bolesnika s preboljelim IM, liječeni su kroz prosječno 3,5 godine visoko pročišćene omega-3 nezasićene masne kiseline(1 g/dan) značajno su smanjile kombinirane ishode - smrtnost, nefatalni IM i CVI (p< 0,05)
značajno je smanjena sveukupna smrtnost posebice iznenadna srčana smrt!
Slide 14
The principal finding from GISSI-Prevenzione was that highly purified omega-3 PUFAs save lives in post-MI patients when added to a contemporary standard secondary prevention regimen.
The GISSI-Prevenzione study is examined in detail in the next part of this slide lecture set.
Reference
GISSI-Prevenzione Investigators. Lancet 1999;354:
GISSI-Prevenzione Investigators. Lancet 1999;354:

37. Stabilna AP: PCI prema medikamentnom liječenju
optimalna medikamentna terapija (OMT)
1,0
0,9
0,8
PCI + OMT
0,7
relativni rizik: 1.05
95% CI (0,87-1,27)
p = 0,62
0,6
0,5
0,0 1 2 3 4 5 6 7
godine
broj rizika
medikamentno
PCI
N Engl J Med. 2007; 356:

38. Smanjenje smrtnosti nakon IM
100%
RRR = 70%
NNT (5g.) = 7
? %
20%
ASK
- blokatori
statini
ACEI
???
ASK
- blokatori
statini
64%
25%
ASK
- blokatori
smanjenje smrtnosti
55%
25%
ASK
- blokatori
40%
trimetazidin
omega-3 ivabradin ?
25%
ACEI
- blokatori
statini
25%
25% 0%
1970.
1980.
1990.
2000.
2008.
Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 3):S37-46.

39. Temeljno (“BASIC”) medikamentno liječenje KB
beta-blokatori A
ASK S
statini I
inhibitori ACE C
kontrola čimbenika rizika

40. Sniženje koronarne smrtnosti u zadnjih 20 godina: primjer SAD♀
1980: 263,3/
2000: 134.4/
↓49% ♂
1980: 542.9/
2000: 266,8/
↓51% 9%
N Engl J Med 2007;356:

41. Sniženje koronarne smrtnosti u zadnjih 20 godina: primjer SAD
Ovi bi rezultati bili i bolji da nije malignog porasta MS i šećerne bolesti: ova stanja odnose isti broj života koje spašava sekundarna prevencija IM, inicijalno liječenje ACS i IM te revaskulariziranje SAP! 9%
N Engl J Med 2007;356:

42. Kronično zatajenje
srca

43. Kronično zatajivanje srca - vodeća zloćudna bolest današnjice
PREVALENCIJA
1% - 2% opće populacije
oko10% iznad 60 godina
PROGNOZA
Prosjek
smrtnosti 50% /4 g.
Teška dekomp.
Smrtnost 50% /1 g.

44. Prevalencija zatajenja srca
(NHANES: ).

45. Predisponirajući čimbenici zatajenja srca
Framingham Heart Study 60
Hypertension is the most common risk factor for HF. In a population-based sample followed for up to 20 years, investigators for the Framingham Heart Study determined that hypertension antedated the development of HF in 91% of cases.1
Hypertension carried the greatest population-attributable risk for development of HF of all risk factors: 39% in men and 59% in women.
The risk for developing HF is ~2 greater in hypertensive men and ~3 greater in hypertensive women compared with normotensive subjects.
Overall, hypertension is present in ~60% of men and women with HF.
In addition, the risk of HF is ~6 greater in men and women who have had a myocardial infarction (MI).
Angina, valvular heart disease, left ventricular (LV) hypertrophy, and diabetes also were predictive of increased risk for HF in both sexes. 40
PAR (%) 20
HTN IM
Angina
Valv.
HLK
Dijabetes HR M
2.1
6.3
1.4
2.5
2.2
1.8 Ž
3.3
6.0
1.7
2.8
3.7
Muškarci
Žene
Levy D at al. JAMA. 1996;275:
1. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KKL. The progression from hypertension to congestive heart failure. JAMA. 1996;275:

46. Kumulativni rizik nastanka zatajenja srca14
12.8
The HERS study demonstrated that women with coronary heart disease (CHD) and diabetes who also have an elevated body mass index (BMI) or depressed creatinine clearance were at highest risk for developing HF, with an annual incidence of 7% and 12.8%, respectively.1
Diabetic women with CHD who did not have renal insufficiency and were not obese had a 2.8% annual incidence of HF, which was more than double the rate for women with CHD who were not diabetic. 12 10
Godišnja
incidencija
(%) 8
7.0 6 4
2.8 2
1.2 KB
KB + DM
KB + DM + BMI >36
KB + DM + CrCl <42.8
CrCl (ml/min) = klirens kreatinina
Bibbons-Domingo K et al. Circulation.2004;110:
1. Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Hulley SB, Grady D, Shlipak MG. Predictors of heart failure among women with coronary disease. Circulation. 2004;110:

47. Čimbenici koji pridonose zatajenju srca
Infarkt miokarda
Povećani unos soli
Povećani unos tekućine
Nepoštivanje preskripcije
Aritmije
Interkurentne bolesti (infekcije npr.)
Stanja sa povećanim metaboličkim potrebama (trudnoća, hipertireoza npr.)
Lijekovi koji djeluju negativno inotropno ili dovode do zadržavanja tekućine u tijelu (kortikosteroidi, NSAR)
Alkohol

48. Prognoza zatajivanja srca je kao u malignih bolesti
The figure shows the one year survival rates for heart failure and the main cancers in England and Wales for the mid-1990s. (All grades of heart failure)
Petersen S, Rayner M, Wolstenholme J. Coronary heart disease statistics: heart failure supplement. London: British Heart Foundation, 2002.
Jednogodišnje preživljavanje (%)
British Heart Foundation, 2002 48

49. Prognoza zatajenja srca
202
Prognoza zatajenja srca 50
<30
Poslije IM
n=196 40
Smrtnost
(%) 30
31-35 20
Prognosis. Hemodynamic factors
The ejection fraction of the left ventricle (LVEF) is one of the few objective and easily reproducible parameters which are closely related to prognosis. Even in patients with subclinical ventricular dysfunction, the decrease in LVEF implies a poor prognosis. In this slide, the relationship between LVEF and cardiac mortality in a group of patients post-myocardial infarction is shown. Note the exponential increase in mortality when the LVEF is less than 40%. An interesting finding is that pharmacologic interventions which improve prognosis in the subgroup of patients with severe depression of ventricular function do not serve the patients with asymptomatic ventricular dysfunction as well. This points up the important clinical role of defining the LVEF.
Brodie B et al. Am J Cardiol 1992;69:1113 10
36-45
46-53
54-60
>60 80 70 60 50 40 30 20
EF (%)
Am J Cardiol 1992;69:1113

50. Nastanak zatajenja srca
HLK
Dijastolička disfunkcija
Pretilost
Dijabetes
Hipertenzija
Zatajenje
srca
Krajnji
stadij
Pušenje
Dislipidemija
Dijabetes
Sistolička
disfunkcija IM
The development of heart failure is a complex, continuous and progressive process usually associated with cardiovascular disease which results from classic risk factors such as hypertension, obesity, diabetes, smoking and dyslipidaemia. In many instances these are present as co-morbidities and, in some instances, there is a synergistic interaction between the various risk factors. Although it is well recognised that heart failure is the final stage of cardiovascular disease resulting from these risk factors, the exact nature of the development process has not been fully elucidated. However a model for the progression from hypertension to heart failure has been proposed by Vasan and Levy (1) and has subsequently been modified by Himmelman (2).
This model provides a single unified hypothesis that effectively links hypertension to heart failure. The model acknowledges that cardiovascular disease is a continuous and progressive disease, with a disparate timescale. In the early stages in the process of progression to heart failure, the left ventricular structure and function will typically be normal, however, with time the pathologic effects of one or more cardiovascular risk factor will result in the development of structural and functional changes with or without left ventricular hypertrophy and myocardial infarction. This may result in left ventricular remodelling and the development of systolic or diastolic dysfunction which in turn often leads to heart failure.
(1) Vasan RS, Levy D. The Role of Hypertension in the Pathogenesis of Heart Failure: A Clinical Mechanistic Overview. Arch Intern Med, 1996;156:
(2) Himmelman A. Hypertension: an important precursor of heart failure. Blood Press 1999;8:
Normalna
struktura i funkcija LK
Subklinička disfunkcija lijeve klijetke
Remodeliranje lijeve klijetke
Manifestno zatajenje srca
Vrijeme: decenije
Vrijeme: mjeseci

51. Patofiziologija zatajenja srca
Bubrezi/
nadbubrezi
Renin-
angiotenzin
Retencija
vode i soli
Aldosteron
Disfunkcija LK
tahikardija
Baroreceptori
(karotide i LA)
Simpatički
živčani sustav
vazokonstrikcija

52. Zatajenje srca – klinička slika
Simptomi
Zapuha
Umor
Nepodnošenje napora
Slab apetit
Kašalj
Znakovi
Otežano disanje
Edemi
Proširene vene vrata
Hropci na plućima
Pleuralni izljev
hepatomegalija
Ascites
Uvećano srce
Protodijastolički galop

53. Klasifikacija zatajenja srca
D Refraktorni, krajnji stadij
zatajenja srca
C Simptomatska strukturna
bolest srca
B Asimptomatska strukturna
A Visoki rizik za nastanak
IV Simptomi u mirovanju
III Simptomi uz minimalni
napor
II Simptomi uz veći napor
I Bez simptoma
ACC-AHA stadiji
NYHA klasifikacija
JAMA 2002;287:

54. Liječenje zatajenja srca nekada ...

55. Ciljevi liječenja zatajenja srca
poboljšati kakvoću života (simptomi!)
smanjiti pobol i smrtnost
usporiti progresiju bolesti (potaknuti “regresiju” bolesti!) 55

56. Nefarmakološko liječenje zatajenja srca
Smanjiti unos soli i tekućine
Na+ – 2-3 g/d (1g Na = 2.5g NaCl)
Mjerenje tjelesne mase dnevno
Tjelovježba
Blago do umjereno aerobno vježbanje
Ukloniti čimbenike rizika
Hipertenzija, pušenje, dijabetes, ... 28 28 48 48 43

57. Angatonist aldosterona
Kontrola volumena
Smanjenje smrtnosti
Diuretik
ACE
inhibitor
Beta-
blokator
Angatonist aldosterona
Digoksin
CRT
I C D ± CRT
Liječenje ostatnih simptoma

58. Liječenje zatajenja srca
Stadij A
Visoki rizik, bez bolesti srca
Stadij B
Asimptomatska bolest srca
Stadij D
Refraktorno zatajenje srca
Liječenje
Antihipertenzivi
Hipolipemici
Tjelovježba
Zabrana alkohola
Kao stadij A
ACE inhibitori
Beta-blokatori
Diuretici
Digitalis
Restrikcija soli
Kao A, B, C
Mehaničke pomoćne naprave
Transplatacija srca
Trajna infuzija inotropa
Hospitalna skrb
Stadij C
Simptomatska bolest srca 58

59. klinički učinci u zatajenju srca
Digitalis:
klinički učinci u zatajenju srca
ublažava simptome
smanjuju učestalost hospitalizacija
ne poboljšavaju preživljavanje
Treatment of Heart Failure.
Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action
ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion.
It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

60. Indikacije u zatajenju srca
Digitalis:
Indikacije u zatajenju srca
tahiaritmije u sklopu fibrilacije atrija
protodijastolički galop
slab odgovor na temeljno liječenje
(diuretik + BB + ACEI)
Treatment of Heart Failure.
Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action
ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion.
It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

61. Digitalis u zatajenju srca50 40 30 20 10
Smrtnost %
Placebo
n=3403
p = 0.8
N=6800
NYHA II-III
Treatment of heart failure.
Digoxin: Effect on survival
The results obtained from 3 controlled studies which included patients at low risk (The German and Austrian Xamoterol Study Group, 1988; The Captopril-Digoxin Multicenter Research Group, 1988; DiBianco et al., 1989) indicate that the mortality was similar in the group of patients with placebo. The results of the Digitalis Investigator Group-DIG study, which included 7788 patients with heart failure in sinus rhythm, functional class II-III and LVEF < 45%. The patients were treated with digoxin or placebo, in addition to conventional therapy over a mean of 37 months ( months). No differences in mortality were observed between the two treatment groups.
Am Coll Cardiol 1996
Digoksin
n=3397
DIG
N Engl J Med 1997;336:525 12 24 36 48
Mjeseci

62. ACE inhibitori: mehanizam djelovanja ACE Kininaze II VAZOKONSTRIKCIJA
VAZODILATACIJA
ALDOSTERON
PROSTAGLANDINi
VAZOPRESIN
Kininogen
tPA
SIMPATIKUS
Kalikrein
Angiotenzinogen
RENIN
BRADIKININ
Treatment of Heart Failure
Angiotensin Converting-Enzyme Inhibitors (ACEI) :Mechanisms of action
ACE-inhibitors competitively block the converting enzyme that transforms angiotensin I into angiotensin II. The reduction in angiotensin II levels explains its arteriovenous vasodilatory actions, as angiotensin II is a potent vasoconstrictor that augments sympathetic tone in the arteriovenous system. Additionally, angiotensin causes vasopressin release and produces sodium and water retention, both through a direct renal effect and through the liberation of aldosterone. Since converting enzyme has a similar structure to kinase II that degrades bradykinin, ACE-inhibitors increase kinin levels that are potent vasodilators (E2 and F2) and increase release of fibrinolytic substances such as tPA.
Angiotensin I
ACE
Inhibitor
Kininaze II
ANGIOTENZIN II
Inaktivni fragmenti

63. klinički učinci u zatajenju srca
ACE inhibitori:
klinički učinci u zatajenju srca
Ublažavaju simptome
Smanjuju remodeliranje/progresiju
Smanjuju učestalost hospitalizacija
Poboljšavaju preživljavanje
Treatment of Heart Failure.
Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action
ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion.
It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

64. ACE inhibitori u zatajenju srca
0.8
0.7
Placebo
0.6
Vjerojatnost
smrti
p< 0.001
0.5
0.4
p< 0.002
0.3
Enalapril
Treatment of Heart Failure.
Angiotensin Converting-Enzyme Inhibitors (ACEI): Survival
CONSENSUS. Prolonged administration of ACE-inhibitors reduces mortality in symptomatic heart failure. The first study to demonstrate this effect was CONSENSUS I. This graph shows the cumulative mortality curves of the treatment and placebo group in this randomized, double-blind trial. The study analyzed the effect of enalapril on prognosis of 253 patients with class IV heart failure, who also received digitalis, diuretics, and conventional vasodilators. At the end of 6 months of treatment, there was a clear-cut improvement in functional class, a reduction in the need for medications, and a 40% reduction in mortality (p<0.002). After 12 months the mortality reduction was 31% (p<0.001). Nonetheless, there were no differences in the incidence of sudden death between the two groups, or in the sub-group that received other conventional vasodilators. Another characteristic of this study was variability of the dose that was used for each patient (adjusted for tolerance and symptoms): mg/day. This aspect shows the importance of individualized treatment for heart failure patients.
The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429.
0.2
0.1 1 2 3 4 5 6 7 8 9 10 11 12
CONSENSUS
N Engl J Med 1987;316:1429
Mjeseci

65. ACE inhibitori % Smrtnost 50 40 30 20 10 n=1284 n=1285 6 12 18 24 30
p =
Placebo
n=1284 %
Smrtnost
Enalapril
n=1285
Treatment of Heart Failure
Angiotensin Converting-Enzyme Inhibitors (ACEI) : Survival
SOLVD study-symptomatic heart failure. Mortality curves in patients with clinical heart failure in the SOLVD treatment study. In this study, 2589 symptomatic heart failure patients with EFs<35% (90% in functional class II – III) were randomized to receive enalapril or placebo. Mortality over a 41 month follow-up period was 39.7% in the enalapril arm and 35.2% in the placebo arm (p<0.004). The mortality reduction was chiefly mediated through less progression of heart failure; deaths due to arrhythmia were not reduced. Additionally, the enalapril group required fewer hospitalizations for heart failure.
The SOLVD Investigators. N Engl J Med 1991;325:293
n = 2589
CHF
- NYHA II-III
- EF < 35% 6 12 18 24 30 36 42 48
SOLVD (Treatment)
N Engl J M 1991;325:293
Mjeseci

66. ACE inhibitori Smrtnost % Godine SAVE 30 Asimptomatska disfunkcija LK
poslije IM
Placebo
n=1116 20
Smrtnost %
Kaptopril
n=1115
Treatment of Heart Failure
Angiotensin Converting-Enzyme Inhibitors (ACEI): Survival
SAVE (Survival and Ventricular Enlargement). Mortality curves in the SAVE study in patients with varying degrees of post-infarct ventricular dysfunction. In this study, 2231 patients with EF < 40% were randomized to receive captopril or placebo between 3 to 16 days after experiencing a transmural infarct. After 42 months, the captopril group had a significant reduction in overall mortality (-19%), number of reinfarctions (-25%), hospitalizations (-22%), and in the number of patients who developed clinical congestive heart failure. The mortality reduction appeared after 1 year of treatment.
Pfeffer MA et al. Survival and Ventricular Enlargement (SAVE) Study. NEngl J Med 1992;327:669. 10
n = 2231
dana poslije IM
EF < 40%
mg/dan
-19%
p=0.019
SAVE
N Engl J Med 1992;327:669 1 2 3 4
Godine

67. ACE inhibitori AIRE Smrtnost % Placebo 30 20 Ramipril 10 p = 0.002
HF after AMI 6 12 18 24 30
AIRE
Lancet 1993;342:821
Mjeseci

68. Antagonisti angiotenzinskih receptora u zatajenju srca
The Val-HeFT paper cited here is a sub-group analysis of study participants not on an ACE inhibitor (N=366); they were not defined as ACE-intolerant. This table shows a reduction in all-cause mortality from 27.1% in the placebo group to 17.3% in the group treated with valsartan.
CHARM-Alternative enrolled 2028 patients not receiving ACEI due to previous intolerance. Primary outcome was composite of cardiovascular death or hospital admission for HF. At median follow up of 33.7 months, 33% of the patients in the candesartan group and 40% of the patients in the placebo group had CV death or HF hospitalization

69. ACE inhibitori vs sartani25
Losartan (n = 499 događaja)
Kaptopril (n = 447 događaja) 20 15
KV događaji (%) 10 5
Relativni rizik = 1.13 (0.99–1.28); P = 0.069
Mjeseci 6 12 18 24 30 36
Losartan
Kaptopril

70. ACE inhibitori, sartani i kombinacija u zatajenju srca
0.3
Kaptopril
Valsartan
0.25
Valsartan + Kaptopril
0.2
Vjerojatnost događaja
0.15
0.1
Mary Ann Sellers and Sue Edwards.
0.05
Valsartan vs. Kaptopril: HR = 1.00; P = 0.982
Valsartan + Kaptopril vs. Kaptopril: HR = 0.98; P = 0.726
Mjeseci 6 12 18 24 30 36
Kaptopril
Valsartan
Valsartan + Kap
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

71. Zatajenje srca: nitrati + hidralazin
0.75
n = 804
HZ + ISDN
0,54
Vjerojatnost
smrti
0.50
0.47
p = 0.016
0,48
0.36
0.42
Enalapril
0.25
0.31
0.25
0.13
0.18
0.09
p = 0.08 60
V-HeFT II
N Engl J Med 1991; 325:303 12 24 36 48
Mjeseci

72. mehanizam učinka u zatajenju srca
Beta blokatori:
mehanizam učinka u zatajenju srca
gustoću β1 receptora
kardiotoksičnost katekolamina
neurohumoralni učinak
antiishemijski učinak
antiaritmijski
antioksidacijski, antiproliferacijski
Treatment of Heart Failure.
Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action
ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion.
It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

73. klinički učinci u zatajenju srca
Beta blokatori:
klinički učinci u zatajenju srca
ublažavaju simptome
remodeliranje/progresiju
učestalost hospitalizacija
preživljavanje
učestalost nagle smrti
Treatment of Heart Failure.
Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action
ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion.
It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

74. Beta blokatori u zatajenju srca
Godišnja
Smrtnost %

76. Učinak beta blokatora u dijabetičara sa zatajenjem srca
Ukupno
randomizirani
Smrtnost (n)
Placebo/-blokatori
CIBIS II
Dijabetes
312
33/27
Bez dijabetesa
2335
195/129
Pooled mortality data from three major beta-blocker trials, including CIBIS-II, COPERNICUS, and MERIT-HF, showed similar survival benefits with beta-blockade in patients with or without diabetes.1
Treatment with beta-blockade reduced the risk of death by 25% in patients with diabetes and by 36% in patients without diabetes (data not shown).
Svi
2647
228/156
MERIT-HF
Dijabetes
985
61/50
Bez dijabetesa
3006
156/95
Svi
3991
217/145
COPERNICUS
Dijabetes
589
Bez dijabetesa
1700
Svi
2289
190/130
Sve 3 studije
Dijabetes
1886
Bez dijabetesa
7041
All
8927
635/431
0.0
1.0
1.8
RR (95% CI)
Deedwania PC et al. Am Heart J. 2005;149:
1. Deedwania PC, Giles TD, Klibaner M, Ghali JK, Herlitz J, Hildebrandt P, et al. Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: Experiences from MERIT-HF. Am Heart J. 2005;149: 76

77. Učinak beta blokatora u starijih osoba za zatajenjem srca
-blokator bolji
Placebo bolji
Hazard ratio
COPERNICUS
0.75 (0.58–0.98)
A meta-analysis of all-cause mortality data in elderly and non-elderly patients with HF from five major beta-blocker trials showed that elderly HF patients derived considerable benefit from treatment.1 These five trials included >12,000 HF patients, including 4617 patients (36%) who were elderly.
Patients classified as elderly ranged in age from 59 years in the Carvedilol US study, to 65 years in COPERNICUS and BEST, and 71 years in CIBIS-II. In MERIT-HF, patients in the upper-age tertile were classified as elderly.
The composite data show that elderly patients who received beta-blocker therapy had a significant 24% reduction in total mortality (P = 0.002). There was no significant difference in mortality reduction between elderly and younger patients.
The analysis challenges the idea that beta-blocker therapy should be withheld from patients on the basis of age. The findings suggest that all patients with systolic HF should receive beta-blockers, unless absolutely contraindicated or not tolerated by the patient.
Carvedilol (U.S.)
0.45 (0.24–0.86)
CIBIS-II
0.70 (0.49–0.99)
MERIT-HF
0.70 (0.52–0.95)
BEST
0.91 (0.78–1.05)
Svi
0.76 (0.64–0.90)
P = 0.002 –1 1 10
Risk ratio (95% CI)
Dulin BR et al. Am J Cardiol.2005;95:896-8.
1. Dulin BR, Haas SJ, Abraham WT, Krum H. Do elderly systolic heart failure patients benefit from beta blockers to the same extent as the non-elderly? Meta-analysis of >12,000 patients in large-scale clinical trials. Am J Cardiol. 2005;95: 77

78. - Inhibitori aldosterona u zatajenju srca Spironolakton ALDOSTERON
Kompetitivni antagonist
aldosteronskih receptora
(miokard, krvne žile, bubrezi)
Retencija Na+
Retencija H2O
Izlučivanje K+
Izlučivanije Mg2+
Odlaganje
kolagena
Fibroza
- miokard
- krvne žile
Edemi
Treatment of congestive heart failure.
Aldosterone inhibitors: Mechanism of action
Aldosterone acts directly on specific receptors. At the renal level it produces retention of sodium and water, resulting in an increase in preload and afterload, edema formation and the appearance of symptoms of pulmonary and systemic venous congestion. In addition, it increases the elimination of potassium and magnesium, creating an electrolyte imbalance which may be responsible in part for cardiac arrhythmias. At the tissue level, aldosterone stimulates the production of collagen, being in large part responsible for the fibrosis that is found in hypertrophied myocardium and in the arterial walls of patients with heart failure. The beneficial effects of spironolactone derive from the direct and competitive blockade of specific aldosterone receptors. Aldosterone inhibitors therefore have three types of effects:
- Diuretic effect, which is most noticeable when fluid retention and increased levels of aldosterone are present.
- Antiarrhythmic effect, mediated by the correction of hypokalemia and hypomagnesemia.
- Antifibrotic effect. This effect, demonstrated in animal models, can contribute to a decrease in the progression of structural changes in patients with heart failure.
Aritmije

79. Antagonisti aldosterona u zatajenju srca

80. Antikoagulacija u zatajenju srca
Niska istisna frakcija (<30%)
Teško zatajenje srca
Tromb u lijevoj klijetki
Prethodne tromboembolije
Fibrilacija atrija
Eur Heart J 2007;28:

81. Peroralni antikoagulansi – neke važnije interakcije
Pojačan učinak Smanjen učinak amiodaron barbiturati acetilsalicilna kiselina ciklosporin eritromicin karbamazepin fluoksetin kolestiramin kotrimoksazol omeprazol levotiroksin rifampicin metromidazol tireostatici nesteroidni antireumatici alkohol

82. Interakcije nekih pripravaka sa varfarinom
Pojačavaju učinak
Bijeli luk
Ginko biloba
Sok od grejpa
Glukozamin/hondroitin
Smanjuju učinak
Ginseng
Gospina trava

83. Lijekovi koje valja izbjegavati u liječenju kroničnoga zatajivanja srca
Blokatori kalcijskih kanala
Antiaritmici (osim BB i amiodarona)
NSAR
Tiazolidinedioni (rosiglitazon, pioglitazon)
Metformin

84. Zatajenje srca i mogućnosti liječenja
Current ACC/AHA chronic HF guidelines emphasize that each stage of HF is associated with unique options for treatment.1,2
Stage A: Treatment should include risk-factor reduction and patient and family education. Hypertension, dyslipidemia, and diabetes should be targeted, and ACE inhibitors or ARBs are also recommended in appropriate patients.
Stage B: ACE inhibitors or ARBs are recommended in all patients; -blockers are recommended in appropriate patients.
Stage C: All patients should receive ACE inhibitors and -blockers. Other treatments may include dietary sodium restriction, diuretics, and digoxin. – Additional options in appropriate patients include cardiac resynchronization (if bundle-branch block is present), revascularization and mitral-valve surgery, and aldosterone antagonists and nesiritide. – A multidisciplinary team approach may be useful.
Stage D: Refractory symptoms require special interventions, which may include inotropes, ventricular assist device (VAD), heart transplantation, and hospice care.
Jessup M, Brozena S. N Engl J Med. 2003;348:
1. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38:
2. Jessup M, Brozena S. Heart failure. N Engl J Med. 2003;348: 84

85. “Faze” u liječenju zatajivanja srca
Farmakološka
Digitalis
Diuretici
Neurohormonski zahvati
Umjetno srce
Ksenotransplantacija
Matične stanice
Genski inženjering
????
Ne-farmakološka
Mirovanje
Inaktivnost
Ograničenje tekućine (digitalis, diuretici)
prije1980’
1980’s
1990’s
2000’s
2020’s 
Farmakološka
Digitalis
Diuretici
Vazodilatatori
Inotropi
Uređaji
CRT
ICDs
LVADs
Ostali?
Abraham WT, 2002