This document discusses the use of statins in chronic heart failure (CHF). It notes that CHF is a major public health problem, with high mortality rates. The goals of CHF therapy are prevention of disease progression, improved quality of life, and increased survival. The document reviews evidence from observational studies and randomized trials suggesting benefits of statin therapy in CHF, including reduced inflammation, improved endothelial function, and lower rates of hospitalization and mortality. However, it also notes the potential for statins to reduce coenzyme Q10 levels, which could offset their protective effects. Overall, the document finds the evidence supports a potential role for statins as an adjunct therapy in CHF, especially for patients with

1. STATINELE IN
INSUFICIENTA CARDIACA
Alexandru Andritoiu
Sp. Clinic de Urgenta Militar
Craiova

2. CHF
• Problema majora de sanatate publica
• 2% din populatie
• Malignant disease
• Mortalitate ridicata
• Rata de suprav. la 1 an 40-50%

3. Obiectivele terapiei CHF
• 1. Prevenirea:
• a) bolilor generatoare de disfunctie cardiaca/insuf card.
(HTA, BCI, valvulopatii, etc.)
• b) progresiei disf. cardice spre insuf. card.
• 2. Imbunatatirea QOL
• 3. Cresterea supravietuirii
ESC Guidelines for the Diagnosis and Treatment of Chronic Heart Failure.
Eur Heart J 2005,26:1115.

4. Terapia CHF
• Terapia non-farmacologica
• Terapia farmacologica
• Device therapy
• Chirugie
ESC Guidelines for the Diagnosis and Treatment of Chronic Heart Failure.
Eur Heart J 2005,26:1115.

5. Terapia farmacologica - CHF
• Inotrop poz.
• Diuretic
• Vasodilatatoare
• Beta-Bloc.
• Antag. neurohormonali (antag. Aldost.)
• +/- Antiaritmic
• +/- Antitrombotic
ESC Guidelines for the Diagnosis and Treatment of Chronic Heart Failure.
Eur Heart J 2005,26:1115.

6. In studiu
• Statine
• Anti-citokine (etanercept)
• Antag. rec. vasopresina (tolvartan)
• Inhib. dual ECA+ NEP (omapatrilat)
• Antag. aldosteron (canrenona)

8. Beneficiile statinelor
• Dislipidemie
• Diabet tip 1-2
• Sdr. X metabolic
• BCI (angina pectorala, IMA)
• HTA

9. Efecte statine
• Stabilizarea placii ATS
• Functia endoteliala
• Neoangiogeneza
• Down-regulation rec. AT-1
• Inhib. citokinelor proinflamatorii
• SN autonom

10. Paradoxul statinelor in CHF
• Reducerea coenzimei Q10 si pierderea
efectului protector al lipoproteinelor
(detoxifierea endotoxinelor)
• Colestrol seric scazut – prognostic prost
Rauchaus M et al. Lancet 2000;356:930
Silver M et al. Am J Cardiol 2004;94:1306.

11. Rolul protector al Colesterolului
Colesterolul are efect protector la pts. CHF:
A. Colesterolul este un antioxidant –
neutralizeaza radicalii liberi cu rol
inflamator;
B. Colesterolul transporta Co-Q10 si alti
antioxidanti protectori in circulatie;
Pacientul cu CHF are nevoie de acest
mecanism de transport.
C. Colesterolul are a rol in transportul si
eliminarea metalelor grele.

12. In patients with CHF, lower serum total
cholesterol is independently associated with
a worse prognosis.
Rauchhaus et al. JACC 200342:1933
Colesterolul tot. – predictor de supravietuire in CHF
Independent de:
Etiologia CHF
Virsta
FEVS%
Capacitatea de efort
Supravietuirea creste cu 25% pentru fiecare mmol/L crestere Col. total !!!.

13. Relatia Colesterol-Deces in CHF

15. Col. scazut – expresia malnutritiei !
 La pacientii cu CHF stabila, niv.
colesterolului seric este in relatie
strinsa cu niv. prealbuminei (marker
al malnutritiei) !.
 Chiar si la pacientii tratati cu statine,
niv. scazut de colesterol ramine un
marker de malnutritie !
Araujo et al. Heart Failure (Helsinki) 2006

16. Dovezi pozitive
• Studii observationale
• Studii randomizate
• Registre nationale

17. 4S
Simvastatin Survivel Study
• 10.3% of patients on placebo were
diagnosed with HF during follow-up
compared with 8.3% of patients on
simvastatin, a difference that was not quite
statistically significant (P < .15).

19. HPS
Heart Protection Study
• Simvastatin
• Efect semnificativ in reducerea internarilor
ptr. CHF la pacientii cu risc inalt.
J Am Coll Cardiol. 2007;49:311-319

20. Effects of Early Statin Treatment on Symptomatic Heart Failure
and Ischemic Events after Acute Myocardial Infarction
in Japanese (The MUSASHI-AMI)

21. STUDII OBSERVATIONALE
• Loturi mici
• Non-randomizate
• Durata scurta
• Non real-life
• Marea majoritate extrem de favorabile !
ATRAG ATENTIA !
NU POT SCHIMBA GHIDURILE !!!

22. Statine favorabile
• Simvastatin (4S)
• Atorvastatin (TNT)

23. Efecte moleculare
• Imbuntateste fct.
endoteliala
• Scade expresia
citokinelor
proinflamatorii
• Scade moleculelor de
adeziune
• Tromboza/fibrinoliza
• FMD%
• IL-6, alfa-TNF
• sVCAM-1;
• AT III, Prt C, fV, tPA,
PAI-1
Antoniades et al. Heart Failure (Hamburg) 2007
Tousoulis et al. Heart Failure (Lisabona) 2005

24. CHF – DZ tip 2
efecte favorabile pe markerii inflamatiei
• Scade hsCRP
• Scade Cls. NYHA
• Creste toleranta la efort
• FEVS - nemodificata
1
10
100
CRP CRP 12 Mo
Simva
Non-Simva
Arutyunov et al. Heart Failure (Lisabona)

25. Efectele neurohormonale
BNP
NT-pro BNP
Angiotensina II
hsCRP (12.9% v 3.2% placebo)
• Aldosteron
• Renina
• NorEpi
Berezin A. Heart Failure (Hamburg ) 2007
Albulhul et al. Heart Failure (Lisabona) 2005
Iakovis et al. Heart Failure (Lisabona) 2005

26. Riscut de mortalitate este influentat de profilul
neurohormonal si metabolic !
• RR = 0.93 in grupul tratat cu statine (p=0.003)
• Grupul cu Col crescut – RR 1.03 (0.96-1.09)
RR 95% CI
hsCRP (+) - Col (-) 1.28 1.18-1.40
hsCRP (+) - Col (+) 1.17 1.08-1.27
PACIENTII CU COLESTEROL SCAZUT SI CRP CRESCUTA
CEL MAI PROST PROGNOSTIC
Windram et al. Heart Failure (Helsinki) 2006

27. Statinele reduc CRP in CHF
• FEVS= <25%
• CHF severa
• Simvastatin 40 mg/zi
• 12 luni tratament
12.5
11.9
7.4
11.04
0
5
10
15
20
25
30
CRP CRP-12 Mo
Simva
non-Simva
Rylova et al. Heart Failure (Helsinki) 2006

28. Efectul pe reducerea mortalitatii
• 1996 -2003
• 1648 pts.
• 20 GP
• Follow-up: 8 yr
• Age: 74.2yr
HR CI
Diuretice 0.73 0.58-0.92
ACE-I 0.90 0.75-1.07
Beta-bloc. 0.63 0.52-0.76
Statine 0.66 0.49-0.89
Dicumarinic 0.72 0.59-0.87
Aspirina 0.68 0.55-0.84
Ruten et al. Heart Failure (Hamburg) 2007

29. Foody et al. Circulation. 2006;113:1086
Statin therapy is associated with better long-term mortality in older patients with HF.
This study suggests a potential role for statins as an adjunct to current HF therapy.

30. Two-year rates of death or urgent transplantation in statin versus no-statin
cohorts. The benefit associated with statin therapy in the total cohort was
compared with subgroups of men and women, those with cholesterol above and
below the median level (163 mg/dl), and a subgroup excluding patients who
underwent elective or urgent transplantation.
HR = hazard ratio with statin therapy (Rx); TC = total cholesterol.
Horwich et al. JACC 2004;43:642

31. Reducerea mortalitatii numai in CHF
ischemica ?
• 401 pts
• non-randomizati
• 2002-2003
• CHF ishemica (n = 288)
• CHF non-ischemica (n =113)
0%
5%
10%
15%
20%
25%
ISCH NON-ISCH
STATINE
NON-STATINE
Stawicki S et al. Heart Failure (Helsinki) 2006

32. Ischemic CHF vs Non-Ischemic CHF

33. One-year hazard ratios (HRs) and 95% confidence intervals (CIs) for death or
urgent transplantation, death from any cause, progressive heart failure death,
and sudden death for patients receiving statins compared with
those not receiving statins.
Horwich et al. JACC 2004;43:642
Statin therapy is associated with improved survival
in ischemic and non-ischemic heart failure

34. CHFpEF
• Amelioreaza parametrii diastolici1
• Reduce mortalitatea la 1 an2
1. Marsaro et al. Heart Failure (Hamburg) 2007
2. Roik et al. Heart Failure (Hamburg) 2007

35. Factorii determinanti ai utilizarii
statinelor in CHF
• Etiologia ischemica a CHF
• Istoric de stroke
• HTA
• Utilizarea ACO
Roik et al. Heart Failure (Hamburg) 2007

36. Terapia cu statine reduce mortalitatea numai la pts.
fara anemie, indiferent de prezenta disfunctiei renale
• N = 501 pts. CHF NYHA II-IV
• Age 69+/-11 yr
• RF = creatinina > 1.4 mg/dl
• A = Hb < 12 g/dl
• Tratament cu statine (Atorva, Simva, Lova)
HR 95%CI P
Gr 1 (non A – non RF) 0.23 0.12-0.42 <0.001
Gr 2 (A – non FR) 0.25 0.10-0.62 0.003
Gr 3 (non A - RF) 0.46 0.24-0.89 0.02
Gr 4 (A + RF) 0.32 0.14-0.74 0.007

37. Statinele reduc PAP in CHF severa
36.8
46.4
37.7 38.6
0
5
10
15
20
25
30
35
40
45
50
PAP PAP -12Mo
non-Simva
Simva
Rylova et al Heart Failure (Helsinki) 2006

38. Statinele scad rata reinternarilor la 12 luni
56%
75%
statine non-statine
statine
non-statine
Stawicki et al. Heart Failure (Lisabona)2005

39. Efecte pe FEVS

42. Efectul statinelor pe Cls. NYHA

43. Interactiuni favorabile
• Beta-blocant – Statine
• CIBIS II1
• OPTIMAAL
• Statine – Eplerenona
• (EFESUS)2
1.Krum et al. Lancet 1999;353:9.
2. White et al. Heart Failure (Lisabona) 2005

44. Exista trialuri ?
• Analize post-hoc
• ELITE II (Losartran)
• N 3127 pts
• 12.7% statine
• Pacientii care au primit statine au avut un risc
mai mic de deces !
• CHARM (Candesartan)
• 41 % statine
• Nu s-a facut evaluarea sublotului tratat cu
statine

45. TNT
Treated to New Targets
• Atorvastatin 80 mg vs 10 mg
• N = 10.001 pts
• Studiu randomizat
• Follow-up: 4.9 yr
• End point: rata spitalizarii ptr CHF
Tratamentul intensiv (80 MG/ZI) cu atorvastatin la pacientii cu BCI stabila
a redus semnifIcativ spItalizariile pentru CHF, comparativ cu doza de 10 mg
LaRosa JC et al. Treating to New Targets (TNT) Investigators.
Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
N Engl J Med 2005;352:1425-1435

46. CORONA
COntrolled ROsuvastatin MultiNAtional
Study in Heart Failure
• N = 4950 pts (NYHA II-IV ischemica)
• Studiu randomizat
• CHF simptomatica
• FEVS <35%
• Rosuvastatin 10 mg/zi vs Placebo
• Durata: 52 luni
END POINTcombinat:
Reducerea mortalitatii CV
Reducerea IM non-fatal
Reducerea Stroke
Kjekshus et al. Eur J Heart Failure 2005;7:1059.

47. GISSI-HF
Gruppo Italiano per lo Studio della
Sopravvivenza nell'Infarto Miocardico -
Heart Failure
• Ac grasi polinesaturati (omega 3) vs Placebo
• Rosuvastatin vs Placebo
• N= 7000 pts
• Randomizat
• End point:
 Mortalitate de orice cauza
 Mortalitatea cardiovasculara
Tavazzi et al. Eur Heart J 2004;6:635.

48. UNIVERSE
The rosUvastatiN Impact on
VEntricular Remodeling
cytokineS and neurohormonEs
• (
• Rosuvastatin 40 mg
• CHF

49. STATINE IN CHF
• DA – la pacientii cu BCI
• DA – CHF cu markeri inflamatori
• DA – asociat cu Coenzima Q 10 ?!

50. Coenzima Q 10
(ubiquinona)
• Coenzime Q10 a fost izolata din mitocondria
cardiaca (Dr. Frederick Crane in 1957- Univ.
Wisconsin-SUA).
• In 1958, Dr. Folkers si lab. Merck sintetizeaza
coenz. Q10 in laborator.
• Din 1980 se comercializeaza ca supliment
nutritiv.
• Metab. energetic (ATP)
• Efecte antioxidante
• Recomandata la cardiaci, asociat tratamentului
antihipertensiv si statinelor.
Ficat
Muschi
Miocard
Alimente:
peste (somon)
Alune
Organe
STAINELE BLOCHEAZA SINTEZA HEPATICA DE Co Q10
SCADEREA CoQ10 75% -- INSUF. CARDIACA !!!