STATINS IN HEART FAILURE

STATINELE IN INSUFICIENTA CARDIACA

Alexandru Andritoiu

Sp. Clinic de Urgenta MilitarCraiova

CHF

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

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.

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.

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.

In studiu

• Statine

• Anti-citokine (etanercept)

• Antag. rec. vasopresina (tolvartan)

• Inhib. dual ECA+ NEP (omapatrilat)

• Antag. aldosteron (canrenona)

Beneficiile statinelor

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

Efecte statine

• Stabilizarea placii ATS

• Functia endoteliala

• Neoangiogeneza

• Down-regulation rec. AT-1

• Inhib. citokinelor proinflamatorii

• SN autonom

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;356:930Silver M et al. Am J Cardiol 2004;94:1306.

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.

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 CHFIndependent de:Etiologia CHFVirsta FEVS%Capacitatea de efort

Supravietuirea creste cu 25% pentru fiecare mmol/L crestere Col. total !!!.

Relatia Colesterol-Deces in CHF

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

Dovezi pozitive

• Studii observationale

• Studii randomizate

• Registre nationale

4SSimvastatin 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).

HPSHeart Protection Study

• Simvastatin

• Efect semnificativ in reducerea internarilor ptr. CHF la pacientii cu risc inalt.

J Am Coll Cardiol. 2007;49:311-319

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

STUDII OBSERVATIONALE

• Loturi mici

• Non-randomizate

• Durata scurta

• Non real-life

• Marea majoritate extrem de favorabile !

ATRAG ATENTIA !NU POT SCHIMBA GHIDURILE !!!

Statine favorabile

• Simvastatin (4S)

• Atorvastatin (TNT)

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) 2007Tousoulis et al. Heart Failure (Lisabona) 2005

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)

Efectele neurohormonale

BNPNT-pro BNPAngiotensina IIhsCRP (12.9% v 3.2% placebo)• Aldosteron• Renina• NorEpi

Berezin A. Heart Failure (Hamburg ) 2007Albulhul et al. Heart Failure (Lisabona) 2005Iakovis et al. Heart Failure (Lisabona) 2005

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

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

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

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.

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

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

Ischemic CHF vs Non-Ischemic CHF

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

CHFpEF

• Amelioreaza parametrii diastolici1

• Reduce mortalitatea la 1 an2

1. Marsaro et al. Heart Failure (Hamburg) 20072. Roik et al. Heart Failure (Hamburg) 2007

Factorii determinanti ai utilizarii statinelor in CHF

• Etiologia ischemica a CHF

• Istoric de stroke

• HTA

• Utilizarea ACO

Roik et al. Heart Failure (Hamburg) 2007

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

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

Statinele scad rata reinternarilor la 12 luni

56%

75%

statine non-statine

statine

non-statine

Stawicki et al. Heart Failure (Lisabona)2005

Efecte pe FEVS

Efectul statinelor pe Cls. NYHA

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

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

TNTTreated 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

CORONACOntrolled 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 CVReducerea IM non-fatalReducerea Stroke

Kjekshus et al. Eur J Heart Failure 2005;7:1059.

GISSI-HFGruppo 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.

UNIVERSEThe rosUvastatiN Impact on

VEntricular Remodeling cytokineS and neurohormonEs

• (

• Rosuvastatin 40 mg• CHF

STATINE IN CHF

• DA – la pacientii cu BCI

• DA – CHF cu markeri inflamatori

• DA – asociat cu Coenzima Q 10 ?!

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 Q10SCADEREA CoQ10 75% -- INSUF. CARDIACA !!!