1. Statinai ir širdies nepakankamumas: naujausi mokslo įrodymai
Aušra Kavoliūnienė
KMU docentė
KMUK Kardiologijos klinikos II skyriaus vadovė
2008m.

2. STATINAI
Labai daug pozityvių RKT įrodyti statinų įtakai ŠKL baigčių (ŪMI, KA, insultas) pagerinimui
Vaistų klasė kilusi iš natūraliosios medicinos – žolinių vaistų , t.y. raudonųjų grybelių , augančių ant ryžių (red yeast rice), kurie pasižymi savybe mažinti cholesterolio koncentraciją
Trys iš statinų yra tiesioginiai natūralūs produktai: pravastatinas, simvastatinas ir lovastatinas, kiti gi yra sintetiniai produktai.

3. Statinai gydant lėtinį ŠN
Potenciali nauda:
Išemijos komplikacijų sumažinimas
Pleiotropinis (priklausomas ne nuo cholesterolio sumažinimo) poveikis
Potencialūs nepageidautini reiškiniai
Ubichinono hipotezė
Endotoksinų hipotezė

4. Retrospektyviniai tyrimai

5. Retrospektyviniai tyrimai (tęsinys)

6. Retrospektyvinė meta-analizė: mirtingumas gydant statinais, kai yra ŠN Heart failure patients using statins (n = 30,107); heart failure patients not using statins (n = 101,323).

7. Išgyvenamumo tikimybė gydant statinais
Foody, J. M. et al. Circulation 2006;113:

8. Class effects of statins in elderly patients with congestive heart failure: A population-based analysis
Background Long-term treatment with statins reduces mortality in patients with congestive heart failure (CHF). Whether statin agents exert a class effect is unknown.
Methods We analyzed long-term mortality in Canadian patients aged ≥65 years who were discharged from hospital with a diagnosis of CHF from January 1998 to December Administrative data from Quebec, Ontario, and British
Columbia were merged. We compared patients prescribed with atorvastatin, simvastatin, pravastatin, and lovastatin.
Results A total of patients hospitalized with a diagnosis of CHF fulfilled the inclusion criteria for this study. In this final dataset, 6670 (43.4%) filled a prescription for atorvastatin, 4261 (27.7%) for simvastatin, 3209 (20.9%) for pravastatin, and 1228 (8.0%) for lovastatin. Clinical characteristics and proportion of days covered with a statin prescription were similar across groups. Drug dosages were relatively low, with 82% of patients who received the agent at a dose of ≤20 mg. Although controlling for time-dependent covariates representing current use and dosage, as well as for age, sex, coronary artery disease, and several other comorbidities, treatment with pravastatin (adjusted hazards ratio [HR] 0.94, 95% CI ), lovastatin (adjusted HR 1.02, 95% CI ), or simvastatin (adjusted HR 0.92, 95% CI ) had a similar effectiveness to prevent mortality compared to atorvastatin (reference in this analysis) in this population with CHF. Time dependent exposure to a statin was highly protective against mortality.
Conclusions Statins exert a class effect in patients with CHF, when used at a relatively low dose. The favorable effects appear largely independent of drug dosage. (Am Heart J 2008;155: )

9. Naudingi (pilkai) ir nepageidaujamas (grūdėta)
statinų poveikai eNOS = endothelial nitric oxide synthase; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LPS = lipopolysaccharide; NAD(P)H = nicotinamide adenine dinucleotide phosphate; NFκB = nuclear factor kappa B; PI3 = phosphatidylinositol-3; PP = pyrophosphate; tRNA = transfer ribonucleic acid.

10. Galimi molekuliniai statinų poveikiai gydant neišeminį ŠN
Uždegimo mažinimas
Endotelio funkcijos gerinimas
Trombogeniškumo mažinimas
Autonominės funkcijos balansavimas
KS funkcijos gerinimas:
MMP 9, 3 and 1 koncentracijos mažinimas, remodeliavimosi prevencija
SNS ir RAAS balansavimas
Hipertrofijos mažinimas
Drug Insight: Statins for Nonischemic Heart Failure -- Evidence and Potential Mechanisms

11. 1 metų išgyvenamumas (%) be indikacijų širdies persodinimui
sergant neišeminiu (n = 298) ir išeminiu (n = 244) ŠN
Fig. 4. Kaplan-Meier curves demonstrate one-year survival (%) without the need for urgent heart transplantation in cohorts of nonischemic (n = 298) and ischemic (n = 244) heart failure patients. Rx = therapy. Reprinted from Journal of the American College of Cardiology, with permission from the American College of Cardiology Foundation.
Horwich TB et al. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. JACC, :642–648

12. prieš gydymą ir 14 sav. po gydymo
B-type natriuretinio peptido (A), TNF-α (B) ir interleukino-6 (C) palyginimas gydant placebu ir simvastatinu
prieš gydymą ir 14 sav. po gydymo
*P < .001 vs. placebo group. #P < .05 vs. before treatment in the statin groups.
Fig. 1. Comparison of plasma levels of B-type natriuretic peptide (A), tumor necrosis factor-α (B), and interleukin-6 (C) in the placebo and simvastatin-treated groups, before and 14 weeks after treatment. *P < .001 vs. placebo group. #P < .05 vs. before treatment in the statin groups. Reprinted with permission from: Node K. et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy.
Node K. et al. Short-term statin therapy improves cardiac function and symptoms in patients with idiopathic dilated cardiomyopathy Circulation 2003;108(7):839–843.

13. Statinai gerina KS funkciją ir simptomus gydant dilatacinę KMP
Node et al. Circulation 2003; 108:839

14. Statinai gerina KS funkciją ir simptomus gydant dilatacinę KMP
Node K, et al. Circulation 2003;108:839-43

15. Širdies ligos klinika ir OMG nepadeda, ŠN simptomai ramybėje
Didelė ŠN rizika
Iki-klinikinis ŠN
Širdies nepakankamumas
LDR ŠN šsivystymui, bet nėra širdies ligos
AH, VAL, CD, MBS; Kardio- toksinai, KMP paveldėjimas
22% A
Yra širdies liga, nėra ŠN simptomų
Persirgtas MI KS remodeliav. Vožtuvų ligos
34% B
Buvusi ar esama ŠN klinika
Širdies ligos klinika ir
ŠN klinika
12%
Atsparus gydymui ŠN
OMG nepadeda, ŠN simptomai ramybėje
0,2% D C
Struktūrinė širdies liga
ŠN simptomai
ŠN simptomai ramybėje
56% asmenų >45m amžiaus turi KS disfunkcijos rizikos veiksnius ar besimptomę KS disfunkciją

16. Širdies ligos klinika ir OMG nepadeda, ŠN simptomai ramybėje
Didelė ŠN rizika
Iki-klinikinis ŠN
Širdies nepakankamumas
LDR ŠN šsivystymui, bet nėra širdies ligos
AH, VAL, CD, MBS; Kardio- toksinai, KMP paveldėjimas
Tikslai
Nerūkyti, riboti alkoholį, didinti fizinį aktyvumą, gydyti hipertenziją, CD, MBS
Vaistai:
AKFI ar ARB, KG ligoms ar CD A
Yra širdies liga, nėra ŠN simptomų
Persirgtas MI KS remodeliav. Vožtuvų ligos
Tikslai
kaip A stadijoje
Vaistai:
AKFI ar ARB BB
Prietaisai:
IKD B
Buvusi ar esama ŠN klinika
Širdies ligos klinika ir
ŠN klinika
Tikslai kaip a ir B stadijose Vaistai: DU, AKFI, BB Vaistai kai kam: ARB, ALA, ŠVG, nitratai / hidralazinas Prietaisai: ŠRG, IKD
Atsparus gydymui ŠN
OMG nepadeda, ŠN simptomai ramybėje
Tikslai kaip A, B, C st. Gydymo pasirinkimas: pasirengimas gyvenimo pabaigai
Specialiosios priemonės: inotropai, š. transplantacija, SPP, eksperimentinė chirurgija ar vaistai D C
Struktūrinė širdies liga
ŠN simptomai
ŠN simptomai ramybėje
Hunt SA, et al. Circulation. 2005;112:

17. Du RKT teigia, kad statinai gali sumažinti hospitalizacijų dėl ŠN skaičių
Pirmasis tyrimas tyrė, ar rosuvastatinas sergantiesiems ŠN vyresniame amžiuje gali pakeiti susirgimo baigtis?
CORONA - Controlled Rosuvastatin Multinational Study in Heart Failure .
Panašus kitas tyrimas tyrė, ar gydymas didele atorvastatino doze gali sumažinti hospitalizacijų dėl ŠN skaičių
TNT - Treating to New Targets- pogrupių analizė.

18. CORONA Controlled rosuvastatin multinational trial in heart failure Kontroliuojamas daugianacionalinis rosuvastatino tyrimas gydyti širdies nepakankamumui

19. 371 centres in 21 countries (Europe, Russia, S. Africa)
CORONA tyrimo planas
371 centres in 21 countries (Europe, Russia, S. Africa)
Išeminės kilmės ŠN
Amžius ≥60 m
IF ≤0.40 (NYHA III/IV) ar ≤0.35 (NYHA II)
Optimalus ŠN gydymas
Rosuvastatinas 10 mg
n=2514
Placebas
n=2497
Randomizacija
Stebėsenos vizitai
0 to 4 weeks
2 to 4 weeks
Baigta 1 2
6 sav
3 mėn
Optiim. ŠN gydymas
Placebas
Vidutinė stebėsenos trukmė 2.7 m
Kjekshus J et al. Eur J Heart Fail 2005;7: Kjekshus J et al. N Engl J Med 2007;357:in press.

20. Kjekshus J et al. N Engl J Med 2007;357:in press.
CORONA pacientai
Rodmuo Visi pacientai
Amžíus (m.) 73
Moterys 24 %
NYHA f.k. II 37 % III 62 % IV 1.5 %
IF 31 %
NT-pro BNP pmol/l median (interquartile range) 173 (73 to 368)
eGFG <60 ml/min/1.73 m2 57 %
Kjekshus J et al. N Engl J Med 2007;357:in press. 21

21. Kiti vaistai gydymo pradžioje
Vaistai Visi pacientai
Diuretikai 88 %
AKFI ar ARB1 92 %
Beta-blokatoriai 75 %
Aldosterono antagonistai 39 %
Digoksinas 33 %
Antiagregantai 59 %
Antikoaguliantai 35 %
Antiagregantai arba antikoagul. 90 %
1 AT1-blocker
Kjekshus J et al. N Engl J Med 2007;357:in press. 22

22. Baigtys Mirtis dėl ŠKL ar nemirtinas MI ar nemirtinas insultas35 30
Placebas
n = 732 (29.3%) 25
Rosuvastatinas
n = 692 (27.5%) 20
Per cent 15 10
Hazard ratio = 0.92
95% CI 0.83 to 1.02
p = 0.12
Fig 1012 primary 5
Kjekshus J et al.
N Engl J Med 2007;357:in press. 6 12 18 24 30 36
Months of follow-up
No. at risk
Placebo
Rosuvastatin

23. Bendras mirtingumas 35 Placebo n = 759 (30.3%) 30 Rosuvastatin25 20
Per cent 15
Hazard ratio = 0.95
95% CI 0.86 to 1.05
p = 0.31 10
Fig 1013 Death 5
Kjekshus J et al.
N Engl J Med 2007;357:in press. 6 12 18 24 30 36
Months of follow-up
No. at risk
Placebo
Rosuvastatin

24. ŠKL įvykiai SŠM,mirtinas ir nemirtinas MI, PVAI, AKJO, IKD , atgaivinimas po širdies sustojimo, hospitalizacija dėl NKA 30
Placebo
n = 588 (23.5%) 25 20
Rosuvastatin
n = 554 (21.6%)
Per cent 15
Hazard ratio = 0.92
95% CI 0.82 to 1.04
p = 0.18 10
Fig 1014 5
Kjekshus J et al.
N Engl J Med 2007;357:in press. 6 12 18 24 30 36
Months of follow-up
No. at risk
Placebo
Rosuvastatin

25. Hospitalizacijos Placebas 4000 Rosuvastatinas 3000 2000 1000 All cause
4074
(1523)
Placebas
3694
(1489)1
4000
Rosuvastatinas
2564
(1164)
3000
2193
(1104)
2000
1510
(840)
1501
(839)
1299
(669)
1109
(622)
1000 90
(71) 74
(65)
All cause
p=0.0072
CV cause
p<0.0012
Heart failure
p=0.012
Unstable
angina
p=0.30
Non-CV
cause
1 Number of patients hospitalized within brackets
2 p-value refers to total number of hospital admissions and not patients
Kjekshus J et al. N Engl J Med 2007;357:in press.

26. Nemirtinas ir mirtinas MI ar insultas (Post hoc analysis)15 12
Placebo
n = 264 (10.6%) 9
Rosuvastatin
n = 227 (9.0%)
Per cent 6
Hazard ratio = 0.84
95% CI 0.70 to 1.00
p = 0.05
Fig 1021 3
Kjekshus J et al.
N Engl J Med 2007;357:in press. 6 12 18 24 30 36
Months of follow-up
No. at risk
Placebo
Rosuvastatin

27. Bendras mirtingumas 35 Placebo n = 759 (30.3%) 30 Rosuvastatin25 20
Per cent 15
Hazard ratio = 0.95
95% CI 0.86 to 1.05
p = 0.31 10
Fig 1013 Death 5
Kjekshus J et al.
N Engl J Med 2007;357:in press. 6 12 18 24 30 36
Months of follow-up
No. at risk
Placebo
Rosuvastatin

28. Šalutinis poveikis Placebas Rosuvastat.
Šalutiniai poveikiai
Šalutinis poveikis Placebas Rosuvastat.
n=2497 n=2514
(n) (n)
Visi šalutiniai poveikiai Sunkūs šalutiniai poveikiai
ALT padidėjimas > 3 x
bent vieną kartą 24 25
dažniau 5 3
Kraujo kreatinino konc padvigubėjimas
Raumenų simptomai
KK > 10 x 3 1
KK > 10 x + raumenų simptomai3 1 0
1 daugiau nei viršutinė normos riba
2Active Aktyvi info apie ŠP
3 Po to, kai pradėta fizioterapija
Kjekshus J et al. N Engl J Med 2007;357:in press.

29. Kjekshus J et al. N Engl J Med 2007;357:in press.
MTL-Ch pokyčiai
Baseline mean values
Placebo 3.56 mmol/L (137 mg/dL)
Rosuvastatin 3.54 mmol/L (137 mg/dL)
% change
in mean
Follow-up time
Closing visit
Mean 36 months
3 months
15 months
+10
-10
LDL cholesterol
-20
-30
-40
-50
Net difference
-45%
-41%
-34%
p<0.0001
p<0.0001
p<0.0001
n= 2339/2366
n= 1980/2021
n= 1553/1618
Kjekshus J et al. N Engl J Med 2007;357:in press.

30. Vidutinio dj-CRB pokyčiai
Baseline median values
Placebo 3.50 mg/L
Rosuvastatin 3.50 mg/L
Follow-up time
Closing visit
Mean 36 months
median
% change
3 months
15 months
+10
-10
hsCRP
-20
-30
-40
Net difference
-25%
-34%
-37%
p<0.0001
p<0.0001
p<0.0001
n= 2310/2336
n= 1957/1993
n= 1534/1599
Kjekshus J et al. N Engl J Med 2007;357:in press.

31. Primary event endpoint
Variable
Limit
Hazard ratio and 95% CI
Age
<77
≥77
Female
Male
NYHA II
NYHA III and IV EF
≥0.30
<0.30
BMI
≥26
<26
SBP
≥122.5
<122.5
Primary event endpoint
Pre-specified subgroups analyzed for
Safety reasons
DBP
≥73
<73 HR
<75.5
≥75.5
Current smoking No
Yes
Previous MI No
Yes
Previous revascularization
Yes No
Previous hypertension
Yes No
Diabetes No
Yes
Sinus rhythm
Atrial fibrillation
LDL
≥3.12
<3.12
ApoB/ApoA1
<0.76
≥0.76
HDL
≥1.05
Highest risk tertile vs other two tertiles or presence/ absence of condition e.g. diabetes
Fig 1010
<1.05 TG
≥2.12
<2.12
eGFRMDRD
≥51
<51
NT-pro BNP
<277.6
≥277.6
hsCRP
<5.8
≥5.8
Antiplatelets
Yes No
Anticoagulants
Yes No
All randomized
0.5
1.0
1.3
Favours rosuvastatin
Favours placebo
Kjekshus J et al. N Engl J Med 2007;357:in press.

32. CORONA tyrimo išvados:
Lyginant su placebu, rozuvastatinu gydyti pacientai turėjo mažesnę MTL-Ch koncentraciją , bet nebuvo statistiškai patikimų skirtumų ŠKL baigtims.
Antrinių baigčių analizė parodė mažesnį hospitalizacijų dėl ŠN dažnį gydant rozuvastatinu vyresnaime amžiuje (73±7 m).
Gydymas rozuvatatinu yra saugus vyresniame amžiuje, kai yra ŠN klinika ir maža IF.

33. TNT Treating to New Targets
Tyrimas siekė nustatyti, ar
agresyvus MTL-Ch sumažinimas iki 1.9 mmol/L (atorvastatino 80 mg)
užtikrina geresnes VAL baigtis lyginant su
įprastu MTL-Ch sumažinimu iki 2,6 mmol/L (atorvastatino 10mg)
JACC, 2004; 93:154-8.

34. Mean change in LDL-C from untreated baseline, %
Daugumos statinų startinė dozė ryškiai sumažina MTL-C, tačiau tolimesnis dozės didinimas neužtikrina adekvataus MTL-C sumažėjimo
Pravastatin
Simvastatin
Atorvastatin
Rosuvastatin –5
–15
–20%
–28%
10 mg
–37%
20 mg
–46%*,†
–4%
–25
40 mg
Mean change in LDL-C from untreated baseline, %
–6%
80 mg
–7%
–35
Key Points:
The majority of LDL-C─lowering efficacy is provided at starting statin doses.
Rosuvastatin 20 mg produced an additional 6% LDL-C reduction, and rosuvastatin 40 mg produced an additional 3% LDL-C reduction.1
Additional Background Information:
This 6-week, parallel-group, open-label, randomized, multicenter trial compared rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction in LDL-C.1
After a dietary lead-in period, 2,431 adults with LDL-C 160 and <250 mg/dL and TG <400 mg/dL were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg.1
Atorvastatin 10 mg, rosuvastatin 10 mg, and simvastatin 10 mg produced reductions in LDL-C of 37%, 46%, and 28%, respectively.1
Rosuvastatin 20 mg and 40 mg produced additional reductions in LDL-C of 6% and 3%, respectively (actual percent reductions of 52% and 55%, respectively).1
Atorvastatin 20 mg, 40 mg, and 80 mg produced additional reductions in LDL-C of 6%, 5%, and 3%, respectively (actual percent reductions of 43%, 48%, and 51%, respectively).1
Simvastatin 20 mg, 40 mg, and 80 mg produced additional reductions in LDL-C of 7%, 4%, and 7%, respectively (actual percent reductions of 35%, 39%, and 46%, respectively).1
Mean baseline LDL-C levels were 187 mg/dL to 194 mg/dL across treatment groups.
Reference:
1. Jones PH, Davidson MH, Stein EA, et al, for the STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol. 2003;92:152–160.
–4%
–6%
–7%
–45
–5%
–3%
–6%
–55
–3%
*P<0.001 vs atorvastatin 10 mg; simvastatin 20 mg and 40 mg; and pravastatin 10 mg, 20 mg, and 40 mg.
†P=0.026 vs atorvastatin 20 mg
Jones PH et al. Am J Cardiol. 2003;92:152.

35. Treating to New Targets (TNT) Study
The TNT hypothesis was tested in a double-blind, parallel-group design.
A total of 18,469 patients were screened; lipid-lowering therapy was withdrawn, and all patients entered a wash-out phase.
15,464 patients with established CHD and an LDL-C level of 130 to 250 mg/dL (3.4 to 6.5 mmol/L) and with triglycerides 600 mg/dL (6.8 mmol/L) were then eligible to enter the 8-week, open-label, run-in period with atorvastatin 10 mg/day.
In order that the 2 groups of patients would meet the LDL-C targets during the double-blind phase—and because it would have been unethical to under-treat patients whose LDL-C remained >130 mg/day (>3.4 mmol/L)—only those patients with a mean LDL-C <130 mg/dL (<3.4 mmol/L) on 10 mg of open-label atorvastatin were entered into the randomized phase of the study.
10,001 patients were randomized to double-blind therapy with either atorvastatin 10 mg/day or 80 mg/day; 5006 patients remained on atorvastatin 10 mg daily and 4995 patients received 80 mg daily.
Using the time of randomization as the baseline for the study, patients were then followed for a median of 4.9 years.
Reference
1. LaRosa JC, et al. N Engl J Med. 2005;352.
Slide 36

36. Treating to New Targets (TNT) Study
Patients were eligible for inclusion in the study if they satisfied the following criteria:
Men and women aged years.
Clinically evident CHD, defined as previous MI, previous or present angina with objective evidence of atherosclerotic CHD, or patients who have undergone a coronary revascularization procedure.
LDL-C mg/dL ( mmol/L) and triglycerides 600 mg/dL (6.8 mmol/L ) at the beginning of the open-label, run-in period.
LDL-C <130 mg/dL (<3.4 mmol/L) at the end of the open-label, run-in period.
Reference
1. Waters DD, et al. Am J Cardiol. 2004;93:154-8.
Slide 37

37. Treating to New Targets (TNT) Study
Major exclusion criteria included any of the following:
Hypersensitivity to statins.
Active liver disease or hepatic dysfunction, defined as ALT or AST 1.5  the upper limit of normal.
Patients with nephrotic syndrome.
Women who are pregnant or breastfeeding.
Uncontrolled diabetes mellitus, hypothyroidism, or hypertension (as defined by the investigator) at the screening visit.
MI, coronary revascularization procedure, or severe/unstable angina within 1 month of screening.
Ejection fraction <30%.
Unexplained CPK levels >6 times the upper limit of normal.
Non-skin malignancy, malignant melanoma, or other survival-limiting disease.
Concurrent therapy with long-term immunosuppressants, or lipid-regulating drugs not specified as study treatment in the protocol.
Any planned surgical procedure for the treatment of atherosclerosis.
Hemodynamically important valvular disease.
Gastrointestinal disease limiting drug absorption or partial ileal bypass.
History of alcohol abuse.
Participation in another clinical trial concurrently or within 30 days before screening.
Reference
1. Waters DD, et al. Am J Cardiol. 2004;93:154-8.
Slide 38

38. Treating to New Targets (TNT) Study
The primary efficacy outcome measure was the time to occurrence of a major cardiovascular event, defined as:
CHD death.
Nonfatal, non–procedure-related MI.
Resuscitated cardiac arrest.
Fatal or nonfatal stroke.
Reference
1. LaRosa JC, et al. N Engl J Med. 2005;352.
Slide 39

39. Treating to New Targets (TNT) Study
Over the course of the study, there was a highly significant reduction in the composite efficacy outcome of major cardiovascular events (death from CHD, nonfatal non–procedure-related MI, resuscitated cardiac arrest, or fatal or nonfatal stroke) in the atorvastatin 80 mg group compared with the atorvastatin 10 mg group.
The Kaplan-Meier analysis demonstrated a hazard ratio of 0.78 (95% CI 0.69, 0.89; P<0.001).
This represented a 22% reduction in relative risk in the atorvastatin 80 mg group relative to the atorvastatin 10 mg group, over and above the low absolute event rate of 10.9% recorded in the atorvastatin 10 mg group.
There was no statistical interaction for age or gender in the primary outcome measure.
Reference
1. LaRosa JC, et al. N Engl J Med. 2005;352.
Slide 40

40. Treating to New Targets (TNT) Study
Because of the potential for severe long-term physical and mental disability, stroke can be a huge economic burden on society.
Reduction of LDL-C substantially below 100 mg/dL (2.6 mmol/L) with atorvastatin 80 mg also provided significant clinical benefit beyond the coronary vasculature, reducing the risk of stroke by 25% (P=0.02).
Reference
1. LaRosa JC, et al. N Engl J Med. 2005;352.
Slide 41

41. Treating to New Targets (TNT) Study
A relative reduction in the risk of the secondary efficacy outcome major coronary events (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest) was observed with atorvastatin 80 mg compared with atorvastatin 10 mg (HR = 0.80; 95% CI 0.69, 0.92; P=0.002).
Reference
1. LaRosa JC, et al. N Engl J Med. 2005;352.
Slide 42

42. Treating to New Targets (TNT) Study
Relative reductions in the secondary outcome measures of any cardiovascular event (19%), major coronary event (20%), any coronary event (21%), cerebrovascular event (23%), and hospitalization with a primary diagnosis of CHF (26%) with atorvastatin 80 mg compared with atorvastatin 10 mg were all consistent with the reduction observed for the primary composite outcome.
The effect of atorvastatin 80 mg on the risk of PAD did not differ significantly from that of atorvastatin 10 mg (HR = 0.97; 95% CI 0.83, 1.15; P=0.76).
Reference
1. LaRosa JC, et al. N Engl J Med. 2005;352.
Slide 43

43. Treating to New Targets (TNT) Study
A relative reduction in the risk of nonfatal MI or CHD death was also observed with atorvastatin 80 mg compared with atorvastatin 10 mg (HR = 0.78; 95% CI 0.68, 0.91; P<0.001).
Reference
1. LaRosa JC, et al. N Engl J Med. 2005;352.
Slide 44

44. Treating to New Targets (TNT) Study
Evaluation of individual components of the primary and secondary efficacy outcome measures showed that treatment with atorvastatin 80 mg had a consistent and significant beneficial effect on most measures of coronary morbidity, including nonfatal non–procedure-related MI, fatal or nonfatal stroke, any cardiovascular event, major coronary events, all coronary events, cerebrovascular events, and hospitalizations with primary diagnosis of CHF.
Reference
1. LaRosa JC, et al. N Engl J Med. 2005;352.
Slide 45

45. Pacientų, gydytų 10- and 80-mg atorvastatino dozėmis ir
Pacientų, gydytų 10- and 80-mg atorvastatino dozėmis ir hospitalizuotų dėl ŠN ambulatorinės stebėsenos metu,
skaičiaus skirtumai
Khush, K. K. et al. Circulation 2007;115:
Copyright ©2007 American Heart Association

46. Hospitalizacija dėl ŠN ,
priklausomai nuo ŠN anamnezės ir atorvastatino dozės
Khush, K. K. et al. Circulation 2007;115:

47. Išvados
Pirmasis RKT, įrodęs MTL-Ch sumažinimo <2,6 mmol/L naudą, gydant stabilią IŠL
Gydant didele atorvastatino doze (80 mg) mažiau ligonių buvo hospitalizuota dėl ŠN (RR sumažėjo 26 %)
Gydant didele atorvastatino doze (80 mg) vaisto saugumas nepakito (nedidelis hepatotoksiškumas, nebuvo rabdomiolizės atvejų).

48. Nepaskelbti tyrimų duomenys apie statinus ŠN
The Gruppo Italiano per lo Studio della Sopravvivenzanell'Infart Miocardico-HF (GISSI-HF) is a large placebo-controlled prospective double blind trial involving 7000 patients with both ischemic and nonischemic CHF etiology randomized to either rosuvastatin or polyunsaturated fatty acids to evaluate mortality and hospitalization.43 The trial is recruiting patients.
Rosuvastatin Impact on Ventricular Remodeling, Lipids, and Cytokines (UNIVERSE) is a placebo-controlled, parallel group, double-blind randomized study to examine the effect of rosuvastatin treatment for 26 weeks on ventricular function, lipids, neurohormonal, and cytokine parameters in 160 patients with systolic CHF of ischemic and nonischemic etiology.44

49. GISSI: ongoing clinical trials
GISSI-HF : Didelės apimties atsitiktinės atrankos daugiacentris dvigubai aklas tyrimas, lyginant gydymo žuvų taukais ar statinu (rozuvastatinas) su placebu įtaką mirtingumui ir sergamumui lėtiniu širdies nepakankamumu Randomized multi-center double blind, placebo controlled clinical trial testing the effects of n-3 PUFA (fish oil) and a statin on mortality and morbidity of patients with symptomatic Congestive Heart Failure. Randomization closed in February 2005, after 7057 patients had been enrolled for omega-3 PUFA vs placebo and 4642 for rosuvastatin vs placebo.[15] Follow-up was scheduled to continue until the number of 1252 fatal events had been accumulated.
ACTIVE: Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events
Investigating the role of clopidogrel and irbesartan in the prevention of vascular events in patients with atrial fibrillation: the ACTIVE trial

50. Statinai gydant lėtinį ŠN
Potenciali nauda:
Išemijos komplikacijų sumažinimas
Plejotropinis (priklausomas ne nuo cholesterolio sumažinimo) poveikis
Potencialūs nepageidautini reiškiniai
Ubichinono hipotezė
Endotoksinų hipotezė

51. Naudingi (pilkai) ir nepageidaujamas (grūdėta)
statinų poveikai eNOS = endothelial nitric oxide synthase; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LPS = lipopolysaccharide; NAD(P)H = nicotinamide adenine dinucleotide phosphate; NFκB = nuclear factor kappa B; PI3 = phosphatidylinositol-3; PP = pyrophosphate; tRNA = transfer ribonucleic acid.

52. Potencialūs nepageidautini reiškiniai
“Ubichinono (kofermento Q10) hipotezė”
Ubichinonas yra antioksidantas,naudingas gydant ŠN
HMG-CoA reduktazė įtakoja jo sintezę
↓ ubichinono gydant statinais
“Endotoksinų hipotezė”
Plazmos lipoproteinai suriša ir inaktyvuoja endotoksinus
↓endotoksinų surišimas gydant statinais
↑citokinų aktyvinimas ir uždegimas
Krum & McMurray, JACC 2002; 39:1567

53. Visi statinai blokuoja tiek cholesterolio, tiek CoQ10 sintezę (statinų NRV: silpnumas, raumenų skausmai ir silpnumas, ŠN progresavimas)

54. Širdies ligos klinika ir OMG nepadeda, ŠN simptomai ramybėje
Didelė ŠN rizika
Iki-klinikinis ŠN
Širdies nepakankamumas
LDR ŠN šsivystymui, bet nėra širdies ligos
AH, VAL, CD, MBS; Kardio- toksinai, KMP paveldėjimas
Tikslai
Nerūkyti, riboti alkoholį, didinti fizinį aktyvumą, gydyti hipertenziją, CD, MBS
Vaistai:
AKFI ar ARB, KG ligoms ar CD A
Yra širdies liga, nėra ŠN simptomų
Persirgtas MI KS remodeliav. Vožtuvų ligos
Tikslai
kaip A stadijoje
Vaistai:
AKFI ar ARB BB
Prietaisai:
IKD B
Buvusi ar esama ŠN klinika
Širdies ligos klinika ir
ŠN klinika
Tikslai kaip a ir B stadijose Vaistai: DU, AKFI, BB Vaistai kai kam: ARB, ALA, ŠVG, nitratai / hidralazinas Prietaisai: ŠRG, IKD
Atsparus gydymui ŠN
OMG nepadeda, ŠN simptomai ramybėje
Tikslai kaip A, B, C st. Gydymo pasirinkimas: pasirengimas gyvenimo pabaigai
Specialiosios priemonės: inotropai, š. transplantacija, SPP, eksperimentinė chirurgija ar vaistai D C
Struktūrinė širdies liga
ŠN simptomai
ŠN simptomai ramybėje
Hunt SA, et al. Circulation. 2005;112:

55. Statinai ŠN gydyti: išvados
Serumo cholesterolio padidėjimas nurodo riziką ŠN išsivystymui
Tai galingas nepriklausomas VAL rizikos veiksnys ir būsimos KS disfunkcijos rizikos veiksnys
Silpna tiesioginė koreliacija su ŠN
atvirkščia priklausomybė tarp cholesterolio ir ŠN prognozės
Lipidus mažinantis gydymas (statinai)
Naudingas tiek ŠN prevencijai, tiek ŠN gydymui, tiek hospitalizacijų dėl ŠN sumažinimui (CORONA, TNT)
Pleotropinis statinų poveikis. Pleotropinis statinų poveikis gydant ŠN gali būti svarbesnis nei gebėjimas sumažinti MTL-Ch
Nėra ir nebus (patentai baigiasi) atlikta lyginamųjų tyrimų sergantiesiems ŠN Retrospektyvinė analizė teigia, kad statinai pasižymi “klasės savybėmis” gydant ŠN.
Laukiama prospektyvinių tyrimų rezultatų
GISSI-HF, UNIVERSE

58. Klinikiniai įrodymai statinų vartojimui gydant ŠN: retrospektyvinių tyrimų duomenys
CARE tyrimas (706 lig. Su KSIF <40 bet >25) pravastatinas buvo vienodai veiksmingas mažinant VA ligą lyginant su lig, kurių KSIF > 40
The Scandinavian Simvastatin Survival Study (4S) reported a 19.6% long-term reduction in the development of HF in patients with a history of myocardial infarction randomized to statin therapy.28 Among patients diagnosed with HF, 10.3% were on placebo and 8.3% were on simvastatin. Baseline lipoprotein characteristics and changes in lipoproteins after 1 year of treatment were similar in patients who developed HF and those who did not develop HF. This finding could be explained by the pleiotropic effects of simvastatin.
Similarly, retrospective analysis of the Evaluation of Losartan in the Elderly Study (ELITE II) showed patients with symptomatic HF treated with statins had lower mortality—10.6% vs. 17.6% A retrospective analysis in the Prospective Randomized Amlodipine Survival Evaluation trial (PRAISE) showed that there was a 42% reduction in mortality in patients on statins compared with nonstatin users over a period of 1.3 years in 134 patients. Adjusting for age, gender, diabetes, smoking, HF etiology, EF, New York Heart Association (NYHA) class, statin therapy was associated with a 62% lower risk of death (HR 0.38; 95% CI 0.23–0.65).30 This was irrespective of etiology of ischemic versus nonischemic.
The GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) trial recently investigated the effects of atorvastatin on several primary cardiovascular endpoints including HF in patients with established CAD. This study reported a reduction in HF from 2.7% to 13% in years of follow-up (relative risk 0.55) in the atorvastatin-treated group compared with usual medical care.31
Statins have also shown to improve survival in patients with diastolic HF. In a recent small series of patients, treatment with atorvastatin, simvastatin, pravastatin, or fluvastatin increased survival rates were noted irrespective of the LDL cholesterol levels (relative risk of death [95% CI] 0.22 [0.07–0.64]; P = .006).32 After baseline adjustment for differences among groups (hypertension, diabetes, CAD, and serum creatinine), statin therapy was associated with lower mortality. Using propensity matching, statin therapy was associated a trend toward improved survival without cardiovascular hospitalization (log rank 3.02; P = .082).32

59. A retrospective study by Horwich and colleagues showed statin therapy was associated with improved survival without the necessity for urgent transplantation in both ischemic and nonischemic HF. On a cohort of 551 patients with systolic HF (EF <40%), 45% were receiving statin therapy. This was associated with improved survival in both ischemic and nonischemic HF (81 vs. 63% P < .001; 91 vs. 72% P < .001) at 1-year follow-up. Adjusting risk for age, gender, CAD, cholesterol, diabetes, medications, hemoglobin, creatinine, and NYHA functional heart class, statin therapy remained an independent predictor of improved survival (HR 0.41; 95% CI 0.18–0.94).33 T
he Optimal Trial in Myocardial Infarction with Angiotensin II antagonist Losartan (OPTIMAAL) compared the Ang-II receptor antagonist losartan with angiotensin-converting enzyme inhibitor captopril on mortality and morbidity in patients with evidence of HF or left ventricular dysfunction in the acute phase after acute myocardial infarction. Analysis of all-cause mortality unadjusted for baseline differences showed that treatment with statins alone was associated with a relative risk reduction of 55.2% (P < .001). The effects of combined statin and β-blockers appeared to be additive with a relative risk reduction of 72.7% (P < .001) compared with no treatment. After adjustment for risk variables before inclusion, statin treatment alone was associated with a reduction of 26.1%; combination was associated with a decrease of 48.3% compared with no treatment.34
A post hoc analysis of 5010 patients enrolled in the VALsartan Heart Failure Trial (Val-Heft), 1602 of whom were taking statins, showed the mortality rate over a 2-year period was 17.9% for patients on statins compared with 20.3% for patients not on statins (P = .029) Similarly, the Cardiac Insufficiency BIsoprolol study (CIBIS) II included 2647 patients with ischemic and nonischemic cardiomyopathy who were randomized to receive bisoprolol or placebo. A total of 226 patients or 8.5% were receiving statins during baseline. This was associated with an improved survival benefit (P < .005).36

60. Prieštaringi požiūriai į statinų vartojimą gydyti ŠN
Didesnė BCh ir MTL-Ch koncentracija – gerenis išgyvenamumas sergant ŠN, nepriklausomai nuo etiologijos, amžiaus, KSIF, fizinio pajėgumo 39
Maža serumo cholesterolio koncentracija yra nepriklausomai susijusi su blogesne ŠN prognoze. Statinai mažina dviejų veiksnių – ubichinono ir lipopolisaccharidų (LPS) koncentraciją, kurie apsaugo nuo ŠN progresavimo.
Ubichinonas (kofermentas Q10) , priklauso nuo HMG-CoA reduktazės, jį mažina statinai. Ubichinonas, kaip maisto paildas, gerina ŠN simptomus41 .
Kofermentas Q10 dalyvauja mitochondrijų fosforilinimo procese ir dalyvauja ATF gamyboje. Jis pasižymi antioksidaciniu ir membranas stabilizuojančiu poveikiu42
Endotoksinai, tokie kaip LPS, gali greitinti ŠN progresavimą per uždegiminius citokinus. LPS koncentracija yra didesnė sergant ŠN. Plazmos lipoproteinai surišą endotoksinus, o gydymas statinais mažina lipoprotrinus ir jų detoksikuojantį poveikį. 39
Hedrich O et al. (2004) Progression of coronary artery disease in non-ischemic dilated cardiomyopathy. Coron Artery Dis 15:
Horwich TB et al. (2002) Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure. J Card Fail 8:
Rauchhaus M et al. (2000) The endotoxin-lipoprotein hypothesis. Lancet 356:
Christ M et al. (2006) Prognostic significance of serum cholesterol levels in patients with idiopathic dilated cardiomyopathy. Eur Heart J 27: