6 studii statine
TRANSCRIPT
Statinele— Dovezi, Eficacitate, Experienta
Aterogeneza
Faza I: InitiereaLDL-C joaca un rol important in initietea si dezvoltarea placii aterosclerotice.
Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co; 2001:995-1009; Libby P. J Intern Med. 2000;247:349-358.
Media
Intima
Faza II: ProgresiaProgresia cu remodelare vasculara. Lumenul nu este afectat semnificativ.
LDL-C
Faza III:Placa complicataAcumularea masiva de lipide poate duce la obstructia completa a lumenului sau ruptura placii
Lumen Instabila
Stabila
Tintele terapeutice (lipide)
Joint European Societies1 LDL-C Goal
Boala cardiovasculara, alte afectiuni < 115 mg/dL (3.0 mmol/L)
aterosclerotice
US NCEP ATP III2
0-1 factori de risc CV <160 mg/dL (4.1 mmol/L)
>2 factori de risc CV <130 mg/dL (3.4 mmol/L)
BCV <100 mg/dL (2.6 mmol/L)
1 Wood D, et al. Atherosclerosis. 1998;140:1434-1503; 2 NCEP Expert Panel. JAMA. 2001;285:2486-2497.
Tratamentul hipolipemiant
• Dovezi
• Eficacitate
• Experienta
Preventie secundara ( )Preventie primara ( )
Studii de referinta
*Extrapolat la 5 ani
Adaptat dupa Kastelein JP. Atherosclerosis. 1999;143(suppl 1):S17-S21.
S = statineP = placebo
Pravastatin
Lovastatin
Simvastatin
Atorvastatin
5.4 (210)2.3 (90) 2.8 (110) 3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190)
0
5
10
15
20
25
AFCAPS-S
WOSCOPS-S
WOSCOPS-PCARE-S
LIPID-P
4S-P
LIPID-S
CARE-P
4S-S
AFCAPS-P
% c
u e
ven
imen
t C
V
LDL-C, mmol/L (mg/dL)
ASCOT-S*
ASCOT-P*
Statine: beneficii extinse
Eveniment coronarian acut
4S
CARE/LIPID
4 luni
Fara istoric de boala CV BCI instabila
3 luni
t = 0
6 luni
BCI stabila
Preventie secundaraPreventie primara
AFCAPS / TexCAPS/WOSCOPS
MIRACL
Hipertensiune
ASCOT-LLA
HPS
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
Hipertensiunen = 8457 (41%)
Cu BCV1458 (7%)
Fara BCV1822 (9%)
Cu BCV4042 (20%)
Fara BCV2701 (13%)
Cu BCV1978 (10%)
Fara BCV3982 (19%)
Non-BCINon-BCI2860 (2860 (14%)%)
Cu BCI5595 (27%)
Cu IMA8510 (41%)
Non-IMA4876 (24%)
20,536pacienti
Pacienti
Statine: protectie cardiovasculara
BCIn = 13,379 (65%)
Diabetn = 5963 (29%)
BAPn = 6748 (33%)
BCVn = 3280 (16%)
S7
Atorvastatina: ASCOT-LLA
ASCOT este un studiu multicentric, international ce a avut ca scop principal comparatia a doua tratamente (clasic/inovator) intr-un design factorial:
• Design PROBE (Prospective, Randomized, Open, Blinded End point) ce a comparat 2 tratamente antihipertensive
• Studiu dublu-orb, controlat placebo ce a inclus tratamentul cu atorvastatina de 10 mg intr-o cohorta extinsa selectata din populatia antihipertensiva a studiului (lipid-lowering arm [ASCOT-LLA])
ASCOT a inclus aproape 20,000 de pacienti hipertensivi cu multipli factori de risc
S10
Atorvastatina 10 mgPlacebo
Inceput 164/95 mm HgDupa tratament138/80 mm Hg
130
140
150
160
170
0 1 2 3
TA
S (
mm
Hg
)
LLA Incheiere
TA
D (
mm
Hg
)
75
80
85
90
95
100
0 1 2 3ANI
LLA Incheiere
Sever PS, et al. Lancet. 2003;361:1149-1158.
Modificarile TA
ASCOT-LLA - rezultate
ASCOT-LLA - rezultateco
lest
ero
l to
tal (
mm
ol/L
)L
DL
-co
lest
ero
l
(mm
ol/L
)6
0 1 2 3
200
150
100
(mg
/dL
)50 mg/dL (1.3 mmol/L)
38.7 mg/dL (1.0 mmol/L)
2
4
Atorvastatina 10 mg
Placebo
150
75
125
100 (mg
/dL
)
AniLLA incheiere
1
2
3
4
0 1 2 3
Sever PS, et al. Lancet. 2003;361:1149-1158.
38.7 mg/dL (1.0 mmol/L)
46.5 mg/dL (1.2 mmol/L)
Atorvastatina 10 mg Nr evenim 89
Placebo Nr evenim 121
0
1
2
3
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cu
mu
lati
ve I
nci
den
ce (
%)
HR = 0.73 (0.56-0.96)P = .0236
-27%
ASCOT-LLA - rezultate
Endpoint primar:
IMA Nonfatal si BCI Fatala
Endpoint secundar:
AVC Fatal si Nonfatal
0
1
2
3
4
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cu
mu
lati
ve
Inc
ide
nc
e (
%)
Atorvastatina 10 mg Nr evenim 100
Placebo Nr evenim 154
-36%
HR = 0.64 (0.50-0.83)P = .0005
Sever PS, et al. Lancet. 2003;361:1149-1158.
Endpoint secundar:
Orice evenim. CV
sau procedura
Endpoint secundar:
Evenimente coronariene
0
2
4
6
8
10
12
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cu
mu
lati
ve
In
cid
en
ce
(%
) -21%
HR = 0.79 (0.69-0.90)P = .0005
Atorvastatina 10 mg Nr evenim 389
Placebo Nr evenim 486
Atorvastatina 10 mg Nr evenim 178
Placebo Nr evenim 247
0
1
2
3
4
5
6
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cu
mu
lati
ve
In
cid
en
ce
(%
) -29%
HR = 0.71 (0.59-0.86)P = .0005
Sever PS, et al. Lancet. 2003;361:1149-1158.
ASCOT-LLA - rezultate
Siguranta
• Fara diferente semnificative intre atorvastatina si placebo in ceea ce priveste:• Incidenta cancerelor• Incidenta evenimentelor adverse severe• Incidenta modificarilor transaminzelor
Sever PS, et al. Lancet. 2003;361:1149-1158.
ASCOT-LLA - rezultate
• Importante, tinand cont de timpul relativ scurtLarge given the short follow-up time (median 3.3 years) and emerged earlier than in many other statin trials (3,3 ani) si au aparut mai repede decat in cazul altor statine
• Nu au diferit semnificativ in cadrul grupurilor
• Nu s-au corelat cu nivelul initial de colesterol
• Au aparut fara aparitia de evenimente adverse
ASCOT-LLA - concluzii
Beneficiile utilizarii tereapiei cu atorvastatina la pacienti cu risc scazut cardiovascular si hipertensivi controlati au fost:
Schwartz GG, et al. JAMA. 2001;285:1711-1718.
MIRACL
Placebo plus tratamentul obisnuit
Spitalizare initiala Randomizare(1-4 zile)
3086 pac.
Perioada dublu orb
Atorvastatina 80 mg/day
Faza de tratament 16-sapt
MIRACL rezultate
RR = 0.84P = .04895% CI 0.701-0.999
Atorvastatin
Placebo
0
5
10
15
0 4 8 12 16
Perioada de la randomizare (sapt)
Inci
den
ta C
um
ula
tiva
(%)
Timp pana la aparitia:• Deces de orice cauza• IMA Nonfatal • Stop cardiac resuscitat• Angina agravata cu
spitalizare
17.4%
14.8%
Eficienta primara
Schwartz GG, et al. JAMA. 2001;285:1711-1718. S23
0
0.5
1
1.5
2
0 4 8 12 16
Perioada de la randomizare (weeks)
Inci
den
ta C
um
ula
tiva
(%
)
RR = 0.49P = .0495% CI 0.24-0.98
Atorvastatin
Placebo
AVC Fatal and Nonfatal
Waters DD, et al. Circulation. 2002;106:1690-1695.
MIRACL rezultate
Αthyros VG, et al. Curr Med Res Opin. 2002;18:220-228.
GREACE
Inceperea recrutarii Januarie 1998
Sfarsitul recrutarii Noiembrie 1999
Sfarsitul studiului Decembrie 2001
Follow-up, 3 ani
(n = 800)Atorvastatin 10 to 80 mg/dTintal: LDL-C < 100 mg/dL
Tratament obisnuit (n = 800)
1600 pts hipercholesterolemici cu BCV
(LDL-C > 100 mg/dL[ > 2.59 mmol/L] dupa 6 sapt
de dieta)
-4
-36
-5
-46
-3
-31
27
-3
-32
-6
-44
-60
-50
-40
-30
-20
-10
0
10
Total-C LDL-C TG HDL-C VLDL-C Non-HDL-C
GREACE - rezultate
Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.
**
**
** **
**
††
Mo
dif
icar
i % v
s B
asel
ine
Trat obisnuit
Atorvastatina
*P < .0001; †P = .0028. Doza medie de atorvastatina, 24 mg/day.
5
2.9
4.8
2.5
6.4
2.6 2.6
1.2
5.6
2.7 2.7
1.3
2.1
1.1
0
2
4
6
8
TotalaMortalitate
CoronarianaMortalitate IMA Nonfatal
InstabilaAngina PTCA/CABG Insuf Card AVC
P = .0021 P = .0017
P = .0011
P = .034
Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.
% d
e p
acie
nti
P = .0001
P = .0032P = .021
GREACE - rezultate
Trat obisnuit
Atorvastatina
Grupul Atorvastatina
• 95% dintre pacienti au atins tintele NCEP LDL-C
• Doza medie de atorvastatina= 24 mg/zi
• 96% dintre pacienti au atins tintele European LDL-C
• Doza medie de atorvastatina= 22 mg/day
Tratament “obisnuit”
• 3% dintre pacienti au atins tintele NCEP LDL-C
• 5.5% dintre pacienti au atins tintele European LDL-C
Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228; Athyros VG, et al. Data on file.
GREACE - rezultate
Beneficiile utilizarii statinelor
• Scaderea semnificativa a mortalitatii si morbiditatii
• Reducerea evenimentelor cardiovasculare a fost
demonstrata atat pentru pacienti cu risc scazut, cat si pentru
cei cu risc inalt
• In plus, reducerea valorilor LDL-c a demonstrat beneficii
chiar si la pacientii cu colesterol normal sau doar usor
crescut
Evolutia statinelor
• Dovezi
• Efficacitate
• Experienta
Clasa LDL-C HDL-C Trigliceride
Statins* 18% - 60%*** 5% - 15% 7% - 37%***
Sechestranti de bila15% - 30% 3% - 5% fara modificari
Acid Nicotinic 5% - 25% 15% - 35% 20% - 50%
Fibrati 5% - 20%** 10% - 20% 20% - 50%
Statine: eficienta
*Lovastatin (20 to 80 mg), pravastatin (20 to 40 mg), simvastatin (20 to 80 mg), fluvastatin (20 to 80 mg), atorvastatin (10 to 80 mg), and rosuvastatin (10 to 40 mg).
**May be increased in patients with high triglycerides.
***Up to 60% reduction in LDL-C, and 37% reduction in triglycerides, as indicated in the atorvastatin PI.
Adapted from NCEP Expert Panel. JAMA. 2001;285:2486-2497.
v
v
v
v
v
v
v
v
v
v
v
Statine: eficienta in reducerea LDL-C
*Simvastatin 80 mg not available at time of study. **Significantly greater than mg-equivalent doses of comparative agents (P <.01). †Significantly less than atorvastatin 10 mg (P <.02). ‡Significantly less than atorvastatin 20 mg (P <.01).
Jones P, et al, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
Atorvastatin
Simvastatin*
Pravastatin
Lovastatin
Fluvastatin
0 -60-50-40-30-20-10
10 mg (n = 73)
20 mg (n = 51)
40 mg (n = 61)
10 mg (n = 70)
20 mg (n = 49)
40 mg (n = 61)
10 mg (n = 14)
20 mg (n = 41)40 mg (n = 25)
20 mg (n = 16)40 mg (n = 16)
40 mg (n = 12)
20 mg (n = 12)
-38%**-46%**
-51%**
-28%†
-35%‡
-41%‡
-19%†
-24%†
-34%‡
-29%†
-31%†‡
-17%†
-23%†‡
80 mg (n = 10) -54%
80 mg (n = 11) -48%
% LDL-C
Parametrul de eficienta evaluat:
Reducerea LDL-C
Barbati/femei
Cu/fara BCV si /sau BAP
Tip IIa/IIb
TG < 400 mg/dL (4.5 mmol/L)
~ 70% cu BCV si/sau BAP
Atorvastatin 10 to 80 mg
Simvastatin 10 to 40 mg
Pravastatin 10 to 40 mg
Lovastatin 10 to 80 mg
Fluvastatin 20 to 80 mg
54 sapt , deschis
Eficienta statinelor: ACCESS
Andrews TC, et al. Am J Med. 2001;111:185-191.
Andrews TC, et al. Am J Med. 2001;111:185-191.
*P < .01 vs celelalte tratamente
Atorvastatina reduce eficient LDL-c
% C
han
ge
LDL-C TG HDL-C
**
**
-42%
-29%
-36%
-28%
-36%
-19%
-7%
-12%
-9%
-13%
5%6%
10
0
-10
-20
-30
-40
-50
5%6% 6%
Atorvastatin 10 to 80 (avg 24) mg (n = 1902)Fluvastatin 20 to 80 (avg 62) mg (n = 477)
Simvastatin 10 to 80 (avg 23) mg (n = 468)
Lovastatin 20 to 80 (avg 52) mg(n = 476) Pravastatin 10 to 40 (avg 31) mg (n = 462)
Eficienta statinelor: ACCESS
*Significant difference vs atorvastatin (P < 0.05)
*
**
*
0
25
50
100
Atorvastatin10 to 80 mg
Per
cen
t o
f p
atie
nts
ach
ievi
ng
go
al
75
Simvastatin10 to 80 mg
Pravastatin10 to 40 mg
Lovastatin20 to 80 mg
Fluvastatin20 to 80 mg
NCEP ATP II LDL-C Goals< 2 CHD risk factors is < 160 mg/dL (4.1 mmol/L)
> 2 CHD risk factors is < 130 mg/dL (3.4 mmol/L)Andrews TC, et al. Am J Med. 2001;111:185-191.
Atingerea tintelor NCEP
Eficienta statinelor: ACCESS
NASDAC study—88% of dyslipidemic patients receiving a starting dose of 10 to 40 mg atorvastatin once daily reached their NCEP ATP III LDL-C goal.
88% Percentage of patients reaching LDL-C goal at 10, 20, or 40 mg
10 mg 20 mg 40 mg
79% 88% 98%(n = 76) (n = 68) (n = 64)
Patients without CHD and no CHD equivalents
Pfizer Inc. Data on file: NASDAC study.
Eficienta statinelor: NASDAC
Eficienta statinelor: atorvastatina
• Excellent efficacy across the dose range for all lipid parameters:
LDL-C -39% to -60%
Triglycerides -19% to -37%
HDL-C +5% to +9%
• In clinical trials, the vast majority of patients onatorvastatin reached LDL-C goal.
Pfizer Inc. Data on file.
Statine
• Dovezi
• Efficacitate
• Experienta
Atorvastatia: siguranta clinica
• Safety of atorvastatin derived from analysis of 44 completed
clinical trials in 9416 patients:
• Involved many different patient types:
• eg, mixed dyslipidemia, diabetes, postmenopausal women, FH
Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.
Atorvastatin (all doses) 9416
Other statins 5290
Placebo 1789
n
Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.
Digestive 4 8 9Body as a whole 5 5 6Musculoskeletal 1 3 4Nervous 2 3 3Skin and appendages 1 2 2Metabolic/Nutritional 1 1 1Special senses < 1 1 < 1Urogenital 1 1 1Cardiovascular 2 1 1
Body system
Placebon = 1789
Atorvastatin(all doses)n = 9416
All other statins combined
n = 5290
(%)
Treatment-Associated AEs > 1% of Patients
(%) (%)
Atorvastatia: siguranta clinica
Patient Withdrawal due to Treatment-Associated AEs
Atorvastatin(all doses)
n = 241/9416
2.6%
5
4
3
2
0All other
statins combined n = 188/5290
3.6%
1
Pat
ien
ts w
ith
dra
win
g d
ue
to t
reat
men
t-as
soci
ated
ad
vers
e ev
ents
(%
)
0.9%
Placebo n = 16/1789
Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.
Atorvastatia: siguranta clinica
• ALT/AST elevations > 3x ULN:
• 0.5% of patients treated with atorvastatin 10 to 80 mg experienced ALT/AST elevations > 3x ULN.
• Myalgia
• Incidence of myalgia across all the atorvastatin doses was low (1.9%) and directly comparable to the incidence of myalgia observed in patients receiving other statins combined.
Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.
Atorvastatia: siguranta clinica
Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.
• A recent analysis of 44 completed clinical trials demonstrated
that atorvastatin is well tolerated and has excellent safety
across the 10 mg to 80 mg atorvastatin dose range.
• The overall incidence of AEs with atorvastatin in clinical trials
does not increase across the dose range, and is similar to
that observed with placebo, and in patients treated with other
statins.
• Specific analysis of musculoskeletal and hepatic AEs showed
that these occurred infrequently and rarely resulted in
treatment discontinuation.
Atorvastatia: siguranta clinica
Atorvastatin Clinical Trial Program (> 44,000 Patients)
Atorvastatin studii
20032002
ALLIANCE
AVALON
2005
SPARCL
IDEAL
2004
TNT
4D
SAGE
BONES
SPARKS
BELLES
CARDS
ASPEN
ASCOT
REVERSAL LEADe