Statinele Dovezi, Eficacitate, Experienta

Aterogeneza

Faza I: Initierea
Media Intima LDL-C
Lumen

LDL-C joaca un rol important in initietea si dezvoltarea placii aterosclerotice.

Instabila

Faza II: Progresia

Progresia cu remodelare vasculara. Lumenul nu este afectat semnificativ.

Stabila

Faza III:Placa complicata

Acumularea masiva de lipide poate duce la obstructia completa a lumenului sau ruptura placii
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.

Tintele terapeutice (lipide)

Joint European Societies1

Boala cardiovasculara, alte afectiuni aterosclerotice

LDL-C Goal
< 115 mg/dL (3.0 mmol/L)

US NCEP ATP III2

0-1 factori de risc CV >2 factori de risc CV <160 mg/dL (4.1 mmol/L) <130 mg/dL (3.4 mmol/L)

BCV

<100 mg/dL (2.6 mmol/L)

Wood D, et al. Atherosclerosis. 1998;140:1434-1503; 2 NCEP Expert Panel. JAMA. 2001;285:2486-2497.

Tratamentul hipolipemiant

Dovezi Eficacitate Experienta

Studii de referinta
4S-P

% cu eveniment CV

25 20 15 10
CARE-S 4S-S LIPID-P CARE-P

Preventie secundara ( Preventie primara (

) )

Simvastatin
Pravastatin
WOSCOPS-P

LIPID-S
ASCOT-P* ASCOT-S* AFCAPS-S WOSCOPS-S AFCAPS-P

Lovastatin Atorvastatin
S = statine P = placebo

5 0

2.3 (90)

2.8 (110)

3.4 (130)

3.9 (150) 4.4 (170)

4.9 (190) 5.4 (210)

LDL-C, mmol/L (mg/dL)

*Extrapolat la 5 ani

Adaptat dupa Kastelein JP. Atherosclerosis. 1999;143(suppl 1):S17-S21.

Statine: beneficii extinse

Eveniment coronarian acut
Fara istoric de boala CV BCI instabila BCI stabila

4 luni
AFCAPS / TexCAPS/ WOSCOPS MIRACL

t=0

CARE/LIPID

3 luni

4S 6 luni

HPS ASCOT-LLA
Hipertensiune

Preventie primara

Preventie secundara

Statine: protectie cardiovasculara

Pacienti
BCI
n = 13,379 (65%)

20,536 pacienti

Hipertensiune
n = 8457 (41%)

Cu IMA 8510 (41%)

Non-IMA 4876 (24%)

Cu BCI 5595 (27%)

Non-BCI 2860 (14%)

BCV
n = 3280 (16%)

BAP
n = 6748 (33%)

Diabet
n = 5963 (29%)

Cu BCV 1458 (7%)

Fara BCV 1822 (9%)

Cu BCV 4042 (20%)

Fara BCV 2701 (13%)

Cu BCV 1978 (10%)

Fara BCV 3982 (19%)

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.

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

ASCOT-LLA - rezultate
Modificarile TA
170
TAS (mm Hg)

Atorvastatina 10 mg Placebo
Inceput 164/95 mm Hg Dupa tratament 138/80 mm Hg

160 150 140 130 0

100 95 90 85 80 75
0 1
ANI

LLA Incheiere

TAD (mm Hg)

LLA Incheiere

Sever PS, et al. Lancet. 2003;361:1149-1158.

ASCOT-LLA - rezultate
6

colesterol total (mmol/L)

4 Atorvastatina 10 mg Placebo 2 0 1 2 3

150 100

150 125 46.5 mg/dL (1.2 mmol/L) 38.7 mg/dL (1.0 mmol/L)

LDL-colesterol

(mmol/L)

3
2

100
75

1
0 1 2 3
LLA incheiere

Ani
Sever PS, et al. Lancet. 2003;361:1149-1158.

(mg/dL)

(mg/dL)

50 mg/dL (1.3 mmol/L)

38.7 mg/dL (1.0 mmol/L)

200

ASCOT-LLA - rezultate
Endpoint primar:

Endpoint secundar:
AVC Fatal si Nonfatal
3

IMA Nonfatal si BCI Fatala

4

Cumulative Incidence (%)

-36%
3
Cumulative Incidence (%) 2

-27%

1
HR = 0.73 (0.56-0.96) P = .0236

HR = 0.64 (0.50-0.83) P = .0005

0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Years

Atorvastatina 10 mg Placebo

Nr evenim Nr evenim

100 154

Atorvastatina 10 mg Placebo

Nr evenim Nr evenim

89 121

Sever PS, et al. Lancet. 2003;361:1149-1158.

ASCOT-LLA - rezultate
Endpoint secundar: Endpoint secundar: Evenimente coronariene
6 Cumulative Incidence (%) 5 4 3

Orice evenim. CV
sau procedura
12 Cumulative Incidence (%) 10 8 6 4 2 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Atorvastatina 10 mg Placebo Nr evenim Nr evenim 389 486
HR = 0.79 (0.69-0.90) P = .0005

-21%

-29%

2
1 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Atorvastatina 10 mg Placebo Nr evenim Nr evenim 178 247
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 - concluzii
Beneficiile utilizarii tereapiei cu atorvastatina la pacienti cu risc scazut cardiovascular si hipertensivi controlati au fost: 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

MIRACL
Perioada dublu orb

Atorvastatina 80 mg/day
Randomizare (1-4 zile) 3086 pac.

Spitalizare initiala

Placebo plus tratamentul obisnuit

Faza de tratament 16-sapt

Schwartz GG, et al. JAMA. 2001;285:1711-1718.

MIRACL rezultate
Eficienta primara

Placebo
15

17.4% 14.8%

Incidenta Cumulativa(%)

Atorvastatin
10 Timp pana la aparitia: Deces de orice cauza IMA Nonfatal Stop cardiac resuscitat Angina agravata cu spitalizare

RR = 0.84 P = .048 95% CI 0.701-0.999

12 16

0 0 4 8

Perioada de la randomizare (sapt)

Schwartz GG, et al. JAMA. 2001;285:1711-1718.

S23

MIRACL rezultate
AVC Fatal and Nonfatal
2

Incidenta Cumulativa (%)

1.5

Placebo

Atorvastatin
RR = 0.49 P = .04 95% CI 0.24-0.98
0 4 8 12 16

0.5

Perioada de la randomizare (weeks)

Waters DD, et al. Circulation. 2002;106:1690-1695.

GREACE
(n = 800) Atorvastatin 10 to 80 mg/d Tintal: LDL-C < 100 mg/dL 1600 pts hipercholesterolemici cu BCV

(LDL-C > 100 mg/dL [ > 2.59 mmol/L] dupa 6 sapt de dieta)

Follow-up, 3 ani

Tratament obisnuit (n = 800)

Inceperea recrutarii Januarie 1998

Sfarsitul recrutarii Noiembrie 1999

Sfarsitul studiului Decembrie 2001

thyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

GREACE - rezultate

10 0
2 7
Trat obisnuit Atorvastatina

-10
-20

-4

-5

-3

-3

-6

-30
-40 -50
-36 -31

*
-46

-32

*
-44

*
Total-C LDL-C TG HDL-C VLDL-C

*
Non-HDL-C

-60
*P < .0001; P = .0028. Doza medie de atorvastatina, 24 mg/day.

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

GREACE - rezultate
Trat obisnuit

8
P = .0001

Atorvastatina
P = .0011

6.4

P = .0021

P = .0017

5.6

4.8

4
2.9 2.5
P = .0032

P = .021

2.6

2.6

2.7

2.7

P = .034

2.1 1.2 1.3 1.1

Mortalitate Totala

Mortalitate Coronariana

IMA Nonfatal

Angina Instabila

PTCA/CABG

Insuf Card

AVC

Athyros VG, et al. Curr Med Res Opin. 2002;18:220-228.

GREACE - rezultate
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.

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

Statine: eficienta

Clasa Statins*
v v

LDL-C 18% - 60%***

v v v v

HDL-C 5% - 15% 3% - 5% 15% - 35% 10% - 20%

v v v

Trigliceride 7% - 37%***

Sechestranti de bila 15% - 30% Acid Nicotinic Fibrati

v v

fara modificari 20% - 50% 20% - 50%

5% - 25% 5% - 20%**

*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.

Statine: eficienta in reducerea LDL-C

10 mg (n = 73) 20 mg (n = 51) 40 mg (n = 61) 80 mg (n = 10) 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) 80 mg (n = 11)

-38%** -46%** -51%** -54% -28% -35% -41% -19% -24% -34% -29% -31% -48% -17% -23%

Atorvastatin Simvastatin* Pravastatin Lovastatin Fluvastatin

20 mg (n = 12) 40 mg (n = 12)

-10

-20

-30 % LDL-C

-40

-50

-60

*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.

Eficienta statinelor: ACCESS

Atorvastatin 10 to 80 mg 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 Pravastatin 10 to 40 mg Simvastatin 10 to 40 mg

Lovastatin 10 to 80 mg

Parametrul de eficienta evaluat: Reducerea LDL-C

Fluvastatin 20 to 80 mg

54 sapt , deschis

Andrews TC, et al. Am J Med. 2001;111:185-191.

Eficienta statinelor: ACCESS

Atorvastatina reduce eficient LDL-c
10
5% 6% 5% 6% 6%

0 -10 -20 -30 -40

-42% -29% -28% -19% -7% -9% -12% -13%

-36%

-36%

Atorvastatin 10 to 80 (avg 24) mg (n = 1902) Fluvastatin 20 to 80 (avg 62) mg (n = 477) Lovastatin 20 to 80 (avg 52) mg (n = 476) Pravastatin 10 to 40 (avg 31) mg (n = 462) Simvastatin 10 to 80 (avg 23) mg (n = 468)

% Change

-50

*
LDL-C TG HDL-C

*P < .01 vs celelalte tratamente

Andrews TC, et al. Am J Med. 2001;111:185-191.

Eficienta statinelor: ACCESS

100

Percent of patients achieving goal

Atingerea tintelor NCEP

75

* * *

50

25

0 Atorvastatin
10 to 80 mg

Simvastatin
10 to 80 mg

Pravastatin
10 to 40 mg

Lovastatin
20 to 80 mg

Fluvastatin
20 to 80 mg

*Significant difference vs atorvastatin (P < 0.05)

Andrews TC, et al. Am J Med. 2001;111:185-191.

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)

Eficienta statinelor: NASDAC

NASDAC study88% of dyslipidemic patients receiving a starting dose of 10 to 40 mg atorvastatin once daily reached their NCEP ATP III LDL-C goal.
Patients without CHD and no CHD equivalents

88%

Percentage of patients reaching LDL-C goal at 10, 20, or 40 mg

10 mg

20 mg

40 mg

79%
(n = 76)
Pfizer Inc. Data on file: NASDAC study.

88%
(n = 68)

98%
(n = 64)

Eficienta statinelor: atorvastatina

Excellent efficacy across the dose range for all lipid parameters: LDL-C HDL-C -39% to -60% +5% to +9%

Triglycerides -19% to -37%

In clinical trials, the vast majority of patients on atorvastatin 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:
n Atorvastatin (all doses) Other statins 9416 5290

Placebo

1789

Involved many different patient types:

eg, mixed dyslipidemia, diabetes, postmenopausal women, FH

Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.

Atorvastatia: siguranta clinica

Treatment-Associated AEs > 1% of Patients
Body system Placebo n = 1789 (%) 4 5 1 2 1 1 <1 1 2 Atorvastatin (all doses) n = 9416 (%) 8 5 3 3 2 1 1 1 1 All other statins combined n = 5290 (%) 9 6 4 3 2 1 <1 1 1

Digestive Body as a whole Musculoskeletal Nervous Skin and appendages Metabolic/Nutritional Special senses Urogenital Cardiovascular

Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.

Atorvastatia: siguranta clinica

Patient Withdrawal due to Treatment-Associated AEs
5 4 3 2 1 0 Placebo n = 16/1789 Atorvastatin (all doses) n = 241/9416 All other statins combined n = 188/5290 0.9% 2.6%

Patients withdrawing due to treatment-associated adverse events (%)

3.6%

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

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.

Source: Pfizer Inc. Data on file. Review of 44 completed clinical trials.

Atorvastatin studii
Atorvastatin Clinical Trial Program (> 44,000 Patients)
REVERSAL BELLES LEADe

CARDS

SAGE

ALLIANCE ASPEN BONES

4D

SPARCL

AVALON

ASCOT

SPARKS

TNT

IDEAL

2002

2003

2004

2005