6 studii statine

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

Dr. J. Genest

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


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%


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 (

%)



-36%

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


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





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



Siguranta

• Fara diferente semnificative intre atorvastatina si placebo in ceea ce priveste:• Incidenta cancerelor• Incidenta evenimentelor adverse severe• Incidenta modificarilor transaminzelor



• 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)


*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


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


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

(%) (%)


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



• 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.




• 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.


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

6 studii statine

Documents

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