Prescribing Information is available at the end of this presentation NHS Surrey Lipid Guidelines Dr...

Prescribing Information is available at the end of this presentation

NHS Surrey Lipid Guidelines

Dr Adam [email protected]

Ashford & St Peter’s Hospital NHS Foundation Trust

The Evidence for Intensive Statin Therapy


Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering

(MIRACL)

Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718


MIRACL

• Effects of early-initiated atorvastatin 80 mg after an acute coronary syndrome on death and recurrent ischaemic events

• Multicentre, randomised, double-blind, placebo-controlled trial

• Patients were assigned to atorvastatin 80 mg or placebo 24–96 hours after hospital admission for ACS



Atorvastatin 14.8%

16% RRRHR 0.84 (0.70-0.99)P=0.048

Placebo 17.4%

0

5

10

15

0 4 8 12 16Time since randomisation (weeks)

Cu

mu

lati

ve in

cid

ence

(%

)

Primary endpoint*

* Primary endpoint=death, non-fatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischaemia with objective evidence and requiring emergency rehospitalisation

Adapted from Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718

16% Relative Risk Reduction


Safety

Placebo

(n=1,548)

Atorvastatin

(n=1,538)P value

Any serious adverse event

< 1% < 1% -

Elevated liver transaminases

(>3 x ULN)0.6% 2.5% P< 0.001

Myositis 0% 0% -

Adapted from Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718


Conclusions

In stable CHD patients with ACS, early lipid-lowering therapy with atorvastatin (80 mg/day) reduces the risk of:

– Early recurrent ischaemic events, primarily recurrent symptomatic ischaemia requiring rehospitalisation

– Non-fatal or fatal stroke



The PRavastatin Or AtorVastatin Evaluation and Infection Therapy–

Thrombolysis In MyocardialInfarction 22

(PROVE IT: TIMI 22)

Cannon CP et al. NEJM 2004; 350 (15): 1495-1504


PROVE IT: TIMI 22

• Intensive versus moderate lipid-lowering with statins after ACS

• Atorvastatin 80 mg vs pravastatin 40 mg (lowering LDL-C to <1.60 mmol/L vs <2.46 mmol/L, respectively)

• Randomised, double-blind, double-dummy non-inferiority trial

• Follow-up: mean 24 months

Cannon CP et al. NEJM 2004; 350:1495-1504


Endpoints

• Primary Endpoint: Composite of death from any cause, MI, documented unstable angina requiring hospitalisation, revascularisation* and stroke

• Secondary Endpoints: Risk of death from CHD, non-fatal MI, or revascularisation*, risk of death from CHD or non-fatal MI, and the risk of the individual components of the primary endpoint

* If performed at least 30 days after randomisation



Median LDL-C levels during the study

0

1

2

3

Baseline 30 Days 4 Mo. 8 Mo. 16 Mo. Final

Pravastatin 40 mg

Atorvastatin 80 mg

49%

21%

Median LDL-C achieved • Pravastatin: 2.5 mmol/L• Atorvastatin: 1.6 mmol/L (P<0.001)

LD

L-C

(m

mo

l/L)

Time of visit

Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504


Primary endpoint: Incidence of all- cause mortality or major CV event*


* Major CV events included: MI, documented unstable angina requiring hospitalisation, revascularisation with either PCI or CABG (if performed at least 30 days after randomisation), and stroke

0 3 18 21 24 27 306 9 12 15

% w

ith

eve

nt

Months of follow-up

Pravastatin 40 mg(event rate 26.3%)

Atorvastatin 80mg(event rate 22.4%)

16% RRR

HR 0.84 (0.74-0.95)

P=0.005

30

25

20

15

10

5

0



Early benefits*

Adapted from Ray KK et al. J Am Coll Cardiol 2005; 46:1405-1410

0 5 10 15 20 25 30

0

1

2

3

4

5

Pravastatin 40 mg4.2 %

Atorvastatin 80 mg3.0 %

28% RRRHR 0.72 (0.52-0.99)P=0.046

Days following randomisation

% o

f p

atie

nts

wit

h d

eath

, MI o

r re

ho

spit

alis

atio

n f

or

AC

S

*Early phase = first 30 days


Different endpoint used - Triple composite of: Death, MI, or rehospitalisation for recurrent ACS


Late benefits*%

of

pat

ien

ts w

ith

dea

th, M

I or

reh

osp

ital

isat

ion

fo

r A

CS

**Analysis excluding patients with events in the first 6 months

0

2

4

6

8

10

12Pravastatin 40 mg

13.1%

Atorvastatin 80 mg9.6%

28% RRRHR 0.72 (0.58-0.89) P=0.003

Months following randomisation246 12 18

*Late Phase = 6 months–2 years**

Adapted from Ray KK et al. J Am Coll Cardiol 2005; 46:1405-1410


Different endpoint used - Triple composite of: Death, MI, or rehospitalisation for recurrent ACS


Safety

Atorvastatin 80mg (n=2,099)

Pravastatin 40mg (n=2,063)

P value

Discontinuation for AE, patient preference or other reasons

30.4% 33.0% 0.11

Discontinuation for myalgia/CKelevation

3.3% 2.7% 0.23

Rhabdomyolysis 0% 0% N/A

ALT ≥3 ULN 3.3% 1.1% <0.001

Dose halving due to side effects or raised LFTs

1.9% 1.4% 0.20



Summary

• In patients hospitalised within 10 days of an acute coronary event:

– ‘Intensive’ lipid-lowering with 80 mg atorvastatin to a median LDL-C of 1.6 mmol/L was associated with a significant reduction in the risk of combined all-cause mortality and major CV events by 16% compared to ‘moderate’ lipid-lowering therapy with 40 mg pravastatin which achieved a median LDL-C of 2.5 mmol/L (P=0.005)

– Benefits emerged within 30 days of randomisation with continued divergence of the event curves over time



The Treating to New Targets Study

(TNT)

LaRosa JC et al. N Engl J Med 2005; 352 (14): 1425-1435


TNT

• Intensive lipid-lowering with atorvastatin in patients with stable coronary disease

• Mean LDL-C of 2 mmol/L with atorvastatin 80 mg vs mean LDL-C of 2.6 mmol/L with atorvastatin 10 mg

• Multicentre, randomised, double-blind trial

• Follow-up: median 4.9 years

LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435


Endpoints

Primary endpoints

• Major CV event

– CHD death

– Non-fatal, non-procedure-related MI

– Resuscitated cardiac arrest

– Fatal or non-fatal stroke



Lipid results

Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435

Study visit (months)

0

20

40

60

80

100

120

140

160

Mean

LD

L-C

(mg

/dL

)

Atorvastatin 80 mg (n=4995)

Atorvastatin 10 mg (n=5006)

FinalScreen 0 3 12

24

36

48

60

P<0.001

Baseline

Mean LDL-C level = 101 mg/dL (2.6 mmol/L)

Mean LDL-C level = 77 mg/dL (2.0 mmol/L)

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

Mea

n L

DL

-C (

mm

ol/

L)


Primary endpoint: Major cardiovascular events*

*CHD death, non-fatal non–procedure-related MI, resuscitated cardiac arrest, fatal or non-fatal stroke


22% RRRHR = 0.78 (95% CI 0.69, 0.89)P< 0.001

Pro

po

rtio

n o

f p

atie

nts

exp

erie

nci

ng

m

ajo

r ca

rdio

vasc

ula

r ev

ent

(%)

0

0.05

0.10

0.15Atorvastatin 10 mg

Atorvastatin 80 mg

0 1 2 3 4 5 6Time (years)



CHD death or non-fatal, non-procedure-related MI

0 1 2 3 4 5 6Time (years)

Pro

po

rtio

n o

f p

atie

nts

exp

erie

nci

ng

C

HD

dea

th o

r n

on

-fat

al n

on

-PR

MI (

%)

0.05

0.10

22% RRRHR = 0.78 (95% CI 0.68, 0.91)P<0.001

0

Atorvastatin 10 mg

Atorvastatin 80 mg




Fatal or non-fatal strokeP

rop

ort

ion

of

pat

ien

ts e

xper

ien

cin

g

fata

l or

no

n-f

atal

str

oke

(%

)

0 1 2 3 4 5 6Time (years)

0

0.01

0.02

0.04

0.0325% RRRHR = 0.75 (95%CI 0.59, 0.96)P=0.02


Atorvastatin 10 mg

Atorvastatin 80 mg



Safety

No. of patients (%)

Atorvastatin 10 mg (n=5,006)

Atorvastatin 80 mg (n=4,995)

Treatment-related AEs1

Treatment-related myalgia2

289 (5.8)

234 (4.7)

406 (8.1)

241 (4.8)

Rhabdomyolysis* 3 (0.06) 2 (0.04)

AST/ALT elevation >3 ULN3 9 (0.2) 60 (1.2)

*No cases were considered by the investigator with direct responsibility for the patient to be causally related to atorvastatin, and none met ACC/AHA/NHLBI criteria4 for rhabdomyolysis

1P<0.001, 2P=0.72, 3P<0.001, 4 Pasternak RC et al. Circulation 2002; 106: 1024-1028


Note: n=197 patients were excluded at baseline due to AEs after 8 weeks open-label 10 mg treatment and n=96 were also excluded at baseline due to ALT/AST > 1.5 x ULN


Summary

• The TNT study is the first randomised trial designed to demonstrate the benefits of lowering LDL-C below 2.6 mmol/L in stable CHD patients

• Significant (>20%) reductions in CV events including stroke were achieved with atorvastatin 80 mg vs atorvastatin 10 mg

• Even at high atorvastatin dose, there was a very low incidence of adverse events and no treatment-related rhabdomyolysis

• The findings add to other data showing the efficacy and safety of high-dose (80 mg) atorvastatin



Effect of Statin Therapy on Lipid Lowering, Ischaemic Heart Disease &

Stroke: Meta-Analyses

Law MR et al. BMJ 2003; 326: 1423-1429


Meta-analysis 1: Percentage reduction in serum LDL-C concentration by statin & daily dose

Adapted from Law MR et al. BMJ 2003; 326: 1423-1429

Adapted from a meta-analysis of 164 randomised, placebo controlled trials involving over 24,000 patients treated with statins and 14,000 treated with placebo. Percentage reductions are independent of pre-treatment LDL-C concentration. Data not shown for fluvastatin and lovastatin. P-values not available.

atorvastatin

pravastatin

simvastatin

rosuvastatin

0

-10

-20

-30

-40

-50

-60

10mg 20mg 10mg 40mg 20mg 40mg 10mg 80mg 10mg 20mg 20mg 40mg 40mg 80mg

-20

-24-27

-29-32

-37 -37

-42 -43 -43

-48 -49

-53-55M

ea

n p

erc

en

tag

e c

ha

ng

e L

DL

-C f

rom

ba

se

lin

e


Safety

Muscle-related adverse effects• In the meta-analysis of 35,000 people treated with statins and

placebo rhabdomyolosis was diagnosed (variable criteria) in eight treated and five placebo patients, none with serious illness or death

• Raised serum creatine kinase activity ( ≥ 10 times the ‘upper limit of normal’) was reported in 55 treated patients (0.17%) and 43 placebo patients (0.13%); muscle symptoms were present in 13 and 4 respectively

Liver-related adverse effects• There were no cases of liver failure in the trials• Raised ALT ( ≥ 3 x ULN) was reported in 449 treated (1.3%) and

383 placebo patients (1.1%)

Law MR et al. BMJ 2003; 326: 1423-1429

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