Post on 18-Dec-2015
Prescribing Information is available at the end of this presentation
NHS Surrey Lipid Guidelines
Dr Adam Jacquesadamjacques@doctors.org.uk
Ashford & St Peter’s Hospital NHS Foundation Trust
Prescribing Information is available at the end of this presentation
Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering
(MIRACL)
Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718
Prescribing Information is available at the end of this presentation
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
Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718
Prescribing Information is available at the end of this presentation
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
Prescribing Information is available at the end of this presentation
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
Prescribing Information is available at the end of this presentation
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
Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718
Prescribing Information is available at the end of this presentation
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
Prescribing Information is available at the end of this presentation
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
Prescribing Information is available at the end of this presentation
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
Cannon CP et al. NEJM 2004; 350:1495-1504
Prescribing Information is available at the end of this presentation
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
Prescribing Information is available at the end of this presentation
Primary endpoint: Incidence of all- cause mortality or major CV event*
Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504
* 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
16% Relative Risk Reduction
Prescribing Information is available at the end of this presentation
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
28% Relative Risk Reduction
Different endpoint used - Triple composite of: Death, MI, or rehospitalisation for recurrent ACS
Prescribing Information is available at the end of this presentation
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
28% Relative Risk Reduction
Different endpoint used - Triple composite of: Death, MI, or rehospitalisation for recurrent ACS
Prescribing Information is available at the end of this presentation
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
Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504
Prescribing Information is available at the end of this presentation
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
Cannon CP et al. NEJM 2004; 350:1495-1504
Prescribing Information is available at the end of this presentation
The Treating to New Targets Study
(TNT)
LaRosa JC et al. N Engl J Med 2005; 352 (14): 1425-1435
Prescribing Information is available at the end of this presentation
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
Prescribing Information is available at the end of this presentation
Endpoints
Primary endpoints
• Major CV event
– CHD death
– Non-fatal, non-procedure-related MI
– Resuscitated cardiac arrest
– Fatal or non-fatal stroke
LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
Prescribing Information is available at the end of this presentation
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)
Prescribing Information is available at the end of this presentation
Primary endpoint: Major cardiovascular events*
*CHD death, non-fatal non–procedure-related MI, resuscitated cardiac arrest, fatal or non-fatal stroke
Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
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)
22% Relative Risk Reduction
Prescribing Information is available at the end of this presentation
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
Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
22% Relative Risk Reduction
Prescribing Information is available at the end of this presentation
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
Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
Atorvastatin 10 mg
Atorvastatin 80 mg
25% Relative Risk Reduction
Prescribing Information is available at the end of this presentation
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
Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
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
Prescribing Information is available at the end of this presentation
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
LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
Prescribing Information is available at the end of this presentation
Effect of Statin Therapy on Lipid Lowering, Ischaemic Heart Disease &
Stroke: Meta-Analyses
Law MR et al. BMJ 2003; 326: 1423-1429
Prescribing Information is available at the end of this presentation
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
Prescribing Information is available at the end of this presentation
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