NHS Surrey Lipid Guidelines
Dr Adam Jacques
adamjacques@doctors.org.uk
Ashford & St Peter’s Hospital NHS
Foundation Trust
Prescribing Information is available at the end of this presentation
Prescribing Information is available at the end of this presentation
Prescribing Information is available at the end of this presentation
Prescribing Information is available at the end of this presentation
The Evidence for Intensive Statin Therapy
Myocardial Ischaemia Reduction with
Aggressive Cholesterol Lowering
(MIRACL)
Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718
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MIRACL
• Effects of early-initiated atorvastatin 80 mg after an
acute coronary syndrome on death and recurrent
ischaemic events
• Multicentre, randomised, double-blind, placebocontrolled 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
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Primary endpoint*
16% Relative
Risk
Reduction
Cumulative incidence (%)
Placebo 17.4%
15
Atorvastatin 14.8%
10
16% RRR
HR 0.84 (0.70-0.99)
P=0.048
5
0
0
4
8
12
Time since randomisation (weeks)
16
* 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
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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
0%
0%
-
Myositis
Adapted from Schwartz GG et al. JAMA 2001; 285 (13): 1711-1718
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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
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The PRavastatin Or AtorVastatin
Evaluation and Infection Therapy–
Thrombolysis In Myocardial
Infarction 22
(PROVE IT: TIMI 22)
Cannon CP et al. NEJM 2004; 350 (15): 1495-1504
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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
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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
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Median LDL-C levels during
the study
3
LDL-C (mmol/L)
Pravastatin 40 mg
21% 
2
49% 
Atorvastatin 80 mg
1
0
Baseline 30 Days
4 Mo.
8 Mo.
Time of visit
Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504
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16 Mo.
Final
Median LDL-C achieved
• Pravastatin: 2.5 mmol/L
• Atorvastatin: 1.6 mmol/L
(P<0.001)
Primary endpoint: Incidence of allcause mortality or major CV event*
30
Pravastatin 40 mg
(event rate 26.3%)
16% Relative
Risk
Reduction
% with event
25
20
Atorvastatin 80mg
(event rate 22.4%)
15
16% RRR
10
HR 0.84 (0.74-0.95)
5
P=0.005
0
0
3
6
9
12
15
18
21
Months of follow-up
24
* 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
Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504
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27
30
Early benefits*
% of patients with death, MI or
rehospitalisation for ACS
Different endpoint used - Triple composite of: Death, MI, or rehospitalisation for
recurrent ACS
5
4
28% RRR
HR 0.72 (0.52-0.99)
P=0.046
3
Pravastatin 40 mg
4.2 %
28%
Relative
Risk
Reduction
Atorvastatin 80 mg
3.0 %
2
1
0
0
5
*Early phase = first 30 days
10
15
20
Days following randomisation
Adapted from Ray KK et al. J Am Coll Cardiol 2005; 46:1405-1410
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25
30
Late benefits*
% of patients with death, MI or
rehospitalisation for ACS
Different endpoint used - Triple composite of: Death, MI, or
rehospitalisation for recurrent ACS
12
Pravastatin 40 mg
13.1%
10
28% RRR
HR 0.72 (0.58-0.89)
P=0.003
8
6
Atorvastatin 80 mg
9.6%
4
2
*Late Phase = 6 months–2 years**
0
6
12
18
Months following randomisation
**Analysis excluding patients with events in the first 6 months
Adapted from Ray KK et al. J Am Coll Cardiol 2005; 46:1405-1410
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24
28%
Relative
Risk
Reduction
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/CK
elevation
3.3%
2.7%
0.23
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
Rhabdomyolysis
Adapted from Cannon CP et al. NEJM 2004; 350:1495-1504
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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’ lipidlowering 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
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The Treating to New Targets Study
(TNT)
LaRosa JC et al. N Engl J Med 2005; 352 (14): 1425-1435
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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
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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
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Lipid results
160
4.0
Atorvastatin 80 mg (n=4995)
3.5
Atorvastatin 10 mg (n=5006)
140
120
3.0
Mean LDL-C level = 101 mg/dL (2.6 mmol/L)
2.5
100
2.0
80
Mean LDL-C level = 77 mg/dL (2.0 mmol/L)
P<0.001
1.5
60
1.0
40
0.5
20
0
0
Screen 0 3
1
2
2
4
3
6
Study visit (months)
Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
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4
8
6
0
Final
Mean LDL-C (mg/dL)
Mean LDL-C (mmol/L)
Baseline
Primary endpoint:
Major cardiovascular events*
Proportion of patients experiencing
major cardiovascular event (%)
0.15
Atorvastatin 10 mg
Atorvastatin 80 mg
22%
Relative
Risk
Reduction
0.10
0.05
22% RRR
HR = 0.78 (95% CI 0.69, 0.89)
P< 0.001
0
0
1
2
Time (years)
3
4
*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
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5
6
Proportion of patients experiencing
CHD death or non-fatal non-PR MI (%)
CHD death or non-fatal,
non-procedure-related MI
0.10
Atorvastatin 10 mg
22%
Relative
Risk
Reduction
Atorvastatin 80 mg
0.05
22% RRR
HR = 0.78 (95% CI 0.68, 0.91)
P<0.001
0
0
1
2
3
Time (years)
Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
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4
5
6
Proportion of patients experiencing
fatal or non-fatal stroke (%)
Fatal or non-fatal stroke
0.04
Atorvastatin 10 mg
Atorvastatin 80 mg
0.03
25% RRR
HR = 0.75 (95%CI 0.59, 0.96)
P=0.02
0.02
25%
Relative
Risk
Reduction
0.01
0
0
1
2
3
Time (years)
Adapted from LaRosa JC et al. N Eng J Med 2005; 352: 1425-1435
Prescribing Information is available at the end of this presentation
4
5
6
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)
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
* 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
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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
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Effect of Statin Therapy on Lipid
Lowering, Ischaemic Heart Disease &
Stroke: Meta-Analyses
Law MR et al. BMJ 2003; 326: 1423-1429
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Meta-analysis 1: Percentage reduction in
serum LDL-C concentration by statin
& daily dose
Mean percentage change LDL-C from baseline
0
10mg 20mg 10mg 40mg
20mg 40mg 10mg
80mg 10mg 20mg 20mg 40mg
40mg 80mg
-10
-20
-20
-24
-27
-30
-29
-32
-37
-40
-42
atorvastatin
pravastatin
-50
-43
-43
-48
simvastatin
-49
-53
rosuvastatin
-60
-37
-55
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.
Adapted from Law MR et al. BMJ 2003; 326: 1423-1429
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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
Prescribing Information is available at the end of this presentation
Prescribing Information is available at the end of this presentation
Prescribing Information is available at the end of this presentation
Prescribing Information is available at the end of this presentation
Prescribing Information is available at the end of this presentation
Prescribing Information is available at the end of this presentation