New Insights into the Benefits of Early Statin Initiation in Acute Coronary Syndromes

1
New Insights into the Benefits of Early Statin
Initiation in Acute Coronary Syndromes
2
Pathophysiology of ACS and potential
pharmacological interventions
1. Downstream from thrombus myocardial
ischaemia/necrosis (?-blockers, nitrates etc)
Fibrin clot
2. Activation of clotting cascade
thrombin (heparin/LMWH)
Fibrinogen
Thrombin
GP IIb/IIIa receptor
3. Platelet adhesion/ activation/aggregation
(aspirin, clopidogrel, GP IIb/IIIa
inhibitors)
Platelet
4. Plaque rupture, cholesterol content,
inflammation (hs-CRP) (statins)
3
Risk of death in patients with coronary heart
disease is greatest early after an ACS
Deaths/100 patients/month
Acute MI Unstable angina Stable angina
Time (months after hospital admission)
Braunwald (1996)
4
PURSUIT Retrospective analysis shows early
mortality reduction with lipid-lowering therapy
Survival ()
100 99 98 97 96 95 94 93 92
Lipid-lowering agents (n2141)
No lipid-lowering agents (n6374)
Log rank ?287, plt0.001
0 30 60 90
120 150 180
Days
Aronow et al (2000)
5
GUSTO IIb/PRISM Early reduction in death/MI in
patients on lipid-lowering therapy

• GUSTO IIb Retrospective analysis of 12,630 ACS
  patients (ST elevation)
• Mortality at 30 days and 6 months was
  significantly reduced in patients receiving
  lipid-lowering agent
• 52 reduction in 6-month mortality (RR 0.48, 95
  CI 0.28-0.83) after adjusting for other variables
• PRISM Retrospective analysis of 1616 patients
• 302 patients were continued on background statin
  therapy
• Death/MI rate at 30 days was significantly lower
  in these patients (plt0.01)

Aronow et al, Hamm et al (AHA 2000)
6
Swedish registry Early statin and
revascularisation significantly reduces mortality
Relative risk reduction in mortality after 1 year
70
64
60
50
36
34
40
30
20
10
0
Combined therapy
Statins
Revascularisation
XXII ESC Congress (2000)
7
Statin therapy after stent placement in ACS
patients

• Prospective study of statin therapy initiation
  immediately after coronary stent implantation in
  224 ACS patients
• Incidence of major cardiovascular events,
  including death and MI, at 6 months were
• 1.0 in statin patients
• 7.9 in control group (plt0.03)
• Statin therapy associated with profound clinical
  benefit
• Suggests pivotal role of statins for plaque
  passivation to reduce death and MI

Walter et al (AHA 2000)
8
Rationale for early statin therapy
Gives constant reduction in risk most effective
when absolute risk is highest May
stabilise plaque maximum benefit when given
early Other non-lipid-lowering effects eg
anti-inflammatory, effects on endothelial
dysfunction Patient already in hospital patient
more likely to adhere to therapy Discharged
on statin therapy underscores need for continued
statins
9
Timing of statin therapy initiation after ACS in
recent clinical studies
Atorvastatin
Pravastatin
PACT
MIRACL
Simvastatin
PTT
PAIS
Fluvastatin
PROVE IT
4S
LAMIL
WOSCOPS
FLORIDA
CARE
L-CAD
ACS
RECIFE
LIPID
Primary prevention
Secondary prevention
3
0
6
2
24
10
6
8
12
12
18
4
6
Days
Months
Hours
10
Clinical evidence for the benefits of early
statin initiation
Study Time to Statin Results initiation PT
T1 6 h pravastatin ? coronary events ?
restenosis rates L-CAD2 6 d pravastatin Improved
outcomes ? mean progression ? coronary
lesion regression RECIFE3 10 d pravastatin Rapid
improvement of (mean) endothelial
function FLORIDA4 8 d fluvastatin No
significant benefit MIRACL5 2496
h atorvastatin ? time to first event
1 Pravastatin and Thrombolytic Therapy 2
Lipids in Coronary Artery Disease 3 Reduction
of Cholesterol in Ischaemia and Function of the
Endothelium 4 FLuvastatin On RIsk Diminishing
after Acute myocardial infarction 5 Myocardial
Ischaemia Reduction with Aggressive Cholesterol
Lowering
11
Timing of statin therapy initiation after ACS in
recent clinical studies
Atorvastatin
Pravastatin
MIRACL
Simvastatin
PTT
PAIS
Fluvastatin
4S
LAMIL
WOSCOPS
FLORIDA
CARE
L-CAD
ACS
RECIFE
LIPID
Primary prevention
Secondary prevention
3
0
6
2
24
10
6
8
12
12
18
4
6
Days
Months
Hours
Kayikcioglu et al (1999)
12
Pravastatin and Thrombolytic Therapy trial
Early therapy improves event-free survival
Patients with event ()
30
Pravastatin (n72) Control (n78)
20


10
0
Non-fatal MI
Recurrentangina
In-hospitaldeath
Within 6 hours of MI 6 months
follow-up p0.01, p0.03
Kayikcioglu et al (1999)
13
Timing of statin therapy initiation after ACS in
recent clinical studies
Atorvastatin
Pravastatin
MIRACL
Simvastatin
PTT
PAIS
Fluvastatin
4S
LAMIL
WOSCOPS
FLORIDA
CARE
L-CAD
ACS
RECIFE
LIPID
Primary prevention
Secondary prevention
3
0
6
2
24
10
6
8
12
12
18
4
6
Days
Months
Hours
Arntz (1999)
14
L-CAD study design
Baseline cholesterol 3.46.5 mmol/L (130250
mg/dL)
126 men and women post acute MI and/or PTCA for UA
Pravastatin 2040 mg (cholestyramine and
nicotinic acid) to achieve an LDL lt3.4 mmol/L
(130 mg/dL)
Usual care
Clinical 2 years, Angiography 6 months and 2
years
QCA and major CV clinical events
L-CAD Lipids in Coronary Artery Disease
15
L-CAD Survival without major cardiovascular
events
1.0
0.8
Pravastatin-basedintensified (n70)
0.6
Conventional (n56)
0.4
0.2
Log rank 0.0024
Breslow 0.0042
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (months)
Arntz et al (1998)
16
Timing of statin therapy initiation after ACS in
recent clinical studies
Atorvastatin
Pravastatin
MIRACL
Simvastatin
PTT
PAIS
Fluvastatin
4S
LAMIL
WOSCOPS
FLORIDA
CARE
L-CAD
ACS
RECIFE
LIPID
Primary prevention
Secondary prevention
3
0
6
2
24
10
6
8
12
12
18
4
6
Days
Months
Hours
Dupuis et al (1999)
17
The RECIFE study Pravastatin rapidly improves
endothelial function after ACS
Flow-mediated dilatation ()
8
7
Pravastatin 40 mg/day
6
Placebo
5
4
0
6
Time (weeks)
60 patients admitted for acute MI or unstable
angina, enrolled before hospital discharge
Dupuis et al (1999)
18
Timing of statin therapy initiation after ACS in
recent clinical studies
Atorvastatin
Pravastatin
MIRACL
Simvastatin
PTT
PAIS
Fluvastatin
4S
LAMIL
WOSCOPS
FLORIDA
CARE
L-CAD
ACS
RECIFE
LIPID
Primary prevention
Secondary prevention
3
0
6
2
24
10
6
8
12
12
18
4
6
Days
Months
Hours
Schwartz et al (1998)
19
What MIRACL was designed to show
The Hypothesis
Diminished incidence of recurrent ischaemic events
Rapid and early cholesterol reduction
Early plaque stabilisation
Objective
To prove that early, rapid, and intensive
cholesterol lowering therapy will reduce early
recurrent ischaemic events in patients with
unstable angina or non-Q-wave MI
MIRACL The Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering study
Schwartz et al (1998)
20
MIRACL study design
Prospective, randomised, multicentre,
double-blind

• Exclusion criteria
• Serum cholesterol gt7 mmol/L (270
  mg/dL)
• Concurrent or previous interventional therapy
  (6 months) or surgery (3 months)
• Concurrent lipid-lowering therapy
• Any agent likely to induce rhabdomyolysis when
  taken with statins

3,086 patients
Inclusion criteriaUA or non-Q-wave MI in
previous 14 days
80 mg atorvastatin, commenced within 2496 h of
event
Placebo, commenced within 2496 h of event
Follow up at 2, 6 and 16 weeks for endpoints,
ECG, labs and AEs
21
MIRACL study outcome measures

• Primary
• Time from randomisation to first occurrence of
  any of the
• following
• Death (any cause)
• Non-fatal MI
• Resuscitated cardiac arrest
• Worsening angina pectoris with new objective
  evidence of myocardial ischaemia, requiring
  urgent rehospitalisation

• Secondary
• Time to occurrence and incidence of each of the
  primary
• outcome components, plus
• Stroke
• Myocardial revascularisation (CABG or PTCA)
• Worsening congestive heart failure
• Worsening angina without new objective evidence
  of ischaemia

22
MIRACL patient disposition
Number of patients Atorvastatin Placebo Rando
mised 1538 1548 Lost to follow-up
8 4
23
Baseline characteristics of patients
Atorvastatin Placebo
n1538 n1548 Mean age
(years) 65 65 Male 64 66 Caucasian 86
85 Prior MI 25 25 Prior CABG or
PTCA 10 11 Current smoking 28 28 Hyperten
sion 55 55 Diabetes 22 24

24
Baseline characteristics of patients
Atorvastatin Placebo n1538
n1548 Inclusion event Unstable
angina 47 46 Non-Q-wave MI
53 55 Median time from hospital
admissionto randomisation 63 h 63 h
25
Primary efficacy measure
Cumulative incidence ()
17.4
Placebo
15
14.8
Atorvastatin
10
Time to first occurrence of composite endpoint
of

• Death (any cause)
• Non-fatal MI
• Resuscitated cardiac arrest
• Worsening angina with new objective evidence and
  urgent rehospitalisation

Risk reduction 16 p0.048
5
95 CI 0.7010.999
0
0
4
8
12
16
Time since randomisation (weeks)
26
Individual endpoint results incidence
Event Atorvastatin
Placebo reduction p Worsening
angina 6.2 8.4 26 0.02 Total
stroke 0.75 1.5 50 0.045 Death ns Non-fatal
acute MI ns Resuscitated cardiac arrest
ns
with new objective evidence of ischaemia
requiring urgent rehospitalisation
27
Blood lipids
BaselineMean of both groupsmg/dl
End of studyPlacebo
Atorvastatinmg/dl ( change)
Total cholesterolLDL cholesterolHDL
cholesterolTriglycerides
20612446182
217(7)135(12)46(4)187(9)
147(-27)72(-40)48(5)139(-16)
28
Safety
Atorvastatin Placebo
n1538 n1548 Elevated liver
transaminases(gt3 times ULN on 2 occasions)
2.5 0.6 Myositis(with CK gt10 times ULNon
2 occasions) 0 0
29
Potential mechanisms of benefit of statins in ACS
Statins
LDL-C reduction
Reduction in chylomicron and VLDL remnants, IDL,
LDL-C

• Restore endothelial function
• Maintain SMC function
• Anti-inflammatory effects
• Decreased thrombosis

Macrophages
Lumen
Statins differ significantly in terms of these
effects/mechanisms
Lipid core
Smooth muscle cells
30
Balancing the stability equation
Increased lipidsLipid oxidationInfection?Geneti
c susceptibility
Lipid-lowering drugs Antioxidants? Antibiotics? Me
chanical injury
Inflammation
Repair
Unstable plaque
Stable plaque
Modified from Weissberg (1999)
31
Timing of statin therapy initiation after ACS in
recent clinical studies
Atorvastatin
Pravastatin
PACT
MIRACL
Simvastatin
PTT
PAIS
Fluvastatin
PROVE IT
4S
LAMIL
WOSCOPS
FLORIDA
CARE
L-CAD
ACS
RECIFE
LIPID
Primary prevention
Secondary prevention
3
0
6
2
24
10
6
8
12
12
18
4
6
Days
Months
Hours
BMS Data on file
32
Pravastatin Acute Coronary Treatment (PACT)

• Design
• safety and short-, medium- and long-term efficacy
• 4 weeks double-blind treatment with pravastatin
• initiation within 24 hours of the onset of
  symptoms in patients with AMI or UA
• 12 months open-label follow-up
• Objective
• to demonstrate conclusively that early treatment
  with a statin is both safe and effective in the
  acute phase after MI or UA

33
PACT design features

• Randomised, double-blind
• Acute MI or unstable angina, n10,000
• Pravastatin 20 or 40 mg daily or placebo for 4
  weeks
• Initiation within 24 hours of the onset of
  symptoms
• Primary endpoint recurrent coronary events
• Ongoing lipid management after 4 weeks open-label
  determined by the patients local physician
• Follow up for clinical and adverse events at 4,
  26, and 52 weeks
• Includes PIMS (Pravastatin Inflammatory Markers
  Study)

34
Timing of statin therapy initiation after ACS in
recent clinical studies
Atorvastatin
Pravastatin
PACT
MIRACL
Simvastatin
PTT
PAIS
Fluvastatin
PROVE IT
4S
LAMIL
WOSCOPS
FLORIDA
CARE
L-CAD
ACS
RECIFE
LIPID
Primary prevention
Secondary prevention
3
0
6
2
24
10
6
8
12
12
18
4
6
Days
Months
Hours
BMS Data on file
35
PROVE IT PRavastatin Or AtorVastatin Evaluation
and Infection TherapyThe definitive
head-to-head comparison of pravastatin and
atorvastatin

• The first major trial to compare the effects of
  pravastatin versus atorvastatin in reducing the
  risk of heart attacks and other cardiac events
• Designed to evaluate further the role of
  infection in cardiovascular disease

36
PROVE IT study design
Double-blind, randomised, 4,000 patients with ACS
lt10 days and total cholesterol lt240 mg/dL (6.2
mmol/L)
Standard medical therapy
Pravastatin 40 mg qhs
Atorvastatin 80 mg qhs
Gatifloxacin
Placebo
Placebo
Gatifloxacin
Follow-up visit 30 days
Minimum duration 18 months
37
Conclusions

• Several clinical trials with pravastatin have
  indicated the benefits of early treatment in ACS
• MIRACL with atorvastatin supports this in a large
  trial
• Effects beyond lipid lowering may contribute to
  the early benefit
• PACT with pravastatin will answer whether even
  earlier initiation (within 24 h) is beneficial
• PROVE IT, a head-to-head trial of pravastatin vs
  atorvastatin, will determine any difference
  between these two agents