nissen se et al. jama 2004; 291(9)1071-1080 reversal 657 chd patients atorvastatin 80mg pravastatin...
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Nissen SE et al. JAMA 2004; 291(9)1071-1080
REVERSAL
657 CHD Patients
Atorvastatin 80mg Pravastatin 40mg
Randomised, double blind multicentre trial performed at 34 community and tertiary care centres in the United States
Primary endpoint: % change in Coronary Plaque Volume by IVUS
253 patients with IVUS at baseline and 18 months
249 patients with IVUS at baseline and 18 months
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Patient Population• Inclusion criteria:
– Patients aged 30-75 years requiring diagnostic coronary angiography
for a clinical indication
– LDL-cholesterol between 3.2 mmol/L and 5.4 mmol/L
• Angiographic inclusion criteria:– Angiographic evidence of CHD defined as ≥ 1 lesion with ≥ 20% reduction in lumen diameter in
any coronary artery
– ≤ 50% reduction in lumen diameter of the left main coronary artery
– The vessel undergoing IVUS evaluation (the ‘target’ vessel) should have ≤ 50% stenosis throughout a segment of minimum length of 30 mm
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Intravascular Ultrasound (IVUS)
REVERSAL: Why was IVUS used?REVERSAL: Why was IVUS used?REVERSAL: Why was IVUS used?
Angiogram IVUS Image
Nissen SE et al. JAMA 2004; 291(9)1071-1080
% Change from Baseline in Lipid Parameters
*P<.001
-40
-30
-20
-10
0
10
Atorvastatin
-50
Cha
nge
from
bas
elin
e (%
)Total cholesterol LDL-cholesterol
-25.2
-18.4
5.6
-6.8
-46.3*
-34.1*
2.9
-20.0*
Triglycerides HDL-cholesterol
Pravastatin
2.04mmol/L
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Percent Change in Total Atheroma Volume
* vs baseline† between groups
p = 0.02†
3.5
3
2.5
2
1.5
1
0.5
0
-0.5
-1
2.7
-0.4
Progression (p=0.001*)
No change (p=0.98*)
% Change in Total Atheroma
Volume
Pravastatin Atorvastatin
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Comparative Adverse Events
Pravastatin
(n=327)
Atorvastatin
(n=327)
Death 1 (0.3%) 1 (0.3%)
Myocardial Infarction 7 (2.1%) 4 (1.2%)
Stroke 1 (0.3%) 1 (0.3%)
A L T > 3 x U L N 5/316 (1.6%) 7/311 (2.3%)
A S T > 3 x U L N 2/316 (0.6%) 2/311 (0.6%)
C K > 10 x U L N 0/316 (0.0%) 0/311 (0.0%)
Nissen SE et al. JAMA 2004; 291(9)1071-1080
Study Limitations
• The REVERSAL study was not powered to assess differences in clinical events
• Morbidity and mortality endpoints are always the preferred efficacy measures in clinical trials
• However, comparison of two statins in a conventional events trial would require approximately 10,000 patients and 5-6 years follow-up
• Furthermore, previous trials have demonstrated a relationship between atherosclerosis progression and vascular events
Cannon CP et al. NEJM 2004; 350(9):15
PROVE IT – TIMI 22 Rationale
• Are statins effective in reducing cardiac events when started early after an acute coronary syndrome (ACS)?
• Do the benefits of “intensive” LDL-C lowering to ~1.8mmol/L with 80mg atorvastatin achieve a greater reduction in clinical events than “standard” LDL-C lowering to ~2.6mmol/L with 40mg pravastatin?
(Pravastatin Or Atorvastatin Evaluation and Infection Therapy - Thrombolysis in Myocardial Infarction 22)
Cannon CP et al. NEJM 2004; 350(9):15
PROVE IT – TIMI 22: Study Design4,162 patients with an Acute Coronary Syndrome < 10 days
ASA + Standard Medical Therapy
Intensive Therapy(Atorvastatin 80 mg)
Standard Therapy(Pravastatin 40 mg)
2x2 Factorial: Gatifloxacin vs.
placebo
Duration: Mean 2 year follow-up (> 925 events)
•Primary Endpoint: Death, MI, Documented UA requiring hospitalisation,Revascularisation (>30 days after randomisation), and Stroke
•Randomised, double blind study•349 sites in 8 countries
•Designed as a non - inferiority trial
Cannon CP et al. NEJM 2004; 350(9):15
Patient Population
Inclusion Criteria:
• Hospitalisation for acute MI or high-risk unstable angina within the last 10 days
• Total cholesterol < 6.2mmol/L (< 5.2mmol/L if on lipid lowering therapy)
• Stabilised (i.e.without ischemia, CHF, post PCI if planned)
Cannon CP et al. NEJM 2004; 350(9):15
Baseline Characteristics
Atorvastatin 80mg(2099)
Pravastatin 40 mg
(2063)
Mean Age (years) 58 58
Male/Female (%) 78/22 78/22
History of Hypertension (%) 51 49
Current Smoker (%) 36 37
History of Diabetes (%) 18 18
Prior MI (%) 18 19
STEMI/NSTEMI/UA (%) 36/36/29 33/37/30
Prior Statin Use (%) 26 25
Cannon CP et al. NEJM 2004; 350(9):15
Concomitant Therapies
PCI for initial ACS pre-randomisation 69%
Aspirin 93%
Warfarin 8%
Clopidogrel/ticlopidine (initial)
(at 1 year)
72%
20%
B-blockers 85%
ACE Inhibitors 69%
AII receptor blockers 14%
Statin Therapy 25%
Cannon CP et al. NEJM 2004; 350(9):15
Baseline Lipid Levels
Median Values* Atorvastatin 80mg(2099)
Pravastatin 40 mg(2063)
Total Cholesterol (mmol/L) 4.7 4.7
LDL Cholesterol (mmol/L) 2.7 2.7
Triglycerides (mmol/L) 1.8 1.7
HDL Cholesterol (mmol/L) 1.0 1.0
* 25% of patients receiving statin therapy prior to randomisation
Cannon CP et al. NEJM 2004; 350(9):15
Changes from (Post-ACS) Baseline in Median LDL-C
0
20
40
60
80
100
120
Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final
LDL-C (mg/dL)
Pravastatin 40mg
Atorvastatin 80mg P<0.001
Median LDL-C achieved2.5mmol/L
1.6mmol/L
Note: Changes in LDL-C may differ from prior trials:•25% of patients on statins prior to ACS event and no washout period•LDL-C is transiently lowered by the acute coronary event itself
Cannon CP et al. NEJM 2004; 350(9):15
Benefits of Intensive Lipid Lowering on
All-Cause Death or Major CV Events (Primary Endpoint at 2 Years)
0
5
10
15
20
25
30
0 3 6 9 12 15 18 21 24 27 30
Pravastatin 40mg(26.3%)
Atorvastatin 80mg(22.4%)
16% RRR (5-26)(P = 0.005)
% withEvent
Months of Follow-up
Criteria for equivalence were not met
Atorvastatin 80mg was superior to Pravastatin 40mg
Cannon CP et al. NEJM 2004; 350(9):15
Tolerability and Safety Profile
Atorvastatin80mg (2099)
Pravastatin40mg (2063)
P-value
Discontinuation for AE, patient preference or other reasons
30.4% 33.0% 0.11
Discontinuation for Myalgia/CK
elevation3.3% 2.7% 0.23
Rhabdomyolysis 0% 0% N/A
ALT ≥3 ULN 3.3% 1.1% <0.001
Dose halving for AE or raised ALT
1.9% 1.4% 0.20
How low should we go?
New Targets
• LDL cholesterol <2.0 mmol/L
• Total cholesterol <4.0 mmol/L)
Joint British Recommendations Dec 1998
What class of drugs?
• ‘The best evidence of cholesterol
lowering in secondary prevention
comes from randomised
controlled trials using statins;
these drugs are thus the preferred
class for CHD patients’
Overview of Early Secondary Prevention Trials
–9–6
–15
–10
–29
–13
–35
–23
-40
-30
-20
-10
0
Pe
rcen
tag
e C
ha
ng
e
Total-C* CHD events*
CDP: clofibraten=8341; P=NS
CDP: niacinn =8341; P=NS
Stockholm: clofibrate + niacinn =555; P=NS
POSCH: partial ileal bypassn =838; P<0.001
CDP, Coronary Drug Projects; NS, not significant; POSCH, Program on Surgical Control of the Hyperlipidaemias. *Net difference between treatment and control groups (P values are for events). Kwiterovich PO. Am J Cardiol 1998;82(12A):3U–17U.
Joint British Recommendations Dec 1998
What class of drugs?
• ‘Generally a statin should be
the initial choice of therapy in
combined hyperlipidaemia,
certainly when the triglycerides
are less than 5.0 mmol/L’
Am J Cardiol 1997; 80: 166-167
Rule of 5 & Rule of 7
• A doubling of each statin lowers
Total cholesterol an additional 5%
• A doubling of each statin lowers
LDL cholesterol an additional 7%
Treating to Target
• Patient with CHD or with CHD risk over 10 years > 30%
with LDL cholesterol of 4.0 mmol/L
–Target LDL cholesterol < 3.0 mmol/L
–Desired LDL cholesterol reduction 25 %
• Choose a drug that can achieve the target
• Note cost and evidence
LDL-C reduction and statins
0 -10 20 -30 -50 -60-5 -15 -25 -35 -45 -55
20mg
‡
40mg
‡
80mg‡
-40
20mg
40mg
80mg
LDL-C: Mean change (%) from baseline at week 6
20mg‡
40mg‡
40mg‡ ‡
20mg
Jones PH for the STELLAR Study Group. JACC 2003;41:in press.
rosuvastatin
simvastatin
atorvastatin
10mg
10mg
10mg
10mg
pravastatin
p<0.002 vs. rosuvastatin 10mg ‡ p<0,002 vs, rosuvastatin 20mg p<0.002 vs. rosuvastatin 40mg
Serum Cholesterol Levels in Men*Framingham Heart Study
% P
op
ula
tio
n
0
10
20
30
40
*During first 16 years of study: Entry ages 30–40 yearsAdapted from Castelli WP Can J Cardiol 1988;4(suppl A):5A-10A.
MINo MI
150 200 250 300 350 400 450
Serum cholesterol
3.9(mg/dl)
(mmol/L)5.2 6.5 7.8 9.1 10.3 11.6
RIGHT SKEWED DISTRIBUTION
PROBLEMS WITH TREATMENT TO TARGET
• Bias
–Analytical
–Biological
• Variation
–Analytical
–Biological
• Combination of both
BIAS
ANALYTICAL BIAS
•Cholesterol
–Probably minimal
•Blood Pressure
–Potentially large
THE NORMAL DISTRIBUTION
TOTAL VARIATION
Biological Analytical Total
Cholesterol
6.5% 2.5% 6.9%
SBP 7% 5% 8.6%
Effect of Variation
• Cholesterol (mmol/L)
–Mean 5.0
–Upper 95% confidence interval 5.7
–Lower 95% confidence interval 4.3
TREATMENT TO TARGET
• Populations are made up of individuals
• If an individuals cholesterol has an average of 5.0 mmol/L, then 50% of the time it is above 5.0 mmol/L
• To be sure that 60% of CHD patients have a cholesterol <5.0 mmol/l means that a lower target cholesterol will be necessary to achieve this
• The mean - 2.8 x CVtotal is the value to ensure that a
patient is always (100%) below the target
• This value is c4.0 mmol/L
TREATMENT TO TARGET
• If you set a target cholesterol of 4.0 mmol/L for 60% of your patients, then you should achieve the contract target
• This allows lee-way for those with diabetes, mixed dyslipidaemia/resistance to therapy, etc.
• Alternatively, you can set a higher target for >60% of your patients
• This target MUST be <5.0 mmol/L to achieve the contract target in practice
RIGHT SKEWED DISTRIBUTION
Raised ALT
• ALT NOT liver function tests
• Stop if consistently above 3 times upper
reference limit (111 U/L in Ipswich)
• Suggest measure ALT only to KEEP IT
SIMPLE
• BNF states assessment only for first year
Risk:Benefit – Liver
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
Persistent ALT >3 × ULN (%)
Rosuvastatin (10–40 mg)
Atorvastatin (10–80 mg)
Fluvastatin (20–80 mg)
Simvastatin (40–80 mg)
Persistent ALT >3 Persistent ALT >3 ×× ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction
Muscle Problems
• Myo-, from Greek: of muscle
• Myopathy: muscle pathology
• Myalgia: muscle pain
• Myositis: muscle inflammation
• Rhabdomyolysis skeletal muscle breakdown
BNF March 2001 p125
Muscle Problems
• ‘Should a patient complain of muscle ache or
other minor muscle related problems, it is
recommended that a Creatine Kinase (CK) level be
analysed. A pre-treatment baseline level is
important for comparison purposes’
• Patient should NOT be started on a statin if the
pre-treatment CK level is >5 times normal (> 1,000
U/l in men, > 750 U/l in women)
BNF March 2001 p125
Muscle Problems
• ‘If the creatine kinase concentration is markedly elevated (>10 times upper limit of normal), and myopathy is suspected or diagnosed, treatment should be discontinued’
• Monitoring of creatine kinase is required if patients of lipid-lowering medications have muscle symptoms
Muscle Problems
• Myositis, defined as muscle inflammation with
CK levels 10 times normal (> 2,000 U/l in men,
>1,500 U/l in women), is rarely reported.
• It is important to note that the CK level returns
to normal within 48 hours of discontinuing lipid
lowering medication.
BNF March 2001 p125
Muscle Problems
• Rhabdomyolysis associated with lipid lowering drugs is rare (1 case in every 100,000 treatment years) but may be increased in those with renal impairment and possibly those with hypothyroidism
• Concomitant treatment with cyclosporin or in combined statin and fibrate therapy may be associated with increased risk of serious muscle toxicity
CK >10 × ULN frequency by % LDL-C reduction
0.00.0
0.50.5
1.01.0
1.51.5
2.02.0
2.52.5
3.03.0
2020 3030 4040 5050 6060 7070
% LDL-C reduction% LDL-C reduction
% C
K >
10
× U
LN
% C
K >
10
× U
LN
Rosuvastatin (10–40mg)Pravastatin (40–80mg)
Cerivastatin (0.2–0.8mg) Atorvastatin (10–80mg)
Simvastatin (40–80mg) (40–80mg)
Brewer HB. Brewer HB. Am J CardiolAm J Cardiol 2003;92(Suppl):23K–29K 2003;92(Suppl):23K–29K
Risk:Benefit – MuscleRisk:Benefit – Muscle
Cumulative post-marketing reporting rate of rhabdomyolysis for rosuvastatin
Reporting rate <1:10,000 = very rare (CIOMS)
Patients = new and switched prescriptions
Update: 08 December 2004
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
04-Jun-2003
30-Jul-2003
24-Sep-2003
19-Nov-2003
14-Jan-2004
10-Mar-2004
05-May-2004
30-Jun-2004
25-Aug-2004
20-Oct-2004
01-Dec-2004
Week starting
Reporting rate per
10,000 patients
Reporting rate - ALL
Reporting rate - ACC/AHA criteria
49
Reporting rates of rhabdomyolysiswith lipid-modifying therapy
Semiannual Reporting Rates for All Reports of Rhabdomyolysis
US Cases*
0
20
40
60
80
100
120
03/99-08/99
09/99-02/00
03/00-08/00
09/00-02/01
03/01-08/01
09/01-02/02
03/02-08/02
09/02-02/03
03/03-08/03
06/03-11/03
12/03-05/04
06/04-11/04
Cerivastatin
Fluvastatin
Atorvastatin
Pravastatin
Simvastatin
Ezetimibe
Rosuvastatin
Reporting Rate Per
1,000,000 US Prescriptions **
Rosuvastatin†
Worldwide Cases‡
Reporting Rate Per 1,000,000
CRESTOR Prescriptions Worldwide‡
80
0
100
120
60
40
20
*All spontaneous reports including expedited, periodic and direct reports. **US reporting rate for all statins and ezetimibe based on FDA Adverse Events Reporting System made available through Freedom of Information Act divided by US prescribing data supplied by IMS through August 2003.†Cerivastatin reports received after September 1, 2001, are excluded.
‡Global reporting rate for rosuvastatin based on spontaneous report counts of rhabdomyolysis within AstraZeneca global drug safety database divided by estimated worldwide prescriptions to end November 2004. Total prescriptions based on IMS data from US, Canada, UK, France, Italy and The Netherlands; rest of world prescriptions based on actual sales calculations.
Update: 08 December 2004
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