REVERSAL

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


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


Intravascular Ultrasound (IVUS)

REVERSAL: Why was IVUS used?REVERSAL: Why was IVUS used?REVERSAL: Why was IVUS used?

Angiogram IVUS Image


% 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


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


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%)


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)


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


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)


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


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%


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


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


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


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

SUFFOLK BEER

THANK YOU

REVERSAL

Documents

mmnissen se

pnissen se

monthsnissen se

vascular eventsnissen

ivus evaluation

ivus imaging

total atheroma volumenissen

typical ivus image