Reversal
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REVERSAL. 657 CHD Patients. Atorvastatin 80mg. Pravastatin 40mg. 253 patients with IVUS at baseline and 18 months. 249 patients with IVUS at baseline and 18 months. Randomised, double blind multicentre trial performed at 34 community and tertiary care centres in the United States

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Reversal

REVERSAL

657 CHD Patients

Atorvastatin 80mg

Pravastatin 40mg

253 patients with IVUS at baseline and 18 months

249 patients with IVUS at baseline and 18 months

  • 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

Nissen SE et al. JAMA 2004; 291(9)1071-1080


Patient population

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

Intravascular Ultrasound (IVUS)

Nissen SE et al. JAMA 2004; 291(9)1071-1080


Change from baseline in lipid parameters

% Change from Baseline in Lipid Parameters

Triglycerides

HDL-cholesterol

Total cholesterol

LDL-cholesterol

10

2.9

5.6

0

-6.8

-10

Change from baseline (%)

-20

-18.4

-20.0*

Pravastatin

-25.2

-30

Atorvastatin

-34.1*

-40

-46.3*

-50

2.04mmol/L

*P<.001

Nissen SE et al. JAMA 2004; 291(9)1071-1080


Percent change in total atheroma volume

Pravastatin

Atorvastatin

Percent Change in Total Atheroma Volume

3.5

Progression (p=0.001*)

3

% Change in Total Atheroma Volume

2.7

2.5

p = 0.02†

2

1.5

1

0.5

0

-0.4

-0.5

No change (p=0.98*)

-1

* vs baseline

† between groups

Nissen SE et al. JAMA 2004; 291(9)1071-1080


Comparative adverse events

Comparative Adverse Events

Nissen SE et al. JAMA 2004; 291(9)1071-1080


Study limitations

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

Nissen SE et al. JAMA 2004; 291(9)1071-1080


Prove it timi 22 rationale

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 design

PROVE IT – TIMI 22: Study Design

4,162 patients with an Acute Coronary Syndrome < 10 days

ASA + Standard Medical Therapy

  • Randomised, double blind study

  • 349 sites in 8 countries

  • Designed as a non - inferiority trial

Standard Therapy

(Pravastatin 40 mg)

Intensive Therapy

(Atorvastatin 80 mg)

2x2 Factorial: Gatifloxacin vs. placebo

  • Primary Endpoint: Death, MI, Documented UA requiring hospitalisation,

  • Revascularisation (>30 days after randomisation), and Stroke

Duration: Mean 2 year follow-up

(> 925 events)

Cannon CP et al. NEJM 2004; 350(9):15


Patient population1

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

Baseline Characteristics

Cannon CP et al. NEJM 2004; 350(9):15


Concomitant therapies

Concomitant Therapies

Cannon CP et al. NEJM 2004; 350(9):15


Baseline lipid levels

Baseline Lipid Levels

* 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

Median LDL-C achieved

2.5mmol/L

1.6mmol/L

P<0.001

Changes from (Post-ACS) Baseline in Median LDL-C

Pravastatin 40mg

Atorvastatin 80mg

  • 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


Reversal

Pravastatin 40mg

(26.3%)

Atorvastatin 80mg

(22.4%)

16% RRR (5-26)

(P = 0.005)

0 3 6 9 12 15 18 21 24 27 30

Benefits of Intensive Lipid Lowering on All-Cause Death or Major CV Events (Primary Endpoint at 2 Years)

Criteria for equivalence were not met

Atorvastatin 80mg was superior to Pravastatin 40mg

% with

Event

Months of Follow-up

Cannon CP et al. NEJM 2004; 350(9):15


Tolerability and safety profile

Tolerability and Safety Profile

Cannon CP et al. NEJM 2004; 350(9):15


How low should we go

How low should we go?


New targets

New Targets

  • LDL cholesterol <2.0 mmol/L

  • Total cholesterol <4.0 mmol/L)


What class of drugs

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’

Joint British Recommendations Dec 1998


Overview of early secondary prevention trials

Overview of Early Secondary Prevention Trials

Total-C*

CHD events*

0

CDP: clofibrate

n=8341; P=NS

–6

–9

–10

-10

–13

CDP: niacin

n =8341; P=NS

–15

Percentage Change

-20

–23

Stockholm: clofibrate + niacin

n =555; P=NS

–29

-30

–35

POSCH: partial ileal bypass

n =838; P<0.001

-40

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.


What class of drugs1

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’

Joint British Recommendations Dec 1998


Rule of 5 rule of 7

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%

Am J Cardiol 1997; 80: 166-167


Treating to target

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 reduction25 %

  • Choose a drug that can achieve the target

  • Note cost and evidence


Ldl c reduction and statins

20

mg

rosuvastatin

10

mg

40

mg

20

mg

40

mg

80

mg

10

mg

atorvastatin

‡

20

mg

10

mg

80

mg

40

mg

simvastatin

‡

‡

‡

10

mg

20

mg

40

mg

pravastatin

‡

‡

LDL-C reduction and statins

LDL-C: Mean change (%) from baseline at week 6

0

-5

-10

-15

20

-25

-30

-35

-40

-45

-50

-55

-60

 p<0.002 vs. rosuvastatin 10mg ‡ p<0,002 vs, rosuvastatin 20mg  p<0.002 vs. rosuvastatin 40mg

Jones PH for the STELLAR Study Group. JACC 2003;41:in press.


Serum cholesterol levels in men

Serum Cholesterol Levels in Men*

Framingham Heart Study

40

MI

No MI

30

% Population

20

10

0

150

200

250

300

350

400

450

(mg/dl)

(mmol/L)

3.9

5.2

6.5

7.8

9.1

10.3

11.6

Serum cholesterol

*During first 16 years of study: Entry ages 30–40 years

Adapted from Castelli WP Can J Cardiol 1988;4(suppl A):5A-10A.


Right skewed distribution

RIGHT SKEWED DISTRIBUTION


Problems with treatment to target

PROBLEMS WITH TREATMENT TO TARGET

  • Bias

    • Analytical

    • Biological

  • Variation

    • Analytical

    • Biological

  • Combination of both


Reversal

BIAS


Analytical bias

ANALYTICAL BIAS

  • Cholesterol

    • Probably minimal

  • Blood Pressure

    • Potentially large


The normal distribution

THE NORMAL DISTRIBUTION


Total variation

TOTAL VARIATION


Effect of variation

Effect of Variation

  • Cholesterol (mmol/L)

    • Mean5.0

    • Upper 95% confidence interval5.7

    • Lower 95% confidence interval4.3


Treatment to target

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 target1

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 distribution1

RIGHT SKEWED DISTRIBUTION


Raised alt

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

Fluvastatin (20–80 mg)

Risk:Benefit – Liver

Rosuvastatin (10–40 mg)

Persistent ALT >3 × ULN: Frequency by LDL-C Reduction

Atorvastatin(10–80 mg)

Simvastatin (40–80 mg)

3.0

2.5

2.0

Persistent ALT >3 × ULN (%)

1.5

1.0

0.5

0.0

20

30

40

50

60

70

LDL-C reduction (%)

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K


Muscle problems

Muscle Problems

  • Myo-, from Greek: of muscle

  • Myopathy:muscle pathology

  • Myalgia:muscle pain

  • Myositis:muscle inflammation

  • Rhabdomyolysisskeletal muscle breakdown


Muscle problems1

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 problems2

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

BNF March 2001 p125


Muscle problems3

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.


Muscle problems4

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 impairmentand possibly those withhypothyroidism

  • Concomitant treatment with cyclosporin or in combined statin and fibrate therapy may be associated with increased risk of serious muscle toxicity

BNF March 2001 p125


Ck 10 uln frequency by ldl c reduction

Risk:Benefit – Muscle

CK >10 × ULN frequency by % LDL-C reduction

Cerivastatin (0.2–0.8mg)

Atorvastatin (10–80mg)

3.0

Pravastatin(40–80mg)

Rosuvastatin (10–40mg)

2.5

Simvastatin (40–80mg)

2.0

1.5

% CK > 10 × ULN

1.0

0.5

0.0

20

30

40

50

60

70

% LDL-C reduction

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K


Cumulative post marketing reporting rate of rhabdomyolysis for rosuvastatin

Cumulative post-marketing reporting rate of rhabdomyolysis for rosuvastatin

Patients = new and switched prescriptions

Reporting rate <1:10,000 = very rare (CIOMS)

Reporting rate - ALL

1.0

0.9

Reporting rate - ACC/AHA criteria

0.8

0.7

0.6

Reporting rate per 10,000 patients

0.5

0.4

0.3

0.2

0.1

0

30-Jul-2003

04-Jun-2003

14-Jan-2004

30-Jun-2004

20-Oct-2004

01-Dec-2004

10-Mar-2004

05-May-2004

24-Sep-2003

19-Nov-2003

25-Aug-2004

Week starting

Update: 08 December 2004


Reporting rates of rhabdomyolysis with lipid modifying therapy

120

100

80

Pravastatin

60

Simvastatin

Ezetimibe

40

Rosuvastatin

20

0

Reporting rates of rhabdomyolysiswith lipid-modifying therapy

Semiannual Reporting Rates for All Reports of Rhabdomyolysis

US Cases*

Worldwide Cases‡

Cerivastatin

120

Rosuvastatin

Fluvastatin

100

Atorvastatin

80

Reporting Rate Per1,000,000 US Prescriptions **

Reporting Rate Per 1,000,000CRESTOR Prescriptions Worldwide‡

60

40

20

0

03/99-

09/99-

03/00-

09/00-

03/01-

09/01-

03/02-

09/02-

03/03-

06/03-

12/03-

06/04-

08/99

02/00

08/00

02/01

08/01

02/02

08/02

02/03

08/03

11/03

05/04

11/04

*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


Reversal

SUFFOLK BEER


Thank you

THANK YOU


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