1. 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

2. 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

3. Nissen SE et al. JAMA 2004; 291(9)1071-1080 Intravascular Ultrasound (IVUS)

4. 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 Change from baseline (%) Total cholesterolLDL-cholesterol -25.2 -18.4 5.6 -6.8 -46.3 * -34.1* 2.9 -20.0 * TriglyceridesHDL-cholesterol Pravastatin 2.04mmol/L

5. 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 2.7 -0.4 Progression (p=0.001*) No change (p=0.98*) % Change in Total Atheroma Volume Pravastatin Atorvastatin

6. Nissen SE et al. JAMA 2004; 291(9)1071-1080 Comparative Adverse Events Pravastatin (n=327) Atorvastatin (n=327) Death1 (0.3%) Myocardial Infarction7 (2.1%)4 (1.2%) Stroke1 (0.3%) A L T > 3 x U L N5/316 (1.6%)7/311 (2.3%) A S T > 3 x U L N2/316 (0.6%)2/311 (0.6%) C K > 10 x U L N0/316 (0.0%)0/311 (0.0%)

7. 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

8. 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)

9. Cannon CP et al. NEJM 2004; 350(9):15 PROVE IT – TIMI 22: Study Design 4,162 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

10. 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)

11. Cannon CP et al. NEJM 2004; 350(9):15 Baseline Characteristics Atorvastatin 80mg (2099) Pravastatin 40 mg (2063) Mean Age (years)58 Male/Female (%)78/22 History of Hypertension (%)5149 Current Smoker (%)3637 History of Diabetes (%)18 Prior MI (%)1819 STEMI/NSTEMI/UA (%)36/36/2933/37/30 Prior Statin Use (%)2625

12. Cannon CP et al. NEJM 2004; 350(9):15 Concomitant Therapies PCI for initial ACS pre-randomisation69% Aspirin93% Warfarin8% Clopidogrel/ticlopidine (initial) (at 1 year) 72% 20% B-blockers85% ACE Inhibitors69% AII receptor blockers14% Statin Therapy25%

13. 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 LDL Cholesterol (mmol/L)2.7 Triglycerides (mmol/L)1.81.7 HDL Cholesterol (mmol/L)1.0 * 25% of patients receiving statin therapy prior to randomisation

14. Cannon CP et al. NEJM 2004; 350(9):15 Changes from (Post-ACS) Baseline in Median LDL-C Pravastatin 40mg Atorvastatin 80mg P<0.001 Median LDL-C achieved 2.5mmol/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

15. 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 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) % with Event Months of Follow-up Criteria for equivalence were not met Atorvastatin 80mg was superior to Pravastatin 40mg

16. Cannon CP et al. NEJM 2004; 350(9):15 Tolerability and Safety Profile Atorvastatin 80mg (2099) Pravastatin 40mg (2063) 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 Rhabdomyolysis0% N/A ALT ≥3 ULN3.3%1.1%<0.001 Dose halving for AE or raised ALT 1.9%1.4%0.20

17. How low should we go?

18. New Targets LDL cholesterol <2.0 mmol/L Total cholesterol <4.0 mmol/L)

19. 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’

20. Overview of Early Secondary Prevention Trials –9 –6 –15 –10 –29 –13 –35 –23 -40 -30 -20 -10 0 Percentage Change Total-C* CHD events* CDP: clofibrate n=8341; P=NS CDP: niacin n =8341; P=NS Stockholm: clofibrate + niacin n =555; P=NS POSCH: partial ileal bypass n =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.

21. 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’

25. 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%

26. 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

27. LDL-C reduction and statins 0-1020-30-50-60-5-15-25-35-45-55 20 mg ‡ 40 mg ‡ ‡  80 mg ‡ ‡  -40 20 mg 40 mg 80 mg LDL-C: Mean change (%) from baseline at week 6 20 mg ‡‡ 40 mg ‡ ‡  40 mg ‡ ‡ ‡‡ 20 mg Jones PH for the STELLAR Study Group. JACC 2003;41:in press. rosuvastatin simvastatin atorvastatin 10 mg  10 mg 10 mg 10 mg  pravastatin   p<0.002 vs. rosuvastatin 10mg ‡ p<0,002 vs, rosuvastatin 20mg  p<0.002 vs. rosuvastatin 40mg

28. Serum Cholesterol Levels in Men* Framingham Heart Study % Population 0 10 20 30 40 *During first 16 years of study: Entry ages 30–40 years Adapted from Castelli WP Can J Cardiol 1988;4(suppl A):5A-10A. MI No MI 150200250300350400450 Serum cholesterol 3.9 (mg/dl) (mmol/L) 5.26.57.89.110.311.6

29. RIGHT SKEWED DISTRIBUTION

30. PROBLEMS WITH TREATMENT TO TARGET Bias –Analytical –Biological Variation –Analytical –Biological Combination of both

31. BIAS

32. ANALYTICAL BIAS Cholesterol –Probably minimal Blood Pressure –Potentially large

33. THE NORMAL DISTRIBUTION

34. TOTAL VARIATION

35. Effect of Variation Cholesterol (mmol/L) –Mean5.0 –Upper 95% confidence interval5.7 –Lower 95% confidence interval4.3

36. 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 CV total is the value to ensure that a patient is always (100%) below the target This value is c4.0 mmol/L

37. 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

38. RIGHT SKEWED DISTRIBUTION

39. 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

40. 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 203040506070 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 × ULN: Frequency by LDL-C Reduction

41. Muscle Problems Myo-, from Greek: of muscle Myopathy:muscle pathology Myalgia:muscle pain Myositis:muscle inflammation Rhabdomyolysisskeletal muscle breakdown

42. 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)

43. 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

45. 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.

46. 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

47. CK >10 × ULN frequency by % LDL-C reduction 0.0 0.5 1.0 1.5 2.0 2.5 3.0 203040506070 % LDL-C reduction % CK > 10 × ULN Rosuvastatin (10–40mg)Pravastatin (40–80mg) Cerivastatin (0.2–0.8mg)Atorvastatin (10–80mg) (40–80mg) Simvastatin (40–80mg) Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K Risk:Benefit – Muscle

48. 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. 49 Reporting rates of rhabdomyolysis with 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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