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REVERSAL

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  1. 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

  2. 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

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

  4. % 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

  5. 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

  6. Comparative Adverse Events Nissen SE et al. JAMA 2004; 291(9)1071-1080

  7. 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

  8. 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

  9. 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

  10. 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

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

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

  13. Baseline Lipid Levels * 25% of patients receiving statin therapy prior to randomisation Cannon CP et al. NEJM 2004; 350(9):15

  14. 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

  15. 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

  16. Tolerability and Safety Profile Cannon CP et al. NEJM 2004; 350(9):15

  17. How low should we go?

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

  19. 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

  20. 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.

  21. 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

  22. 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

  23. 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

  24. 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.

  25. 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.

  26. RIGHT SKEWED DISTRIBUTION

  27. PROBLEMS WITH TREATMENT TO TARGET • Bias • Analytical • Biological • Variation • Analytical • Biological • Combination of both

  28. BIAS

  29. ANALYTICAL BIAS • Cholesterol • Probably minimal • Blood Pressure • Potentially large

  30. THE NORMAL DISTRIBUTION

  31. TOTAL VARIATION

  32. Effect of Variation • Cholesterol (mmol/L) • Mean 5.0 • Upper 95% confidence interval 5.7 • Lower 95% confidence interval 4.3

  33. 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

  34. 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

  35. RIGHT SKEWED DISTRIBUTION

  36. 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

  37. 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

  38. Muscle Problems • Myo-, from Greek: of muscle • Myopathy: muscle pathology • Myalgia: muscle pain • Myositis: muscle inflammation • Rhabdomyolysis skeletal muscle breakdown

  39. 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

  40. 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

  41. 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.

  42. 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

  43. 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

  44. 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

  45. 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

  46. SUFFOLK BEER