1. BRIAN CLAYTON INTERNAL MEDICINE ADVISOR: ANNA MAE SMITH PRECEPTOR: DR. RAJESH PATEL Evidence Based Medicine Spring 2009

2. PICO Question Patient: Patients with low LDL cholesterol and high C-reactive-protein Interventions: Rosuvastatin (Crestor) Comparison: Treatment with other 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors (statins) Outcome: Reduction of myocardial infarction (MI), stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes

3. Purpose To explore the possibility of one statin drug to be superior over the others in reducing CRP levels and, subsequently, cardiovascular risk in otherwise ‘healthy’ people

4. Background Information Lipid-lowering drugs decrease the incidence of total cardiovascular events

5. Background Information Statins are the only drug class that have showed consistent, clear evidence of decreasing cardiovascular events

6. Background Information To prevent MI, stroke, and death from cardiovascular causes, current treatment algorithms recommend statin therapy for patients with  Established vascular disease  Diabetes  Hyperlipidemia

7. Background Information LDL-C is the most commonly used marker of cardiovascular risk

8. Background Information LDL-C is considered normal at  <160mg/dL without risk factors  <130mg/dL if risk factors present  <100mg/dL for patients with proven atherosclerotic disease, coronary heart disease (CHD) equivalent, or diabetes

9. Background Information The Framingham score  a risk assessment that determines the 10-year risk of developing CAD  based on gender, age group, total cholesterol, smoking status, HDL level, systolic blood pressure and blood pressure treatment status

10. Background Information LDL-C goals for statin therapy  <100mg/dL at moderate risk  <70mg/dL at high risk

11. Problems with Current Recommendations Approximately one half of all MI’s and strokes occur  in apparently healthy men and women  at LDL-C levels that are below recommended thresholds for treatment (<130mg/dL )

12. Problems with Current Recommendations Currently, individuals with LDL-C levels <130mg/dL are not considered eligible for statin therapy

13. Problems with Current Recommendations PROVE IT-TIMI 22  the achieved LDL-C levels in the trial did not independently impact the rate of cerebrovascular events (CVE)  patients with LDL levels both above and below 70 mg/dL had similar rates of CVE

14. Statins and C-reactive Protein (CRP) Additional non-lipid-lowering properties of statins (anti-inflammatory & antioxidant effects) may contribute to their benefits of lowering cardiovascular events

15. Statins and C-reactive Protein (CRP) Statins lower CRP levels (an inflammatory biomarker)

16. Statins and C-reactive Protein (CRP) Statin therapy results in greater clinical benefits in patients with previously elevated CRP levels that were decreased after treatment independent of LDL- C levels

17. Statins and C-reactive Protein (CRP) Measurement of CRP levels may independently predict future vascular events and improve global classification of risk, regardless of the LDL cholesterol level

18. Statins and C-reactive Protein (CRP) The JUPITER trial was designed to answer the question of whether CRP screening combined with traditional LDL screening would provide an improved strategy for statin use in primary prevention of cardiovascular disease

19. C-reactive Protein Levels and Outcomes After Statin Therapy (PROVE IT-TIMI 22) Evaluated relationships between the LDL-C and CRP levels achieved after treatment with 80 mg of atorvastatin or 40 mg of pravastatin daily and the risk of recurrent MI or death from coronary causes among 3745 patients with acute coronary syndromes

20. C-reactive Protein Levels and Outcomes After Statin Therapy (PROVE IT-TIMI 22)

27. Conclusion  Patients with acute coronary syndromes that achieve low CRP levels after statin therapy have better clinical outcomes (less recurrent MI’s and/or deaths from coronary causes) than those with higher CRP levels, regardless of the resultant level of LDL- C

28. C-reactive Protein Levels and Outcomes After Statin Therapy (PROVE IT-TIMI 22) Conclusion  As stated by Ridker et al. (2005), “Although atorvastatin was more likely than pravastatin to result in low levels of LDL cholesterol and CRP, meeting these targets was more important in determining the outcomes than was the specific choice of therapy.”

29. Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy (PROVE IT-TIMI 22) Randomized trial of atorvastatin 80 mg/day and pravastatin 40 mg/day therapy in 4,162 patients with acute coronary syndromes used serial biomarkers to assess the lipid and non-lipid effects of statins as they relate to CVE

30. Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy (PROVE IT-TIMI 22)

34. Conclusion  Achieved LDL levels do not independently impact the rate of CVE in patients with acute coronary syndromes

35. Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy (PROVE IT-TIMI 22) Conclusion  Patients with elevated CRP levels are at higher risk of stroke or TIA which reinforces the link between inflammation and CVE

36. JUPITER trial Randomly assigned 17,802 men and women with LDL-C levels of less than 130 mg/dL and CRP levels of 2.0 mg/L or higher to rosuvastatin (20 mg daily) or placebo

37. JUPITER trial Patients were followed for the occurrence of the combined primary end point of  MI  Stroke  Arterial revascularization  Hospitalization for unstable angina  Death from cardiovascular causes.

38. JUPITER trial

40. Trial was stopped at 1.9 years

41. JUPITER trial Rosuvastatin therapy lowered LDL-C levels by 50% and CRP levels by 37%, along with a 44% reduction in end point cardiovascular events

42. JUPITER trial Conclusion  Rosuvastatin reduces the incidence of first major cardiovascular events in apparently healthy people without hyperlipidemia but with elevated CRP levels

43. PICO Question Patient: Patients with low LDL cholesterol and high C-reactive-protein Interventions: Rosuvastatin (Crestor) Comparison: Treatment with other 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors (statins) Outcome: Reduction of myocardial infarction (MI), stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes

44. PICO Answer We don’t know

45. PICO Answer No head-to-head trials comparing rosuvastatin with other statins to evaluate their effectiveness in lowering cardiovascular events in populations with low LDL levels but high CRP levels

46. PICO Answer Due to differences in inclusion criteria among the previously mentioned studies  difficult to draw meaningful conclusions about the superiority of one of these statins over the others.

47. PICO Answer Other more important concerns  finding more sensitive and specific markers of risk rather than determining which statin therapy is most effective in lowering CRP levels

48. Application US Centers for Disease Control and Prevention and the American Heart Association  Measuring CRP levels in those at intermediate cardiovascular risk may be reasonable

49. Application In those with dyslipidemia  the optimal LDL-C goal of 70 mg/dL may need to be extended to others at higher global risk, such as those with elevated CRP levels

50. Application In those without dyslipidemia  statin therapy can be beneficial for apparently healthy persons who have elevated CRP levels

51. Application In those with acute coronary syndromes  aggressive statin therapy to achieve target levels of both LDL-C and CRP can decrease the risk of recurrent MI or death from coronary causes

52. Bibliography Aung, P. P., Maxwell, H., Jepson, R. G., Price, J., & Leng, G. C. (2007). Lipid-lowering for peripheral arterial disease of the lower limb. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD000123. DOI: 10.1002/14651858.CD000123.pub2. Hodgson, J. M., & Schleyer, A. M. (2007). Hyperlipidemia. MD Consult. Retrieved February 8, 2009 from http://www.mdconsult.com/das/pdxmd/body/119496415- 3/801771642?type=med&eid=9-u1.0-_1_mt_1014732#Contributors http://www.mdconsult.com/das/pdxmd/body/119496415- 3/801771642?type=med&eid=9-u1.0-_1_mt_1014732#Contributors Mega, J. L., Morrow, D. A., Cannon, C. P., Murphy, S., Cairns, R., Ridker, P. M., & Braunmald, E. (2006). Cholesterol, C-reactive protein, and cerebrovascular events following intensive and moderate statin therapy. Journal of Thrombosis and Thrombolysis, 22, 71-76. Mora, S., & Ridker, P. M. (2006). Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)--can C-reactive protein be used to target statin therapy in primary prevention? The American Journal of Cardiology, 97, 33-41. Ridker, P. M., Cannon, C. P., & Morrow, D. (2005). C-reactive protein levels and outcomes after statin therapy. New England Journal of Medicine, 352, 20-28. Ridker, P. M., Danielson, E., & Fonseca, F. A. (2008). Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New England Journal of Medicine, 359, 2195-2207. Shishehbor, M. H., & Hazen, S. L. (2009). JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean? Cleveland Clinic Journal of Medicine, 76(1), 37-44.