Effects of Two Intensive Statin Regimens on Progression of Coronary Disease

1. Scott Morgan MSIII November 2012 Effects of Two Intensive Statin Regimens on Progression of Coronary Disease

2. Funding • AstraZeneca Pharmaceuticals • Designed by Cleveland Clinic Coordinating Center For Clinical Research

3. Purpose • Previous studies • Repeatedly show favorable LDL effects from statins • Slow progression of CAD • Might even lead to CAD regression • Comparison of LDL lowering capabilities between rosuvastatin and atorvastatin • Lack of randomized clinical trials showing efficacy for rosuvastatin vs atorvastatin in CAD modification leading to changes in clinical outcomes • Tested the 2 most potent statins for slowed progression or reversal of atherosclerosis in coronary arteries

4. Background • Statins • Inhibit hydroxymethylglutaryl (HMG) CoA reductase • Block rate-limiting step in cholesterol synthesis • Major effect is from increased hepatic LDL receptors • Average 20-40% decrease in LDL • Can raise HDL by 10%

5. Statins For Study • Most effective statins for lowering LDL • Atorvastatin • Yield average decrease in LDL approaching 50% • Rosuvastatin • Yield average decrease in LDL exceeding 50% • Greater increase in HDL than atorvastatin

6. Methods • Randomized double-blind • Treatment with atorvastatin 80 mg daily or rosuvastatin 40 mg daily • Serial intravascular ultrasonography of coronary arteries • Baseline at beginning of study • After 104 weeks of treatment

7. Criteria • 1039 patients 18-75 years old • At least one vessel with 20% stenosis and a target vessel for imaging with <50% stenosis • Not treated with statins in preceding 4 weeks – LDL >100 mg/dL • If treated – LDL > 80 mg/dL • Exclusions: • intensive lipid-lowering therapy >3 months in last year • Uncontrolled HTN • Heart failure • Renal dysfunction • Liver disease

8. Results

9. Intention-to-Treat • When all patients in a study are included in the final results even when they are lost to follow up • Prevents non-randomized loss of participants • Without this number there can be artifact that makes a variable appear more/less effective

10. Intention-to-Treat Example • Using this study as a hypothetical example • If 50 from the rosuvastatin that would have had a large LDL decrease drop out • 35 had decreased LDL levels during the trial • Results of the study will not show how efficacious rosuvastatin therapy • Sample size is smaller • Smaller percentage of patients show results • Reality: 250/520 = 48% • With ITT: 235/520 = 45% • Without ITT: 200/470 = 43% • LDL decrease will appear smaller than reality

11. Problems With ITT • Missing data • Lack of adherence to methods used for experiment • In example: • What is 25 of the 35 would have seen an increase in LDL levels if they had stayed in?

12. Discussion • Rosuvastatin and atorvastatin caused a significant decrease in atherosclerotic plaque size • Significant difference in regression of total atherosclerotic volume between medications • Difference between percent atheroma volume was not significant

13. Summary • Patients can have a decrease in coronary atherosclerosis when using rosuvastatin or atorvastatin • Reduction in atherosclerotic plaques is not significant enough to justify one over the other • Larger decrease in LDL and increase in HDL with rosuvastatin during study

14. Limitations • Did not use ITT • Thought the groups were still randomized and unaffected • Not ethically possible to measure disease progression in placebo-treated patients • Did not look at asymptomatic patients • Did not look at alternative methods vs statins • Some newer methods of evaluating atherosclerotic plaques might be more accurate • Funded by pharmaceutical company • Rating: IIa

15. Citation • Nicholls, Stephen J. et al. Effect of Two Intensive Statin Regimens on Progression of Coronary Disease. New England Journal of Medicine. 2011; 365:2078-2087. Dec 1, 2011