1. Why Statins? Polly Rimtepathip Pharm.D. Candidate October 28, 2011 Preceptor: Dr. Rahimi, Ali R.

2. Background Coronary heart disease (CHD) is the leading cause of death in the US, causing one in every six deaths in the US. However, the death rates for cardiovascular disease (CVD) and CHD have decreased substantially from 1996-2006 by about 30%. Studies have suggested that the decrease in CHD-related mortality rates is associated with the reduction in modifiable risk factors and improvements in evidence-based therapies.

3. Background An important factor contributing to this trend is the lipid-lowering therapies, especially statins. The current National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines recommend the use of statins for primary prevention based on a patient’s cardiovascular risk profile and low-density lipoprotein cholesterol (LDL-C) level.

4. Statins Statins, also known as HMG-CoA reductase inhibitors, are lipid-lowering drugs that works by inhibiting the enzyme HMG-CoA reductase, a rate-limiting step in cholesterol synthesis in the liver. Therefore, the effects of statins are inhibition of cholesterol synthesis and increase in LDL uptake. In addition, statins may also help reabsorb cholesterol that has built up on the artery walls, preventing further blockage in the blood vessels.

5. Brugts JJ, Yetgin T, Hoeks SE, et al. BMJ 2009;338:b2376 Funding: None

6. Background The use of statins in patients without established cardiovascular disease or the use of statins as a primary prevention has an important public health implications. The use of statins as a primary prevention is still ambiguous because of inconsistent findings in research.

7. Purpose/Design Meta-analysis of randomized trials that focused on primary prevention to determine whether statins reduce all cause mortality and the incidence of major coronary and cerebrovascular events in people without established cardiovascular disease but with cardiovascular risk factors

8. Methods Databases: Cochrane Central Register of Controlled Trials, Medline, Embase, DARE, and the ACP Journal Inclusion Criteria: ▫ randomized trials of statins versus controls (placebo, active control, or usual care) ▫Had a mean follow-up of at least a year ▫Reported on mortality or cardiovascular disease events as primary outcomes ▫Included at least 80% of people without established cardiovascular disease or reported data separately on a sole primary prevention group with a specific numbers of patients and events in that group reported

9. Methods 1230 studies was searched and 10 fulfilled the inclusion criteria. In total, 70,388 participants were randomized. 35,138 were allocated to statin therapy and 35,250 to control. The mean age was 63 years, and the mean follow-up was 4.1 years. The mean baseline LDL was 3.63 mmol/L.

10. Methods The Jadad scale was used to score study quality, and the study quality was four or more for all included randomized clinical trials. For each trial, the summary odds ratios and 95% confidence intervals for the clinical outcomes were calculated.

11. Outcomes Primary end point was all cause mortality. Secondary end points were the composite of major coronary events, including death from CHD and non-fatal myocardial infarction (MI), and the composite of major cerebrovascular events, defined as fatal and non-fatal stroke. Death from CHD, non-fatal MI, revascularizations and cancer were also assessed.

12. Results The mean reduction in levels of total cholesterol was 17.1%, low density lipoprotein cholesterol was 25.6%, and triglyceride was 9.3%. High density lipoprotein cholesterol increased by a mean 3.3%. 5.7% of participants died in the control group compared with 5.1% in the statin group; therefore, statin therapy was associated with a 12% risk reduction in all cause mortality compared with the control.

13. Results 5.4% of participants in the control group had a major coronary event compared with 4.1% in the statin group, a 30% risk reduction. Overall, 2.3% of participants in the control group had a major CV event compared with 1.9% in the statin group, a 19% risk reduction. The association between statin therapy and risk of cancer was not significant.

14. Discussion Statin therapy was associated with a significant risk reduction in all cause mortality of 12%, in major coronary events of 30%, and in major cerebrovascular events of 19%. Statin use was not associated with an increased risk of cancer. Side effects such as increase in creatinine kinase levels and myopathy have been reported relatively frequently, but rhabdomyolysis and hepatotoxicity are rare.

15. Limitations 3 trials in the analyses had a small proportion of patients with clinical CVD. The dose and type of statin differed between included trials. The included trials represented participants with a clinically heterogenous level of risk, although statistical heterogeneity was low.

16. Conclusion In patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.

17. Mills EJ, Wu P, Chong G, et al. Q J Med 2011; 104:109-124 Funding: None

18. Background Statins have been extensively studied in a large variety of patient populations including both primary and secondary prevention of cardiovascular disease (CVD). It is widely used because of its effectiveness and relatively inexpensive costs now that three of them are available in generic form (lovastatin, simvastatin and pravastatin). 10mg simvastatin is currently available OTC in the UK.

19. Purpose Large and up-to-date systematic reviews with meta-analyses can help to provide clinicians with the most reliable and precise estimates of treatment effects and rare adverse events. The study assembled randomized controlled trials (RCT) to date in order to quantify the effects of statin therapy on a wide range of clinical outcomes and populations

20. Methods Inclusion Criteria: ▫RCT of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin for CVD event prevention among both primary and secondary prevention populations ▫Studies had to compare a statin to placebo, standard therapy, or no-treatment ▫Studies had to report on important cardiovascular outcomes: All-cause mortality, CVD mortality, fatal myocardial infarction (MI), non-fatal MI, and major CV events (stroke, revascularization).

21. Methods Exclusion Criteria: ▫RCT of cerivastatin (removed from the market) ▫Studies that only reported on surrogate outcomes such as LDL and HDL ▫Follow-up studies where randomization had been subverted ▫Head-head statin evaluations

22. Methods Search strategy ▫12 databases (from inception to August 2010): MEDLINE, EMBASE, Cochrane CENTRAL, AMED, Web of Science, etc. ▫Original authors were contacted for clarifications when needed. ▫Two investigators worked independently, in duplicate, scanned all the abstracts and collected information.

23. Methods Relative Risk (RR) and 95% confidence intervals were calculated according to the number of events reported in the original studies or sub-studies intent-to-treat analyses. For adverse events, Peto’s Odds Ratio (OR) was used to calculate event rates Co-variates (absolute LDL change, proportion of men in the studies, had a history of coronary heart disease (CHD), had baseline diabetes, were hypertensive or current studies) were examined for impact by a multivariable meta-regression analysis.

24. Outcomes Primary outcome is CVD mortality.

25. Results 76 RCTs were included in the study. Data were available on 170,255 participants with the average age of 59.6, ranging from 38-75. Trials used four distinct controls: placebo (52 RCTs), usual care (18 RCTs), no treatment (4 RCTs) and conventional therapy (2 RCTs). Trials follows patients for an average of 2.7 years, ranged from 0.5-6.1 years. Mean pre-treatment LDL cholesterol was 180 mg/dL, ranged from 95-195 mg/dL.

26. Results In all trials combined, there was a 8.1% death among patients receiving statin therapy and 9.5% deaths among patients with control intervention. ▫10% reduction in all-cause mortality Each 10% change in absolute LDL levels was associated with a 1.1% risk reduction. The large risk reduction was mainly attributed to the 20% risk reduction in CVD deaths (4.1% vs. 5.1%) A consistent reduction in fatal MI with an 18% risk reduction was also noted

27. Results Reduction of deaths from stroke and non-CVD causes were found statistically insignificant. A highly significant effect of statins on revascularization status was also noted (6.2% vs. 8.1%). Low incidence of hemorrhagic strokes was found in the treatment of statins. The analysis did not find a significant difference between any statins.

28. Results The incidence of cancer was not different between the statin and the control groups. No significant difference was found for rhabdomyolysis between groups. A significantly increased rate of diabetes and elevated AST were found.

29. Discussion The meta-analysis demonstrated consistent benefits from LDL-lowering effects with statin therapy: reduces major CVD events and all- cause mortality. Only trials evaluating statins with inert controls were included because previous analysis of head-to-head trials have demonstrated that these trials evaluated dosing rather than the effectiveness of individual statins.

30. Discussion There was an evidence of increased diabetes incidence with statin therapy; however, this seems to be poorly monitored in clinical trials. The authors believe that, based on available evidence, generic of statins exert similar therapeutic effects to brand-label statins across populations. Meta-analyses are limited in assessing continuous outcome changes because they do not have the individual level data.

31. Conclusion Statins play an important role in reducing clinically relevant cardiovascular outcomes across broad populations, most likely by reducing LDL-C levels. Current guidelines aim to establish target LDL-C reductions to improve a patients long-term reduction in clinical events.

32. Crouse III JR, Raichlen JS, Riley WA, et al. JAMA 2007;297:1344-1353. Funding: AstraZeneca

33. Purpose The METEOR study was designed to investigate the effect of a 40-mg dose of rosuvastatin on CIMT over 2 years in middle-aged individuals with low Framingham risk scores but with subclinical atherosclerosis.

34. Methods Study design ▫2-year, double-blind, placebo-controlled trial comparing a 40mg dose of rosuvastatin ▫Sample: middle-aged asymptomatic individuals with moderately elevated cholesterol and low risk of CVD according to ATP III guidelines. All participants were provided counseling regarding therapeutic lifestyle changes. Participants had evidence of thickening of the walls of the extracranial carotid arteries as measured by B-mode ultrasound.

35. Methods Inclusion criteria (low-risk but with subclinical atherosclerosis): ▫Men age 45-70, Women age 55-70 ▫LDL-C level of 120 - < 190mg/dL for those with only age as a coronary heart disease risk factor ▫LDL-C level of 120 - < 160mg/dL for individuals with 2 or more coronary heart disease risk factors and a 10-year risk of < 10% ▫HDL-C level of ≤ 60mg/dL ▫Triglycerides < 500mg/dL ▫Maximum CIMT measurements of 1.2 – 3.5mm from 2 ultrasound examinations

36. Methods Exclusions: ▫Use of lipid-lowering therapies in previous 12 months ▫Clinical evidence of coronary artery disease or other peripheral atherosclerotic disease ▫Prior revascularization procedures ▫10-year coronary heart disease risk of ≥ 10% ▫Diabetes Mellitus, uncontrolled hypertension or familial hypercholesterolemia, or Scr > 2mg/dL

37. Methods Carotid ultrasound examinations were performed twice before randomization and once each at 6, 12, and 18 months after randomization, and then twice at the end of 24 months of study treatment. Adverse events were reported every 3 months at clinic visits or at interim periods when notified. Investigators checked for adherence but were unaware of treatment allocations.

38. Outcomes Primary outcome was annualized rate of change in maximum CIMT based on all scans performed during the 2-year study from each of the 12 carotid artery sites (near and far walls of the right and left common carotid artery, carotid bulb, and internal carotid artery). Secondary CIMT end points were annualized rate of change in maximum CIMT derived from the near and far walls of : the right and left common carotid artery, the right and left carotid bulb, the right and left internal carotid artery; and annualized rate of change in mean CIMT for the near and far walls of the right and left common carotid artery.

39. Statistics The study assumed statistically significant regression at 2 years, assuming a 2-sided level of statistical significant of 0.05, 80% power, and a mean (SD) decrease in CIMT of -0.0008mm/yr. 415 individuals were required for the rosuvastatin group. Sample size of 167 in the placebo group was calculated to provide > 90% power for the between-group comparison. 30% withdrawal rate was predicted.

40. Results 5751 individuals were screened and 984 were randomized. Rosuvastatin treatment was associated with a 49% reduction in LDL-C, a 34% reduction in total cholesterol, an 8% increase in HDL-C, and a 16% reduction in level of triglycerides Compared with placebo, rosuvastatin significantly slowed progression of the maximum CIMT for the 12 carotid sites (-0.0014 vs. +0.0131mm/yr)

41. Results In the placebo, there was a significant progression for the primary and secondary CIMT end points Significant progression was not observed in the rosuvastatin group for either the primary or secondary CIMT end points. The frequency of adverse events was similar between the treatment groups. ▫Myalgia was the most common event (12.7% vs. 12.1%) There was 1 death during the study but was not considered related to the treatment.

42. Results There were no cases of hepatitis, rhabdomyolysis, or renal failure. The frequency of proteinuria was low. Overall, the frequency of adverse renal effects was low and similar in both groups.

43. Discussion 40mg of rosuvastatin significantly slowed progression of atherosclerosis both overall and for individual carotid segments as assessed by CIMT measurements. Rosuvastatin lowered LDL-C by 48.8% and raised HDL- C by 8.0% compared to baseline. 40mg dose is not a starting dose but was chosen to provide the maximum efficacy expected to slow or delay progression of atherosclerosis The METEOR trial expands findings to asymptomatic patients who do not have meet the requirement for statin use but have evidence of subclinical carotid atherosclerosis

44. Discussion Low-risk individuals with only mild atherosclerosis were chosen to justify the use of a placebo group. The results show that rosuvastatin can have an effect on small increases of CIMT associated with early abnormalities of arterial structure. 40mg dose was well tolerated and showed a similar safety profile to that of placebo.

45. Conclusion In middle-aged adults with Framingham risk scores < 10% and evidence of subclinical atherosclerosis, rosuvastatin treatment results in statistically significant reductions in the rate of progression of maximum CIMT during a 2-year period compared with placebo. Larger, longer-duration randomized trials focused on clinical events are needed to determine the practice implications of these findings.

46. Comments Even though the study specifically looked at rosuvastatin, other statins in the class should possess the same effect but may be to a different extent. The study should compare different doses of rosuvastatin to help determine whether the maximum dose or aggressive therapy of statin will be needed to reduce the CIMT.

47. Seminarian’s Conclusion Statins are effective agents for primary and secondary prevention of cardiovascular events. In addition, statins also show reduction in all- cause mortality. Statins are relatively safe to use with low incidence of major adverse events.