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VOYAGER

VOYAGER. An indi V idual patient data meta-analysis O f statin therap Y in A t risk G roups: E ffects of R osuvastatin, atorvastatin and simvastatin. Please see slide 27 for prescribing information. VOYAGER. A unique Individual Patient Data Meta-analysis (of 32 258 patients)

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VOYAGER

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  1. VOYAGER An indiVidual patient data meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin Please see slide 27 for prescribing information

  2. VOYAGER • A unique Individual Patient Data Meta-analysis (of 32 258 patients) • Review of individual patient data from comparative randomised studies comparing rosuvastatin with either atorvastatin or simvastatin in high-risk populations • Studies were identified by a comprehensive search of the Cochrane Controlled Trials Registry, Medline, EMBASE, Citeline, Trialtrove, and collection of all published research on rosuvastatin. • 37 randomised comparative studies >4 weeks duration were identified as suitable for inclusion in the VOYAGER database, in which baseline and on-treatment lipids were recorded for each patient, as well as lab methods for determining these parameters • Integrated database of >30 000 patients

  3. VOYAGERWhole population and high-risk goal analysis Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

  4. Background • Statins are used widely to reduce cardiovascular risk in primary and secondary prevention • Consequently, treatment guidelines have been developed which take into account a patient’s estimated risk of cardiovascular disease • However, the incremental benefit of increasing statin dose on lipid levels and goal attainment has not been fully established Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

  5. Objectives • To use the VOYAGER individual patient data meta-analysis to explore relationships between increasing dose of rosuvastatin, atorvastatin and simvastatin, and the ability of these agents to • decrease the levels of atherogenic lipids • allow patients to achieve treatment goals Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

  6. Patient baseline characteristicsWhole population ApoB=apolipoprotein B; HDL-C=high-density lipoprotein cholesterol; IQR=interquartile range; LDL-C=low-density lipoprotein cholesterol; SD=standard deviation †Defined as established atherosclerotic disease, diabetes or atherogenic dyslipidaemia (TG ≥150 mg/dL or HDL-C <40 mg/dL) Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  7. Change in LDL-C levels with increasing dose of each statinResults from the whole population VOYAGER individual patient data meta-analysis Dose (log scale) Change in LDL-C from baseline (%) 5 mg 10 mg 20 mg 40 mg 80 mg -27(n=365) -33 (n=2929) -36(n= 7837) -39 (n=548) -39(n=670) -41#(n=3908) -45 (n=479) -44*(n=11690) -46(n=1324) -50##(n=2072) -50† (n=3554) -55‡(n=2983) *p<0.001 rosuvastatin 10 mg vs atorvastatin 10 mg and 20 mg; simvastatin 10 mg, 20 mg and 40 mg †p<0.001 rosuvastatin 20 mg vs atorvastatin 20 mg and 40 mg; simvastatin 20 mg ,40 mg and 80mg ‡p<0.001 rosuvastatin 40 mg vs atorvastatin 40 mg and 80 mg; simvastatin 40 mg and 80 mg #p<0.05 atorvastatin 20 mg vs rosuvastatin 5 mg ##p<0.05 atorvastatin 80 mg vs rosuvastatin 5 mg and 10 mg Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  8. Dosage n RSV 5 mg versus: *** ATV 10 mg 861 † ATV 20 mg 77 ATV 40 mg 80 ††† ATV 80 mg 79 RSV 10 mg versus: *** ATV 10 mg 17 295 *** ATV 20 mg 4583 ATV 40 mg 399 ††† ATV 80 mg 406 RSV 20 mg versus: *** 4624 ATV 20 mg *** ATV 40 mg 1316 1651 ATV 80 mg RSV 40 mg versus: *** 2182 ATV 40 mg *** ATV 80 mg 3358 -25 -20 -15 -10 -5 0 5 10 15 20 25 Difference between treatments in mean % change from baseline (95% CI) Effect of increasing statin dose on reduction of LDL-CResults from the whole population VOYAGER individual patient data meta-analysisrosuvastatin (RSV) versus atorvastatin (ATV) Favours rosuvastatin Favours atorvastatin ***p<0.001 vs ATV; †p<0.05 vs RSV; †††p<0.001 vs RSV Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

  9. Dosage n RSV 5 mg versus: SIM 10 mg 0 *** SIM 20 mg 489 SIM 40 mg 0 SIM 80 mg 0 RSV 10 mg versus: *** SIM 10 mg 321 *** SIM 20 mg 6001 *** SIM 40 mg 314 SIM 80 mg 319 RSV 20 mg versus: *** SIM 20 mg 1090 *** SIM 40 mg 1084 *** 323 SIM 80 mg RSV 40 mg versus: *** SIM 40 mg 315 *** SIM 80 mg 943 -25 -20 -15 -10 -5 0 5 10 15 20 25 Difference between treatments in mean % change from baseline (95% CI) Effect of increasing statin dose on reduction of LDL-CResults from the whole population VOYAGER individual patient data meta-analysisrosuvastatin (RSV) versus simvastatin (SIM) Favours rosuvastatin Favours simvastatin ***p<0.001 vs SIM Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

  10. High-risk patients achieving LDL-C goals <100 mg/dL, stratified according to baseline LDL-C levels ≤160mg/dL Baseline LDL-C level (mg/dL): <130 130–160 † † NA NA NA Dose (mg) Atorvastatin Simvastatin Rosuvastatin †Represents <10 patients. NA=no data available Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  11. High-risk patients with baseline LDL-C ≥160mg/dL achieving LDL-C goals <100 mg/dL Dose (mg) Atorvastatin Atorvastatin Simvastatin Simvastatin Rosuvastatin Rosuvastatin Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  12. High-risk patients achieving LDL-C goals <70 mg/dL, stratified according to baseline LDL-C levels ≤160 mg/dL Baseline LDL-C level (mg/dL): <130 130–160 Baseline LDL-C level (mg/dL): <130 130–160 † † † † NA 0 NA 0 NA 0 NA 0 NANA NA Dose (mg) Dose (mg) Atorvastatin Atorvastatin Simvastatin Simvastatin Rosuvastatin Rosuvastatin †Represents <10 patients. NA=no data available Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  13. High-risk patients with baseline LDL-C ≥160mg/dL achieving LDL-C goals <70 mg/dL 0 0 Dose (mg) Dose (mg) Atorvastatin Simvastatin Rosuvastatin Atorvastatin Simvastatin Rosuvastatin Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  14. Dosage n RSV 5 mg versus: *** ATV 10 mg 864 † ATV 20 mg 77 ATV 40 mg 80 ††† ATV 80 mg 79 RSV 10 mg versus: *** ATV 10 mg 17 355 *** ATV 20 mg 4590 ATV 40 mg 399 ††† ATV 80 mg 406 RSV 20 mg versus: *** ATV 20 mg 4635 *** 1317 ATV 40 mg ATV 80 mg 1651 RSV 40 mg versus: *** 2182 ATV 40 mg *** ATV 80 mg 3362 -25 -20 -15 -10 -5 0 5 10 15 20 25 Difference between treatments in mean % change from baseline (95% CI) Effect of increasing statin dose on reduction of nonHDL-CResults from the whole population VOYAGER individual patient data meta-analysisrosuvastatin (RSV) versus atorvastatin (ATV) Favours rosuvastatin Favours atorvastatin ***p<0.001 vs ATV; †p<0.05 vs RSV; †††p<0.001 vs RSV Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

  15. Change in nonHDL-C levels with increasing dose of each statin Rosuvastatin Rosuvastatin Atorvastatin Atorvastatin Simvastatin Simvastatin Dose (mg) Dose (mg) 5 5 80 80 80 80 10 10 10 10 20 20 40 40 20 20 40 40 10 10 20 20 40 40 *** ‡ *** ††† *** ††† *** ***p<0.001 rosuvastatin vs equivalent or double dose of atorvastatin and simvastatin and rosuvastatin 10 mg vs simvastatin 40 mg and rosuvastatin 20 mg vs simvastatin 80 mg; ‡p<0.05 atorvastatin 20 mg vs rosuvastatin 5 mg; †††p<0.001 atorvastatin 80 mg vs rosuvastatin 5 mg and rosuvastatin 10 mg Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  16. Dosage n RSV 5 mg versus: SIM 10 mg 0 *** SIM 20 mg 491 SIM 40 mg 0 SIM 80 mg 0 RSV 10 mg versus: *** SIM 10 mg 321 *** SIM 20 mg 5992 *** SIM 40 mg 314 SIM 80 mg 319 RSV 20 mg versus: *** SIM 20 mg 1091 *** SIM 40 mg 1090 *** 323 SIM 80 mg RSV 40 mg versus: *** SIM 40 mg 315 *** SIM 80 mg 944 -25 -20 -15 -10 -5 0 5 10 15 20 25 Difference between treatments in mean % change from baseline (95% CI) Effect of increasing statin dose on reduction of nonHDL-CResults from the whole population VOYAGER individual patient data meta-analysisrosuvastatin (RSV) versus simvastatin (SIM) Favours rosuvastatin Favours simvastatin ***p<0.001 vs SIM Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

  17. High-risk patients achieving nonHDL-C levels <130 mg/dL, stratified according to baseline levels Baseline nonHDL-C level (mg/dL): <160 160-190 ≥190 † NA NA NA Dose (mg) Simvastatin Rosuvastatin Atorvastatin Atorvastatin Simvastatin Rosuvastatin Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  18. Rosuvastatin Atorvastatin Simvastatin 5 80 80 10 10 20 40 20 40 10 20 40 Change in TG levels with increasing dose of each statinResults from the whole population VOYAGER individual patient data meta-analysis Dose (mg) Dose (mg) *** *** § *** † ¶ *** § *** † ¶ *** †‡ # †‡ # ***p<0.001 rosuvastatin 10 mg vs atorvastatin 10 mg and simvastatin 20 mg, rosuvastatin 20 mg vs simvastatin 20 and 40 mg and rosuvastatin 40 mg vs simvastatin 40 and 80 mg; §p<0.01 rosuvastatin 10 mg vs simvastatin 10 mg; ¶p<0.05 rosuvastatin 20 mg vs simvastatin 80 mg; †p<0.05 atorvastatin 80 mg vs rosuvastatin 5 mg and 40 mg and atorvastatin 40 mg vs rosuvastatin 10 mg; ‡p<0.01 atorvastatin 80 mg vs rosuvastatin 10 mg; #p<0.001 atorvastatin 80 mg vs rosuvastatin 20 mg Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  19. RSV 5 mg versus: ATV 10 mg 864 ATV 20 mg 77 ATV 40 mg 80 † ATV 80 mg 79 RSV 10 mg versus: *** ATV 10 mg 17 355 ATV 20 mg 4591 † ATV 40 mg 399 †† ATV 80 mg 407 RSV 20 mg versus: ATV 20 mg 4636 1317 ATV 40 mg ††† ATV 80 mg 1650 RSV 40 mg versus: 2182 ATV 40 mg † ATV 80 mg 3362 -25 -20 -15 -10 -5 0 5 10 15 20 25 Difference between treatments in mean % change from baseline (95% CI) Effect of increasing statin dose on reduction of TGResults from the whole population VOYAGER individual patient data meta-analysisrosuvastatin (RSV) versus atorvastatin (ATV) n Dosage Favours rosuvastatin Favours atorvastatin ***p<0.001 vs ATV; †p<0.05 vs RSV; ††p<0.01 vs RSV; †††p<0.001 vs RSV Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

  20. RSV 5 mg versus: SIM 10 mg 0 SIM 20 mg 491 SIM 40 mg 0 SIM 80 mg 0 RSV 10 mg versus: ** SIM 10 mg 321 *** SIM 20 mg 6014 SIM 40 mg 314 SIM 80 mg 319 RSV 20 mg versus: *** SIM 20 mg 1091 *** SIM 40 mg 1091 * 323 SIM 80 mg RSV 40 mg versus: *** SIM 40 mg 315 *** SIM 80 mg 944 -25 -20 -15 -10 -5 0 5 10 15 20 25 Difference between treatments in mean % change from baseline (95% CI) Effect of increasing statin dose on reduction of TGResults from the whole population VOYAGER individual patient data meta-analysisrosuvastatin (RSV) versus simvastatin (SIM) Dosage n Favours rosuvastatin Favours simvastatin *p<0.05 vs SIM; **p<0.01 vs SIM; ***p<0.001 vs SIM Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

  21. High-risk patients achieving TG levels <150 mg/dL, stratified according to baseline TG levels Baseline TG level (mg/dL): <200 200-300 >300 Baseline TG level (mg/dL): <200 200-300 >300 † 0 0 † 0 0 Dose (mg) Dose (mg) Atorvastatin Simvastatin Rosuvastatin Atorvastatin Simvastatin Rosuvastatin †Represents less than 10 patients Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  22. Rosuvastatin Rosuvastatin Atorvastatin Atorvastatin Simvastatin Simvastatin Dose (mg) Dose (mg) 5 5 80 80 80 80 10 10 10 10 20 20 40 40 20 20 40 40 10 10 20 20 40 40 Change in ApoB levels with increasing dose of each statinResults from the whole population VOYAGER individual patient data meta-analysis *** *** *** *** *** †††‡ *** *** †††‡ *** ***p<0.001 rosuvastatin vs equivalent or double doses of atorvastatin or simvastatin, except rosuvastatin 10 mg vs atorvastatin 20 mg (p<0.01) and p<0.001 rosuvastatin 10 mg vs simvastatin 40 mg and rosuvastatin 20 mg vs simvastatin 80 mg; †††p<0.001 atorvastatin 80 mg vs rosuvastatin 5 mg and 10 mg; ‡p<0.01 atorvastatin 80 mg vs rosuvastatin 20 mg. ApoB levels were determined in 24 340 (75.5%) of patients only Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  23. Dosage n RSV 5 mg versus: *** ATV 10 mg 833 ATV 20 mg 76 ATV 40 mg 79 ††† ATV 80 mg 76 RSV 10 mg versus: *** ATV 10 mg 7631 ** ATV 20 mg 4436 ATV 40 mg 370 ††† ATV 80 mg 379 RSV 20 mg versus: *** ATV 20 mg 3905 *** 1251 ATV 40 mg †† ATV 80 mg 1562 RSV 40 mg versus: *** 1542 ATV 40 mg *** ATV 80 mg 3230 -25 -20 -15 -10 -5 0 5 10 15 20 25 Difference between treatments in mean % change from baseline (95% CI) Effect of increasing statin dose on reduction of ApoBResults from the whole population VOYAGER individual patient data meta-analysisrosuvastatin (RSV) versus atorvastatin (ATV) Favours rosuvastatin Favours atorvastatin **p<0.01 vs ATV; ***p<0.001 vs ATV; ††p<0.01 vs RSV; †††p<0.001 vs RSV Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

  24. Dosage n RSV 5 mg versus: SIM 10 mg 0 *** SIM 20 mg 469 SIM 40 mg 0 SIM 80 mg 0 RSV 10 mg versus: *** SIM 10 mg 300 *** SIM 20 mg 1824 *** SIM 40 mg 291 SIM 80 mg 296 RSV 20 mg versus: *** SIM 20 mg 1052 *** SIM 40 mg 1049 *** 295 SIM 80 mg RSV 40 mg versus: *** SIM 40 mg 293 *** SIM 80 mg 888 -25 -20 -15 -10 -5 0 5 10 15 20 25 Difference between treatments in mean % change from baseline (95% CI) Effect of increasing statin dose on reduction of ApoBResults from the whole population VOYAGER individual patient data meta-analysisrosuvastatin (RSV) versus simvastatin (SIM) Favours rosuvastatin Favours simvastatin ***p<0.001 vs SIM Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Reprinted by permission from Elsevier Inc.

  25. High-risk patients achieving ApoB levels <90 mg/dL, stratified according to baseline levels Baseline ApoB level (mg/dL): <120 120-150 >150 † † NA NA † NA 0 Dose (mg) Dose (mg) Atorvastatin Rosuvastatin Rosuvastatin †Represents <10 patients. NA=no data available Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 Adapted by permission from Elsevier Inc.

  26. Conclusions • Increasing the dose of rosuvastatin, atorvastatin and simvastatin resulted in incremental greater reductions in atherogenic lipids and allowed patients to achieve treatment goals • The VOYAGER large individual patient database of more than 32 000 patients highlights the importance of choice of statin and dose when selecting treatment Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

  27. CRESTOR (rosuvastatin) adverse events Undesirable effects (refer to the SmPC for a full list of side effects): Side effects most frequently reported in controlled clinical studies and post marketing experience: headache, dizziness, constipation, nausea, abdominal pain, myalgia, asthenia, and diabetes mellitus in patients with fasting glucose 5.6–6.9 mmol/L. Rarely: myopathy (including myositis), rhabdomyolysis with or without acute renal failure, hypersensitivity reactions including angioedema, pancreatitis. Very rarely: arthralgia, jaundice, hepatitis, polyneuropathy, haematuria, memory loss. Unknown frequency: diarrhoea, Stevens-Johnson syndrome. Other usually transient side effects: elevations in transaminases and CK levels, proteinuria. The following side effects have been reported with some statins: depression, sleep disturbances, sexual dysfunction and in exceptional cases, interstitial lung disease. MARKETING AUTHORISATION HOLDER:AstraZeneca UK Ltd., 600 Capability Green, Luton LU1 3LU United Kingdom. Telephone: +44 (0)1582 836 000 Fax: +44 (0)1582 838 000. Medical Information Direct Line: +44 (0)1582 836 836 Medical Information e-mail: medical.informationuk@astrazeneca.com Licensed from Shionogi & Co. Ltd., Osaka, Japan. Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to AstraZeneca on 0800 783 0033.

  28. CRESTOR™ (rosuvastatin) Summary of Product CharacteristicsFebruary 2011 Click on the icon below to access the Summary of Product Characteristics. Consult full prescribing information for CRESTOR before prescribing. CRESTOR exhibition VOYAGER non EU ppt, 2011 CRESTOR is a trademark of the AstraZeneca group of companies

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