Astra Zeneca :Výzkum v metabolismu Aktuality a perspektivy Dr Asri Benkritly

CRESTOR® : nová data Ve světě : Ve Francii : Schválený k léčbě v 70 zemích, komerčně užitý v 56 zemích Za období 26 měsíců 5.2 millionů léčených pacientů 20 milionů předpisů 46 000 pacientů zařazených do klinických studií Ve Francii : více než 350 000 léčených pacientů

Change in LDL-C from baseline (%) Rosuvastatin 10 mg versus Atorvastatin 10 mg Dlouhodobé lepší snížení LDL-C 6 weeks 6 weeks 8 weeks 8 weeks 12 weeks 12 weeks STELLAR STELLAR MERCURY I MERCURY I Pooled data Pooled data Change in LDL-C from baseline (%) Jones Schuster Davidson Schwartz Olsson Blasetto –10 n=156 n=158 n=158 n=539 n=539 n=529 n=529 n=529 n=529 n=129 n=129 n=127 n=127 n=128 n=128 n=127 n=127 n=132 n=132 n=139 n=139 n=389 n=389 n=393 n=393 –20 –30 –35 –35 –37 –37 –36 –39 –40 –43 –46 –47 * –47 –47 –50 –50 * * * * Rosuvastatin 10 mg has consistently been shown to be superior to atorvastatin 10 mg at lowering LDL-C in a number of different trials in different countries and patient settings. This greater low dose efficacy offers a clear advantage to rosuvastatin in terms of getting patients to goal simply and reducing the need to titrate to higher doses. References Jones PH et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial) Am J Cardiol 2003;92:152–160 Schuster H et al. Effect of switching to rosuvastatin from atorvastatin or other statins on achievement of international low-density lipoprotein cholesterol goals: MERCURY I trial. Am Heart J 2004;147:705-712 Davidson M et al. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol 2002;89:268–275 Schwartz GG et al. Efficacy and safety of rosuvastatin and atorvastatin in patients with hypercholesterolemia and a high risk of coronary heart disease: a randomized, controlled trial. Am Heart J 2004:148:e4:H1-H9 Olsson AG et al. Effect of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Am Heart J 2002;144:1044–1051 Blasetto JW et al. Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. Am J Cardiol 2003;91(Suppl):3C–10C * –60 *p<0.001 vs atorvastatin Jones PH et al. Am J Cardiol 2003;92:152–160 Schuster H et al. Am Heart J 2004; 147: 705-712 Davidson M et al. Am J Cardiol 2002;89:268–75 Schwartz G et al. Am Heart J 2004: 148:e4:H1-H9 Olsson AG et al. Am Heart J 2002;144:1044–51 Blasetto JW et al. Am J Cardiol 2003;91(Suppl):3C–10C Rosuvastatin 10 mg Atorvastatin 10 mg

Rosuvastatin 10 mg versus Atorvastatin 20 mg Poskytuje větší snížení LDL-C 6 weeks 8 weeks STELLAR Jones MERCURY I Schuster Jukema Franken Change in LDL-C from baseline (%) n=156 n=155 n=230 n=231 n=128 n=131 n=539 n=925 -10 -20 -30 -38 -40 -41 -43 -44 -46 -46 -44 -47 Additionally, rosuvastatin 10 mg has also been shown to lower LDL-C to a significantly greater extent than atorvastatin 20 mg in a number of different trials in different countries and patient settings. This greater low dose efficacy offers a clear advantage to rosuvastatin in terms of getting patients to their LDL-C goal simply and reducing the need to titrate to higher doses. References Jones PH et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial) Am J Cardiol 2003;92:152–160 Jukema J et al. LDL/HDL-C ratio in patients with coronary artery disease and low HDL-C: the RADAR study. Atherosclerosis Supplements 2004;5(1):125 Abs M.542 Franken A et al. Cholesterol-lowering effects of rosuvastatin compared with atorvastatin in patients with type 2 diabetes, Atherosclerosis Supplements 2004;5(1):118 Abs M.513 Schuster H et al. Effect of switching to rosuvastatin from atorvastatin or other statins on achievement of international low-density lipoprotein cholesterol goals: MERCURY I trial. Am Heart J 2004;147:705-712 ns * -50 * ** Rosuvastatin 10 mg Atorvastatin 20 mg -60 *p<0.05, **p<0.0001 vs atorvastatin 20 mg Jones PH et al. Am J Cardiol 2003;92:152–160. Schuster H et al. Am Heart J 2004;147:705–712. Franken A et al. Atherosclerosis Supplements 2004; 5 (1): 118 Abs M.513. Jukema J et al. Atherosclerosis Supplements 2004; 5 (1): 125 Abs M.542.

Rosuvastatin versus Atorvastatin Změny v HDL-C The STELLAR Study Change in HDL-C from baseline (%) 12 Rosuvastatin Atorvastatin * † 10 ns n=473 8 6 4 2 n=634 Data from STELLAR demonstrates that rosuvastatin produces a significant HDL-C raising effect which is maintained across the dose range, in contrast to atorvastatin where the HDL-C raising effect diminishes with increasing dose1. In practice, this means that increasing the atorvastatin dose to achieve the same level of LDL-C reduction as rosuvastatin will result in less favourable effect on HDL-C. rosuvastatin 10 mg raised HDL-C statistically significantly more than pravastatin 10 mg (p<0.002). rosuvastatin 20 mg raised HDL-C statistically significantly more than atorvastatin 20, 40 and 80 mg, simvastatin 40 mg, and pravastatin 20, 40 mg (p<0.002). rosuvastatin 40 mg raised HDL-C statistically significantly more than atorvastatin 40 and 80 mg, simvastatin 40 mg, and pravastatin 40 mg (p<0.002). Mean baseline HDL-C for rosuvastatin group: 51 mg/dL. Remember that the NCEP Expert Panel have estimated, based on data from epidemiology studies as well as intervention studies, that every 1% increase in HDL-C equates to a 3% reduction in CHD risk2. References Jones PH et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial) Am J Cardiol 2003;92:152–160 Third report of the NCEP expert panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm Adapted from Am J Cardiol 2003;92:152-160 with permission from Excerpta Medica Inc. 10 20 40 80 Dose (mg); log scale *p<0.002 vs atorvastatin 20, 40 and 80 mg †p<0.002 vs atorvastatin 40 and 80 mg Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin versus ostatní statiny Změny v HDL-C The STELLAR Study Change in HDL-C from baseline (%) Rosuvastatin 2 4 6 8 10 12 Atorvastatin † 9.5 Simvastatin ‡ 9.6 Pravastatin * 7.7 5.3 6.0 5.2 6.8 5.7 4.8 4.4 2.1 3.2 4.4 5.6 The HDL-C raising efficacy of rosuvastatin also compares very favourably with that of simvastatin and pravastatin. Rosuvastatin resulted in a statistically significant greater increase in HDL-C compared with atorvastatin for rosuvastatin 20-mg and 40-mg-dose comparisons (p<0.002). rosuvastatin 10 mg raised HDL-C statistically significantly more than pravastatin 10 mg (p<0.002). rosuvastatin 20 mg raised HDL-C statistically significantly more than atorvastatin 20, 40 and 80 mg, simvastatin 40 mg, and pravastatin 20, 40 mg (p<0.002). rosuvastatin 40 mg raised HDL-C statistically significantly more than atorvastatin 40 and 80 mg, simvastatin 40 mg, and pravastatin 40 mg (p<0.002). Mean baseline HDL-C for rosuvastatin group: 51 mg/dL. Reference 1. Jones PH et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92:152–160 Adapted from Am J Cardiol 2003;92:152-160 with permission from Excerpta Medica Inc. 10 20 40 10 20 40 80 10 20 40 80 10 20 40 Dose (mg) *p<0.002 vs pravastatin 10 mg †p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg ‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mg Observed data in ITT population Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin versus ostatní statiny Dosažení cílových hladin LDL-C různými dávkami Patients achieving NCEP ATP III LDL-C goals# Rosuvastatin 100 Atorvastatin † ‡ 89% 89% Simvastatin * 85% Pravastatin 82% 82% 82% 80 75% 69% 66% 63% 60 Patients achieving their NCEP ATP III LDL-C goals (%) 55% 51% 44% 40 31% 20 Additionally, data from STELLAR demonstrates the greater efficacy of rosuvastatin in bringing patients to their NCEP ATP III LDL-C goals compared to the same and some higher doses of atorvastatin, simvastatin and pravastatin. Reference 1. Jones PH et al for the STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial) Am J Cardiol 2003;92:152–160 Adapted from Am J Cardiol 2003;92:152-160 with permission from Excerpta Medica Inc. n=156 n=160 n=157 n=158 n=155 n=156 n=165 n=165 n=162 n=158 n=163 n=160 n=164 n=161 10mg 20mg 40mg 10mg 20mg 40mg 80mg 10mg 20mg 40mg 80mg 10mg 20mg 40mg #LDL-C goal <100mg/dl for high-risk; <130 for medium risk & <160 for low-risk patients *p<0.002 vs. simvastatin 10 mg and 20 mg; pravastatin 10 mg, 20 mg and 40 mg †p<0.002 vs. atorvastatin 20 mg, simvastatin 20mg and 40 mg; pravastatin 20 mg and 40 mg ‡p<0.002 vs. simvastatin 40 mg and pravastatin 40 mg Jones PH et al. Am J Cardiol 2003;92:152–160

Rosuvastatin versus Atorvastatin Dosažení cílových hladin LDL-C nízkými dávkami Rosuvastatin 10 mg vs atorvastatin 10 and 20 mg; patients achieving NCEP ATP III LDL-C goals‡ 100 Rosuvastatin 10 mg # Atorvastatin 10 mg 80 * 80% Atorvastatin 20 mg 76% 74% * 60 63% Patients achieving NCEP ATP III LDL-C goals (%) 60% 53% 40 20 19% In a pooled analysis of three 12-week studies, rosuvastatin 10 mg enabled significantly more patients to achieve their NCEP ATP III LDL-C goal than atorvastatin 10 mg (76% vs. 53%, p<0.001),1 thus reducing the need for titration to higher doses to achieve LDL-C goal with rosuvastatin. The superiority of rosuvastatin 10 mg over atorvastatin 10 mg was confirmed in MERCURY I. In this study, significantly more patients achieved their NCEP ATP III LDL-C goal when treated with rosuvastatin 10 mg than with atorvastatin 20 mg (80% vs. 74%, p<0.01).2 In patients with documented atherosclerosis or Type 2 diabetes who have a more challenging NCEP ATP III LDL-C goal of <100 mg/dL (<2.6 mmol/L), the superiority of rosuvastatin 10 mg over atorvastatin 10 mg was particularly marked (60% vs. 19%, p<0.001).1 References Shepherd J, Hunninghake DB, Barter B et al. Am J Cardiol 2003;91(Suppl):11C–19C. 2. Schuster H, Barter PJ, Stender S et al. Am Heart J 2004;147:705–712. Reproduced from Eur Heart J Suppl 2004;6(suppl A): A12-A18 with permission from the European Society of Cardiology. n=189 n=539 n=529 n=925 n=389 n=393 n=199 n=196 All patients All patients Patients with established CVD or type 2 diabetes 8 weeks MERCURY I Schuster1 12 weeks Pooled data Shepherd2 #LDL-C goal <100mg/dl for high-risk; <130 for medium risk & <160 for low-risk patients #p<0.001 vs atorvastatin 10mg & 20mg; *p<0.001 vs atorvastatin 10mg 1. Schuster H et al. Am Heart J 2004;147:705-712 2. Shepherd J et al. Am J Cardiol 2003;91(Suppl):11c-19c

Rosuvastatin vs Simvastatin a Pravastatin Dosažení cílových hladin LDL-C nízkými dávkami Rosuvastatin 10 mg vs simvastatin 20 mg and pravastatin 20 & 40 mg; patients achieving NCEP ATP III LDL-C goals# 100 Rosuvastatin * † Simvastatin 80 86% Pravastatin 80% * 60 64% 63% Percentage of patients reaching NCEP ATP III LDL-C goal (%) 54% 49% 40 45% 20 22% 5% Similarly, data from the MERCURY I study and pooled data from two comparative phase III studies clearly demonstrate the advantage of rosuvastatin 10 mg in bringing patients to their NCEP ATP III goals compared to simvastatin 20 mg and pravastatin 20 and 40 mg. References 1 Kritharides L. Reducing low-density lipoprotein cholesterol – treating to target and meeting new European goals. Eur Heart J Suppl 2004;6(Suppl A):A12-A18. 2 Schuster H, Fox J, Investigating cardiovascular risk reduction – the Rosuvastatin GALAXY Programme. Exp Opin Pharmacother 2004;5 (5):1187-1200 Reproduced from Eur Heart J Suppl 2004;6(suppl A): A12-A18 with permission from the European Society of Cardiology. 10mg 20mg 40mg 10mg 20mg 20mg 10mg 20mg 20mg n=538 n=543 n=521 n=226 n=249 n=252 n=64 n=86 n=74 All patients All patients Patients with CVD or type 2 diabetes 8 weeks MERCURY I Schuster1 12 weeks Pooled data Kritharides2 #LDL-C goal <100mg/dl for high-risk; <130 for medium risk & <160 for low-risk patients †p<0.001 vs simvastatin 20 mg & pravastatin 40 mg; *p<0.001 vs simvastatin 20 mg & pravastatin 20 mg 1. Schuster H & Fox J. Exp Opin Pharmacother 2004;5:1187-1200 2. Kritharides L. Eur Heart J Suppl 2004;6(Suppl A):A12-A18

Průměrné změny v hladinách CRP ve studii ANDROMEDA 8 weeks 16 weeks RSV 10 mg ATV 10 mg RSV 20 mg ATV 20 mg n=240 n=240 n=227 n=229 Median change from Baseline in hsCRP (%) -21.2 -34.0 -33.8 -39.8 RSV= rosuvastatin; ATV=atorvastatin; hsCRP=high sensitivity C-reactive protein Rosuvastatin highlight – American Heart Association (AHA) Congress New Orleans, USA 7-10 november 2004

Názor kategorizační komise Crestor 2 únor 2005 Analýza dat o snášenlivosti Crestoru od 1,5 milionu pacientů. Tolerance svalová : případy rhabdomyolyse jsou závislé na dávce a jsou nejčastěji pozorovány při dávce 40 mg.Všechny(43) byly vratné. Tolerance renální : Proteinurie: nízká frekvence výskytu ( 1% na dávce 10 et 20 mg Crestoru a 1,2% na dávce 40 mg Crestoru ) a ve stejném rozsahu jako u ostatních statinů a placeba. « obecná tolerance rosuvastatinu 10 a 20mg se neliší od ostatních statinů »

Názor kategorizační komise Crestor 2 únor 2005 Role v terapeutické strategii « v dnes dostupných studiích prokázal rosuvastatin efekt na redukci LDL-c bez projevů v morbi-mortalitě Měl by být tedy užíván jako lék druhé linie u pacientů nedosahujících terapeutické cíle při léčba ostatními statiny v obvyklém dávkování »

Zpráva FDA CRESTOR (2 březen 2005)* Zpráva o datech z klinických studií a z post-komerčního sledování vydaná FDA o léku CRESTOR (1.5 M pac) uvádí, že: Svaly : riziko rhabdomyolýzy není u CRESTORu vyšší než u ostatních statinů Ledviny : pacienti u kterých uvažujeme o léčbě statiny (diabetici, hypertonici, pac.se srdečním selháním ad.)jsou více rizikoví z renální insuficience bez ohledu na léčbu statiny * FDA Public health advisory for Crestor, 2005

Rosuvastatin- bezpečnost případy rhabdomyolýzy při léčbě statiny Semiannual Reporting Rates for All Reports of Rhabdomyolysis US Cases* Worldwide Cases‡ Rosuvastatin Cerivastatin 120 80 100 120 60 40 20 -20 † Fluvastatin 100 Atorvastatin Lovastatin 80 Pravastatin Reporting Rate Per 1,000,000 US Prescriptions ** Simvastatin 60 Reporting Rate Per 1,000,000 rosuvastatin prescriptions worldwide‡ Ezetimibe 40 Rosuvastatin AZ global database ‡ 20 UPDATED VERSION 17 MARCH 2005 Key Point: Postmarketing surveillance clearly demonstrates that the rate of rhabdomyolysis for rosuvastatin is in line with to that for other currently marketed statins. Rhabdomyolysis is an expected adverse event that occurs with all marketed statins,1 and rare cases with acute renal failure secondary to myoglobinuria have been reported with rosuvastatin and other drugs in this class.2 To address concerns of rhabdomyolysis with rosuvastatin, a comparison of postmarketing data for rosuvastatin, other statins and ezetimibe was performed. Data for comparator statins and ezetimibe were obtained from the Federal Drug Administration (FDA) Adverse Event Reporting System (AERS), available to the public through the Freedom of Information Act (FOI); these data are presented on the left hand side of this chart, reported as semiannual rates from 1999 up to August 2004. US prescription data obtained from the IMS were used to calculate the reporting rate of rhabdomyolysis per 1,000,000 prescriptions. The addition of rosuvastatin data to the FDA database has only recently started and currently is too limited to allow a semi-annual rate trend to be plotted. The left hand side of the above chart does not therefore include rosuvastatin data. However, data relating to worldwide spontaneous reports up to and including February 2005 is held within the internal global safety database of AstraZeneca and for completeness, the right hand side of this chart presents data from this database as a semi-annual reporting rate (calculated by dividing the worldwide spontaneous reports of rhabdomyolysis by the number of worldwide prescriptions for rosuvastatin). This worldwide data, which covers the time frame from March 2003 to the end of February 2005, therefore represents the most up to date and comprehensive information for rosuvastatin available. As shown here, the worldwide semiannual reporting rate for rosuvastatin was in line with the reporting rates of other statins. This is particularly noteworthy because new drugs are expected to have higher reporting rates of adverse events in their first year of launch.3 As clearly depicted on the slide, the reporting rate of rhabdomyolysis for cerivastatin was much higher compared with the other currently marketed statins. The increase in reporting rate of rhabdomyolysis with cerivastatin over the time period shown may be due in part to the US launch of higher doses - cerivastatin 0.4 mg in May 1999 and subsequently 0.8 mg in July 2000. The increase in reporting rate of rhabdomyolysis was clearly seen within 1 year of the launch of these higher doses. It is important to note that this type of analysis has the following limitations: The FDA AERS safety reports are spontaneous, not fully investigated, and do not imply a causal relationship; spontaneous reporting rates are likely to be lower than the actual incidence of adverse events due to underreporting; the spontaneous reporting rates of rhabdomyolysis for rosuvastatin, other comparator statins and ezetimibe do not represent head-to-head comparative studies and must be interpreted with caution; and the use of reporting rates as proxy measures of risk also has the limitation of secular trends.4 References 1. Pasternak RCD, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:568-573. 2. CRESTOR® (rosuvastatin calcium) Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2003. 3. Weber JCP. Epidemiology of adverse reactions to nonsteroidal anti-inflammatory drugs. In: Rainsford KD, Velo GP, eds. Advances in Inflammation Research. Vol. 6. New York, NY: Raven Press;1984:1-7. 4. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539-540. 03/99- 09/99- 03/00- 09/00- 03/01- 09/01- 03/02- 09/02- 03/03- 09/03- 03/04- 03/03- 09/03- 03/04- 09/04- 08/99 02/00 08/00 02/01 08/01 02/02 08/02 02/03 08/03 02/04 08/04 08/03 02/04 08/04 02/05 *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 2004. †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 February 2005. 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: 17 March 2005

Rosuvastatin-bezpečnost; hlášení fatální rhabdomyolýze při terapii statiny Semiannual Reporting Rates for All Reports of Fatal Rhabdomyolysis US Cases* Worldwide Cases‡ Reporting Rate Per 1,000,000 rosuvastatin prescriptions worldwide‡ 15 20 25 10 5 Rosuvastatin Cerivastatin 25 † Fluvastatin Atorvastatin 20 Lovastatin 15 Pravastatin Reporting Rate Per 1,000,000 US Prescriptions ** Simvastatin 10 Ezetimibe Rosuvastatin AZ global database ‡ 5 UPDATED VERSION 17 MARCH 2005 This slide depicts the reporting rates of fatal rhabdomyolysis observed with statin therapy and ezetimibe. Data for comparator statins and ezetimibe were obtained from the Federal Drug Administration (FDA) Adverse Event Reporting System (AERS), available to the public through the Freedom of Information Act (FOI); these data are presented on the left hand side of this chart, reported as semiannual rates from 1999 up to August 2004. US prescription data obtained from the IMS were used to calculate the reporting rate of fatal rhabdomyolysis per 1,000,000 prescriptions. The addition of rosuvastatin data to the FDA database has only recently started and currently is too limited to allow a semi-annual rate trend to be plotted. The left hand side of the above chart does not therefore include rosuvastatin data. However, data relating to worldwide spontaneous reports up to and including February 2005 is held within the internal global safety database of AstraZeneca and for completeness, the right hand side of this chart presents data from this database as a semi-annual reporting rate (calculated by dividing the worldwide spontaneous reports of fatal rhabdomyolysis by the number of worldwide prescriptions for rosuvastatin). This worldwide data, which covers the time frame from March 2003 to the end of February 2005, therefore represents the most up to date and comprehensive information for rosuvastatin available. The expected rate of rhabdomyolysis related fatalities for the statin class is 1/1,000,000. Thus, the actual rate observed with rosuvastatin in this analysis is below that anticipated. This is particularly noteworthy because new drugs are expected to have higher reporting rates of adverse events in their first year of launch.1 The increase in reporting rate of fatal rhabdomyolysis with cerivastatin over the time period shown may be due in part to the US launch of higher doses - cerivastatin 0.4 mg in May 1999 and subsequently 0.8 mg in July 2000. The increase in reporting rate of fatal rhabdomyolysis was clearly seen within 1 year of the launch of these higher doses. It may be noted that the FDA data appears to show a rosuvastatin related case of fatal rhabdomyolysis in the period 09/03 to 02/04. Although initially reported as a case of fatal rhabdomyolysis (and hence listed as a report within the FDA database) subsequent post-mortem confirmed that the cause of death was myocardial infarction unrelated to the use of rosuvastatin. It is important to note that this type of analysis has the following limitations: The FDA AERS safety reports are spontaneous, not fully investigated, and do not imply a causal relationship; spontaneous reporting rates are likely to be lower than the actual incidence of adverse events due to underreporting; the spontaneous reporting rates of rhabdomyolysis for rosuvastatin, other comparator statins and ezetimibe do not represent head-to-head comparative studies and must be interpreted with caution; and the use of reporting rates as proxy measures of risk also has the limitation of secular trends.2 References 1. Weber JCP. Epidemiology of adverse reactions to nonsteroidal anti-inflammatory drugs. In: Rainsford KD, Velo GP, eds. Advances in Inflammation Research. Vol. 6. New York, NY: Raven Press;1984:1-7. 2. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539-540. 3. Chang JT, Staffa JA, Parks M, Green L. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiology and drug safety 2004;13:417-426. -5 03/99- 09/99- 03/00- 09/00- 03/01- 09/01- 03/02- 09/02- 03/03- 09/03- 03/04- 03/03- 09/03- 03/04- 09/04- 08/99 02/00 08/00 02/01 08/01 02/02 08/02 02/03 08/03 02/04 08/04 08/03 02/04 08/04 02/05 *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 2004. †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 February 2005. Total prescriptions based on IMS data from US, Canada, UK, France, Italy and The Netherlands; rest of world prescriptions based on actual sales calculations. Approximately 10% of cases of rhabdomyolysis for all statins are fatal (Chang et al 2004) Update: 17 March 2005

Rosuvastatin : The GALAXY mission Atherogenic lipid profile +/- inflammatory markers Atherosclerosis Reduction in CV morbidity & mortality METEOR ASTEROID ORION AURORA CORONA GISSI-HF JUPITER MERCURY I STELLAR MERCURY II ORBITAL DISCOVERY COMETS LUNAR PLUTO The studies in the GALAXY Programme are designed to confirm each step in the hypothesis. These are currently: Studies designed to investigate the effect of Rosuvastatine on the ‘atherogenic lipid profile’ are STELLAR, MERCURY I, MERCURY II, ORBITAL, DISCOVERY, COMETS, LUNAR and PLUTO. Two of these studies, COMETS and LUNAR also assess the effects of Rosuvastatine on inflammatory markers.   Studies designed to investigate the effect of Rosuvastatine on ‘atherosclerosis’ are METEOR, ASTEROID and ORION. Studies designed to investigate the effect of Rosuvastatine on ‘cardiovascular morbidity and mortality’ are AURORA, CORONA and JUPITER. The GALAXY Programme currently includes 16 clinical studies. However, as the GALAXY Programme is constantly evolving new studies will be included as the statin environment changes, research needs dictate and the clinical development of Rosuvastatine continues.

Zahrnuto 49 000 pacientů

Studie o ateroskleróze Outcome of Rosuvastatin Treatment on Carotid Artery Atheroma: a Magnetic Resonance Imaging ObservatioN Měření změn velikosti aterosklerotického plátu na karotidě pomocí MR u asymptomatických pacientů s hypercholesterolémií léčených 5mg rosuvastatinu nebo 40 mg rosuvastatinu. Core slide The early detection of atherosclerosis allows more effective targeting of preventive intervention. Magnetic resonance imaging (MRI) is a non-invasive technique that permits the quantification of atherosclerotic lesion size and the identification of plaque characteristics (Zhao et al 2001). In a study of asymptomatic patients with hypercholesterolaemia, the vascular effects of statin treatment have been monitored using MRI (Corti et al 2001). After 12 months’ treatment, significant reductions in vessel wall thickness and vessel wall area were observed (Corti et al 2001). The primary objective is to measure the change in carotid atheroma volume as assessed by MRI in hypercholesterolaemic patients with asymptomatic carotid disease after 24 months’ treatment with rosuvastatin 5 mg or rosuvastatin 40 mg. The secondary objectives are to evaluate the effects of rosuvastatin on lesion composition, intima media thickness of the carotid arteries, and lipids, lipoprotein and markers of inflammation. Safety and tolerability will also be assessed. References Corti R et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001; 104: 249–252. Zhao XQ et al. Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case-control study. Arterioscler Thromb Vasc Biol 2001; 21: 1623–1629. Hatsukami TS et al. Study design for a randomized, double-blind trial to assess the effect of 24 months of dosing with rosuvastatin on progression of carotid artery atheroma in moderately hypercholesterolemic patients with asymptomatic carotid stenosis. Atheroscler Suppl 2001; 2: 47 (Poster presented at the European Atherosclerosis Society Congress, 20–23 May, 2001, Glasgow, UK).

Dietary run in / eligibility Schema studie Pacienti (n=39) Hypercholesterolemie 16–79% stenóza ≥1 karotidy nebo plát s lipidovým/nekrotickým jádrem ≥18 years rosuvastatin 5 mg (n~19) rosuvastatin 40 mg (n~19) Visit: Week: 1 –6 2 –2 3 –1 4 5 2 6 4 7 8 8 12 9 20 10 28 11 40 12 52 13 65 14 78 15 91 16 104 Dietary run in / eligibility Core slide ORION is a randomised, double-blind, parallel-group study to assess the effect of rosuvastatin on progression of carotid artery atheroma in moderately hypercholesterolaemic patients with asymptomatic carotid stenosis. Approximately 200 individuals from 2 centres in the US were screened and after an initial enrolment period, 39 patients were randomised to receive either rosuvastatin 5 mg or rosuvastatin 40 mg once daily for 24 months. The primary end point is change from baseline in carotid atheroma volume after 24 months. The secondary end points are: carotid wall composition (as assessed by index of lesion MRI signal), unilateral and bilateral measurements minimal carotid lumen cross-sectional area, unilateral and bilateral measurements carotid artery wall volume, unilateral measurement mean intima media thickness (IMT) of the carotid arteries by B-mode ultrasound cell infiltration, expression of markers of vascular inflammation (eg intercellular adhesion molecule-1 and CD-40 ligand) and possible rosuvastatin content in patients progressing to endarterectomy change (%) from baseline in CRP, IL-6 and homocysteine change (%) from baseline in TC, TG, LDL-C, HDL-C and lipoprotein particle size safety. Reference Hatsukami TS et al. Study design for a randomized, double-blind trial to assess the effect of 24 months of dosing with rosuvastatin on progression of carotid artery atheroma in moderately hypercholesterolemic patients with asymptomatic carotid stenosis. Atheroscler Suppl 2001; 2: 47 (Poster presented at the European Atherosclerosis Society Congress, 20–23 May 2001, Glasgow, UK). Lipids Inflammatory markers MRI Safety Carotid ultrasound

Studie aterosklerózy: IMT 24 měsíční randomisovaná dvojitě slepá studie vs placebo hodnotící účinnost CRESTORu 40 mg na progresi aterosklerózy na úrovní karotické tepny, pomocí měření tloušťky intima-media u pacientů s hypercholesterolemií asymptomatických a s nízkým rizikem. N= 983 pacientů Výsledky v r. 2006 JPP Kastelein et al – Atherosclerosis supplements 4 (2003):31-36

Studie aterosklerózy : IVUS 24 měsíční, non comparativní studie, používající endokoronární ultrasonografie k vyhodnocení účinnosti CRESTOR 40 mg na regresi ateromového plátu na úrovni koronárních tepen u pacientů s ICHS N= 508 pacientů Výsledky v r.2006 S. Nissen – Abs ISA (Oct 2003)

Studie morbi-mortality : Hemodialýza Randomisovaná studie,dvojitě slepá vs placebo hodnotící účinky CRESTOR 10 mg na výskyt kardiovaskulárních příhod u hemodyalizovaných pacientů. N= 2950 pacientů Výsledky v r.2007 Fellström B et al. Nephrology Dialysis & Transplantation 2003; 18 (suppl): W520

Studie morbi-mortality : Srdeční nedostatečnost Randomisovaná dvojitě slepá studie vs placebo hodnotící účinek CRESTOR 10 mg na výskyt významných kardiovaskulárních příhod u pacientů se srdeční nedostatečností ischemického původu. N= 4950 pacientů Výsledky v r. 2008

praktičtí lékaři: Sidéral / Trajectoire Studie ve Francii : praktičtí lékaři: Sidéral / Trajectoire Studie Sidéral : studie účinnosti Rosuvastatinu 10mg u pacientů s mírným kor. rizikem sdruř¨ženým nebo ne s metabolickým syndromem. n=1973 výsledky v 4. Q 2005 Studie Trajectoire : Rosuvastatine 10mg vs obvyklá léčba u pacientů s hypercholesterolemií a mírným KV rizikem. n= 1563 Výsledky 2.Q 2005

specialisté: ARIANE / SOLAIRE Studie ve Francii : specialisté: ARIANE / SOLAIRE Hlavní cíl : Porovnat Rosuvastatin a Atorvastatin, na procentu pacientů dosahujících cílové hladiny LDL-C <2,6 mmol/l po12 týdnech léčby u pacientů s vysokým kardiovaskulárním rizikem (KVR) včetně diabetu. N=1052 (Ariane) N= 1105 (Solaire)

Průměrné procento proměny lipidových parametrů během 3 měsíců * * * * * *p<0.05 versus Atorvastatine *p<0.05 versus Atorvastatine LDL-C HDL-C CT TG LDL-C HDL-C CT TG

Procento pacientů dosahujících cílové hodnoty LDL-C < 2,6 mmol/l