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Crestor (Rosuvastatin) May Be Associated With Arrested Progression of Atherosclerosis and Regression of Plaques at Sites With The Most Disease

LONDON, UK -- May 6, 2005 -- The ORION study, presented at the 75th European Atherosclerosis Society Congress (EAS), is the first study to assess and visualise the effect of a statin on the composition of plaques using advanced, non-invasive and high-resolution magnetic resonance imaging (MRI) techniques.1,2 The findings from this preliminary study suggest substantial reductions in LDL-cholesterol (LDL-C) with Crestor™ (rosuvastatin) are associated with arrested progression of carotid atherosclerosis and result in regression of the lipid-rich core in the most diseased sites within atherosclerotic plaques.2 Plaques with a lipid-rich core are recognised by medical experts to be vulnerable to rupture, which can result in sudden cardiovascular events, such as heart attacks and strokes, often without any prior symptoms.3

Atherosclerosis is a progressive disease and the main cause of cardiovascular disease - the number one killer worldwide.4,5 It results in a build-up of fatty or fibrous deposits, called plaques, in the artery wall. The build-up of plaques causes the artery to narrow which can reduce the blood supply to vital organs, such as the heart and brain, resulting in symptoms such as angina or transient ischaemic attacks. Plaques can also rupture leading to a sudden, complete blockage of the blood flow. In the heart, this causes a heart attack and in the carotid arteries this can cause a stroke. It is estimated that atherosclerosis accounts for more than 70% of all deaths from cardiovascular disease in the US.6

Professor Hatsukami, principal investigator of the ORION study, comments: "Previous studies suggest that a subset of plaques, for example those with large lipid-rich cores, may pose a higher risk for heart attack or stroke. So, treatment aimed at stabilising the plaque structure, such as reducing the lipid-rich core, may emerge as a vital intervention in reducing the risk of cardiovascular events."

He continues "Results from ORION, a novel study that uses advanced MRI techniques to characterise plaque size and composition, suggest that intensive LDL-C lowering treatment with rosuvastatin may reduce the lipid-rich areas at the most diseased sites within carotid plaques, and is associated with arrested progression in overall plaque burden."

In ORION, 35 patients with moderate hypercholesterolaemia and established carotid atherosclerosis were treated with either Crestor 5mg or 40mg for two years and the results show:1
· Crestor 5mg and 40mg significantly reduced LDL-C from baseline by 39% and 58%, respectively (p<0.001 from baseline and Crestor 40mg versus Crestor 5mg)
· Crestor is associated with arrested progression of carotid atherosclerosis as 5mg and 40mg resulted in no significant median (mean) % change in carotid artery wall volume from baseline: 0.5% (-1.2%) and -1.4% (1.1%), respectively (p=NS)
· Where regression of carotid atherosclerosis was observed, this was associated with more intensive LDL-C lowering as patients whose artery wall volume regressed had an LDL-C reduction of 56% from baseline and achieved a mean LDL-C level of 69mg/dL
· Crestor reduces the proportion of the lipid-rich necrotic core (% LRNC) in the most diseased area of atherosclerotic plaques: 5mg and 40mg reduced % LRNC at this site by 17.6% (p=NS) and 35.5% (p=0.006), with 75% and 90%, respectively, of these plaques showing regression over two years from the start of the study
· In patients without LRNC plaques at baseline, none developed these plaques over the two year study duration with Crestor 5mg or 40mg
· No significant difference was observed between Crestor 5mg and 40mg for the atherosclerosis endpoints
· Both Crestor 5mg and 40mg were well tolerated.
More/…
The results from ORION suggest that intensive reductions (>50%) in LDL-C have a beneficial effect on the composition of atherosclerotic plaques. Numerous head-to-head clinical studies have consistently shown Crestor to be the most effective statin at lowering LDL-C.7-20 The superior efficacy benefits of Crestor are further confirmed by the first results from the PULSAR21 study, also presented at EAS. This study highlights that the Crestor 10mg dose is more effective than double the dose of atorvastatin:
· In PULSAR, Crestor 10mg is significantly more effective than atorvastatin 20mg in reducing LDL-C by 44.6% versus 42.7% (p=0.033), raising HDL-cholesterol (HDL-C, or 'good' cholesterol) by 6.4% versus 3.1% (p<0.001) and ensuring significantly more patients with hypercholesterolaemia achieve their 2003 European LDL-C guideline goals (68% vs. 63%, respectively; p=0.043) and NCEP ATP III LDL-C guideline goals (69% vs. 63%, respectively; p=0.022)21
· Crestor was well tolerated in this study

Crestor (rosuvastatin) 10-40mg
In the majority of countries where Crestor is approved, the 10mg, 20mg and 40mg doses are available:
· All patients should be started on Crestor 10mg, including those who have never been on a statin before and patients who are switched over from any dose of any other statin. The majority of patients achieve their LDL-C goal with Crestor 10mg
· If necessary, dose adjustment to Crestor 20mg can be made. Patients with severe hypercholesterolaemia and at high cardiovascular risk who do not achieve their LDL-C goal with Crestor 20mg may be titrated to the maximum dose of Crestor 40mg
· Crestor should be prescribed with caution in patients with pre-disposing factors for myopathy/rhabdomyolysis. Such factors include renal impairment; hypothyroidism; personal or family history of hereditary muscular disorders; previous history of muscular toxicity with another statin or fibrate; alcohol abuse; age >70 years; situations where an increase in plasma levels may occur; concomitant use of fibrates.
However, please note that prescribing information may differ between countries. Therefore, doctors should always consult their local prescribing information before using Crestor.

Crestor has now received regulatory approvals in 73 countries across five continents and has been launched in over 58 countries worldwide, including 19 European markets, the US and Canada. Over 4.5 million patients have been prescribed Crestor and 19 million prescriptions have been written worldwide. The post-marketing experience supports the favourable benefit:risk profile of Crestor. Crestor 10mg is the usual recommended start dose for patients new to statin treatment and also for those switching to Crestor from other statins regardless of prior dose.


The importance and advantages of MRI techniques
There are several techniques available for the study of atherosclerosis and the level of detail required largely dictates the technique used. High-resolution MRI imaging is a valuable tool not only for the detection of atherosclerosis, but also for studying the size, shape and composition of atherosclerotic plaques, the effects on vascular haemodynamics and the effects of therapeutic intervention. Through using this technique, valuable insight into the effect of statin therapy on atherosclerosis can be obtained.


Atherosclerosis
The main cause of cardiovascular disease (CVD) is atherosclerosis (a general term for the narrowing and hardening of the arteries).4
· The World Health Organization (WHO) reports that CVD is the world's number one killer and accounts for approximately one in three of all deaths5
· It has been estimated that there is one death from CVD every two seconds, one heart attack every five seconds and one stroke every six seconds5
· Over 70% of CVD deaths in the US are related to atherosclerosis6
· In westernised societies, atherosclerosis is the underlying cause of 50% of all deaths.4

The Crestor GALAXY Programme™
The GALAXY Programme is a large, comprehensive, long-term, and evolving global research initiative sponsored by AstraZeneca to investigate cardiovascular risk reduction and patient outcomes with Crestor.

METEOR22 and ASTEROID23 are two further ongoing studies in the AstraZeneca GALAXY Programme™ which are evaluating the effects of Crestor™ on atherosclerosis. Baseline patient characteristic data from METEOR has also been presented as a late-breaking poster at this year's EAS congress.

References:
1. Chu B, Hatsukami TS, Polissar NL, et al. Determination of carotid artery atherosclerosis lesion type and distribution in hypercholesterolemic patients with moderate carotid stenosis using noninvasive magnetic resonance imaging. Stroke 2004;35:2444-448.
2. Hatsukami TS, Saam T, Yuyan C, et al. Rosuvastatin treatment arrests the progression of carotid atherosclerosis in moderately hypercholesterolaemic subjects: a high-resolution magnetic resonance imaging trial. 75th European Atherosclerosis Society Congress, Prague, Czech Republic 2005.
3. Maseri A, Fuster V. Is there a vulnerable plaque? Circulation 2003;107:2068-71.
4. Lusis AJ. Atherosclerosis. Nature 2000;407:233-41.
5. World Health Report 2004. World Health Organization. http://www.who.int.
6. National Center for Health Statistics. http://www.cdc.gov/nchs/hus.htm
7. Blasetto JW, Stein EA, Brown WV, et al. Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. American Journal of Cardiology 2003;91(suppl):3C-10C.
8. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). American Journal of Cardiology 2003;92:152-60.
9. Schuster H, Barter PJ, Stender S, et al. Effects of switching statins on achievement of lipid goals: measuring effective reductions in cholesterol using rosuvastatin therapy (MERCURY I) study. American Heart Journal 2004;147:705-12.
10. Franken A, Wolffenbuttel B, Vincent J. Cholesterol-lowering effects of rosuvastatin compared with atorvastatin in patients with Type 2 diabetes. Atherosclerosis Supplements 2004;5(1):118, Abs M.513.
11. Jukema J, Liem A, Dunselman P, et al. LDL/HDL-C ratio in patients with coronary artery disease and low HDL-C: the RADAR study. Atherosclerosis Supplements 2004;5:125, Abs M.542.
12. Berne C, Siewert-Delle A. Use of rosuvastatin versus atorvastatin in Type 2 diabetes mellitus subjects. Atherosclerosis Supplements 2004;5(1):107,Abs M.463.
13. Betteridge DJ, Gibson M. Effect of rosuvastatin and atorvastatin on LDL-C and CRP levels in patients with Type 2 diabetes; results of the ANDROMEDA study. Atherosclerosis Supplements 2004;5(1):107-8 Abs M.464.
14. Davidson M, Ma P, Stein EA, 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. American Journal of Cardiology 2002;89:268-75.
15. Schwartz GG, Bolognese MA, Tremblay BP, et al. Efficacy and safety of rosuvastatin and atorvastatin in patients with hypercholesterolemia and a high risk of coronary heart disease: a randomised, controlled trial. American Heart Journal 2004;148:e4, H1-H9.
16. Olsson AG, Istaad H, Luurilla O, et al. Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolaemia. American Heart Journal 2002;144:1044-51.
17. Schneck DW, Knopp RH, Ballantyne CM, et al. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. American Journal of Cardiology 2003;91:33-41.
18. Stein E, Strutt KL, Miller E, Southworth H. Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia. American Journal of Cardiology 2003;92:1287-93.
19. Paoletti R, Fahmy M, Mahla G, et al. Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: A randomized, double-blind study. Journal of Cardiovascular Risk 2001;8:383-90.
20. Brown W, Bays HE, Hassman DR, et al. Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: A randomized, double-blind, 52-week trial. American Heart Journal 2002;144:1036-43.
21. Clearfield M, Kallend D, Palmer M for the PULSAR study investigators. Efficacy and safety of rosuvastatin 10mg versus atorvastatin 20mg: Results of the PULSAR study. 75th European Atherosclerosis Society Congress, Prague, Czech Republic 2005.
22. Nissen S. Design and methodology of a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden: The ASTEROID study. Atherosclerosis Supplements 2003;4:27. Abs 1P-0037.
23. Crouse III JR, Grobbee DE, O'Leary DH, et al. Measuring effects on intima media thickness: An evaluation of rosuvastatin in subclinical atherosclerosis - the rationale and methodology of the METEOR Study. Cardiovascular Drugs & Therapy 2004;18:231-38.


SOURCE: AstraZeneca

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