In recent years, there has been ongoing debate regarding the prevention of secondary stroke; that is, a subsequent acute stroke or transient ischemic attack (TIA) after the diagnosis of a previous stroke or TIA.1 Since the mortality rate of acute stroke has decreased in recent years and the prevalence of stroke has remained somewhat stable, more patients and their physicians are concentrating on preventing secondary stroke.² Most of these patients possess many of the same risk factors, such as hypertension, diabetes, peripheral arterial disease (PAD), and previous myocardial infarction (MI). Many studies have attempted to search out the most efficacious agent or combination of agents targeted at the secondary prevention of stroke.^1-,3

Recent studies have attempted to find the ideal agents for stroke prevention, including the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, which concluded that the combination of clopidogrel and aspirin is superior to aspirin alone in the prevention of vascular events in patients with non-S-T-segment elevation acute coronary syndrome (unstable angina or non-Q-wave MI).^3,4 Also, the Second European Stroke Prevention Study (ESPS-2) concluded that the combination of aspirin and dipyridamole was more effective than either agent alone in the prevention of secondary stroke.² The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study demonstrated that clopidogrel was superior to aspirin in reducing the risk of major thrombotic events in patients with recent MI, ischemic stroke, or established PAD.^3,5

The Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Attack or Ischaemic Stoke (MATCH) study attempted to determine whether the combination of clopidogrel and aspirin is superior to clopidogrel alone in a population with recent stroke or TIA and one or more additional vascular risk factors. Each of the patients in the study (n=7599) was given clopidogrel and either 75mg/day aspirin or a placebo, and then monitored for compliance via regular follow up clinic visits and telephone contact. The patients had to possess at least one of the following five vascular risk factors: previous ischaemic stroke (27%), previous MI (5%), history of angina pectoris (13%), symptomatic PAD (10%), and/or a history of diabetes mellitus (68%). The primary end points included ischemic stroke, MI, vascular death, or rehospitalization for ischemic events.³ This study is unique to previous studies in that patients not only possessed these risk factors, but many possessed one or more of these risk factors. This group models a more realistic, high-risk patient population.

The study shows that adding aspirin to clopidogrel in these high-risk cerebrovascular patients does not show a significant benefit in preventing secondary stroke when compared to placebo (relative risk reduction = 6.4%; p=0.244). Moreover, the addition of aspirin leads to more significant, life threatening bleeding (2.6%) when compared with patients receiving clopidogrel plus placebo (1.3%). Therefore, patients in this high-risk patient population who have not experienced a recent acute coronary syndrome, adding aspirin to clopidogrel should no longer be used for secondary stroke prevention.⁶ The completed study is published in Lancet.⁷

Authored by Joel Melroy

1. O'Rourke F, Dean N, Akhtar N, et al. Current and future concepts in stroke prevention. Canadian Medical Association Journal 2004;170(7):1123-1133.

2. Diener H, Cunha L, Forbes C, et al. European Stroke Prevention Study 2: Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. Journal of Neurological Sciences 1996;143:1-13.

3. Diener HC, Bogousslavsky J, Brass L, et al. Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Attack or Ischaemic Stroke (MATCH): Study Design and Baseline Data. Cerebrovasc Dis 2004;17:253-261.

4. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators: Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndrome Without S-T Segment Elevation. N Eng J Med 2001;345:494-502.

5. Bhatt DL, Marso SP, Hirsch AT, et al. Amplified Benefit of Clopidogrel Versus Aspirin in Patients with Diabetes Mellitus. Am J Cardiol 2002;90:625-628.

6. The MATCH Steering Committee. Acetylsalicylic Acid Provides No Additional Clinical Benefit in High Risk Patients with Stroke or TIA when Added to Clopidogrel and Other Standard Therapies. Press Release: May 13, 2004.

7. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and Clopidogrel Compared with Clopidogrel Alone After Recent Ischaemic Stroke or Transient Ischaemic Attack in High-Risk Patients (MATCH): Randomised, Double-Blind, Placebo-Controlled Trial. Lancet 2004;364:331-337.

New Medication
Crestor (rosuvastatin calcium)

Crestor^® (rosuvastatin calcium), manufactured by AstraZeneca Pharmaceuticals and FDA approved in August 2003 to treat cholesterol disorders in patients in addition to diet and exercise, is available in 5mg, 10mg, 20mg, and 40mg tablets. Rosuvastatin is a selective and competitive inhibitor of HMG-CoA reductase, a rate-limiting enzyme in cholesterol biosynthesis. Observed effects are reductions in LDL-C as well as triglycerides (TG) and total cholesterol (TC), and an increase in HDL-C. Crestor^® joins the other "statins" currently on the market; this group includes Lipitor^® (atorvastatin), Lescol^® (fluvastatin), Mevacor^® (lovastatin), Pravachol^® (pravastatin), Zocor^® (simvastatin), and formerly Baycol^® (cerivastatin) which was removed from the market. Retail cost information (drugstore.com) shows that all four strengths are offered at $70.00 for a 30 day supply.

Crestor^® is approved to treat hypercholesterolemia, hypertriglyceri-demia, and homozygous familial hypercholesterolemia. In the Statin Therapies for Elevated Lipid Levels Compared Across Doses to Rosuvastatin (STELLAR) trial (Jones et al. 2003), various doses of rosuvastatin were compared to atorvastatin, pravastatin, and simvastatin. A dose of 10mg of rosuvastatin produced marked reductions in LDL-C (45.8%), TG (19.8%), and TC (32.9%). An increase of 7.7% is seen in HDL-C.¹ A large percentage of patients (82%) met the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL goals while taking rosuvastatin 10mg.

Crestor^® is not approved for use in pediatric patients as the safety and efficacy have not been established. Most patients should be started on 10mg daily, and titration up to 40mg daily may be needed to help patients meet their cholesterol goals. Liver function tests (LFTs) should be performed before and at 12 weeks following initiation of therapy and after any increase in dose. Therapeutic effects occur within 1 week, and maximum response is usually achieved within 4 weeks. Renal dosing starting at 5mg daily and a maximum of 10mg daily is suggested in patients with a creatinine clearance of less than 30ml/min. Metabolism is primarily performed in the liver by cytochrome P450-2C9. Patients taking cyclosporine should be limited to 5mg daily, and patients taking gemfibrozil should be limited to 10mg daily, as co-administration can lead to higher levels of rosuvastatin and increased risk for myopathy and rhabdomyolysis. Caution should be exercised in patients taking warfarin, as co-administration can lead to increased INR values.²

Overall, rosuvastatin is well tolerated by patients. The most common side effects are muscle pain, constipation, weakness, stomach pain, and nausea. Women who are or may become pregnant or breast-feeding, patients with elevated serum transaminases, and patients who have shown a hypersensitivity to other statins should not take rosuvastatin. Rare cases of rhabdomyolysis with acute renal failure have been reported with rosuvastatin at a similar rate as with other statins. Thus, patients should be advised to promptly report muscle pain, tenderness, or weakness, particularly if accompanied by fever. Therapy should be discontinued if LFTs are elevated or if myopathy occurs. While rare, damage to the muscle, kidneys, or liver can occur.

For information about Crestor^®'s assistance program, contact the MAP office at (706) 721-0131.

Authored by Josh Marshall

1. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW; STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol. 2003 Jul 15;92(2):152-60.

2. Product insert/prescribing information from AstraZeneca, PCC 630100 Rev 8/03.

Available at: http://www.astrazeneca-us.com/cgi-bin/az_pi.cgi?product=crestor&country=us&popup=no Accessed June 11, 2004

MAP Personnel

Marie Chisholm, Pharm.D., RPh.
MAP Founder / Director

Miriam Benson, CPhT
Charlene J. Garrett, CPhT
Debbie Martin, RN
Bridget M. Mills, PharmD, RPh.
Gene McGinty, BS Pharm., RPh.
Kimberly E. Smith, CPhT
J. Chinaye Turner, BS