Issue 9 January 2002
MAP Status Report	The HOPE Study Warfarin and Aspirin for the Prevention of Recurrent Ischemic Stroke	New Medications Starlix® (Nateglinide)

MAP Helps Transplant Patients Receive Over $2 Million in Medications The mission of the Medication Access Program (MAP) is to increase access to medications for solid-organ transplant patients who reside in the State of Georgia. From October 1999 through December 2001, MAP has aided over 250 Georgia solid-organ transplant patients in the enrollment process required to participate in medication assistance programs. Through MAP's services, these patients have received over $2 million in medications, based on average wholesale prices. These medications mostly represent immunosuppressants, cardiovascular, antimicrobial, gastrointestinal, and other necessary prescription medications. MAP also serves as a valuable resource to healthcare professionals and transplant patients by providing the most up-to-date information concerning medication assistance programs. MAP is made possible by the Carlos and Marguerite Mason Trust and the University of Georgia College of Pharmacy. For more information, MAP personnel may be reached Monday through Friday from 9am to 5pm by calling 706-721-0131 or 800-736-2273 EXT. 0131.

The HOPE Study The activation of the renin-angiotensin-aldosterone system (RAS) has an important role in increasing the risk of cardiovascular events. Angiotensin-converting-enzyme (ACE) inhibitor drugs block the activation of the RAS and could slow the progression of cardiovascular events. The Heart Outcomes Prevention Evaluation (HOPE) study was designed to determine if the ACE inhibitor, ramipril, was effective in preventing a composite of myocardial infarction, stroke, or death from cardiovascular causes. Each outcome was assessed separately in patients who were at high risk for cardiovascular events, but who did not have left ventricular dysfunction or heart failure. The HOPE study was a randomized, multi-center, double-blind, placebo controlled trial. It included more than 9000 patients who were 55 or older, with evidence of vascular disease or diabetes plus one other cardiovascular risk factor, and who were not known to have a low ejection fraction or heart failure. There were 4645 patients randomly assigned to receive ramipril 10mg once a day, 4652 to receive a matching placebo, and 244 to receive ramipril 2.5mg once a day (low-dose ramipril participants included in a sub-study) for a 5-year period. Reasons for discontinuing ramipril included cough, hypotension or dizziness, and angioedema. A total of 651 (14%) patients in the ramipril group died of cardiovascular causes or had a myocardial infarction or stroke, compared with 826 (18%) patients in the placebo group (p<0.001). There were also significant reductions of risk within the ramipril group when each of these end points was analyzed separately. The ramipril group also experienced significantly fewer episodes of cardiac arrest, worsening angina, heart failure, new diagnosis of diabetes, and complications related to diabetes, compared to the placebo group. The decreased incidence of each of these outcomes with ramipril was observed in patients who were already taking several effective treatments including aspirin, beta-blockers, and lipid-lowering agents. This indicates that the inhibition of ACE adds an additional approach to preventing cardiovascular events. The HOPE study supports the suggestion that inhibiting ACE, thereby blocking the activation of the RAS, has a major role in preventing cardiovascular events in patients at high risk, especially diabetics. For more information regarding this trial, refer to the study (NEJM 2000;342:145). Authored by Melanie S. Jones Warfarin and Aspirin for the Prevention of Recurrent Ischemic Stroke The use of warfarin in the prevention of cardioembolic stroke has been well documented. However, in patients with acute non-cardioembolic stroke, there is no conclusive evidence that warfarin is the most effective prophylaxis. The WARSS, Warfarin-Aspirin Recurrent Stroke Study, was a double-blind, randomized, placebo-controlled trial that sought to determine whether aspirin or warfarin would be more efficacious in the prevention of recurrent non-cardioembolic stroke. The 2,206 participants of the study were randomized to either aspirin 25mg and placebo daily, or warfarin and placebo daily. Those in the warfarin group were given doses adequate to achieve an INR of 1.4 to 2.8. Patients were followed for two years 1 month via telephone or in person when the blood samples were drawn. The primary endpoints were met if the patient experienced a recurrent ischemic stroke or death from any cause. To maintain the double blind status, all patients had blood samples drawn. All samples were processed through a central location and the results were reported back to the local centers. Those patients on the aspirin therapy received fabricated INR values appropriate to the placebo warfarin dose they were taking. There was no significant difference in the reduction of recurrent stroke between the aspirin and warfarin groups (warfarin=17.8% vs. aspirin=16.0%, p=0.10). The rate of major hemorrhage was not significantly different either (2.22/100 patient-years warfarin vs. 1.49/100 patient-years aspirin, p=0.16). However, patients in the warfarin group experienced significantly more minor hemorrhages (warfarin=20.8% vs. aspirin=12.9%, p<0.001). The authors concluded that, while both treatments prevented recurrence of non-cardioembolic stroke, warfarin requires much more time, monitoring, and expense than aspirin, and aspirin is much safer to use. Therefore, aspirin should be preferred as prophylaxis of recurrent non-cardioembolic stroke. For more information concerning this trial, refer to the study (NEJM 2001;345:1444). Authored by Marshall Frost

New Medications Starlix® (Nateglinide) Starlix® (nateglinide) is an oral antidiabetic agent for Type 2 diabetes mellitus that was FDA approved in December 2000. It is available in 60mg tablets and 120mg tablets. Starlix® is indicated as monotherapy for patients with Type 2 diabetes that cannot be controlled with diet and exercise, and who have not been treated with other antidiabetic agents, and in combination with metformin, when metformin alone does not control hyperglycemia. It interacts with the ATP-sensitive potassium channel on pancreatic beta cells, which causes the secretion of insulin. Starlix® is an amino-acid derivative that is structurally unrelated to sulfonylureas. Starlix® is highly protein bound (98%) and is metabolized by the cytochrome P450 isoenzymes CYP2C9 and CYP3A4. The potential for drug interactions exists due to the fact that these pathways metabolize many drugs, however, none were reported when Starlix® was studied with digoxin and warfarin. Peak plasma concentrations occur within one hour after oral dosing. No dose adjustments are required in elderly patients or in patients with mild-to-severe renal insufficiency. NSAIDS, salicylates, monoamine oxidase inhibitors, and non-selective beta-blockers may potentiate the hypoglycemic effect of Starlix®, whereas thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce the hypoglycemic effect. In clinical studies, Starlix® monotherapy resulted in significant reductions in mean HbA1c and mean fasting plasma glucose (FPG) compared to placebo. The combination of Starlix® and metformin resulted in statistically significant greater reductions in HbA1c and FPG, than in either agent alone. Starlix® alone, or in combination with metformin, significantly reduced the prandial glucose elevation from pre-meal to two hours post-meal compared to both placebo and metformin alone. Adverse effects of Starlix® include flu-like symptoms, dizziness, upper respiratory infection, and hypoglycemia. The recommended starting and maintenance dosage of Starlix® is 120mg three times daily, 1 to 30 minutes before meals. The 60mg dose may be used in patients who are near goal HbA1c upon initiation of treatment. Patients should be instructed to skip their scheduled dose of Starlix® if they skip a meal to avoid hypoglycemia. A patient assistance program is available for Starlix®. For further information please contact Novartis Patient Assistance Program at 1-800-277-2254. Authored by Melanie S. Jones

The MAP newsletter is published quarterly to present topics of interest to the transplant community. If you would like to submit material to be considered for publication in the newsletter, please contact MAP at: Medication Access Program University of Georgia at the Medical College of Georgia Clinical Pharmacy Program CJ-1020 Augusta, Georgia 30912-2450 (706) 721-0131 or 1-800-736-2273 ext. 0131 E-mail - map@mapuga.com

The Medication Access Program is a statewide program for solid-organ transplant patients in Georgia that offers information about medication assistance programs and helps with the enrollment into these programs.