POSTERS POSTER PRESENTATIONS

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1 POSTER PRESENTATIONS The following are based on posters presented at the American Heart Association s 75th Annual Scientific Sessions, held November 17-20,2002 in Chicago, Illinois THE CHANGING NATURE OF THE TREATMENT GAP IN HYPERLIPIDEMIA AND THE EMERGING CHALLENGE OF UNDERTREATMENT Based on a presentation by Foley KA,* Massing MW, Simpson RJ Jr, Alexander CM,* Markson LE* *Merck and Co. Inc, West Point, Pennsylvania; University of North Carolina, Chapel Hill, North Carolina; Chapel Hill, North Carolina. INTRODUCTION AND BACKGROUND The National Cholesterol Education Program and the American Heart Association/American College of Cardiology clinical guidelines recommend a lowdensity lipoprotein (LDL) cholesterol level of less than 100 mg/dl for high-risk patients, such as those with coronary heart disease (CHD). Studies of clinical practice have shown that large numbers of patients go untreated, and among those who are treated, few achieve the recommended LDL goal. The objective of this study was to determine the implications of changes in the rates of treatment and goal attainment on the treatment and undertreatment in CHD patients. Published treatment and goal attainment rates from 2 time periods were applied to a population of US adults with CHD and elevated LDL derived from the 2001 Census and data from the third National Health and Nutrition Examination Survey (NHANES III). The number of patients a) not treated, b) treated but not at goal (undertreated), and c) treated at goal were estimated using the 2 sets of treatment and goal attainment rates. Applying treatment and goal attainment rates from a study conducted during the mid-1990s to the CHD population would result in an untreated population of 5.7 million patients, with an undertreated population of 2.7 million. Using treatment and goal attainment rates taken from the late 1990s, however, 3.7 million CHD patients with elevated LDL are estimated to receive no lipid-lowering therapy, and 3.2 million would receive treatment but would not be treated to goal. DISCUSSION Using treatment and goal attainment rates from the mid-1990s, the treatment gap would be dominated by untreated patients. While the number of untreated patients would decrease substantially with the improvements in treatment and goal attainment rates, the number of undertreated patients would actually increase and 74% of CHD patients would remain either untreated or undertreated. CONCLUSIONS The nature of the treatment gap among CHD patients with elevated levels of LDL appears to be changing, with undertreatment emerging as a public health issue. Despite improvement in the overall number of patients being treated and the number treated to goal, the majority of CHD patients with elevated LDL levels are estimated to remain untreated or undertreated. EZETIMIBE IS ANEFFECTIVE TREATMENT FOR HOMOZYGOUS SITOSTEROLEMIA Based on a presentation by Salen G,* von Bergmann K, Kwiterovich PO, Jr, Musser B, O Grady L, Stein P, Musliner T *University of Medicine and Dentistry of New Jersey, Newark, New Jersey; University of Bonn, Bonn, Germany; Johns Hopkins University, Baltimore, Maryland; Merck Research Laboratories, Rahway, New Jersey. Advanced Studies in Medicine S329

2 INTRODUCTION AND BACKGROUND Homozygous sitosterolemia is a recessively inherited disorder resulting from a gene mutation, characterized by increased gut absorption and decreased clearance of plant sterols, such as sitosterol and campesterol. Patients with sitosterolemia have markedly elevated plasma and tissues level of sitosterol and campesterol, which greatly increase the risk of atherosclerosis. Ezetimibe inhibits absorption of cholesterol from dietary and biliary sources but does not affect absorption of bile acids, fatty acids, fat-soluble vitamins, or triglycerides. Clinical trials have shown that ezetimibe effectively lowers plasma cholesterol and has a safety profile similar to that of placebo. Plant sterols are structurally similar to cholesterol, and a multicenter clinical trial was organized to determine whether ezetimibe can reduce concentrations of plant sterols in patients with homozygous sitosterolemia. Table. Change in Plant Sterol Values Enrollment in the trial was limited to patients older than 10 years who had a diagnosis of sitosterolemia and plasma sitosterol levels that exceeded 5 mg/dl on current therapy. The normal plasma concentration of sitosterols is less than 1 mg/dl. Patients entered a 3-week dietary run-in and decreased or discontinued bile- salt binding resins if feasible to do so safely. Patients were randomized to ezetimibe 10 mg/day or placebo at a 4:1 ratio and continued double-blind treatment for 8 weeks. The primary endpoint was the percentage change in sitosterol concentrations in ezetimibetreated patients. The change was determined by comparing baseline values and the mean of the week 6 and week 8 values. Plasma samples of cholesterol, campesterol, sitosterol, and the cholesterol precursor lathosterol were analyzed by capillary gas-liquid chromatography. The trial involved 37 patients. Levels of sitosterol and campesterol increased by 4% and 3.2%, respectively, during the study. In contrast, sitosterol decreased by 21% and campesterol by 24.3% in patients treated with ezetimibe (Table 2). Levels of sitosterol and campesterol decreased significantly and progressively in patients treated with ezetimibe. Response to ezetimibe was consistent in men and women, in patients who had sitosterol levels above or below the median value, in patients on or off statin therapy, and in patients on or off bile-salt binding resins. Low-density lipoprotein cholesterol levels decreased by 13.6% in the ezetimibe group and increased by 16.7% in placebo-treated patients. ApoB and total sterol concentration decreased with ezetimibe. The lathosterol/cholesterol ratio increased, suggesting increased cholesterol synthesis. CONCLUSIONS/IMPLICATIONS Ezetimibe 10 mg resulted in statistically significant and progressive reductions in plasma plant sterol concentrations in patients with homozygous sitosterolemia during 8 weeks of treatment. The results are consistent with the hypothesis that ezetimibe inhibits intestinal absorption of plant sterols, leading to reductions in plasma concentrations. Additionally, the results suggest that ezetimibe 10 mg is indicated as adjunctive therapy to diet for reducing elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. Placebo Ezetimibe Baseline % Change Baseline % Change Sitosterol 10.5 mg/dl mg/dl Campesterol 9.2 mg/dl mg/dl Lathosterol 18.1 mg/dl mg/dl 12.2 S330 Vol. 3 (4C) April 2003

3 STATIN USE WITHIN THE FIRST 24 HOURS OF ADMISSION FOR ACUTE MYOCARDIAL INFARCTION IS ASSOCIATED WITH A REDUCTION IN EARLY MORBIDITY AND MORTALITY Based on a presentation by Fonarow GC,* Wright RS, Spencer F, Frederick P, Dong W, Every N, French WJ, for the National Registry of Myocardial Infarction IV (NRMI IV) Investigators *University of California, Los Angeles, California; Mayo Clinic, Rochester, Minnesota; University of Massachusetts, Worcester, Massachusetts; National Registry of Myocardial Infarction, San Francisco, California; Harbor-UCLA Medical Center, Los Angeles, California. BACKGROUND Overwhelming scientific evidence shows that statins reduce the long-term risk of recurrent coronary events and improve survival in patients after acute myocardial infarction (AMI). Experimental models of ischemia and reperfusion have shown that statins reduce reperfusion injury and limit infarct size, suggesting a possible early cardioprotective effect. Postulated mechanisms for the early benefits of statin therapy in AMI include effects on the inflammatory response, platelet aggregation, endothelial nitric oxide, metalloproteinases, plasminogen activator inhibitor, and free radical production. The effects of statin use within the first 24 hours after admission for AMI on early morbidity and mortality have not been well studied. The purpose of this study was to compare in-hospital outcomes in AMI patients who continued or began statin therapy within 24 hours of hospital admission and in AMI patients who did not receive early statins or whose statin therapy was discontinued. Data were collected on AMI patients who presented to 1230 National Registry of Myocardial Infarction Phase IV hospitals between July 2000 and January After exclusion of transfers, patients had complete data. The primary objective was to compare in-hospital events in patients who continued or began statin therapy within 24 hours after hospitalization with the in-hospital event rate in patients who did not receive early statins or whose existing statin therapy was discontinued upon admission. Overall, patients (9.8%) continued existing statin therapy and (12.6%) began statin therapy within 24 hours of admission. Among patients not receiving statins, 9411 (5.4%) discontinued existing therapy, and (72.2%) did not receive early statin therapy after admission. The total incidence of in-hospital events included shock in 4.8%, heart failure in 23.1%, rupture in 0.6%, reinfarction in 1.5%, ventricular tachycardia/ fibrillation in 5.4%, and death in 13%. With the exception of reinfarction, the incidence of each of the individual clinical events was significantly lower in patients who continued statin therapy or started therapy early after admission, as compared with patients who did not begin statin therapy within 24 hours of admission. Patients whose statin therapy was discontinued at hospital admission had a significantly higher incidence of shock, heart failure, and ventricular tachycardia/ventricular fibrillation, compared with patients who never received statin therapy. CONCLUSIONS Use of statins in the first 24 hours after hospitalization for AMI is associated with a significant reduction in the rate of early complications and in-hospital mortality. The risk of in-hospital events was reduced whether statins were newly started in the first 24 hours after hospitalization for AMI or continued from prior use. The results support the hypothesis that early use of statins after AMI have direct cardioprotective effects. Prospective randomized clinical trials should be conducted to confirm whether the initiation of statins in the first 24 hours after AMI reduces early morbidity and mortality. Table. Clinical Events (%) by Statin Use Prehospital and First 24 Hours of Hospital Admission Y/Y N/Y N/N Y/N Shock 2.3* 2.3* * Heart Failure 22.7* 15.7* * Rupture 0.2* 0.2* Reinfarction VT/VF 3.7* 4.5* * Death 5.3* 4.0* Y/Y indicates continued existing statin therapy; N/Y, started statin therapy within 24 hours of admission; N/N, did not receive early statin therapy; Y/N, discontinued existing statin therapy; and VT/VF, ventricular tachycardia/ventricular fibrillation. *P<.001. Advanced Studies in Medicine S331

4 INHIBITION OF INTESTINAL CHOLESTEROL ABSORPTION BY EZETIMIBE IN HUMANS Sudhop T*, Lütjohann D*, Kodal A*, Tribble D, Shah S, Perevozskaya I ; von Bergmann K* *University of Bonn, Bonn, Germany; Merck Research Laboratories, Rahway, New Jersey. INTRODUCTION Ezetimibe is the first of a novel class of lipid-lowering agents known as direct cholesterol absorption inhibitors. When orally administered, ezetimibe is rapidly absorbed and undergoes extensive conjugation to ezetimibe glucuronide and enterohepatic circulation. Ezetimibe glucuronide is excreted into bile and binds to the surface of the intestinal brush border, thereby inhibiting cholesterol absorption in a manner that remains incompletely understood. During enterohepatic circulation, ezetimibe has a long terminal half-life of approximately 24 hours, allowing oncedaily dosing. Ezetimibe has no known clinically relevant interactions with the various cytochrome metabolic pathways, making it suitable for use in combination with statins. To investigate the influence of ezetimibe on cholesterol absorption in humans, we conducted a randomized, double-blind, placebo-controlled crossover trial in healthy male volunteers who had mild-to-moderate hypercholesterolemia. The primary objective was to assess the effects of ezetimibe on intestinal cholesterol absorption. Secondary and exploratory objectives were to assess the effects of ezetimibe on cholesterol synthesis, plasma lipids, and plasma noncholesterol sterols, such as the plant sterols sitosterol, campesterol, and lathosterol. METHODS The investigation included 18 male patients aged 18 to 55 years. The patients had low-density lipoprotein (LDL) cholesterol levels in the range of mg/dl, triglyceride levels of less than 300 mg/dl, and mean dietary cholesterol consumption in the range of mg/day. After a 14-day, single-blind run-in period, patients were randomized to ezetimibe 10 mg/day or placebo for 14 days. After a 2-week washout period, patients crossed over to the opposite treatment assignment for an additional 14 days. During the last week of every treatment period, patients received microcapsules containing deuterium-labeled cholesterol and sitosterol, and during the last 4 days of each week, stool samples were obtained for calculation of cholesterol absorption and synthesis. Cholesterol absorption was evaluated by the continuous feeding dual-isotope method, using deuterium-labeled cholesterol as the target and deuterium-labeled sitosterol as the nonabsorbed flow marker. We calculated the cholesterol absorption fraction from the relative rate of disappearance of deuterium-cholesterol to deuterium-sitosterol in feces. Cholesterol synthesis was calculated by the fecal balance method. Noncholesterol sterols were measured by gas chromatography/mass spectrometry. During placebo treatment, mean cholesterol absorption within each patient ranged between 25% and 77%, which was reduced to a range of 2% to 49% during ezetimibe treatment, representing a 54% overall reduction in cholesterol absorption. Cholesterol absorption was reduced in all but 1 patient during ezetimibe treatment. The marked reduction in cholesterol absorption during ezetimibe treatment was associated with a 13.2% reduction in total cholesterol as compared with placebo, and a 22.3% reduction in LDL cholesterol. High-density lipoprotein cholesterol and triglyceride levels did change significantly. Fecal sterol excretion was approximately 1 g/day with placebo and was associated with a rate of cholesterol synthesis of approximately 930 mg/day. During ezetimibe treatment, fecal sterol excretion decreased by 72%, leading to an 89% increase in cholesterol synthesis. Excreted neutral sterols were calculated from the difference of mean dietary cholesterol intake and mean cholesterol absorption. Excess excretion totaled approximately 700 mg, less than 100 mg from dietary cholesterol and more than 600 mg from biliary cholesterol, demonstrating that the effect of excess excretion of cholesterol is based primarily in biliary cholesterol. Analysis of plasma plant sterols revealed a 48% reduction in campesterol and 41% reduction in sitosterol. The lathosterol/cholesterol ratio, which is a good indicator of hepatic cholesterol synthesis, increased by 72% during ezetimibe treatment. CONCLUSION Treatment with ezetimibe reduces intestinal cholesterol absorption by 54%, LDL cholesterol by 22.3%, and total cholesterol by 13.2%, as compared with placebo. The reduction in plasma plant sterols was S332 Vol. 3 (4C) April 2003

5 more pronounced. The decrease in cholesterol absorption was accompanied by an increase in cholesterol synthesis, which underscores the potential value of coadministration of ezetimibe with statins. ADEQUACY OF LIPID MANAGEMENT IN SUBJECTS WITH TYPE 2 DIABETES WITHOUT SYMPTOMATIC CORONARY ARTERY DISEASE Based on a presentation by Chyun DA, Davey JA, Inzucchi SE, Young LH, Wackers FJT Yale University, New Haven, Connecticut INTRODUCTION AND BACKGROUND Individuals with diabetes have an increased risk of coronary artery disease (CAD), and achieving lipid goals is a key component of managing coronary risk in patients with diabetes. The target for low-density lipoprotein (LDL) cholesterol in patients with diabetes is less than 100 mg/dl. Therapeutic lifestyle changes should be initiated when LDL levels exceed 100 mg/dl, and drug therapy should be considered for patients whose LDL exceeds 130 mg/dl. Drug therapy is optional for patients whose LDL levels fall between 100 and 129 mg/dl. Noncompliance with lipid-lowering therapy is a common problem and may hamper risk-reduction efforts in this high-risk population. The objectives of this study were to determine the prevalence of abnormal LDL and high-density lipoprotein (HDL) in a population of patients with type 2 diabetes without CAD and to determine the frequency of lipidlowering therapy and the efficacy in achieving target LDL and HDL goals in patients with type 2 diabetes without CAD. Lipid levels and the frequency of treatment were evaluated in 734 type 2 diabetic patients enrolled in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. The study ultimately will include 1124 type 2 diabetic patients, half of whom will be randomized to Adenosine-Tc99m-Sestamibi SPECT imaging (AdSPECT) and half to follow-up. The primary aims of the DIAD study are to determine the prevalence of ischemia, predictors of ischemia, and the incidence of cardiovascular events during 5 years of follow-up. Patients enrolled in the DIAD study are aged 50 to 75 years, and their diabetes diagnosis occurred at age 30 years or later. They have no history of coronary disease by history or angiogram and no symptoms suggestive of angina. At enrollment, the mean LDL cholesterol (LDL-C) was 114 mg/dl, and the mean HDL cholesterol (HDL-C) was 50 mg/dl. Baseline LDL-C was <100 mg/dl in 35% of patients, mg/dl in 36%, and 130 mg/dl in 29%. HDL-C was <35 mg/dl in men or <45 mg/dl in women in 20% of the population, mg/dl for men or mg/dl for women in 35%, and >45 mg/dl in men or 55 mg/dl in women for 45% of the population. With respect to lipid-lowering therapy, 38% of the patients were on a statin alone, 3% on a statin plus another drug, 7% on a drug other than a statin, and 52% on no lipid-lowering therapy. Among patients on lipid-lowering therapy, 52% had LDL-C levels of 100 mg/dl and thus were not achieving goal. Among patients who were not on lipid-lowering therapy, 23% had LDL-C levels of <100 mg/dl, meaning that 77% were not at goal. After combining treated and untreated patients, 65% overall did not meet the LDL- C target of <100 mg/dl. Additionally, 55% of the total population did not meet goals for HDL-C. CONCLUSIONS Preliminary results of this study show that 65% of patients with type 2 diabetes in a CAD screening trial do not meet target goals for LDL-C, and 55% do not meet goals for HDL-C. Fewer than half of the patients (48%) were on lipid-lowering treatment. Among those on lipid-lowering therapy, more than half had LDL-C levels that exceeded the target level of 100 mg/dl. HDL-C levels were independent of LDL-C levels and use of lipid-lowering therapy. Strategies are needed to improve treatment rates and compliance with lipidlowering therapy in the high-risk population with type 2 diabetes. Advanced Studies in Medicine S333

6 NOTES S334 Vol. 3 (4C) April 2003