- Email: [email protected]
1P-0292 Vitamin E can reduce blood pressure in mild hypertensives
Monday September 29, 2003: Poster Session Prevention of atherosclerosis Methods: 31 WHHL rabbits were divided into three groups, and were fed a standard diet, alone as controls (n=10), or with the addition of 500 mg α-tocopherol/kg feed (n = 11) or 100 mg astaxanthin/kg feed (n = 10). The segments from aortas were stained with Oil Red O for lipids and immunostained with anti-rabbit RAM11 for macrophages. Apoptosis was detected by TUNEL. Collagen and smooth muscle cells were stained with Van Gieson method. Results: Astaxanthin, but not α-tocopherol, significantly decreased both lesion areas and the amount of macrophages in the plaques, and that all lesions in the astaxanthin-treated rabbits were classified as early plaques according to the distribution of collagen and smooth muscle cells. Both antioxidants, particularly α-tocopherol, diminished apoptosis, mainly macrophage apoptosis. Moreover, lesion size positively correlated with lipid accumulation and macrophage infiltration in all three groups, whereas lesion size and apoptosis positively correlated only in the control group. Conclusions: Astaxanthin may improve plaque stability by decreasing lesion size and macrophage infiltration in this atherosclerotic setting. The decrease of apoptosis by α-tocopherol and astaxanthin may be new antiatherogenic properties of these antioxidants.
may then enter an extension period for >/=12 wks with rosuvastatin patients continuing at the same dose and atorvastatin patients switching to R10. In the extension period, patients not achieving their LDL-C goal by wk 6 will have the dose doubled until they achieve their goal or reach the maximum dose of rosuvastatin (40 mg). Analysis: The primary end point of each trial will be % change from baseline in LDL-C at 6 wks. Secondary end points include % change from baseline in other lipid measures and lipid ratios, % of patients who achieve Adult Treatment Panel III (ATP III) LDL-C goals, % who achieve LDL-C <100 mg/dL and % with triglycerides >/=200 mg/dL who achieve ATP III goals, all at 6 wks, as well as safety at 6 wks and during the extension period. Statistical comparisons will be made between R10 and A10 and A20 and between R20 and A20 using analysis of variance for % change from baseline in lipid measures. Goal and safety data will be summarized by descriptive statistics. Conclusions: These will be the first prospective trials comparing the effects of statins in these distinct patient populations at risk for CHD.
Atorvastatin in patients with type 2 diabetes on hemodialysis: Design and baseline characteristics of a double-blind clinical trial (Die Deutsche Diabetes Dialyse Study)
W. März 1 , V. Krane 2 , M. Olschewski 1 , G. Ruf 3 , E. Ritz 4 , C. Wanner 2 . 1 University Clinic Freiburg; 2 University Clinic Würzburg; 3 Pfizer Ltd; 4 University Clinic Heidelberg, Germany Objective: Diabetic patients on dialysis are at substantially increased risk of cardiovascular (CV) disease. The 4D-Study (Die Deutsche Diabetes Dialyse Study) investigates the potential of atorvastatin to decrease the rate of cerebro-/CV events in patients with type 2 diabetes on hemodialysis (HD). Methods: The 4D-Study is a randomized, double-blind trial involving 171 dialysis centers throughout Germany. As soon as the predefined number of 424 combined endpoints is reached [i.e., CV death, nonfatal myocardial infarction (MI) or fatal/nonfatal strokes] the study will be stopped. Between 1998 and 2002, 1252 patients were randomized to either atorvastatin 20 mg or placebo. Men or women, aged 33 to 80 years, were entered into the trial with minimum exclusion criteria. Results: Analysis based on 826 patients revealed the following baseline characteristics: 55% were men (mean age: 64 years) and 45% were women (mean age: 68 years). Mean time between diagnosis of diabetes and first dialysis was 17.8 years; 17% had a prior MI; 82% of patients with a history of CV disease had a diagnosed hypertension. Mean lipid/lipoprotein levels were 221 mg/dl (Total-C), 128 mg/dl (LDL-C), 37 mg/dl (HDL-C), 57 mg/dl (VLDL-C) and 257 mg/dl (triglycerides, TG) with a mean LDL/HDL ratio of 3.9. For LDL-C, 81% of patients showed values higher than the NCEP ATP III target level for high risk patients (i.e., 100 mg/dl). Approximately 68% (HDL-C) and 63% (TG) of patients had values <40 mg/dl and >180 mg/dl, respectively. Of those patients with a history of MI, 84% had LDL-C levels >100mg/dl and 60% had TG >180 mg/dl. Conclusions: The baseline data suggest that the sample selected for this study is representative of patients with type 2 diabetes on HD. No selection bias was detected. A substantial portion of patients could be identified as candidates for lipid-modifying therapy. Full baseline data will be presented. 1P-0290
Designs of 3 trials comparing rosuvastatin and atorvastatin in African American, South Asian, and Hispanic patients: ARIES, IRIS and STARSHIP trials
K. Ferdinand 1 , P.C. Deedwania 2 , S. Haffner 3 , R.J. Caplan 4 , A. Gold 4 . 1 Heartbeats Life Center, New Orleans; 2 University of California, San Francisco, California; 3 University of Texas Health Science Center, San Antonio, Texas; 4 AstraZeneca, Wilmington, Delaware, USA Objective: Coronary heart disease (CHD) risk in many ethnic groups is similar to or higher than in whites, yet these populations are often underrepresented in clinical trials. We will compare lipid-lowering effects of rosuvastatin (Crestor® ) and atorvastatin in 3 separate US open-label trials: ARIES in African American patients (4522US/0002), IRIS in South Asian patients (4522US/0006) and STARSHIP in Hispanic patients (4522US/0007). Design: In each trial, after a 6-wk dietary lead-in, ∼700 hypercholesterolemic adults will be randomized to receive rosuvastatin 10 or 20 mg (R10 or R20) or atorvastatin 10 or 20 mg (A10 or A20) for 6 wks. Patients
Switching to rosuvastatin from other statins has beneficial effects on apolipoprotein (Apo) B and the Apo B:Apo A-I ratio
P. Barter 1 , S. Stender 2 , J. Morrell 3 , C. Watkins 4 , D. Kallend 4 . 1 The Heart Research Institute, Australia; 2 Gentofte Hospital, Hellerup, Denmark; 3 The Conquest Hospital, Hastings, East Sussex; 4 AstraZeneca, Alderley Park, Cheshire, United Kingdom Objective: Apo B may be a better marker of coronary heart disease (CHD) risk than low-density lipoprotein cholesterol. We assessed the effects of switching to rosuvastatin from other statins on Apo B levels and the Apo B:Apo A-I ratio in the MERCURY I study (4522IL/0081). Methods: After a 6-wk dietary lead-in, 3140 hypercholesterolemic adults with CHD, atherosclerosis or type 2 diabetes were randomized to open-label rosuvastatin 10 mg (R10), atorvastatin 10 mg (A10), atorvastatin 20 mg (A20), simvastatin 20 mg (S20), or pravastatin 40 mg (P40) for 8 wks (Period 1). Patients either remained on these treatments for another 8 wks or switched treatments from A10, S20, and P40 to R10 or from A20 to R10 or R20 (Period 2). Pairwise comparisons were made between switch groups within each original treatment arm at wk 16 using analysis of variance for % change from baseline for Apo B and the Apo B:Apo A-I ratio. Results: Table shows % change from baseline at wk 16. Period 1 (wks 0-8) R10 (n=521) A10 (n=516) A20 (n=897)
S20 (n=527) P40 (n=506)
Period 2 (wks 9-16)
Apo B
Apo B:Apo A-I
R10 (n=521) A10 (n=240) R10 (n=276) A20 (n=299) R10 (n=293) R20 (n=305) S20 (n=250) R10 (n=277) P40 (n=253) R10 (n=253)
-37% -30% -36% (P<0.0001) -35% -37% (P=NS)* -42% (P<0.0001)* -29% -35% (P<0.0001) -25% -37% (P<0.0001)
-40% -32% -40% (P<0.0001) -36% -40% (P=.0066)* -43% (P<0.0001)* -32% -38% (P<0.0001) -28% -40% (P<0.0001)
P<0.05 is statistically significant (R10 vs A10, S20 & P40), except *P<0.025 due to Bonferroni correction (R10 & R20 vs A20). NS=not significant.
Conclusions: Compared with patients who remained on atorvastatin, simvastatin or pravastatin, patients who switched to rosuvastatin had greater improvements in Apo B and the Apo B:Apo A-I ratio. 1P-0292
Vitamin E can reduce blood pressure in mild hypertensives
M. Boshtam, M. Rafiei, K. Sadeghi. Isfahan Cardiovascular Research Center, Isfahan, Iran Objective: Because of high prevalence of hypertension in Iranian populations, This triple-blind placebo-controled clinical trial was performed to determine the effects of antioxidant vitamin E on blood pressure and heart rate in patients with mild hypertension. Methods: A total of 70 new mild hypertensive subjects systolic blood pressure (SBP: 140-160 mmHg, diastolic blood pressure DBP: 90-100 mmHg) without secondary hypertension were selected from among people referred to the Hypertension Unit of Isfahan Cardiovascular Research Center and divided randomly into two groups of drug (DG) and placebo (PG). All subjects were aged 20 to 60 years old, without any other cardiovascular risk factors.
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
MONDAY
1P-0291 1P-0289
83
84
Monday September 29, 2003: Poster Session Prevention of atherosclerosis
The drug group received vitamin E tablets (200 IU/day) and the placebo group received placebo only for 27 weeks. At the beginning and the end of the study, the blood vitamin E level was measured flourimetrically in all subjects, according to Hansen & Warwick method. Blood pressure and heart rate were measured at the beginning, during and at the end of the study. Blood pressure was measured by a physician using one random zero mercury sphygmomanometer. Personal information and dietary habit of subjects were collected by separate questionnaire. Results: At the end of the study, it was found that the vitamin E supplement had caused a remarkable decrease SBP (-24% in DG versus –1.6% in PG) and a less remarkable decrease in DBP (-12.5% in DG versus –6.2% in PG) (p<0.05). The change in heart rate was –4.3% in DG, and –14.0% in PG (p<0.05). Conclusion: It is concluded that a vitamin E supplement of 200 IU/day can be effective in mild hypertensive patients in the long-term, probably due to nitiric oxide, and improve their blood pressure status. Therefore, vitamin E supplement can be recommended to such patients. 1P-0293
Long term effects of oral vitamin E supplement in type II diabetic patients
M. Rafiei 1 , M. Boshtam 1 , I. Golshadi 1 , M. Ani 2 . 1 Isfahan Cardiovascular Research Center; 2 Isfahan University of Medical Sciences, Iran Objective: Diabetes mellitus has increasing prevalence in Iranian population. So, this triple-blind placebo-controlled clinical trial was conducted to determine the effect of the vitamin E (VE) on fasting blood sugar (FBS), serum insulin (IN), and glycated hemoglobin (GHb) in type II diabetic patients (NIDDM). Methods: A total of 100 uncomplicated patients 20-60 years old were chosen from those consulting the Isfahan Social Security Service Diabetes Clinic and divided randomly into 2 equal groups- the drug group (DG) and the placebo group (PG). The 2 groups were similar as regards age, sex, level of education, and occupation. The DG and PG were given VE tablets (200 IU/day) and placebo respectively. Serum VE, total cholesterol, triglycerides, FBS, IN, and GHb were measured initially and at the end of the study period (27weeks); FBS, GHb, and IN levels were also determined at several time points during the period. Blood lipids and FBS were measured using the ELAN 2000 autoanalyzer, while for measuring IN the ELIZA method was used; GHb was determined calorimetrically (thio–barbituric acid), and for VE measurements the Warwick and Hansen method was used, the VE being determined flourimetrically. Results: The findings of the study show no effect of VE supplement in the patients: GHb did not change appreciably, FBS was reduced non-significantly (4.3% in PG vs. 14.0% in DG, p<0.05), and there was no statistically significant increase in the IN level (slightly more than 17% in the 2 groups, p=0.15). No changes were observed in the levels of blood lipids either. Conclusion: It is concluded that a daily VE supplement of 200 IU for a period of 27 weeks does not affect IN, GHb, or FBS in NIDDM. However, since this antioxidant vitamin is beneficial in other ways in these patients, it is justified to recommend its use. Certainly more extensive research is necessary to draw definite conclusions. 1P-0295
Analysis of the musculoskeletal safety of atorvastatin in a broad spectrum of patients with dyslipidemia
G. Palmer, H. Silbershatz, M. Szarek, C. Newman. Pfizer Inc., USA Background: This report summarizes the musculoskeletal safety data from >9000 patients exposed to atorvastatin for up to 2 years in completed clinical trials. These data are especially important in light of the withdrawal of cerivastatin, which has placed the safety of all chronic medications under increased scrutiny. Methods: Data were analyzed from 16,731 dyslipidemic patients (9976 male/6755 female; median age 61 yrs) enrolled in 44 multi-national clinical trials. The studies included 9416 atorvastatin-treated (Atv), 1789 placebotreated (PBO) and 5526 patients treated with other statins (O). A broad spectrum of dyslipidemic patients with varying risks for cardiovascular events were evaluated for up to 2 years. Results: In the 44 studies analyzed, no Atv-treated patients experienced myopathy or rhabdomyolysis. Persistent elevation in CPK >10 fold ULN was seen in 1 patient who did not have muscle symptoms. For both the Atv and O groups, the most common musculoskeletal adverse event (AE) was myalgia; in both groups this was experienced by 4% of patients. During the first treatment interval of a study, prior to titration of Atv or change in treatment
the incidence was 2.7, 2.1, 3.2 and 2.6% in patients treated with Atv 10, 20, 40 and 80 mg vs 1.5% with PBO. Myalgia did not appear to be dose related and was recorded as a serious AE for only 3 Atv patients (0.03%) and for only 1 patient receiving O (0.02%). Discontinuations considered related to musculoskeletal AEs were rare (<1%). Conclusion: Specific analysis of musculoskeletal AEs showed that these occurred infrequently with Atv and rarely resulted in discontinuation of treatment. There were no cases of myopathy in these studies. The incidence of myalgia was low and did not increase across the 10-80 mg dose range. These data provide further evidence to support the favorable clinical safety profile of atorvastatin 10-80 mg in a broad range of patients. 1P-0296
An examination of atorvastatin safety when used in combination with amiodarone: Evidence from 44 completed clinical trials
W. Sasiela, M. Szarek, H. Silbershatz, G. Palmer. Pfizer Inc, USA Background: Amiodarone is the most widely globally prescribed anti-arrhythmic drug. Utilization with other medications may have safety issues and recently, questions about the concomitant utilization of amiodarone with statins have been raised – particularly if the statin is primarily metabolized through the cytochrome p450 3A4 enzyme pathway. Methods: Atorvastatin is a well-established statin that effectively lowers LDL cholesterol and triglycerides across the 10-80 mg dose range. We looked for any evidence implying an interaction between atorvastatin and amiodarone as indicated by an increased rate of common statin-associated adverse events in the atorvastatin clinical trial program. Results: To date, the program consists of 44 completed clinical trials with 9416 patients that have received atorvastatin. Of these, 114 (1.2%) have received amiodarone (39% on 10 mg atorvastatin, 61% on 80 mg atorvastatin). Among this cohort there were no incidences of myopathy, rhabdomyolysis or CPK elevations >10×ULN. The rate of treatment-emergent myalgia in patients taking atorvastatin/amiodarone was 4/114 (3.5%). Of the patients taking atorvastatin/amiodarone, 3/114 (2.6%) were thought to have myalgia that was treatment-related. This rate of myalgia is comparable to the overall rate of treatment-related myalgia seen in the entire 9416 patients exposed to atorvastatin in the clinical program (1.9%). None of the atorvastatin/amiodarone patients displayed persistent ALT elevations >3×ULN, an incidence comparable to the overall rate of 0.5% seen in the entire atorvastatin cohort across all doses. Conclusion: Current data from the atorvastatin clinical trial program does not indicate an increased rate of muscle or hepatic adverse events when atorvastatin is used concomitantly with amiodarone. Additional data will be collected with over 44000 patients currently ongoing in clinical trials with atorvastatin. 1P-0297
More Western hypercholesterolemic patients achieve Japan Atherosclerosis Society LDL-C goals with rosuvastatin therapy than with atorvastatin therapy
K. Strutt 1 , J. Shinagawa 2 , K. Izuishi 1 , A. Dane 3 , H. Hutchinson 4 . United Kingdom; 2 AstraZeneca KK, Osaka, Japan; Alderley Park, Cheshire, United Kingdom; 4 AstraZeneca, Wilmington, DE, USA
1 AstraZeneca, 3 AstraZeneca,
Background: Rosuvastatin (RSV, Crestor® ) reduced LDL-C dose dependently and to a similar magnitude in Western and Japanese hypercholesterolemic patients. Data from comparative trials of RSV and atorvastatin (ATV) (prospectively designed for pooling) in which drugs were administered at a fixed dose to Western hypercholesterolemic patients were analyzed to assess achievement of the revised 2002 Japan Atherosclerosis Society (JAS) LDL-C goals. Methods: JAS LDL-C goals by risk categories are: A (no coronary heart disease [CHD], no risk factors other than LDL-C) <160 mg/dL; B1/B2 (no CHD, 1-2 other risk factors) <140 mg/dL; B3/B4 (no CHD, 3 or more other risk factors) <120 mg/dL; and C (existing CHD) <100 mg/dL. Achievement of JAS goals was assessed in 3 trials in patients with LDL-C ≥160 and <250 mg/dL comparing RSV 5 mg and RSV 10 mg vs ATV 10 mg for 12 weeks. Results: The vast majority of patients fell into categories B1-B4 or C. The number of patients in category A was too small to enable meaningful interpretation, and data are not shown. Proportions of patients achieving treatment goals with RSV 5 mg, RSV 10 mg, and ATV 10 mg were as follows (number of patients in risk group): Total: 67%*** (390), 82%*** (389), and 58% (393). Category C: 32%*** (131), 64%*** (133), and 16% (124). Category
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
may then enter an extension period for >/=12 wks with rosuvastatin patients continuing at the same dose and atorvastatin patients switching to R10. In the extension period, patients not achieving their LDL-C goal by wk 6 will have the dose doubled until they achieve their goal or reach the maximum dose of rosuvastatin (40 mg). Analysis: The primary end point of each trial will be % change from baseline in LDL-C at 6 wks. Secondary end points include % change from baseline in other lipid measures and lipid ratios, % of patients who achieve Adult Treatment Panel III (ATP III) LDL-C goals, % who achieve LDL-C <100 mg/dL and % with triglycerides >/=200 mg/dL who achieve ATP III goals, all at 6 wks, as well as safety at 6 wks and during the extension period. Statistical comparisons will be made between R10 and A10 and A20 and between R20 and A20 using analysis of variance for % change from baseline in lipid measures. Goal and safety data will be summarized by descriptive statistics. Conclusions: These will be the first prospective trials comparing the effects of statins in these distinct patient populations at risk for CHD.
Atorvastatin in patients with type 2 diabetes on hemodialysis: Design and baseline characteristics of a double-blind clinical trial (Die Deutsche Diabetes Dialyse Study)
W. März 1 , V. Krane 2 , M. Olschewski 1 , G. Ruf 3 , E. Ritz 4 , C. Wanner 2 . 1 University Clinic Freiburg; 2 University Clinic Würzburg; 3 Pfizer Ltd; 4 University Clinic Heidelberg, Germany Objective: Diabetic patients on dialysis are at substantially increased risk of cardiovascular (CV) disease. The 4D-Study (Die Deutsche Diabetes Dialyse Study) investigates the potential of atorvastatin to decrease the rate of cerebro-/CV events in patients with type 2 diabetes on hemodialysis (HD). Methods: The 4D-Study is a randomized, double-blind trial involving 171 dialysis centers throughout Germany. As soon as the predefined number of 424 combined endpoints is reached [i.e., CV death, nonfatal myocardial infarction (MI) or fatal/nonfatal strokes] the study will be stopped. Between 1998 and 2002, 1252 patients were randomized to either atorvastatin 20 mg or placebo. Men or women, aged 33 to 80 years, were entered into the trial with minimum exclusion criteria. Results: Analysis based on 826 patients revealed the following baseline characteristics: 55% were men (mean age: 64 years) and 45% were women (mean age: 68 years). Mean time between diagnosis of diabetes and first dialysis was 17.8 years; 17% had a prior MI; 82% of patients with a history of CV disease had a diagnosed hypertension. Mean lipid/lipoprotein levels were 221 mg/dl (Total-C), 128 mg/dl (LDL-C), 37 mg/dl (HDL-C), 57 mg/dl (VLDL-C) and 257 mg/dl (triglycerides, TG) with a mean LDL/HDL ratio of 3.9. For LDL-C, 81% of patients showed values higher than the NCEP ATP III target level for high risk patients (i.e., 100 mg/dl). Approximately 68% (HDL-C) and 63% (TG) of patients had values <40 mg/dl and >180 mg/dl, respectively. Of those patients with a history of MI, 84% had LDL-C levels >100mg/dl and 60% had TG >180 mg/dl. Conclusions: The baseline data suggest that the sample selected for this study is representative of patients with type 2 diabetes on HD. No selection bias was detected. A substantial portion of patients could be identified as candidates for lipid-modifying therapy. Full baseline data will be presented. 1P-0290
Designs of 3 trials comparing rosuvastatin and atorvastatin in African American, South Asian, and Hispanic patients: ARIES, IRIS and STARSHIP trials
K. Ferdinand 1 , P.C. Deedwania 2 , S. Haffner 3 , R.J. Caplan 4 , A. Gold 4 . 1 Heartbeats Life Center, New Orleans; 2 University of California, San Francisco, California; 3 University of Texas Health Science Center, San Antonio, Texas; 4 AstraZeneca, Wilmington, Delaware, USA Objective: Coronary heart disease (CHD) risk in many ethnic groups is similar to or higher than in whites, yet these populations are often underrepresented in clinical trials. We will compare lipid-lowering effects of rosuvastatin (Crestor® ) and atorvastatin in 3 separate US open-label trials: ARIES in African American patients (4522US/0002), IRIS in South Asian patients (4522US/0006) and STARSHIP in Hispanic patients (4522US/0007). Design: In each trial, after a 6-wk dietary lead-in, ∼700 hypercholesterolemic adults will be randomized to receive rosuvastatin 10 or 20 mg (R10 or R20) or atorvastatin 10 or 20 mg (A10 or A20) for 6 wks. Patients
Switching to rosuvastatin from other statins has beneficial effects on apolipoprotein (Apo) B and the Apo B:Apo A-I ratio
P. Barter 1 , S. Stender 2 , J. Morrell 3 , C. Watkins 4 , D. Kallend 4 . 1 The Heart Research Institute, Australia; 2 Gentofte Hospital, Hellerup, Denmark; 3 The Conquest Hospital, Hastings, East Sussex; 4 AstraZeneca, Alderley Park, Cheshire, United Kingdom Objective: Apo B may be a better marker of coronary heart disease (CHD) risk than low-density lipoprotein cholesterol. We assessed the effects of switching to rosuvastatin from other statins on Apo B levels and the Apo B:Apo A-I ratio in the MERCURY I study (4522IL/0081). Methods: After a 6-wk dietary lead-in, 3140 hypercholesterolemic adults with CHD, atherosclerosis or type 2 diabetes were randomized to open-label rosuvastatin 10 mg (R10), atorvastatin 10 mg (A10), atorvastatin 20 mg (A20), simvastatin 20 mg (S20), or pravastatin 40 mg (P40) for 8 wks (Period 1). Patients either remained on these treatments for another 8 wks or switched treatments from A10, S20, and P40 to R10 or from A20 to R10 or R20 (Period 2). Pairwise comparisons were made between switch groups within each original treatment arm at wk 16 using analysis of variance for % change from baseline for Apo B and the Apo B:Apo A-I ratio. Results: Table shows % change from baseline at wk 16. Period 1 (wks 0-8) R10 (n=521) A10 (n=516) A20 (n=897)
S20 (n=527) P40 (n=506)
Period 2 (wks 9-16)
Apo B
Apo B:Apo A-I
R10 (n=521) A10 (n=240) R10 (n=276) A20 (n=299) R10 (n=293) R20 (n=305) S20 (n=250) R10 (n=277) P40 (n=253) R10 (n=253)
-37% -30% -36% (P<0.0001) -35% -37% (P=NS)* -42% (P<0.0001)* -29% -35% (P<0.0001) -25% -37% (P<0.0001)
-40% -32% -40% (P<0.0001) -36% -40% (P=.0066)* -43% (P<0.0001)* -32% -38% (P<0.0001) -28% -40% (P<0.0001)
P<0.05 is statistically significant (R10 vs A10, S20 & P40), except *P<0.025 due to Bonferroni correction (R10 & R20 vs A20). NS=not significant.
Conclusions: Compared with patients who remained on atorvastatin, simvastatin or pravastatin, patients who switched to rosuvastatin had greater improvements in Apo B and the Apo B:Apo A-I ratio. 1P-0292
Vitamin E can reduce blood pressure in mild hypertensives
M. Boshtam, M. Rafiei, K. Sadeghi. Isfahan Cardiovascular Research Center, Isfahan, Iran Objective: Because of high prevalence of hypertension in Iranian populations, This triple-blind placebo-controled clinical trial was performed to determine the effects of antioxidant vitamin E on blood pressure and heart rate in patients with mild hypertension. Methods: A total of 70 new mild hypertensive subjects systolic blood pressure (SBP: 140-160 mmHg, diastolic blood pressure DBP: 90-100 mmHg) without secondary hypertension were selected from among people referred to the Hypertension Unit of Isfahan Cardiovascular Research Center and divided randomly into two groups of drug (DG) and placebo (PG). All subjects were aged 20 to 60 years old, without any other cardiovascular risk factors.
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
MONDAY
1P-0291 1P-0289
83
84
Monday September 29, 2003: Poster Session Prevention of atherosclerosis
The drug group received vitamin E tablets (200 IU/day) and the placebo group received placebo only for 27 weeks. At the beginning and the end of the study, the blood vitamin E level was measured flourimetrically in all subjects, according to Hansen & Warwick method. Blood pressure and heart rate were measured at the beginning, during and at the end of the study. Blood pressure was measured by a physician using one random zero mercury sphygmomanometer. Personal information and dietary habit of subjects were collected by separate questionnaire. Results: At the end of the study, it was found that the vitamin E supplement had caused a remarkable decrease SBP (-24% in DG versus –1.6% in PG) and a less remarkable decrease in DBP (-12.5% in DG versus –6.2% in PG) (p<0.05). The change in heart rate was –4.3% in DG, and –14.0% in PG (p<0.05). Conclusion: It is concluded that a vitamin E supplement of 200 IU/day can be effective in mild hypertensive patients in the long-term, probably due to nitiric oxide, and improve their blood pressure status. Therefore, vitamin E supplement can be recommended to such patients. 1P-0293
Long term effects of oral vitamin E supplement in type II diabetic patients
M. Rafiei 1 , M. Boshtam 1 , I. Golshadi 1 , M. Ani 2 . 1 Isfahan Cardiovascular Research Center; 2 Isfahan University of Medical Sciences, Iran Objective: Diabetes mellitus has increasing prevalence in Iranian population. So, this triple-blind placebo-controlled clinical trial was conducted to determine the effect of the vitamin E (VE) on fasting blood sugar (FBS), serum insulin (IN), and glycated hemoglobin (GHb) in type II diabetic patients (NIDDM). Methods: A total of 100 uncomplicated patients 20-60 years old were chosen from those consulting the Isfahan Social Security Service Diabetes Clinic and divided randomly into 2 equal groups- the drug group (DG) and the placebo group (PG). The 2 groups were similar as regards age, sex, level of education, and occupation. The DG and PG were given VE tablets (200 IU/day) and placebo respectively. Serum VE, total cholesterol, triglycerides, FBS, IN, and GHb were measured initially and at the end of the study period (27weeks); FBS, GHb, and IN levels were also determined at several time points during the period. Blood lipids and FBS were measured using the ELAN 2000 autoanalyzer, while for measuring IN the ELIZA method was used; GHb was determined calorimetrically (thio–barbituric acid), and for VE measurements the Warwick and Hansen method was used, the VE being determined flourimetrically. Results: The findings of the study show no effect of VE supplement in the patients: GHb did not change appreciably, FBS was reduced non-significantly (4.3% in PG vs. 14.0% in DG, p<0.05), and there was no statistically significant increase in the IN level (slightly more than 17% in the 2 groups, p=0.15). No changes were observed in the levels of blood lipids either. Conclusion: It is concluded that a daily VE supplement of 200 IU for a period of 27 weeks does not affect IN, GHb, or FBS in NIDDM. However, since this antioxidant vitamin is beneficial in other ways in these patients, it is justified to recommend its use. Certainly more extensive research is necessary to draw definite conclusions. 1P-0295
Analysis of the musculoskeletal safety of atorvastatin in a broad spectrum of patients with dyslipidemia
G. Palmer, H. Silbershatz, M. Szarek, C. Newman. Pfizer Inc., USA Background: This report summarizes the musculoskeletal safety data from >9000 patients exposed to atorvastatin for up to 2 years in completed clinical trials. These data are especially important in light of the withdrawal of cerivastatin, which has placed the safety of all chronic medications under increased scrutiny. Methods: Data were analyzed from 16,731 dyslipidemic patients (9976 male/6755 female; median age 61 yrs) enrolled in 44 multi-national clinical trials. The studies included 9416 atorvastatin-treated (Atv), 1789 placebotreated (PBO) and 5526 patients treated with other statins (O). A broad spectrum of dyslipidemic patients with varying risks for cardiovascular events were evaluated for up to 2 years. Results: In the 44 studies analyzed, no Atv-treated patients experienced myopathy or rhabdomyolysis. Persistent elevation in CPK >10 fold ULN was seen in 1 patient who did not have muscle symptoms. For both the Atv and O groups, the most common musculoskeletal adverse event (AE) was myalgia; in both groups this was experienced by 4% of patients. During the first treatment interval of a study, prior to titration of Atv or change in treatment
the incidence was 2.7, 2.1, 3.2 and 2.6% in patients treated with Atv 10, 20, 40 and 80 mg vs 1.5% with PBO. Myalgia did not appear to be dose related and was recorded as a serious AE for only 3 Atv patients (0.03%) and for only 1 patient receiving O (0.02%). Discontinuations considered related to musculoskeletal AEs were rare (<1%). Conclusion: Specific analysis of musculoskeletal AEs showed that these occurred infrequently with Atv and rarely resulted in discontinuation of treatment. There were no cases of myopathy in these studies. The incidence of myalgia was low and did not increase across the 10-80 mg dose range. These data provide further evidence to support the favorable clinical safety profile of atorvastatin 10-80 mg in a broad range of patients. 1P-0296
An examination of atorvastatin safety when used in combination with amiodarone: Evidence from 44 completed clinical trials
W. Sasiela, M. Szarek, H. Silbershatz, G. Palmer. Pfizer Inc, USA Background: Amiodarone is the most widely globally prescribed anti-arrhythmic drug. Utilization with other medications may have safety issues and recently, questions about the concomitant utilization of amiodarone with statins have been raised – particularly if the statin is primarily metabolized through the cytochrome p450 3A4 enzyme pathway. Methods: Atorvastatin is a well-established statin that effectively lowers LDL cholesterol and triglycerides across the 10-80 mg dose range. We looked for any evidence implying an interaction between atorvastatin and amiodarone as indicated by an increased rate of common statin-associated adverse events in the atorvastatin clinical trial program. Results: To date, the program consists of 44 completed clinical trials with 9416 patients that have received atorvastatin. Of these, 114 (1.2%) have received amiodarone (39% on 10 mg atorvastatin, 61% on 80 mg atorvastatin). Among this cohort there were no incidences of myopathy, rhabdomyolysis or CPK elevations >10×ULN. The rate of treatment-emergent myalgia in patients taking atorvastatin/amiodarone was 4/114 (3.5%). Of the patients taking atorvastatin/amiodarone, 3/114 (2.6%) were thought to have myalgia that was treatment-related. This rate of myalgia is comparable to the overall rate of treatment-related myalgia seen in the entire 9416 patients exposed to atorvastatin in the clinical program (1.9%). None of the atorvastatin/amiodarone patients displayed persistent ALT elevations >3×ULN, an incidence comparable to the overall rate of 0.5% seen in the entire atorvastatin cohort across all doses. Conclusion: Current data from the atorvastatin clinical trial program does not indicate an increased rate of muscle or hepatic adverse events when atorvastatin is used concomitantly with amiodarone. Additional data will be collected with over 44000 patients currently ongoing in clinical trials with atorvastatin. 1P-0297
More Western hypercholesterolemic patients achieve Japan Atherosclerosis Society LDL-C goals with rosuvastatin therapy than with atorvastatin therapy
K. Strutt 1 , J. Shinagawa 2 , K. Izuishi 1 , A. Dane 3 , H. Hutchinson 4 . United Kingdom; 2 AstraZeneca KK, Osaka, Japan; Alderley Park, Cheshire, United Kingdom; 4 AstraZeneca, Wilmington, DE, USA
1 AstraZeneca, 3 AstraZeneca,
Background: Rosuvastatin (RSV, Crestor® ) reduced LDL-C dose dependently and to a similar magnitude in Western and Japanese hypercholesterolemic patients. Data from comparative trials of RSV and atorvastatin (ATV) (prospectively designed for pooling) in which drugs were administered at a fixed dose to Western hypercholesterolemic patients were analyzed to assess achievement of the revised 2002 Japan Atherosclerosis Society (JAS) LDL-C goals. Methods: JAS LDL-C goals by risk categories are: A (no coronary heart disease [CHD], no risk factors other than LDL-C) <160 mg/dL; B1/B2 (no CHD, 1-2 other risk factors) <140 mg/dL; B3/B4 (no CHD, 3 or more other risk factors) <120 mg/dL; and C (existing CHD) <100 mg/dL. Achievement of JAS goals was assessed in 3 trials in patients with LDL-C ≥160 and <250 mg/dL comparing RSV 5 mg and RSV 10 mg vs ATV 10 mg for 12 weeks. Results: The vast majority of patients fell into categories B1-B4 or C. The number of patients in category A was too small to enable meaningful interpretation, and data are not shown. Proportions of patients achieving treatment goals with RSV 5 mg, RSV 10 mg, and ATV 10 mg were as follows (number of patients in risk group): Total: 67%*** (390), 82%*** (389), and 58% (393). Category C: 32%*** (131), 64%*** (133), and 16% (124). Category
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan