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Treatment with fluvastatin decreases soluble thrombomodulin in cardiac transplant patients
Thursday. 27 May 1999 Poster session: Lipid lowering drugs
26
to decreased purine degradation. TC decreased markedly, from 9.07 (0.34) before, to 4.88 (0.19) mmol/I after treatment (P < 0.001). TG also decreased with treatment, from 2.74 (0.46) to 1.80 (0.25) mmol/1 (P < 0.001). Total plasma vitamin E decreased, however lipid standardised vitamin E, expressed as !ttmol per mmol TC + TG, increased after treatment with atorvastatin, from 4.82, (0.28) to 5.73 (0.37) (P < 0.002), indicating a relative enrichment of vitamin E within plasma lipoproteins. Results indicate that oxidant:antioxidant balance in uivo may improve with atorvastatin treatment. This may be due to direct antioxidant effects of atorvastatin, and/or indirect effects mediated by the marked decrease in plasma lipids, or some other mechanism yet to be identified. Further study of possible antioxidant therapeutic effects of atorvastatin is needed.
THE DUTCH EXPRESS FH G E N E T I C SUBSTUDY: EFFICACY AND SAFETY OF SIMVASTATIN 80 MG IN FAMILIAL H Y P E R C H O L E S T E R O L E M I A (FH) ER.W. de Sauvage Nolting, M.D. Trip, J.J.P. Kastelein. Tire D,ach EXPRESS FH inuestigators group; Academic Medical Center. Amsterdam. The Netherlands Rationale: FH patients very often have LDL-C levels too high to reach target goals with the 40 mg Simvastatin (S) dose. Recent studies with S 80 mg have demonstrated a further LDL-C reduction. We studied whether the same effect could be reached in FH patients. Methods and Results: FH patients who have not achieved LDL-C goals on 40 mg S are included in this open label study and begun on S 80 mg after a washout period of six weeks. A total of 500 FH patients will be included from 38 lipid clinics. We show the results of the first 267 patients that have completed at least 6 weeks of therapy. All meet clinical criteria for FH and in 101 the LDL-receptor mutation has been identified. At baseline mean TC and mean LDL-C were 10.6 and 8.5 mmol/L, respectively. All analyses are performed in the 38 different laboratories which are standardized by a central laboratory. Mean % change from baseline at 6 and 12 weeks are shown below.
Total C LDL-C TG (all) < 2.27 >2.27 HDL-C
week6 (n = 267)
week 12 (n = 2t2)
-38 -45 -26 -20 -38 10
-39 -46 -28 -21 -43 10
Parameter (mg/dl)
Fluvaslatin 80 mg MR (n = 43)
Conventionalfluvastatin40 mg bid (n = 3q)
Baseline
% change
Baseline
% change
LDL-C TG HDL-C
204+46 1635:68 54:t-17
-37+ I I -16+22 +35:10
193±32 141±54 56-I-14
-36+ 12 -95:22 +7+10
No patient developed notable elevations in transaminases or creatine kinase. No new or unexpected adverse events were observed. Conclusion: These data suggest that bedtime administration of fluvastatin 80 mg MR is of comparable efficacy and tolerability to conventional fluvastatin (40 mg bid). and support continued investigation of this new formulation. T R E A T M E N T W I T H FLUVASTATIN DECREASES SOLUBLE T H R O M B O M O D U L I N IN C A R D I A C T R A N S P L A N T PATIENTS P. Ambrosi, M.R. Aillaud, G. Habib, B. Kreitmann, D. M~tras, I. Juhan, R. Luccioni, G. Bouvenot. Aix-Marseille UniuersiO; Marseille, France Objective and Methods: To determine if treatment with fluvastatin (a HMG CoA reductase inhibitor) can prevent endothelial injury in hypercholesterolaemic cardiac transplant recipients, we conducted a randomised, placebocontrolled, double-blind, cross-over trial in 19 patients (mean age 59 years. mean total cholesterol 7.1 mmol/L), 525:26 months after transplantation. The active treatment period consisted of fluvastatin 40 mg/day for 4 weeks. Results: Plasma concentrations of thrombomodulin, von Willebrand factor antigen (VWF Ag). PAI-I activity. PAI-I antigen and t-PA antigen were determined at the end of each period (mean±SD):
Thrombomodulin(ng/ml) VWF Ag (ng/ml) PAI-I Ag ( n g / m l ) PA[-I activity( | U / m l ) t-PA Ag (ng/ml)
Flu~astatin
Placebo
59.9+28.5 • 236+ 1(13 26.3±26.1 1095:12.6 11.5+4.8
655:1:33.8 239+86 268:t. 199 10.8:1-I 1.9 119±5.9
• p < 0.05 vs placebo. Conclusions: We confirmed the high levels ofthrombomodulin, VWF Ag, PAI-I and t-PA Ag in transplanted heart recipients. Fluvastatin significantly decreased thrombomodulin without significant variation of PAl-I, VWF and t-PA, suggesting that fluvastatin reduces injury to the plasma membrane of endothelial cells.
Differences from baseline were highly significant (p < 0.0001). The 80 mg dose was well tolerated. The incidence of myopathy and increases (>3 fold upper limit of normal) in transaminases were 0% and 2.4%, respectively. Conclusions: Simvastatin 80 mg produces excellent lipid lowering efficacy and is well tolerated in FH patients.
A COMPARATIVE STUDY ON THE EFFICACY AND T O L E R A B I L I T Y OF P O L I C O S A N O L AND LOVASTATIN IN PATIENTS W I T H H Y P E R C H O L E S T E R O L E M I A AND HIGH CORONARY RISK G. Castafio, R. Mils I , J.C. Fermindez1, L.E. L6pez, V. Pontigas, M. Lescay.
SHORT-TERM EFFICACY AND SAFETY OF A NEW MODIFIEDRELEASE F O R M U L A T I O N OF FLUVASTAT1N M. Farnier, E Paillard. On behalf of the study inoestigators; Point Mrdical,
Dijon; Department of Cardiology, Uniuersity Hospital. Rennes, France Objective: To maximise first-pass hepatic extraction and reduce systemic exposure of higher doses of fluvastatin, a modified-release (MR) formulation o f fluvastatin 80 mg (matrix tablet) has been developed (Lescol XL). This formulation shows extended duration of drug release, markedly lower systemic drug levels and no dose-dumping with meals. Two phase II, randomised, observer-blind-to-lipids variables, parallel-group trials have been performed to evaluate the efficacy and tolerability of this formulation compared with conventional fluvastatin 40 mg capsules. Methods: After a 4-week placebo/dietary run-in phase, patients (mean age 53 years) with primary hypercholesterolaemia (type lla/IIb) defined by LDL-cholesterol > 160 mg/dl and triglycerides (TG) < 350 mg/dl were randomised to receive fluvastatin 80 mg MR (at bedtime) or conventional fluvastatin 40 mg twice daily (bid) for 4 weeks. Results: Pooled results (mean+SD) are presented in the table.
Center for Medical Surgical Research; /Center of Natural Products, National Center for Scientific Research, Hauana. C,lba This study compares the short-term efficacy, safety and tolerability of policosanol vs Iovastatin in patients with type II hypercholesterolemia and >2 non lipid risk factors. After 4 weeks on a standard cholesterol-lowering diet 59 patients were randomized to receive, under double-blind conditions, policosanol or Iovastatin (20 mg/d) tablets which were taken for 12 weeks. Policosanol significantly reduced (p < 0.000 01) cholesterol (22.4%); LDLC (32.8%) and the ratios of (p < 0.000 1) LDL-C to HDL-C (39.3%) and cholesterol to HDL-C (32%). Lovastatin significantly reduced total cholesterol (p < 0.000 I) (18.9%); LDL-C (25.4%) and the ratios of (p < 0.001) LDL-C to HDL-C (22.3%) and cholesterol to HDL-C (17.8%). Policosanol, but not Iovastatin, significantly raised HDL-C (p < 0.05) by 25.5%. LDL-C to HDL-C ratio was significantly lower (p < 0.05) in the policosanol group than in the Iovastatin group. Both drugs were safe and well tolerated Lovastatin significantly increased (p < 0.01) creatinphosphokinase levels; but individual values remained within the normal limits. Six patients (1 policosanol, 5 Iovastatin) withdrew from the study, two of them, (Iovastatin), because of adverse experiences (AE): gastrointestinal disturbances and skin rash. The frequency of patients referring AE, was
71st EAS. Congress and Satellite Symposia
26
to decreased purine degradation. TC decreased markedly, from 9.07 (0.34) before, to 4.88 (0.19) mmol/I after treatment (P < 0.001). TG also decreased with treatment, from 2.74 (0.46) to 1.80 (0.25) mmol/1 (P < 0.001). Total plasma vitamin E decreased, however lipid standardised vitamin E, expressed as !ttmol per mmol TC + TG, increased after treatment with atorvastatin, from 4.82, (0.28) to 5.73 (0.37) (P < 0.002), indicating a relative enrichment of vitamin E within plasma lipoproteins. Results indicate that oxidant:antioxidant balance in uivo may improve with atorvastatin treatment. This may be due to direct antioxidant effects of atorvastatin, and/or indirect effects mediated by the marked decrease in plasma lipids, or some other mechanism yet to be identified. Further study of possible antioxidant therapeutic effects of atorvastatin is needed.
THE DUTCH EXPRESS FH G E N E T I C SUBSTUDY: EFFICACY AND SAFETY OF SIMVASTATIN 80 MG IN FAMILIAL H Y P E R C H O L E S T E R O L E M I A (FH) ER.W. de Sauvage Nolting, M.D. Trip, J.J.P. Kastelein. Tire D,ach EXPRESS FH inuestigators group; Academic Medical Center. Amsterdam. The Netherlands Rationale: FH patients very often have LDL-C levels too high to reach target goals with the 40 mg Simvastatin (S) dose. Recent studies with S 80 mg have demonstrated a further LDL-C reduction. We studied whether the same effect could be reached in FH patients. Methods and Results: FH patients who have not achieved LDL-C goals on 40 mg S are included in this open label study and begun on S 80 mg after a washout period of six weeks. A total of 500 FH patients will be included from 38 lipid clinics. We show the results of the first 267 patients that have completed at least 6 weeks of therapy. All meet clinical criteria for FH and in 101 the LDL-receptor mutation has been identified. At baseline mean TC and mean LDL-C were 10.6 and 8.5 mmol/L, respectively. All analyses are performed in the 38 different laboratories which are standardized by a central laboratory. Mean % change from baseline at 6 and 12 weeks are shown below.
Total C LDL-C TG (all) < 2.27 >2.27 HDL-C
week6 (n = 267)
week 12 (n = 2t2)
-38 -45 -26 -20 -38 10
-39 -46 -28 -21 -43 10
Parameter (mg/dl)
Fluvaslatin 80 mg MR (n = 43)
Conventionalfluvastatin40 mg bid (n = 3q)
Baseline
% change
Baseline
% change
LDL-C TG HDL-C
204+46 1635:68 54:t-17
-37+ I I -16+22 +35:10
193±32 141±54 56-I-14
-36+ 12 -95:22 +7+10
No patient developed notable elevations in transaminases or creatine kinase. No new or unexpected adverse events were observed. Conclusion: These data suggest that bedtime administration of fluvastatin 80 mg MR is of comparable efficacy and tolerability to conventional fluvastatin (40 mg bid). and support continued investigation of this new formulation. T R E A T M E N T W I T H FLUVASTATIN DECREASES SOLUBLE T H R O M B O M O D U L I N IN C A R D I A C T R A N S P L A N T PATIENTS P. Ambrosi, M.R. Aillaud, G. Habib, B. Kreitmann, D. M~tras, I. Juhan, R. Luccioni, G. Bouvenot. Aix-Marseille UniuersiO; Marseille, France Objective and Methods: To determine if treatment with fluvastatin (a HMG CoA reductase inhibitor) can prevent endothelial injury in hypercholesterolaemic cardiac transplant recipients, we conducted a randomised, placebocontrolled, double-blind, cross-over trial in 19 patients (mean age 59 years. mean total cholesterol 7.1 mmol/L), 525:26 months after transplantation. The active treatment period consisted of fluvastatin 40 mg/day for 4 weeks. Results: Plasma concentrations of thrombomodulin, von Willebrand factor antigen (VWF Ag). PAI-I activity. PAI-I antigen and t-PA antigen were determined at the end of each period (mean±SD):
Thrombomodulin(ng/ml) VWF Ag (ng/ml) PAI-I Ag ( n g / m l ) PA[-I activity( | U / m l ) t-PA Ag (ng/ml)
Flu~astatin
Placebo
59.9+28.5 • 236+ 1(13 26.3±26.1 1095:12.6 11.5+4.8
655:1:33.8 239+86 268:t. 199 10.8:1-I 1.9 119±5.9
• p < 0.05 vs placebo. Conclusions: We confirmed the high levels ofthrombomodulin, VWF Ag, PAI-I and t-PA Ag in transplanted heart recipients. Fluvastatin significantly decreased thrombomodulin without significant variation of PAl-I, VWF and t-PA, suggesting that fluvastatin reduces injury to the plasma membrane of endothelial cells.
Differences from baseline were highly significant (p < 0.0001). The 80 mg dose was well tolerated. The incidence of myopathy and increases (>3 fold upper limit of normal) in transaminases were 0% and 2.4%, respectively. Conclusions: Simvastatin 80 mg produces excellent lipid lowering efficacy and is well tolerated in FH patients.
A COMPARATIVE STUDY ON THE EFFICACY AND T O L E R A B I L I T Y OF P O L I C O S A N O L AND LOVASTATIN IN PATIENTS W I T H H Y P E R C H O L E S T E R O L E M I A AND HIGH CORONARY RISK G. Castafio, R. Mils I , J.C. Fermindez1, L.E. L6pez, V. Pontigas, M. Lescay.
SHORT-TERM EFFICACY AND SAFETY OF A NEW MODIFIEDRELEASE F O R M U L A T I O N OF FLUVASTAT1N M. Farnier, E Paillard. On behalf of the study inoestigators; Point Mrdical,
Dijon; Department of Cardiology, Uniuersity Hospital. Rennes, France Objective: To maximise first-pass hepatic extraction and reduce systemic exposure of higher doses of fluvastatin, a modified-release (MR) formulation o f fluvastatin 80 mg (matrix tablet) has been developed (Lescol XL). This formulation shows extended duration of drug release, markedly lower systemic drug levels and no dose-dumping with meals. Two phase II, randomised, observer-blind-to-lipids variables, parallel-group trials have been performed to evaluate the efficacy and tolerability of this formulation compared with conventional fluvastatin 40 mg capsules. Methods: After a 4-week placebo/dietary run-in phase, patients (mean age 53 years) with primary hypercholesterolaemia (type lla/IIb) defined by LDL-cholesterol > 160 mg/dl and triglycerides (TG) < 350 mg/dl were randomised to receive fluvastatin 80 mg MR (at bedtime) or conventional fluvastatin 40 mg twice daily (bid) for 4 weeks. Results: Pooled results (mean+SD) are presented in the table.
Center for Medical Surgical Research; /Center of Natural Products, National Center for Scientific Research, Hauana. C,lba This study compares the short-term efficacy, safety and tolerability of policosanol vs Iovastatin in patients with type II hypercholesterolemia and >2 non lipid risk factors. After 4 weeks on a standard cholesterol-lowering diet 59 patients were randomized to receive, under double-blind conditions, policosanol or Iovastatin (20 mg/d) tablets which were taken for 12 weeks. Policosanol significantly reduced (p < 0.000 01) cholesterol (22.4%); LDLC (32.8%) and the ratios of (p < 0.000 1) LDL-C to HDL-C (39.3%) and cholesterol to HDL-C (32%). Lovastatin significantly reduced total cholesterol (p < 0.000 I) (18.9%); LDL-C (25.4%) and the ratios of (p < 0.001) LDL-C to HDL-C (22.3%) and cholesterol to HDL-C (17.8%). Policosanol, but not Iovastatin, significantly raised HDL-C (p < 0.05) by 25.5%. LDL-C to HDL-C ratio was significantly lower (p < 0.05) in the policosanol group than in the Iovastatin group. Both drugs were safe and well tolerated Lovastatin significantly increased (p < 0.01) creatinphosphokinase levels; but individual values remained within the normal limits. Six patients (1 policosanol, 5 Iovastatin) withdrew from the study, two of them, (Iovastatin), because of adverse experiences (AE): gastrointestinal disturbances and skin rash. The frequency of patients referring AE, was
71st EAS. Congress and Satellite Symposia