- Email: [email protected]
A comparative study on the efficacy and tolerability of policosanol and lovastatin in patients with hypercholesterolemia and high coronary risk
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
Thursday, 27 May 1999 Poster session: Lipid lowering drugs higher in Iovastatin group (27.6%) than in policosanol groups (6.9%) most of them related with gastrointestinal AE. It is concluded that both drugs are suitable alternatives for patients with type 11 hypercholesterolemia and high coronary risk, policosanol shows advantages regarding to the tolerability of the treatment. A ONE YEAR OPEN STUDY ON THE EFFICACY, AND TOLERABILITY OF POLICOSANOL (20 mg/day) IN PATIENTS WITH HYPERCHOLESTEROLEMIA AND HIGH GLOBAL CORONARY RISK
Center for Medical Surgical Research: l Center of Natural Products, National Center fiJr Scientific Research. Hauana, Cuba G. Castafio, R. M~is 1 , J.C. Fernhndez 1 , L.E. L t p e z , V. Pontigas.
The present open study investigated the efficacy, safety and tolerability of policosanol (20 mg/d) in patients with type 1I hypercholesterolemia and high coronary risk. After 5 weeks on a step 1 cholesterol-lowering diet, 68 patients received policosanol 10 mg tablets and were instructed to take two daily tablets once-a-day with the evening meal for one year. All patients showed type 11 hypercholesterolemia and >2 non lipid coronary risk factors. At 2 months, policosanol significantly lowered (p < 0.000 01) levels of lowdensity lipoprotein cholesterol (LDL-C) (24.7%); total cholesterol (15.9%) and significantly raised HDL-C values by 31.1%. In consequence, the ratios of total cholesterol to HDL-C and LDL-C to HDL-C lowered by 29.8% and 38.2%, respectively. These effects were not wear off during the one year follow up. even enhanced. So, at 12 months the following percent reductions were obtained: LDL-C (44.8%), cholesterol (30.0%) and the ratios of cholesterol to HDL-C (54.1%) and LDL-C to HDL-C (62.7%), meanwhile HDL-C increased by 44.5%. Triglycerides significantly decreased from the 4th month up to study completion when decreased by 21.2%. The treatment was safe and well tolerated. No drug-related clinical or blood biochemical adverse experiences (AE) were detected. Nine patients withdrew from the study, but none because of AE. Four patients refered mild AE tdizziness, fatigue, muscle cramps and diaphoresis) during the study. The present work demonstrates that policosanol administered at 20 mg/d for one year in patients with type II hypercholesterolemia and high global coronary risk was very effective, safe and well tolerated. PLASMA LIPOPROTEINS, HEMORHEOLOGY AND DEVELOPEMENT OF CAROTID ATHEROSCLEROSIS UNDER LDL APHERESIS BY CASCADE FILTRATION H.C. Geiss, MG. Donner, C. Otto, P. Schwandt. Medical Department IL Klinikum Grosshadern. UniversiO, of Munich. Marchioninistl: 15. 81377 Ahtnich. Germany LDL apheresis is a lipid lowering means of therapy for patients with coronary heart disease and hereditary forms of hypercholesterolemia not adequately responsive to therapy with HMG CoA reductase inhibitors. We report on the acute (treatment 1-4) and long term (pretreatment concentrations under regular therapy) changes of lipoprotein and hemorheological parameters and the results of carotid intimal-medial thickness determinations in patients with severe familial hyperlipidemia and coronary heart disease (3 male, 1 female, age 41.3-I-3.3 years) regularly treated with LDL apheresis by cascade filtration and concomitant drug treatment with an HMG CoA reductase inhibitor for 23+14 (range 7--40) months. LDL apheresis was carried out with the H~imomat-Plasmomat (Diamed, Ktln, Germany) equipped with a plasma filter (Plasmaflow OR Asashi Medical Co. Tokyo, Japan) and cascade tilter with a pore size of 15 nm (Cascadeflow, AC-1770, Asashi Medical Co.). Acute cascade filtration decreased LDL cholesterol from 158+62 to 80+20 mg/dL, HDL cholesterol from 43:t:13 to 34+9 mg/dL and Lp (a) from 584-25 to 274-15 mg/dL. Erythrocyte aggregation declined from 5.44-0.6 to 1.84-0.5 U at stasis and from 8.9-t-l.3 to 6.4+0.9 U at a shear rate of 3/s. Whole blood viscosity at native hematocrit was only altered slightly (from 4.48+ 0.54 to 4.104-0.53 mPa*s at 25/s and from 3.884-0.35 to 3.53±0.37 mPa*s at 92/s). Plasma viscosity felt from 1.195:0.05 to 1.014-0.03 mPa*s. Two major determinants of plasma viscosity, fibrinogen and alpha-2-macroglobulin, fell by a mean of 45.5% and 47.5%, respectively. Under regular LDL apheresis pretreatment concentrations of LDL cholesterol, HDL cholesterol and Lp(a) were 125-1-27 mg/dL, 35-1-10 mg/dL and 57+18 mg/dL, respectively. Pretreatment fibrinogen and alpha2-macroglobulin were reduced by 16.6% and 20.2% as compared to concentrations before starting LDL apheresis, however hemorheological parameters were not altered. Ultrasonography o f the common carotid artery revealed no
27
change o f intimal-medial thickness (0.68+0.13 mm at baseline, n = 3) after an observation period of 21 + 1 months. We conclude that cascade filtration beside the sustained reduction of atherogenic lipoproteins acutely improves hemorheology and has a beneficial long term on major determinants of plasma viscosity. In patients with severe hereditary hyperlipidemia carotid intimal-medial thickness was found to be unchanged after a mean observation period of 21 months. This study was supported by a grant from Diamed. ACHIEVEMENT AND MAINTENANCE OF A TARGET PLASMA TOTAL CHOLESTEROL LEVEL OF <5.0 MMOL/L WITH LOW DOSE THERAPY WITH ATORVASTATIN OR SIMVASTATIN P.J. Barter, R.C. O'Brien. Department of Medicine. University of Adelaide. South; Department of Medicine, Monash University, Victoria. Australia
i
"1
A study was conducted in a primary care setting with 1028 patients being randomised in an open label design to receive 6 weeks of a daily dose of l0 mg of either atorvastatin or simvastatin. The randomisation was 2:1 in favour of atorvastatin, with 691 receiving atorvastatin and 337 simvastatin. The subjects were matched for age, gender, BMI, smoking, alcohol, the presence of coronary disease and baseline lipids. Mean lipid levels (retool/L) in the atorvastatin and simvastatin groups, respectively, were: plasma total cholesterol, %38 and 7.22; triglyceride, 2.07 and 1.98; HDL-cholesterol, 1.23 and 1.22. The percentages of patients achieving the plasma total cholesterol target of <5.0 mmol/L with l0 mg of either drug varied with the baseline level. In those with a baseline cholesterol levels ranging from 5.2 to 6.5 mmol/L, 71% of the atorvastatin group and 54% of the simvastatin group achieved the target. With baselines from 6.6 to 7.5 mmol/L, the target was achieved in 43% and 27% of the atorvastatin and simvastatin groups, respectively. Even with baseline total cholesterol levels ranging from 7.6 to 8.5 mmolFL, 21% and 7%, respectively, of the atorvastatin and simvastatin groups achieved the target. When the baseline was >8.5 retool/L, the target was achieved in 7 of the 95 patients on atorvastatin but in none of the 43 on simvastatin. Overall, the total cholesterol target was reached in 262 (38.0%) of the 691 subjects taking atorvastatin. When these 262 subjects were maintained on l0 mg atorvastatin and retested at weeks 12, 18 and 24, the numbers still at target were, respectively, 186 (26.9% of the total aturvastatin group), 189 (27.4%) and 174 (25.2%). Of those taking simvastatin, the target was reached initially in 86 (25.5%) of the 337 subjects. When these 86 subjects were maintained on l0 mg simvastatin and retested at weeks 12, 18 and 24, the numbers still at target were, respectively, 54 (16.0% of the total simvastatin group), 52 (15.4%) and 39 (11.6%).~ It may be concluded that: (i) even the lowest l0 mg dose of either atorvastatin or simvastatin has the capacity to achieve a target plasma total cholesterol of <5.0 mmol/L in a substantial proportion of patients being treated in primary care; (ii) it is necessary to retest plasma cholesterol levels periodically to ensure that the target is maintained. ROLE OF THROMBOXANE A2 AND ENDOTHEL1N ON ENDOTHELIAL DYSFUNCTION IN DYSLIPIDEM1C RABBITS. EFFECT OF ATORVASTATIN TREATMENT V. Cachofeiro, R. Maeso, J. Navarro-Cid, G. HernfindezI , C. Diaz 1, L.M. Ruilope, V. Lahera. I R&D Dept Parke Daois, Barcelona; Dept of
PhysioloKv. School of Medicine. UCM, 28040 Madrid, Spain We have studied the role of endothelin (ET) and thromboxane A2 (TX2A) on the endothelial dysfunction associated with dyslipidemia. Likewise, the effect of atorvastastin treatment was also evaluated. To this end, we studied acetylcholine (Ach)-indueed relaxations and contractions in aortic rings from rabbits treated or not with atorvastatin (2.5 mg/Kg/day) and fed a diet containing 0.5% cholesterol + 14% coconut oil for 14 weeks. Responses were studied in presence or either the TXA2 receptor antagonist, Ifetroban (10 --4 mol/L) or the ET-I receptor antagonist BQ 123 (10 4 ,mol/L). Plasma cholesterol and triglyceride concentrations were higher in rabbits fed the experimetal diet than control group (p < 0.05). Relaxing responses to Ach (10-9-10 -5 mol/L) were blunted in dyslipidemic rabbits. Incubation of aortic rings with either Ifetroban or BQI23 increased these responses in dyslipidemic and control rabbits. Constrictor responses to Ach in presence o f the NO synthase inhibitor LNAME (10 --4 mol/I) were higher in dyslipidemic rabbits than in control ones (P < 0.05). The presence of either ifetroban or BQI23 reduced this response only in dyslipidemic rabbits. Atorvastatin treatment reduced lipid levels only in dyslipidemie rabbits. Likewise, atorvastain enhanced the relaxing response to Ach in
71st EAS Congress and Satellite Symposia
C 0 C
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
Thursday, 27 May 1999 Poster session: Lipid lowering drugs higher in Iovastatin group (27.6%) than in policosanol groups (6.9%) most of them related with gastrointestinal AE. It is concluded that both drugs are suitable alternatives for patients with type 11 hypercholesterolemia and high coronary risk, policosanol shows advantages regarding to the tolerability of the treatment. A ONE YEAR OPEN STUDY ON THE EFFICACY, AND TOLERABILITY OF POLICOSANOL (20 mg/day) IN PATIENTS WITH HYPERCHOLESTEROLEMIA AND HIGH GLOBAL CORONARY RISK
Center for Medical Surgical Research: l Center of Natural Products, National Center fiJr Scientific Research. Hauana, Cuba G. Castafio, R. M~is 1 , J.C. Fernhndez 1 , L.E. L t p e z , V. Pontigas.
The present open study investigated the efficacy, safety and tolerability of policosanol (20 mg/d) in patients with type 1I hypercholesterolemia and high coronary risk. After 5 weeks on a step 1 cholesterol-lowering diet, 68 patients received policosanol 10 mg tablets and were instructed to take two daily tablets once-a-day with the evening meal for one year. All patients showed type 11 hypercholesterolemia and >2 non lipid coronary risk factors. At 2 months, policosanol significantly lowered (p < 0.000 01) levels of lowdensity lipoprotein cholesterol (LDL-C) (24.7%); total cholesterol (15.9%) and significantly raised HDL-C values by 31.1%. In consequence, the ratios of total cholesterol to HDL-C and LDL-C to HDL-C lowered by 29.8% and 38.2%, respectively. These effects were not wear off during the one year follow up. even enhanced. So, at 12 months the following percent reductions were obtained: LDL-C (44.8%), cholesterol (30.0%) and the ratios of cholesterol to HDL-C (54.1%) and LDL-C to HDL-C (62.7%), meanwhile HDL-C increased by 44.5%. Triglycerides significantly decreased from the 4th month up to study completion when decreased by 21.2%. The treatment was safe and well tolerated. No drug-related clinical or blood biochemical adverse experiences (AE) were detected. Nine patients withdrew from the study, but none because of AE. Four patients refered mild AE tdizziness, fatigue, muscle cramps and diaphoresis) during the study. The present work demonstrates that policosanol administered at 20 mg/d for one year in patients with type II hypercholesterolemia and high global coronary risk was very effective, safe and well tolerated. PLASMA LIPOPROTEINS, HEMORHEOLOGY AND DEVELOPEMENT OF CAROTID ATHEROSCLEROSIS UNDER LDL APHERESIS BY CASCADE FILTRATION H.C. Geiss, MG. Donner, C. Otto, P. Schwandt. Medical Department IL Klinikum Grosshadern. UniversiO, of Munich. Marchioninistl: 15. 81377 Ahtnich. Germany LDL apheresis is a lipid lowering means of therapy for patients with coronary heart disease and hereditary forms of hypercholesterolemia not adequately responsive to therapy with HMG CoA reductase inhibitors. We report on the acute (treatment 1-4) and long term (pretreatment concentrations under regular therapy) changes of lipoprotein and hemorheological parameters and the results of carotid intimal-medial thickness determinations in patients with severe familial hyperlipidemia and coronary heart disease (3 male, 1 female, age 41.3-I-3.3 years) regularly treated with LDL apheresis by cascade filtration and concomitant drug treatment with an HMG CoA reductase inhibitor for 23+14 (range 7--40) months. LDL apheresis was carried out with the H~imomat-Plasmomat (Diamed, Ktln, Germany) equipped with a plasma filter (Plasmaflow OR Asashi Medical Co. Tokyo, Japan) and cascade tilter with a pore size of 15 nm (Cascadeflow, AC-1770, Asashi Medical Co.). Acute cascade filtration decreased LDL cholesterol from 158+62 to 80+20 mg/dL, HDL cholesterol from 43:t:13 to 34+9 mg/dL and Lp (a) from 584-25 to 274-15 mg/dL. Erythrocyte aggregation declined from 5.44-0.6 to 1.84-0.5 U at stasis and from 8.9-t-l.3 to 6.4+0.9 U at a shear rate of 3/s. Whole blood viscosity at native hematocrit was only altered slightly (from 4.48+ 0.54 to 4.104-0.53 mPa*s at 25/s and from 3.884-0.35 to 3.53±0.37 mPa*s at 92/s). Plasma viscosity felt from 1.195:0.05 to 1.014-0.03 mPa*s. Two major determinants of plasma viscosity, fibrinogen and alpha-2-macroglobulin, fell by a mean of 45.5% and 47.5%, respectively. Under regular LDL apheresis pretreatment concentrations of LDL cholesterol, HDL cholesterol and Lp(a) were 125-1-27 mg/dL, 35-1-10 mg/dL and 57+18 mg/dL, respectively. Pretreatment fibrinogen and alpha2-macroglobulin were reduced by 16.6% and 20.2% as compared to concentrations before starting LDL apheresis, however hemorheological parameters were not altered. Ultrasonography o f the common carotid artery revealed no
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change o f intimal-medial thickness (0.68+0.13 mm at baseline, n = 3) after an observation period of 21 + 1 months. We conclude that cascade filtration beside the sustained reduction of atherogenic lipoproteins acutely improves hemorheology and has a beneficial long term on major determinants of plasma viscosity. In patients with severe hereditary hyperlipidemia carotid intimal-medial thickness was found to be unchanged after a mean observation period of 21 months. This study was supported by a grant from Diamed. ACHIEVEMENT AND MAINTENANCE OF A TARGET PLASMA TOTAL CHOLESTEROL LEVEL OF <5.0 MMOL/L WITH LOW DOSE THERAPY WITH ATORVASTATIN OR SIMVASTATIN P.J. Barter, R.C. O'Brien. Department of Medicine. University of Adelaide. South; Department of Medicine, Monash University, Victoria. Australia
i
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A study was conducted in a primary care setting with 1028 patients being randomised in an open label design to receive 6 weeks of a daily dose of l0 mg of either atorvastatin or simvastatin. The randomisation was 2:1 in favour of atorvastatin, with 691 receiving atorvastatin and 337 simvastatin. The subjects were matched for age, gender, BMI, smoking, alcohol, the presence of coronary disease and baseline lipids. Mean lipid levels (retool/L) in the atorvastatin and simvastatin groups, respectively, were: plasma total cholesterol, %38 and 7.22; triglyceride, 2.07 and 1.98; HDL-cholesterol, 1.23 and 1.22. The percentages of patients achieving the plasma total cholesterol target of <5.0 mmol/L with l0 mg of either drug varied with the baseline level. In those with a baseline cholesterol levels ranging from 5.2 to 6.5 mmol/L, 71% of the atorvastatin group and 54% of the simvastatin group achieved the target. With baselines from 6.6 to 7.5 mmol/L, the target was achieved in 43% and 27% of the atorvastatin and simvastatin groups, respectively. Even with baseline total cholesterol levels ranging from 7.6 to 8.5 mmolFL, 21% and 7%, respectively, of the atorvastatin and simvastatin groups achieved the target. When the baseline was >8.5 retool/L, the target was achieved in 7 of the 95 patients on atorvastatin but in none of the 43 on simvastatin. Overall, the total cholesterol target was reached in 262 (38.0%) of the 691 subjects taking atorvastatin. When these 262 subjects were maintained on l0 mg atorvastatin and retested at weeks 12, 18 and 24, the numbers still at target were, respectively, 186 (26.9% of the total aturvastatin group), 189 (27.4%) and 174 (25.2%). Of those taking simvastatin, the target was reached initially in 86 (25.5%) of the 337 subjects. When these 86 subjects were maintained on l0 mg simvastatin and retested at weeks 12, 18 and 24, the numbers still at target were, respectively, 54 (16.0% of the total simvastatin group), 52 (15.4%) and 39 (11.6%).~ It may be concluded that: (i) even the lowest l0 mg dose of either atorvastatin or simvastatin has the capacity to achieve a target plasma total cholesterol of <5.0 mmol/L in a substantial proportion of patients being treated in primary care; (ii) it is necessary to retest plasma cholesterol levels periodically to ensure that the target is maintained. ROLE OF THROMBOXANE A2 AND ENDOTHEL1N ON ENDOTHELIAL DYSFUNCTION IN DYSLIPIDEM1C RABBITS. EFFECT OF ATORVASTATIN TREATMENT V. Cachofeiro, R. Maeso, J. Navarro-Cid, G. HernfindezI , C. Diaz 1, L.M. Ruilope, V. Lahera. I R&D Dept Parke Daois, Barcelona; Dept of
PhysioloKv. School of Medicine. UCM, 28040 Madrid, Spain We have studied the role of endothelin (ET) and thromboxane A2 (TX2A) on the endothelial dysfunction associated with dyslipidemia. Likewise, the effect of atorvastastin treatment was also evaluated. To this end, we studied acetylcholine (Ach)-indueed relaxations and contractions in aortic rings from rabbits treated or not with atorvastatin (2.5 mg/Kg/day) and fed a diet containing 0.5% cholesterol + 14% coconut oil for 14 weeks. Responses were studied in presence or either the TXA2 receptor antagonist, Ifetroban (10 --4 mol/L) or the ET-I receptor antagonist BQ 123 (10 4 ,mol/L). Plasma cholesterol and triglyceride concentrations were higher in rabbits fed the experimetal diet than control group (p < 0.05). Relaxing responses to Ach (10-9-10 -5 mol/L) were blunted in dyslipidemic rabbits. Incubation of aortic rings with either Ifetroban or BQI23 increased these responses in dyslipidemic and control rabbits. Constrictor responses to Ach in presence o f the NO synthase inhibitor LNAME (10 --4 mol/I) were higher in dyslipidemic rabbits than in control ones (P < 0.05). The presence of either ifetroban or BQI23 reduced this response only in dyslipidemic rabbits. Atorvastatin treatment reduced lipid levels only in dyslipidemie rabbits. Likewise, atorvastain enhanced the relaxing response to Ach in
71st EAS Congress and Satellite Symposia
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