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W16-IS-002 Treating to new targets: Anatomy of a clinical trial
Workshops W16 Treatment of atherosclerosis risk
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Wl 6-1S-002 / TREATING TO NEW TARGETS: ANATOMY OF A CLINICAL TRIAL J. Shepherd. Vascular Biochemistry, Royal Infirmary, Glasgow, Scotland,
UK Objective: Statins have revolutionised the clinician's ability to control hypercholesterolaemia and in consequence reduce vascular risk. Nevertheless, there is still debate over the value of reducing low density lipoprotein (LDL) cholesterol levels below current guideline targets (in the USA) of 2.6 mmol/1 (100 mg/dl) in individuals with overt coronary heart disease (CHD). The Treating to New Taxgets (TNT) study was established in an attempt to address that issue. Methods: Ten thousand and one 35-75 year old men and women with clinically evident CHD and LDLc between 3.4 and 6.5 mmol/1 (130-250 mg/dl) were randomised to receive, double blind, either 10 or 80 mg of atorvastatin/day following washout of their existing lipid lowering drug regimen and an 8 week open label treatment period with 10 nag atorvastatin daily. The mean age of the cohort was 61 years and their mean LDLc at baseline was 2.5 mmol/l (98 mg/dl). Subjects were followed for an average of 5 years and the primary endpoint of the project was the time to occurrence of a major cardiovascular event (defined as CHD death, nonfatal myocardial infarction, resuscitated cardiac arrest and fatal or nonfatal stroke). Outcome: The trial was stopped in June 2004, by which time the prespecified number (approximately 950) of endpoints had occurred. This presentation will describe the primary results of the study and provide the first randomised clinical trial evidence of the merit (or lack thereof) of very aggressive LDLc lowering in patients with established CHD. Presented on behalf of the TNT Investigators.
W16-O-001 ] FLUVASTATIN ADDITIONAL BENEFIT BEYOND LDL-C REDUCTION: A COMPARISON OF CARDIOVASCULAR EVENTS RISK IN PATIENTS W I T H THE SAME LEVEL OF ON TREATMENT LDL K. Boguerts 1, S. Tsonaka 1, D. Rizopoulous 1, E. Lessafre 1, C. Gimpelewicz 2, J.O. Logan 2, M. Bortolini 2 . iBioastatistical Centre,
Katholieke University Lueven, Belguim; 2Novartis Pharma AG, Base~ Switzerland Objective: Over the past few years there has been much debate on the clinical meaning and the impact of the non lipid-related (pleiotropic) effects of statins on cardiovascular outcome. Fluvastatin has shown pleiotropic effects in several in vitro and ex vivo models. In order to evaluate whether the clinical benefit of fluvastatin treatment related to a non-lipid reduction effect, we conducted this post-hoc analysis aimed at evaluating the effect of treatment in a subgroup of "matching patients" who reached the same level of cholesterol in the fluvastatin and placebo arms during the study. Methods: A total of 1,677 patients with stable or unstable angina or silent ischemia were randomized to receive treatment with fluvastatin 80 mg/day (40 mg twice daily) or corresponding placebo. Patients compliant with study medication in the placebo group were matched with compliant patients in the Fluvastatin group who had the same gender, age + 5 years and on treatment LDL-values -4- 5% of the range of the on-treatment LDL-values in the placebo group. Cox regression, adjusted for important prognostic factors, was used to estimate any residual treatment effect. Remits: A total of 338 patients were matched on a one-to-one basis, resulting in 169 patients in each treatment arm. The mean age was 59.9 years for the fluvastatin arm and 60.2 years for the placebo arm, 87.9% of the patients were males in the both treatment arms. The mean on ~.reatment LDL cholesterol values were 3.03 mmol/L (SD 0.49) for the placebo group and 2.99 mmol/L (SD 0.48) in the fluvastatin group. Fifty two MACEs were observed overall, 20/169 (11.83%) events in the fluvastatin group and 32/169 (18.93%) in the placebo group with a risk reduction of 39%, p= 0.086 (HR 0, 61, 95% CI 0.35-1.07). Conclusion: A favourable trend with a non significant 39% reduction in the risk of MACE was observed in the Fluvastatin group compared to the placebo group of matched patients with similar on-treatment LDL values. This analysis suggests that fluvastatin may exert additional benefits beyond the reduction of LDL-C.
] W l 6-O-002 /J EFFECT OF FLUVASTATIN AND FENOFIBRATE ON ATHEROSCLEROTIC PLAQUES IN CAROTID ARTERIES - NEUROLOGICAL ULTRASONIC STUDY D. Skoloudik 1, M. Bar 1, O. Skoda 2, D. Vaclavik 3, J. Korsa4 . 1Dept. of
Neurology, University Hospital Ostrava-Poruba; 2Dept. of Neurology, City Hospital Pelhrimov; ~Dept. of Neurology, BMA Hospital Ostrava; "Dept. of Neurology, Faculty Hospital KV Praha, Czech Republic Introduction: In NUS study we directly compared statin and fibrate in progression of atherosclerotic (AS) plaque width and number of vascular events. Methods: Neurological ultrasonic study is a multicenter, blinded, randomized study tested effect of fluvastatin (40mg) and fenofibrate (200mg) in progression of AS plaque in carotid bifurcation among patients with central neurological symptoms, hypercholesterolaemia and AS plaque in carotid bifurcation over 2 mm width. Patients were randomized to two therapeutical groups. They underwent US examination of carotids with plaque width measurement every 3 months in time period of 2 years (9 measurements). We registered all vascular events and plasma levels of lipids after 12 and 24 months. Results: To the NUS study we randomised 376 patients, 355 patients passed through all inclusion and exclusion criteria. 297 patients underwent all 9 US examinations. Mean progression of AS plaque width in fluvastatin group was 0.08mm, in fenofibrate group 0.20mm. This result was statistically significant (P<0.02). In both groups were no differences in distribution of risk factors (plasma levels of lipids, TIA/stroke, CHD, hypertension, diabetes mellitus, smoking, BMI). No significant difference was detected between both therapeutic groups in number of vascular events - 36 (fluvastatin) vs. 29 (fenofibrate) events. In fenofibrate/fluvastatin group was detected decrease of total cholesterol plasma level by 15/20%, LDL-c by 16/26%, TAG by 36/23% and increase of HDL-c by 8/9%. Progression of AS plaque width was not dependent on any other observed risk factor. Conclusion: Fluvastatin statistically significant reduce progression of AS plaque width in carotid bifurcation.
Wl 6-O-003 / EFFICACY AND SAFETY OF ROSUVASTATIN 40 M G IN PATIENTS W I T H SEVERE TYPE IIA AND IIB HYPERCHOLESTEROLAEMIA E.A. Stein 1, H. Melezinkova 2 , F. Le Maulf 2, A. Gold 3 . 1Metabolic & Atherosclerosis Research Center, Cincinnati, Ohio, USA; 2AstraZeneca, Alderley Park, UK; 3AstraZeneca, Wilmington, Del, USA This open-label, noncomparative, multicentre study (4522IL/ 0091) assessed the efficacy and safety of rosuvastatin (RSV) 40 nag in pts with severe type IIa and lib dyslipidaemia, including heterozygous familial hy percholesterolue mia. Methods: After a 6-wk dietary lead-in, 1382 pts (aged >18 years) with fasting LDL-C _>4.9 and <6.7 mmol/L and triglycerides <4.5 mmol/L were allocated to treatment with RSV 40 mg for 48 wks. The 2 primary end points were % of pts achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-C goal after 12 wks' treatment, and safety, as assessed by occurrence and severity of adverse events and abnormal laboratory values. Primary efficacy end point was assessed using means and 95% confidence intervals, using intention-to-treat population with last observation carried forward; safety end points were summarized by descriptive statistics. Results: PropoaJon of pts treated with RSV 40 nag who achieved their NCEP ATP III LDL-C goal was 83% (95% CI = [81, 85]) at 12 wks and 80% (95% CI = [78, 83]) at48 wks. European LDL-C goal of <3.0 mmol/L was achieved by 78% of pts at 12 wks. After 48 wks RSV significantly reduced LDL-C from baseline by 52% and increased HDL-C by 11% (both p<0.0001). There was improvement in all other lipids and lipoproteins: apelipoprotein (apt) B 43% decrease, apt A-I 8% increase, apt B/apt A-I 46% decrease (all p <0.0001). In all study pts, occurrence of persistent elevations in alanine aminotransferase (>3 x ULN on _>2 consecutive occasions) was low (0.7%). During 48 wks, transient creatine kinase (CK) elevations (>10 x ULN) were observed in 15 pts (1.1%); in 14 pts, these elevations were related to exercise, and 12 pts continued in the study without further significant CK increases. No cases of rhabdomyolysis or drug-related renal failure occurred. At 48 wks, proteinuria (shift in dipstick urine protein from none or trace at baseline to _> ++) occurred in 1.5% of pts, and the mean calculated glomerular filtration rate increased from 69.96 mL/min/1.73m2 at baseline to 71.14 mL/min/1.73m2. The % of pts withdrawing from the study because of adverse events was low (5.3%). Objective:
75th EAS Congress, 23-26 April 2005, Prague, Czech Republic
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Wl 6-1S-002 / TREATING TO NEW TARGETS: ANATOMY OF A CLINICAL TRIAL J. Shepherd. Vascular Biochemistry, Royal Infirmary, Glasgow, Scotland,
UK Objective: Statins have revolutionised the clinician's ability to control hypercholesterolaemia and in consequence reduce vascular risk. Nevertheless, there is still debate over the value of reducing low density lipoprotein (LDL) cholesterol levels below current guideline targets (in the USA) of 2.6 mmol/1 (100 mg/dl) in individuals with overt coronary heart disease (CHD). The Treating to New Taxgets (TNT) study was established in an attempt to address that issue. Methods: Ten thousand and one 35-75 year old men and women with clinically evident CHD and LDLc between 3.4 and 6.5 mmol/1 (130-250 mg/dl) were randomised to receive, double blind, either 10 or 80 mg of atorvastatin/day following washout of their existing lipid lowering drug regimen and an 8 week open label treatment period with 10 nag atorvastatin daily. The mean age of the cohort was 61 years and their mean LDLc at baseline was 2.5 mmol/l (98 mg/dl). Subjects were followed for an average of 5 years and the primary endpoint of the project was the time to occurrence of a major cardiovascular event (defined as CHD death, nonfatal myocardial infarction, resuscitated cardiac arrest and fatal or nonfatal stroke). Outcome: The trial was stopped in June 2004, by which time the prespecified number (approximately 950) of endpoints had occurred. This presentation will describe the primary results of the study and provide the first randomised clinical trial evidence of the merit (or lack thereof) of very aggressive LDLc lowering in patients with established CHD. Presented on behalf of the TNT Investigators.
W16-O-001 ] FLUVASTATIN ADDITIONAL BENEFIT BEYOND LDL-C REDUCTION: A COMPARISON OF CARDIOVASCULAR EVENTS RISK IN PATIENTS W I T H THE SAME LEVEL OF ON TREATMENT LDL K. Boguerts 1, S. Tsonaka 1, D. Rizopoulous 1, E. Lessafre 1, C. Gimpelewicz 2, J.O. Logan 2, M. Bortolini 2 . iBioastatistical Centre,
Katholieke University Lueven, Belguim; 2Novartis Pharma AG, Base~ Switzerland Objective: Over the past few years there has been much debate on the clinical meaning and the impact of the non lipid-related (pleiotropic) effects of statins on cardiovascular outcome. Fluvastatin has shown pleiotropic effects in several in vitro and ex vivo models. In order to evaluate whether the clinical benefit of fluvastatin treatment related to a non-lipid reduction effect, we conducted this post-hoc analysis aimed at evaluating the effect of treatment in a subgroup of "matching patients" who reached the same level of cholesterol in the fluvastatin and placebo arms during the study. Methods: A total of 1,677 patients with stable or unstable angina or silent ischemia were randomized to receive treatment with fluvastatin 80 mg/day (40 mg twice daily) or corresponding placebo. Patients compliant with study medication in the placebo group were matched with compliant patients in the Fluvastatin group who had the same gender, age + 5 years and on treatment LDL-values -4- 5% of the range of the on-treatment LDL-values in the placebo group. Cox regression, adjusted for important prognostic factors, was used to estimate any residual treatment effect. Remits: A total of 338 patients were matched on a one-to-one basis, resulting in 169 patients in each treatment arm. The mean age was 59.9 years for the fluvastatin arm and 60.2 years for the placebo arm, 87.9% of the patients were males in the both treatment arms. The mean on ~.reatment LDL cholesterol values were 3.03 mmol/L (SD 0.49) for the placebo group and 2.99 mmol/L (SD 0.48) in the fluvastatin group. Fifty two MACEs were observed overall, 20/169 (11.83%) events in the fluvastatin group and 32/169 (18.93%) in the placebo group with a risk reduction of 39%, p= 0.086 (HR 0, 61, 95% CI 0.35-1.07). Conclusion: A favourable trend with a non significant 39% reduction in the risk of MACE was observed in the Fluvastatin group compared to the placebo group of matched patients with similar on-treatment LDL values. This analysis suggests that fluvastatin may exert additional benefits beyond the reduction of LDL-C.
] W l 6-O-002 /J EFFECT OF FLUVASTATIN AND FENOFIBRATE ON ATHEROSCLEROTIC PLAQUES IN CAROTID ARTERIES - NEUROLOGICAL ULTRASONIC STUDY D. Skoloudik 1, M. Bar 1, O. Skoda 2, D. Vaclavik 3, J. Korsa4 . 1Dept. of
Neurology, University Hospital Ostrava-Poruba; 2Dept. of Neurology, City Hospital Pelhrimov; ~Dept. of Neurology, BMA Hospital Ostrava; "Dept. of Neurology, Faculty Hospital KV Praha, Czech Republic Introduction: In NUS study we directly compared statin and fibrate in progression of atherosclerotic (AS) plaque width and number of vascular events. Methods: Neurological ultrasonic study is a multicenter, blinded, randomized study tested effect of fluvastatin (40mg) and fenofibrate (200mg) in progression of AS plaque in carotid bifurcation among patients with central neurological symptoms, hypercholesterolaemia and AS plaque in carotid bifurcation over 2 mm width. Patients were randomized to two therapeutical groups. They underwent US examination of carotids with plaque width measurement every 3 months in time period of 2 years (9 measurements). We registered all vascular events and plasma levels of lipids after 12 and 24 months. Results: To the NUS study we randomised 376 patients, 355 patients passed through all inclusion and exclusion criteria. 297 patients underwent all 9 US examinations. Mean progression of AS plaque width in fluvastatin group was 0.08mm, in fenofibrate group 0.20mm. This result was statistically significant (P<0.02). In both groups were no differences in distribution of risk factors (plasma levels of lipids, TIA/stroke, CHD, hypertension, diabetes mellitus, smoking, BMI). No significant difference was detected between both therapeutic groups in number of vascular events - 36 (fluvastatin) vs. 29 (fenofibrate) events. In fenofibrate/fluvastatin group was detected decrease of total cholesterol plasma level by 15/20%, LDL-c by 16/26%, TAG by 36/23% and increase of HDL-c by 8/9%. Progression of AS plaque width was not dependent on any other observed risk factor. Conclusion: Fluvastatin statistically significant reduce progression of AS plaque width in carotid bifurcation.
Wl 6-O-003 / EFFICACY AND SAFETY OF ROSUVASTATIN 40 M G IN PATIENTS W I T H SEVERE TYPE IIA AND IIB HYPERCHOLESTEROLAEMIA E.A. Stein 1, H. Melezinkova 2 , F. Le Maulf 2, A. Gold 3 . 1Metabolic & Atherosclerosis Research Center, Cincinnati, Ohio, USA; 2AstraZeneca, Alderley Park, UK; 3AstraZeneca, Wilmington, Del, USA This open-label, noncomparative, multicentre study (4522IL/ 0091) assessed the efficacy and safety of rosuvastatin (RSV) 40 nag in pts with severe type IIa and lib dyslipidaemia, including heterozygous familial hy percholesterolue mia. Methods: After a 6-wk dietary lead-in, 1382 pts (aged >18 years) with fasting LDL-C _>4.9 and <6.7 mmol/L and triglycerides <4.5 mmol/L were allocated to treatment with RSV 40 mg for 48 wks. The 2 primary end points were % of pts achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-C goal after 12 wks' treatment, and safety, as assessed by occurrence and severity of adverse events and abnormal laboratory values. Primary efficacy end point was assessed using means and 95% confidence intervals, using intention-to-treat population with last observation carried forward; safety end points were summarized by descriptive statistics. Results: PropoaJon of pts treated with RSV 40 nag who achieved their NCEP ATP III LDL-C goal was 83% (95% CI = [81, 85]) at 12 wks and 80% (95% CI = [78, 83]) at48 wks. European LDL-C goal of <3.0 mmol/L was achieved by 78% of pts at 12 wks. After 48 wks RSV significantly reduced LDL-C from baseline by 52% and increased HDL-C by 11% (both p<0.0001). There was improvement in all other lipids and lipoproteins: apelipoprotein (apt) B 43% decrease, apt A-I 8% increase, apt B/apt A-I 46% decrease (all p <0.0001). In all study pts, occurrence of persistent elevations in alanine aminotransferase (>3 x ULN on _>2 consecutive occasions) was low (0.7%). During 48 wks, transient creatine kinase (CK) elevations (>10 x ULN) were observed in 15 pts (1.1%); in 14 pts, these elevations were related to exercise, and 12 pts continued in the study without further significant CK increases. No cases of rhabdomyolysis or drug-related renal failure occurred. At 48 wks, proteinuria (shift in dipstick urine protein from none or trace at baseline to _> ++) occurred in 1.5% of pts, and the mean calculated glomerular filtration rate increased from 69.96 mL/min/1.73m2 at baseline to 71.14 mL/min/1.73m2. The % of pts withdrawing from the study because of adverse events was low (5.3%). Objective:
75th EAS Congress, 23-26 April 2005, Prague, Czech Republic
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