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Cost-effectiveness of statins for primary and secondary prevention: A continuum of risk model linking WOSCOPS and care
Thursday. 27 May 1999 Poster session: Lipid lowering drugs COST-EFFECTIVENESS OF STATINS FOR PRIMARY AND SECONDARY PREVENTION: A C O N T I N U U M OF RISK M O D E L LINKING WOSCOPS AND CARE l.J. Caro 1 , W. Klittich 1, A, McGuire 2, G. Ultalien 3, J. O'Brien 1, ~ 4 j. Ehreth s. t Caro Research; -~BristoI-Myers Squibb, USA," :City
University UK," 4Paris University." 5Bristol-M),erw Squibb. France Economic analyses on cardiovascular disease (CVD) prevention by lowering cholesterol with statin therapy have generated controversy on the most efficient allocation of health care funds: primary prevention, secondary ~r both? To derive the cost-effectiveness and the incremental benefit of each prevention strategy, our economic model of pravastatin use in primary prevention of CVD based directly on WOSCOPS data was modified to include sequential secondary prevention data from CARE. The primary prevention module follows a cohort starting on pravastatin or placebo until first fatal CVD, acute myocardial infarction (MI), angina, CABG, PTCA, :oronary angiography, stroke or TIA occurs. Patients with non-fatal MI, angina, CABG, or PTCA, are considered for secondary prevention, and all subsequent CVD events over a maximum of five years corresponding to the average follow-up from CARE are counted. Life expectancy was derived separately for primary and secondary events. The inpatient costs for each event type were estimated for France and UK. The differences in events, costs and life years gained were calculated. Cost-effectiveness ratios were derived for various possible prevention scenarios. The development of an integrated primary to secondary prevention model will help identify the most cost-effective prevention strategy and guide proper allocation of health care funds. CHANGES IN PARAOXONASE AND A P O L I P O P R O T E I N S / A I, A II, B, C Ill, E/ DURING T H E R A P Y OF C O M B I N E D FAMILIAL H Y P E R L I P I D E M I A BY C I P R O F I B R A T E J. Turay, V. Grniakov~i, J. Vfilka. Department of Clinical Biochemistr3:
Regional Ho.wital. Zvolen, Slovakia Fibrates are very often used in the therapy of combined familiar hyperlipidemia /CFH/. During the treatment CFH we investigated changes of paraoxonase which has anti-oxidating and antiatherogenic characteristics and changes of apolipoproteins which are determined by activating of nuclear receptors PPARs. We investigated efficiency of these changes on 15. pacients with CFH treated by Lipanor 100 during 24 weeks. We have been found significant changes p < 0.01 of apo C 111. apo E in B particles and also apo A I during the screend intervals. Despite of the fact that there is the association paraoxonase with HDL we did not find correlation in changes of paraoxonase with HDL or with HDL subfractions. During the treatment paraoxonase decreased. We may assess that Ciprofibrate influences apo C 111 by means activating of nuclear receptors which are able to change gene expresion. Ciprofibrate also causes changes in level of paraoxonase which is important enzyme in antioxidating process. DIFFERENCES IN I N T E R A C T I O N OF H M G - C o A REDUCTASE INHIBITORS W I T H VARIOUS C Y T O C H R O M E - P 4 5 0 ENZYMES IN H U M A N LIVER M I C R O S O M E S , AND IN HUMAN AND SIMIAN HEPATOCYTES L.H. Cohen, R.E.W. Van Leeuwen, Ch. Van Thiel. TNO-PG, Gaubhts Laboratoo'. Zernikedreef 9, PO. Box 2215. 2301 CE Leiden, The Netherlands
Drug-drug interaction must be taken into account for cholesterol lowering drugs, because they are used daily up to a high age and therefore are most probably coadministered with other drugs. Several cytochromeP450 (CYP) isoenzymes are involved in drug metabolism in the liver and different drugs interact with specific members of this enzyme family. We investigated which of these enzymes are influenced by the HMG-CoA reductase inhibitors Iovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), aturvastatin (A) and cerivastatin (C). Using three different human liver microsomal preparations the effect of various concentrations (up to 400 p.M) of these statins was studied on the following reactions: nifedipine aromatization (CYP3A), testosterone 6~-hydroxylation (CYP3A4), tolbutamide hydroxylation (CYP2C8/9), S-mephenytoin 4-hydroxylation (CYP2CI9), bufuralol l-hydroxylation (CYP2D6), aniline 4-hydroxylation (CYP2EI), coumarin 7-hydroxylation (CYP2A6) and 7-ethoxyresorufin O-dealkylation (CYPIAI/2). The statins did not influence the CYPIAI/2 activity and only
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very slightly the CYP2A6 and CYP2EI activities. Except P, the other statins inhibited these activities for 25% at 400 p.M. The latter drugs were stronger inhibitors of the CYP2CI9 activity with ICso-values around 200 P.M and the same holds for the effect of A, C and F on the CYP2D6 activity. L and S were weaker inhibitors of the latter enzyme activity, whereas P did not influence both activities. About the same was observed for the statin effect on CYP2C8/9 activity, except that F was a strong inhibitor of this CYP (ICso-value 4 p.M). CYP3A4 activity was similarly inhibited by C, S, A, F and L (ICs0-values 100--200 p.M), but not by P. The inhibitory effects observed in oitro were verified in suspension culture of freshly isolated hepatocytes from Cynomolgus monkey (as a readily available model) and in cells isolated from human liver. In general the same trends were seen as in the human microsomes, except that in some cases the inhibition of the CYP activity was less or even increased, possibly by the induction of the particular CYP enzyme by incubation of the cells with a particular statin. A was the most potent inhibitor o f CYP3A(4) activity and F remained a very strong inhibitor of CYP2C8/9 activity in human and monkey hepatocytes. S, L, and C were moderate inhibitors of CYP3A (4) and CYP2C8/9 in human hepatocytes. CYP2D6 was inhibited at higher concentrations of S, L, C, A and F in both cellular systems. P hardly affected any of the CYP activities in the three systems studied. It is concluded that the statins differ in their effects on different CYP isoenzymes and differences between these drugs in their interaction with other drugs are to be expected. SERUM LP(n), INSULIN RESISTANCE, M E T A B O L I C RISK FACTORS FOR CARDIOVASCULAR DISEASE, AND T H E LONG T E R M EFFECTS OF BEZAFIBRATE IN TYPE 2 DIABETES R.S. Elkeles, J.R. Diamond, G. Salerno, C. Hughes, W. Richmond, V. Anyaoku. The SENDCAP Study Group: Imperial College School of
Medicine at St. Ma~. ~ Hospital, London W2 INY UK We investigated the relationship of serum lipoprotein Ca) [Lp(a)] to insulin resistance and other risk factors for cardiovascular disease, in Type 2 diabetic subjects. We studied 241 established Type 2 diabetic men and women, mean age 51 years, with no known cardiovascular disease, screened for entry into the SENDCAP intervention study with bezafibrate. Median concentration of Lp(a) was higher in 27 Afro-Caribbeans (36.2 mg d l-I ) than in 119 Caucasians (8.1 mg dl -I ) or 84 Asians (10.4 mg d1-1) (p = 0.0007). Serum Lp(a) was inversely related to serum triglyceride, serum insulin and insulin resistance as measured by HOMA-IR and positively related to HDL cholesterol and Apo AI. Multiple regression analysis confirmed the inverse relationship of Lp(a) to serum triglyceride together with a positive relationship to non-HDL cholesterol and higher concentrations in the AfroCaribbean group. Bezafibrate was effective in reducing serum triglyceride, total and LDL cholesterol and in increasing HDL cholesterol in Type 2 diabetic subjects over at least four years but had no significant effect on Lp(a) concentration. There was a small reduction in insulin resistance but neither change in serum triglyceride nor in HDL cholesterol during treatment could be explained by baseline insulin resistance or by change in insulin resistance. ATORVASTATIN T R E A T M E N T - R E L A T E D C H A N G E S T O IN VIVO OXIDANT:ANTIOXIDANT BALANCE AS ASSESSED BY P L A S M A A L L A N T O I N AND LIPID STANDARDISED VITAMIN E LEVELS I.EE Benzie 1, B. Tomlinsonz, W.Y. Chung 1, Y.T. Szeto 1. tDepartment of Nursing & Health Sciences. Hong Kong Pol.vtechnic UniversiO" Kowloon. Hong Kong." 2Division of Clinical Pharmacology, Chinese University of Hong Kong, Hong Kong, China Atorvastatin has been reported to have anfioxidant properties in vitro. We have now studied in vioo atorvastatin treatment-related changes in oxidant:antioxidant balance using allantoin, an oxidative product of unite, as a biomarker of oxidative stress, and vitamin E, the major in oioo lipophilic ,antioxidant, as a marker of antioxidant status. Fasting plasma samples from 26 hypercholesterolaemic patients were collected before and after 16 weeks' treatment with increasing doses of atorvastatin up to 40 or 80 mg/day. Plasma urate and allantoin were measured simultaneously using an HPLC method; vitamin E was measured using a fluorimetrie technique; total cholesterol (TC) and triglycerides (TG) were measured using enzymatic methods. Allantoin decreased (P < 0.001) with atorvastafin treatment; from mean (SEM) 19.2 (1.62) to 6.2 (1.25) p.mol/I. Urate did not change: 346 (15.2) and 343 (17.1) p.mol/l, indicating the change in allantoin was not related
71st EAS Congress and Satellite Symposia
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University UK," 4Paris University." 5Bristol-M),erw Squibb. France Economic analyses on cardiovascular disease (CVD) prevention by lowering cholesterol with statin therapy have generated controversy on the most efficient allocation of health care funds: primary prevention, secondary ~r both? To derive the cost-effectiveness and the incremental benefit of each prevention strategy, our economic model of pravastatin use in primary prevention of CVD based directly on WOSCOPS data was modified to include sequential secondary prevention data from CARE. The primary prevention module follows a cohort starting on pravastatin or placebo until first fatal CVD, acute myocardial infarction (MI), angina, CABG, PTCA, :oronary angiography, stroke or TIA occurs. Patients with non-fatal MI, angina, CABG, or PTCA, are considered for secondary prevention, and all subsequent CVD events over a maximum of five years corresponding to the average follow-up from CARE are counted. Life expectancy was derived separately for primary and secondary events. The inpatient costs for each event type were estimated for France and UK. The differences in events, costs and life years gained were calculated. Cost-effectiveness ratios were derived for various possible prevention scenarios. The development of an integrated primary to secondary prevention model will help identify the most cost-effective prevention strategy and guide proper allocation of health care funds. CHANGES IN PARAOXONASE AND A P O L I P O P R O T E I N S / A I, A II, B, C Ill, E/ DURING T H E R A P Y OF C O M B I N E D FAMILIAL H Y P E R L I P I D E M I A BY C I P R O F I B R A T E J. Turay, V. Grniakov~i, J. Vfilka. Department of Clinical Biochemistr3:
Regional Ho.wital. Zvolen, Slovakia Fibrates are very often used in the therapy of combined familiar hyperlipidemia /CFH/. During the treatment CFH we investigated changes of paraoxonase which has anti-oxidating and antiatherogenic characteristics and changes of apolipoproteins which are determined by activating of nuclear receptors PPARs. We investigated efficiency of these changes on 15. pacients with CFH treated by Lipanor 100 during 24 weeks. We have been found significant changes p < 0.01 of apo C 111. apo E in B particles and also apo A I during the screend intervals. Despite of the fact that there is the association paraoxonase with HDL we did not find correlation in changes of paraoxonase with HDL or with HDL subfractions. During the treatment paraoxonase decreased. We may assess that Ciprofibrate influences apo C 111 by means activating of nuclear receptors which are able to change gene expresion. Ciprofibrate also causes changes in level of paraoxonase which is important enzyme in antioxidating process. DIFFERENCES IN I N T E R A C T I O N OF H M G - C o A REDUCTASE INHIBITORS W I T H VARIOUS C Y T O C H R O M E - P 4 5 0 ENZYMES IN H U M A N LIVER M I C R O S O M E S , AND IN HUMAN AND SIMIAN HEPATOCYTES L.H. Cohen, R.E.W. Van Leeuwen, Ch. Van Thiel. TNO-PG, Gaubhts Laboratoo'. Zernikedreef 9, PO. Box 2215. 2301 CE Leiden, The Netherlands
Drug-drug interaction must be taken into account for cholesterol lowering drugs, because they are used daily up to a high age and therefore are most probably coadministered with other drugs. Several cytochromeP450 (CYP) isoenzymes are involved in drug metabolism in the liver and different drugs interact with specific members of this enzyme family. We investigated which of these enzymes are influenced by the HMG-CoA reductase inhibitors Iovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), aturvastatin (A) and cerivastatin (C). Using three different human liver microsomal preparations the effect of various concentrations (up to 400 p.M) of these statins was studied on the following reactions: nifedipine aromatization (CYP3A), testosterone 6~-hydroxylation (CYP3A4), tolbutamide hydroxylation (CYP2C8/9), S-mephenytoin 4-hydroxylation (CYP2CI9), bufuralol l-hydroxylation (CYP2D6), aniline 4-hydroxylation (CYP2EI), coumarin 7-hydroxylation (CYP2A6) and 7-ethoxyresorufin O-dealkylation (CYPIAI/2). The statins did not influence the CYPIAI/2 activity and only
25
very slightly the CYP2A6 and CYP2EI activities. Except P, the other statins inhibited these activities for 25% at 400 p.M. The latter drugs were stronger inhibitors of the CYP2CI9 activity with ICso-values around 200 P.M and the same holds for the effect of A, C and F on the CYP2D6 activity. L and S were weaker inhibitors of the latter enzyme activity, whereas P did not influence both activities. About the same was observed for the statin effect on CYP2C8/9 activity, except that F was a strong inhibitor of this CYP (ICso-value 4 p.M). CYP3A4 activity was similarly inhibited by C, S, A, F and L (ICs0-values 100--200 p.M), but not by P. The inhibitory effects observed in oitro were verified in suspension culture of freshly isolated hepatocytes from Cynomolgus monkey (as a readily available model) and in cells isolated from human liver. In general the same trends were seen as in the human microsomes, except that in some cases the inhibition of the CYP activity was less or even increased, possibly by the induction of the particular CYP enzyme by incubation of the cells with a particular statin. A was the most potent inhibitor o f CYP3A(4) activity and F remained a very strong inhibitor of CYP2C8/9 activity in human and monkey hepatocytes. S, L, and C were moderate inhibitors of CYP3A (4) and CYP2C8/9 in human hepatocytes. CYP2D6 was inhibited at higher concentrations of S, L, C, A and F in both cellular systems. P hardly affected any of the CYP activities in the three systems studied. It is concluded that the statins differ in their effects on different CYP isoenzymes and differences between these drugs in their interaction with other drugs are to be expected. SERUM LP(n), INSULIN RESISTANCE, M E T A B O L I C RISK FACTORS FOR CARDIOVASCULAR DISEASE, AND T H E LONG T E R M EFFECTS OF BEZAFIBRATE IN TYPE 2 DIABETES R.S. Elkeles, J.R. Diamond, G. Salerno, C. Hughes, W. Richmond, V. Anyaoku. The SENDCAP Study Group: Imperial College School of
Medicine at St. Ma~. ~ Hospital, London W2 INY UK We investigated the relationship of serum lipoprotein Ca) [Lp(a)] to insulin resistance and other risk factors for cardiovascular disease, in Type 2 diabetic subjects. We studied 241 established Type 2 diabetic men and women, mean age 51 years, with no known cardiovascular disease, screened for entry into the SENDCAP intervention study with bezafibrate. Median concentration of Lp(a) was higher in 27 Afro-Caribbeans (36.2 mg d l-I ) than in 119 Caucasians (8.1 mg dl -I ) or 84 Asians (10.4 mg d1-1) (p = 0.0007). Serum Lp(a) was inversely related to serum triglyceride, serum insulin and insulin resistance as measured by HOMA-IR and positively related to HDL cholesterol and Apo AI. Multiple regression analysis confirmed the inverse relationship of Lp(a) to serum triglyceride together with a positive relationship to non-HDL cholesterol and higher concentrations in the AfroCaribbean group. Bezafibrate was effective in reducing serum triglyceride, total and LDL cholesterol and in increasing HDL cholesterol in Type 2 diabetic subjects over at least four years but had no significant effect on Lp(a) concentration. There was a small reduction in insulin resistance but neither change in serum triglyceride nor in HDL cholesterol during treatment could be explained by baseline insulin resistance or by change in insulin resistance. ATORVASTATIN T R E A T M E N T - R E L A T E D C H A N G E S T O IN VIVO OXIDANT:ANTIOXIDANT BALANCE AS ASSESSED BY P L A S M A A L L A N T O I N AND LIPID STANDARDISED VITAMIN E LEVELS I.EE Benzie 1, B. Tomlinsonz, W.Y. Chung 1, Y.T. Szeto 1. tDepartment of Nursing & Health Sciences. Hong Kong Pol.vtechnic UniversiO" Kowloon. Hong Kong." 2Division of Clinical Pharmacology, Chinese University of Hong Kong, Hong Kong, China Atorvastatin has been reported to have anfioxidant properties in vitro. We have now studied in vioo atorvastatin treatment-related changes in oxidant:antioxidant balance using allantoin, an oxidative product of unite, as a biomarker of oxidative stress, and vitamin E, the major in oioo lipophilic ,antioxidant, as a marker of antioxidant status. Fasting plasma samples from 26 hypercholesterolaemic patients were collected before and after 16 weeks' treatment with increasing doses of atorvastatin up to 40 or 80 mg/day. Plasma urate and allantoin were measured simultaneously using an HPLC method; vitamin E was measured using a fluorimetrie technique; total cholesterol (TC) and triglycerides (TG) were measured using enzymatic methods. Allantoin decreased (P < 0.001) with atorvastafin treatment; from mean (SEM) 19.2 (1.62) to 6.2 (1.25) p.mol/I. Urate did not change: 346 (15.2) and 343 (17.1) p.mol/l, indicating the change in allantoin was not related
71st EAS Congress and Satellite Symposia
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