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Attualità nell’impiego delle statine

Attualità nell’impiego delle statine. Prof. P. Pauletto Dip. di Medicina Clinica e Sperimentale Università degli Studi di Padova U.O. di Medicina Interna I^ U.L.S.S. n° 9, Ospedale di Treviso. Risk Factors and Attributable Mortality Reduction.

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Attualità nell’impiego delle statine

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  1. Attualità nell’impiego delle statine Prof. P. Pauletto Dip. di Medicina Clinica e Sperimentale Università degli Studi di Padova U.O. di Medicina Interna I^ U.L.S.S. n° 9, Ospedale di Treviso

  2. Risk Factors and Attributable Mortality Reduction — which one stands out as best therapeutic target — Contribution from RF modification • Cholesterol (LDL/HDL) 37% • Blood pressure 14% • Cigarette smoking 6% Contribution comparators • Medical Rx of acute MI 21% • PCI or CABG 16%

  3. COLESTEROLO COME FATTORE DI RISCHIO PER LA CARDIOPATIA ISCHEMICA 35 30 Stati Uniti RA 200 = 11.5% RA 240 = 13.6% RR = 1,18 25 20 Tassi di mortalità per CHD (%) 15 Europa Meridionale RA 200 = 8.5% RA 240 = 10.1% RR = 1,18 10 5 RA = rischio assoluto RR = rischio relativo 0 2.60 (100) 3.25 (125) 3.90 (150) 4.50 (175) 5.15 (200) 5.80 (225) 6.45 (250) 7.10 (275) 7.75 (300) 8.40 (325) 9.05 (350) Il contributo del FR è lo stesso, ma si parte da livelli basali diversi Colesterolemia totale, mmol/L (mg/dL) Dati dallo studio Seven Countries su 12,467 uomini dell’Europa, USA e Giappone. Verschuren WM et al. JAMA 1995;274:131–136. Correlazione tra CT e mortalità da CHD in uno studio di 25 anni su 12.467 uomini, abitanti in cinque paesi europei, negli USA e in Giappone (da Verschuren et al 1995).

  4. Le Linee Guida

  5. Relationship Between LDL-C Levels and CHD Events — data derived from epidemiologic studies and clinical trials — 3.7 2.9 2.2 1.7 1.3 1.0 0 • • Relative Risk ofCHD (log scale) • • • “Rule of One” applies when LDL < 100 mg/dl • 40 70 100 130 160 190 220 LDL-Cholesterol (mg/dl) S. Grundy et al. Circulation 2004;110:227-39

  6. HEART PROTECTION STUDY Lancet November 30, 2002, pag 1783

  7. Le Linee Guida: i livelli di LDL-C • NCEP Adult Treatment Panel III update 2004 †National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel, ATP) *TLC: therapeutic lifestyle change (cambiamenti terapeutici dello stile di vita) Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227–239 Rischio alto: CHD o equivalenti del rischio di CHD (rischio di CHD a 10 aa >20%) Obiettivo LDL-C < 100 mg/dl valore ideale opzionale < 70 mg/dl • Joint British Societes 2005 † JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice; Formerly British Heart Journal Journal of the British Cardiac Society Volume 91 Supplement V December 2005 Rischio alto: CHD o equivalenti del rischio di CHD (Total CVD risk† ≥ 20%) Obiettivo LDL-C < 80 mg/dl • European Guidelines On Vascular Disease Prevention in Clinical Practice 2007 Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in ClinicalPractice (Constituted by representatives of nine societies and by invited experts) European Heart Journal (2007) 28, 2375–2414 Rischio alto: CHD o equivalenti del rischio di CHD (rischio di CHD a 10 aa >20%) Obiettivo LDL-C < 100 mg/dl valore auspicabile < 80 mg/dl

  8. Le opzioni di trattamento farmacologico

  9. Bile acid Down Down Up Neutral Poor 3 – 5% sequestrants 15 – 30% or up Nicotinic acid Down Down Up Down Poor to reasonable 15 – 30% 25% 25% 20 – 50% Fibrates Down Down Up Down Good 5 – 15% 15% 20% 20 – 50% Probucol Down Down Down Neutral Reasonable 25% 10 – 15% 20 – 30% Statins* Down Down Up Down Good 15 – 30% 24 – 50% 6 – 12% 10 - 29% Ezetimibe - Down Up Down Good 1% 18% 8% - total cholesterol, LDL- low density lipoprotein, HDL- - high density lipoprotein, TG- - triglyceride. TC rosuvastatin. *Daily dose of 40mg of each drug. This slide does not include Adapted from Yeshurun D, Gotto AM. Southern Med J 1995; 88 (4):379- 391, Knopp RH. N Engl J Med 1999; 341 :498 – 511, Ezetimibe Prescribing Information. Effect of lipid-modifying therapies - Patient Therapy TC LDL HDL TG tolerability 20% ,

  10. Estimated change in the five-year relative risk of non-fatal myocardial infarction or CHD death associated with mean LDL-C reduction for the diet, bile-acid sequestrant, surgery, and statin trials (dashed line) along with the 95% probability interval (dotted line). The solid line has a slope=1 J.G. Robinson,J Am Coll Cardiol 2005; 46: 1855-62

  11. CHD EVENTS AND LDL-C IN STATIN TRIALS Lancet 367, 69, 2006

  12. L’ intensità del trattamento con statine e coronaropatia

  13. Published at www.nejm.org March 8, 2005

  14. Published at www.nejm.org March 8, 2005

  15. NEJM 350, 2004

  16. ┌ - - - 0.017 - - - ┐ ┌ - n.s. - ┐ ┌ - - - 0.004 - - - ┐ C-S ┌ 0.046 ┐ AT-10 Percentage of plaque area (ANOVA p=0.031) (ANOVA p=0.003) (ANOVA n.s.=0.621) ┌ - n.s. - ┐ AT-80 ┌ - n.s. - ┐ Smooth muscle cells Macrophages Lymphocytes Effect of a 3-month lipid lowering therapy on cell composition of carotid plaque P. Pauletto et al, AHA meeting 2009

  17. Plasma LDL-Chol levels before and after a 3-month lipid lowering therapy mg/dL NS NS

  18. Effect of a 3-month lipid lowering therapy on cell composition of carotid plaque Cells per area unit

  19. Il rimodellamento coronarico nei pazienti trattati con statine

  20. Intravascular Ultrasound Images at Baseline and Follow-up — an example of plaque regression — Nissen et al. JAMA 2004;291:1079

  21. JAMA 2004;291:1071-1080

  22. JAMA 2006; 295, 13 March

  23. JAMA 2006; 295, 13 March

  24. Correggendo i livelli di infiammazione si riduce il rischio CV ?

  25. CRP in 3745 patients wiht ACS (PROVE IT-TIMI22) Ridker PM et al. NEJM 2005

  26. JUPITER - Primary Endpoint MI, Stroke, UA/Revascularization, CV Death Placebo 251 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 0.08 Number Needed to Treat (NNT2) = 95 Number Needed to Treat (NNT5) = 25 * -44% 0.06 109 Fewer Events *Extrapolated figure based on Altman and Andersen method Cumulative Incidence 0.04 Rosuvastatin 142 / 8901 0.02 Ridker P et al. N Eng J Med 2008;359: 2195-2207 0.00 0 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 Placebo 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

  27. JUPITER - Primary Endpoint Components • Placebo Rosuvastatin HR 95% CI p-value [n=8901][n=8901] • n (rate**) n (rate**) Primary Endpoint 251 (1.36) 142 (0.77) 0.56 0.46-0.69 <0.001* (Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation) Non-fatal MI 62 (0.33) 22 (0.12) 0.35 0.22-0.58 <0.001* Fatal or non-fatal MI 68 (0.37) 31 (0.17) 0.46 0.30-0.70 0.0002 Non-fatal stroke 58 (0.31) 30 (0.16) 0.52 0.33-0.80 0.003 Fatal or non-fatal stroke 64 (0.34) 33 (0.18) 0.52 0.34-0.79 0.002 Arterial Revascularization 131 (0.71) 71 (0.38) 0.54 0.41-0.72 <0.0001 Unstable angina† 27 (0.14) 16 (0.09) 0.59 0.32-1.10 0.09 CV death, stroke, MI 157 (0.85) 83 (0.45) 0.53 0.40-0.69 <0.001* Revascularization or unstable angina 143 (0.77) 76 (0.41) 0.53 0.40-0.70 <0.001* ** Rates are per 100 person years;† Hospitalisation due to unstable angina; *Actual p-value was < 0.00001 HR – Hazard Ratio; CI – Confidence Limit Ridker P et al. N Eng J Med 2008;359: 2195-2207

  28. JUPITER - Total MortalityDeath from any cause Placebo N=247 0.06 Hazard Ratio 0.80 (95% CI 0.67-0.97) p=0.02 -20% 0.05 Rosuvastatin 20mg N=198 0.04 Cumulative Incidence 0.03 0.02 0.01 0.00 0 1 2 3 4 Follow-up (years) Number at Risk Rosuvastatin 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 Placebo 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246 Ridker P et al. N Eng J Med 2008;359: 2195-2207

  29. LDL-CT and hs-CRP Levels during the Follow-up Period Baseline level: LDL-CT=108 mg/dL both groups; hs-CRP=4.2 vs 4.3 mg/L in placebo PM Ridker, et al. N Engl J Med 2008;359:2195-207

  30. Cumulative Incidence of Cardiovascular Events According to Study Group PM Ridker, et al. N Engl J Med 2008;359:2195-207

  31. Relationship of the proportional reduction in cardiovascular event rate and mean LDL cholesterol difference between treatment groups in published statin trials PM Ridker, et al. N Engl J Med 2008;359:2195-207 - Online Supplemental Appendix

  32. The results of JUPITER • and the primary prevention of CHD • Should indications for statin treatment be expanded? • How should measurements of hs-CRP be used?

  33. JUPITER: potential limitations / warnings • Hard cardiac events 1.8% (157 of 8901 subjects) in the placebo group • vs 0.9% (83 of 8901 subjects) in the rosuvastatin group: 120 participants were treated for 1.9 years to prevent one event. • Significantly higher HbA1levels and incidence of diabetes in the rosuvastatin group (3.0%, vs. 2.4% in the placebo group;P=0.01) • The trial did not compare subjects with and those without hs-CRP measurements • Since statins lower both LDL cholesterol and hs-CRP we cannot determine whether CT, a reduction in inflammation, or a combination of both are responsible for the benefit • Meta-regression is not a reliable technique, and the early termination of the trial owing to the efficacy data probably exaggerated the results to some degree

  34. Statine e cardiopatie non ischemiche

  35. - 53,6% - 61,3%

  36. ENDPOINT PRIMARIO • 22% • p=0,02

  37. GISSI-HF trial: all-cause death (A) and admission for cardiovascular reasons (B)

  38. Terapia di associazione ?

  39. Statine + Niacina • Negli USA è entrata in commercio l’associazione Lovastatina 20 mg + niacina a lento rilascio (Advicor*) • Possibili vantaggi: maggiore riduzione del colesterolo e trigliceridi, maggior incremento del colesterolo HDL e maggior riduzione delle LDL piccole e dense • Potenziali rischi: maggior rischio di miopatia e rialzo degli enzimi epatici. Peggioramento del controllo metabolico del diabete o della gotta Brown BG, NEJM 2001 - Wolfe ML, Am J Cardiol 2001 - Bays HE, Am J Cardiol 2003

  40. Strategie di incremento del colesterolo HDL • Storiche • Uso dei fibrati (studio VA-HIT, Helsinki Heart Study) • Uso della niacina (studi CLAS, FATS) • Future • Infusione di Apo A1 Milano (Nissen JAMA 2003) • Inibitori della CETP (Brousseau NEJM 2004)

  41. Benefici del decremento ponderale (2- 9 kg) Riduzione dei fattori di rischio: Riduzione p.a.: 5- 20 mm Hg/ 10 kg Riduzione colesterolo LDL 10- 15% Riduzione della mortalità totale (16- 65%) (Chaturvedi 1995, Eriksson 1998) Benefici dell’esercizio fisico moderato (20’- 30’ al dì / a gg alterni) Riduzione dei fattori di rischio: Aumento HDL Riduzione p.a. Riduzione insulino- resistenza Riduzione della patologia coronarica del 35-55% (Manson 1992, Lakka 1994) Riduzione della mortalità cv (31%) e totale (29%) (Bijnen 1998) Intervento: misure igienico dietetiche

  42. Ezetimibe associato con simvastatina: efficacia sul C-LDL Ezetimibe 10 mg + simvastatina 20 mg Simvastatina 20 mg 40 mg 80 mg 0 –10 –20 Variazione % media dal basale del C-LDL calcolato (settimana 12) –30 –36* –36* –40 –44 –44 –50 –60 *p<0.01 terapia di associazione vs. statina da sola Tratto da Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134.

  43. Ezetimibe associato con atorvastatina: efficacia sul C-LDL Ezetimibe 10 mg + atorvastatina 10 mg Atorvastatina 10 mg 20 mg 40 mg 80 mg 0 –10 –20 Variazione % media dalbasale del C-LDL calcolato (settimana 12) –30 –37* –42* –40 –45* –53 –54 –50 –60 *p<0,01 terapia di associazione vs. statina da sola Tratto da Ballantyne CM et al Circulation 2003;107:2409-2415.

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