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I nuovi obiettivi terapeutici allo studio con statine.

I nuovi obiettivi terapeutici allo studio con statine. “Difendiamo il cuore” ANMCO – Toscana 9 febbraio 2008 Hotel Le Dune Lido di Camaiore. A. Del Carlo. Statine: troppe o troppo poche. 05 ottobre 2004 - BMJ 2004; 329: 645. Rapporto OsMed 2006.

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I nuovi obiettivi terapeutici allo studio con statine.

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  1. I nuovi obiettivi terapeutici allo studio con statine. “Difendiamo il cuore” ANMCO – Toscana 9 febbraio 2008 Hotel Le Dune Lido di Camaiore A. Del Carlo

  2. Statine: troppe o troppo poche 05 ottobre 2004 - BMJ 2004; 329: 645

  3. Rapporto OsMed 2006 Costo territoriale per farmaci più elevato: Atorvastatina: da 19,4 a 21,9 DDD Simvastatina stabile su 17 DDD Rosuvastatina da 4,6 a 7,1 DDD Pravastatina da 5,9 a 5,7 DDD

  4. Nuove indicazioni allo studioper le signore inibitrici del3-idrossi-3-metiglutaril Coenzima A reduttasi • Nuovi dosaggi (alti!) • Nuove indicazioni (oltre CHD) • Nuove suggestioni

  5. TRIALS con STATINE Acute coronary event Cooyright 2000 – 2004 QUBIsoft No history of CAD Unstable CAD Stable CAD 4 mo AFCAPS/TexCAPS,WOSCOPS, ASCOT, CARDS MIRACL,PROVE IT t=0 CARE1,LIPID2,SEARCH,IDEAL 4S, HPS, TNT 3 mo 6 mo Randomization:24–96 h Randomization:CARE - 3–20 moLIPID - 3–36 mo Randomization:>6 mo Primary prevention Secondary prevention Duration of follow-up:15.0 years; 26.1 years; 35.4 years. Schwartz GG et al. Am J Cardiol 1998;81:578–581.

  6. PROVE IT – TIMI 22 Figure 1. Median Low-Density Lipoprotein (LDL) Cholesterol Levels during the Study.

  7. PROVE IT – TIMI 22 Figure 2. Kaplan–Meier Estimates of the Incidence of the Primary End Point of Death from Any Cause or a Major Cardiovascular Event. Intensive lipid lowering with the 80-mg dose of atorvastatin, as compared with moderate lipid lowering with the 40-mg dose of pravastatin, reduced the hazard ratio for death or a major cardiovascular event by 16 percent.

  8. PROVE IT – TIMI 22 Figure 3. Hazard Ratio for the the Primary End Point of Death from Any Cause or a Major Cardiovascular Event at 30, 90, and 180 Days and at the End of Follow-up in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group. Event rates are Kaplan–Meier estimates censored at the time points indicated with the use of the average duration of follow-up (two years). CI denotes confidence interval.

  9. Figure 4. Estimates of the Hazard Ratio for the Secondary End Points and the Individual Components of the Primary End Point in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group. CI denotes confidence interval, CHD coronary heart disease, and MI myocardial infarction. Revascularization was performed at least 30 days after randomization.

  10. Ideal studyPrev. sec. Atorva 80 vs Simva 20 o 40 Table 1. Lipid Levels During Treatment HDL = high-density lipoprotein; LDL = low-density lipoprotein

  11. Ideal study Table 2. Primary Composite Endpoint CHD = coronary heart disease; CI = confidence interval; HR = hazard ratio; MI = myocardial infarction

  12. MIRACL: study design Placebo + diet Hospitalizationforunstable anginaor non-Q MI n=3086 Randomized 24–96 hours after admission Atorvastatin 80 mg + diet 16 weeks Assessments conducted at weeks 0, 2, 6 and 16 Schwartz GG et al. Am J Cardiol 1998;81:578–581.

  13. MIRACL: plasma LDL-C valuesat baseline, 6 and 16 weeks Cooyright 2000 – 2004 QUBIsoft 240 180 Placebo LDL-C (mg/dL) 120 Atorvastatin 80 (- 40%) * 60 * 0 Baseline 6 Weeks End of study *p<0.0001 vs placebo at 6 and 16 weeks. Schwartz GG et al. Jama 2001; 285: 1711-1718

  14. MIRACL: primary efficacy measure Placebo 17.4% Cooyright 2000 – 2004 QUBIsoft 15 14.8% Atorvastatin 10 • Time to first occurrence of: • Death (any cause) • Nonfatal MI • Resuscitated cardiac arrest • Worsening angina with new objective evidence requiring urgent rehospitalization Cumulative Incidence (%) Relative risk = 0.84p=0.048 5 0 0 4 8 12 16 Time since randomization (weeks) Schwartz GG et al. Jama 2001; 285: 1711-1718

  15. MIRACL: worsening angina with new objective evidence of ischemia requiring urgent rehospitalization 9 8.4% Placebo 6.2% 6 Atorvastatin Cumulative Incidence (%) 3 Relative risk = 0.74 p=0.02 0 0 4 8 12 16 Time since randomization (weeks) Schwartz GG et al. Jama 2001; 285: 1711-1718

  16. MIRACL: fatal or nonfatal stroke 2 Placebo 1.6% 1.5 Cumulative Incidence (%) 1 Atorvastatin 0.8% 0.5 Relative risk = 0.50 p=0.045 0 0 4 8 12 16 Time since randomization (weeks) Schwartz GG et al. Jama 2001; 285: 1711-1718

  17. Is lower better?

  18. SAGE Trial: Background • The purpose of the SAGE study was to compare the effects of intensive versus moderate statin therapy on the reduction of myocardial ischemia, as assessed by ambulatory ECG, in older men and women with stable CAD. Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707.

  19. SAGE Trial: Study Design 893 ambulatory CAD patients 65-85 years with ≥ 1 MI that lasted ≥ 3 minutes during 48-hour ambulatory ECG at screening Prospective. Randomized. Double-blind. Double-dummy. Multi-Center. International. Mean follow-up 12 months R Atorvastatin 80 mg/d n=377 Pravastatin 40 mg/d n=374 3 and 12 mos. follow-up • Primary Efficacy Parameter: Absolute change from baseline in total duration of myocardial ischemia on 48-hour Holter Monitor • Secondary Efficacy Parameters: (1) absolute change in total duration of ischemia from baseline to month 3; from baseline to month 3 and to month 12: (2) the % change in total duration of ischemia, (3) the absolute and % change in no. of ischemic episodes, (4) the % change in ischemic burden, (5) the proportion of patients who were totally free of ischemia, and (6) the % change in the levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B. Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707.

  20. SAGE Trial: Primary Efficacy Endpoint Mean total duration of myocardial ischemia over 48 hours • The total duration of myocardial ischemia at month 12 was significantly reduced from baseline in both atorvastatin- and pravastatin-treated patients. • There was no significant difference between atorvastatin and pravastatin. P<0.001 P<0.001 Total duration of Myocardial Ischemia (min) Atorvastatin (n=408) Pravastatin (n=396) Baseline Month 3 Month 12 Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707.

  21. SAGE Trial: Lipid Parameters Least Squares Mean Percent Changes in Lipid Parameters from Baseline Total LDL HDL Atorvastatin Pravastatin Atorvastatin Pravastatin Atorvastatin Pravastatin LS mean percent change p=0.009 Month 3 p<0.001 Month 12 p<0.001 Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707.

  22. Statine e stroke

  23. Efficacia delle statine nella prevenzione dell’ictus Eventi cerebrovascolari maggiori(ictus fatali e non fatali) RR e IC 95% sulla base di un modello per effetti random RR A favore della statina A favore del controllo Studi su simvastatina 4S 0,74 (0,52 – 1,94) HPS 0,76 (0,67 – 0,86) Unificati (IC 95%) 0,76 (0,69 – 0,85) Studi su pravastatina CARE 0,60 (0,40 – 0,57) LIPID 0,03 (0,60 – 1,61) PROSPER 1,04 (0,02 – 1,31) WOSCOPS 0,90 (0,61 – 1,34) Unificati (IC 95%) 0,87 (0,76 – 1,02) Con ALLHAT-LLT ALLHAT-LLT 0,91 (0,76 – 1,09) CARE 0,60 (0,40 – 0,97) LIPID 0,01 (0,60 – 1,01) PROSPER 1,04 (0,02 – 1,31) WOSCOPS 0,90 (0,61 – 1,34) Unificati (IC 95%) 0,66 (0,73 – 0,55) Studi su atorvastatina ASCOT-LLA 0,75 (0,56 – 0,95) CARDS 0,53 (0,51 – 0,90) Unificati (IC 95%) 0,68 (0,55 – 0,88) Con GREACE ASCOT-ILA 0,73 (0,56 – 0,96) CARDS 0,53 (0,31 – 0,90) GREACE 0,53 (0,34 – 1,16) Unificati (IC 95%) 0,68 (0,59 – 0,06) 0,76 0,87 0,88 0,68 0,68 0,2 0,5 1,0 2,0 5,0 Zhou et al. Am H J. 2006; 151:273-81.

  24. Heart Protection Study con simvastatina 40mgRiduzione del rischio di ictus TUTTI I PAZIENTI -25% (p=0,0001) 5.7 4.3 Riduzione % Del rischio di ictus (n=444) (n=585)

  25. CARDS: atorvastatina 10 e ictus in pazienti diabetici senza CHD Evento Placebo* Atorva* Rapporto di rischio Rischio relativo (IC) A favore atorvastatina A favore placebo Endpoint primario 127 (9,0) 83 (5,8) –37% (–52, –17) Eventi coronarici acuti 77 (5,5) 51 (3,6) –36% (–55, –9) Rivascolarizzazione coronarica 34 (2,4) 24 (1,7) –1% (–59, +16) Ictus 39 (2,8) 21 (1,5) –48% (–69, –11) p=0,001 0,2 0,4 0,6 0,8 1,0 1,2 (n=2.841) * Numero di pazienti con evento (%). Modificato da Colhoun HM et al. Lancet. 2004; 364:685-696; Newman C et al. Accettato per presentazione all’American Heart Association Scientific Sessions 2005; Dallas, TX. 13-16 novembre 2005.

  26. PROSPER Study Group Obiettivo dello studio Determinare se pravastatina al dosaggio di 40 mg/die riduca gli eventi cardio e cerebro vascolari (morte, IMA, ictus) nei pazienti anziani ad alto rischio o affetti da patologia vascolare. Follow up medio 3,2 a. PROSPER Study Group. Lancet. 2002

  27. Risultati • 5804 pazienti (70–82 anni) ad alto rischio • Terapia: pravastatina 40 mg vs. placebo • 19% di riduzione di eventi coronarici maggiori • 24% riduzione di mortalità cardiovascolare • 25% riduzione in TIA (non stroke riduzione) Shepherd J et al. Lancet 2002;360:1623–1630.

  28. Statine e ictus cerebrale Trials randomizzati * p<0,001 Le statine riducono apparentemente tutti gli ictus del 20%, ma tale riduzione è dovuta a una riduzione del 28% dell’ictus tromboembolico. Ciò spiega perché la riduzione degli ictus per effetto delle statine sia stata osservata soprattutto negli studi condotti in pazienti con pregresse malattie cardiovascolari, nei quali è più frequente l’ictus ischemico. Law MR et al. Br Med J. 2003; 326:1423-9.

  29. La terapia con statine non è associata ad aumento del rischio di ictus emorragico Trial Odds ratio (IC 95%) A favore della statina A favore del controllo HPS* GREACE† MIRACL‡ KLIS§ LIPIDıı CAREıı SSSS* AFCAPS¶ Complessivo (IC 95%)Eterogeneità 0,90 (0,65–1,22)p=0,15 0,05 0,2 0,5 1,0 3,0 10,0 * Simvastatina vs placebo. † Atorvastatina vs cure abituali. ‡ Atorvastatina vs placebo. § Pravastatina vs trattamento convenzionale. II Pravastatina vs placebo. ¶ Lovastatina vs placebo. Amarenco P et al. Stroke. 2004; 35:2902-2909; Yano K et al. Stroke. 1989; 20:1460-1465;Iso H et al. N Engl J Med. 1989; 320:904-910.

  30. Randomly assigned 4,731 patients who had had a stroke or TIA within 1 to 6 months before the study entry, had low LDL levels (100-190 mg/dL) and had no knonw CHD 2,366 placebo 2,365 atorvastatin 80 mg Median follow-up time: 4.9 years SPARCL investigators, N Engl J Med 2006

  31. Kaplan-Meier for fatal or non-fatal stroke in the SPARCL study (n=4,731); follow-up 4.9 years 20 Placebo (n=2,366) HR 0.84 (0.71-0.99) p<0.0001 16 Fatal or non-fatal stroke (%) Atorvastatin (n=2,365) 12 8 4 0 0 5 3 Years SPARCL investigators, N Engl J Med 2006

  32. Kaplan-Meier for stroke or TIA in the SPARCL study (n=4,731); follow-up 4.9 years 25 Placebo (n=2,366) HR 0.77 (0.67-0.88) p<0.0001 20 Stroke or TIA event (%) 15 Atorvastatin (n=2,365) 10 5 0 0 5 3 Years SPARCL investigators, N Engl J Med 2006

  33. SPARCL: Main results Welch M et al. 15th European Stroke Conference; May 16-19, 2006; Brussels, Belgium.

  34. SPARCL L’Incremento di stroke emorragico è dovuto all’effetto pleiotropico antiaggregante? I dati in letteratura sono ancora controversi (HPS +; Prosper -) Il Pharmacovigilance Working Party dell’EMEA probabilmente inserirà una modifica sul riassunto delle caratteristiche del prodotto.

  35. Statine e scompenso cardiaco Small prospective clinical studies of atorvastatin and simvastatin in systolic HF are promising, documenting improved ventricular systolic function and decreased inflammatory biomarkers with statin therapy. Expert Opin Pharmacother. 2007 Dec;8(17):3061-8. Links Atorvastatin and statins in the treatment of heart failure. Horwich TB, MacLellan WR.

  36. Rosuvastatina e rimodellamento ventricolare Despite being safe and effective at decreasing plasma cholesterol, high-dose ROS did not beneficially alter parameters of LV remodeling. J Card Fail. 2007 Feb;13(1):1-7. Double-blind, randomized, placebo-controlled study of high-dose HMG CoA reductase inhibitor therapy on ventricular remodeling, pro-inflammatory cytokines and neurohormonal parameters in patients with chronic systolic heart failure. Krum H, Ashton E, Reid C, Kalff V, Rogers J, Amarena J, Singh B, Tonkin A.

  37. Studio CORONARosu 10 vs plb – paz. > 60 aascompenso ischemico Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. N Engl J Med. 2007 Nov 29;357(22):2301-4. Rosuvastatin in older patients with systolic heart failure. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Jánosi A, Kamenský G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ, Ranjith N, Schaufelberger M, Vanhaecke J, van Veldhuisen DJ, Waagstein F, Wedel H, Wikstrand J; CORONA Group.

  38. Rimaniamo in attesa …. …dei risultati del GISSI – HF Paz. con diagnosi di SC randomizzati a n3 PUFA, Rosuvastatina e Placebo. Follow up di 3 aa.

  39. Statine e glaucoma • Arch Ophthalmol. 2004 Jun;122(6):822-6. Links • Statins and other cholesterol-lowering medications and the presence of glaucoma. • McGwin G Jr, McNeal S, Owsley C, Girkin C, Epstein D, Lee PP. • Studio caso-controllo: • Sia l’uso di Statine che altri ipolipemizzanti indicherebbero la riduzione del rischio di glaucoma ad angolo aperto.

  40. Statine e maculopatia • Br J Ophthalmol. 2003 Sep;87(9):1121-5. Links • The association between statin use and age related maculopathy. • McGwin G Jr, Owsley C, Curcio CA, Crain RJ. • Studio caso – controllo • Possibile correlazione tra uso di statine e maculopatia.

  41. Statine e rischio di frattura • Calcif Tissue Int. 2006 Jul;79(1):27-36. Epub 2006 Jul 24. Links • Statin but not non-statin lipid-lowering drugs decrease fracture risk: a nation-wide case-control study. • Rejnmark L, Vestergaard P, Mosekilde L. • La correlazione è presente per tutte le statine eccetto la Prava e le non-statine.

  42. Statine e cancro pancreatico • Pancreas. 2007 Mar;34(2):260-5. Links • Statins reduce the risk of pancreatic cancer in humans: a case-control study of half a million veterans. • Khurana V, Sheth A, Caldito G, Barkin JS. • Effetto protettivo con riduzione statistica del 67% per > 6 mesi e fino all’80% > 4 anni !!!

  43. Statine e cancro prostatico • Am J Epidemiol. 2005 Aug 15;162(4):318-25. Epub 2005 Jul 13. Links • Statins and prostate cancer risk: a case-control study. • Shannon J, Tewoderos S, Garzotto M, Beer TM, Derenick R, Palma A, Farris PE. • Correlazione favorevole in particolare per cancri aggressivi. • J Natl Cancer Inst. 2006 Dec 20;98(24):1819-25. Links • Statin drugs and risk of advanced prostate cancer. • Platz EA, Leitzmann MF, Visvanathan K, Rimm EB, Stampfer MJ, Willett WC, Giovannucci E. • Studio di coorte: • correlazione favorevole solo per cancri invasivi e metastatici.

  44. Statine e cancro colorettale • Gastroenterology. 2007 Aug;133(2):393-402. Epub 2007 May 21. Links • Risk of colorectal cancer in patients prescribed statins, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors: nested case-control study. Vinogradova Y, Hippisley-Cox J, Coupland C, Logan RF. • Correlazione positiva con FANS, non con statine. • J Natl Cancer Inst. 2007 Jan 3;99(1):32-40. Links • Statin use and risk of colorectal cancer. • Coogan PF, Smith J, Rosenberg L. • Nessuna correlazione con statine • N Engl J Med. 2005 May 26;352(21):2184-92. Links • Statins and the risk of colorectal cancer. • Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G. • Riduzione RR 47%.

  45. Statine e cancro mammario • J Natl Cancer Inst. 2006 May 17;98(10):700-7. Links • Statin use and breast cancer: prospective results from the Women's Health Initiative. • Cauley JA, McTiernan A, Rodabough RJ, LaCroix A, Bauer DC, Margolis KL, Paskett ED, Vitolins MZ, Furberg CD, Chlebowski RT; Women's Health Initiative Research Group. • Nessuna associazione di classe. Possibile lieve correlazione con statine idrofobiche. • Cancer Epidemiol Biomarkers Prev. 2007 Mar;16(3):416-21. Links • Statin use and breast cancer risk in a large population-based setting. • Boudreau DM, Yu O, Miglioretti DL, Buist DS, Heckbert SR, Daling JR. • Nessuna associazione

  46. Statine e cancro in generale • J Natl Cancer Inst. 2008 Jan 16;100(2):134-9. Epub 2008 Jan 8. Links • The association between statins and cancer incidence in a veterans population. • Farwell WR, Scranton RE, Lawler EV, Lew RA, Brophy MT, Fiore LD, Gaziano JM. • Rischio ridotto. • Circulation. 2007 Jan 2;115(1):27-33. Epub 2006 Dec 18. Links • Statins and the risk of lung, breast, and colorectal cancer in the elderly. • Setoguchi S, Glynn RJ, Avorn J, Mogun H, Schneeweiss S. • Nessuna correlazione.

  47. Statine e demenza • Dement Geriatr Cogn Disord. 2007;23(3):194-201. Epub 2007 Jan 25. Links • Prevention and treatment of dementia or Alzheimer's disease by statins: a meta-analysis. • Zhou B, Teramukai S, Fukushima M. • Nessun beneficio su rischio di demenza. • Arch Gen Psychiatry. 2005 Feb;62(2):217-24. Links • Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. • Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M, Welsh-Bohmer KA, Breitner JC; Cache County Study investigators. • Nessuna associazione

  48. Statine e AR • Lancet. 2004 Jun 19;363(9426):2015-21. Links • Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. • McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N. • Piccolo trial (n=116) con breve F.U. (6 mesi). • Modesto effetto antiinfiammatorio

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