Correlazione lineare tra le variazioni aggiustate delle percentuali di stenosi coronarica e le variazioni assolute di C-LDL plasmatico, tratta da un'analisi di metaregressione su 14 studi angiografici in pazienti con aterosclerosi coronarica trattati con farmaci ipolipemizzanti (da Watts et al 1997).da Watts et al 1997 CARE-Rx LIPID-Rx 4S-Rx CARE-PI LIPID-PI 4S-PI AFCAPS-Rx AFCAPS-PI WOS-Rx WOS-PI Prevenzione secondaria Prevenzione primaria Studi Clinici Cooyright 2000 – 2004 QUBIsoft

(-194) (-155) (-135) (-77) (-39) (0) (39) Variazioni aggiustate delle percentuali di stenosi Variazione LDL-C, mmol/L (mg/dL) Studi Clinici Minori i livelli di C-LDL, maggiore il beneficio. Il grafico mostra la forte correlazione tra mortalità da CHD /IM non fatale e i livelli di C-LDL nei 5 studi principali sulle statine, e conferma le osservazioni di Yusuf e Anand. La correlazione emerge sia negli studi di prevenzione secondaria (linea superiore), sia in quelli di prevenzione primaria (linea inferiore) Cooyright 2000 – 2004 QUBIsoft

Outcomes in primary prevention, stable and unstable coronary disease Death/nonfatal MI (%) Months of follow-up Unstable angina/non-Q-wave MI (FRISC II) Stable angina (SAPAT) Wallentin L et al. Lancet 2000;356:9–16. Juul-Moller S et al. Lancet 1992;340:1421–1425. Shepherd J et al. N Engl J Med 1995;333:1301–1307. Primary prevention (WOSCOPS) Cooyright 2000 – 2004 QUBIsoft

Early secondary prevention trials only focussed on long-term event reductions in stable patients Proportion alive Risk reduction, 30% Log-rank p= Simvastatin Placebo 4S 0 0 Fatal CHD/nonfatal MI (%) Risk reduction, 24% p<0.001 Pravastatin Placebo LIPID Fatal CHD/nonfatal MI (%) Risk reduction, 24% p=0.003 Pravastatin Placebo CARE Years 4S Study Group. Lancet 1994;344:1383–1389. Sacks FM et al. N Engl J Med 1996;335:1001–1009. LIPID study group. N Engl J Med 1998;339:1349–1357. Cooyright 2000 – 2004 QUBIsoft

MIRACL: addressed a treatment gap Acute coronary event MIRACL 4S 3 AFCAPS / TexCAPS/ WOSCOPS CARE 1 /LIPID 2 4 mo No history of CADUnstable CAD Randomization: 24–96 h 3 mo t=0 6 mo Randomization: CARE - 3–20 mo LIPID - 3–36 mo Randomization: >6 mo Stable CAD Primary preventionSecondary prevention Schwartz GG et al. Am J Cardiol 1998;81:578–581. Duration of follow-up: years; years; years. Cooyright 2000 – 2004 QUBIsoft

MIRACL: study design (cont’d) Hospitalization for unstable angina or non-Q MI n=3086 Randomized 24–96 hours after admission Placebo + diet 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. Cooyright 2000 – 2004 QUBIsoft

MIRACL: baseline characteristics Demographics Schwartz GG et al. Jama 2001; 285: PlaceboAtorvastatin Characteristic(n=1548)(n=1538) Gender Male, n (%) 1020 (65.9) 992 (64.5) Female, n (%) 528 (34.1) 546 (35.5) Race White, n (%)1324 (85.5)1317 (85.6) Black, n (%)44 (2.8)51 (3.3) Asian, n (%)58 (3.7)40 (2.6) Other, n (%)122 (7.9)130 (8.5) Age (years), Median6566 Min–Max 26–9430–93 Mean (SE)65 (0.30)65 (0.30) Cooyright 2000 – 2004 QUBIsoft

MIRACL: baseline characteristics Demographics (cont’d) PlaceboAtorvastatin Characteristic [n (%)] (n=1548)(n=1538) Current smokers430 (27.8)429 (27.9) Past MI 392 (25.3)382 (24.8) Q-wave 191 (12.3)180 (11.7) Revascularization173 (11.2)153 (9.9) CABG121 (7.8)112 (7.3) PTCA52 (3.4)41 (2.7) Inclusion Event Unstable angina705 (45.5)726 (47.2) Non-Q-wave acute MI843 (54.5)812 (52.8) Schwartz GG et al. Jama 2001; 285: Cooyright 2000 – 2004 QUBIsoft

MIRACL: baseline characteristics Plasma lipids PlaceboAtorvastatin Lipid [mean, mg/dL (mmol/L)] (n=1548)(n=1538) Total cholesterol207 (5.34)205 (5.29) Total triglycerides184 (2.04)181(2.01) HDL-C46 (1.18)47 (1.21) LDL-C125 (3.20)123 (3.18) Time from hospital admission6363 to randomization (hrs) Schwartz GG et al. Jama 2001; 285: Cooyright 2000 – 2004 QUBIsoft

MIRACL: concurrent medications according to treatment group Medications during and/or followingPlaceboAtorvastatin hospitalization for Index Event [n (%)](n=1548) (n=1538) Aspirin 1412 (91.2)1400 (91.0) Platelet GPIIb/IIIa RAs19 (1.2)14 (0.9) Other antiplatelet agents 176 (11.4)176 (11.3) Heparin1154 (74.6)1147 (74.6) Oral anticoagulants (coumarites)129 (8.3)119 (7.7) Fibrinolytic agents137 (8.9)109 (7.1) Nitrates1396 (90.2)1389 (90.3) Beta-blockers1200 (77.5)1192 (77.5) Calcium-channel blockers745 (48.1)735 (47.8) ACE inhibitors or ARBs 769 (49.7)746 (48.5) Digoxin 171 (11.1)182 (11.8) Schwartz GG et al. Jama 2001; 285: Cooyright 2000 – 2004 QUBIsoft

Baseline End of study Mean of both groups Placebo Atorvastatin mg/dL mg/dL (% change) Total cholesterol (+ 7%) (- 27%) LDL cholesterol (+ 12%) (- 40%) HDL cholesterol (+ 4%) ( + 5%) Triglycerides (+ 9%) (- 16%) MIRACL: plasma lipids Schwartz GG et al. Jama 2001; 285: Cooyright 2000 – 2004 QUBIsoft

MIRACL: plasma LDL-C values at baseline, 6 and 16 weeks *p< vs placebo at 6 and 16 weeks. Schwartz GG et al. Jama 2001; 285: Baseline6 WeeksEnd of study LDL-C (mg/dL) * * Atorvastatin Placebo Cooyright 2000 – 2004 QUBIsoft

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

MIRACL: worsening angina with new objective evidence of ischemia requiring urgent rehospitalization Time since randomization (weeks) Cumulative Incidence (%) Relative risk = 0.74 p=0.02 Atorvastatin Placebo 8.4% 6.2% Schwartz GG et al. Jama 2001; 285: Cooyright 2000 – 2004 QUBIsoft

MIRACL: fatal or nonfatal stroke Time since randomization (weeks) Cumulative Incidence (%) Relative risk = 0.50 p=0.045 Atorvastatin Placebo 1.6% 0.8% Schwartz GG et al. Jama 2001; 285: Cooyright 2000 – 2004 QUBIsoft

MIRACL: safety PlaceboAtorvastatin (n=1548)(n=1538) Elevated liver transaminases0.6%2.5% (>3xULN on 2 occasions) Myositis0%0% (with CPK >10xULN on 2 occasions) Any serious adverse event8.0%9.0% Schwartz GG et al. Jama 2001; 285: Cooyright 2000 – 2004 QUBIsoft