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Jupiter Study
- 1. JUPITER J ustificacion para el U so de estatinas en P revención : un estudio I n T ervencional E valuando R osuvastatina
- 3. JUPITER – diseño del estudio Lípidos PCR Tolerabilidad Placebo run-in 1 –6 2 –4 3 0 4 13 Final 3–4 años 6-mensual Visita: semana: Aleatorización Rosuvastatina 20 mg (n 8.901) Placebo (n 8.901) Eligibilidad Sin antecedentes de enfermedad arterial coronaria hombres ≥50 años mujeres ≥60 años C- LDL <130 mg/dL PCR ≥2.0 mg/L CAD= Enfermedad Arterial Coronaria C-LDL= Lipoproteína Colesterol baja densidad PCR= Proteína C-reactiva HbA 1c = Hemoglobina Glicosilada Lípidos PCR Tolerabilidad HbA 1C Lípidos PCR Tolerabilidad
- 6. JUPITER – FLUJO DE PACIENTES 89.890 pacientes reclutados 17.802 aleatorizados Rosuvastatina 20mg n=8.901 Placebo n=8.901 Pérdida en seguimiento n=44 Estudio finalizado n=8.857 Pérdida en seguimiento n=37 Estudio finalizado n=8.864
- 7. Años 66 (60-71) 66 (60-71) Hombres (%) 61.5 62.1 Raza (%) Caucásicos 71.4 71.1 Negros 12.4 12.6 Hispánicos 12.6 12.8 Otros 3.6 3.5 IMC (kg/m 2 ) 28.3 (25.3-32.0) 28.4 (25.3-32.0) PA Sistólica (mmHg) 134 (124-145) 134 (124-145) PA Diástolica (mmHg) 80 (75-87) 80 (75-87) Rosuvastatina Placebo n=8901 n=8901 JUPITER - Características de la Población
- 8. Colesterol total (mg/dL) 186 (168-200) 185 (169-199) Colesterol LDL (mg/dL) 108 (94-119) 108 (94-119) Colesterol HDL (mg/dL) 49 (40-60) 49 (40-60) Triglicéridos (mg/dL) 118 (85-169) 118 (86-169) PCRus ( mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2) Glucosa (mg/dL) 94 (87-102) 94 (88-102) HbA 1c (%) 5.7 (5.4-5.9) 5.7 (5.5-5.9) Tasa de filtrado glomerular, (ml/min/1.73m 2 ) 73.3 (64.6-83.7) 73.6 (64.6-84.1) Rosuvastatina Placebo n=8901 n=8901 JUPITER - Parámetros Basales de laboratorio
- 9. Tabaquismo (%) 15.7 16.0 Historia familiar † (%) 11.2 11.8 Síndrome Metabólico ‡ (%) 41.0 41.8 Uso de Aspirina (%) 16.6 16.6 Antecedentes previos Rosuvastatina Placebo n=8901 n=8901 JUPITER - Antecedentes previos
- 10. hsCRP (mg/L) LDL (mg/dL) 0 12 24 36 48 TG (mg/dL) HDL (mg/dL) Meses LDL disminuyó 50 % a 12 meses PCRus disminuyó 37% a 12 meses HDL incrementó de 4 % a 12 meses TG disminuyó 17 % a 12 meses JUPITER – Efectos de Rosuvastatina 20mg en LDL, HDL, TG y PCRus Meses
- 11. Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 - 44 % 0 1 2 3 4 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Seguimietno (años ) Rosuvastatin Placebo 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 JUPITER – Objetivo Principal IAM, Stroke, Revascularización o Muerte CV
- 12. Placebo 251 / 8901 Rosuvastatin 142 / 8901 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 - 44 % 0 1 2 3 4 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Seguimiento (años) Rosuvastatin Placebo 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 JUPITER – Objetivo Principal IAM, Stroke, Revascularización o Muerte CV NNT a 2años = 95 5años* = 25 * Extrapolated figure based on Altman and Andersen method
- 13. HR 0.53, CI 0.40-0.70 P < 0.00001 Rosuvastatin Placebo IAM, Stroke, o Muerte Cardiovascular Revascularización Arterial o Hospitalización por Angina Inestable HR 0.53, CI 0.40-0.69 P < 0.00001 0 1 2 3 4 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence 0 1 2 3 4 0.00 0.01 0.02 0.03 0.04 0.05 Cumulative Incidence Seguimiento (años) Placebo Rosuvastatin - 47 % - 47 % JUPITER – Objetivos Principales Seguimiento (años)
- 14. Placebo 247 / 8901 Rosuvastatin 198 / 8901 HR 0.80, 95%CI 0.67-0.97 P= 0.02 - 20 % 0 1 2 3 4 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Cumulative Incidence Number at Risk Seguimiento (años) Rosuvastatin Placebo 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227 8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246 JUPITER – Mortalidad Total Muerte por cualquier causa
- 15. JUPITER – Análisis Subgrupo A favor Rosuvastatina A favor Placebo 0 0.2 0.4 0.6 0.8 1 1.2 Hazard ratio (95% CI) N P- value* Edad 0.32 ≤ 65 años 8,541 >65 años 9,261 Género 0.80 Hombres 11,001 Mujeres 6,801 Raza 0.57 Blanco 12,683 No-Blanco 5,117 Fumadores SI 2,820 0.63 No 14,975 Hipertensión 0.53 Si 10,208 No 7,586 Región 0.51 US o Canada 6,041 Otros 11,761 Síndrome Metabólico 0.14 Si 7,375 No 10,296 Historia Familiar de ECV 0.07 Yes 2,045 No 15,684 Indice Riesgo Framingham 0.99 ≤ 10% 8,882 >10% 8,895
- 18. JUPITER WOSCOPS AFCAPS/TexCAPS HTN - Diuretics HTN – Beta Blockers Aspirin - Men Aspirin - Women JUPITER NNT a 5 años. Valores para Prevención Primaria de ECV Number Needed to Treat (5 years)
- 19. JUPITER Objetivo Dual: LDLC<70 mg/dL, PCRus<2 mg/L LDL > 70 mg/dL and / or hsCRP > 2 mg/L HR 0.64 (0.49-0.84) LDL < 70 mg/dL and hsCRP < 2 mg/L HR 0.35 (0.23-0.54) Placebo HR 1.0 (referent) P < 0.0001 0 1 2 3 4 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168
- 20. JUPITER Objetivo Dual: LDLC<70 mg/dL, PCRus<1 mg/L LDL > 70 mg/dL and / or hsCRP > 1 mg/L HR 0.59 (0.46-0.75) LDL < 70 mg/dL and hsCRP < 1 mg/L HR 0.21 (0.09-0.51) Placebo HR 1.0 (referent) P < 0.0001 0 1 2 3 4 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168
- 21. JUPITER Tromboembolismo Venoso Total 0 1 2 3 4 0.000 0.005 0.010 0.015 0.020 0.025 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161 8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182 HR 0.57, 95%CI 0.37-0.86 P= 0.007 Placebo 60 / 8901 Rosuvastatin 34 / 8901 - 43 %
- 22. JUPITER TEV + Endpoint Primario + Mortalidad Total Placebo 483 / 8901 Rosuvastatin 320 / 8901 HR 0.66, 95% CI 0.57-0.76 P < 0.00001 Number Needed to Treat (NNT 5 ) = 18 0 1 2 3 4 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 Cumulative Incidence Number at Risk Follow-up (years) Rosuvastatin Placebo 8,901 8,624 8,400 6,525 3,880 1,951 1,348 979 536 157 8,901 8,612 8,338 6,486 3,854 1,949 1,320 945 525 170 163 Eventos Menos
- 23. En varones y mujeres, mayores de 50 años, aparentemente sanos, con bajo LDL pero con alto PCRus, rosuvastatina redujo 47 % la incidencia de infarto de miocardio, stroke y muerte CV . A pesar de evaluar una población con niveles lipídicos considerados casi “optimos” en los algorritmos usuales en prevención, el beneficio relativo observado en JUPITER fue mayor que en otros estudios previos con estatinas. En este estudio sujetos con bajo LDL/alta PCRus que no califican para terapia con estatinas, rosuvastatina significativamente redujo 20% la mortalidad por toda causa. JUPITER – Conclusiones
- 24. Los beneficios con rosuvastatina fueron consistentes en todos los subgrupos independientemente de la edad, sexo, etnia, u otras características clínicas basales incluyento la sola elevación de PCR y ningún otro FR. La tasa de hospitalización y revascularización se redujo un 47 % en un período de 2 años y el Número Necesario de Tratar a 5 años fue de 25 pacientes, para cualquier evento primario, el más bajo observado hasta aquí en Prevención Primaria con Hipolipemiantes. JUPITER – Conclusiones
- 25. En varones mayores de 45 años y mujeres posmenopáusicas: Si es diabético o tiene fuerte historia familiar, tratar Si tiene LDLC > 160 mg/dL, tratar Si tiene PCRus > 3 mg/L, tratar Enfoque para el tratamiento con estatinas en prevención primaria basado en la evidencia. IMPLICANCIAS
Notas del editor
- Last updated: 09 November 2008
- Reference Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207 Abbreviations LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein
- JUPITER es un estudio aleatorio, doble ciego, placebo controlado, multicéntrico, fase III de rosuvastatina 20 mg en la prevención primaria de eventos vasculares entre pacientes con niveles bajos de colesterol LDL-C ( 3.36 mmol/L [130 mg/dL]) y niveles elevados de PCR ( 2.0 mg/L) efectuado en 15,000 pacientes de 24 países.
- Further information about the secondary endpoints: Venous thromboembolic events are defined as deep vein thrombosis or pulmonary embolism. The diagnosis of incident diabetes mellitus will be based upon physician diagnosis, confirmed either by the new use of insulin or an oral hypoglycaemic agent, evidence of a positive glucose tolerance test, or evidence of a repeated fasting glucose >7.0 mmol/L (126 mg/dL). Analyses of incident diabetes mellitus will include all study participants as well as those in whom baseline HbA 1c measurement was <6.5%. Additional analyses will examine the development of diabetes mellitus as reflected by plasma levels of fasting glucose and HbA 1c measured during study follow-up. Reference Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003; 108 : 2292–2297. Abbreviations MI=myocardial infarction; HbA 1c =glycated haemoglobin
- Further information about the secondary endpoints: Venous thromboembolic events are defined as deep vein thrombosis or pulmonary embolism. The diagnosis of incident diabetes mellitus will be based upon physician diagnosis, confirmed either by the new use of insulin or an oral hypoglycaemic agent, evidence of a positive glucose tolerance test, or evidence of a repeated fasting glucose >7.0 mmol/L (126 mg/dL). Analyses of incident diabetes mellitus will include all study participants as well as those in whom baseline HbA 1c measurement was <6.5%. Additional analyses will examine the development of diabetes mellitus as reflected by plasma levels of fasting glucose and HbA 1c measured during study follow-up. Reference Ridker PM. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003; 108 : 2292–2297. Abbreviations MI=myocardial infarction; HbA 1c =glycated haemoglobin
- 89,890 patients were initially screened into the study at 1,315 sites in 26 countries. Following completion of a four week placebo run-in period, 17,802 patients met the eligibility criteria and were randomized into the study. A small number of patients, 44 in the rosuvastatin group and 37 in the placebo group, were lost to follow up during the study. Reference Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207
- Patients in each group were similar at entry and had a median age of 66 years. The study population was diverse and included a large female population (38.2%) and a large proportion of black or hispanic individuals (25.2%). Reference Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207
- Patients had low to normal LDL-C at baseline (median 108 mg/dL). The treatment groups were well matched in terms of laboratory parameters at baseline. Reference Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207
- Patients recruited into the JUPITER study would not usually be eligible for statin therapy according to current treatment guidelines. In order to be eligible for the study, men had to be 50 years of age and women had to be 60 years of age. As a result, all eligible study patients had age as a risk factor as defined by the NCEP ATP III treatment guidelines (NCEP ATP III definition: men 45, women 55 yrs) 1 . A substantial number of patients also had other cardiovascular risk factors including hypertension, low HDL-C, family history of premature CHD and smoking amongst others. 2,3 Reference Grundy SM et al . Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110 : 227-239. Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207 Ridker PM et al . Baseline characteristics of participants in the JUPITER trial, a randomised placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol 2007; 100 : 1659-1664.
- This slide presents the effects of rosuvastatin on the primary endpoint, according to baseline characteristics. Results achieved statistical significance in all subgroups according to age, race or ethnic group, region of origin, risk factor status and Framingham risk score, including the first demonstrated benefit in women without established CHD. Relative risk reductions in the rosuvastatin group were similar for women (46%) and men (42%). Reference Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207
- Tolerability and safety: Rosuvastatin 20 mg was well tolerated during the course of the study, with no significant difference between treatment groups in terms of muscle weakness, newly diagnosed cancer or disorders of the haematologic, gastrointestinal, hepatic or renal systems. One case of non-fatal rhabdomyolysis was reported in the rosuvastatin treatment group after the study completion date. This case involved a 90 year old individual with febrile influenza, pneumonia and trauma-induced myopathy. No increase in intracranial hemorrhagic stroke was seen following treatment with rosuvastatin (6 patients treated with rosuvastatin and 9 patients treated with placebo, p=0.44). Physician-reported diabetes was more frequent among those allocated to rosuvastatin therapy (270 patients in rosuvastatin group and 216 patients in placebo group, p=0.01); these events were not adjudicated by the endpoint committee. This result is despite no difference being observed between study groups for fasting glucose (98 vs 98 mg/dL; p=0.12) or newly diagnosed glycosuria (36 vs 32, p=0.64) [see next slide] . However, a minimal difference in HbA1c was observed (5.9 vs 5.8%, p<0.001). This less than 1% difference in HbA1C was statistically significant, but is unlikely to be of clinical significance. The effect on glucose and diabetes in this study is consistent with the data observed in other large, prospectively designed, placebo controlled statin trials. 2,3 Reference Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207 Sever PS, Dahlöf B, Poulter NR et al . Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandanavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA); a multicentre randomised controlled trial. Lancet 2003; 361 : 1149-58. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361 : 2005-2016.
- Laboratory safety data: There was no difference between study groups during follow-up for fasting plasma glucose (98 mg/dL rosuvastatin group vs 98 mg/dL placebo group, p=0.12), or glycosuria (36 rosuvastatin group vs 32 placebo group, p=0.53). However, there was a minimal increase in haemoglobin A1c observed between groups during the course of the study (5.9 rosuvastatin group vs 5.8% placebo group, p=0.001). Reference Ridker P et al . Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359 : 2195-2207