Dr François Diévart Clinique Villette Dunkerque Place des statines dans la prise en charge du patient à haut risque cardiovasculaire Dr François Diévart Clinique Villette Dunkerque

Rosuvastatin in Older Patients with Systolic Heart Failure CORONA: Controlled Rosuvastatin Multinational Trial In Heart Failure Rosuvastatin in Older Patients with Systolic Heart Failure John Kjekshus, M.D., Ph.D., Eduard Apetrei, M.D., Ph.D., Vivencio Barrios, M.D., Ph.D., Michael Böhm, M.D., Ph.D., John G.F. Cleland, M.D., Jan H. Cornel, M.D., Ph.D., Peter Dunselman, M.D., Ph.D., Cândida Fonseca, M.D., Assen Goudev, M.D., Ph.D., Peer Grande, M.D., Ph.D., Lars Gullestad, M.D., Ph.D., Åke Hjalmarson, M.D., Ph.D., Jaromir Hradec, M.D., Ph.D., András Jánosi, M.D., D.Sc., Gabriel Kamensky, M.D., Ph.D., Michel Komajda, M.D., Jerzy Korewicki, M.D., Ph.D., Timo Kuusi, M.D., Ph.D., François Mach, M.D., Vyacheslav Mareev, M.D., Ph.D., John J.V. McMurray, M.D., Naresh Ranjith, M.D., Maria Schaufelberger, M.D., Ph.D., Johan Vanhaecke, M.D., Ph.D., Dirk J. van Veldhuisen, M.D., Ph.D., Finn Waagstein, M.D., Ph.D., Hans Wedel, Ph.D., John Wikstrand, M.D., Ph.D., for the CORONA Group Publié sur www.nejm.org le 5 novembre 2007 (10.1056/NEJMoa0706201)

Primary Endpoint CV death or non-fatal MI or non-fatal stroke 35 Placebo n = 732 (29.3%) 30 25 Rosuvastatin n = 692 (27.5%) Per cent Per cent 20 15 10 Hazard ratio = 0.92 95% CI 0.83 to 1.02 p = 0.12 5 Months of follow-up 36 30 24 18 12 6 No. at risk Placebo 2497 2315 2156 2003 1851 1431 811 Rosuvastatin 2514 2345 2207 2068 1932 1484 855 Kjekshus J et al, N Engl J Med 2007;357, sous presse

QUESTIONS Explication possible Statut des statines chez l’insuffisant cardiaque Effet classe des statines Posologie élevée chez les patients à risque élevé

QUESTIONS Explication possible Statut des statines chez l’insuffisant cardiaque Effet classe des statines Posologie élevée chez les patients à risque élevé

Prespecified Composite CV Outcomes and Fatal and Nonfatal Events Variable Placebo (n = 2497) Rosuvastatin (n = 2514) Hazard Ratio (95% CI) P Value No. of Pts Event Rate Outcome Primary outcome 732 12.3 692 11.4 0.92 (0.83–1.02) 0.12 Secondary outcome Death from any cause 759 12.2 728 11.6 0.95 (0.86–1.05) 0.31 Any coronary event 588 10.0 554 9.3 0.92 (0.82–1.04) 0.18 Fatal event Death from CV causes 593 9.6 581 0.97 (0.87–1.09) 0.60 Sudden death 327 5.3 316 5.0 0.96 (0.82–1.12) 0.57 Worsening heart failure 191 3.1 193 1.00 (0.82–1.22) 1.00 Myocardial infarction 9 0.2 15 Stroke 32 0.5 35 0.6 NEJM. En ligne, nov. 2007

Prespecified Composite CV Outcomes and Fatal and Nonfatal Events Variable Placebo (n = 2497) Rosuvastatin (n = 2514) Hazard Ratio (95% CI) P Value No. of Pts Event Rate Outcome Primary outcome 732 12.3 692 11.4 0.92 (0.83–1.02) 0.12 Secondary outcome Death from any cause 759 12.2 100% 11.6 0.95 (0.86–1.05) 0.31 Any coronary event 588 10.0 554 9.3 0.92 (0.82–1.04) 0.18 Fatal event Death from CV causes 593 9.6 581 0.97 (0.87–1.09) 0.60 Sudden death 327 5.3 316 5.0 0.96 (0.82–1.12) 0.57 Worsening heart failure 191 3.1 193 1.00 (0.82–1.22) 1.00 Myocardial infarction 9 0.2 15 Stroke 32 0.5 35 0.6 NEJM. En ligne, nov. 2007

Prespecified Composite CV Outcomes and Fatal and Nonfatal Events Variable Placebo (n = 2497) Rosuvastatin (n = 2514) Hazard Ratio (95% CI) P Value No. of Pts Event Rate Outcome Primary outcome 732 12.3 692 11.4 0.92 (0.83–1.02) 0.12 Secondary outcome Death from any cause 759 12.2 100% 11.6 0.95 (0.86–1.05) 0.31 Any coronary event 588 10.0 554 9.3 0.92 (0.82–1.04) 0.18 Fatal event Death from CV causes 593 9.6 78% 0.97 (0.87–1.09) 0.60 Sudden death 327 5.3 316 5.0 0.96 (0.82–1.12) 0.57 Worsening heart failure 191 3.1 193 1.00 (0.82–1.22) 1.00 Myocardial infarction 9 0.2 15 Stroke 32 0.5 35 0.6 NEJM. En ligne, nov. 2007

Prespecified Composite CV Outcomes and Fatal and Nonfatal Events Variable Placebo (n = 2497) Rosuvastatin (n = 2514) Hazard Ratio (95% CI) P Value No. of Pts Event Rate Outcome Primary outcome 732 12.3 692 11.4 0.92 (0.83–1.02) 0.12 Secondary outcome Death from any cause 759 12.2 100% 11.6 0.95 (0.86–1.05) 0.31 Any coronary event 588 10.0 554 9.3 0.92 (0.82–1.04) 0.18 Fatal event Death from CV causes 593 9.6 78% 0.97 (0.87–1.09) 0.60 Sudden death 327 5.3 43.4% 5.0 0.96 (0.82–1.12) 0.57 Worsening heart failure 191 3.1 193 1.00 (0.82–1.22) 1.00 Myocardial infarction 9 0.2 15 Stroke 32 0.5 35 0.6 NEJM. En ligne, nov. 2007

Prespecified Composite CV Outcomes and Fatal and Nonfatal Events Variable Placebo (n = 2497) Rosuvastatin (n = 2514) Hazard Ratio (95% CI) P Value No. of Pts Event Rate Outcome Primary outcome 732 12.3 692 11.4 0.92 (0.83–1.02) 0.12 Secondary outcome Death from any cause 759 12.2 100% 11.6 0.95 (0.86–1.05) 0.31 Any coronary event 588 10.0 554 9.3 0.92 (0.82–1.04) 0.18 Fatal event Death from CV causes 593 9.6 78% 0.97 (0.87–1.09) 0.60 Sudden death 327 5.3 43.4% 5.0 0.96 (0.82–1.12) 0.57 Worsening heart failure 191 3.1 25.4% 1.00 (0.82–1.22) 1.00 Myocardial infarction 9 0.2 15 Stroke 32 0.5 35 0.6 NEJM. En ligne, nov. 2007

Prespecified Composite CV Outcomes and Fatal and Nonfatal Events Variable Placebo (n = 2497) Rosuvastatin (n = 2514) Hazard Ratio (95% CI) P Value No. of Pts Event Rate Outcome Primary outcome 732 12.3 692 11.4 0.92 (0.83–1.02) 0.12 Secondary outcome Death from any cause 759 12.2 100% 11.6 0.95 (0.86–1.05) 0.31 Any coronary event 588 10.0 554 9.3 0.92 (0.82–1.04) 0.18 Fatal event Death from CV causes 593 9.6 78% 0.97 (0.87–1.09) 0.60 Sudden death 327 5.3 43.4% 5.0 0.96 (0.82–1.12) 0.57 Worsening heart failure 191 3.1 25.4% 1.00 (0.82–1.22) 1.00 Myocardial infarction 9 0.2 1.6% Stroke 32 0.5 35 0.6 NEJM. En ligne, nov. 2007

Prespecified Composite CV Outcomes and Fatal and Nonfatal Events Variable Placebo (n = 2497) Rosuvastatin (n = 2514) Hazard Ratio (95% CI) P Value No. of Pts Event Rate Outcome Primary outcome 732 12.3 692 11.4 0.92 (0.83–1.02) 0.12 Secondary outcome Death from any cause 759 12.2 100% 11.6 0.95 (0.86–1.05) 0.31 Any coronary event 588 10.0 554 9.3 0.92 (0.82–1.04) 0.18 Fatal event Death from CV causes 593 9.6 78% 0.97 (0.87–1.09) 0.60 Sudden death 327 5.3 43.4% 5.0 0.96 (0.82–1.12) 0.57 Worsening heart failure 191 3.1 25.4% 1.00 (0.82–1.22) 1.00 Myocardial infarction 9 0.2 1.6% Stroke 32 0.5 4.0% 0.6 NEJM. En ligne, nov. 2007

QUESTIONS Explication possible Les événements survenus dans CORONA ne sont pas ceux prévenus par les statines

QUESTIONS Explication possible Statut des statines chez l’insuffisant cardiaque Effet classe des statines Posologie élevée chez les patients à risque élevé

Relation entre la réduction de l’incidence des événements vasculaires majeurs et la réduction moyenne du LDL-C à 1 an 50% Evènements vasculaires majeurs 40% 30% Réduction des évènements 21% 20% 10% 0% mmol/L 1.0 0.5 1.5 2.0 (0.4 g/l) -10% Réduction du LDL-C Lancet 2005;366:1267-78. 15

Intensive Statin Therapy and the Risk of Hospitalization for Heart Failure After an Acute Coronary Syndrome in the PROVE IT–TIMI 22 Study Benjamin M. Scirica MD, MPH, David A. Morrow MD, MPH, Christopher P. Cannon MD, Kausik K. Ray MD, Marc S. Sabatine MD, MPH, Petr Jarolim MD, PhD†, Amy Shui BS, Carolyn H. McCabe BS, Eugene Braunwald MD and PROVE IT–TIMI 22 Investigators A to Z results add to evidence from other trials of aggressive lipid lowering The direction of the results in A to Z are consistent with those of MICRACL and PROVE IT-TIMI 22. A to Z and other investigators have and hypothesized that the failure to reach clinical significance may have been due, in part, to the lack of an early anti-inflammatory effect. Late benefits of statin therapy may be due to removal of lipids from plaque and subsequent remodeling. J American Coll Cardio 2006;47:2326-31 16

Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure Subgroup Analysis of the Treating to New Targets (TNT) Study Kiran K. Khush, MD; David D. Waters, MD; Vera Bittner, MD; Prakash C. Deedwania, MD; John J.P. Kastelein, MD; Sandra J. Lewis, MD; Nanette K. Wenger, MD A to Z results add to evidence from other trials of aggressive lipid lowering The direction of the results in A to Z are consistent with those of MICRACL and PROVE IT-TIMI 22. A to Z and other investigators have and hypothesized that the failure to reach clinical significance may have been due, in part, to the lack of an early anti-inflammatory effect. Late benefits of statin therapy may be due to removal of lipids from plaque and subsequent remodeling. Circulation. 2007;115:576-583. 17

Intensive Statin Therapy and the Risk of Hospitalization for Heart Failure After an Acute Coronary Syndrome in the PROVE IT–TIMI 22 Study Benjamin M. Scirica MD, MPH, David A. Morrow MD, MPH, Christopher P. Cannon MD, Kausik K. Ray MD, Marc S. Sabatine MD, MPH, Petr Jarolim MD, PhD†, Amy Shui BS, Carolyn H. McCabe BS, Eugene Braunwald MD and PROVE IT–TIMI 22 Investigators A to Z results add to evidence from other trials of aggressive lipid lowering The direction of the results in A to Z are consistent with those of MICRACL and PROVE IT-TIMI 22. A to Z and other investigators have and hypothesized that the failure to reach clinical significance may have been due, in part, to the lack of an early anti-inflammatory effect. Late benefits of statin therapy may be due to removal of lipids from plaque and subsequent remodeling. J American Coll Cardio 2006;47:2326-31. 18

Statut des statines chez l’insuffisant cardiaque QUESTIONS Statut des statines chez l’insuffisant cardiaque Statut inchangé Les statines ne préviennent pas les événements spécifiques à l’insuffisance cardiaque (mort subite, aggravation de l’insuffisance cardiaque) Chez le coronarien, elles diminuent le risque d’hospitalisation pour insuffisance cardiaque

QUESTIONS Explication possible Statut des statines chez l’insuffisant cardiaque Effet classe des statines Posologie élevée chez les patients à risque élevé

MIRACL : dessin de l’étude Placebo Hospitalisation pour angor instable ou IDM non-Q n = 3086 24–96 heures après l’admission Atorvastatine 80 mg 16 semaines TChol < 7 mmol/L MIRACL study was an important addition to our knowledge in the area of dyslipidemia management. MIRACL study focused on the very high risk patient population that has not been studied before and applied a very intense therapy with atorvastatin 80 mg by comparison to placebo. Between 24 and 96 hours after hospital admission, eligible patients were randomly assigned with stratification by center to double-blind treatment with atorvastatin (80 mg daily) or matching placebo for 16 weeks. The protocol did not otherwise restrict or specify any diagnostic or therapeutic measures during the study period. All patients received instruction and counseling to promote compliance with a National Cholesterol Education Program step I diet. Patients were seen in follow up 2, 6, and 16 weeks after the initiation of therapy to reinforce dietary counseling and to monitor for compliance, study end points, and adverse events, and to monitor laboratory parameters at 6 and 16 weeks. Laboratory testing was performed centrally. Study medication was discontinued if serum alanine or aspartate aminotransferase exceeded 3 times the upper limit of normal on two determinations 1 week apart, or if a patient developed muscle pain, weakness, or tenderness consistent with myositis and serum creatine kinase level exceeded 10 times the upper limit of normal on two determinations 1 week apart . Schwartz GG et al. JAMA. 2001;285:1711-1718. 21

MIRACL : variations lipidiques 20 Placebo 12 9 Atorvastatine 7 10 4 5 -10 %  -20 -16 -30 -27 MIRACL: CHANGE IN LIPID LEVELS At baseline, serum lipid levels were nearly identical in both groups. The mean TC was 206 mg/dL, mean LDL-C 124 mg/dL, mean HDL-C 46 mg/dL, mean TG 184 mg/dL. At the end of the study, there were slight increases from baseline in each lipid fraction in the placebo group. TC rose to a mean of 217 mg/dL, LDL-C to a mean of 135 mg/dL, HDL-C to a mean of 47 mg/dL, and TG to a mean of 187 mg/dL. These increases most likely reflect recovery from acute-phase depression of lipoproteins, since the baseline measurements were performed soon after the index ischemic event. In contrast, in the atorvastatin group, TC at the end of the study declined by a mean of 27% from baseline (to 147 mg/dL), LDL-C declined by a mean of 40% (to 72 mg/dL), and TG declined by a mean of 16% (to 139 mg/dL). HDL-C rose by a mean of 5% (to 48 mg/dL). Schwartz GG et al. JAMA. 2001;285:1711-1718. Additional data courtesy of GG Schwartz -40 -40 -50 TC LDL-C HDL-C TG LDL initial : ~ 3,23 mmol/L Schwartz GG et al. JAMA. 2001;285:1711-1718. 22

MIRACL : résultats sur le critère primaire 20 Risque relatif = 0.84 p=0.048 17,4 % Placebo 15 14,8 % Atorvastatine 10 Incidence cumulée (%) Critère primpaire Mortalité totale IDM non fatal Arrêt cardiaque ressuscité Agravation d’un angor avec nécessité d’hospitaisation urgente 5 After 16 weeks follow-up, the primary end point measure (time to first occurrence of death, nonfatal acute MI, resuscitated cardiac arrest, or worsening angina with new objective evidence requiring urgent rehospitalization) occurred in 228 patients in the atorvastatin group (14.8%) and 269 patients in the placebo group (17.4%). Compared with placebo, atorvastatin treatment produced a significant (p=0.048) 16% reduction in the risk of the primary composite end point (95% confidence interval, 0.701–0.999). 4 8 12 16 Durée (semaines) Schwartz GG et al. JAMA. 2001;285:1711-1718. 23

MIRACL : conclusions et implications MIRACL démontre pour la 1re fois, qu’un traitement hypolipidémiant intensif (l’atorvastatine à 80 mg/j) prescrit dès la phase précoce d’un syndrome coronaire aigu (SCA), procure un bénéfice clinique net en seulement 4 mois. Ce bénéfice est observé chez des patients ayant des valeurs initiales basses de cholestérol LDL. Cette étude supporte l’utilisation d’un traitement précoce, lors de l’hospitalisation pour un SCA, indépendamment de la valeur de base du LDL. Schwartz GG et al. JAMA. 2001;285:1711-1718.

Traiter précocement PROVE IT A to Z MIRACL Phase aiguë – 4 mois jusqu’à 2 ans PROVE IT A to Z MIRACL The 4S trial, published in 1994, raised intriguing questions about the role of statins in secondary prevention. Since then, results of 4 seminal studies published between 1995 and 2004 have answered some of these questions. The Cholesterol and Recurrent Events (CARE) study further expanded our understanding of the effectiveness of statins in secondary prevention of CVD by demonstrating that cholesterol-lowering therapy with statins can benefit patients with coronary disease and average cholesterol levels. Pravastatin reduced the risk of the primary end point of a fatal coronary event or nonfatal MI by 24% compared with placebo (P=.003).1 The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study supported the validity of the 4S trial and provided further evidence for the role of statins in secondary prevention by showing that, compared with placebo, lowering cholesterol with pravastatin reduced overall mortality, CHD mortality, and the risk of MI and stroke in patients with a broad range of initial cholesterol levels and a history of MI or unstable angina (UA).2 The Heart Protection Study (HPS) demonstrated that use of simvastatin 40 mg reduced the risk of first occurrence of major vascular events, including stroke, in at-risk individuals. This effect was observed even in patients whose initial LDL cholesterol was below 3.0 mmol/L (116 mg/dL) or whose TC was below 5.0 mmol/L (193 mg/dL). The HPS showed that statin therapy adds benefit to other postcardiac event treatments in patents at high risk.3 The Treating to New Targets (TNT) study considered whether reducing LDL cholesterol levels to well below 100 mg/dL in patients with stable CHD and slightly elevated LDL cholesterol levels could result in incremental clinical benefit. Results of this double-blind study demonstrated that use of 80 mg atorvastatin in patients with clinically evident CHD was associated with greater reduction in risk of coronary event, risk of cerebrovascular event, hospitalization with a primary diagnosis of congestive heart failure, and any cardiac event, compared with atorvastatin 10 mg.4 References: 1. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009. 2. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357. 3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7-22. 4. LaRosa JC, Grundy SM, Waters DD, et al, for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435. 25

Bénéfice précoce et soutenu démontré PROVE IT-TIMI 22 Dessin 4162 patients avec un angor instable ; randomisés atorvastatin 80 mg ; vs pravastatine 40 mg Suivi 2 ans Critère primaire Mortalité totale, IDM, hospitalisation pour angor instable, revascularisation, AVC Bénéfice précoce et soutenu démontré 30 n = 4162 P = 0,005 40 mg Pravastatine 20 80 mg Atorvastatine Décès ou événement CV majeur (%) Early, high-dose statin therapy is associated with early benefit Baseline LDL-C was 106 mg/dL in each group, and was reduced to 95 mg/dL and 62 mg/dL in the pravastatin and atorvastatin groups, respectively (P < 0.001). The primary outcome occurred in 26.3% and 22.4% of the pravastatin and atorvastatin groups, respectively (16% RRR in favor of atorvastatin, P = 0.005). Separation of the curves occurred as early as 30 days. Statistically significant benefit was evident at 4 months. 10 o = 0,03 à 4 mois 3 6 9 12 15 18 21 24 27 30 Suivi (mois) Ray KK and Cannon CP Am J Cardiol. 2005;96(suppl):54F-60F. D’après Cannon CP et al. N Engl J Med. 2004;350:1495-504. 26

PROVE IT-TIMI 22 Implications cliniques Chez les patients avec un SCA, une stratégie ayant pour objectif de baisser puissamment et précocement le LDL-C procure un bénéfice clinique net par rapport à une autre stratégie hypolipidémiante, précoce mais moins puissante, avec une réduction relative de 16 % des événements CV majeurs. Le bénéfice clinique apparaît dès le 30e jour Results show favorable benefit/risk for lower LDL-C goals No cases of rhabdomyolysis occurred in either group. Muscle-related study drug discontinuation occurred in 2.7% and 3.3% of pravastatin and atorvastatin groups, respectively (P = 0.23). In a separate analysis, Wiviott et al classified the incidence of muscle-related or liver-related side effects according to on-treatment LDL-C. No increased risk was noted even at LDL-C below 40 mg/dL. Cannon CP et al. N Engl J Med. 2004;350:1495-504. Ray KK et al. Am J Cardiol. 2005;96(suppl):54F-60F. Ridker PM et al. N Engl J Med. 2005;352:20-8. Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-6. 27

Rapid effect of simvastatin 40 mg vs placebo Etude A to Z : Aggrastat to Zocor Population 4497 patients avec un SCA Traitements Simvastatine 40 mg/j pour 1 mois, puis 80 mg/j Placebo pour 4 mois, puis simvastatine 20 mg/j Suivi médian 721 jours Critère primaire décès CV, IDM non fatal, réhospitalisation pour angor instable, AVC 140 122 124 Variation du LDL-C 111 112 100 * 81 77 LDL-C (mg/dL) * * * 68 66 Rapid effect of simvastatin 40 mg vs placebo During the placebo-controlled phase, there was a large LDL-C differential between the two arms. This differential diminished when simvastatin 20 mg was initiated in the placebo arm after 4 months. 62 63 60 20 Etat de base 1 4 8 24 *p < 0,001 vs placebo/sim-vastatine 20 mg mois Placebo/simvastatine 20 mg/j Simvastatine 40/80 mg/j de Lemos JA et al. JAMA. 2004;292:1307-16. 28

Etude A to Z Résultat sur le critère primaire 20 Réd. relative du risque 11 % RR = 0,89 (0,76-1,04) p = 0,14 Taux cumulé (%) 15 10 11% RRR Delayed benefit with higher-dose simvastatin strategy The primary outcome occurred in 14.4% and 16.7% of the intensive therapy and less-intensive therapy groups, respectively (11% relative risk reduction, P = 0.14). Post hoc analysis revealed benefits after 4 months. There was no difference between groups during the first 4 months of the study; but a 25% relative risk reduction in favor of the intensive-therapy group occurred between 4 months and study end (P = 0.02). The lack of early benefit in A to Z was unexpected, given that the LDL-C differential achieved at 4 months was 62 mg/dL. The lack of an early anti-inflammatory effect may have contributed to the delay in benefit.1 27% RRR P = 0.02 5 4 8 12 16 20 24 mois Placebo/simvastatine 20 mg/j Simvastatine 40/80 mg/j de Lemos JA et al. JAMA. 2004;292:1307-16. 1. Nissen SE. High-dose statins in acute coronary syndromes: Not just lipid levels. JAMA. 2004;292:1365-1367. 29

Etude A to Z : synthèse Chez les patients avec un syndrome coronaire, l’initiation précoce d’un traitement à posologie modérée puis forte de simvastatine par rapport à l’initiation différée d’une posologie standard, n’apporte pas de bénéfice significatif. A to Z results add to evidence from other trials of aggressive lipid lowering The direction of the results in A to Z are consistent with those of MICRACL and PROVE IT-TIMI 22. A to Z and other investigators have and hypothesized that the failure to reach clinical significance may have been due, in part, to the lack of an early anti-inflammatory effect. Late benefits of statin therapy may be due to removal of lipids from plaque and subsequent remodeling. de Lemos JA et al. JAMA. 2004;292:1307-16. Ray KK et al. Am J Cardiol. 2005;96(suppl):54F-60F. 30

A Tale of Two Trials A Comparison of the Post–Acute Coronary Syndrome Lipid-Lowering Trials A to Z and PROVE IT–TIMI 22 Stephen D. Wiviott, MD; James A. de Lemos, MD; Christopher P. Cannon, MD; Michael Blazing, MD; Sabina A. Murphy, MPH; Carolyn H. McCabe, BS; Robert Califf, MD; Eugene Braunwald, MD CONCLUSIONS “An early benefit was seen in PROVE IT but not in A to Z. Late-phase results were similar. Factors that may explain this disparity include the intensity of therapy in the early phase, timing, and magnitude of LDL and C-reactive protein lowering, differences in early revascularization, and the play of chance. Taken together, the results of these trials support a strategy of early intensive statin therapy coupled with revascularization when appropriate in patients after ACS.” A to Z results add to evidence from other trials of aggressive lipid lowering The direction of the results in A to Z are consistent with those of MICRACL and PROVE IT-TIMI 22. A to Z and other investigators have and hypothesized that the failure to reach clinical significance may have been due, in part, to the lack of an early anti-inflammatory effect. Late benefits of statin therapy may be due to removal of lipids from plaque and subsequent remodeling. Circulation. 2006;113:1406-1414. 31

Intensive Statin Therapy and the Risk of Hospitalization for Heart Failure After an ACS in the PROVE IT–TIMI 22 Study Scirica B et al. 5 Pravastatin 40 mg PROVE IT-TIMI 22 4 Acute phase 3 Death, MI, or Rehospitalization (%) 2 Atorvastatin 80 mg Pravastatin (n = 2063) Atorvastatin (n = 2099) 1 HR = 0.72 (CI = 0.52-0.99) P =0.046 5 10 15 20 25 30 Days following randomization MIRACL A-to-Z A to Z results add to evidence from other trials of aggressive lipid lowering The direction of the results in A to Z are consistent with those of MICRACL and PROVE IT-TIMI 22. A to Z and other investigators have and hypothesized that the failure to reach clinical significance may have been due, in part, to the lack of an early anti-inflammatory effect. Late benefits of statin therapy may be due to removal of lipids from plaque and subsequent remodeling. 15 Placebo 17.2% 15 14.6% 10 Simvastatin 40 mg/80 mg 8.2% Atorvastatin 80 mg Death, acute MI, cardiac arrest, unstable angina Death, acute MI, stroke, unstable angina 10 8.1% Placebo 5 5 RR = 1.01 RR = 0.84 P = NS P =0.048 1 2 3 4 1 2 3 4 Months of randomized treatment Months of randomized treatment RR = risk reduction; NS = not significant. Expert Opin. Investig. Drugs 2006;15(10):1151-1159. 32

Synthèse : quelle place pour les effets anti-inflammatoires des statines ? Différences de variation de la CRP selon les études A to Z MIRACL PROVE-IT C-reactive protein differentiel (%) 17 34 38

Synthèse : quelle place pour les effets anti-inflammatoires des statines ? Différences de variation de la CRP selon les études A to Z MIRACL PROVE-IT C-reactive protein differentiel (%) 17 34 38 Hypothèse Bénéfice précoce d’une statine : effet anti-inflammatoire Bénéfice tardif d’une statine : effet sur le LDL-C

Effet classe des statines QUESTIONS Effet classe des statines L’effet classe en chronique reste l’hypothèse la plus valide Dans les situations aiguës, cette hypothèse n’est pas validée Utiliser les statines validées comme bénéfiques dans les essais

QUESTIONS Explication possible Statut des statines chez l’insuffisant cardiaque Effet classe des statines Posologie élevée chez les patients à risque élevé

Essais d’intervention ayant démontré le bénéfice clinique d’un abaissement du LDL < 1 g/L MIRACL PROVE IT TNT IDEAL SPARCL LDL initial 1,24 g/l 1,06 g/l 0,98 g/l 1,22 g/l 1,33 g/l LDL obtenu dans le groupe contrôle 1,35 g/l 0,95 g/l 1,01 g/l 1,04 g/l 1,29 g/l LDL obtenu sous atorvastatine 80 mg/j 0,72 g/l 0,62 g/l 0,77 g/l 0,81 g/l 0,73 g/l Différence de LDL 0,63 g/l 0,33 g/l 0,24 g/l 0,23 g/l 0,56 g/l Durée moyenne de l’étude 4 mois 2 ans 4,9 ans 4,8 ans Risque relatif d’événements coronaires 0,84 0,80 0,89 0,65 Risque relatif de mortalité totale 0,94 0,72 1,01 0,98 1,00

Essais d’intervention ayant démontré le bénéfice clinique d’un abaissement du LDL < 1 g/L MIRACL PROVE IT TNT IDEAL SPARCL LDL initial 1,24 g/l 1,06 g/l 0,98 g/l 1,22 g/l 1,33 g/l LDL obtenu dans le groupe contrôle 1,35 g/l 0,95 g/l 1,01 g/l 1,04 g/l 1,29 g/l LDL obtenu sous atorvastatine 80 mg/j 0,72 g/l 0,62 g/l 0,77 g/l 0,81 g/l 0,73 g/l Différence de LDL 0,63 g/l 0,33 g/l 0,24 g/l 0,23 g/l 0,56 g/l Durée moyenne de l’étude 4 mois 2 ans 4,9 ans 4,8 ans Risque relatif d’événements coronaires 0,84 0,80 0,89 0,65 Risque relatif de mortalité totale 0,94 0,72 1,01 0,98 1,00

Essais d’intervention ayant démontré le bénéfice clinique d’un abaissement du LDL < 1 g/L MIRACL PROVE IT TNT IDEAL SPARCL LDL initial 1,24 g/l 1,06 g/l 0,98 g/l 1,22 g/l 1,33 g/l LDL obtenu dans le groupe contrôle 1,35 g/l 0,95 g/l 1,01 g/l 1,04 g/l 1,29 g/l LDL obtenu sous atorvastatine 80 mg/j 0,72 g/l 0,62 g/l 0,77 g/l 0,81 g/l 0,73 g/l Différence de LDL 0,63 g/l 0,33 g/l 0,24 g/l 0,23 g/l 0,56 g/l Durée moyenne de l’étude 4 mois 2 ans 4,9 ans 4,8 ans Risque relatif d’événements coronaires 0,84 0,80 0,89 0,65 Risque relatif de mortalité totale 0,94 0,72 1,01 0,98 1,00

Posologie élevée chez les patients à risque élevé QUESTIONS Posologie élevée chez les patients à risque élevé Le bénéfice de posologies élevées est démontré dans 5 études avec l’atorvastatine à 80 mg, contre placebo ou contre comparateur actif à posologie moins élevée. Les posologies élevées apportent un bénéfice additionnel. Les posologies élevées sont bien tolérées.