Θεραπεύοντας προς νέους στόχους

Παρουσίαση με θέμα: "Θεραπεύοντας προς νέους στόχους"— Μεταγράφημα παρουσίασης:

1 Θεραπεύοντας προς νέους στόχους
ΔΥΝΑΜΙΚΗ ΔΙΑΜΟΡΦΩΣΗ ΤΩΝ ΟΔΗΓΙΩΝ ΓΙΑ ΤΗΝ ΑΝΤΙΜΕΤΩΠΙΣΗ ΤΩΝ ΔΥΣΛΙΠΙΔΑΙΜΙΩΝ Θεραπεύοντας προς νέους στόχους Βασίλειος ΑΘΥΡΟΣ, MD, FESC, FASA, FACS Ιατρεία Αθηροσκλήρωσης και Μεταβολικού Συνδρόμου, Β’ Προπ. Παθολογική Κλινική ΑΠΘ, Ιπποκράτειο Νοσοκομείο, Θεσσαλονίκη.

2 Fatal CHD/nonfatal MI (%) Fatal CHD/nonfatal MI (%)
Early secondary prevention trials only focused on long-term event reductions in stable patients 1.00 0.95 0.90 0.85 0.80 0.00 1 2 3 4 5 6 Proportion alive Risk reduction, 30% Log-rank p=0.0003 Simvastatin Placebo 4S Fatal CHD/nonfatal MI (%) 5 10 15 20 1 2 3 4 6 7 Risk reduction, 24% p<0.001 Pravastatin Placebo LIPID 1 2 3 4 5 6 15 10 Fatal CHD/nonfatal MI (%) Risk reduction, 24% p=0.003 Pravastatin Placebo CARE Years Slide 7 Three randomized, placebo-controlled trials – 4S, CARE and LIPID – have established that long-term lipid-lowering therapy with statins reduces mortality and recurrent ischemic cardiovascular events in patients with stable coronary heart disease. However, approximately two years of treatment were required before a significant reduction in death and cardiovascular events could be discerned. Importantly, each of these trials excluded patients who had experienced unstable angina or acute MI within 3 to 6 months prior to randomization [8–10]. References 8. Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389. 9. Sacks FM et al. N Engl J Med 1996;335:1001–1009. 10. The long-term intervention with pravastatin in ischaemic disease (LIPID) study group. N Engl J Med 1998;339:1349–1357. 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.

3 NCEP ΑTP III (2001) : Θεραπευτικοί στόχοι LDL-Χ και επίπεδα έναρξης ΑΤΖ και φαρμακευτικής θεραπείας σε διάφορες κατηγορίες κινδύνου. 100 <100 10-ετής κίνδυνος 10–20%: 130 10-ετής κίνδυνος <10%: 160 130 <130 2+ παράγοντες κινδύνου (10-ετής κίνδυνος 20%) 160 <160 Επίπεδο LDL-Χ για φαρμακευτική αγωγή (mg/dL) Επίπεδο LDL-Χ για ΑΤΖ (mg/dL) Στόχος LDL-Χ Κατηγορία κινδύνου 190 (160–189: προαιρετική) 0–1 παράγοντες κινδύνου 130 (100–129 mg/dL : προαιρετική) ΣΝ ή ισοδύναμα (10-ετής κίνδυνος >20%) NCEP : ATP III JAMA 2001;285:

4 ATP III ισοδύναμα ΣΝ Ο στόχος αυτός παραμένει στο ΑΤΡ ΙΙΙ και επεκτείνεται σε άλλες κατηγορίες ασθενών με ισοδύναμα ΣΝ που αθροιστικά αυξάνουν το 10-ετή κίνδυνο ΣΝ > 20% : Α. Σακχαρώδης διαβήτης Β. Άλλες αγγειακές νόσοι α. περιφερική αγγειοπάθεια β. ανεύρυσμα της αορτής γ. συμπτωματική νόσο των καρωτίδων NCEP : ATP III JAMA 2001;285:

5 Σταθερή Στεφανιαία Νόσος

6 HPS: Συμβάματα με βάση τα αρχικά επίπεδα της LDL
Risk ratio and 95% CI Baseline LDL (mg/dl) Statin (10,269) Placebo (10,267) <100 282 358 100–129 668 871 130 1083 1356 All patients 2033 (19.8%) 2585 (25.2%) Statin better Statin worse 24% HPS: statin benefit is entirely independent of baseline LDL In the Heart Protection Study, approximately 3500 patients had baseline LDL-C of <100 mg/dl. Remarkably, this study showed that not only did patients with LDL-C <100 mg/dl at baseline benefit from statin treatment, but these patients benefit to a similar degree to patients with higher LDL-C. Thus, this study demonstrated that all patients with atherosclerosis and/or diabetes, regardless of LDL-C, benefit from statin treatment. This study has important clinical implications and should lead to further revision of the guidelines. This study further validates the approach of in-hospital initiation of statin treatment regardless of baseline LDL-C. Reference: MRC/BHF Heart Protection Study. HPS info: slideshow presentation. Available at (accessed 9 July 2002). Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in high-risk individuals: a randomised plcebo-controlled trial. Lancet 2002;360:7-22. 0.4 0.6 0.8 1 1.2 1.4

7 GREACE: Νοσηρότητα & Θνητότητα: Ποσοστιαία μεταβολή Δομημένη έναντι Συνήθους Φροντίδας
% ελάττωση ΣΚ p=0.0021 p=0.0017 p<0.0001 p=0.034 Athyros et al Current Medical Research & Opinion 2002;18(4):

8 ALLIANCE: Χρόνος έως το μη θανατηφόρο ΕΜ ατορβαστατίνη έναντι συνήθους φροντίδας
100 Ατορβα % vs. συνήθης φροντίδα p=0.0002 98 96 Percentage Free of Nonfatal MI 94 Ατορβαστατίνη 92 90 Συνήθης φροντίδα 1 2 3 4 5 6 Years Since Randomization Hunninghake D at al. JACC 2004 ;44 (9) 2 November 2004 :

9 ALLHAT-LLA: Primary Endpoint Pravastatin 75% on Statin
20 11% RRR (P = NS) Usual Care 35% on statins 15 % With Event 10 Pravastatin 75% on Statin 5 1 2 3 4 5 6 7 Years ALLHAT Study Group.

10 NCEP ATP III: 2004 Updated LDL-C Goals, Treatment Cutpoints
CG: ATP III 1.75A Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Lower risk: 0–1 risk factor <160 mg/dL 160 mg/dL 190 mg/dL Moderate risk: 2 risk factors (10-year risk<10%) <130 mg/dL 130 mg/dL Moderately high risk: 2 risk factors (10-year risk 10%–20%) High risk: CHD or CHD risk equivalents* (10-year risk >20%) <130 mg/dL optional: <100 mg/dL <100 mg/dL optional: <70 mg/dL 100 mg/dL 130 mg/dL (100–129 mg/dL: consider drug options) 100 mg/dL (<100 mg/dL: consider drug options)

11 Σακχαρώδης Διαβήτης

12 Incidence of MI during a 7-Year Follow-up in a Finnish Population
Fatal or Non-fatal MI (%) 45.0 P<0.001 P<0.001 20.2 18.8 3.5 Incidence of MI during a 7-year follow-up in a Finnish population In a population-based study conducted in eastern and western Finland, more than 1,000 diabetic subjects and almost 1,400 nondiabetic subjects were followed up for 7 years. Subjects were stratified by baseline status for both prior MI and diabetes. Subjects who had both a prior MI and diabetes had a higher risk of a future MI. Subjects with diabetes but without a prior MI had a similar risk of future MI as nondiabetic subjects with a prior MI. This study thus supports the concept of diabetes as a CHD risk equivalent. Reference: Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339: Prior MI No prior MI Prior MI No prior MI Nondiabetic subjects Diabetic subjects (n=1373) (n=1059) Haffner SM et al. N Engl J Med 1998;339:

13 OASIS Study Event Rate 3 6 9 12 15 18 21 24 Months RR=1.00
Diabetes/CVD (n = 1148) RR=2.88 (2.37–3.49) Diabetes/No CVD (n = 569) No Diabetes/CVD (n = 3503) No Diabetes/No CVD (n = 2796) RR=1.99 (1.52–2.60) Event Rate RR=1.71 (1.44–2.04) RR=1.00 OASIS study: total mortality The OASIS study also supports the concept of diabetes as a CHD risk equivalent. This study is more generalizable than the Finnish East-West study since it was based in 6 different countries and has a larger population. Reference: Malmberg K, Yusuf S, Gerstein HC, Brown J, Zhao F, Hunt D, Piegas L, Calvin J, Keltai M, Budaj A. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000;102: 3 6 9 12 15 18 21 24 Months Malmberg K et al. Circulation 2000;102:

14 Τελικά σημεία σε διαβητικούς ασθενείς : 3-ετής ΕΣΚ νοσηρότητας και θνητότητας
% Relative Risk Reduction Slide 24 The reductions in relative risk of primary end points for structured care compared with usual care after 3 years of treatment are highlighted in this slide. Total mortality was decreased by 43% (P=0.0021), coronary mortality by 47% (P=0.0017), nonfatal MI by 59% (P=0.0001), and stroke by 47% (P=0.034) in patients treated with structured care using atorvastatin compared with usual care. P=0.049 P=0.046 P=0.002 P=0.046 P=0.0001 Athyros VG, et al. Angiology 2003;54:

15 Ασθενείς με ΣΔ : Καμπύλες συμβαμάτων
Ασθενείς με ΣΔ : Καμπύλες συμβαμάτων 59% Ελάττωση κινδύνου P=0.0001 Ποσοστό ασθενών με σύμβαμα Slide 25 This slide shows the cumulative percentage of patients surviving (reflecting the incidence of total mortality) up to 48 months of patient follow-up. In the structured care group, 97.1% of patients were alive at the end of follow-up, compared with 95% of patients in the usual care group (P=0.0021). These numbers reflect the 43% reduction in relative risk of total mortality associated with structured care (atorvastatin treatment) vs usual care. Μήνες Athyros VG, et al. Angiology 2003;54:

16 CARDS: 37% Reduction in primary Outcome in DM without CVD
LDL=120 mg/dl 1410 1351 1306 1022 651 305 Placebo 1428 1392 1361 1074 694 328 Atorvastatin 15 10 5 Years 1 2 3 4 Cumulative hazard (%) 4.75 Placebo 127 events Atorvastatin 83 events Relative risk reduction 37% P = 0.001 LDL=80 mg/dl Colhoun HM et al. Lancet 2004;364:

17 CARDS Μελέτη CARDS (Collaborative AtoRvastatin Diabetes Study)
% Ελάττωση σχετικού κινδύνου Colhoun HM et al. Lancet 2004;364:

18 CARDS CARDS Trial : Σημαντικότητα ελάττωσης Πρωγενούς Τελικού Σημείου με το χρόνο 30 Ημέρες p=0.058 90 Ημέρες p=0.008 Τέλος μελέτης p=0.001 0.5 0.75 1.0 1.25 1.5 Ατορβαστατίνη καλύτερη Placebo καλύτερο Colhoun HM et al. Lancet 2004;364:

19 NCEP ATP III: 2004 Updated LDL-C Goals, Treatment Cutpoints
CG: ATP III 1.75A Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Lower risk: 0–1 risk factor <160 mg/dL 160 mg/dL 190 mg/dL Moderate risk: 2 risk factors (10-year risk<10%) <130 mg/dL 130 mg/dL Moderately high risk: 2 risk factors (10-year risk 10%–20%) High risk: CHD or CHD risk equivalents* (10-year risk >20%) <130 mg/dL optional: <100 mg/dL <100 mg/dL optional: <70 mg/dL 100 mg/dL 130 mg/dL (100–129 mg/dL: consider drug options) 100 mg/dL (<100 mg/dL: consider drug options)

20 NCEP ATP III: 2004 Updated LDL-C Goals, Treatment Cutpoints
CG: ATP III 1.75A Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Lower risk: 0–1 risk factor <160 mg/dL 160 mg/dL 190 mg/dL Moderate risk: 2 risk factors (10-year risk<10%) <130 mg/dL 130 mg/dL Moderately high risk: 2 risk factors (10-year risk 10%–20%) High risk: CHD or CHD risk equivalents* (10-year risk >20%) <130 mg/dL optional: <100 mg/dL <100 mg/dL optional: <70 mg/dL 100 mg/dL 130 mg/dL (100–129 mg/dL: consider drug options) 100 mg/dL (<100 mg/dL: consider drug options)

21 Αρτηριακή υπέρταση

22 Συνδυασμένη επίδραση της ΣΑΠ και ΟΧ στην Κ/Α θνητότητα
Συνδυασμένη επίδραση της ΣΑΠ και ΟΧ στην Κ/Α θνητότητα 34 (11 Χ) MRFIT n= 23 21 17 18 12 17 Θάνατοι / Ανθρωπο-έτη 13 12 (4 Χ) 11 14 (4 Χ) 8 10 9 8 8 6 6 5 6 6 6 >245) 142+ Using data from the Multiple Risk Factor Intervention Trial (MRFIT), Neaton and Wentworth examined the additive effect of TC levels and systolic blood pressure (SBP) on CHD death rates. Note the generally strong graded relationship between increasing cholesterol levels and CHD death across SBP levels, and the generally strong relationship between small increases in SBP and CHD death across TC levels. When risk factors were analyzed together, patients in both the highest TC and the highest SBP quintiles had an approximately 11-fold greater risk of CHD death than patients who were in both the lowest TC and the lowest SBP quintiles. This study demonstrates that for any given BP an increase in cholesterol levels increases risk. Likewise, for any given cholesterol level, increases in BP increase risk. Even mild to moderate levels of concomitant hypertension and dyslipidemia impart a substantial CV risk. 4 3 3 ΣΑΠ (mm Hg) Ολική Χοληστερόλη mg/dL <182 <118 Neaton JD, MIRF. Arch Intern Med. 1992;152:56-64. Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for white men. Arch Intern Med. 1992;152:56-64. 22

23 ASCOT: Πρωτεύον Τελικό Σημείo: Μη Θανατηφόρα Έμφραγμα Μυοκαρδίου - Θανατηφόρα Στεφανιαία Συμβάματα
Aτορβαστατίνη 10 mg Αριθμός επεισοδίων 100 Placebo Αριθμός επεισοδίων 154 LDL=130 mg/dl 36% Μείωση LDL=90 mg/dl HR = 0.64 ( ) p=0.0005 Sever PS, et al, for the ASCOT Investigators. Lancet. 2003;361:

24 ASCOT: Δευτερεύον Τελικό Σημείο: Θανατηφόρο και μη Θανατηφόρο ΑΕΕ
Ατορβαστατίνη10 mg Αριθμός επεισοδίων 89 Placebo Αριθμός επεισοδίων 121 27% Μείωση HR = 0.73 ( ) p=0.0236 Sever PS, et al, for the ASCOT Investigators. Lancet. 2003;361:

25 Μελέτες Ορόσημα : Συμβάματα σε σχέση με τα επίπεδα LDL-X
10 9 8 7 WOSCOPS-P WOSCOPS-S 6 Ποσοστό συμβαμάτων ΣΝ 5 AFCAPS-S AFCAPS-P Πρωτογενής πρόληψη 4 Πραβαστατίνη 3 ASCOT-P Λοβαστατίνη 2 ASCOT-S Ατορβαστατίνη 1 90 110 130 150 170 190 210 LDL-C mg/dL S = χορήγηση στατίνης, P = χορήγηση placebo Kastelein JJP. Atherosclerosis 1999;143(suppl 1):S17-S21

26 NCEP ATP III: 2004 Updated LDL-C Goals, Treatment Cutpoints
CG: ATP III 1.75A Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Lower risk: 0–1 risk factor <160 mg/dL 160 mg/dL 190 mg/dL Moderate risk: 2 risk factors (10-year risk<10%) <130 mg/dL 130 mg/dL Moderately high risk: 2 risk factors (10-year risk 10%–20%) High risk: CHD or CHD risk equivalents* (10-year risk >20%) <130 mg/dL optional: <100 mg/dL <100 mg/dL optional: <70 mg/dL 100 mg/dL 130 mg/dL (100–129 mg/dL: consider drug options) 100 mg/dL (<100 mg/dL: consider drug options)

27 Οξέα Στεφανιαία Σύνδρομα

28 Fonarow GC at al. Am J Cardiol 2005;96 (Sep 2005):611-616
Effect of Statin Use Within the First 24 Hours of Admission for Acute Myocardial Infarction on Early Morbidity and Mortality N= Fonarow GC at al. Am J Cardiol 2005;96 (Sep 2005):

29 PROVE IT Trial : Primary Endpoint* Reduced vs. Pravastatin
16% Reduction 30 Pravastatin 40mg 26.3% 25 20 (P=0.005) % Patients With Event 15 Atorvastatin 80mg 22.4% 10 5 3 6 9 12 15 18 21 24 27 30 Months of Follow-up * All-cause mortality or major CV event Cannon CP et al. N Engl J Med 8 April 2004.

30 50 % Reduction 60 % Reduction
PROVE IT: Patients With the Lowest Levels of LDL-C and CRP Experienced Fewer Recurrent Events 0.10 LDL-C >70 mg/dL, CRP >2 mg/L 0.08 LDL-C 70 mg/dL, CRP <2 mg/L LDL-C <70 mg/dL, CRP >2 mg/L 0.06 Recurrent myocardial infarction or coronary death (%) LDL-C <70 mg/dL, CRP <2 mg/L 0.04 LDL-C <70 mg/dL, CRP <1 mg/L 50 % Reduction Although statin therapy is proven to lower levels of CRP, there is a lack of evidence showing that greater reductions in CRP provide CV benefits. The PROVE IT investigators examined the effects of atorvastatin 80 mg and pravastatin 40 mg and the impact of reductions in LDL-C and CRP on the risk of recurrent CV events in patients with ACS1 Patients were divided into groups with LDL-C levels above and below 70 mg/dL, the approximate median LDL-C level attained by the patient population. Analyses were performed to measure the risk of recurrent events in patients with LDL-C levels above and below this value. Similarly, patients were divided into groups according to the approximate median CRP value of 2 mg/L, and the relationship between the CRP level attained and rate of recurrent events was determined1 Although LDL-C and CRP were both reduced by statin therapy, there was only a slight correlation between the levels achieved. Despite this, however, there was a linear relationship between the reduction in CRP and recurrence of MI and coronary death1 The figure above shows that, in patients with LDL-C levels 70 mg/dL, those with a CRP value <2 mg/L were less likely to experience a recurrent MI or die from coronary causes than patients with CRP 2 mg/dL. Correspondingly, patients with LDL-C <70 mg/dL and CRP <2 mg/L were at lower risk of experiencing a recurrent event compared with those with low LDL-C but CRP 2 mg/L. In general, patients with CRP levels <2 mg/L had better clinical outcomes than those with higher levels, regardless of LDL-C1 Reference: 1. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28. 0.02 60 % Reduction 0.00 0.0 0.0 0.0 0.5 0.5 0.5 1.0 1.0 1.0 1.5 1.5 1.5 2.0 2.0 2.0 2.5 2.5 2.5 Follow-up (years) Adapted from Ridker PM et al. N Engl J Med. 2005;352:20-28; Ridker PM et al. Presented at AHA Scientific Sessions; 2004.

31 A to Z: Changes in LDL cholesterol
Group Baseline LDL-C (mg/dL) 4 months (mg/dL) 24 months (mg/dL) Placebo/ simvastatin 20 mg 111 124 81 Simvastatin 40 mg/ simvastatin 80 mg 112 62 66 De Lemos J et al. JAMA, September 15, 2004;292(11):

32 A to Z: CRP differential in A to Z, MIRACL, and PROVE-IT
C-reactive protein differential (%) 17 34 38 Nissen SE. JAMA, (Editorial) September 15, 2004;292(11):

33 NCEP ATP III: 2006 (?) Updated LDL-C Goals, Treatment Cutpoints
CG: ATP III 1.75A Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Lower risk: 0–1 risk factor <160 mg/dL 160 mg/dL 190 mg/dL Moderate risk: 2 risk factors (10-year risk<10%) <130 mg/dL 130 mg/dL Moderately high risk: 2 risk factors (10-year risk 10%–20%) High risk: CHD or CHD risk equivalents, ACS (10-year risk >20%) <130 mg/dL optional: <100 mg/dL <100 mg/dL optional: <70 mg/dL 100 mg/dL 130 mg/dL (100–129 mg/dL: consider drug options)

34 Σταθερή Στεφανιαία Νόσος

35 Secondary prevention trials in stable patients
1.00 0.95 0.90 0.85 0.80 0.00 1 2 3 4 5 6 Proportion alive Risk reduction, 30% Log-rank p=0.0003 Simvastatin Placebo 4S Fatal CHD/nonfatal MI (%) 5 10 15 20 1 2 3 4 6 7 Risk reduction, 24% p<0.001 Pravastatin Placebo LIPID HPS 1 2 3 4 5 6 15 10 Fatal CHD/nonfatal MI (%) Risk reduction, 24% p=0.003 Pravastatin Placebo CARE Years Placebo Events (%) Simvastatin Risk reduction, 24% p<0.001 Slide 7 Three randomized, placebo-controlled trials – 4S, CARE and LIPID – have established that long-term lipid-lowering therapy with statins reduces mortality and recurrent ischemic cardiovascular events in patients with stable coronary heart disease. However, approximately two years of treatment were required before a significant reduction in death and cardiovascular events could be discerned. Importantly, each of these trials excluded patients who had experienced unstable angina or acute MI within 3 to 6 months prior to randomization [8–10]. References 8. Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389. 9. Sacks FM et al. N Engl J Med 1996;335:1001–1009. 10. The long-term intervention with pravastatin in ischaemic disease (LIPID) study group. N Engl J Med 1998;339:1349–1357. 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. HPS Collaborative Group. Lancet 2002;360:7–22.

36 TNT Ασθενείς και Κέντρα
Καναδάς 1052 Βρετανία 299 Βέλγιο 300 Ιρλανδία 53 Ολλανδία 788 ΗΠΑ 5309 Γαλλία 207 Γερμανία 144 Ισπανία 525 Αυστρία 29 Ελβετία 91 Ιταλία 75 Ένα σύνολο 10,001 ασθενών από 256 κέντρα σε 14 χώρες παγκοσμίως τυχαιοποιήθηκαν και πήραν θεραπεία στη μελέτη ΤΝΤ. Νότια Αφρική 523 Αυστραλία 608 Ασθενείς: 10,001* Κέντρα: 256 La Rosa JC, et al. N Engl J Med. 2005:352 Reference 1. LaRosa JC, et al. N Engl J Med. 2005;352.

37 TNT: Σκοπός της μελέτης
Η TNT είναι η πρώτη τυχαιοποιημένη κλινική μελέτη με στόχο να εκτιμηθεί προοπτικά η αποτελεσματικότητα και η ασφάλεια της θεραπευτικής μείωσης της LDL-C σε επίπεδα πολύ χαμηλότερα από 100mg/dl σε ασθενείς με σταθερή στεφανιαία νόσο Η μελέτη TNT εκτίμησε κατά πόσον η επιθετική μείωση της LDL-C στα 75 mg/dL (1.9 mmol/L υπό ατορβαστατίνη 80 mg/ημέρα) οδηγεί σε μεγαλύτερη μείωση των στεφανιαίων συμβαμάτων σε σύγκριση με τη μετριότερη μείωση της LDL-C στα 100 mg/dL (2.6 mmol/L υπό ατορβαστατίνη 10 mg/ημέρα). Waters DD et al. Am J Cardiol. 2004;93:154-8 Reference 1. Waters DD, et al. Am J Cardiol. 2004;93:154-8.

38 Όφελος από την επιθετική ελάττωση της LDL-Χ LDL cholesterol (mg/dL)
30 4S Statin Placebo 25 4S 20 Event (%) 15 LIPID LIPID CARE CARE 10 HPS HPS 5 70 90 110 130 150 170 190 210 LDL cholesterol (mg/dL) LaRosa JC et al. N Engl J Med. 2005;352.

39 TNT: Σχεδιασμός Patient population
250 centers in 14 countries (N = 10,001) LDL 130–250 mg/dL TG <600 mg/dL Atorvastatin 10 mg Atorvastatin 10 mg Atorvastatin 80 mg 8 εβδομάδες 4.9 έτη Waters DD et al. Am J Cardiol. 2004;93:154-8.

40 TNT ? LDL-C mg/dl Ασθενείς με στεφανιαία συμβάματα (%) 30 25 20 15 10
ΤΝΤ (Treating to New Targets): Λογική της μελέτης 30 25 20 15 10 5 TNT ? Ασθενείς με στεφανιαία συμβάματα (%) Αρχικός έλεγχος Ατορβαστατίνη 10mg Η κύρια υπόθεση της μελέτης ΤΝΤ (Treating to New Targets) ήταν ότι η επίτευξη μείωσης των επιπέδων της LDL-C σε επίπεδα πολύ χαμηλότερα από τους ισχύοντες στόχους μπορεί να οδηγήσει σε ακόμη μεγαλύτερη μείωση του καρδιαγγειακού κινδύνου.1 Ατορβαστατίνη 80mg LDL-C mg/dl Kastelein JJP. Atherosclerosis 1999;143(suppl 1):S17-S21 Reference 1. Waters DD, et al. Am J Cardiol. 2004;93:154-8.

41 TNT: Επίδραση της θεραπείας στην LDL-Χ
160 140 Ατορβαστατίνη 10 mg 120 100 LDL-Χ (mg/dL) 80 60 Ατορβαστατίνη 80 mg 40 20 Αρχικό 3 12 24 36 48 60 Τελικό Μήνες LaRosa JC et al. N Engl J Med. 2005;352.

42 TNT: Επίδραση της θεραπείας στο πρωτογενές τελικό σημείο
ΚΑ Θάνατος, μη-θανατηφόρο ΕΜ, αναταχθείσα ανακοπή, ΑΕΕ. 0.15 Ατορβαστατίνη 10 mg 22% ελάττωση κινδύνου 0.10 Μείζον ΚΑ Σύμβαμα (%) 0.05 Ατορβαστατίνη 80 mg 0.00 1 2 3 4 5 6 Έτη HR = 0.78 (0.69–0.89) P < 0.001 LaRosa JC et al. N Engl J Med. 2005;352.

43 Μείωση της επίπτωσης της ΣΝ στις Μελέτες Δευτερογενούς Πρόληψης
Μελέτη Στατίνη Placebo/Παράγοντας σύγκρισης* Επίπεδα LDL-C, mg/dL Επίπτωση ΣΝ (% ασθενών) Επίπεδα LDL-C, mg/dL Επίπτωση ΣΝ (% ασθενών) 4S1 LIPID2 CARE3 HPS4 TNT*5 122 112 98 89 77 19.4 12.3 10.2 8.7 6.7 190 150 135 128 101 28.0 15.9 13.2 11.8 8.3 Τόσο με τη χορήγηση 80 mg όσο και 10 mg ατορβαστατίνης, η επίπτωση των στεφανιαίων συμβαμάτων στη μελέτη TNT5 ήταν μικρότερη σε σύγκριση με τις προηγούμενες μελέτες δευτερογενούς πρόληψης των στατινών.1-4 Αυτή η μικρότερη επίπτωση συμβαμάτων είναι ενδεικτική της ποσοτικής συσχέτισης μεταξύ της μείωσης των επιπέδων της LDL-C και της μείωσης του στεφανιαίου κινδύνου που περιγράφηκε στις προηγούμενες μελέτες δευτερογενούς πρόληψης των στατινών ακόμη και για τα πολύ χαμηλά επίπεδα LDL-C. *Ο παράγοντας σύγκρισης στη μελέτη TNT ήταν η ατορβαστατίνη σε δόση 10mg 1. 4S Group. Lancet. 1994;344:1383-9 2. LIPID. N Engl J Med. 1998;339: 3. Sacks FM, et al. N Engl J Med. 1996;335:1001-9 4. HPS. Lancet. 2002;360:7-22 5. LaRosa JC, et al. N Engl J Med. 2005;352 References 1. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344: 2. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339: 3. Sacks FM, et al. N Engl J Med. 1996;335: 4. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22. 5. LaRosa JC, et al. N Engl J Med. 2005;352.

44 TNT: Επίδραση της θεραπείας στον ΚΑ Θάνατο και ΕM
Ατορβαστατίνη 10 mg 0.10 22% ελάττωση κινδύνου Μείζον ΚΑ Σύμβαμα (%) 0.05 Ατορβαστατίνη 80 mg 0.00 1 2 3 4 5 6 Έτη HR = 0.78 (0.68–0.91) P < 0.001 LaRosa JC et al. N Engl J Med. 2005;352.

45 TNT: Επίδραση της θεραπείας στο ΑΕΕ
0.04 Ατορβαστατίνη 10 mg 0.03 25% ελάττωση κινδύνου ΑΕΕ (%) 0.02 0.01 Ατορβαστατίνη 80 mg 0.00 1 2 3 4 5 6 Έτη HR = 0.75 (0.59–0.96) P = 0.02 LaRosa JC et al. N Engl J Med. 2005;352.

46 TNT diabetes analysis: Μείζονα Κ/Α συμβάματα
0.20 N=1.500 Ατορβαστατίνη 10 mg (n= 753) 0.15 25% ελάττωση κινδύνου (%) 0.10 0.05 Ατορβαστατίνη 80 mg (n= 748) 0.00 1 2 3 4 5 6 ‘Ετη HR = 0.75, P = 0.026 Shepherd J. American Diabetes Association; San Diego, CA.

47 TNT diabetes analysis: Επίδραση της θεραπείας στο ΑΕΕ
0.15 N=1.500 Ατορβαστατίνη 10 mg (n= 753) 0.10 31% ελάττωση κινδύνου (%) 0.05 Ατορβαστατίνη 80 mg (n= 748) 0.00 1 2 3 4 5 6 ‘Ετη HR = 0.69, P = 0.037 Shepherd J. American Diabetes Association San Diego, CA.

48 Metabolic syndrome: analysis of the Treating to New Targets study
Deedwania P, et al. Lancet 2006;368:

49 NCEP ATP III: 200? Updated LDL-C Goals, Treatment Cutpoints
CG: ATP III 1.75A Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Lower risk: 0–1 risk factor <160 mg/dL 160 mg/dL 190 mg/dL Moderate risk: 2 risk factors (10-year risk<10%) <130 mg/dL 130 mg/dL Moderately high risk: 2 risk factors (10-year risk 10%–20%) High risk: CHD or CHD risk equivalents* (10-year risk >20%) <130 mg/dL optional: <100 mg/dL <100 mg/dL optional: <70 mg/dL 100 mg/dL 130 mg/dL (100–129 mg/dL: consider drug options

50 Αγγειακά Εγκεφαλικά Επεισόδια

51 CVD Is a Leading Cause of Death Worldwide
Injuries Cancer Respiratory Diseases 9.0% 13.0% Stroke 13.0% 30.0% 33.0% Diabetes 2.0% 43.0% CVD (16.7 M) Other Chronic Diseases CHD 9.0% 14.4% 30.0% Other CVD Rheumatic Heart Disease – 2.4% All Other Inflammatory Heart Disease – 2.4% Hypertensive Heart Disease – 5.4% Adapted from WHO. Preventing Chronic Diseases – A Vital Investment 2005. Adapted from WHO. The Atlas of Heart Disease and Stroke 2004.

52 A meta-analysis of 26 randomized statin trials demonstrated that statins reduced stroke by 21% versus placebo or control (hazard ratio 0.79; 95% confidence interval , P<.0001). There was no evidence of heterogeneity between trials (P=.35). The “small trials” point in the Forest Plot contains data from 13 trials that recruited in the range of 126 to 1062 participants. All other trials recruited >1500 participants.1 Reference 1. Amarenco P, Labreuche J, Lavallée P, Touboul P-J. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 2004;35:

53 In the cohort of patients with prior cerebrovascular disease in the Heart Protection Study (HPS), there was a reduction in major vascular events, but no reduction in stroke (169 strokes events in simvastatin-treated patients vs 170 strokes in those treated with placebo).1 Reference 1. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:

54 High-Dose Atorvastatin after Stroke or Transient Ischemic Attack
Original Article High-Dose Atorvastatin after Stroke or Transient Ischemic Attack The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators Amarenco et al. N Engl J Med Volume 355(6):

55 At baseline, the mean level of low-density lipoprotein cholesterol (LDL-C) was mg/dL in the atorvastatin group and mg/dL in the placebo group. At Month 1, LDL-C levels decreased by 53% from baseline in the atorvastatin group and were unchanged in the placebo group (LDL-C=61 mg/dL and LDL-C=133.5, respectively).1 Reference 1. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:

56 After a median follow-up of 4
After a median follow-up of 4.9 years, a 16% reduction in risk of recurrent stroke was observed with atorvastatin relative to placebo, after adjusting for geographical region, entry event, time since entry event, gender, and baseline age (hazard ratio [HR] 0.84, 95% confidence interval [CI] , P=.03).1 Reference 1. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:

57 Atorvastatin 80 mg was associated with a 23% reduction in risk of stroke or transient ischemic attack compared with placebo (hazard ratio 0.77, 95% confidence interval [CI] , P<.001).1 Reference 1. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:

58 A secondary analysis of time to any coronary heart disease (CHD) event revealed significant reductions in this end point, too, in atorvastatin- versus placebo-treated patients (hazard ratio 0.58, 95% confidence interval , P<.001). A total of 123 CHD events were experienced by the atorvastatin group and 204 events were experienced by patients randomized to placebo.1 Reference 1. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:

59 Time to any cardiovascular event was also analysed as a secondary end point. Patients receiving atorvastatin experienced a significant reduction in cardiovascular events compared with patients receiving placebo (hazard ratio 0.74, 95% confidence interval , P<.001).1 Reference 1. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:

60 ελαττώνει σημαντικά την εμφάνιση νέου ΑΕΕ ή ΚΑ Συμβαμάτων.
SPARCL ΣΥΜΠΕΡΑΣΜΑ Σε ασθενείς με πρόσφατο ΑΕΕ ή παροδικό ΑΕΕ ακόμη και χωρίς ύπαρξη ΣΝ η χορήγηση 80 mg ατορβαστατίνης ελαττώνει σημαντικά την εμφάνιση νέου ΑΕΕ ή ΚΑ Συμβαμάτων.

61 NCEP ATP III: 2008 (?) Updated LDL-C Goals, Treatment Cutpoints
CG: ATP III 1.75A Risk Category LDL-C Goal Initiate TLC Consider Drug Therapy Lower risk: 0–1 risk factor <160 mg/dL 160 mg/dL 190 mg/dL Moderate risk: 2 risk factors (10-year risk<10%) <130 mg/dL 130 mg/dL Moderately high risk: 2 risk factors (10-year risk 10%–20%) High risk: CHD or CHD risk equivalents* (10-year risk >20%) <130 mg/dL optional: <100 mg/dL <80 mg/dl optional: <70 mg/dL 130 mg/dL (100–129 mg/dL: consider drug options)

62 Αλγόριθμος φαρμακευτικής θεραπευτικής προσέγγισης ασθενών με δυσλιπιδαιμία
ΔΥΣΛΙΠΙΔΑΙΜΙΑ* ΣΤΑΤΙΝΗ** ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ ΤΗΣ ΣΤΑΤΙΝΗΣ*** ΦΥΣΙΟΛΟΓΙΚΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ HDL CHOL CHOL ΥΨΗΛΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΧΑΜΗΛΗ HDL CHOL Hellenic Journal of Atherosclerosis 2014;5(3): ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ + ΦΑΙΝΟΦΙΜΠΡΑΤΗ ΣΤΑΤΙΝΗ + ω-3 ΛΙΠΑΡΑ ΟΞΕΑ ΣΤΑΤΙΝΗ + ΕΖΕΤΙΜΙΜΠΗ ΣΤΑΤΙΝΗ + ΚΟΛΕΣΕΒΕΛΑΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL, ΤΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΤΗΝ HDL CHOL  ΜΕΓΙΣΤΟ ΚΑΡΔΙΑΓΓΕΙΑΚΟ ΟΦΕΛΟΣ *Αν τριγλυκερίδια νηστείας >500 mg/dL συνιστάται η άμεση χορήγηση μίας φιμπράτης ή/και ω-3 λιπαρών οξέων **Για την επίτευξη του στόχου της αγωγής συνιστάται η χορήγηση μιας στατίνης σε δόση που αναμένεται να επιτύχει το στόχο της θεραπείας ***Κάθε διπλασιασμός της δόσης μίας στατίνης οδηγεί σε 6% περαιτέρω ελάττωση της LDL CHOL

63 Αλγόριθμος φαρμακευτικής θεραπευτικής προσέγγισης ασθενών με δυσλιπιδαιμία
ΔΥΣΛΙΠΙΔΑΙΜΙΑ* ΣΤΑΤΙΝΗ** ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΤΙΤΛΟΠΟΙΗΣΗ ΤΗΣ ΔΟΣΗΣ ΤΗΣ ΣΤΑΤΙΝΗΣ*** ΦΥΣΙΟΛΟΓΙΚΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ HDL CHOL CHOL ΥΨΗΛΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΧΑΜΗΛΗ HDL CHOL Hellenic Journal of Atherosclerosis 2014;5(3): ΜΗ ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL ΣΤΑΤΙΝΗ + ΦΑΙΝΟΦΙΜΠΡΑΤΗ ΣΤΑΤΙΝΗ + ω-3 ΛΙΠΑΡΑ ΟΞΕΑ ΣΤΑΤΙΝΗ + ΕΖΕΤΙΜΙΜΠΗ ΣΤΑΤΙΝΗ + ΚΟΛΕΣΕΒΕΛΑΜΗ PCSK9i ΕΠΙΤΕΥΞΗ ΣΤΟΧΟΥ ΓΙΑ ΤΗΝ LDL CHOL, ΤΑ ΤΡΙΓΛΥΚΕΡΙΔΙΑ ΚΑΙ ΤΗΝ HDL CHOL  ΜΕΓΙΣΤΟ ΚΑΡΔΙΑΓΓΕΙΑΚΟ ΟΦΕΛΟΣ *Αν τριγλυκερίδια νηστείας >500 mg/dL συνιστάται η άμεση χορήγηση μίας φιμπράτης ή/και ω-3 λιπαρών οξέων **Για την επίτευξη του στόχου της αγωγής συνιστάται η χορήγηση μιας στατίνης σε δόση που αναμένεται να επιτύχει το στόχο της θεραπείας ***Κάθε διπλασιασμός της δόσης μίας στατίνης οδηγεί σε 6% περαιτέρω ελάττωση της LDL CHOL

64

65 Recycling of LDLR Enables Efficient Clearance of LDL Particles
Increased LDL-R surface concentration LDL-R recycling Lysosomal degradation Brown MS, Goldstein JL. Proc Natl Acad Sci U S A. 1979;76: Steinberg D, Witztum JL. Proc Natl Acad Sci U S A. 2009;106: Goldstein JL, Brown MS. Arterioscler Thromb Vasc Biol. 2009;29:

66 Impact of an PCSK9 mAb on LDL Receptor Expression
66

67 Administration PSCK9 inhibitors is indicated when LDL-C is > 30 mg/dl of the predetermined target according to the degree of patient CVD risk achieved with conventional available lipid-lowering monotherapy or in combination therapy. Hormones (Athens) 2016 Jan-Mar;15(1):8-14.

68 LDL Cholesterol Standard of care alone
Evolocumab plus standard of care Standard of care alone Sabatine NEJM – Fig 1 61% reduction (95%CI 59-63%), P<0.001 Absolute reduction: 73 mg/dL (95%CI mg/dL), P<0.001 The dashed line indicate that patients were receiving either evolocumab or placebo during the period from baseline to enrollment into OSLER. Before randomization, the median LDL-C was 120 mg/dL At week 12 in the OSLER trials, evolocumab vs SOC reduced mean LDL-C by 61%. The reduction in LDL-C was consistent over time. At week 12, the LDL-C was reduced to 100 mg/dL in 90.2% of patients and to 70 mg/dL or less in 73.6% of patients in the evolocumab group (vs 26.0% and 3.8% in the SOC group). Reference: Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med Apr 16;372(16):1500-9(suppl):1-21. Sabatine NEJM B-4 (Parent study) (OSLER) N=4465 N=1258 N=4259 N=4204 N=1243 N=3727 Abs. reduction (mg/dL) 60.4 73.4 70.4 72.7 70.5 1.56 1.90 1.82 1.88 Abs. reduction (mmol/L) Sabatine et al. N Engl J Med Apr 16;372(16): (Suppl.):1-21 Sabatine et al. N Engl J Med Apr 16;372(16): (Suppl.):1-21

69 Cardiovascular Outcomes
Sabatine NEJM – Fig 2 3 Composite Endpoint: Death, MI, UA  hosp, coronary revascularization, stroke, TIA, or CHF  hosp Evolocumab plus standard of care (N=2,976) Standard of care alone (N=1,489) 0.95% 2.18% 2 HR 0.47 95% CI P=0.003 Cumulative Incidence (%) 1 When the CV events were combined into a composite of all cardiovascular events (MACE; a post hoc composite that includes death, major coronary events, and major cerebrovascular events.), the results demonstrate that patients in the evolocumab group had a significantly lower incidence of CV events vs those in the SOC group. The cumulative incidence curves diverged progressively over time. The included CV events were: death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack or hospitalization for heart failure. CV events were reported in 29 of 2976 patients in the evo group and in 31 of 1489 patients in the SOC group. Reference: Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med Apr 16;372(16):1500-9(suppl):1-21. Sabatine NEJM A-2 30 60 90 120 150 180 210 240 270 300 330 365 Days since Randomization Sabatine NEJM – Fig 2 Sabatine et al. N Engl J Med Apr 16;372(16): (Suppl.):1-21

70 Η μελέτη ODYSSEY LONG TERM
Sabatine NEJM A-3; 1508-B-1 These study limitations are worth noting: The study was an open-label study which could influence the reporting of events The number of CV events were relatively small The patients who enrolled in OSLER studies were those who tolerated the drug well in the parent studies. Hence the AE and SAE data is from a cohort of patients who were known to have good tolerability. The OSLER program included a mix of patients with varying degree of CV risk. It was not accurately optimized. Reference: Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med Apr 16;372(16):1500-9(suppl):1-21. Robinson JG et al. NEJM 2015, 372:

71 Post hoc ανάλυση τεκμηριωμένων μειζόνων καρδιαγγειακών συμβαμάτων*
1,0 0,06 Εικονικό φάρμακο + μέγιστη ανεκτή δόση στατίνης ± άλλη υπολιπιδαιμική αγωγή 0,8 0,04 Alirocumab + μέγιστη ανεκτή δόση στατίνης ± άλλη υπολιπιδαιμική αγωγή 0,6 0,02 Πιθανότητα εκδήλωσης συμβάντος 0,4 0,00 12 24 36 52 64 78 86 Cox model analysis 0,2 HR= 0,52 (ΔΕ 95%, 0,31-0,90) Ονομαστική p-τιμή = 0,02 0,0 12 24 36 52 64 78 86 Χρόνος (εβδομάδες) Αρ. σε κίνδυνο Εικονικό φάρμακο 788 776 731 700 670 653 644 597 Alirocumab 1550 1533 1445 1392 1342 1306 1266 1170 Robinson JG et al. NEJM 2015, 372:

72 Το μέλλον της υπολιπιδαιμικής αγωγής
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