Πρωτογενής φαρμακεστική πρόληψη»

Πρωτογενής φαρμακεστική πρόληψη» Γεκήηξηνο Ρίρηεξ, MD, FESC, FAHA -Γηεπζπληήο Καξδηνινγηθήο Κιηληθήο Δπξσθιηληθήο Αζελώλ --Μέινο Γ ΔΛΙΚΑΡ -- Γεληθόο Γξακκαηέαο Διιεληθήο Δηαηξείαο Ληπηδηνινγίαο.

Akira Endo HO Compactin O H 3 C O H O O CH 3

Patients with CHD event (%) Effects of lipid-lowering therapy on CHD events in statin trials 25 20 15 10 5 0 4S-S LIPID-S CARE-P HPS-P CARE-S WOSCOPS-S HPS-S ASCOT-S* ASCOT-P* AFCAPS-S LIPID-P 4S-P AFCAPS-P WOSCOPS-P 90 110 130 150 170 190 210 LDL-C (mg/dl) Secondary Prevention Primary Prevention Simvastatin Pravastatin Lovastatin Atorvastatin S=statin treated P=placebo treated *Extrapolated to 5 years Modified from Kastelein JJP. Atherosclerosis. 1999;143(Suppl 1): S17-S21.

WOSCOPS: Effects of Lipid Lowering on Coronary Events in Primary Prevention Trial in Men 10 5 0-5 TC LDL-C 5 HDL-C Nonfatal MI/CHD death CHD death All-cause mortality Subjects: 6,595 men Age range: 45-64 yr -10 %+ -15-20 -25-30 -35-20 -26-31* -33-22 Mean baseline TC: 272 mg/dl Mean baseline LDL-C: 192 mg/dl Duration: 5 yr Intervention: Pravastatin 40 mg/day * P<0.0005. P=0.042. P=0.051. Shepherd J et al. N Engl J Med. 1995;333:1301-1307.

AFCAPS/TexCAPS: Effects of LDL-C Lowering in Patients With Average Cholesterol Levels % 10 5 0-5 -10-15 -20-25 -30-35 -40-45 TC -18 LDL-C -25 6 HDL-C MI C UA RV -37 P<0.001-32 -33 P=0.02 P=0.001-40 P=0.002 Subjects: 6,605 85% men, 45-73 yr 15% women, 55-73 yr Baseline lipids: TC: 221 mg/dl LDL-C: 150 mg/dl HDL-C: men, 36 mg/dl women, 40mg/dL Intervention: Lovastatin 20-40 mg/day C=coronary events defined as fatal/nonfatal myocardial infarction, sudden death, and unstable angina; MI=fatal/nonfatal myocardial infarction; UA=unstable angina; RV=revascularizations. Downs JR et al. JAMA. 1998;279:1615-1622.

Heart Protection Study (HPS): Eligibility 20,536 participants (men=15,454, women=5,082) aged 40 80 years Nonfasting TC 135 mg/dl At increased 5-year risk of CHD death due to prior disease myocardial infarction or other CHD occlusive disease of noncoronary arteries type 1 or type 2 diabetes treated hypertension Statin or antioxidant vitamins not clearly indicated or contraindicated by patient s own doctor HPS Collaborative Group. Lancet. 2002;360:7-22. HPS Collaborative Group. Eur Heart J. 1999;20:725-741.

HPS: Effects of Simvastatin on Cause-Specific Mortality Cause of death Statin (10,269) Placebo (10,267) CHD 587 707 Other vascular 194 230 All vascular 781 (7.6%) 937 (9.1%) Statin better Placebo better 0.83 (0.75-0.91) 17% reduction (P<0.0001) Neoplastic 359 345 Respiratory 90 114 Other medical 82 90 Nonmedical 16 21 All nonvascular 547 (5.3%) 570 (5.6%) All causes 1,328 (12.9%) 1,507 (14.7%) 0.95 (0.85-1.07) 5% reduction (P=0.4) 0.87 (0.81-0.94) 13% reduction (P=0.0003) 0.4 0.6 0.8 1.0 1.2 1.4 RR with 95% CIs HPS Collaborative Group. Lancet. 2002;360:7-22.

CARDS ρεδηαζκόο Δηθνληθό θάξκαθν 2838 Αζζελείο Δικονικό θάρμακο Αηορβαζηαηίνη 10mg Γηεμαγσγή θάζεο 6 εβδνκάδσλ κε ρνξήγεζε εηθνληθνύ θαξκάθνπ πξηλ ηελ ηπραηνπνίεζε θαη ελ ζπλερεία επηζθέςεηο ζηνπο κήλεο 1, 3, 6 θαη 6 κεληαίσο

Αζξνηζηηθόο θίλδπλνο(%) Αζξνηζηηθόο θίλδπλνο νιηθήο ζλεηόηεηαο 10 8 Μείσζε ζρεηηθνύ θηλδύλνπ 27% (95%CI: -1-48) p=0.059 Placebo 82 ζάλαηνη 6 4 2 Αηνξβαζηαηίλε 61 ζάλαηνη 0 0 1 2 3 4 4.75 Years Placebo Atorva 1410 1428 1395 1418 1370 1401 1094 1110 709 730 332 351

JUPITER Baseline Clinical Characteristics Ridker et al NEJM 2008 Rosuvastatin Placebo (N = 8901) (n = 8901) Age, years (IQR) 66.0 (60.0-71.0) 66.0 (60.0-71.0) Female, N (%) 3,426 (38.5) 3,375 (37.9) Ethnicity, N (%) Caucasian 6,358 (71.4) 6,325 (71.1) Black 1,100 (12.4) 1,124 (12.6) Hispanic 1,121 (12.6) 1,140 (12.8) Blood pressure, mm (IQR) Systolic 134 (124-145) 134 (124-145) Diastolic 80 (75-87) 80 (75-87) Smoker, N (%) 1,400 (15.7) 1,420 (16.0) Family History, N (%) 997 (11.2) 1,048 (11.8) Metabolic Syndrome, N (%) 3,652 (41.0) 3,723 (41.8) Aspirin Use, N (%) 1,481 (16.6) 1,477 (16.6) All values are median (interquartile range) or N (%)

JUPITER Baseline Blood Levels (median, interquartile range) Ridker et al NEJM 2008 Rosuvastatin Placebo (N = 8901) (n = 8901) hscrp, mg/l 4.2 (2.8-7.1) 4.3 (2.8-7.2) LDL, mg/dl 108 (94-119) 108 (94-119) HDL, mg/dl 49 (40 60) 49 (40 60) Triglycerides, mg/l 118 (85-169) 118 (86-169) Total Cholesterol, mg/dl 186 (168-200) 185 (169-199) Glucose, mg/dl 94 (87 102) 94 (88 102) HbA1c, % 5.7 (5.4 5.9) 5.7 (5.5 5.9) All values are median (interquartile range). [ Mean LDL = 104 mg/dl ]

JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Ridker et al NEJM 2008 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 0 1 2 3 4 Placebo 251 / 8901-44 % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 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 Secondary Endpoint All Cause Mortality HR 0.80, 95%CI 0.67-0.97 P= 0.02 Cumulative Incidence Ridker et al NEJM 2008 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0 1 2 3 4 Placebo 247 / 8901-20 % Rosuvastatin 198 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 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 Women Subgroup Data Primary Endpoint: Time to first occurrence of a CV death, non fatal stroke, non-fatal MI, unstable angina or arterial revascularization Rosuva No. (Rate)* Placebo No. (Rate)* HR 95% CI P Value Women 39 (0.57) 70 (1.04) 0.54 0.37-0.80 P=0.002 Men 103 (0.88) 181 (1.54) 0.58 0.45-0.73 P<0.0001 * Rates are per 100 person-years Mora S et al. Circulation 2009; 120 (Suppl): S500-S501; Abs 1426

Aspirin-Primary Prevention

Hypertension Optimal Treatment (HOT) trial: design HOT trial (1998) Design Objective Patients Regimen Mean follow-up Randomised, double-blind To assess whether aspirin, in addition to antihypertensive therapy, reduces the incidence of major CV events 18 790 men and women (aged 50 80 years; mean 61.5 years) 9399 patients received aspirin and 9391 received placebo Aspirin 75 mg/day was randomly added to antihypertensive treatment (felodipine and if necessary stepwise ACE inhibitors in 35 45% cases, beta-blockers, diuretics) 3.8 years (range 3.3 4.9 years) ACE, angiotensin converting enzyme; CV, cardiovascular; MI, myocardial infarction. 1. Hansson L, et al. Lancet 1998;351:1755 62. Section 4 20

Hypertension Optimal Treatment (HOT) trial: results MI, myocardial infarction. 1. Hansson L, et al. Lancet 1998;351:1755 62. Section 4 21

Primary Prevention Project (PPP): design PPP trial (2003) Design Objective Patients Regimen Primary endpoint Mean follow-up Randomised, open-label, factorial trial To test whether chronic treatment with aspirin and vitamin E reduces the frequency of major CV events 4495 patients (mean age 64.4 years) with one or more of the following: hypertension, hypercholesterolaemia, diabetes, obesity, family history of premature MI, or individuals who are elderly 2226 patients received aspirin 100 mg/day and 2269 patients did not receive aspirin Cumulative rate of CV death, nonfatal MI and nonfatal stroke 3.6 years (terminated early) CV, cardiovascular; MI, myocardial infarction. 1. Sacco M, et al. Diabetes Care 2003;26:3264 72. Section 4 22

Primary Prevention Project (PPP): results *Statistical significance not specified. CV, cardiovascular; MI, myocardial infarction. 1. Sacco M, et al. Diabetes Care 2003;26:3264 72. Section 4 23

Antithrombotic Trialists Collaboration meta-analysis 2009 Metaanalysis Trials (n) Patients (n) Outcomes with aspirin ATTC 6 95 000 First events (2009) 1 12% reduction in serious vascular events (p=0.0001) 18% reduction in major coronary events 23% reduction on nonfatal MIs (p<0.0001) 14% reduction in ischaemic stroke (p=ns) ATTC 16 17 000 Recurrent events (2009) 1 20% reduction in major coronary events 31% reduction in nonfatal MIs 13% reduction in coronary mortality 22% reduction in ischaemic stroke 9% reduction in vascular death 19% reduction in serious vascular events* Section 4 24 ATTC. Lancet 2009;373:1849 60

Antithrombotic Trialists Collaboration meta-analysis 2009-Primary Prevention Section 4 25 ATTC. Lancet 2009;373:1849 60

US Preventive Services Task Force 2009 recommendations for aspirin in primary prevention The USPSTF recommends the use of aspirin for men age 45 to 79 years when the potential benefit due to a reduction in myocardial infarctions outweighs the potential harm due to an increase in gastrointestinal hemorrhage The USPSTF recommends the use of aspirin for women age 55 to 79 years when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of aspirin for cardiovascular disease prevention in men and women 80 years or older The USPSTF recommends against the use of aspirin for stroke prevention in women younger than 55 years and for myocardial infarction prevention in men younger than 45 years Section 6 27 USPSTF. Ann Intern Med 2009;150:396 404;

USPSTF recommendations for aspirin Section 6 28 USPSTF. Ann Intern Med 2009;150:396 404.

reasonable for those at increased CVD risk (>10%) but not increased risk for bleeding (most men >50 y and women > 60 y with 1 or more major risk factors not recommended for those at low CVD risk (<5%) (men < 50 y and women <60 y with no major risk factors might be considered for those with at intermediate CVD risk Circulation 2010

Benefit of low-dose ASA therapy increases with increased risk for CHD events Outcome Estimated 5-year risk for CHD events at baseline 1% 3% 5% CHD events avoided 3 (1 4) 8 (4 12) 14 (6 20) Haemorrhagic stroke caused 1 (0 2) 1 (0 2) 1 (0 2) Major gastrointestinal bleeding events caused 3 (2 4) 3 (2 4) 3 (2 4) CHD = coronary heart disease US Preventive Services Task Force. Ann Intern Med 2002;136:157 60

Η Γηαθνπή ηνπ Καπλίζκαηνο ζε Οπνηαδήπνηε Ηιηθία Μπνξεί λα Απμήζεη ην Πξνζδόθηκν Δπηβίσζεο Απνηειέζκαηα από κία Μειέηε Αλδξώλ Γηαηξώλ Καπληζηώλ ζην Ηλσκέλν Βαζίιεην Δπηβίσζε ζε Κάζε Ηιηθηαθό εκείν (%) 60 100 90 80 70 60 50 40 30 20 10 0 Με θαπληζηέο Γηέθνςαλ ζε ειηθία 55-64 εηώλ Καπληζηέο 40 50 60 70 80 90 100 Ηιηθία (Έηε) 1. Doll R, et al. BMJ. 2004;328:1519 1527.

Απνηειεζκαηηθόηεηα Θεξαπείαο Υπνθαηάζηαζεο Νηθνηίλεο (NRT) 1,2 ύγθξηζε N Μειέηεο N πκκεηέρνληεο πγθεληξσηηθή OR (95% CI) Σζίκλα 52 17.783 1,66 (1,52 1,81) Δπίθεμα 37 16.691 1,81 (1,63 2,02) Ρινικό εκνέθωμα 4 887 2,35 (1,63 3,38) σζκεσή ειζπνοών 4 976 2,14 (1,44 3,18) Γιζκία/παζηίλιες 4 2739 2,05 (1,62 2,59) σνδσαζμός ένανηι ενός ηύποσ 7 3202 1,42 (1,14 1,76) Οπνηαδήπνηε NRT έλαληη παξάγνληα ειέγρνπ 103 39.503 1,77 (1,66 1,88) 1. Silagy C et al. Cochrane Database Syst Rev. 2004;(3):CD000146. 2. Stead L, Lancaster T. Int J Epidemiol. 2005;34:1001 1003.

Βνππξνπηόλε SR θαη Ννξηξηπηπιίλε γηα ηελ Δμάξηεζε από ηνλ Καπλό ύγθξηζε Μονοθεραπεία βοσπροπιόνης SR ένανηι εικονικού θαρμάκοσ Βοσπροπιόνη SR και επίθεμα νικοηίνης ένανηι εικονικού θαρμάκοσ ύνολο βοσπροπιόνης SR ένανηι εικονικού θαρμάκοσ Μονοθεραπεία νορηριπησλίνης ένανηι εικονικού θαρμάκοσ Νορηριπησλίνη και επίθεμα νικοηίνης ένανηι εικονικού θαρμάκοσ ύνολο νορηριπησλίνης ένανηι εικονικού θαρμάκοσ N Μειέηεο N πκκεηέρνληεο πγθεληξσηηθή OR (95% CI) 19 6443 2,06 (1,77 2,40) 2 728 1,60 (1,09 2,34) 21 7171 1,99 (1,73 2,30) 4 703 2,79 (1,70 4,59) 2 318 1,53 (0,90 2,61) 6 1021 2,14 (1,49 3,06) 1. Hughes JR, et al. Cochrane Database Syst Rev. 2004;(4):CD000031.

Αληαπόθξηζε πλερνύο Απνρήο (CA) 4 Δβδνκάδσλ θαηά ηηο Δβδνκάδεο 9 12 1 60 OR VAR ένανηι Pbo 3,91 P<0,0001 VAR ένανηι BUP 1,96 P<0,0001 Μειέηε 1 Μειέηε 2 60 OR VAR ένανηι Pbo 3,85 P<0,0001 VAR ένανηι BUP 1,89 P<0,0001 50 44,4% 50 44,0% Ποζοζηό Ανηαπόκριζης CA (%) 40 30 20 10 29,5% 17,7% Ποζοζηό Ανηαπόκριζης CA (%) 40 30 20 10 30,0% 17,7% 0 VAR 1 mg bid (n=344) BUP 150 mg bid (n=342) Pbo (n=341) 0 VAR 1 mg bid (n=352) BUP 150 mg bid (n=329) Ναστία αναυέρθηκε από το 28,6% των ασθενών ποσ έλαβαν θεραπεία με βαρενικλίνη 1 mg bid. Το ποσοστό απόσσρσης για αστή την ανεπιθύμητη ενέργεια ήταν 2,7%. Η ναστία περιγράυηκε γενικά ως ήπιας ή μέτριας βαρύτητας. VAR = βαρενικλίνη, Pbo = εικονικό θάρμακο, BUP = βοσπροπιόνη, OR = Αναλογία πιθανοηήηων. 1. ύνοψη ηων Χαρακηηριζηικών ηοσ Προϊόνηος Champix. Pfizer Ltd, Sandwich, UK. 2006. Pbo (n=344)

Effects of Systolic and Diastolic Blood Pressures on CHD Mortality: MRFIT * CHD Death Rate Per 10,000 Person-Years 23.8 31.0 48.3 25.5 37.4 34.7 43.8 38.1 80.6 20.6 16.9 10.3 11.8 13.9 100+ 8.8 90-99 8.5 Diastolic 80-89 Blood Pressure 75-79 (mm Hg) 70-74 <70 * Data shown only for 316,099 white men 35 to 57 years of age who were followed for a mean of 12 years. CHD = coronary heart disease MRFIT = Multiple Risk Factor Intervention Trial 24.6 25.3 25.2 12.8 12.6 Neaton JD, et al. Arch Intern Med. 1992;152:56-64. 9.2 11.8 <120 24.9 120-139 160+ 140-159 Systolic Blood Pressure (mm Hg) Slide Source Hypertension Online www.hypertensiononline. org

Relative Risk of Stroke Death 9 8 7 6 5 4 3 2 1 0 Risk of Stroke Death According to Blood Pressure (mm Hg): MRFIT Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP) 1 2 3 4 5 6 7 8 9 10 * * * * * SBP DBP <112 112 118 121 125 <71 71 76 79 81 Decile (Lowest 10%) (Highest 10%) 129 132 137 142 151 84 86 89 92 98 MRFIT = Multiple Risk Factor Intervention Trial; *P < 0.01; P < 0.001. Stamler J, et al. Arch Intern Med. 1993;153:598-615; He J, Whelton PK. Am Heart J. 1999;138(Pt 2):211-219. Slide Source Hypertension Online www.hypertensiononline. org

ηόρνη ΑΠ ζεξαπείαο (Ι) (1) Υπάξρνπλ ζπλνιηθά επαξθείο απνδείμεηο γηα ζύζηαζε κείσζεο ηεο ΑΠ<140 mmhg (θαη ηεο ΓΑΠ<90 mmhg) ζε όινπο ηνπο ππεξηαζηθνύο αζζελείο, ηόζν ζε εθείλνπο κε κε ρακειό/κέηξην θίλδπλν, όζν θαη ζε εθείλνπο κε πςειό θίλδπλν. (2) Η ζύζηαζε ησλ πξνεγνύκελσλ θαηεπζπληήξησλ νδεγηώλ λα απνζθνπνύλ ζε ρακειόηεξν ζηόρν ΑΠ (<130 mmhg) ζε δηαβεηηθνύο αζζελείο θαη ζε αζζελείο κε πνιύ πςειό θαξδηαγγεηαθό θίλδπλν (πξνεγνύκελα θαξδηαγγεηαθά ζπκβάληα), κπνξεί λα είλαη ζώθξσλ, αιιά δελ ππνζηεξίδεηαη ζηαζεξά από απνδείμεηο κειεηώλ. (3) ε θακία ηπραηνπνηεκέλε κειέηε κε δηαβεηηθνύο αζζελείο δελ κεηώζεθε ε ΑΠ θάησ από ηα επίπεδα ησλ 130 mmhg, κε απνδεδεηγκέλα νθέιε. Δπηπξόζζεηα δε κειέηεο ζηηο νπνίεο ε ΑΠ κεηώζεθε θάησ από ηα επίπεδα ησλ 130 mmhg απέδσζαλ αληηθαηηθά απνηειέζκαηα.

BP target in patients with diabetes melitus No clear evidence for < 130 mmhg SBP

BP target in patients with previous CV disease No clear evidence for < 130 mmhg SBP

Proportion of Stroke Events (%) Incidence of Fatal and Nonfatal Stroke The Anglo-Scandinavian Cardiac Outcomes Trial 10 8 6 4 2 Atenolol-Based Regimen (422 Events) Amlodipine-Based Regimen (327 Events) p = 0.0003 Number At Risk Amlodipine Atenolol 0 0 1 2 3 4 5 6 9639 9618 9483 9461 9331 9274 Time (Years) 9156 9059 8972 8843 7863 7720 Dahlof B, et al. Lancet. 2005;355:895-906. Slide Source Hypertension Online www.hypertensiononline. org

2007 ESH/ESC Guidelines Combinations between Some Classes of Antihypertensive Drugs Thiazide diuretics Thiazide diuretics ß- blockers AT 1 - receptor antagonists ACCOMPLIS H ADVANCE HYVET ASCOT ONTARGET AT 1 - receptor antagonists α-blockers Calcium antagonists Calcium antagonists ACE inhibitors ACE inhibitors Pronounced antihypertensive effect CV protection Optimal tolerability J of hypertension 2009;27:2121 58

ΠΡΟΕΚΛΟΓΙΚΗ ΑΦΙΑ 1985