Θεραπεία της υπέρτασης σε ειδικές καταστάσεις: Στεφανιαία νόσος

Θεραπεία της υπέρτασης σε ειδικές καταστάσεις: Στεφανιαία νόσος Θωµάς Κ. Μακρής, MD FACC, FESC Συντονιστής ιευθυντής Καρδιολογικού Τµήµατος ΓΝΜ ΕΛΕΝΑ ΒΕΝΙΖΕΛΟΥ

Cardiovascular disease Europe s No. 1 killer Main cause of disease More than 4.3 million deaths/year 48% of all deaths Coronary heart disease most common cause of death in Europe 1.9 million deaths/year Stroke more than 500,000 deaths/year burden (23%) Cost to EU estimated at 192 billion per year Allender et al. European Heart Network 2008

Risk Factors Sex Uncontrollable Hereditary Race Age Controllable High blood pressure 140 /90mmHg High blood cholesterol Smoking Physical activity Obesity Diabetes Stress and anger

Hypertension: A Risk Factor for Cardiovascular Disease

Multiple Risk Factor Intervention Trial (MRFIT): Effect of BP on CHD-Related Mortality (N=316,099)* Death Rate per 10,000 Person-Years 100 DBP (mm Hg) 90-99 80-89 75-79 70-74 <70 <120 120-139 140-159 160 SBP (mm Hg) *Men aged 35-57 y followed for a mean of 12 y. Neaton JD, Wentworth D. Arch Intern Med. 1992;152:56-64.

Blood Pressure and Risk for Coronary Heart Disease in Men Age-adjusted Annual Incidence per 1000 60 50 40 30 20 10 0 <120 Age 35-64 Age 65-94 140-159 180+ 120-139 160-179 Systolic Blood Pressure (mm H Age-adjusted Annual Incidence per 1000 60 Age 35-64 Age 65-94 50 40 30 20 10 0 <75 85-94 105+ 75-84 95-104 Diastolic Blood Pressure (mm Based on 30 year follow-up of Framingham Heart Study Subjects free of CHD at base line but not adjusted for other risk factors.

Hypertension Co-Morbidities % of patients with BP >140/90 mm Hg: 69% of patients with 1 st MI 77% of patients with 1 st stroke 74% of patients with HF Hypertension precedes HF in 91% of cases Hypertension is associated with a 2- to 3-times higher risk for HF BP, blood pressure; HF, heart failure; MI, myocardial infarction. Thom T et al. Circulation. 2006;113:e85-e151. e151.

CV Risk Factor Clustering With Hypertension: Framingham Offspring, Aged 18 to 74 Years > 50% of Hypertension Occurs in Presence of 2 or More Risk Factors Men Women 1 RF 2 RFs 1 RF 2 RFs 26% 25% 27% 24% No Additional RFs 19% 22% 17% 20% 8% 12% 4 or More RFs 3 RFs No Additional RFs 4 or More RFs 3 RFs RF = risk factor. Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S.

Synergistic Interaction of Multiple CV Risk Factors 5-Year CVD Risk (per 100 people) 50 40 30 20 10 3% 6% SBP (mm Hg) 110 120 130 140 12% 150 160 170 180 18% 24% 33% 44% 0 Reference TC = Smoker HDL-C C = 270 mg/dl 39 mg/dl Male Diabetes Aged 60 Years Additive Risk Factors Jackson R et al. Lancet. 2005;365:434-441. 441.

Benefits of Treating Hypertension Younger than 60 reduces the risk of stroke by 42% reduces the risk of coronary event by 14% Older than 60 reduces overall mortality by 20% reduces cardiovascular mortality by 33% reduces incidence of stroke by 40% reduces coronary artery disease by 15% Staessen JA, et al. Lancet 2000; 355: 865-872

Risk stratification Blood pressure (mm Hg) Other risk factors and disease history Normal SBP 120 129 or DBP 80 84 High normal SBP 130 139 or DBP 85 89 Grade 1 SBP 140 159 or DBP 90 99 Grade 2 SBP 160 179 or DBP 100 109 Grade 3 SBP >180 or DBP >110 No other risk factors Average risk Average risk Low added risk Moderate added risk High added risk 1 2 risk factors Low added risk Low added risk Moderate added risk Moderate added risk Very high added risk 3 risk factors, TOD or diabetes Moderate added risk High added risk High added risk High added risk Very high added risk Coronary artery disease Average risk Very high added risk Very high added risk Very high added risk Very high added risk 1. TOD = target organ damage SBP = systolic blood pressure DBP = diastolic blood pressure Mancia G. et al. J Hypertens 2007;25:1105 1187

Post-MI and Chronic IHD : Prevention Plan Aggressive Reduction Modifiable CVD Risk Factors Therapeutic goal to Slow, Stop, Reverse disease progression Blood Pressure Lipids Diabetes Diet Weight Physical Activity Tobacco Cessation

Initiation of antihypertensive treatment 2007 ESC/ESH Guidelines for the Management of Hypertension 1 Other risk factors, OD or Disease Normal SBP 120-129 or DBP 80-84 High normal SBP 130-139 or DBP 85-89 Grade 1 HT SBP 140-159 or DBP 90-99 Grade 2 HT SBP 160-179 or DBP 100-109 Grade 3 HT SBP >180 or DBP >110 No other risk factors No BP intervention No BP intervention Lifestyle changes for several months then drug treatment if BP uncontrolled Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes + immediate drug treatment 1-2 risk factors Lifestyle changes Lifestyle changes Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes + immediate drug treatment 3 or more risk factors, MS, OD Diabetes Lifestyle changes Lifestyle changes Lifestyle changes and Lifestyle consider changes drug and treatment consider drug treatment Lifestyle changes + drug treatment Lifestyle changes + drug treatment Lifestyle changes + drug treatment Lifestyle changes + immediate drug treatment Established CV or renal disease Lifestyle changes + immediate drug treatment Lifestyle changes + immediate drug treatment Lifestyle changes + immediate drug treatment Lifestyle changes + immediate drug treatment Lifestyle changes + immediate drug treatment 1. Mancia G. et al. J Hypertens 2007;25:1105 1187 15

Τι µπορεί να γίνει ΘΕΡΑΠΕΙΑ ΠΡΩΤΗΣ ΓΡΑΜΜΗΣ ΑΛΛΑΓΗ ΤΟΥ ΤΡΟΠΟΥ ΖΩΗΣ ΜΕΙΩΣΗ ΒΑΡΟΥΣ ΙΑΙΤΗΤΙΚΕΣ ΤΡΟΠΟΠΟΙΗΣΕΙΣ ΦΥΣΙΚΗ ΡΑΣΤΗΡΙΟΤΗΤΑ ΜΕΙΩΣΗ ΒΑΡΟΥΣ : Μείωση προσλαµβανόµενων θερµίδων και άσκηση Μείωση 1 kg σωµατικού βάρου 2-5% του σπλαχνικού λίπους. Ρεαλιστικός στόχος. 7-10 του σωµατικού βάρους σε 6-12 µήνες.

Modifiable Risk Factors and Weight Control Obesity Low HDL Cholesterol Diabetes Hypertension

Secondary Prevention and Long Term Management Goals Recommendations Weight management: Goal: BMI 18.5 to 24.9 kg/m 2 Waist circumference: Women: < 88cm Men: < 102cm Calculate BMI and measure waist circumference as part of evaluation. Monitor response of BMI and waist circumference to therapy. Start weight management and physical activity as appropriate. Desirable BMI range is 18.5 to 24.9 kg/m 2. If waist circumference is 88 cm in women or 102 cm in men, initiate lifestyle changes and treatment strategies for metabolic syndrome. American Heart Acociation / American College Cardiology

Modifiable Risk Factors and Physical Activity Inactivity Obesity High LDL Cholesterol Low HDL Cholesterol Diabetes Hypertension

Secondary Prevention and Long Term Management Goals Recommendations Physical activity: Minimum goal: 30 minutes 3 to 4 days per week; Optimal daily Assess risk, preferably with exercise test, to guide prescription. Encourage minimum of 30 to 60 minutes of activity, preferably daily but at least 3 or 4 times weekly (walking, jogging, cycling, or other aerobic activity) supplemented by an increase in daily lifestyle activities (e.g., walking breaks at work, gardening, household work). Cardiac rehabilitation programs are recommended for patients with STEMI. American Heart Acociation / American College Cardiology

Περπάτηµα - 30 min./day

Modifiable Risk Factors and Diet Obesity High LDL Cholesterol Low HDL Cholesterol Diabetes Hypertension Initiate lifestyle modification (weight control, physical activity, alcohol moderation, moderate sodium restriction, and emphasis on fruits, vegetables, and low-fat dairy products) in all patients American Heart Acociation / American College Cardiology

Prevention of Diabetes Through Lifestyle Changes Among Individuals With IGT: Finnish Diabetes Prevention Study 1.0 Intervention group 0.9 Cumulative probability of remaining free of diabetes 0.8 0.7 0.6 Control group 0.5 Relative risk = 0.4 (P<0.001) 0.4 IGT, impaired glucose tolerance. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350. 0 1 2 3 4 5 6 Year

Κάπνισµα ιακοπή / Αποφυγή: Βλαβερή τόσο η ενεργητική όσο και η παθητική έκθεση Μείζον παράγοντας κινδύνου για: Αντίσταση στην ινσουλίνη και µεταβολικό σύνδροµο Μακροαγγειακή νόσο (PVD, ΕΜ, ΑΕΕ) Μικροαγγειακές επιπλοκές του διαβήτη Πνευµονικές νόσους, κλπ.

Forecasted mortality trend due to tobacco use 1990-2030 ( WHO) 12 10 10 millions 8 6 6 8 4 2 3 4 0 1990 2000 2010 2020 2030

Death due to smoking 50% of smokers will die of diseases related to smoking. 25% of all death due to heart disease 30% of all death due to cancer 25% of all death due to stroke 90% of all death due to lung cancer 85% of all death due to COPD

Antihypertensive treatment: Preferred drugs Subclinical organ damage LVH Asymptomatic atherosclerosis Microalbuminuria Renal dysfunction Clinical event Previous stroke Previous MI Angina pectoris Heart failure Atrial fibrillation Recurrent Permanent ESDR/proteinuria Peripheral artery disease Condition ISH (elderly) Metabolic syndrome Diabetes mellitus Pregnancy Blacks ACEI, CA, ARB, CA, ACEI ACEI, ARB ACEI, ARB Any BP lowering agent BB, ACEI, ARB BB, CA Diuretics, BB, ACEI, ARB, antialdosterone agents ARB, ACEI BB, non-dihydropyridine CA ACEI, ARB, loop diuretics CA Diuretics, CA ACEI, ARB, CA ACEI, ARB CA, methyldopa, BB Diuretics, CA 2007 ESH-ESC ESC Hypertension Guidelines

υνητικά καρδιακά οφέλη από την χορήγηση των β-αναστολέων σε ασθενείς µε αρτηριακή υπέρταση και στεφανιαία νόσο. Αντιαθηρωµατική δράση Ελάττωση φλεγµονής,τοιχωµατικού stress, δυσλειτουργίας του ενδοθηλίου, και του κινδύνου ρήξης της αθηρωµατικής πλάκας. Αντιαρρυθµική δράση Μείωση ΚΣ Μείωση δραστηριότητας ΣΝΣ Αύξηση της καρδιακής παρασυµπαθητικοτονίας Αντιισχαιµική δράση Μείωση ΚΣ και ΑΠ. Παράταση της διαστολικής φάσης (πλήρωση στεφανιαίων) Υποστροφή του καρδιακού remodeling. 1. Tse WY et al. Diabet Med. 1994;11(2):137-144. 144. 2. Fonarow GC. Am J Med. 2004;116(Suppl 5A):76S-88S. 3. Bell DS. The Endocrinologist. 2003;13:116-123 123.

Risk Reduction With β-blockers in Post-MI Patients 15 Trials (n =18,995) 0% Overall mortality Sudden cardiac death Non- sudden death Nonfatal MI 10% 20% 30% 40% 22% 33% 20% 20% Hanes DS et al. J Clin Hypertens (Greenwich). 2001;3(4):236-243. 243.

Effect of Long-term β-blockade after AMI 26 randomized trials 10 (%) 9,5 beta-blockers Placebo 8 7,5 7,3 6 4 5,5 5,2 3,6 2 0 Death Reinfarction Arrest (VF) Reduction 23 ± 4 27 ± 4 32 ± 5 2p <0.0001 <0.0001 <0.0001

Relative Risk Risk of of CHD Events in in Single Drug BP BP Difference Trials according to to Drug (β-blocker or or Other), Presence of of CHD, and and for for β-blockers according to to Acute MI MI on on Entry No. of trials No. of events Relative Risk (95% CI) Relative Risk Trials of -blockers People with history of CHD Entry after acute MI Entry after long term CHD People with no history of CHD 37 27 11 6 2524 255 369 851 0.71 0.69 0.87 0.89 Trials of drugs other than β-blockers People with history of CHD 37 People with no history of CHD 24 5834 3217 0.85 0.84 All trials except ones of β-blockers in people with history of CHD 64 9417 0.85 0.5 Treatment better 1.0 2.0 Placebo better Law et al., BMJ 2009; 338: b 1665

Beta-blockers CHD Prevention Superior to other drugs in CHD patients Similar to other drugs in patients with no CHD Stroke Prevention Inferior to CA Similar to other drugs CHF Prevention Superior to CA Similar to other drugs Law et al., BMJ 2009; 338: b1665

Reduction in Relative Risk of CV Events with BB Treatment in Post-MI Patients with DM 0 Gothenburg 8.5 Miami 7.1 ISIS I 6.0 Norway 5.3 BHAT 11.2 % DM -10-20 -30-24 -40-39 -50-50 -60-59 -70 % -69

b-blocker Trials in Heart Failure: Overview Annual Mortality Mean Follow-up RR P Value % Patients BEST placebo 17% bucindolol 15% 24 months 10% P=.10 CIBIS-II II placebo 13.2% bisoprolol 8.8% 15 months 34% P=.0001 MERIT-HF placebo 11.0% metoprolol succinate 7.2% 12 months 34% P=.0062 COPERNICUS 10.4 months placebo 18.5% carvedilol 11.4% 35% P=.0014 0 0.25 0.5 0.75 1.0 1.25 1.5 1.75 2.0 Relative Risk and 95% Confidence Intervals Lancet.. 1999:353:2001-2007; 2007; CIBIS II Investigator and Committees. Lancet.. 1999;353:9-13; 13; Packer M et al. N Engl J Med. 2001;344:1651-1658; 1658; Beta-blockers Evaluation Survival Trial Investigators. N Engl J Med.. 2001;344:1659-1667. 1667.

Secondary Prevention and Long Term Management Goals Recommendations Beta- Blockers Start in all patients. Continue indefinitely. Observe usual contraindications. I IIa IIb III AHA/ACC Secondary Prevention

Major Clinical Outcome Trials of RAAS Manipulation ACE inhibition Angiotensin receptor blockade HOPE EUROPA ALLHAT ANBP2 INVEST LIFE GISSI-3 ISIS-4 AIRE SAVE SOLVD-Prevention TRACE CHARM-Preserved OPTIMAAL VALIANT SOLVD-Treat CHARM-Added CHARM-Alternative ELITE II Val-HeFT CONSENSUS

ACE Inhibition for Secondary Prevention of CAD Rationale Anti-atherosclerotic effects Improvement in vascular endothelial function Vasodilation: reduce preload and afterload LV hypertrophy reduction Blood pressure lowering Angiotensin II reduction / bradykinin increase

HOPE: Additive Risk Reduction with Ramipril 10 mg Effects beyond baseline therapy Aspirin β-blockade Lipid-lowering agents Size: 9541 patients followed for 4 to 6 years Diuretics Other antiplatelets Calcium channel blockade + Ramipril 10 mg 0 Stroke CV death Nonfatal MI All-cause mortality -5-10 % RR -15-20 -25-30 26%* 20%* 16% *P = 0.0001 P = 0.005-35 32%* The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.

ACE Inhibitor Evidence: Secondary Prevention European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) 12,218 patients with CAD and presumed normal LV function randomized to perindopril (8 mg) or placebo for 4 years Cardiovascular death (0.86; 0.72-1.03) Non-fatal MI (0.78; 0.20-0.90) Cardiac arrest (0.54; 0.20-1.47) Combined endpoint (0.80; 0.71-0.91) 0 0.5 1 1.5 2 Favors Perindopril Favors Placebo ACE-I reduce CV events in intermediate-risk individuals ACE-I=Angiotensin converting enzyme inhibitors, CAD=Coronary artery disease, CV=Cardiovascular, MI=Myocardial infarction EUROPA Investigators. Lancet 2003;362:782-788 24

ACE Inhibitor Evidence: Secondary Prevention Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial 8,290 patients with stable CAD and normal LV function randomized to trandolapril (4 mg) or placebo for 5 years Primary End Point (%)* 30 25 20 15 10 5 0 Placebo Trandolapril 0 1 2 3 4 5 6 Years After Randomization ACE-I do not reduce CV events in lower-risk individuals *Includes death from cardiovascular causes, myocardial infarction, or coronary revascularization The PEACE Trial Investigators. NEJM 2004;351:2058-68 25

ACE Inhibitor Evidence: Secondary Prevention Meta-Analysis of the HOPE, EUROPA, and PEACE Trials* Clinical Trial N Deaths RR of Mortality HOPE 9,297 1051 EUROPA 12,218 795 PEACE 8,290 633 HR=0.84 P=0.005 HR=0.89 P=0.10 HR=0.89 P=0.13 All Trials 33,960 >3000 HR=0.86 P<0.001 0.4 0.6 0.8 1.0 1.2 1.4 1.6 ACE-I Better Placebo Better *7 RCTs, 33,960 randomized patients, and 4.4 years of mean follow-up. Other findings include a CVD HR=0.81, MI HR=0.82, and stroke HR=0.77 ACE-I=Angiotensin converting enzyme inhihbitors, CVD=Cardiovascular disease, MI=Myocardial infarction Danchin N et al. Arch Intern Med 2006;166:787-796 27

ACE Inhibitor Evidence: Secondary Prevention SAVE Radionuclide EF <40% AIRE Clinical and/or radiographic signs of HF TRACE Echocardiogram EF <35% Probability of Event 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 Placebo ACE-I OR 0.74 (0.66 0.83) 0 0 1 2 3 4 Years ACE-I provide substantial benefit in post-mi LVSD ACE-I=Angiotensin converting enzyme inhibitors, EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, OR=Odds ratio Flather MD et al. Lancet 2000;355:1575 1581 28

ACE Inhibitor AHA/ACC Secondary Prevention I IIa IIb III An ACE inhibitor in those following a MI, regardless of EF or in those with CAD* along with hypertension (SBP >120 mmhg), LVSD (EF <0.40), heart failure, DM, or CKD Mortality risk reductions up to 27% in this group I IIa IIb III Optional use of an ACE inhibitor in those with low risk CAD*, well controlled risk factors, normal EF, and successful revascularization ACE=Angiotensin converting enzyme, CAD=Coronary artery disease, CKD=Chronic kidney disease, CV=Cardiovascular, DM=Diabetes mellitus, EF=Ejection *Defined fraction, LVSD=Left by previous ventricular MI or angiographically systolic dysfunction, significant MI=Myocardial CADinfarction, SBP=Systolic blood pressure Circulation 2006; 113:2363-72.

Angiotensin receptor blockade : A revolution in organ protection Heart : Regress LVH and improve left ventricular function Reduce in-stent restenosis and need for reintervention Reduce cardiovascular morbidity and mortality Reduce heart failure hospitalizations Vessels : Reduce vascular oxidation and inflammation, improve endothelial function Attenuate morphological changes, DNA synthesis, and cell proliferation leading to atherosclerosis Reduce stroke J Hum Hyperten 2002;16:S34-S41 Clin Sci 2001;100:13-17, Circulation 2000;103:799-805

ΑΜΕΑ vs. ΑΑ ΙΙ σε ασθενείς µε Καρδιακή Ανεπάρκεια ή ΟΕΜ ΑΠΟΤΕΛΕΣΜΑ ΜΕΛΕΤΗ Συµβάµατα/N ARB ACE-I Υπέρ ARB Υπέρ ACE-I Σχετικός Κίνδυνος (95% CI) ΑΕΕ ELITE II OPTIMAAL 18/1578 11/1574 140/2744 132/2733 1.63 ( 0.77, 3.44) 1.06 ( 0.84, 1.33) VALIANT 157/4909 166/4909 0.95 ( 0.76, 1.17) Overall 1.02 ( 0.87, 1.19) Μείζων ΣΝ ELITE II OPTIMAAL VALIANT Overall 161/1578 129/1574 1.24 ( 1.00, 1.55) 576/2744 533/2733 1.08 ( 0.97, 1.20) 868/4909 896/4909 0.97 ( 0.89, 1.05) 1.06 ( 0.94, 1.19) Καρδιακή Ανεπάρκεια ELITE II OPTIMAAL 46/1578 53/1574 363/2744 318/2733 0.87 ( 0.59, 1.28) 1.14 ( 0.99, 1.31) VALIANT 813/4909 801/4909 1.01 ( 0.93, 1.11) Overall 1.05 ( 0.95, 1.15) 0.5 1.0 2.0 Relative risk BPLTTC, Journal of Hypertension 2007, 25:951 958

Η Τελµισαρτάνη 80mg είναι εξίσου προστατευτική µε τη ραµιπρίλη 10mg όσον αφορά στην Καρδιοπροστασία Τελµισαρτάνη 80mg Σύνθετο καρδιαγγειακό τελικό σηµείο* Ραµιπρίλη 10mg * Σύνθετο Καρδιαγγειακό Τελικό Σηµείο = Καρδιαγγειακός θάνατος + µη θανατηφόρο έµφραγµα µυοκαρδίου + νοσηλεία για συµφορητική καρδιακή ανεπάρκεια + µη θανατηφόρο εγκεφαλικό ευτερεύον Σύνθετο τελικό σηµείο Πρωτεύον τελικό σηµείο µελέτης HOPE (Καρδιαγγειακός θάνατος + έµφραγµα µυοκαρδίου + εγκεφαλικό ) 0.8 0.9 1.0 1.1 1.2 Υπέρ τελµισαρτανης Υπέρ ραµιπρίλης p< 0.01 vs. όριο µηκατωτερότητας (1.13)

Telmisartan is the Only ARB Indicated for CV Protection in CV High-risk Patients Based on the Data From The ONTARGET Trial Program ( EMA ) 47 Losarta n Eprosartan Irbesartan Olmesartan Valsartan Candesartan Telmisartan Hypertension - Treatment of renal disease - Prevention of stroke in LVH CV high risk Atherothrombotic CV disease such as: - Coronary heart disease - Peripheral vascular disease - Stroke Type 2 diabetes with target organ damage Heart failure or LV dysfunction

Angiotensin Receptor Blocker Recommendations I IIa IIb III Use in patients who are intolerant of ACE inhibitors with HF or post MI with LVEF less than or equal to 40%. I IIa IIb III Consider in other patients who are ACE inhibitor intolerant. I IIa IIb III Consider use in combination with ACE inhibitors in systolic dysfunction HF. ACE=Angiotensin converting enzyme inhibitor, LVEF=Left Ventricular Ejection fraction, HF=Heart failure, MI=Myocardial infarction

Blood Pressure Evidence: Secondary Prevention International Verapamil-Trandolapril Study (INVEST) 22,576 patients with HTN and CAD randomized to a BP lowering strategy with verapamil SR (240 mg) or atenolol (50 mg) for 2.7 years Incidence of death, MI, or stroke 25 20 15 10 5 0 Calcium antagonist strategy (CAS)* Non-calcium antagonist strategy (NCAS)* 0 6 12 18 24 30 36 42 48 54 60 Months There is comparable efficacy with a CAS or NCAS RR=0.98, P=0.57 BP=Blood pressure, DM=Diabetes mellitus, HTN=Hypertension, MI=Myocardial infarction *Trandolapril (up to 4 mg) was added in those with DM, chronic kidney disease, or heart failure. Pepine CJ et al. JAMA 2003;290:2805-2816 12

Αµλοδιπίνη: Πληθώρα εδοµένων σχετικά µε τις Καρδιαγγειακές Επιπτώσεις από την χορήγηση της PREVENT 825 ασθενείς µε ΣΝ ( 30%): Πολυκεντρική, τυχαιοποιηµένη, ελεγχόµενη µε εικονικό φάρµακο µελέτη CAMELOT 1,991 ασθενείς µε ΣΝ (>20%): ιπλά τυφλή, τυχαιοποιηµένη µελέτη placebo-enalapril 20mg ASCOT-BPLA/CAFE 19,257 υπερτασικοί ασθενείς: Πολυκεντρική, τυχαιοποιηµένη, προοπτική µελέτη έναντι της ατενολόλης ALLHAT 18,102 υπερτασικοί ασθενείς: Τυχαιοποιηµένη προοπτική µελέτη έναντι της λισινοπρίλης Πρωτεύον καταληκτικό σηµείο: Καµία διαφορά στις στεφανιογραφικές µεταβολές στα 3 έτη έναντι placebo 35% νοσηλείες για ΚΑ, στηθάγχη 33% επεµβάσεις επαναγγείωσης Πρωτεύον καταληκτικό σηµείο : 31% στα καρδιαγγειακά συµβάµατα έναντι placebo 41% νοσηλείες για στηθάγχη 27% στεφανιαίας επαναγγείωσης Πρωτεύον καταληκτικό σηµείο : 10% στα µη θανατηφόρα ΟΕΜ και θανατηφόρα ΣΝ 16% συνολικά καρδ/κά συµβάµατα και επεµβάσεις 30% νέα περιστατικά διαβήτη 27% εγκεφαλικά 11% συνολική θνητότητα κεντρικής αορτικής πίεσης κατά 4.3 mmhg Πρωτεύον καταληκτικό σηµείο : Καµία διαφορά στη θανατηφόρα ΣΝ και στο µη θανατηφόρο ΟΕΜ έναντι λισινοπρίλης 6% συνδυαστική καρδιαγγειακή νόσο 23% εγκεφαλικά

Υποµελέτη για τους υπερτασικούς A Coronary disease Trial Investigating Outcome with Nifedipine GITS (n=3,977) Υπερτασικοί ασθενείς

Κλινικά οφέλη από τη χορήγηση νιφεδιπίνης Gits σε ασθενείς µε χρόνια σταθερή στηθάγχη και υπέρταση 38% µείωση των νέων περιστατικών καρδιακής ανεπάρκειας 33% µείωση των εγκεφαλικών που προκαλούν αναπηρία Η νιφεδιπίνη GITS προσφέρει πολλά επιπλέον µακροπρόθεσµα κλινικά οφέλη 16% µείωση της ανάγκης για νέες στεφανιογραφίες 28% µείωση οποιουδήποτε εγκεφαλικού επεισοδίου

Θεραπευτικοί στόχοι -BP < 140 / 90 mmhg in all hypertensive patients < 130 / 80 mmhg in hypertensive patients with diabetes, CHD, stroke or renal disease - Control of all cardiovascular risk factors ESH - ESC Guidelines, J Hypertens 2007

J hypertension 2009;27:2121 58

60 50 INVEST (CAD pts) 30 ONTARGET (high risk pts, mainly with CAD) 3 CV events (%) 40 30 20 CV events (%) 20 10 2 1 Adjusted HR 10 0 110 >110 to 120 to >120 130 to >130 140 to >140 150 to >150 160 >160 On-treatment SBP (mmhg) 0 112 121 126 130 133 136 140 144 149 160 On-treatment SBP (mmhg) 0 30 VALUE (High risk pts) 35 TNT (CAD pts) 5 Cardiac events (%) 20 10 CV events (%) 30 25 20 15 10 5 4 3 2 1 Adjusted HR 0 < 120 >120 to 130 to >130 140 to >140 150 >150 >160 to 160 to 170 to >170 180 180 On-treatment SBP (mmhg) 0 60 61-70 71-80 81-90 91-100 100 > 100 On-treatment DBP (mmhg) 0 J hypertension 2009;27:2121 58

Example Framingham Study Note: J-curves have also been observed for stroke events

DBP & Risk for Primary Outcome: INVEST Subanalysis Incidence (%) of Primary Outcome 50 40 30 20 10 0 60 60< to 70 Nadir = 84.1 mm Hg Primary Outcome 70< to 80 DBP (mm Hg) 80< to 90 Hazard Ratio 90< to 100 Total patients 176 2239 11306 7376 1230 248 100< 6 5 4 3 2 1 0 Estimated Hazard Ratio Messerli FH et al. Ann. Int. Med. July 2006

Incidence of MI and Stroke Stratified by Diastolic Blood Pressure in the INVEST Study Messerli, F. H. et al. J Am Coll Cardiol 2009;54:1827-1834 Copyright 2009 American College of Cardiology Foundation.

Incidence of Primary Composite Endpoint by Mean Diastolic Blood Pressure Categories: All Subjects ( TNT stady CAD pts ) 100% 20 Primary Outcomes Hazard Ratio 18 Incidence (%) of Primary Outcome 80% 60% 40% 20% 16 14 12 10 8 6 4 Estimated Hazard Ratio 2 0% <= 60 > 60 to 70 > 70 to 80 > 80 to 90 > 90 to 100 > 100 to 110 > 110 0 Mean DBP (mmhg) Bangalore S, Messerli FH et al 2010

Interaction of the J-Curve With Coronary Revascularization Messerli, F. H. et al. J Am Coll Cardiol 2009;54:1827-1834

Overview of J Curve 23 clinical trials over the last 20 years in over 110,000 people QUESTION is there presence of a J curve on CV events. 12 studies showed a J curve with adverse CV outcomes at low diastolic BPs between 60-70 mmhg 8 of those 12 studies did NOT have a history of coronary artery disease events Messerli F and Panjrath G J Am Coll Cardiol, 2009; 54:1827-1834

The Dilemma of the J-curveJ In lack of evidence on the J-curve, J recourse has been made to an indirect approach: incident outcomes in randomized trials are plotted against achieved BP, independently of the randomized group J-curve denied: HOT, PROGRESS, UKPDS J-curve found: IDNT, INVEST, ONTARGET J-curve found in both actively and placebo treated group: INDANA (7 trials) J-curve independent of antihypertensive therapy: TNT A.Zanchetti Eur Heart J 2010;31:2837-40

Το φαινόµενο της καµπύλης J Η έλλειψη προοπτικών και αναδροµικών µελετών καθώς και µεταναλυσεων οδηγεί στην άποψη, ότι για ασθενείς υψηλού καρδιαγγειακού κινδύνου υπάρχουν λόγοι ανησυχίας για τυχόν µείωση της ΑΠ <120/70mmHg Οι τιµές ΑΠ κάτω των οποίων αυξάνουν τα συµβάµατα, φαίνεται να είναι διαφορετικές για κάθε ασθενή, ανάλογα µε την ηλικία/τα κλινικά κριτήρια/ και την ικανότητα αυτορρύθµισης της κυκλοφορίας Οι συστάσεις για επιθετική µείωση της ΑΠ σε ασθενείς υψηλού κινδύνου πιθανόν θα πρέπει να είναι λιγότερο αυστηρές J hypertension 2009;27:2121 58

2007 AHA Guidelines: Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease In achieving a target BP < 130/80 mmhg for secondary prevention, the BP should be lowered slowly and caution is advised in inducing falls of diastolic BP below 60mmg. Rosendorff C et al., Circulation 2007,115:2761-2788.

Post-MI and ICD Prevention Plan Aggressive Reduction Modifiable CVD Risk Factors Therapeutic goal to Slow, Stop, Reverse disease progression Blood Pressure Lipids Diabetes Diet Weight Physical Activity Tobacco Cessation

Ρύθµιση αρτηριακής πίεσης και λιπιδιων Στόχος ΑΠ: <130/80 mmhg Στόχος: LDL <100 mg/dl (<3.0 mmol /l) (ιστορικό καρδιαγγειακής νόσου <70 mg/dl- <2.6 mmol/l) TG <150 mg% (<1.7 mmol /l) HDL >40 mg% (>1.1 mmol /l) Θεραπεία της υπεργλυκαιµίας και της αντίστασης στην ινσουλίνη Circulation 2004;110:227 239. ESH - ESC Guidelines, J Hypertens 2007

Statins reduce all-cause death: Meta-analysis of 14 trials Cholesterol Treatment Trialists Collaboration Cause of death Vascular causes: CHD Stroke Other vascular Any non-chd vascular Events (%) Treatment Control (n = 45,054) (n = 45,002) Treatment Control better better 3.4 4.4 0.81 0.6 0.6 1.2 0.6 0.7 1.3 0.91 0.95 0.93 Any vascular Nonvascular causes: Cancer Respiratory Trauma Other/unknown Any nonvascular Any death 4.7 2.4 0.2 0.1 1.1 3.8 5.7 2.4 0.3 0.1 1.2 4.0 8.5 9.7 0.83 1.01 0.82 0.89 0.87 0.95 0.88 0.5 1.0 1.5 Relative risk CTT Collaborators. Lancet. 2005;366:1267-78.

Secondary Prevention and Long Term Management Goals Recommendations In the absence of contraindications, start aspirin 75 to 162 mg/d and continue indefinitely. Antiplatelet agents/ anticoagulants If aspirin is contraindicated, consider clopidogrel 75 mg/day or warfarin. Manage warfarin to INR 2.5 to 3.5 in post-stemi patients when clinically indicated or for those not able to take aspirin or clopidogrel. American Heart Acociation / American College Cardiology

Medication adherence declines within 6 months post-mi 0 ACE inhibitors Statins β-blockers Aspirin 5 Decline in use (%) 10 15 13 12 8 20 20 Global Registry of Acute Coronary Events Eagle KA et al. Am J Med. 2004;117:73-81.

Συµπεράσµατα Η σωστή και έγκαιρη αντιµετώπιση της ΑΥ σε συνδυασµό µε τους άλλους παράγοντες κίνδυνου σε ασθενείς µε στεφανιαία νόσο έχει ευεργετικά αποτελέσµατα µε µείωση νοσηρότητας και θνησιµότητας. Ο συνδυασµός υγιεινοδιαιτιτικών παρεµβάσεων και φαρµακευτικής αγωγής είναι απαραίτητος για την επίτευξη των θεραπευτικών στόχων. Οι β-αναστολείς τα φάρµακα του άξονα και επί σταθερής στηθάγχης οι ανταγωνιστές Ca είναι οι βασικές επιλογές. Τιµές ΑΠ < 120/70mmHg φαίνεται να συνδέονται µε αύξηση της νοσηρότητας και θνησιµότητας. (καµπύλης J). Η ΘΕΡΑΠΕΥΤΙΚΗ ΠΡΟΣΕΓΓΙΣΗ ΠΡΕΠΕΙ ΝΑ ΕΞΑΤΟΜΙΚΕΥΕΤΑΙ

HOPE Study Population: Patients did not have heart failure CV events 11% had previous stroke Patients had normal or controlled blood pressure (53% normal) 80% had history of CAD 42% had history of PVD Patients were 55 years or older Diabetes 39% had diabetes + 1 or more CVD risk factors Size: 9541 patients followed for 4 to 6 years The HOPE Study Investigators. N Engl J Med. 2000;342:145-153.

HOPE: Primary Outcome Reductions in MI, Stroke, or Cardiovascular Death % of Patients Reaching Endpoints 0.20 0.15 0.10 0.05 22% Reduction in Events P=.0001* Placebo 15% Reduction in Events at 1 year Ramipril 0 0 500 1000 1500 Days of Follow-up Note: Trial halted early due to the highly significant risk reductions seen with Ramipril

HOPE, QUIET, EUROPA, PEACE: Primary outcomes % Patients % Patients 20 15 10 5 0 30 25 20 15 10 5 0 0 1 HOPE 22% Risk reduction RR 0.78 (0.70 0.86) P = 0.001 PEACE Placebo 2 3 4 Time (years) 4% Risk reduction HR 0.96 (0.88 1.06) P = 0.43 Placebo 1 2 3 4 5 Time (years) Ramipril 10 mg Trandolapril 4 mg 6 50 40 30 20 10 0 14 12 10 8 6 4 2 0 0 0 EUROPA 20% Risk reduction RR 0.80 (0.71 0.91) P = 0.0003 1 2 3 4 Time (years) 4% Risk increase RR 1.04 (0.89 1.22) P = 0.6 1 QUIET Placebo Perindopril 8 mg HOPE Study Investigators. N Engl J Med. 2000;342:145-53. EUROPA Investigators. Lancet. 2003;362:782-8. PEACE Trial Investigators. N Engl J Med. 2004;351:2058-68. Pitt B et al. Am J Cardiol. 2001;87:1058-63. 5 Quinapril 20 mg Placebo 2 3 Time (years)

Επίπτωση CV Θανάτων: Α- ΜΕΑ και ARBs vs placebo Μετανάλυση 11 µελετών: : 84300 άτοµα, µέσο Fu= 5 έτη p<0,01 American Journal of hypertension epub ahead of print feb. 2011