ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmhg)

Η Σημασία της διαχείρησης του συνολικού καρδιαγγειακού κινδύνου στην θεραπευτική αντιμετώπιση του υπερτασικού ασθενούς. Τα ωφέλη της θεραπείας με ΑRΒs Ι.Ε.ΚΑΝΟΝΙΔΗΣ

ESH/ESC Guidelines: Definitions and Classification of BP Levels (mmhg) Category Systolic Diastolic Optimal Normal High normal Grade 1 hypertension (mild) Grade 2 hypertension (moderate) Grade 3 hypertension (severe) Isolated systolic hypertension < 120 120-129 130-139 140-159 160-179 >180 > 140 < 80 80-84 85-89 90-99 100-109 >110 < 90 When a patient s SBP and DBP fall into different categories, the higher category should apply. Isolated systolic hypertension can also be graded (grades 1, 2, 3) according to SBP values in the ranges indicated, provided diastolic values are < 90

3

1. ESH/ESC Guidelines Committee. J Hypertens 2003;21:1011 1053 Treatment Guidelines (ESH/ESC ) Goals of therapy Uncomplicated hypertension: <140/90mmHg Hypertension + diabetes: <130/80mmHg Hypertension + renal insufficiency: <130/80mmHg Hypertension + renal insufficiency when proteinuria >1g/day: ESH: European Society of Hypertension ESC: European Society of Cardiology + <125/75mmHg Reduce total cardiovascular risk

ESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis Blood Pressure (mmhg) 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 Moderate High 1-2 risk factors Low Low Moderate Moderate Very high 3 or more risk factors or TOD or diabetes Moderate High High High Very high High Very high Very high Very high Very high ACC: associated clinical conditions; TOD: target organ damage; SBP: systolic blood pressure; DBP: diastolic blood pressure 0 5

Treatment guidelines (ESH/ESC ) BP (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 No BP intervention No BP intervention Lifestyle changes for several months, then drug treatment if preferred by the patient and resources available Lifestyle changes for several months, then drug treatment Immediate drug treatment and lifestyle changes 1 2 risk factors Lifestyle changes Lifestyle changes Lifestyle changes for several months, then drug treatment Lifestyle changes for several months, then drug treatment Immediate drug treatment and lifestyle changes 3 or more risk factors or TOD or diabetes Lifestyle changes Drug treatment and lifestyle changes Drug treatment and lifestyle changes Drug treatment and lifestyle changes Immediate drug treatment and lifestyle changes ACC Drug treatment and lifestyle changes Immediate drug treatment and lifestyle changes Immediate drug treatment and lifestyle changes Immediate drug treatment and lifestyle changes Immediate drug treatment and lifestyle changes ACC, associated clinical conditions; TOD, target organ damage Average risk Low Moderate High Very high ESH ESC Guidelines Committee. J Hypertens 2003; 21: 1011 1053

Στόχευση της Αντιυπερτασικής Αγωγής Μείωση της τιμής της αρτηριακής πίεσης στις προβλεπόμενες φυσιολογικές τιμές (τιμές στόχους). Προστασία των οργάνων στόχων (καρδιά, νεφροί, εγκέφαλος) από την εμφάνιση παθολογικών καταστάσεων που σχετίζονται με την υπέρταση. Αντιμετώπιση ήδη υπαρχόντων νοσημάτων που είτε συνδέονται είτε όχι παθοφυσιολογικά με την υπέρταση.

ΘΕΡΑΠΕΥΤΙΚΗ ΕΠΙΛΟΓΗ Όλες οι κατηγορίες των αντιυπερτασικών φαρμάκων εμφανίζουν κατά μέσο όρο την ίδια περίπου αποτελεσματικότητα στη μείωση της αρτηριακής υπέρτασης Διαφέρουν όμως σημαντικά μεταξύ τους ως προς τις επί μέρους φαρμακολογικές ιδιότητες και δράσεις, δηλαδή ως προς την ικανότητά τους να προστατεύουν ή να θεραπεύουν παθολογικές καταστάσεις που προσβάλλουν τα όργανα στόχους. Επομένως, η συνολική κλινική αποτελεσματικότητα των αντιυπερτασικών φαρμάκων διαφέρει σημαντικά ανά κατηγορία, κάθε μία από τις οποίες έχει ένδειξη σε ειδικό υποπληθυσμό υπερτασικών ασθενών.

Ο Καθορισμός του υπο θεραπείαν πληθυσμού γίναται με βάση την εκτίμηση συνολικού καρδιαγγειακού κινδύνου 1.Η βαρύτητα της υπέρτασης 2.Η συνύπαρξη άλλων επιβαρυντικών παραγόντων ( δυσλιπιδιμία, διαβήτης κάπνισμα, παχυσαρκία κ.λπ.) 3.Η παρουσία νοσημάτων, που αφορούν όργανα στόχους,

Αναστολείς ΜΕΑ Υποστροφή της υπερτροφίας Μείωση της θνητότητας στην καρδιακή ανεπάρκεια Μείωση της θνητότητας στην οξεία φάση του εμφράγματος Βελτίωση της καρδιακής δυσλειτουργίας μετά από έμφραγμα Αντιαθηρωματική δράση και δευτερογενής πρόληψη του εμφράγματος Πρόληψη καρδιαγγειακών εγκεφαλικών επεισοδίων Βελτίωση της διαβητικής και μη διαβητικής νεφροπάθειας Πρόληψη της κλινικής εκδήλωσης του σακχαρώδη διαβήτη

Αποκλειστές ΑΤ1 Υποδοχέων (ΑRBs) Υποστροφή της υπερτροφίας Μείωση της θνητότητας στην καρδιακή ανεπάρκεια Βελτίωση της καρδιακής δυσλειτουργίας μετά από έμφραγμα Πρόληψη καρδιαγγειακών εγκεφαλικών επεισοδίων Βελτίωση της διαβητικής και μη διαβητικής νεφροπάθειας Πρόληψη της κλινικής εκδήλωσης του σακχαρώδη διαβήτη Αντιαρρυθμική Δράση.

Υποστροφή της υπερτροφίας της αριστερής κοιλίας

LVH as a Risk Factor for CV morbidity and mortality LV hypertrophy ECG-LV hypertrophy has been shown to be an independent predictor of CV events LVH is an important risk factor for CV morbidity and mortality (Framingham Study) LVH associated with a 3 to 15-fold increase of CV events Greatest risk ratios for heart failure and stroke Regression of LVH: gave a 4-fold decrease in the risk of developing a CV event Levy D. J Cardiovasc Pharmacol. 1991;17(suppl 2):1-6. Muiesan ML et al. J Hypertens.1995;13:1091-1095. Verdecchia P et al. Circulation.1998;97:48-54. Kannel WB. J Hypertens.1991;9(suppl 2):53-59.

Prevalence of LVH in Hypertension Stage of Hypertension Stage 3 sbp >180 dbp >110 Stage 2 sbp 160-179 dbp 100-110 Stage 1 sbp 140-159 dbp 90-99 3% 12% 8% 30% 90% 10 20 30 80 90 100 Hypertensive Patients (%) 1 Tedesco MA et al. Clin Cardiol. 2001;24:603-607. 2 Scmieder RE, Messerli FH. J Hum Hyperten. 2000;14:597-604. 3 Kahan T. J Hypertens. 1998;16(suppl 7):23-29.

Evidence for a Linear Relation Between LV Mass and Cardiovascular Risk General Population (Framingham Heart Study) Essential Hypertension Age-adjusted 4-year event risk 18 16 14 12 10 8 6 4 2 0 Men Women < 90 90-114 115-139 > 139 Quartile of LV mass (g/height[m]) Event-free survival 1.0 0.9 0.8 0.7 0.6 0.0 1st quintile 2nd quintile 3rd quintile 4th quintile 5th quintile 0 2 4 6 8 Follow-up, years Levy D, Garrison RJ, Savage DD, et al. N Engl J Med 1990; 322: 1561-1566 Schillaci G, Verdecchia P, Perticone F, et al. Hypertension 2000; 35: 580-586

LV hypertrophy ARBs have demonstrated a significantly greater regression in LV hypertrophy than the ß-blocker atenolol The LIFE study also demonstrated that the greater regression of LV hypertrophy with an ARB (losartan) was accompanied by a reduced incidence of CV events

Drug choice and LVH reduction 17

Meta-analysis of Randomized, Controlled Trials of LV Hypertrophy Regression in Essential Hypertension LV Mass reduction, % 0-2 -4-6 -8-10 -12-14 -16-8% - 6% - 11% 80 randomized controlled trials; 4113 patients Diuretics β-blockers Ca-antagonists ACE-Inhibitors - 10% AII-antagonists - 13% Schmieder RE et al. Am J Med 2003; 115:41-6

SILVHIA: Irbesartan Provides Greater regression of Left Ventricular Hypertrophy (LVH) than Atenolol LVMI (%) 0-5 -10-15 Left ventricular mass index (LVMI) reduction 12-4.8% Week 24 48-7.9% -15.8% 12-0.6% Irb. vs Ate. Irbesartan Atenolol Week 24-4.2% 48-9.1% p=0.024 p<0.001 p<0.001-20 Irbesartan 150 mg (n= 56) Atenolol 50 mg (n= 58) Malmqvist K et al. J Hypertens. 2001; 19: 1167 1176.

Βελτιώνουν την επιβίωση καθώς και τη λειτουργική κατάσταση των ασθενών με καρδιακή ανεπάρκεια.

Effect of Hypertension on The Risk of HF During 30 Year Follow-up (Framingham) 20 16 Age - adjusted annual rate of heart failure per 1000 Men 12 Age-adjusted annual rate of heart failure per 1000 Women 12 8 8 4 4 0 Years 35-64 65-94 0 35-64 Years 65-94 Normal Mild hypertension (140-159/90-94 mmhg) Definite hypertension (>160/95 mmhg) Kannel WB, Belanger AJ. Am Heart J 1991

Ang II and Survival Rates in HF Level of Angiotensin II 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Normal Ang II Ang II > 16 pg.ml -1 P =.0002 2 4 6 8 10 12 Months Kaplan-Meier analysis of cumulative rates of survival in patients with heart failure stratified into two subgroups on the basis of increased plasma anglotensin II levels (>16 pg.ml -1 or 16 pg.ml -1 ). Roig E et al. Eur Heart J 2000;21:53-57.

Val-HeFT: Combined Morbidity End Point 1.000 Subgroup without ACE-I background therapy 0.914 0.829 Valsartan (n = 185) Event-Free Probability 0.743 0.657 0.571 44% risk reduction* P <0.0002 0.486 0.400 0 3 6 9 12 15 18 21 24 27 Time Since Randomization (mo) *For morbidity; 34% RR for mortality. Adapted from Maggioni AP et al. J Am Coll Cardiol. 2002;40:1414-1421. Placebo (n = 181)

CHARM-Alternative Primary outcome, CV death or CHF hospitalisation % 50 40 Placebo 406 (40%) 334 (33%) 30 Candesartan 20 10 HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001 0 Number at risk 0 1 2 3 3.5 years Candesartan 1013 929 831 434 122 Placebo 1015 887 798 427 126 Granger et al, Lancet 2003

Προφυλάσσουν από την εκδήλωση εμφράγματος μυοκαρδίου δευτερογενώς και βελτιώνουν τις λειτουργικές του επιπτώσεις (δυσλειτουργία αριστερής κοιλίας).

Εχουν νεφροπροστατευτική δράση επιβραδύνοντας τη λειτουργική έκπτωση και την εξέλιξη προς το τελικό στάδιο της νεφρικής ανεπάρκειας.

Προφυλάσσουν από την κλινική εμφάνιση σακχαρώδους διαβήτου σε προδιαθεσικά άτομα Βελτιώνουν τη μικρολευκωματινουρία.

Αντιαρρυθμική Δράση Κοιλιακές Αρρυθμίες Κολπική Μαρμαρυγή

Κοιλιακές Αρρυθμίες Η Καρδιακή Υπερτροφία αποτελεί κατάλληλο ανατομικό και λειτουργικό (ηλεκτροφυσιολογικό) υπόστρωμα για την ανάπτυξη κοιλιακών αρρυθμιών

Arrhythmogenic Effects of Angiotensin II 1. Increases wall stress & stretch 2. Facilitates local NA release locally; inhibits central vagal activity 3. Fibrosis 4. Decreased conduction velocity, disorganized cell-to-cell coupling, increased dispersion of action potential durations 5. Stimulates myocyte growth 6. Structural vascular changes; ischemia Kahan T & Bergfeldt L.Heart. 2005;91:250-56.

LVH leads to QT Dispersion QT dispersion Variability in QT interval recorded by 12-lead ECG Reflects heterogeneity of the ventricular recovery times in the ventricular myocardium leading to the creation of reentry circuits Long QT interval Increased QT intervals reflect prolonged action potential in the myocardium Prolongation of QT interval and increased QT dispersion associated with risk of life-threatening ventricular arrhythmias (e.g. torsades de pointes) and sudden death Chapman N et al. Am J Hypertens. 2001;14:455-462. Oikarinen L et al. J Hypertens. 2001;19:1883-1891.

Significance of Changes in QT Indexes Myocardial fibrosis and LVH together increase QT dispersion Myocardial fibrosis and ischemia affect ventricular repolarization and may generate arrhythmic vulnerability in hypertensive patients Oikarinen L et al. J Hypertens. 2001;19:1883-1891.

QT Dispersion in Hypertensive Patients QT dispersion increased by LVH and hypertension QT dispersion provides an early indication of end-organ damage ARBs Action Reduction in QT dispersion with irbesartan is achieved beyond BP lowering Irbesartan,by reducing QT dispersion, independently of changes in LVMI, BP or heart rate, may reduce sudden death in hypertensive patients Clarkson PBM et al. QJM. 1995;88:327-332. Lim PO et al. J Hypertens. 1999;33:713-718 Kahan T et al. AJH VOL 15, N 4, Part 2, P-188.

SILVHIA: Irbesartan Decreases QT Dispersion in Hypertensive Patients with Left Ventricular Hypertrophy 60 Irb.: p<0.001 Ate.: p=0.246 Irb. vs Ate.: p=0.006 60 Irb.: p<0.001 Ate.: p=0.820 Irb. vs Ate.: p=0.033 ms ms 40 40 0 12 48 0 12 48 Time (weeks) 0 12 48 0 12 48 Time (weeks) Irbesartan (n = 44) Atenolol (n = 48) Malmqvist K et al. Am J Cardiol 2002; 90: 1107 1112.

Κολπική Μαρμαρυγή

The Atrial Fibrillation Epidemic in the US 7.0 5.61 Adults with AFib (millions) 6.0 5.0 4.0 3.0 2.0 1.0 0.0 2.08 2.26 2.44 2.66 2.94 3.33 Year 3.80 % 4.34 80 60 40 20 0 4.78 37 5.16 5.42 Proportion Aged 80 Yr 36 53 2000 2025 2050 Year 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Go A et al. JAMA, 2001; 2370-2375

Prevalence of Atrial Fibrillation in the US US population x 1000 Population with AF x 1000 30,000 Population with atrial fibrillation 500 20,000 US population 400 300 10,000 200 100 0 <5 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 >95 0 Age (y) Feinberg WM et al. Intern Med 1995; 155: 469 473.

Development of AF in Hypertensive Patients Cumulative Incidence of Atrial Fibrillation (%) 25 20 15 10 5 0 Echocardiographic LV Hypertrophy LV mass > 49.2 g/height 27 (men) LV mass > 46.7 g/height 27 (woman) 0 2 4 6 8 1012 1 Follow-up (years) 4 LV Hypertrophy Norman LV mass 16 No Yes 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Echocardiographic LV Hypertrophy Rate of Atrial Fibrillation (per 100 person-year) your age adjusted risk of chronic atrial fibriliation (%) 2.5 2.0 1.5 1.0 0.5 0.0 3.19 3.54 3.95 Left Atrial Diameter (cm) 56.5 47.1 39.4 LV mass (g/h 27 ) Verdecchia P et al. Hypertension 2003; 41: 218-223

Mortality and AF % Mortality Over 3 Years 80 70 60 50 40 30 20 10 38.6 30.2* With AF (n=13,558) 54.5 47.4* 47.5 34.0 25.4 Without AF (n=13,195) 71.3 65.1* 62.4 51.1* 36.1* 0 65-74 75-84 85-89 * Significantly different from patients with AF at P<.05. Wolf PA et al. Arch Intern Med. 1998;158:229-234.

Late Outcomes SOLVD Trials 1.0 1.0 Event-free survival 0.8 0.6 0.4 0.2 Death Due to Pump Failure Sinus rhythm (n=6,098) 0.8 0.6 0.4 0.2 Death or Hospitalization for CHF Atrial fibrillation (n=419) P<0.001 P<0.001 0.0 0.0 0 365 770 1,095 1,460 0 365 770 1,095 1,460 Follow-up (days) Dries DL et al. JACC 1998; 32:695-703

Candesartan and Atrial Fibrosis 25 20 15 Sham Placebo Candesartan 10 5 0 RAA RAFW LAA LAFW RA pacing at 400 bpm for five weeks RA free wall (masson trichrome stain) Sham Placebo ARB Kumagai K. et al. JACC 2003; 41:2197-204

ACE I and ARB prevent electrical remodelling in pacing model of AF Nakashima H, et al. Circulation 2000; 101:2612-2617.

Κλινικά Δεδομένα

Valsartan Reduces AF in CHF The Val-HeFT Study Variable Valsartan Placebo p Sample 2205 2190 - NYHA II-III 98.2% 97.7% - Hx of AF 12% 12.2% - 0.15 0.1 Probability of AF Placebo Valsartan New AF 113 174 5.12% 7.95% 0.0002. 0.05 0 0 3 6 9 12 15 18 21 24 27 Age > 70 yrs Male gender BNP > 97 pg/ml 1.51 (1.17 1.95) 1.53 (1.07 2.18) 2.28 (1.75 2.98) Months Valsartan 0.63 (0.49 0.81) 0 0.5 1 1.5 2 2.5 3 No AF AF Atrial fibrillation (AF) Congestive Heart Failure (HF) Maggioni AP et al. Am Heart J 2005;149:548-557

Losartan in Hypertensive Patients with AF The LIFE Study 1995-1997 9,193 HTN, 8,804 no AF Losartan vs Atenolol Follow-up ~ 4.9 years 8 6 4 Incidence of AF (%) HR 0.67 [0.55-0.83], p < 0.001 Developed AF per 1000 person-years 6.8 (Losartan) vs 10.1 (Atenolol) 2 0 Losartan Atenolol 0 6 12 18 24 30 36 42 48 54 60 66 Months Wachtell K et al. JACC 2005;45:712-719

Madrid et al.: Addition of irbesartan to amiodarone in reducing recurrence of Atrial Fibrillation (AF) Patients free of recurrences (%) n=186 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Inclusion criteria: Patients with persistent AF amiodarone 400 mg + irbesartan 150/300 mg (n= 79) amiodarone 400 mg (n= 75) 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Primary endpoint: the length of time to first recurrence of AF Follow-up (days) Log Rank p=0.007 Madrid AH et al. Circulation 2002; 106: 331 336.

Madrid 2004: Primary endpoint Fibrillation (AF) in Lone AF Kaplan-Meier curves of the percentage of patients remaining free from recurrence of atrial fibrillation. Time to first ECG-documented recurrence of atrial fibrillation since randomization. Days of follow-up (days), timed after cardioversion. Patients free of recurrences (%) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Key: Amiodarone N=30 Amiodarone + irbesartan 150mg N=30 Amiodarone + irbesartan 300mg N=30 0 200 400 77% 65% 52% P = 0.001 Follow-up (days) p=0.01 amiodarone versus amiodarone + irbesartan 300mg Madrid AH et al. JRAAS 2004; 5:114-120

Madrid et al.: Addition of Irbesartan to Amiodarone in Reducing Recurrence of Atrial Fibrillation Hemodynamic effect: Decreased atrial stretch Lowering end-diastolic left ventricular pressure Prevention of electrical remodeling: Direct action on ionic currents at the atrial level Modifying the sympathetic tone Preventing structural remodeling Reduction of atrial fibrosis Reduction of atrial dilation and apoptosis Madrid AH et al. Circulation 2002; 106: 331 336.

Prevention of AF with ACEI and ARBs Meta-Analysis 11 studies 47,457 patients CHF: 4, 10,314 pts MI: 2, 10,441 pts HTN: 3, 26,403 pts AF: 2, 299 pts Congestive Heart Failure (CHF) 0.56 (0.37 0.85) Hypertension (HTN) 0.88 (0.66 1.19) Myocardial Infarction (MI) 0.94 (0.42 1.31) Atrial Fibrillation (AF) 0.52 (0.35 0.79) ACEI 0.71 (0.54 0.93) ARB 0.71 (0.60 0.84) Total 0.71 (0.59 0.85) 0 0.2 0.4 0.6 0.8 1 1.2 1.4 ACEI/ARB better Control better Healey JS et al. JACC 2005; 45:1832-1839.

Συμπερασματικά Οι ARBs αποτελούν σημαντική κατηγορία αντιϋπερτασικών φαρμάκων με πολλαπλές δράσεις οι οποίες τους καθιστούν φάρμακα πρώτης εκλογής στη θεραπεία της υπέρτασης στην κλινική πράξη.

Κατευθυντήριες οδηγίες 2007

ΕΥΧΑΡΙΣΤΩ

ESH/ESC Guidelines: Stratification of Risk to Quantify Prognosis Blood Pressure (mmhg) 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 Moderate High 1-2 risk factors Low Low Moderate Moderate Very high 3 or more risk factors or TOD or diabetes Moderate High High High Very high High Very high Very high Very high Very high ACC: associated clinical conditions; TOD: target organ damage; SBP: systolic blood pressure; DBP: diastolic blood pressure 0

Inflammation and AF: Cardiovascular Health Study 5806 subjects 65 years 897 developed AF during 7.8 years of follow-up Median CRP 2.42 mg/l (1.29-5.02) in AF, 1.89 mg/l (0.95-3.37) in non-af 100 95 90 85 80 75 Atrial fibrillation free survival, % CRP > 1.92 mg/l Hazard ratio 1.33 (1.18-1.49) unadjusted, p < 0.001 Hazard ration 1.24 (1.08-1.58) adjusted, p < 0.001 CRP < 1.92 mg/l 1 2 3 4 5 6 7 8 Years Aviles RJ et al. Circulation 2003;108:3006-10

TRACE - AF Post MI AMI + EF (<35%) 10 Placebo ACE I Prospective randomized % Atrial fibrillation 8 6 4 2 0 P < 0.05 1577 pts in SR at start 64 AF on follow-up Trandolapril reduced risk of developing AF 0 1 2 3 4 Pedersen OD et al. Circulation 1999; 100:376-380

Ueng KC et al. EHJ 2003; 24:2090-2098 Prospective Study of Enalapril in AF 2001-2003, n = 145 Scheduled DCC Randomization Amio alone Amio + Enalapril 20 mg Pre-treatment 4 weeks Follow-up 270 d F r e e f r o m r e c u r r e n c e, % 100 80 60 20 0 0 1 6 12 18 100 80 60 20 LA 4 cm 4 W: HR 0.31 [0.11-0.87], p = 0.0026 LA > 4 cm: HR 0.48 [0.25-0.91], p=0.026 0 0 1 6 12 18 Months LA > 4 cm Amio+Enap Amio Amio+Enap Amio