Η θέση της αντισπερτασικής αγωγής στην πρόληψη της κολπικής μαρμαρσγής. Ανδρέας Πιηηαράς. Σεμινάριο ΟΕ ΕΚΕ Θεζζαλονίκη 2012

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1 Η θέση της αντισπερτασικής αγωγής στην πρόληψη της κολπικής μαρμαρσγής Ανδρέας Πιηηαράς Σεμινάριο ΟΕ ΕΚΕ Θεζζαλονίκη 2012

2 AF May Present with a Wide Range of Symptoms LIGHT- HEADEDNESS PALPITATIONS SYNCOPE DYSPNEA FATIGUE CHEST PAIN ACC/AHA/ESC 2006 guidelines Eur Heart J 2006;27(16):

3 EHRA score of AF-related symptoms EHRA class EHRA I EHRA II EHRA III EHRA IV No symptoms Explanation Mild symptoms ; normal activity not affected Severe symptoms normal daily activity affected Disabling symptoms ; normal daily activity discontinued EHRA = European Heart Rhythm Association

4 ACC/AHA/ESC 2006 guidelines Eur Heart J 2006;27(16):

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6 Presence of AF in Different Stages of CV Continuum Myocardial Infarction Neurohormonal activation CAD Subclinical Organ Damage AF Remodeling Ventricular dilation Risk factors Hypertension Diabetes Smoking Obesity LV H & Atrial Dilation Heart Failure

7 AF costs USA $26 billion ( 17.5 billion) each year Circulation Cardiovasc. Qual. Outcomes June 2011

8 Age-adjusted odds ratio Risk Factor for the Development of AF 38-year follow-up of the Framingham study Cigarettes Diabetes ECG LVH HTN BMI Alcohol Risk factors

9 Influence of SBP and DBP on the Risk of Incident AF in Women SBP mmhg DBP mmhg Conen D et al. Circulation 2009;119:2146

10 5 year age adjusted risk of chronic atrial fibrillation (%) AF in Hypertension Age-adjusted 5-year risk of chronic AF in hypertensive subjects in sinus rhythm Reported values are the three division points for quartiles Left atrial diameter (cm) LV mass (g/h 2.7 ) Hypertension 2003;41:218 23

11 Pulse Pressure and Risk of New-Onset AF Incidence of AF according to quartiles of PP 23.3% 5.6% 20 mm Hg increase in pulse pressure was associated with a 34% increase in the risk for developing AF Mitchell et al, JAMA 2007; 297: 709

12 Patients with hypertension, % Prevalence of Hypertension in AF Trials 90 AF populations

13 Over Time AF Causes Atrial Remodelling Electrical remodelling Shortening of atrial refractory periods Occurs rapidly (within several days) and contributes to the increased stability of AF Contractile remodelling Reduced atrial contractility Sets the stage for thrombus formation May lead to atrial dilation further altering electrophysiologic properties Occurs rapidly -80 mv Shortened refractory period Structural remodelling Histologic changes Left atrium and left atrial appendage enlargement Decrease in cardiac output Occurs after a period of weeks to months Van Gelder et al. Europace 2006;8:

14 Mechanisms of initiation AF Catecholamine excess, Ηemodynamic stress, Αtrial ischemia, Atrial inflammation, Μetabolic stress, and Νeurohumoral cascade activation are all purported to promote AF. AF appears to require both an initiating event and a permissive atrial substrate.

15 Risk Factors, Clinical Conditions and Markers for the Development of AF Risk factors Age Hypertension Diabetes mellitus Obesity Metabolic syndrome Alcohol consumption Smoking Clinical conditions Left ventricular hypertrophy Myocardial infarction Heart failure Obstructive sleep apnoea Renal dysfunction Valvular heart disease Thyroid disease Markers Increased arterial stiffness Left atrial enlargement Increased PR interval P wave dispression Birth weight hs-crp Inflammatory markers Neurohormones Genetic variants Pulse pressure

16 Male, 55 yrs, hypertensive, hyperlipidemia, obese, LVH, ETT(+), Th201(+), CA(-), NE:480 pg/ml, E:0.2 pg/ml, AVP:2.2 pg/ml, PRA:2.4ng/ml

17 2007 ESH/ESC Guidelines Preferred Drugs Condition Subclinical OD Clinical Event ISH (elderly) D / CA MS (or risk of incident DM) ACEI / ARB (+CA / low dose D) DM ACEI / ARB Pregnancy CA / MD / BB Blacks D / CA LVH Asympt. atherosclerosis MA Renal dysfunction Previous stroke Previous MI Angina pectoris CHF AF (recurrent) AF (permanent) ESRF/proteinuria PAD ACEI / CA / ARB CA / ACEI ACEI / ARB ACEI / ARB any BP lowering agent BB / ACEI / ARB BB / CA D / BB / ACEI / ARB / antialdo agents ARB / ACEI BB / nondhca ACEI / ARB / loop D CA

18 The Role of RAAS in the pathogenesis of AF Angiotensinogen Angiotensin I Renin ACE ACE I Angiotensin II ARB Cardiac fibrosis Electrical remodeling Cardiac Hypertrophy Hypertension Atrial Pressure and stretch Sympathetic overactivity Pro-inflammatory effects

19 How Did RAS Blockers Reduce the Risk of Stroke Beyond Blood Pressure? Cardiac remodeling/ enlargement Vascular remodeling Reduced ECG LVH Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy Endothelial dysfunction Improved endothelial function Prothrombotic state Inhibition of platelet aggregation Reduced proaggregatory factors

20 LV mass Reduction (%) Meta-analysis of randomized, controlled trials of LV hypertrophy regression in essential hypertension 0 Diuretics -blockers Caantagonist ACEinhibitors ARBs % -6% -11% -10% % randomized controlled trials; 4,113 patients Schmieder RE et al. Am J Med 2003; 115:41-6.

21 Angiotensin II in the Pathogenesis of AF Spironolactone Aldosterone? Bradykinin ACE Atrial stretch ACEI ARB MARK AT II Ca² overload ARB Fibroblast proliferation Collagen accumulation Hypertrophy Apoptosis Conduction block AERP shortening Electrical remodelling Delayed depolarisations Enhanced automaticity Atrial dilatation AF

22 Atrial fibrillation reduces myocardial perfusion reserve Myocardial perfusion Coronary resistance 5 Controls AF 200 Controls AF 4 p< p= p=0.029 p< Baseline Adenosin Baseline Adenosin

23 Repair of Coronary Arterioles After Treatment with Perindopril in Hypertensive Heart Disease % Morphological and Haemodynamic changes before and after treatment. 70 # 54% # 67% 0 LVMI * 12% CBF CVR CR PCA TIC # 33% * 22% -70 PCA: Periarteriolar collagen area TIC: Total Interstitial Collagen * 54% * p < 0,04 # p < Hypertension 2000

24 Percent Seconds ARB reduces AF by suppression the process of the structural remodelling Persistent atrial fibrillation in 20 dogs, fibrosis induced by rapid pacing of the right atrium over 5 weeks Interstitial fibrosis Duration of AF *** *** 0 0 ** p<0.01 vs controls ***p<0.001 vs controls Controls Candesartan

25 P-wave dispersion (PWD) has been shown to be a noninvasive electrocardiographic predictor for development of atrial fibrillation (AF). Thus, it may be possible to attenuate AF risk through improvement of PWD. In this study, we compared the effects of quinapril, and irbesartan, on PWD. Antihypertensive treatment with either irbesartan or quinapril is associated with significant reductions in Pmax and PWD. Guntekin Pacing & Electrophysiology Journal31 July 2009

26 Blood pressure control and risk of incident AFib Background AF is a common arrhythmia that affects over 2 million people in the US. We sought to determine whether the risk of incident AF among patients treated for HTN differs by the degree of BP control. Methods A population based, case-control study of 433 patients with verified incident AF and 899 controls was conducted to investigate the relationship between average achieved SBP and DBP and risk of AF. All patients were members of an integrated health care delivery system and were pharmacologically treated for HTN. Medical records were reviewed to confirm the diagnosis of new onset AF and to collect information on medical conditions, health behaviors, and measured blood pressures. Average achieved SBP and DBP were calculated from the three most recent outpatient blood pressure measurements.

27 Blood pressure control and risk of incident atrial fibrillation Results Compared with the reference level of mm Hg, for categories of average achieved SBP of <120, , , , and 170 mm Hg, the odds ratios (95% confidence interval) for incident AF were 1.99 (1.10, 3.62), 1.19 (0.78, 1.81), 1.40 (0.93, 2.09), 2.02 (1.30, 3.15), 2.27 (1.31, 3.93) and 1.84 (0.89, 3.80), respectively. Based on the population attributable fraction (PAF), we estimated that, among patients with treated hypertension, 17.2% (95% CI 4.3%, 28.3%) of incident AF was attributable to an average achieved SBP 140 mmhg. Conclusion Among patients treated for hypertension, uncontrolled elevated SBP and SBP <120 mm Hg were associated with an increased risk of incident AF. Am J Hypertens April 1.

28 Atrial Fibrillation (AF) - Primary Prevention In 2007 ESH / ESC guidelines recommendation to preferentially use ARBs / ACEIs Evidence mainly from post-hoc analyses Also plausible pathophysiological explanation, i.e. effectiveness of RAS blocker on LVH regression and relationship of LVH regression with AF No consistent support from recent trials - TRANSCEND - PROFESS - I-Preserve

29 Atrial Fibrillation In a meta-analysis on almost patients with systolic HF BBs were found to reduce (-27%) AF In patients with an AF history and systolic HF BBs are a specific indication

30 Protection against Recurrent AF In 2007 ESH/ESC guidelines preferential use of ARBs / ACEIs recommended, with stress on small number of patients / need for new studies No support from two new studies - CAPRAF - GISSI-AF (85% HTs) Support from recent meta-analysis by Schmieder et al (?)

31 Proportion of patients with first event (%) LIFE Study Primary Composite Endpoint 16 Intention-to-treat 14 Adjusted risk reduction 13 0%, P=0 021 Unadjusted risk reduction 14 6%, P= Atenolol 8 6 Losartan 4 2 Study Month Losartan (n) Atenolol (n) Dahlof B, et al. Lancet. 2002; 359:

32 Proportion of patients with first event (%) LIFE Study: Fatal and Non-Fatal Stroke Intention-to-treat Adjusted risk reduction 24 9%, P=0 001 Unadjusted risk reduction 25 8%, P= Atenolol Losartan Study Month

33 Proportion of patients with first event (%) Losartan Significantly Reduced the Risk of New-Onset AF by 33% HR: 0.67 [95% CI: ], p<0.001 Adj HR: 0.67 [95% CI: ], p<0.001 Losartan group Atenolol group Time (months) HR = hazard ratio; CI = confidence interval Adapted from Wachtell et al J Am Coll Cardiol 2005;45:

34 Percent LIFE Study: Patients with new onset AF had an increased risk of cardiovascular events % 10.7% 15.4% Patients with new onset AF (n=371) Patients with sinus rhythm (n=8480) % 4.2% 5% 6.7% 4% 0 (n=82) (n=911) (n=28) (n=352) (n=57) (n=428) (n=25) (n=342) Composite end-point Cardiovascular mortality Fatal or non Fatal stroke MI

35 Proportion of patients with first event (%) Reduction in Risk of Stroke in Patients with AF Fatal and nonfatal stroke Atenolol 15 Losartan Adjusted risk reduction 49%, p = Time (months)

36 CONCLUSIONS: In this high-risk hypertensive population, pre-existing and new-onset AF/AFL were associated with increased mortality. Excluding doxazosin, treatment assignment to either antihypertensive drugs or pravastatin versus usual care did not affect AF/AFL incidence. J Am Coll Cardiol Nov 24;54(22): (ALLHAT GROUP)

37 Occurrence of Atrial Fibrillation According to Antihypertension Treatment: IR per 1,000 Person-Years of Atrial Fibrillation Related Hospitalization, Adjusted Incidence Ratio, and 95% CI Matched Cohorts ACEI IR CCB IR ACEI Versus CCB Ration (95% CI)* Three years ( ) Five years ( ) Entire follow up ( ) *Poisson regression L Allier PL et al. J Am Coll Cardiol 2004

38 ACE-Inhibition in HTN Patients is Associated with a Reduction in the Occurrence of AF Kaplan-Meir curves for the time to first occurrence of AF L Allier PL et al. J Am Coll Cardiol 2004

39 Prevention of recurrence in patients with lone AF. The dose dependent effect of ARB s Madrid a. et al JRAAS 2004

40 Prospective randomised study comparing amiodarone vs amiodarone plus losartan vs amiodarone plus perindopril for the prevention of AF recurrence in pts with lone paroxysmal AF AF recurence-free Survival LA Diameter A+L A+P A A A+L A+P Yin Y et al. Eur Heart J 2006

41 Kaplan-Meier Curves for the Primary Outcome Massie B et al. N Engl J Med 2008; /NEJMoa

42 Valsartan for Prevention of Recurrent AF The GISSI-AF Investigators N Engl J Med 2009;360:1606

43 Prevention of Recurrent Lone AF by ACE-I Ramipril in Normotensive Patients Belluzzi F et al. J Am Coll Cardiol 2009;53:24

44 Atrial Fibrillation: ANTIPAF study OBJECTIVE: The Angiotensin II-Antagonist in Paroxysmal Atrial Fibrillation Trial (ANTIPAF Trial) is testing whether the ARB, OLMESARTAN (40 mg/day) reduces the incidence of episodes of AF in patients with paroxysmal AF during 12 months by more than 25% compared to standard medication Number Of Patients: 422 Patients

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47 Meta-analysis: Inhibition of RAAS prevents new-onset AF 95% CI RR Lower Limit Upper Limit % Weight Hypertension trials CAPPP STOP LIFE VALUE Pooled RR Post-myocardial infarction trials GISSI TRACE Pooled RR Heart failure trials Val-HeFT SOLVD CHARM Pooled RR Kishlay A. et al., Am. Hear J 2006; 152:

48 Risk for Incidence AF in Patients who Receive Antihypertensive Drugs UK-based General Practice Research Database hypertensive pts 4661 pts with new AF Hypertensive pts receiving long-term monotherapy with ACE-I, ARB s, or β-blockers were less likely to develop AF than those whose received only CCB s CCB s vs ACE-I OR 0.75 vs ARB s OR 0.71 vs β-blockers OR 0.78 Schaer B et al. Ann Intern Med 2010;152:78

49 Prevention of AF by RAS Inhibition A Meta-Analysis 23 randomized controlled trials 87,048 patients In primary prevention 6 trials in HTN 2 trials in MI 3 trials in HF In In secondary prevention 8 trials after cardioversion and 4 trials on medical prevention of recurrence Schneider M. J. Am. Coll. Cardiol : A27

50 Prevention of AF by RAS Inhibition A Meta-Analysis RAS inhibition reduced the odds ratio for AF by 33% (p < ) In primary prevention, RAS inhibition in pts with heart failure (+) HTN and LVH (+) Post-MI patients overall (-). In secondary prevention, RAS inhibition was often administered on top of antiarrhythmics (amiodarone), further reducing the odds for AF recurrence after cardioversion by 45% (p = 0.01) and in patients on medical therapy by 63% (p < ) Schneider M. J. Am. Coll. Cardiol : A27

51 Prevention of AF by RAS Inhibition A Meta-Analysis Conclusions: This analysis supports the concept of RAS inhibition as an emerging treatment for the primary and secondary prevention of AF but acknowledges the fact that some of the primary prevention trials were post-hoc analyses. Further areas of uncertainty include potential differences among specific RAS inhibitors and possible interactions or synergistic effects with antiarrhythmic drugs. Schneider M. J. Am. Coll. Cardiol : A27

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56 Primary outcome (%) The SENIORS trial subgroup analysis: atrial fibrillation Placebo % 36.7% 33.8% 29.1% Nebivolol Atrial fibrillation Non-atrial fibrillation

57 Agents with antialdosterone properties should be the preferred diuretics for reducing hypertension related atrial fibrillation. Jolobe OM. Eur J Intern Med Feb;21(1):55. Epub 2009 May 17.

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60 Hypertension and atrial fibrillation: diagnostic approach, prevention and treatment. Position paper of the Working Group 'Hypertension Arrhythmias and Thrombosis' of the European Society of Hypertension A. Manolis et al. J Hypertens Feb;30(2):

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