Prevention of Atrial Fibrillation and Heart Failure in the Hypertensive Patient

Transcription

1 Prevention of Atrial Fibrillation and Heart Failure in the Hypertensive Patient The Issue of Primary Prevention of A.Fib. (and Heart Failure) and not the Prevention of Recurrent A.Fib. after Electroconversion or Treatment of Patients With Established Heart Disease Prof. Sverre E. Kjeldsen, MD, PhD Department of Cardiology, Oslo University Hospital, Ullevaal, Oslo, Norway

2 Prevalence of HT in AF Trials Manolis AJ et al. ESH Position Paper. J Hypertens 2011; 30:

3 Kaplan-Meier Curves Showing Participants Free From AF Related to Quartiles of Systolic BP (N=2014) N=272 detected with new onset atrial fibrillation. 100% 90% Free from atrial fibrillation 80% 70% 60% Q1 (88-116) Q2 ( ) Q3 ( ) Q4 ( ) Observation time (Years) High normal SBP predicts incident atrial fibrillation Grundvold I, Kjeldsen SE et al. J Hypertension 2012; 59:

4 Diuretic and beta-blocker treatment mainly Prevention of Heart Failure and LVH in Hypertension Strongly Suggests Similar Prevention of Atrial Fibrillation 4

5 Possible Preventive Mechanisms of ARBs in Atrial Fibrillation Aksnes TA, Flaa A, Strand A, Kjeldsen SE. J Hypertens 2007;25:15-23

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7 Prevention of Atrial Fibrillation by RAAS-Inhibtion (JACC 2010) Study Treatment Control OR (random) Weight OR (random) or sub-category n/n n/n 95% CI % 95% CI Hypertension studies Hansson (CAPPP) 117/ / [0.67, 1.11] Hansson (STOP-2) 200/ / [0.95, 1.37] Wachtell (LIFE) 150/ / [0.52, 0.80] Salehian (HOPE) 86/ / [0.66, 1.20] Schmieder (VALUE) 252/ / [0.71, 1.00] Yusuf (TRANSCEND) 182/ / [0.82, 1.26] Subtotal (95% CI) [0.75, 1.05] Total events: 987 (Treatment), 1283 (Control) Test for heterogeneity: Chi² = 17.98, df = 5 (P = 0.003), I² = 72.2% Test for overall effect: Z = 1.39 (P = 0.17) Post-MI studies Pedersen (TRACE) 22/790 42/ [0.30, 0.86] Pizzetti (GISSI-3) 665/ / [0.82, 1.02] Subtotal (95% CI) [0.41, 1.27] Total events: 687 (Treatment), 763 (Control) Test for heterogeneity: Chi² = 4.59, df = 1 (P = 0.03), I² = 78.2% Test for overall effect: Z = 1.13 (P = 0.26) Heart Failure studies Vermes (SOLVD) 10/186 45/ [0.09, 0.37] Ducharme (CHARM) 177/ / [0.66, 1.00] Maggioni (Val-HeFT) 113/ / [0.49, 0.80] Subtotal (95% CI) [0.31, 0.87] Total events: 300 (Treatment), 434 (Control) Test for heterogeneity: Chi² = 16.40, df = 2 (P = ), I² = 87.8% Test for overall effect: Z = 2.48 (P = 0.01) Post-cardioversion studies Van den Berg 2/7 7/ [0.03, 1.77] Madrid 9/79 22/ [0.13, 0.73] Ueng 18/70 32/ [0.23, 0.94] Madrid 2 8/30 14/ [0.14, 1.23] Grecu 10/16 16/ [0.09, 1.85] Tveit 48/68 45/ [0.62, 2.63] Belluzzi 3/31 10/ [0.06, 0.92] GISSI-AF CAPPP adverse 371/722 event 375/720 reports [0.79, 1.20] Subtotal (95% CI) [0.34, 0.89] Total events: 469 (Treatment), 521 (Control) Test for heterogeneity: Chi² = 18.59, df = 7 (P = 0.010), I² = 62.3% Test for overall effect: Z = 2.44 (P = 0.01) STOP-2 adverse event reports LIFE secondary endpoint and annual ECGs first HT study Medical Therapy studies Yin 25/118 24/ [0.20, 0.78] Fogari 1 13/111 39/ [0.12, 0.49] Fogari 2 42/246 46/ [0.21, 0.56] Fogari 3 28/148 48/ [0.28, 0.83] Subtotal HOPE (95% CI) not a hypertension study [0.27, 0.49] Total events: 108 (Treatment), 157 (Control) Test for heterogeneity: Chi² = 2.45, df = 3 (P = 0.49), I² = 0% Test for overall effect: Z = 6.73 (P < ) VALUE secondary endpoint and annual ECGs second HT study TRANSCEND not a hypertension study Total (95% CI) [0.57, 0.78] Total events: 2551 (Treatment), 3158 (Control) Test for heterogeneity: Chi² = , df = 22 (P < ), I² = 78.2% Test for overall effect: Z = 5.24 (P < ) Favours treatment Favours control

8 Primary Prevention of Atrial Fibrillation in the Treatment of Hypertension Need hypertensive population with high risk of incidental atrial fibrillation Need pre-specified protocol Need AF detection from systematic taking of ECGs and central ECG readings Need double-blinded head-to-head randomized comparison Two trials fullfil these criteria LIFE and VALUE

9 LIFE Baseline Characteristics-1 n=9193 Age, years 66.9 (7.0) Female, n 4963 (54%) Body mass index, kg/m (4.8) Blood pressure, mmhg 174.4/97.8 (14.3/8.9) Heart rate, bpm 73.8 (11.1) Cornell product, mm msec (1049.5) Sokolow-Lyon, mm 30.0 (10.5) Framingham risk score (0.096) Smokers, n 1499 (16%) Values are mean (SD) or n (%) when indicated.

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11 LIFE: Patient Recruitment ECG-Criterion (n=9192) Sokolow-Lyon 22 % Both 10 % Cornell Product 68 % Dahlöf B, Kjeldsen SE et al. Hypertension 1998;32:

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13 LIFE Atrial Fibrillation: Losartan vs. Atenolol Reduces New Onset AF/Flutter Proportion of patients with first event (%) RR: 0.70 [95% CI: ], p< Time (months) Losartan Atenolol Wachtell, Kjeldsen SE et al.: J Am Coll Cardiol 2005;45:

14 LIFE Atrial Fibrillation: Stroke in Patients with and without AF Strokes in Losartan-Treated Patients Strokes in Atenolol-Treated Patients Hazard Ratio (95% CI) Patients with Pre-existing AF (n=342) ( ) p=0.039 Patients with New-onset AF (n=371) (n=150 with new AF) (n=221 with new AF) ( ) p=0.01 Patients with No AF (n=8480) ( ) p=0.04 Wachtell K, Kjeldsen SE et al.: J Am Coll Cardiol 2005;45: and

15 Circ Arrhythm Electrophysiol 2013;6:

16 Regression of Cornell Product LVH with Losartan vs Atenolol Treatment 0 6 Months 1-Year 2-Year 3-Year 4-Year 5-Year Last Cornell Product (mm msec) p< p< p< p< p< p< p< Dahlöf B, Devereux RB, Kjeldsen SE et al. Lancet Losartan Atenolol

17 New Onset of AF According to the Presence or Absence of ECG LVH by Time-Varying Cornell Voltage-Duration Product 0.09 <= 2440 (n=2931, 3950, 3832) >2440 (n=5604, 4156, 3641) 0.08 New-Onset AF Rate Adapted from Okin et al.: JAMA 2006;296: Follow-Up (Months) * n= number of patients in each group at baseline, 2 and 4 years of LIFE 23

18 Incidence of Atrial Fibrillation in Relation to Changing Heart Rate Over Time in Hypertensive Patients. The LIFE Study. Okin PM, Wachtell K, Kjeldsen SE et al. Circ Arrhythmia Electrophysiol 2008; 1:

19 HF: Framingham Criteria Major Criteria Clinical Findings Diagnostic Findings Minor Criteria* Clinical Findings Diagnostic Findings Minimum requirement 2 major findings, or 1 major finding plus 2 minor findings In both cases at least 1 clinical finding, and 1 diagnostic finding * Minor findings are accepted only if they cannot be attributed to another disease process

20 MAJOR CRITERIA LIFE: Criteria for Heart Failure CLINICAL Paroxysmal nocturnal dyspnea or orthopnea Jugular venous distention Pulmonary rales Ventricular S 3 gallop Hepatojugular reflux Diuresis 10 lbs/5kg in response to diuretic; clinical improvement in congestive symptoms DIAGNOSTIC Acute pulmonary edema on chest x-ray PCWP 20 mmhg LVEF 35 CI < 2,0 Evidence of severe valvular heart disease Pulmonary edema or visceral congestion on autopsy MINOR CRITERIA* FINDINGS Night cough Dyspnea on ordinary exertion Bilateral ankle edema Hepatomegaly FINDINGS Pleural effusion or pulmonary vascular engorgement or redistribution on x-ray PCWP mmhg LVEF CI 2,0 2,4 Evidence of moderate valvular heart disease * Minor criteria will be accepted only if they can not be attributed to another disease process

21 147:

22 * 147:

23 Electrocardiographic Strain Pattern and Prediction of New-Onset Congestive Heart Failure in Hypertensive Patients: The LIFE Study Okin P, Kjeldsen SE et al. Circ 2006; 113:

24 Okin P, Kjeldsen SE et al. Circ 2009; 119:

25 Pulse Pressure and Incident Atrial Fibrillation in LIFE Larstorp AC, Kjeldsen SE et al. Hypertension 2012; 60:

26 Hypertension 2015; 66:

27 Summary New Atrial Fibrillation in LIFE 1) LIFE included n=9193 patients with ECG-LVH 2) In LIFE, losartan reduced new AF with 30% compared to atenolol 3) In LIFE, regression of ECG-LVH was strongly related to less new AF. Lower heart rate was also related to less new AF suggesting HR lowering therapy (ivabradin study) 4) In LIFE, prevention of new AF was related to less stroke 5) In LIFE, new AF predicted sudden cardiac death and incident heart failure 6) In LIFE, baseline BP predicts new AF despite treatment and lower achieved BP (in-treatment BP) gives less AF 27

28 VALUE: Patient Characteristics Associated Risk Factors Associated Diseases Increased serum creatinine 3.6 LVH with Strain 6.1 LVH Proteinuria PAD 13.9 Active smoker 24.0 Stroke 19.8 Diabetes 31.6 High Cholesterol 33.3 CAD Patients (%) LVH = left ventricular hypertrophy. PAD = peripheral artery disease; CAD = coronary artery disease. Kjeldsen SE, Julius S et al. Blood Press. 2001;10: Patients (%)

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31 Reduced First Occurence of Incident Atrial Fibrillation With ARB: the VALUE Trial Schmieder RE, Kjeldsen SE, Julius SE et al. J Hypertens 2008; 26:

32 Reduced First Occurence of Persistent Atrial Fibrillation With ARB: the VALUE Trial Schmieder RE, Kjeldsen SE, Julius SE et al. J Hypertens 2008; 26:

33 Importance of Incident Atrial Fibrillation for Primary Cardiac Endpoint: the VALUE Trial Schmieder RE, Kjeldsen SE, Julius SE et al. J Hypertens 2008; 26:

34 VALUE: Baseline Characteristics Aksnes TA, Kjeldsen SE, et al. Hypertension 2007; 50: Never DM (8697) New-onset DM (1298) Baseline DM (5250) Age (years) 67.5 ± ± ± 7.9 Gender (% male) 57.8 % 63.1% 55.9%* Caucasian 91.8 % 86.8 % 85.9 % BMI (kg/m²) 27.7 ± ± ± 5.4 SBP (mmhg) ± ± ± 18.9 DBP (mmhg) 87.8 ± ± ± 10.8 HR (bpm) 71.1 ± ± ± 10.8 Glucose (mmol/l) 5.38 ± ± ± 3.26 Potassium (mmol/l) 4.36 ± ± ± 0.46 Pair-wise comparison with never DM; *0.01 p-value<0.05, p-value<0.01, p-value <0.0001

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37 Patients Developing Atrial Fibrillation Have More Heart Failure Heart failure (%) 20 No Atrial Fibrillation New Atrial Fibrillation Aksnes TA, Kjeldsen SE et al. Am J Cardiol 2008; 101: Never DM New-onset DM Baseline DM

38 Obesity Diabetes LVH Diastolic dysfunction BP Atrial Fibrillation HEART FAILURE Myocardial ischemia Systolic dysfunction

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40 2013 ESH/ESC Hypertension Guidelines

41 ACEI ARB BB* MRA* CCB Diuretic HYPERTENSION ATRIAL FIBRILLATION