NT-proBNP For The Detection of Silent Paroxysmal Atrial Fibrillation In Patients With Recent Cerebral Ischemia results from the Find-AF trial

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NT-proBNP For The Detection of Silent Paroxysmal Atrial Fibrillation In Patients With Recent Cerebral Ischemia results from the Find-AF trial R. Wachter a, R. C. Lahno a, B. Haase a, M.

1 NT-proBNP For The Detection of Silent Paroxysmal Atrial Fibrillation In Patients With Recent Cerebral Ischemia results from the Find-AF trial R. Wachter a, R. C. Lahno a, B. Haase a, M. Weber-Krüger a, J. Seegers, F. Edelmann, G. Gelbrich c, D. Vollmann, K. Gröschel b, R. Stahrenberg a Department of Cardiology and Pneumology a and Department of Neurology b, University of Goettingen and C Center for Clinical Trials, Leipzig, Germany. European Society of Cardiology Meeting, Paris August 29 th, 2011

2 Disclosure Grant support: German Heart Failure Network (public), Roche Diagnostics (significant, ) Consulting: Novartis Speaker: Berlin Chemie, Boehringer Ingelheim, Medtronic, Novartis, Servier Travel grants: Medtronic, Novartis, Sanofi, Servier Trials: CVRx, Johnson&Johnson, Medtronic, Novartis, Pfizer, Relypsa, Sanofi, Servier

3 Background Natriuretic peptides are elevated in patients with atrial fibrillation and NT-proBNP is a predictor of incident atrial fibrillation Patton, K. K. et al. Circulation 2009;120:

4 Natriuretic peptides fall after cardioversion to sinus rhythm Δ NT-proBNP n = h 2h 4h 8h 24h time

5 NT-proBNP (pg/ml) Pilot study in patients with arterial hypertension p = No AFib/Aflu Paroxysmal Afib/Aflu n=153 n=10

6 ISRCTN Study flow Find-AF Suspected stroke/tia no CT/MRT ICB? yes Exclusion criteria Afib on admission ECG? yes no Inclusion FIND-AF (A) FIND-AF (B) Standard stroke therapy + Holter-ECG (7 days) Standard stroke therapy Follow up d90 and 1a (NIH-SS, MRS, Stroke)

7 Hypotheses for Find-AF Patients with cerebral ischemia have a high prevalence of paroxysmal atrial fibrillation NT-proBNP is elevated in patients with paroxysmal atrial fibrillation In patients with paroxysmal atrial fibrillation, the ratio early(0h)/late(24hrs) NT-proBNP is higher than in patients with permanent sinus rhythm

8 Definition of endpoints 1. Patients with NT-proBNP > Median are more likely to have atrial fibrillation than patients with NT-proBNP < Median NTproBNP(0h) 2. Patients with NTproBNP(24h) > Median are more likely to NTproBNP(0h) have atrial fibrillation than patients with < Median NTproBNP(24h) Estimation of sample size: We assumed that 5 % of the patients with NT-proBNP < Median and 20 % of the patients above the Median have paroxysmal atrial fibrillation. To detect a difference between the two groups with a power of 90 % and α = 0,05, we needed 101 patients per group (202 total)

9 Methods This single center study was performed from March 2009 to February 2010 at the Emergency Department and the Stroke unit of the Göttingen University Medical Center All patients with suspected cerebral ischemia (TIA or stroke) were offered to participate (after exclusion of intracerebral bleeding) 7-day Holter ECG was started quickly after hospital admission (mean lag time 5.5 hrs) Blood was drawn at admission (0 h) and after 6 and 24 hours

10 Study flow Find-AF (ISRCTN ) 281 patients included 44 atrial fibrillation at presentation (Find-AF B) 237 Holter monitorings performed (Find-AF A) 1 consent withdrawn 224 AFib-naive 5 with previously known paroxysmal AFib 7 with final diagnosis other than cerebral ischemia 4 not evaluable 1 not evaluable 28 atrial fibrillation 192 no atrial fibrillation 1 atrial fibrillation 3 no atrial fibrillation 0 atrial fibrillation 7 no atrial fibrillation Stahrenberg et al., Stroke 2010, 41:

11 Baseline characteristics (1) No atrial fibrillation in Holter (n = 192) Atrial fibrillation in Holter (n = 28) Age 67 ± ± 12 * Female gender 80 (41.7 %) 12 (42.9 %) BMI 27.5 ± ± 4.7 Heart rate 72 ± ± 16 Systolic blood pressure 143 ± ± 26 * Diastolic blood pressure 79 ± ± 14 History of stroke 29 (15.1 %) 5 (17.9 %) History of TIA 18 (9.4 %) 2 (7.1 %) Heart failure 10 (5.2 %) 2 (7.1 %) Hypertension 136 (70.8 %) 23 (82.1 %) Diabetes 43 (22.4 %) 7 (25.0 %) Smoker 51 (26.6 %) 4 (14.3 %) Hyperlipidemia 60 (31.3 %) 14 (50.0 %) Coronary artery disease 22 (11.5 %) 11 (39.3 %) * p < 0.05

12 Baseline characteristics (2) No atrial fibrillation in Holter (n = 192) Atrial fibrillation in Holter (n = 28) NIH-SS score 3 ± 4 7 ± 4 * Modified rankin scale 2 ± 1 3 ± 1 * Stroke classification TIA 68 (35.4 %) 2 (7.1 %) * Minor stroke 52 (27.1 %) 6 (21.4 %) * Major stroke 72 (37.5 %) 20 (71.4 %) * TOAST classification Large artery atherosclerosis 39 (20.3 %) 7 (25.0 %) * Cardioembolic 28 (14.6 %) 11 (39.3 %) * Lacunar / small vessels 27 (14.1 %) 4 (14.3 %) * Rare / other causes 5 (2.6 %) 1 (3.6 %) * Undetermined cause 93 (48.4 %) 5 (17.9 %) * * p < 0.05

13 Detection rate [%] Detection of atrial fibrillation Monitoring interval [d] Stahrenberg et al., Stroke 2010, 41:

14 NT-proBNP (pg/ml) Time course of NT-proBNP p = p = p = Sinus rhythm Paroxysmal AF

15 Percent paroxysmal atrial fibrillation Percent paroxysmal atrial fibrillation Endpoints p = p = n.s. (0.200) < Median > Median 0 < Median > Median NT-proBNP (Median 239) NTproBNP(0h) NTproBNP(24h) (Median 0,78)

16 ROC analysis 475 pg/ml 373 pg/ml All study participants (n=220) Sensitivity 64 % Specificity 62 % PPV 20 % NPV 92 % Study participants 60 years (n=60) Sensitivity 100 % Specificity 83 % PPV 24 % NPV 100 %

17 Conclusion NTproBNP is significantly elevated in patients with cerebral ischemia and paroxysmal atrial fibrillation The ratio of early (0h) to late (24 hrs) NT-proBNP plasma levels is not different between patients with and without atrial fibrillation NT-proBNP may be a promising biomarker for risk stratification especially in younger patients with ischemic cerebral event and should be further investigated in prospective clinical trials

The Find-AF Study Group Ephys PD Dr. Dirk Vollmann Dr. Jochen Seegers Cardio Neuro Dr. Rolf Wachter Dr. Raoul Stahrenberg PD Dr. Klaus Gröschel Dr. Frank Edelmann Prof. Pawel Kermer Cand. med.

18 The Find-AF Study Group Ephys PD Dr. Dirk Vollmann Dr. Jochen Seegers Cardio Neuro Dr. Rolf Wachter Dr. Raoul Stahrenberg PD Dr. Klaus Gröschel Dr. Frank Edelmann Prof. Pawel Kermer Cand. med. Beatrice Haase Cand. med. Rosine Lahno Cand. med. Mark Weber-Krüger Biometrics Cand. med. Cord-Friedrich Niehaus Dr. Dr. Götz Gelbrich Prof. Dr. Gerd Hasenfuß Dr. Meinhard Mende Waldeck,

19 Paroxysmal atrial fibrillation [%] Age and paroxysmal atrial fibrillation 45,0 40,0 35,0 30,0 25,0 20,0 15,0 10,0 5,0 0,0 60 (n=60) (n=20) (n=32) (n=34) (n=32) (n=24) > 85 (n=18) Age [years]

No indication or contraindication for oral antioagulation? yes Patient age between 60-85y?

20 Perspective Patient with clinical symptoms of stroke yes no No ICB on CT / MRI no No inclusion yes no Symptom duration > 24h yes no MRI with lesion on DWI yes Sinus rhythm on admission ECG? No indication or contraindication for oral antioagulation? yes Patient age between 60-85y? Informed consent? yes no no R Prolonged Holter-monitoring (7days and 3x3days) or ILR 1:1 randomisation, 2550 patients usual stroke-unit care

Natriuretic Peptides for the Detection of Paroxysmal Atrial Fibrillation in Patients with Cerebral Ischemia the Find-AF Study

Natriuretic Peptides for the Detection of Paroxysmal Atrial Fibrillation in Patients with Cerebral Ischemia the Find-AF Study Rolf Wachter 1 *, Rosine Lahno 1, Beatrice Haase 1, Mark Weber-Krüger 1, Joachim