Jesper Hastrup Svendsen, Jens Cosedis Nielsen, Gunnar V.H. Jensen, Leif Spange Mortensen, Henning R. Andersen & the DANPACE Investigators

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1 CHADS 2 and CHA 2 DS 2 -VASc score predicts risk of stroke and death in patients with Sick Sinus Syndrome treated with single lead atrial or dual chamber pacing Jesper Hastrup Svendsen, Jens Cosedis Nielsen, Gunnar V.H. Jensen, Leif Spange Mortensen, Henning R. Andersen & the DANPACE Investigators Rigshospitalet and the Danish National Research Foundation Centre for Cardiac Arrhythmia; Aarhus University Hospital; Uni-C, Aarhus; Roskilde Hospital

2 Disclosures Jesper Hastrup Svendsen Member of Advisory Boards: Medtronic Research grants from: Medtronic, Biotronic, St. Jude, Boston Scientific Speaker Bureau: Medtronic, St. Jude, Boston Scientific

3 Background In patients with AF the risk of stroke can be assessed by the CHADS 2 and CHA 2 DS 2 -VASc scores The CHADS 2 score is based on presence of Congestive heart failure, Hypertension, Age 75 years, Diabetes, previous Stroke/transient ischaemic attack (double weight) and has a range from 0 to 6 The CHA 2 DS 2 -VASc score supplements the CHADS 2 score by 2 additional items: Vascular disease and (female) Sex category and has an alternative scoring of age with doubled weight to age 75 years ( Age years) and has a range from 0 to 9 Patients with Sick Sinus Syndrome may have AF as part of their arrhythmia disease and thromboembolic complications are common. It is unknown if CHADS 2 -score and CHA 2 DS 2 -VASc score have similar value in SSS patients as in AF patients

4 Aim We hypothesized that the risk of stroke and the risk of death could be assessed by applying the CHADS 2 and CHA 2 DS 2 -VASc score to patients with Sick Sinus Syndrome treated with pacemaker therapy

5 The DANPACE trial

6 The DANPACE trial Main results from the primary publication: No significant difference in mortality between single-lead atrial pacing vs. dual-chamber pacing Single-lead atrial pacing was associated with higher incidence of PAF and a 2-fold increased risk of pacemaker re-operation

7 Methods: The DANPACE Trial Randomised Clinical Trial Inclusion criteria: Symptomatic bradycardia and documented sinus-pause >2s or sinus bradycardia <40bpm >1 minute whilst awake, Exclusion criteria: AV block (1 st ; 2 nd or 3 rd degree) Bundle branch block (QRS > 0.12s) Persistent atrial fibrillation >12 months Atrial fibrillation with QRS < 40 bpm for 1 min or pauses >3s A positive test for carotid sinus hypersensitivity

8 Methods Data for CHA 2 DS 2 -VASc score were recorded on inclusion in study CRFs Strokes were recorded during follow-up Death was recorded from the Danish Civil Registration System Cause of Death and confirmation of stroke diagnosis was evaluated by an independent event committee

9 Results 1,415 patients were randomized in DANPACE Mean follow-up time until death, or end of study was 5.4 years (SD 2.6 years) which comprises 7,643 patient-years of follow-up. No patients were lost for follow-up During follow up: 92 stroke events

10 Baseline Characteristic AAIR DDDR p-value (N=707) (N=708) Female gender no. (%) 472 (66.8) 441 (62.3) 0.08 Age (years, mean±sd) 73.5 ± ± Brady-tachy syndrome no. (%) 303 (42.9) 318 (44.9) 0.44 Hypertension 241 (34.1) 239 (33.8) 0.90 Previous myocardial infarction no. (%) 94 (13.3) 90(12.7) 0.74 Diabetes no. (%) 68 (9.6) 72 (10.2) 0.73 Previous transient cerebral ischemia no. (%) 35 (5.0) 37 (5.2) 0.81 Previous stroke no. (%) 61 (8.6) 53 (7.5) 0.43 LVEF reduced (< 50%) no. (%) 59 (10.6) 54 (9.5) 0.55 Left ventricular end-diastolic diameter (mm, 47.7 ± ± mean±sd) Left atrial diameter (mm, mean±sd) 39.3 ± ± Symptoms before pacemaker no. (%) Syncopes 359 (50.8) 349 (49.3) 0.58 Dizzy spells 597 (84.4) 587 (82.9) 0.44 Heart failure 86 (12.2) 79 (11.2) 0.56 Medication at randomization no. (%) Anticoagulation 108 (15.3) 89 (12.6) 0.14 Sotalol 43 (6.1) 44 (6.2) 0.91 Beta-blocker other than sotalol 159 (22.5) 132 (18.7) 0.08 Calcium-channel blocker 137 (19.4) 142 (20.1) 0.75 Digoxin 73 (10.3) 62 (8.8) 0.32 Amiodarone 25 (3.5) 24 (3.4) 0.88 Class I Antiarrhythmics 14 (2.0) 20 (2.8) 0.30 Angiotensin-converting-enzyme inhibitors 160 (22.6) 170 (24.0) 0.53 Diuretics 304 (43.0) 263 (37.2) 0.03

11 End point stroke Univariate analysis, covariates known at baseline Variable N HR (95% CI) p Randomized to (AAIR vs. DDDR) 1, ( ) 0.56 Gender (F vs. M) 1, ( ) 0.82 Age (continuous) 1, ( ) <0.001 Age (>median (75) vs. <=median) 1, ( ) <0.001 PQ-interval (continuous) 1, ( ) 0.51 PQ-interval (>median (180) vs. <=median) 1, ( ) 0.62 Partial bundle-branch block 1, ( ) 0.52 Moist rales at lung auscultation 1, ( ) 0.44 Dyspnoea 1, ( ) 0.48 Oedema 1, ( ) 0.82 SBP (continuous) 1, ( ) 0.13 SBP (>median (140) vs. <=median) 1, ( ) 0.87 DBT (continuous) 1, ( ) 0.74 DBT (>median (76) vs. <=median) 1, ( ) 0.81 NYHA (>I vs. I) 1, ( ) 0.35 NYHA (>II vs <=II) 1, ( ) 0.21

12 End point stroke Univariate analysis, covariates known at baseline Variable N HR (95% CI) p Previous myocardial infarction 1, ( ) 0.50 Valvular disease or valve-operated 1, ( ) 0.85 Previous TCI 1, ( ) 0.04 Previous stroke 1, ( ) 0.01 Claudication 1, ( ) 0.51 Medical treatment for hypertension 1, ( ) 0.14 DM 1, ( ) 0.44 Previous CABG 1, ( ) 0.42 Previous PCI 1, ( ) 0.78 Anticoagulation treatment at baseline 1, ( ) 0.54 Aspirin treatment at baseline 1, ( ) 0.52 LVEF >=50% 1, ( ) 0.32 LVEF >=40% 1, ( ) 0.34 LVEDD (continuous) ( ) 0.24 LVEDD (>median (48) vs. <=median) ( ) 0.01 LAD (continuous) 1, ( ) 0.09 LAD (>median (39) vs. <=median) 1, ( ) 0.19 Bradycardia-tachycardia 1, ( ) 0.66 Ischemic heart disease 1, ( ) 0.13 Two related variables combined: Previous TCI or previous stroke 1, ( ) <0.001

13 End point stroke Univariate analysis, time-dependent covariates Variable N HR (95% CI) p AF at latest follow-up 1, ( ) 0.37 Ongoing oral anticoagulation 1, ( ) 0.02

14 Cumulative Stroke rate during FU stratified by CHADS 2 -score

15 Cumulative Stroke rate during FU stratified by CHA 2 DS 2 -VASc score

16 End point stroke CHADS 2 : Patients without AF at baseline N = 794 (1, ) All combined: Variable Weight HR (95% CI) p CHADS2 (continuous, 0-6) 1.51 ( ) <0.001 Five individual parts of CHADS2: C (NYHA at baseline > I or EF<40%) ( ) 0.54 H (med therapy for hypertension) ( ) 0.22 A (age>=75) ( ) D (diabetes) ( ) 0.20 S2 (prev TCI, stroke, arterial embolism) ( ) 0.003

17 End point stroke CHA 2 DS 2 -VASc score: Patients without AF at baseline N = 794 (1, ) All combined: Variable Weight HR (95% CI) p CHA2DS2-VASc (continuous, 0-9) 1.27 ( ) Eight individual parts of CHA2DS2-VASc C (NYHA at baseline > I or EF<40%) ( ) 0.64 H (med therapy for hypertension) ( ) 0.22 A2 (age>=75) ( ) D (diabetes) ( ) 0.20 S2 (previous TCI, stroke, arterial embolism) ( ) Peripheral Vascular Disease ( ) 0.88 A (65<=age<75) 1 See A2 above - Sc (Female) ( ) 0.70

18 End point death CHADS2: Patients without AF at baseline N= 794 (1, ) Variable Weight HR (95% CI) p All combined: CHADS2 (continuous, 0-6) ( ) <0.001 Five individual parts of CHADS2: C (NYHA at baseline > I) * ( ) <0.001 H (medical treatment for hypertension) ( ) 0.17 A (age>=75) ( ) <0.001 D (diabetes) ( ) <0.001 S2 (previous TCI or previous stroke) ( ) patients died during FU

19 End point death CHA2DS2-VASc: Patients without AF at baseline N= 794 (1, ) All combined: Variable Weight HR (95% CI) p CHA2DS2-VASc (continuous, 0-9) ( ) <0.001 Eight individual parts of CHA2DS2-VASc: C (NYHA at baseline > I or LVEF<40%) * ( ) <0.001 H (medical treatment for hypertension) ( ) 0.17 A2 (age>=75) ( ) ** <0.001** D (diabetes) ( ) <0.001 S2 (previous TCI, stroke or arterial embo) ( ) Vasc (peripheral vascular disease) ( ) A (65<=age<75) 1 See A2 above - Sc (Female) ( ) patients died during FU

20 Conclusion In patients with sick sinus syndrome treated with pacemaker the risk of stroke and death could be assessed by use of either the CHADS 2 or the CHA 2 DS 2 -VASc score. Age and previous stroke were the most important risk factors for stroke. Age, Heart Failure, Diabetes, Stroke (and Vascular disease) were the strongest risk factors for death Despite the scoring systems were originally constructed for patients with AF they can be applied also to patients with sick sinus syndrome. AF at baseline or during follow-up did not add predictive information to the occurrence of stroke or death in SSS patients

21 DANPACE investigators Steering Committee (numbers of patients included): Henning Rud Andersen (chairman) and Jens Cosedis Nielsen (co-chairman), Aarhus University Hospital, Skejby (337); Poul-Erik Bloch-Thomsen, Gentofte Hospital (180); Søren Højberg, Bispebjerg Hospital (121); Mogens Møller, Odense University Hospital (114); Thomas Vesterlund, Aalborg Hospital (111); Dorthe Dalsgaard, Herning Hospital (108); Tonny Nielsen, Esbjerg Hospital (77); Mogens Asklund, Kolding Hospital (72); Elsebeth Vibeke Friis, Haderslev Hospital (70); Per Dahl Christensen, Viborg Hospital (56); Erik Hertel Simonsen, Hillerød Hospital (47); Ulrik Hedegaard Eriksen, Vejle Hospital (39); Gunnar Vagn Hagemann Jensen, Roskilde Hospital (28); Jesper Hastrup Svendsen, Rigshospitalet (24). From United Kingdom: William D. Toff (UK coordinating investigator), J. Douglas Skehan, Kieran Brack, Glenfield Hospital, Leicester (8); Craig Barr, Andreas Tselios, Nicola Gordon, Russells Hall Hospital, Dudley (6); John Cleland, Andrew Clark, Sarah Hurren, Castle Hill Hospital, East Cottingham (3); David McEneaney, Andrew Moriarty, Anne Mackin, Craigavon Area Hospital, Craigavon (2); Arif Ahsan, Jane Burton, Ruth Oliver, Nottingham City Hospital (2), Barry Kneale, Lynda Huggins, Worthing Hospital (2). From Canada: Jeffrey S. Healey, Hamilton (8).

22 ACKNOWLEDGEMENT

23 Baseline Score distribution (N = 1,415) Score CHADS 2 CHA 2 DS 2 -VASc % 6.6 % 56 % 28 % % 11.5 % % 16.5 % % 21.8 % % 20.3 % % 14.4 % % 4.7 % % % %

24 End point stroke Multivariate analysis Model 1 variables known at baseline 1,415 N HR (95% CI) p Age (continuous) ( ) <0.001 Previous TCI or previous stroke 2.27 ( ) Model 2 baseline and time-dep covars 1,415 Age (continuous) ( ) <0.001 Previous TCI or previous stroke 2.38 ( ) <0.001 Ongoing oral anticoagulation therapy 0.46 ( ) 0.02

25 End point death Total cohort (N = 1,415) 402 patients died during FU Both CHADS 2 score (HR 1.46) and CHA 2 DS 2 -VASc score (HR 1.39) were associated with increased mortality (p<0.001) Multivariate model of the individual components of the CHADS 2 score: Congestive Heart Failure (HR 2.80) Age 75 years (HR 4.48) and Diabetes (HR 1.88) were independent factors associated with mortality. When analysing the individual components of the CHA 2 DS 2 -VASc score these showed independent association of Congestive Heart Failure (HR 3.08) Age 65 + age 75 years (HR 2.87) Diabetes (HR 1.81) and Vascular Disease (HR 1.29) with mortality.