Outcomes of thrombolysis treatment in patients with dementia and acute ischemic stroke A longitudinal cohort study from SveDem and Riksstroke, Swedish Dementia and Stroke Registries Eva Zupanic, MD

Objectives ~10% of patients with first stroke have a pre-existing dementia. Patients with dementia are postulated to have worse functional prognosis and increased mortality after stroke. Clinical trials often exclude >80 years, thus a large proportion of patients pre-existing dementia.

IV thrombolysis (IVT) in dementia Dementia is not a contraindication for thrombolysis in acute ischemic stroke (AIS). AHA/ASA scientific statement: dementia patients may benefit from IVT, however, decisions should be made individually. National Swedish Stroke Guidelines did not recommend IVT in patients >80 until 2014 (except in particular cases after careful consideration). There is an inconsistency in use of thrombolytic agent alteplase: it is not indicated in patients >80 according to the European Medicines Agency. it is recommended in selected patients in this age range according to European stroke guidelines.. There is a deep-rooted fear of increased risk of cerebral hemorrhage (e.g. amyloid angiopathy, microbleeds), however, increased incidence of symptomatic intracranial hemorrhage (sICH) has so far not been reported. Stroke physicians might adopt a more conservative approach when treating patients with dementia and AIS. taking into account clinically meaningful benefit, patients’ life expectancy and premorbid functional level

Methods Large nationwide cohort longitudinal study Merge of two Swedish national quality registries: SveDem, Swedish Dementia Registry Riksstroke, Swedish Stroke Registry

Patient selection process 58 154 registrations in SveDem 2007-2014 55 921 excluded patients: all strokes before dementia diagnosis 8963 matched controls from Riksstroke 2233 patients with stroke after dementia 3085 excluded patients: previous strokes stroke before 2010 hemorrhagic stroke 2010-2014 NON-DEMENTIA GROUP 6755 patients with ischemic stroke without dementia DEMENTIA GROUP 1356 patients with dementia and subsequent first ischemic stroke

Characteristics of patients with dementia DEMENTIA GROUP (n=1356) Age at dementia diagnosis, median (IQR) 82 (9) Age at stroke event, median (IQR) 83 (8) Time from dementia dg to stroke dg in days, median (IQR) 546 (705) MMSE at dementia dg, median (IQR) 21 (5) MMSE groups, n (%) >24 354 (27.9) 20-24 525 (41.3) <20 391 (30.8) DEMENTIA TYPE, n (%): AD and mixed dementia 628 (46.3) VD 311 (22.9) Other (LBD, FTD, PDD, unspecified, other) 417 (30.8)

Patients>80 years (n=5270) Demographics, medication and comorbidities prior to stroke in patients with AIS   Patients≤80 years (n=2841) Patients>80 years (n=5270) WITH DEMENTIA (n=436) WITHOUT DEMENTIA (n=2405) p-value (n=920) (n=4350) Age at first stroke, median (IQR) 77 (6) 76 (7) 0.190 86 (6) 0.871 Female sex 197 (45.2) 1124 (46.7) 0.550 567 (61.6) 2714 (62.4) 0.666 Nursing home placement 96 (22.3) 63 (2.6) <0.001 327 (35.8) 441 (10.2) Lives alone at home 119 (27.7) 896 (37.5) 327 (35.9) 2485 (57.4) ADL-independent 262 (62.7) 2237 (93.7) 412 (48.0) 3548 (83.4) No. of medication, median (IQR) 6 (5) 4 (5) 5 (5) Antiaggregants 181 (41.5) 732 (30.4) 460 (50.0) 1768 (40.6) Statins 107 (24.5) 543 (22.6) 0.369 139 (15.1) 797 (18.3) 0.021 Hypertension 222 (50.9) 1079 (44.9) 0.020 552 (60.0) 2402 (55.2) 0.008 Antihypertensives 272 (62.4) 1460 (60.7) 0.509 620 (67.4) 3080 (70.8) 0.040 Atrial fibrillation (AF) 108 (24.8) 449 (18.7) 0.003 345 (37.5) 1425 (32.8) 0.006 Warfarin in AF patients 24 (22.2) 101 (22.5) 0.951 29 (8.4) 241 (16.9) Diabetes 445 (18.5) 0.002 165 (17.9) 729 (16.8) 0.388 Femur fracture 41 (9.4) 90 (3.7) 133 (14.5) 465 (10.7) 0.001 History of hemorrhage 61 (14.0) 210 (8.7) 126 (13.7) 479 (11.0) Ischemic heart disease 105 (24.1) 230 (22.0) 0.346 267 (29.0) 1312 (30.2) 0.493 Heart failure 69 (15.8) 277 (11.5) 0.011 207 (22.5) 1001 (23.0) 0.737

Access to IVT

Patients > 80 years (n=5270) Access to IVT   Patients ≤ 80 years (n=2841) Patients > 80 years (n=5270) WITH DEMENTIA (n=436) WITHOUT DEMENTIA (n=2405) p-value (n=920) (n=4350) Thrombolysis 29 (6.7) 282 (11.8) 0.002 65 (7.1) 357 (8.2) 0.255

Model 3 (propensity scores) Odds of receiving intravenous thrombolysis (IVT) Comparison of patients with dementia and patients without dementia (reference category) Thrombolysis performed Model 1 Model 2 Model 3 (propensity scores) All patients (n=8074) 0.73 (0.58-0.91) 0.68 (0.54-0.86) 0.72 (0.57-0.91) ≤80 years (n=2827) 0.55 (0.37-0.81) 0.51 (0.34-0.76) 0.53 (0.35-0.79) >80 years (n=5247) 0.85 (0.65-1.12) 0.78 (0.59-1.03) 0.86 (0.65-1.14) Only ADL-independent (n=6445) 0.85 (0.64-1.12) 0.74 (0.55-1.00) 0.83 (0.62-1.09) ≤80 years (n=2494) 0.63 (0.40-1.00) 0.60 (0.38-0.97) 0.58 (0.36-0.94) >80 years (n=3951) 1.03 (0.73-1.46) 0.94 (0.66-1.34) 1.02 (0.72-1.46) Name Surname Odds ratios with 95% confidence intervals are reported.

Outcomes?

Outcomes after IVT Out of 8111 patients, 9% (n=733) received thrombolysis WITH DEMENTIA (n=94) WITHOUT DEMENTIA (n=639) p-value   sICH 7 (7.4) 46 (7.3) 0.960 Inhospital death 12 (12.8) 85 (13.3) 0.886 mRS at 3 months 0-2 4 (4.9) 189 (33.2) <0.001 3 20 (24.4) 155 (27.2) 0.592 4 12 (14.6) 66 (11.6) 0.425 5 28 (34.1) 53 (9.3) (dead) 6 18 (22.0) 107 (18.8) 0.494 New nursing home placement 23 (35.9) 64 (13.6)

Model 4 (propensity scores) Outcomes after IVT Outcomes of thrombolysis Model 1 Model 2 Model 3 Model 4 (propensity scores) mRS at 3 months 5.63 (3.41-9.30) 3.49 (2.02-6.01) 3.65 (2.06-6.45) 4.67 (2.81-7.75) Death at 3 months 1.06 (0.60-1.90) 0.83 (0.44-1.53) 0.71 (0.36-1.8) 1.03 (0.58-1.84) New nursing home placement 3.19 (1.78-5.72) 3.83 (1.98-7.42) 4.39 (2.07-9.31) 3.29 (1.79-6.07) Odds ratios with 95% confidence intervals are reported.

Conclusions Younger patients with dementia were less likely to receive IVT. The frequency of sICH, inhospital and 3-month mortality after IVT was similar in dementia and controls. Among patients who received IVT, dementia was associated with greater disability and new nursing home placement.

Limitations Observational study  selection bias. Patients who were not referred to hospitals were not included in the study, as Riksstroke does not cover out od hospital events. In selected patients who do receive IVT, this procedure is safe with similar rates of complications.

Aknowledgements Project supervisior: Sara Garcia-Ptacek Coauthors: Milica G. Kramberger, Mia von Euler, Bo Norrving, Bengt Winblad, Ingemar Kåreholt, Beatriz Contreras Escamez, Johan Fastbom, Dorota Religa, Kristina Johnell, Maria Eriksdotter Home institution Department of Neurology, Ljubljana, Slovenia Patients, families, health care providers, administrators, coordinators of SveDem and Riksstroke. PROJECT‘S SPONSORS: Johanniterorden Foundation for research on diseases of aging at Karolinska Institutet The Loo and Hans Osterman Medical Research Foundation Swedish Stroke Association Stohne’s Foundation Foundation to the memory of Sigurd and Elsa Goljes