Serious hemorrhage and secondary prevention after

stroke and TIA

Joachim Ögren

Department of public health and clinical medicine Umeå university 2018

Responsible publisher under Swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7601-982-5 ISSN: 0346-6612 New Series No: 1997 Cover illustration: Helene Gedda Electronic version available at: http://umu.diva-portal.org/ Printed by: UmU Print Service, Umeå university Umeå, Sweden 2018

”Någon älskare av piller är jag inte men jag förstår att vetenskapen vet vad som är bra för mig och ändrar där det behöver ändras.”

Birgit, deltagare i NAILED-studien

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Table of Contents

Abstract iii

Original papers v

Abbreviations and acronyms vi

Sammanfattning på svenska viii

Introduction 1 Etiology and Pathophysiology 1 Epidemiology 2 Risk factors 2 Prognosis 3 Secondary prevention 3

Antithrombotic treatment 3 Antihypertensive treatment 5 Lipid-lowering treatment 5 Secondary prevention in clinical practice 6

Summary of introduction 7

Aims 8

Material and methods 9 Datasources 9

Riksstroke 10 National Patient Register 10 The Swedish cause of death register 11 Statistics Sweden and National civil registry 11

NAILED 11 Follow-up and intervention 12

Outcomes and statistical methods 13 Paper I 13 Paper II 14 Papers III and IV 16

Ethical considerations 17

Results 18 Baseline characteristics of study participants 18 Serious hemorrhage (paper I and II) 19

Incidence rate and cumulative incidence of ICrH 20 Incidence rate and cumulative incidence of serious hemorrhage 22 Mortality 24 Predictors of serious hemorrhage and ICrH 25

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NAILED stroke trial (paper III and IV) 26 Mean BP, LDL-C and proportions reaching treatment target 28 Time trends 28

Discussion 32 Methodological considerations 32

Information bias 32 Missing data 34 Confounding 34 Selection bias, coverage and generalizability 35

General discussion 36 Serious hemorrhages 36 NAILED 40

Conclusions 43

Future perspectives 44

Acknowledgements 46

References 48

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Abstract Background The number of stroke survivors is growing worldwide, and these patients have an increased risk of new vascular events and death. This risk decreases with secondary treatment medications recommended in guidelines. However, the characteristics of unselected stroke patients differ from patients included in randomized controlled trials (RCTs). Thus, the efficacy of these treatments based on RCT results may not be directly transferable to the patients treated in clinical practice. A treatment may be associated with a higher risk of serious side-effects or less benefit than expected: 1) Antithrombotic treatment increases the risk of a serious hemorrhage, a risk that is not well studied in an unselected population with older age and more comorbidities; 2) Treatment of modifiable risk factors after a stroke can be improved. Many patients do not reach treatment targets, which indicates a need for strategies to improve secondary prevention and increase treatment benefit. It is therefore essential to evaluate recommended treatments through studies in a real-world setting.

Aims The aims of this thesis were to assess incidence, temporal trends, effect on mortality, and factors associated with an increased risk of a serious hemorrhage after ischemic stroke (IS) or transient ischemic attack (TIA); and if a nurse-led, telephone-based intervention including medical titration could improve modifiable risk factors in patients after stroke or TIA.

Methods In paper I, all patients registered with an IS in the national stroke register Riksstroke during 1998–2009 were studied. The register was combined with the In-Patient Register and a diagnosis of intracranial haemorrhage (ICrH) within 1 year after IS was identified. In paper II, any diagnosis of serious hemorrhage was identified during follow-up up to 2015 in all patients with an IS or TIA diagnosis, 2010–2013, at Östersund hospital. The incidences of ICrH (papers I and II) and all serious hemorrhages (paper II) were calculated. Kaplan–Meier analysis was used to assess any temporal trend in paper I and if a serious hemorrhage affected survival in study II. Cox regression analysis was used in both studies I and II to assess any factor associated with hemorrhage.

In the randomized controlled NAILED stroke trial, all patients with acute stroke or TIA treated at Östersund hospital during 2010–2013 were screened for participation. Patients whose condition permitted a telephone-based follow-up were randomized to either a control group with follow-up according to usual care or to an intervention group with a nurse-led, telephone-based follow-up including titration of medication. Blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) were assessed at 1, 12, 24, and 36 months. We assessed the effect of the intervention on mean levels of BP and LDL-C and on the proportion

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of patients reaching treatment targets at 12 months (Study III) and at 36 months (Study IV). Study III also assessed for interactions between group allocation and measurement levels at baseline with BP and LDL-C at the 12-month follow-up. Study IV also explored temporal trends.

Results

The risk of an ICrH was 1.97% per year at risk, within the first year after IS, and 0.85% excluding the first 30 days. Between 1998 and 2009, the risk of an ICrH increased during the first 30 days after an IS but decreased during days 31–365. The risk of a serious hemorrhage was 2.48% per year at risk in paper II. It was more common in elderly. The incidence rate was higher in patients discharged with AP compared with RCTs. A hemorrhage increased the risk of death in patients with good functional status but did not affect the already high mortality in patients with impaired functional status. Male sex and previous ICrH were associated with an increased risk of ICrH during the first year after IS, thrombolytic treatment, atrial fibrillation and warfarin were associated with an increased risk in the acute phase. A previous diagnosis of hypertension was associated with an increased risk of all serious hemorrhages.

The NAILED trial intervention group had a significantly lower mean systolic BP (SBP), diastolic BP (DBP), and LDL-C at 12 and 36 months. The mean SBP at 36 months was 128.1 mmHg (95% confidence interval (CI): 125.8–130.5) in the intervention group, 6.1 mmHg (95% CI: 3.6–8.6; p<0.001) lower than the control group. The interaction analysis at 12 months showed that the effect of the intervention was confined to patients whose values were above the respective targets at baseline and therefore had their medication adjusted. At 36 months, a significantly higher proportion of patients in the intervention group reached treatment targets for SBP, DBP, and LDL-C. The mean differences and differences in proportions reaching treatment target for BP increased during the 36 months of follow-up.

Conclusion

A serious hemorrhage after an IS or TIA is fairly common. It is more common in elderly and patients with impaired functional status. The incidence is higher in patients discharged with AP compared with RCTs. A serious hemorrhage could affect survival in patients with good functional status. The nurse-led, telephone-based intervention including medical titration used in the NAILED stroke trial improved risk factor levels after stroke and TIA, and more patients reached treatment targets. The effect increased over time.

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Original papers

This thesis is based on the following papers, referred to in the text by their Roman numerals (I-IV). The papers are appended in the end of this thesis.

I: Ögren J, Irewall AL, Bergström L, Mooe T. Intracranial hemorrhage after ischemic stroke: Incidence, time trends, and predictors in a swedish nationwide cohort of 196 765 patients. Circulation. Cardiovascular quality and outcomes. 2015;8:413-420

II: Ögren J, Irewall AL, Soderstrom L, Mooe T. Serious hemorrhages after ischemic stroke or tia - incidence, mortality, and predictors. PLoS One. 2018;13:e0195324

III: Irewall AL, Ögren J, Bergstrom L, Laurell K, Soderstrom L, Mooe T. Nurse-led, telephone-based, secondary preventive follow-up after stroke or transient ischemic attack improves blood pressure and ldl cholesterol: Results from the first 12 months of the randomized, controlled nailed stroke risk factor trial. PLoS One. 2015;10:e0139997

IV: Ögren J, Irewall AL, Soderstrom L, Mooe T. Long-term, telephone-based follow-up after stroke and tia improves risk factors: 36-month results from the randomized controlled nailed stroke risk factor trial. BMC Neurol. 2018;18:153

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Abbreviations and acronyms AC Anticoagulant AP Antiplatelet AF Atrial fibrillation ASA Acetylsalicylic acid AT Antithrombotic (i.e., anticoagulants and

antiplatelets) BMI Body mass index BP Blood pressure CDR Cause of Death Register CI Confidence interval DAPT Dual antiplatelet therapy DBP Diastolic blood pressure GI Gastrointestinal GP General practitioner HR Hazard ratio ICD International Classification of Diseases ICH Intracerebral hemorrhage ICrH Intracranial hemorrhage IPR In-patient register IS Ischemic stroke K-M Kaplan–Meier LDL-C Low-density lipoprotein cholesterol mRS Modified Rankin scale NAILED Nurse based Age independent Intervention to

Limit Evolution of Disease after stroke or TIA NOAC Non-vitamin K antagonist oral anticoagulant NPR National Patient Register OR Odds ratio PIN Personal identification number PPV Positive predictive value

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PRoFESS Prevention Regimen for Effectively Avoiding Second Strokes

PROGRESS Preventing Strokes by Lowering Blood Pressure in Patients with Cerebral Ischemia

RCT Randomized controlled trial RRR Relative risk reduction SAH Subarachnoid hemorrhage SBP Systolic blood pressure SD Standard deviation SPARCL Stroke Prevention by Aggressive Reduction in

Cholesterol Levels SPS3 Secondary Prevention of Small Subcortical Strokes TIA Transient ischemic attack WHO World Health Organization

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Sammanfattning på svenska Vid en stroke skadas hjärnan på grund av syre- och näringsbrist orsakat av påverkad cirkulation på grund av en propp eller blödning. En blodpropp är orsaken i ca 85% av fallen, så kallad ischemisk stroke. Vid symtom som vid stroke men där symtomen försvinner inom ett dygn talar man om en TIA. En TIA innebär en ökad risk för att få en stroke.

Varje år drabbas drygt 25 000 svenskar av en stroke och ca 10 000 av en TIA. Var fjärde person med en stroke har haft det tidigare. Det är färre som dör i samband med en stroke och andelen i varje åldersgrupp som får en stroke i Sverige minskar förutom hos de yngsta. Efter en stroke eller TIA är risken stor för död, bestående handikapp eller en ny stroke.

Flera så kallade riskfaktorer ökar risken för att få en stroke. Vissa, så som hög ålder och manligt kön går inte att påverka. Andra, som till exempel förhöjt blodtryck, höga blodfetter, rökning, inaktivitet och förmaksflimmer är faktorer som kan påverkas och livsstilsförändringar och/eller läkemedel kan minska risken. Stroke och TIA patienter skrivs därför ut med läkemedel i syfte att minska risken för ny stroke eller TIA och denna avhandling fokuserar på denna behandling, så kallad sekundär prevention. Jag har studerat två olika delar av denna behandling:

1) Efter en ischemisk stroke eller TIA får patienter med förmaksflimmer antikoagulantia för att minska risken för en ny propp medan övriga patienter får trombocythämmare i samma syfte. Båda dessa ökar risken för blödning men i de läkemedelsstudier som behandlingsriktlinjer baseras på är nyttan i form av minskad risk för nya blodproppar klart större än risken för blödning. Deltagarna i dessa studier är ofta yngre och friskare jämfört med patienter på en strokeavdelning och därför undersöktes risken för allvarlig blödning, inklusive intrakraniell blödning, som har högst dödlighet, i en oselekterad sjukhuspopulation.

Risken för intrakraniell blödning undersöktes med hjälp av data från det rikstäckande strokeregistret Riksstroke samt data från det Nationella patientdataregistret som omfattar alla vårdtillfällen på sjukhus. Nästan 200 000 patienter med ischemisk stroke 1998–2009 studerades. Risken för all allvarlig blödning undersöktes hos samtliga patienter som vårdats för ischemisk stroke eller TIA på Östersunds sjukhus 2010–2013.

Risken för en intrakraniell blödning var ca 2% under det första året. Risken var 0.9% efter den akuta fasen, vilket var ca 15 gånger mer än i en referenspopulation.

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Mellan 1998 – 2009 minskade risken för intrakraniell blödning efter den akuta fasen något, trots att fler blev utskrivna med blodförtunnande läkemedel. Risken för all allvarlig blödning inklusive intrakraniell blödning var cirka 2,5% per år. För patienter utskrivna med antikoagulantia är den risken i nivå med den som visats i läkemedelsstudier medan den var mer än dubbelt så hög för all allvarlig blödning för de som skrivits ut med trombocythämmare jämfört med läkemedelsstudier. Vi såg en högre andel med blödning bland de som var över 75 år liksom bland de som hade betydande kvarstående symtom efter sin stroke. Dessa grupper är sällan representerade i stora läkemedelsstudier vilket skulle kunna förklara skillnaden mellan min studie och läkemedelsstudier. Dödligheten efter en stroke skiljer sig beroende på vilken funktionsnivå patienten har vid utskrivning. Av de som skrevs ut med en bra funktionsnivå avled 18% av patienterna under de närmaste fem åren och en allvarlig blödning ökade risken för död. Av patienter med betydande hjälpbehov efter sin stroke avled 59% inom fem år och en allvarlig blödning påverkade inte prognosen.

Sammanfattningsvis påvisades en ökad blödningsrisk efter en stroke eller TIA. Risken var högre hos de som blev utskrivna med trombocythämmare jämfört med läkemedelsstudier. Risken var högre hos äldre och patienter med betydande handikapp. Samtidigt är risken för nya proppar högre hos dessa patienter varför vi inte kan avgöra om balansen mellan risk och nytta är påverkad. Cirka 40 % av strokepopulationen är över 80 år och med den osäkerhet som finns kring behandling av dessa patienter finns ett behov av fler studier för att undersöka risk jämfört med nytta vid trombocythämmande behandling.

2) Efter en stroke eller TIA strävar man efter att ha kontroll på blodtryck och blodfetter för att minska risken för nya händelser. Nästan alla patienter får läkemedelsbehandling men många når inte uppsatta målvärden. På Östersunds sjukhus startades därför en studie 2010 för att undersöka om en systematisk, sköterskeledd, telefonbaserad uppföljning med möjlighet till justering av läkemedelsbehandling, kunde förbättra behandlingen av blodtryck och blodfetter efter stroke och TIA ytterligare.

Samtliga patienter vårdade för stroke eller TIA på Östersunds sjukhus 2010–2013 som bedömdes kunna klara av ett telefonsamtal tillfrågades om att delta i studien. Hälften av de som accepterade att delta lottades till en kontrollgrupp med uppföljning enligt gällande rutin i primärvården, medan den andra hälften lottades till interventionsgruppen, med uppföljning enligt studiemetoden. Blodtryck och blodfetter undersöktes vid 1, 12, 24 och 36 månader efter utskrivning och deltagarna kontaktades efter varje uppföljning av en studiesköterska för återkoppling, samtal om läkemedelsanvändning, levnadsvanor mm. Om blodtrycket eller blodfetterna inte nådde målvärde så

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kontaktades en studieläkare för korrigering av läkemedel och proceduren upprepades efter 4 veckor tills målen var uppnådda.

Den slutgiltiga uppföljningen efter 36 månader visade att interventionsgruppen hade ett systoliskt medelblodtryck på 128,1 mm Hg jämfört med 134,2 mm Hg i kontrollgruppen. Det diastoliska medeltrycket samt blodfettvärdet LDL-C var också tydligt lägre i interventionsgruppen samt andelen som nådde målvärde för blodtryck och LDL-C högre. Skillnaden mellan de två grupperna ökade under hela studietiden för blodtryck medan den skillnad som uppnåddes vid 1 år för LDL-C kvarstod oförändrad. Nästan alla var dock i behov av justering av läkemedelsbehandling vid något tillfälle under studietiden och många som hade ett bra värde vid en uppföljning kunde ha hamnat över målvärde vid nästa uppföljning. Sammanfattningsvis visar dessa studier att den sköterske- och telefonbaserade interventionen med möjlighet till läkemedelsjustering leder till lägre blodtryck och blodfetter samt att fler når aktuella målvärden. Det finns ett behov av kontinuerlig långsiktig uppföljning även om man vid ett tillfälle nått målvärde.

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Introduction Stroke is a serious event associated with increased risk of death, disability, and new events. Prevention with lifestyle changes and medication to reduce the risk of a recurrent stroke event (secondary prevention) is an important part of stroke care. This thesis focuses on prognosis after stroke or transient ischemic attack (TIA) in terms of hemorrhage, a feared condition and potential side effect of antithrombotic (AT) treatment and on optimized implementation of secondary preventive treatment.

Etiology and Pathophysiology The World Health Organization (WHO) defines stroke as “rapidly developing clinical signs of focal (at times global) disturbance of cerebral function, with symptoms, lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin”1. Thus, the origin of a stroke is vascular, caused by an occlusion (ischemic) or rupture (hemorrhagic) of a cerebral vessel. Both subtypes result in lack of oxygen and nutrients to the brain, causing damage and symptoms that depend on where the brain is damaged.

Transient ischemic attacks (TIAs) are “episodes of temporary and focal cerebral dysfunction of vascular origin, rapid in onset [...], are variable in duration, commonly lasting 2 to 15 minutes [...] Each attack leaves no persistent neurological deficit”2. Improved imaging techniques have shown that a considerable number of TIA patients actually have an irreversible brain lesion3, 4. The International Classification of Diseases (ICD), maintained by the WHO, is the most used classification system worldwide. In the 11th edition of the ICD (ICD-11), the TIA definition was changed from a time-based definition to a tissue-based one4. ICD-11 was released in 2018 and will be implemented over the coming years, but for this thesis, all definitions of TIA and codes used for cerebrovascular diseases and other conditions are according to the 10th edition (ICD-10)5.

The mechanisms underlying the arterial occlusion that leads to an ischemic stroke (IS) or TIA are heterogeneous. Thus, the secondary preventive strategies described below can differ depending on cause. The etiologies of IS and TIA are often divided into large-artery atherosclerosis, cardioembolism including atrial fibrillation (AF), small-vessel occlusion, stroke of other determined etiology including arterial dissection, and stroke of undetermined etiology6, 7. Large-artery atherosclerosis, cardioembolism, and small-vessel occlusion are the causes in most IS and TIA cases, but in a considerable portion, the cause remains undetermined8, 9. Cardioembolism as the etiology increases with age, whereas the

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category of other determined etiology constitute the larger proportion in younger stroke patients9.

In a hemorrhagic stroke caused by a vessel rupture, the hemorrhage could either be into the brain parenchyma (an intracerebral hemorrhage; ICH) or into the subarachnoid space (subarachnoid hemorrhage; SAH). Epidural and subdural hemorrhages are forms of intracranial hemorrhage (ICrH) that are not included in the stroke definition10. The vast majority of all ICHs are situated in the deep parts of the brain or in the brainstem (deep ICH) or are more superficially located (lobar ICH). A deep ICH is most often associated with the same vessels as in ischemic small vessel disease, while the lobar ICH is associated with deposition of B-amyloid in the vessels (cerebral amyloid angiopathy)11. In the national stroke register Riksstroke, 88% of all registered strokes are IS, and 12% are ICH12.

Epidemiology Stroke is the second leading cause of death globally. Although the age-standardized mortality rate decreases, the mean age is increasing worldwide, leading to a growth in absolute numbers of stroke deaths13, 14. The temporal trends in different countries vary: incidence and mortality are falling in high-income countries but rising in low- and middle-income countries14, 15. Sweden, where 26,500 people were discharged with a stroke diagnosis in 2016, shows the same trend as other high-income countries: a decrease (40% in Sweden) in the age-standardized incidence from 2002–201616. The incidence varies widely with age and is roughly 100 times greater among those 85 and older compared with people ages 35–44 years17, 18; more than 80% of patients are 65 years and older19. However, the falling incidence in the total population is not the pattern in people under age 65 years20, with an upward trend among the youngest patients21, 22.

Risk factors Several factors change the risk of stroke. Unadjustable contributors are called non-modifiable risk factors and include age23 and male sex24, 25, both of which increase the risk for IS and ICH. Modifiable risk factors are adjustable with lifestyle changes and/or medical treatment. Important modifiable risk contributors for both IS and ICH are hypertension, smoking, obesity, diet, inactivity, alcohol, diabetes, and psychosocial factors26.

Hypertension is the premier risk factor for all stroke, both IS and ICH26. The relationship between blood pressure (BP) and stroke is strong, continuous, and consistent across sexes, ages, regions, stroke subtypes, and fatal and non-fatal strokes27. Also, treating high BP reduces stroke risk over a broad range of different subgroups28.

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Two modifiable risk factors for IS but not ICH are cardiac source and dyslipidemia26. The dominant cardiac source is AF; approximately 2.9% of the Swedish population has known AF29, and prevalence increases with age. The risk of stroke is almost fivefold with AF30. Serum cholesterol includes low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. For cholesterol levels, higher levels are positively associated with stroke risk. However, the association with ICH is an inverse one, with lower levels increasing the risk of hemorrhage31. Treatment of cholesterol levels in primary prevention reduces LDL-C and the risk of IS in a high-risk population without increasing the ICH risk32, 33.

Prognosis After a stroke, risk of death or persistent disability climbs considerably. In Riksstroke, the 1-month and 1-year fatality rates are 15% and 23% after an IS. Corresponding rates after an ICH are 30%–40% and 37%–55%19, 34. Increasing age and decreased functional status increase the risk of death after stroke34, 35.

Following a stroke or TIA, the risk of a new stroke and other vascular events is high8, 36-40. The cumulative incidence of a recurrent IS the first year varies among different populations but is approximately 10%37, 38. About one in four strokes in Sweden is a recurrent event12. The risk of a new stroke is equally common after an IS and an ICH39, 41. After an IS, a recurrent stroke is usually a new IS39, 42, although not necessarily of same etiological origin42, 43. An IS also is the cause in at least half of recurrent strokes after an ICH39, 44. The risk of stroke after a TIA is also increased. In a 2007 meta-analysis, it was at least 8% at 30 days after a TIA45. A more recent multicentre study found a lower risk of 3% after 30 days and 5% after 1 year8.

Secondary prevention To reduce the increased risk of vascular events after stroke and TIA, patients are prescribed medical treatments according to guidelines46-48. For all stroke and TIA patients, the recommendation is to treat hypertension. In patients with an IS or TIA, AT and lipid-lowering treatments are also recommended. The use of medical treatments in secondary prevention and their risks and possible benefits are the foundation of this thesis and described below.

Antithrombotic treatment In the absence of contraindication, mainly high risk of hemorrhage, guidelines recommend AT treatment for all patients with an IS or TIA46, 47. The type of AT treatment depends on the stroke etiology; anticoagulant (AC) treatment is recommended for patients with AF and antiplatelets (APs) for those without AF.

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Antiplatelets For recurrent stroke, with AP therapy with acetylsalicylic acid (ASA) compared with placebo, the relative risk reduction (RRR) is 15%49. The RRR for a new vascular event with any AP compared with placebo was 22% in a 2002 meta-analysis50. The effect of adding dipyridamole to ASA is slightly greater than with ASA alone (absolute risk reduction, 1% for new vascular events compared to ASA alone)51, and the effect of clopidogrel is comparable to the combination of ASA and dipyridamole52. All three alternatives have been used in parallel during the period of this thesis and considered as alternatives in guidelines46, 47, 53.

More recent trials investigating the effect of dual antiplatelet therapy (DAPT) with ASA + clopidogrel vs ASA after stroke and TIA have shown no benefit against recurrent stroke in patients with small vessel disease during long-term follow-up; however, they did find an increase in hemorrhages54. That said, two trials showed a reduction in new events among the DAPT group55, 56 after a minor stroke or TIA with use during a limited time of 1–3 months. However, these trials on DAPT published from 2012 to 2018 did not influence treatment in the population included in this thesis.

Anticoagulants In patients with AF, AC treatment with warfarin decreases stroke risk, and in patients with ischemic stroke, the RRR is 68% with warfarin compared with placebo57. During the 2010s, non-vitamin K antagonist oral anticoagulants (NOACs) were introduced58-60 as alternatives to warfarin. The NOACs were associated with the same rate of new vascular events as warfarin in participants with prior stroke or TIA61-63. ACs have been underused, especially in women and the elderly29, but the proportion of stroke patients discharged with ACs today has increased radically from approximately 20% and 50% in patients over and under age 80 years in 2000–2005 to almost 75% and >80% in 201764.

Risk for hemorrhage after IS and TIA Thus, AP or AC treatment is recommended for most patients after an IS or TIA. Both treatments carry an increased risk of hemorrhage. A history of vascular disease and IS increases the risk of ICH65. For ICrH, cases are few, or incidence rates are not reported in many randomized controlled trials (RCTs). In a recent RCT of NOACs, ICrH incidence rates were 0.8%–1.4% per year at risk in patients using warfarin and with a recent stroke61-63 and 0.2%–0.4% per year at risk in patients with single or double AP treatment (the SPS3 trial)54. For all serious hemorrhage, the risk of a serious hemorrhage varies in RCTs between 2%–5% per year at risk in patients treated with warfarin and 1%–2% for different AP regimens54, 61-63, 66-70. Participants in these RCTs were younger, 59–70 years, and with less comorbidity than patients in clinical practice. Smaller observational studies in patients with stroke report only a few cases with serious hemorrhage71-

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73. In a Swedish registry study, the incidence rates of serious hemorrhage were 2.5% and 2.4% for AC and AP treatment, respectively. The incidence in patients treated with AP was higher than in the RCTs, and the patients in the study had a mean age of 75 years; age was an apparent factor associated with increased risk74. Of all hemorrhages, ICrH is the most feared. In one study, a reported 76% of patients with a warfarin-caused ICrH died or became disabled, whereas only 3% of patients with extracranial hemorrhages did so75. The incidence and fatality of gastrointestinal (GI) hemorrhages also increases with age76.

Antihypertensive treatment Treating hypertension reduces the risk of new events after stroke and TIA. A meta-analysis of RCTs on BP treatment after stroke showed a mean BP reduction of 5.1/2.5 mmHg in the treatment arm, with a 22% RRR for recurrent stroke77. The question has been when to treat and to what target. The PROGRESS trial, included in the same meta-analysis, showed an effect of BP reduction down to 120 mmHg regardless of baseline pressure78. In a post-hoc analysis on another RCT, PRoFESS, showed an increased risk of recurrent stroke in patients with a BP <120 mmHg79. However, the only trial so far on secondary treatment in stroke patients that has randomized patients to different treatment targets with reduction in stroke as primary endpoint is the SPS3 trial. In this trial, patients were randomly allocated to a target of <130 mmHg or 130–149 mmHg, and the results showed a small but not significant effect in the intensive target group80. Guidelines recommend treatment of hypertension and that normotensive patients can be considered for treatment. The treatment target varies but should be at least <140/90 mmHg, but lower targets could be considered in some cases46,

47, 81, 82.

Lipid-lowering treatment In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, the only trial designed for secondary prevention in stroke patients, the RRR for new stroke was 22% and the RRR for new major coronary events was 35% in patients treated with high-dose statin83; both values were significant. The included patients were stroke patients with a non-cardioembolic stroke. There was an increased risk of ICH in the treatment arm that could not be confirmed in meta-analysis with patients on secondary prevention from other trials33. Guidelines recommend statins, but the recommendation varies. No study has investigated what the treatment target should be. Since 2012, the treatment target has been 1.8 mmol/L in European and later specifically Swedish guidelines48, 81, 84; however, in US guidelines85, it was changed from the same target to a high-dose regimen with no specific target in 201447

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Addition of PCSK9 inhibitors or ezetimibe to statins further reduces LDL-C and could possibly decrease new events in stroke patients86, 87. So far, though, these combinations have not been used in any trial focused on secondary prevention in stroke patients.

Secondary prevention in clinical practice Although the effect of secondary prevention treatments on new events after stroke is proven in RCTs and recommended in guidelines, many patients do not receive these treatments88-90, especially elderly patients88, 90, or stop taking the medicines soon after their stroke91, 92. Taking medicine or not, many patients do not reach treatment targets. In observational studies, only 25%–49% of all patients reach their treatment target for BP and 14%–77% for LDL-C93-97.

Thus, interventions and methods are needed to improve modifiable risk factors. Several published studies have focused on this need, but the methods, outcomes, follow-up periods, and results are heterogeneous97-110. In a meta-analysis that allocated studies into two broad groups, educational interventions were not associated with any differences in outcomes. However, interventions at the organizational level were associated with improvements in BP achievement targets but with non-significant improvements in BP levels111 and no effects on lipid profile. Some programs associated with improved BP levels included the possibility of titrating medical treatment104, 105, 108. Despite long-term increased risk for new events after a stroke37, 40, few of the intervention studies had follow-up beyond 12 months, and any effect seemed to decline over time99, 110.

Considering the high prevalence of stroke survivors and limited available resources for public health care, a long-term, cost-effective intervention to improve secondary prevention after stroke or TIA would be desirable. Involving health care professionals other than physicians and the use of telemedicine might be two strategies to achieve this aim.

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Summary of introduction

• Stroke is a common cause of death and disability worldwide. The age-specific stroke-associated mortality is decreasing globally. In Sweden, the incidence in most age categories also is falling, but many low- and middle-income countries have seen increases. With decreasing mortality, the numbers of stroke survivors are growing.

• Stroke survivors are at increased risk of new events. To reduce the risk, most stroke and TIA patients are discharged with secondary prevention according to guidelines that are based on RCTs.

• Participants in RCTs do not always reflect patients in real-world clinical practice. RCT patients are often younger and have fewer comorbidities. AT treatment increases the risk of hemorrhage, and the risk–benefit ratio might be different in an unselected stroke and TIA population.

• Many patients do not reach treatment targets for BP and LDL-C. A new strategy to improve follow-up and use the full potential of antihypertensive and lipid-lowering treatments is needed.

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Aims

The aims of this thesis were as follows:

I – To assess the risk of ICrH within 1 year after an IS in an unselected population, identify factors associated with an increased risk of ICrH, and determine if the risk changes over time.

II – To assess the risk of serious hemorrhage after IS and TIA in an unselected population, identify factors associated with an increased risk of a serious hemorrhage, and study if a serious hemorrhage affects survival.

III – To investigate if a nurse-led, telephone-based follow-up including pharmacological titration is more efficient than usual care at improving risk factor levels in short-term follow-up after stroke or TIA.

IV - To investigate if a nurse-led, telephone-based follow-up including pharmacological titration is more efficient than usual care at improving risk factor levels in long-term follow-up after stroke or TIA and to explore trends over the study period.

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Materials and Methods Table 1 summarizes the study design, population, and outcomes for the four studies included in this thesis. Details on data sources and specific details on methods used for outcome assessments are described below.

Table 1 - Study design and population, papers I-IV

Paper I II III IV

Type of study Hospital-based cohort study

Hospital-based cohort study

RCT RCT

Data source Riksstroke, IPR, National Civil register

NAILED – screening phase, local IPR

NAILED NAILED, CDR

N 196,765 1528 537 660

Inclusion criteria

IS IS or TIA Stroke (IS/ICH) or TIA and able to participate in a telephone-based follow-up

Stroke (IS/ICH) or TIA and able to participate in a telephone-based follow-up

Inclusion period

1998–2009 2010–2013 2010 to June 2012 2010–2013

Follow-up time

12 months Discharge - 31 Dec 2015

12 months 36 months

Outcome 1) Incidence of ICrH after IS

2) Difference in incidence over the study period

3) Factors associated with ICrH after IS

1) Incidence of serious hemorrhage after IS and TIA

2) Difference in survival with or without serious hemorrhage

3) Factors associated with serious hemorrhage after IS or TIA

1) Mean difference in SBP, DBP, and LDL-C between intervention and control groups

1) Mean difference in SBP, DBP, and LDL-C between intervention and control groups

2) Difference in proportion reaching treatment target for SBP, DBP, and LDL-C between intervention and control groups

2) Difference in proportion reaching treatment target for SBP, DBP, and LDL-C between intervention and control groups

Data sources The almost 100 nationwide quality registers in Sweden today collect information on background, diagnosis, treatment, and outcome for different disorders to provide feedback and stimulate improvements in the quality of health care112.

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Also, Swedish authorities such as the National Board of Health and Welfare and Statistics Sweden maintain nationwide registers. Information from linking these registers can serve as the foundation for register-based research. The linking is made possible by the unique personal identification number (PIN) that each resident in Sweden has. The Swedish Tax Agency is responsible for maintenance of civil registration113. The registers used in this thesis are described below, and Table 1 describes which papers used specific registers.

Riksstroke Riksstroke is the Swedish national quality register for stroke care. It was established in 1994 and is the world’s longest running stroke register114. Patients eligible for registration are diagnosed with IS (ICD-10 code I63), ICH (I61), or an unspecified acute cerebrovascular event (I64). Since 1998, all hospitals in Sweden admitting stroke patients report to the register. Riksstroke contains data on age, sex, cardiovascular risk factors, drug therapy, and dependency in activities of daily living. Cardiovascular risk factors comprise diabetes mellitus, AF, hypertension, and smoking history.115 Until 2004, Riksstroke registered only AT drugs, but statins and antihypertensive drugs since have been included. The numbers of stroke patients registered and the coverage increased during the first years of the register and were stabilized around 2003114. Until 2006, the coverage assumed that the stroke incidence was (250–)300 per 100,000 years at risk, while the coverage after 2007 was calculated by dividing numbers registered in Riksstroke with those registered in the National Patient Register (NPR) (described below). The coverage was approximately 80% in 2000 and 85% in 2009. However, because of false-positive diagnoses of stroke in NPR116, the method used after 2007 probably underestimates the coverage, which could be above 90%117. Patient groups at risk of not being included are those who die early, who are not treated at a stroke unit, or who receive care in a nursing home118.

National Patient Register The Swedish In-patient Register (IPR) is a part of the NPR, maintained by the National Board of Health and Welfare. The IPR contains data for all inpatient care in Sweden with variables on admission and discharge date and primary and secondary diagnoses at discharge. Caregivers in Sweden are required to report to the register, and since 1987, it has contained data for all in-patient care in Sweden119. The register has been validated in multiple studies and has a positive predictive value (PPV) for stroke of 98.6% and sensitivity of 84%–98%120. The PPV is lower for a recurrent stroke event and for fatal stroke cases116, as is the sensitivity.

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The Swedish Cause of Death Register The Cause of Death Register (CDR) is also maintained by the National Board of Health and Welfare. The register is updated annually and contains data for deaths of all Swedish citizens since 1952. The data, based on death certificates, include date and cause of death and the underlying and contributing causes of death based on the ICD system. All deaths are reported, but a small proportion (0.9% in 2015) are missing an underlying cause of death121. The specificity of the CDR is lower than for the IPR121-123. A 2009 study showed that the underlying cause of death in hospital deaths was correct in CDR in 77% of cases but in only 68% of cerebrovascular disease cases124.

Statistics Sweden and National Civil Registry For comparing the risk of an ICrH after ischemic stroke with the risk in a general population in paper I, a reference population was used. The administrative authority Statistics Sweden created the population by matching each patient in Riksstroke (1:1) to an individual of the same sex, age, and county of residence in the National Civil Registry. Data from the IPR were then obtained for the reference population. The matching was made by January 1 of the year of the index stroke in the corresponding stroke patient. Therefore, some of the patients in the reference group died before the index event and had to be excluded (n=5763). It was also impossible to find a matching control in some cases (n=845). The reference group is therefore smaller than the Riksstroke population.

NAILED All patients treated for an ICH, IS, or TIA at Östersund hospital between January 1, 2010, and December 31, 2013, were screened and considered for participation in the Nurse-based Age-independent Intervention to Limit Evolution of Disease after stroke or TIA (NAILED) stroke trial (flow chart, Figure 1). The identification of patients with a stroke or TIA was made by study nurses through daily review of the stroke unit and of all patients undergoing a computed tomography brain scan at the hospital. The final stroke or TIA diagnosis was made by physicians not involved in the study. Study nurses collected all baseline data for all stroke and TIA patients during the screening process. All patients in a condition permitting a telephone-based follow-up were considered eligible for the intervention part of the trial and offered to participate. Patients with aphasia, impaired hearing, cognitive impairment, or severe, often terminal disease were therefore excluded.

All eligible and consenting patients were randomized 1:1 to either the intervention or control group and stratified for sex and for degree of disability (modified Rankin Scale (mRS) <3 or ≥3). Allocation was not blinded to participants, study

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team, or other caregivers. The mRS were estimated and registered by study nurses at discharge.

Follow-up and intervention All participants in the intervention trial were contacted to measure BP and blood lipids at 1, 12, 24, and 36 months. The measurements were performed at the patient’s nearest health station and reported to the study team. BP was measured in a seated position after 5 minutes of rest, and LDL-C was calculated using the Friedwald formula. A BP <140/90 mmHg and LDL-C <2.5 mmol/L (1.8 mmol/L in patients with diabetes in measurements after March 31, 2013) was considered within treatment target in the NAILED stroke trial.

Figure 1 - Flow of participants in NAILED stroke trial

Participants in the control and intervention groups were contacted shortly after the measurements by a study nurse and asked systematically according to the variables in the study protocol about sense of well-being, tobacco use, physical

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activity, and persistence to prescribed pharmacological treatment. Participants in the intervention group had lifestyle counselling. If the BP and/or lipid measurement did not reach treatment target, the study nurse contacted a study physician for evaluation and adjustment of the pharmacological treatment. The treatment was individualized to each participant and not fixed to any prespecified algorithm. For LDL-C, lipid-lowering treatment was synonymous with statins. A few were treated with ezetimibe when not reaching treatment target despite full-dose statin. After approximately 4 weeks, a new measurement was made in participants who did not reach target at baseline, and the procedure was repeated if necessary. Lipid-lowering treatment was restricted to participants with an ischemic stroke or TIA. BP and LDL-C measurement in the control group were forwarded to each participant’s general practitioner (GP) for further assessments. No evaluation of the pharmacological treatment was made by the study team, and the control group received no lifestyle counselling.

Outcomes and statistical methods In all four studies, descriptive statistics such as means and proportions are presented. Comparisons between groups were made using the chi-square test for categorical variables and t-test for continuous variables. Outcomes and specific statistics used for each paper are presented below.

Paper I Patients registered with an IS (ICD-10 code: I63) in Riksstroke 1998–2009 were included. In case of more than one registration, only the first event was used. Data from Riksstroke were combined with data from NPR. A reference population was also developed as described above.

Outcomes: - Incidence rate and cumulative incidence of ICrH 0-30 and 31–365 days after an

IS - Time trends for ICrH 0–30 and 31–365 days after an IS - Factors associated with the risk of an ICrH 0-30 and 31–365 days after an IS

We divided the follow-up period into two phases, 0–30 days after an IS and 31–365 days after IS, to reflect possible differences in mechanisms of ICrH in the acute phase. The patients were followed from their stroke and until ICrH, death, or end of follow-up, depending on which occurred first. The ICD-10 codes I60, I61, or I62 in the IPR were used to identify an ICrH. If more than one event of ICrH was found, only the first event was included.

Incidence rates was calculated for ICrH but also separately for ICH (ICD-10: I61). Kaplan–Meier (K-M) analysis, with the log-rank test for group comparisons, was

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used to assess the cumulative incidences and explore temporal trends. For exploring temporal trends, the patients were divided into four groups depending on the year of inclusion in Riksstroke (1998–2000, 2001–2003, 2004–2006, or 2007–2009).

Cox proportional hazard (PH) regression analysis125 was used to explore factors associated with an increased risk of ICrH during days 31–365. It assess if one (uni-) or more (multi-) variables are associated with time to an event. An important assumption in this model is the PH assumption, i.e., the hazard ratio, the ratio between an exposed and an unexposed objects likelihood to experience an event, should remain unchanged during the time they are followed. The PH assumption was verified with K-M analysis in the univariable analysis and by examination of the Schoenfeld’s residuals in the final multivariable analysis. We have no knowledge on what day medication was withdrawn or started during hospitalization and we do not know on what day any ICrH occurred. This makes Cox PH regression analysis less suited during the acute period, so logistic regression analysis was performed to explore factors associated with an ICrH in the first 30 days.

In paper I, both the logistic and Cox PH regression multivariable models contained all variables from the univariable analysis to adjust for factors associated with vascular disease. However, for the results in the introduction to this thesis, we made changes to the multivariable Cox PH regression and logistic regression analysis for two reasons: 1) In paper I, age is a continuous variable, so to fulfil the PH assumption, age was changed from a continuous to a categorical variable; and 2) as a sensitivity analysis, we wanted to see if another approach changed the outcome in the multivariable analyses we used in paper II. In the introduction to this thesis, therefore, factors with a p-value <0.10 in the univariable model along with age and sex were included in a multivariable model. A second model was then made with all significant variables from the first multivariable model, age and sex. Some variables were added to Riksstroke in 2004, and to obtain a fairly complete dataset, the analysis of factors associated with an ICrH includes data from 2004–2009.

Paper II All patients discharged from Östersunds hospital after hospitalization for an IS or TIA during 2010–2013 were included. Patients who died or experienced a serious hemorrhage during hospitalization were excluded. Patients were identified in the screening process of the NAILED stroke trial as described above. Events of serious hemorrhage were searched for in the local IPR. ICD-10 codes searched for are shown in Table 2. Data regarding date of death were obtained from CDR.

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Outcomes: - Incidence rate and cumulative incidence of serious hemorrhage after IS

or TIA - Risk of death after IS or TIA and if a serious hemorrhage affected the risk - Factors associated with an increased risk of serious hemorrhage after IS

or TIA

All hemorrhages were classified as ICrH, GI, or other. All observed hemorrhages, both primary and secondary diagnoses, were validated against the patient records and classified as serious if they were (1) an ICrH, (2) the main cause of admission, or (3) required transfusion or surgery. In case of more than one serious hemorrhage, only the first was included. The patients were followed from discharge until an event of serious hemorrhage, death, move out of the county, or end of follow-up on 31 December 2015, whichever occurred first.

Cumulative incidence was obtained using a competing risk approach instead of the ordinary K-M technique. This approach allows for multiple competing fatal events in relation to the one under investigation. A drawback with ordinary K-M analysis is that the risk of an event is the same in a censored patient (who is no longer observed for prespecified reasons) as in an observed patient. In this population, there was a high mortality, and taking the competing risk of death and other serious hemorrhages into account could give a more accurate description.

The risk of death was analysed with K-M analysis. Patients were divided into groups of good versus impaired functional status. Good functional status was defined as mRS 0–2 at discharge and impaired functional status as mRS 3–5. The effect of serious hemorrhage on mortality in the two groups was analysed, and the log-rank test was used for comparisons.

To identify factors associated with an increased risk of a serious hemorrhage, the Cox proportional hazards regression model was used. Factors with a p-value <0.10 in the univariable model along with age and sex were included in a multivariable model. Factors with a p-value <0.10 in this model, age and sex were included in the final model. This model was also performed with a competing risk analysis.

Table 2 - ICD-10 codes included in the screening for serious hemorrhage

D62.9 Acute post-hemorrhagic anaemia D50.0 Iron deficiency anaemia secondary to blood loss H11.3 Conjunctival hemorrhage H31.3 Choroidal hemorrhage H35.6 Retinal hemorrhage

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H43.1, H45.0 Vitreous hemorrhage H92.2 Hemorrhage from the ear I60 Subarachnoidal hemorrhage I61 Intracerebral hemorrhage I62 Non-traumatic intracranial hemorrhage I 69.0-2 Sequel of intracranial hemorrhage I84 Hemorrhoids I85.0, I98.3 Esophageal varices K22.6 Gastro-esophageal laceration hemorrhage K25 – 28 Acute peptic ulcer K29 Acute hemorrhagic gastritis K62.5 Hemorrhage of anus and rectum K92.0 Hematemesis K92.1 Melena K92.2 Gastrointestinal hemorrhage, unspecified M25.0 Hemarthrosis N42.1 Congestion and hemorrhage of prostate N93.8-9 Abnormal uterine and vaginal bleeding N95.0 Postmenopausal hemorrhage R04 Hemorrhage from throat and airways R31.9 Hematuria S06.4-6 Epidural hemorrhage, traumatic subarachnoidal and subdural R58.9 Unspecified hemorrhage T81.0 Hemorrhage as complication to surgery

Papers III and IV Participants, eligibility criteria, and intervention in the NAILED stroke trial are described above. Paper III presents the results of the 12-month follow-up, and paper IV presents the results of the 36-month follow-up.

Outcomes - Mean BP and LDL-C, differences from baseline and difference between

groups - Proportion reaching treatment target for BP and LDL-C

Participants who completed follow-up were analysed for outcomes. Paired sample t-tests were used to analyse mean differences between baseline (1-month measurement) and final follow-up within a single group. For mean value at last follow-up and difference between groups, a general linear model adjusted for sex and degree of disability, to reflect the randomization, was used as prespecified126. In paper III, a second general linear model was used to assess if any difference between the groups was attributable to participants in the intervention group with a measurement value above treatment target at baseline. This model also included an indicator variable denoting if the participants were above or below treatment target at baseline. The model also contained an interaction variable between the treatment target variable and the treatment group allocation. Participants who did not complete the 36 months of follow-up were analysed for

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any between-group differences, including death rates and cause of death, with information from the CDR.

SPSS versions 20.0, 22.0, and 24.0 and SAS version 9.4 (paper II) were used for the statistical analysis. A p-value of 0.05 was considered significant in all analyses.

Ethical considerations All patients treated for stroke are informed that they will be registered in Riksstroke, that the register aims to develop and ensure the quality of stroke treatment in Sweden, and that the register might be used for research purposes. The patients are informed that they have the right to decline registration and that they can have the registered data erased at any time.

The unique PIN is the foundation of the register-based research and makes it possible to combine registers, but it is also a possible source of identification. To preserve the integrity of the patient, the PIN was removed before the data were delivered to us, and with more than 195,000 patients registered in the database, it is impossible to identify a unique person.

In papers III and IV, all participants received written and oral information about the NAILED stroke trial and then signed an informed written consent.

All studies were approved by the ethical review board in Umeå. Study using Riksstroke (paper I) on August 13, 2010 (Dnr: 2010-167-31M) and the NAILED study (papers II–IV) on October 28, 2009 (Dnr: 09-142M), with supplements on June 10, 2013 (Dnr: 2013-204-32M) and January 13 (Dnr: 2014-416-32) to approve studies of baseline characteristics and follow-up regarding new events among participants not included for randomization.

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Results

Baseline characteristics of study participants Table 3 shows baseline characteristics of analysed patients in papers I–IV. The mean age is lower in papers III and IV compared with paper II, reflecting that patients not fulfilling the inclusion criteria for the intervention trial where older with more comorbidity.

Table 3 - Baseline characteristics of the study populations in papers I–IV

Paper I II III IV

N 196765 1528 484 660

Age, mean 76.0 75.1 70.8 69.9

Female sex 98425 (50.0) 681 (44.6) 208 (43.0) 269 (40.8)

Atrial fibrillation 52169 (27.4) 391 (25.6) 78 (16.1) 99 (15.0)

Diabetes 30568 (20.5) 305 (20.0) 86 (17.8) 113 (17.1)

Smoking 21273 (16.2) 191 (12.7) 69 (14.3) 90 (13.6)

Index event

IS 196765 (100.0) 1083 (70.9) 289 (59.7) 387 (58.6)

TIA 0 445 (29.1) 176 (36.8) 250 (37.9)

ICH 0 0 17 (3.5) 23 (3.5)

Previous diagnosis of

Hypertension 56136 (55.5) 985 (64.5) 289 (59.7) 384 (58.2)

Myocardial infarction 24248 (12.3) 182 (11.9) 59 (12.2) 52 (7.9)

IS 28716 (14.6) 235 (15.4) 62 (12.8) 68 (10.3)

ICrH 3367 (1.7) 39 (2.6) n/s n/s

Treatment at discharge

Statins 41588 (43.1) 951 (62.2) 384 (79.3) 529 (80.2)

Antihypertensives 65825 (68.1) 1184 (77.5) 363 (75.0) 495 (75.0)

Antiplatelets 109211 (75.8) 1233 (80.7) 390 (80.6) 529 (80.2)

Anticoagulants 16359 (11.4) 244 (16.0) 67 (13.8) 93 (14.1)

mRS 0–2 n/s 1002 (65.7) 419 (86.6) 598 (89.7)

Data presented as n (%) unless otherwise noted. IS indicates ischemic stroke; TIA, transient ischemic attack; ICH, intracerebral hemorrhage; ICrH, intracranial hemorrhage; and mRS, modified Rankin Scale.

In paper I, a reference population of 190,157 participants was developed. This group had a mean age of 75.8 years, 49.8% were women, and they had fewer comorbidities than patients with stroke: previous myocardial infarction, 7.7% versus 12.3%; previous IS, 3.6% versus 14.6%; and previous ICrH, 0.9% versus 1.7%.

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Serious hemorrhage (papers I and II) In paper I, a total of 196,765 patients diagnosed with an IS during 1998–2009 were followed in the first year after an ischemic stroke; in paper II, 1528 patients diagnosed with an IS or TIA during 2010–2013 were followed from discharge until 31 December 2015. The median observation time was 1099 days (interquartile range: 734–1556). Baseline characteristics of study populations in papers I and II are shown in Table 3 and Figure 2. The figure shows an increase in secondary prevention medication in the study population in the 2000s with a decreasing proportion of patients without any AT discharge and increasing proportion of patients with statins and antihypertensives.

Figure 2 - Treatment at discharge in the study populations in papers I (2001–2009) and II (2010–2013) – proportions of the study population with antihypertensive treatment, statins, antiplatelet (AP), anticoagulant (AC), or no AP or AC treatment at discharge

0

10

20

30

40

50

60

70

80

90

100

01 02 03 04 05 06 07 08 09 10 11 12 13

%

Paper I Paper II

Antihypertensive Statins Antiplatelet

Anticoagulant No AP or AC

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Incidence rate and cumulative incidence of ICrH In paper I, a total of 3186 patients had a diagnosis of ICrH during the first year after an IS, 1932 within the first 30 days and 1254 during days 31–365. The incidence rate was 1.97% (95% CI: 1.91–2.03) per year at risk for the first year and 0.85% (95% CI: 0.81–0.89) excluding the first 30 days. In the NAILED population (paper II), the incidence rate of an ICrH after discharge, including traumatic ICrH, was 0.96% (95% CI: 0.71–1.28) per year at risk. The incidence rates of ICH after the acute phase were 0.59 (95% CI: 0.55–0.63) and 0.40% (95% CI: 0.25–0.62) per year at risk in papers I and II, respectively, and 0.04% (95% CI: 0.03-0.05) per year at risk in the reference population in paper I (see Table 4 for incidence rates).

Table 4 - Incidence rates (% per year at risk) of intracranial hemorrhage (ICrH) and intracerebral hemorrhage (ICH) in paper I (days 31–365) and paper II (from discharge until end of study)

Paper I Paper II ICrH ICH ICrH ICH % per year at risk (N) % per year at risk (N)

All 0.85 (1254) 0.59 (874) 0.96 (45) 0.40 (19) IS patients only 0.85 (1254) 0.59 (874) 1.07 (34) 0.50 (16) Age at discharge <75 years 0.68 (495) 0.49 (362) 0.64 (15) 0.34 (8) ³75 years 0.86 (759) 0.58 (512) 1.28 (30) 0.46 (11) Treatment at discharge Anticoagulants 1.04 (144) 0.62 (94) 1.20 (9) 0.40 (3) Antiplatelets 0.75 (657) 0.47 (456) 0.93 (36) 0.41 (16) Reference pop, study I 0.13 (231) 0.04 (74) IS indicates ischemic stroke; ICrH, intracranial hemorrhage; and ICH, intracerebral hemorrhage

Time-trends Between 1998 and 2009, the cumulative incidence of ICrH and ICH increased from 0.94%–1.21%, the first 30 days after an IS (p<0.001). The cumulative incidence decreased from 0.89%–0.72%, during days 31–365 (p=0.021), The cumulative incidence in the reference-population was between 0.10–0.13% during the study-period (Figure 3 and 4).

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Figure 3 - Cumulative incidence of intracranial hemorrhage (ICrH) and intracerebral hematoma (ICH), days 0–30 and 31–365 after ischemic stroke and for a reference population (ref) matched for age and sex (1998–2000, 2001–2003, 2004–2006, 2007–2009).

Figure 4 - Cumulative incidence of intracranial hemorrhage, days 31–365 after ischemic stroke (1998–2000, 2001–2003, 2004–2006, 2007–2009) and for a reference population matched for age and sex

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1998-2000 2001-2003 2004-2006 2007-2009

Cum

ulat

ive

inci

denc

e (%

)

ICrH 0-30 ICrH 31-365 ICrH ref 31-365

ICH 0-30 ICH 31-365 ICH ref 31-365

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Incidence rate and cumulative incidence of serious hemorrhage Of the 1528 patients in paper II, 125 had at least one new hospitalization with a hemorrhage diagnosed after discharge. Twelve of the hemorrhages were not considered serious according to our criteria. Thus, 113 (7.4%) had a serious hemorrhage: 45 ICrH, 41 GI, and 27 in other locations (flow chart, Figure 5). The median time to an event was 535 days (interquartile range: 209–942). The incidence rate of a serious haemorrhage after IS or TIA was 2.48% (95% CI: 2.05–2.97) per year at risk. Cumulative incidence of hemorrhage during the study period and incidence rates in different patient categories are shown in Tables 5 and 6.

Figure 5 - Study flow chart, paper II

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Table 5 - Cumulative incidence of serious hemorrhage, intracranial hemorrhage (ICrH), gastrointestinal hemorrhage (GI), and other hemorrhages within 5 years after discharge from ischemic stroke or TIA (paper II).

Years All ICrH GI Others % (N)

1 3.08 (47) 0.85 (13) 1.11 (17) 1.11 (17) 2 4.66 (71) 1.64 (25) 1.71 (26) 1.31 (20) 3 6.56 (96) 2.62 (38) 2.32 (34) 1.62 (24) 4 7.64 (106) 3.07 (42) 2.85 (39) 1.72 (25) 5 8.50 (111) 3.59 (45) 3.02 (40) 1.89 (26)

Table 6 - Incidence rates of serious hemorrhage, ICrH, GI hemorrhage, and other hemorrhages within 5 years after discharge from IS or TIA in different patient groups (paper II).

All ICrH GI Others % per year at risk (N)

All 2.48 (113) 0.96 (45) 0.88 (41) 0.58 (27) Index event Ischemic stroke 2.72 (84) 1.07 (34) 0.94 (30) 0.63 (20) TIA 1.98 (29) 0.74 (11) 0.74 (11) 0.47 (7) Antithrombotic treatment at discharge Anticoagulant 2.74 (20) 1.20 (9) 1.07 (8) 0.40 (3) Antiplatelet 2.37 (89) 0.93 (36) 0.78 (30) 0.60 (23) Functional level at discharge mRS 0–2 2.19 (74) 0.93 (32) 0.66 (23) 0.55 (19) mRS 3–5 3.31 (39) 1.06 (13) 1.48 (18) 0.65 (8) Age at discharge <75 years 1.70 (39) 0.64 (15) 0.64 (15) 0.39 (9) ³75 years 3.26 (74) 1.28 (30) 1.11 (26) 0.77 (18)

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Mortality During the first year after admission, 22.3% and 13.4% (16.7% of IS patients) of patients died in papers I and II respectively. In paper II, 494 (32.3%) patients died during the entire follow-up (Figure 6). Among patients with a functional status of mRS 0–2 at discharge, the mortality in paper II was 4.2% in the first year and 18.4% during the follow-up. Corresponding numbers in the group with mRS 3–5 were 31.0% and 58.9%. The 30-day case fatality of a serious hemorrhage in paper II (all events) was 15.9%. The corresponding percentages were 12.2% for GI hemorrhages, 24.4% for ICrH, and 42.1% for ICH. In paper I, the 30-day case fatality values for non-traumatic ICrH and ICH were 31.5% and 35.5%, respectively. In paper II, a serious hemorrhage during follow-up was associated with higher 5-years mortality in the group with mRS 0–2 at discharge, compared to no hemorrhage (37.8% vs 16.8%, p<0.001). In the group with mRS 3–5, a hemorrhage had no effect on mortality (p=0.319; Figure 6).

Figure 6 - Cumulative survival 5 years after discharge from hospitalization for ischemic stroke or transient ischemic attack. (A) All patients (n=1528, of whom 485 died). (B) Patients stratified by functional level at discharge (p<0.001). (C) Patients with mRS 0–2 at discharge, with or without a serious hemorrhage during follow-up (p<0.001). (D) Patients with mRS 3–5 at discharge, with or without a serious hemorrhage during follow-up (p=0.319); mRS: modified Rankin Scale.

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Predictors of serious hemorrhage and ICrH In paper I, male sex and a prior ICrH or ICH were associated with a new ICrH or ICH after an IS during both days 0–30 and days 31–365. Thrombolysis, atrial fibrillation and warfarin at admission were associated with an ICrH/ICH within 30 days. Age over 75 years was associated with a decreased risk of ICrH the first 30 days and an increased risk day 31-365. In paper II, a prior diagnosis of hypertension was associated with an increased risk of serious hemorrhage after an IS or TIA. AT at discharge was not associated with an increased risk of hemorrhage in papers I and II. For multivariable Cox regression analyses, see Tables 7, 8, and 9.

Table 7 - Multivariable logistic regression analysis of predictors of ICrH / ICH after IS, days 0–30.

ICrH ICH

OR (95% CI) p OR (95% CI) p Age ≥75 years 0.82 (0.72–0.93) 0.002 0.84 (0.72–0.99) 0.033 Female sex 0.82 (0.72–0.93) 0.002 0.78 (0.67–0.90) 0.001 Atrial fibrillation 1.22 (1.06–1.40) 0.007 1.36 (1.15–1.61) <0.001 Warfarin at admission 1.32 (1.03–1.69) 0.007 1.45 (1.09–1.93) 0.010 ICrH prior IS 7.54 (6.06–9.34) <0.001 5.29 (3.46–8.10) <0.001 Thrombolysis 4.50 (3.72–5.44) <0.001 6.58 (5.37–8.05) <0.001 Antihypertensives

at admission

0.86 (0.76–0.97) 0.015

Table 8 - Multivariable Cox regression analysis of predictors of ICrH /ICH after IS, days 31–365.

ICrH ICH

HR (95% CI) p HR (95% CI) p Age ≥75 years 1.25 (1.05–1.49) 0.012 1.15 (0.93–1.42) 0.197 Female sex 0.74 (0.63–0.88) 0.001 0.76 (0.62–0.94) 0.010 ICrH prior IS 3.06 (2.05–4.56) <0.001 5.31 (3.11–9.05) <0.001 Statins at discharge 0.81 (0.68–0.96) 0.015 0.71 (0.57–0.88) 0.001 Thrombolysis 0.47 (0.24–0.90) 0.024

Table 9 - Multivariable Cox regression analysis of predictors of serious hemorrhage after IS or TIA.

Serious hemorrhage HR (95% CI) p

Age ≥75 years 1.30 (0.85–1.99) 0.220 Female sex 0.75 (0.52–1.09) 0.127 Prior hypertension 1.72 (1.10–2.68) 0.017 Statins at discharge 0.81 (0.55–1.20) 0.300

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NAILED stroke trial (papers III and IV) Figure 1 shows the flow of participants in papers III and IV. During the inclusion period between 1 January 2010 and 31 December 2013, a total of 871 participants were included. Of these, 537 were included until 30 June 2012 and compose the study population in paper III. In the 12-month follow-up (paper III), 53 participants (9.9%) discontinued, and in the 36-month follow-up (paper IV), 211 participants (24.2%) discontinued. Baseline data for all participants followed up in papers III and IV at 12 and 36 months are given in Table 11. Except for a borderline significant higher prevalence of diabetes in the control group, the groups were well balanced in terms of baseline characteristics at follow-up. The participants who did not complete the 12- and 36-month follow-up periods were older and had more co-morbidities. In paper III, the numbers of BP and LDL-C measurements were fairly equal between the control and intervention groups, including the measurement in the trial, between 1 and 12 months. Table 10 shows the numbers of participants screened and randomized, reasons for exclusion, numbers at last follow-up, and reasons for discontinuation. In total, 99 participants died during the 36 months of follow-up, 55 in the intervention and 44 in the control group. The intervention and control groups did not differ significantly in terms of proportion of cardiovascular or all-cause mortality (p=0.51 and 0.24, respectively).

Table 10 - Flow of participants in papers III and IV – Numbers of participants, screened, randomized, and followed up and reasons for being lost to final follow-up

12 months follow-up Paper III

36 months follow-up Paper IV

N N Screening 1102 1776 In-hospital mortality 90 130 Excluded 356 548 Declined to participate 119 225 Missing 2 Randomization 537 871

Intervention Control Intervention Control 266 271 433 438

Died 9 9 40 31 Active withdrawal 15 16 46 34 Unable to continue 0 3 25 29 No measurment 1 0 2 4 12/36 m follow-up 241 243 320 340

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Table 11 - Baseline characteristics of all participants randomized 2010–2013 and of participants at 12 and 36 months of follow-up in papers III and IV

Data presented as n (%) unless otherwise noted. There were no significant differences between the intervention and control groups for any of the variables presented in the table except for diabetes in paper IV, 36 months follow-up, p=0.049.

12-month follow-up,

paper III 36-month follow-up,

paper IV

Intervention Control Intervention Control

N 241 243 320 340

Mean age, years 71.5 70.1 69.9 69.3

Women 104 (43.2) 104 (42.8) 130 (40.6) 139 (40.9)

Qualifying event

Ischemic stroke 143 (59.3) 146 (60.1) 181 (56.6) 206 (60.6)

Intracerebral hematoma 9 (3.7) 8 (3.3) 11 (3.4) 12 (3.5)

TIA 89 (36.9) 89 (36.6) 128 (40.0) 122 (35.9)

mRS 3–5 38 (16.2) 27 (11.1) 37 (11.6) 31 (9.1)

Medical history

Ischemic stroke 41 (17.0) 32 (13.2) 41 (12.9) 37 (10.9)

Myocardial infarction 30 (12.4) 29 (11.9) 22 (6.9) 30 (8.8)

Heart failure 10 (4.1) 7 (2.9) 8 (2.5) 9 (2.6)

Atrial fibrillation 39 (16.2) 39 (16.0) 47 (15.2) 52 (15.4)

Diabetes 40 (16.6) 46 (18.9) 45 (14.1) 68 (20.1)

Smoker 28 (11.6) 41 (16.9) 42 (13.1) 48 (14.1)

Medication at 1 month

Antihypertensive drug 177 (73.4) 186 (76.5) 231 (72.2) 264 (77.6)

Statin 191 (79.3) 193 (79.4) 253 (79.8) 276 (81.7)

Antiplatelet drug 191 (79.3) 199 (81.9) 253 (79.1) 276 (81.2)

Anticoagulant drug 36 (14.9) 31 (12.8) 48 (15.1) 45 (13.3)

Health care contacts 1–12 m

Contact with primary care centre 234 (97.1) 231 (95.1)

No. of BP and/or LDL-C evaluations, median (iqr)

Primary care centre 1.0 (0.0–2.0)

3.0 (1.0–4.0)

Within NAILED stroke trial 2.0 (1.0–3.0)

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Mean BP, LDL-C, and proportions reaching treatment target The systolic BP (SBP) values at 12 and 36 months were 3.3 (95% CI: 0.3–6.3) and 6.1 mmHg (95% CI: 3.6–8.6) lower in the intervention compared with the control group. For diastolic (DBP), the corresponding numbers were 2.3 (95% CI: 0.5–4.2) and 3.4 mmHg (95% CI: 1.8–5.1), and for LDL-C, they were 0.3 (95% CI: 0.1–0.4) and 0.3 mmol/L (95% CI: 0.2–0.5) lower. Mean BP, LDL-C, and difference between intervention and control group at 36 months are shown in table 12.

An interaction analysis on the 12-month measurement in paper III is shown in Figure 7 A-C. It shows a significant interaction effect between group allocation (intervention vs control) and baseline values for BP/LDL-C (reaching or not reaching treatment target), SBP (p=0.001), and LDL-C (p<0.001). The adjusted SBP and LDL-C in the intervention group with baseline measurement above treatment target was 8.0 mmHg (95% CI: 4.0–12.1) and 0.6 mmol/L (95% CI: 0.4–0.9) lower than in the control group, respectively. The corresponding difference in SBP at 36 months was 9.2 mmHg (95% CI: 5.6-12.8) favouring the intervention group after decrease in SBP of 20.9 mmHg (95% CI: 17.9 – 23.9), down to 130.8 mmHg (95% CI: 128.2 – 133.4) over the study period.

Figure 7 shows the proportions reaching treatment target at 12 months follow-up in paper III and the proportion that changed from over treatment target at 1 month to below target at 12 months follow-up. The difference in proportion reaching treatment target were significant for SBP (p=0.008) and LDL-C (p<0.001) at 12 months (paper III, figure 7 D-F) and for SBP, DBP and LDL-C (p<0.001 for all) at 36 months (paper IV, table 12 and figure 9)

Time trends The difference in proportion reaching treatment target as well as the difference in mean value between the two groups increased during the whole study period for SBP and DBP. For LDL-C, the difference seen at the 12-month follow-up in paper IV remained unchanged at 24 and 36 months (Figure 8 and 9). Figure 10 shows the number of follow-ups with a measurement above treatment target for SBP, DBP, and LDL-C. It shows that 20%–30% were within treatment target at all follow-ups (0) for SBP and LDL-C in both groups, but that almost no participants in the intervention group had no measurement within target (4) for SBP, DBP, and LDL-C. At 36 months, 44.1% in the intervention group and 72.9% in the control group (p<0.001) had at least one measurement above target. During the whole study period, only 5.9% and 4.7% (p=0.493) of the participants in the two groups reached treatment target values at all measurements for SBP, DBP, and LDL-C.

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Figure 7 – Analyses at 12-months follow up (paper III). A-C: Effect of the interaction between group allocation and the baseline level of BP or LDL-C level on the 12-month adjusted mean (A) SBP (p=0.001), (B) DBP (p=0.054), and (C) LDL-C (p<0.001) values. D-F: Proportion of participants below treatment target at 1 and 12 months. The lightly shaded portion of each 12-month stack represents the proportion whose values changed from above to below target between 1- and 12-months follow-up.

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Discussion

Methodological considerations The studies presented in this thesis were hospital-based cohort studies (papers I and II) and results from the RCT NAILED stroke trial (papers III and IV). Paper I was based on registered data from Riksstroke. Paper II was based on data from the screening phase of the NAILED stroke trial, and papers III and IV on data from the NAILED intervention phase. Possible methodological issues within these papers, such as information bias, missing data, confounding, and selection bias, are discussed below.

Information bias The use of registers with large number of patients, as in paper I, enables precise estimates, even in subsets of patients and in outcomes involving approximately 1% of the study population, as with ICrH in an IS population. The observations in these studies complement the RCTs and can help reveal outcomes in patient groups not otherwise represented in the randomized trials. However, register studies have their weakness and depend on the quality of the data used. The IPR has high PPV and sensitivity for first-time stroke events but is lower in recurrent events116, 120. No specific validation is available for ICrH or ICH, but the incidence rates for ICH in IS patients in papers I and II are similar. In addition, the rate of ICH in the reference population in paper I is similar to the incidence in a non-stroke population in previous studies34, suggesting fairly reliable results for ICH. With decreasing PPV in recurrent events in IPR, there is a risk of overestimation of ICrH in patients with an ICrH prior to the IS in paper I. However, any overestimation should be constant over time and not alter the result on time trends.

The CDR comprises data on cause of death. The information from the register is completed by a physician. It has been validated, and together with the NPR, it has a high PPV and sensitivity for capturing stroke events, especially for first-ever stroke116, 122, when compared with stroke registers. However, when used alone, CDR has a PPV of 62%116 for all stroke, not discriminating IS from ICH, and the PPV decreases in patients who are not hospitalized. Another study shows that CDR alone has an all-stroke specificity of 68% 124. In the database, we have information from the CDR, but because the diagnosis of an ICH or ICrH compared with any stroke or other cause of death outside the hospital without a certain diagnostic work-up was too uncertain, we did not include these events in the analysis. With inclusion of patients with an ICrH as a major cause of death in the CDR without a diagnosis in the IPR, the ICrH incidence rate during days 31–365 days after IS was 0.93% (n=1368) per year at risk instead of 0.85% (n=1254).

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The incidence in paper I might be underestimated, but the slightly higher incidence do not change any conclusions.

Data on medication in papers I and II have to be interpreted carefully because the information is from discharge without numbers on persistence. The use of data from the Swedish Prescribed Drug Register, which holds information on all prescriptions dispensed to Swedish patients, could have increased the accuracy of and knowledge about treatment at the time of the event in papers I and II, but these data was not part of our analysis.

In papers I and II, there are some differences in which ICD-10 codes are used for defining ICrH. In paper I, as prespecified, we investigated diagnoses of non-traumatic ICrH and ICH. The cause of some ICrH, especially subdural hematoma, might be difficult to determine regarding trauma or not. In paper I, we could not validate the diagnoses from IPR, which carries a risk of either over- or underestimating non-traumatic ICrH. Therefore, we included all diagnosis of ICrH in paper II. However, the use of the ICH diagnosis (ICD-61) should be comparable in papers I and II so that in this thesis, results for ICH and ICrH are both reported.

The definitions of a serious hemorrhage in RCTs are heterogeneous and rates of hemorrhage difficult to compare among trials127-130. Many definitions also require knowledge about changes in hemoglobin values. In paper II, the last hemoglobin value before admission could be more than 2 years old, precluding any use of these definitions. Instead, we searched for both primary and secondary diagnoses of hemorrhages as in other observational trials70, 74, 131. We evaluated these diagnoses by scrutinizing patient records to assess their correctness and used both primary and secondary diagnoses if they met our criteria. The possibility of validating the diagnosis should increase the internal validity. The severity of GI and other hemorrhages might range from mild to life-threatening. We included only hospitalized cases in our definition of serious hemorrhages. Thus, incidence rates of all GI and other hemorrhages might be underestimated.

In papers III and IV, measurement of BP and LDL-C was conducted at each participant’s closest health station by the local staff. The participant brought instructions. However, many health workers and health stations were involved in the measurements, leaving a possibility for measurement error or equipment issues. These potential errors should, however, be randomly distributed among the participants and randomized groups and should not affect between-group comparisons.

The NAILED stroke trial was an open trial. There was no blinding of the groups, so both participants and staff were aware of allocation. The protocol and the

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nature of the intervention made blinding impossible. This factor could, of course, affect the results of the study. The measurement values in the control group were forwarded by the study team to each participant’s GP without any further actions or instructions. We cannot exclude that this step led to measurements that would not otherwise have been conducted, greater awareness by the patient, and more adjustments and control of the risk factors by the GP than would have otherwise been the case. If so, a decrease in differences between the groups and underestimation of the intervention’s effects are possible.

Missing data In paper I, data were missing for variables included in the Cox PH regression analysis in 1%–6% of cases. Smoking was omitted from the analysis because of missing data in 13% of cases. In paper II, data were missing in less than 2% of any variable in the univariable analysis and in only single cases in the multivariable analysis. Complete cases were used in all analyses. In papers III and IV, participants were lost to follow-up for three main reasons: death, unable to continue because of severe disease, or active withdrawal; thus, these were not complete cases. Fifty-three and 211 participants did not complete the 12 and 36 months of follow-up, respectively.

In statistical analysis, imputation is a possible process to adjust for a potential systematic bias of the missing data. However, imputation still requires invented values. With small proportions of missing data in papers I and II, and thereby low risk that it would affect the results, we chose not to impute values.

In papers III and IV, last value carried forward could have been a possible solution to handle missing follow-up measurements. The main reasons for participants being lost to follow-up were natural causes, reflecting the clinical reality of this stroke/TIA population and we therefore chose not to imputate values. The participants lost to follow-up were older with more comorbidities, but the distribution of baseline characteristics remained similar between the groups. In addition, there were no significant between-group differences in mortality, including cardiovascular deaths.

Confounding Confounders are factors that affect both an exposure and the outcome, thus producing all or part of an effect. The multivariable analysis in the Cox regression model is one way to handle possible confounders. Still, we can try to adjust only for the known variables. In non-randomized observational studies such as papers I and II, there certainly are unknown confounders for which we cannot adjust.

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In investigations of different treatments, confounding by indication is a risk. In papers I and II, we found no significant association between AP and AC treatment and serious hemorrhages, except for warfarin at admission for ICrH days 0–30 in paper I. We do not know the reason for decisions on discharge treatment, but the risk of hemorrhage and severe disease is a probable cause to abstain in many cases. Therefore, associations from these analyses in observational studies should not lead to any conclusions regarding causality.

Selection bias, coverage, and generalizability Riksstroke had a coverage of approximately 80%–90% during the years included in paper I 114, 117. The coverage increased over time, especially during the first years. The lower coverage in the first years could be a result of selective registration, which would decrease the internal validity of paper I. On the other hand, mean age and the proportions of men and women were similar during the years studied with little variation in 1-year mortality, indicating that the different time-cohorts in paper I should be comparable. Patients at risk of not being included in Riksstroke are those who die early, are not treated at a stroke unit, or receive care in a nursing home118.

In paper II, all patients treated for a stroke or TIA at Östersund hospital were included. The case-finding methods in the NAILED stroke trial were validated against set diagnoses prior to the start of inclusion, and no missed cases of patients with a discharge code of stroke or TIA were found 126. Studies report that 84%–92% of all stroke patients are treated in-hospital122, 132, 133. Patients more likely to not be treated in the hospital are institutionalized patients, those with very mild symptoms, or those who die outside of the hospital133.

Thus, there is a selection bias at inclusion in papers I and II, and patients with stroke or TIA not admitted to hospital are not included. As hospital-based cohort studies, however, the internal validity must be considered high. The inclusion was not restricted by age, functional status, or co-morbidity in this otherwise unselected cohort. The results should be generalizable to other hospital-treated cohorts in Sweden and to other countries with similar demographics and stroke epidemiology.

Within the NAILED stroke trial, an analysis of which patients were eligible or considered unable to participate in a telephone-based follow-up showed that 35.7% of stroke and TIA patients could not participate, mainly because of physical or cognitive disability134. Age >85 years, impaired functional status with mRS >3, and lower educational level were associated with increased risk of exclusion. Exclusion also was associated with a 12-fold greater risk of death within the first year, similar to mortality in patients with mRS 3–5 in paper II. The determination

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of eligibility or not at discharge might, however, have excluded patients who with a few weeks of rehabilitation could have been suited for the intervention. Also, a strategy that would fit patients with aphasia or hearing problems who now had to be excluded could have made inclusion of this ~7% of the patient group possible. Thus, a higher proportion of the stroke population might have been eligible for the NAILED intervention. Nevertheless, with the estimated inability to participate in the intervention as the only exclusion criterion, with a screening process with all patients admitted to Östersund hospital during 4 years considered for participation, the results with this study population must be considered generalizable to similar settings.

In paper III and IV, differences in strategy of risk factor follow-up between the intervention and “usual care”, i.e. the control group, resulted in differences in outcome. Consequently, generalizability of the result will depend mainly on whether the achievements of “usual care” in our population can be considered representable of “usual care” in other populations. Compared to the NAILED control group, the proportions reaching treatment targets has been similar or lower in observational studies from Sweden97 and internationally93-96, indicating that the results from the NAILED stroke trial should be reproducible in other populations.

General discussion

Serious hemorrhages

Incidence rate of ICrH The risk of an ICrH after the acute phase was 0.9%–1.1%, depending on the definition of ICrH in papers I and II. For ICH after IS, the risk was 0.4%–0.6% per year at risk in papers I and II and 0.04% in the reference population in paper I. The incidence rates of ICH in patients discharged with AP (0.4%–0.5%), was comparable with rates in the clopidogrel arm in the PROFESS study52 and higher than in the ASA arm in the SPS3 study54. The ICH rates in patients discharged with warfarin are comparable with the warfarin arm in IS and TIA patients included in studies of the NOACs rivaroxaban63 and dabigatran61. In the trial on apixaban, the incidence of ICH was, however, higher than in our populations62.

Incidence rate of all serious hemorrhage The risk of a serious hemorrhage in paper II was 2.5% per year at risk, 2.7% in patients discharged with AC treatment, and 2.4% in those discharged with AP. These rates are comparable with those in a Swedish Riksstroke-based study in patients with IS, 2001–200574. They also are comparable with rates of serious hemorrhages in AC-treated patients in a meta-analysis of RCTs of warfarin and

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AP-treated stroke patients with a definition of major hemorrhage similar to ours. However, they are more than double the risk of AP-treated patients in that meta-analysis70.

Factors associated with an increased risk of hemorrhage Thus, the incidence rates of ICH is 15 times higher after IS compared to the reference group in paper I. The rate of ICH in the IS population was roughly similar to rates in RCTs. For all serious hemorrhage incidence rates are comparable to rates in RCTs for AC, but higher for AP than in the RCTs.

Three mechanisms that can explain the increased risk of hemorrhage in IS and TIA patients are 1) Most IS and TIA patients are discharged with AT, associated with increased risk of hemorrhage. 2) Risk factors associated with vascular disease including ischemic stroke also increase the risk of hemorrhage. These factors include age, diabetes, hypertension, smoking and male sex23-26. The prevalence of these risk factors are high in the study- population in papers I and II. 3) The risk of hemorrhage seems to be higher in patients with manifest vascular disease than in patients with risk factors only, and particularly so in stroke patients. In RCTs patients with stroke had higher risk of ICrH compared with other patients with other cardiovascular diseases65, 135, 136.

In papers I and II the study populations were older and had more comorbidities compared with many RCTs. Higher prevalence of factors known to be associated with an increased risk of hemorrhagic events probably contributed to the higher incidence of serious hemorrhage in AP treated patients in paper II compared with AP RCTs. Consequently, we found higher incidence rates in older patients and patients with impaired functional status at discharge - two groups sparsely represented in clinical trials. The incidence rates was almost twice those of patients over compared to under age 75 years. An increased risk of hemorrhage in elderly is also observed in Åsberg et al and Li et al and is driven by an increase of upper GI hemorrhage74, 76. With a mean age of 75 years in paper II compared with 59-70 in the AP RCTs the increase in GI hemorrhages could explain some of the higher hemorrhage rates in our study.

In RCTs of recommended AT the benefit of decreased risk of new ischemic events outweighs the risk of a hemorrhage. Also, the cumulative incidence of serious hemorrhage observed in paper II (3.1% in 1 year and 8.5% in 5 years) is considerably lower than the risk of a new IS (11% and 26%) in meta-analysis of observational studies on the risk of recurrent IS37. However, in papers I and II, more than 40% of the patients were over 80 years age, representing patients who are not included in the RCTs. With the increased rate of hemorrhage in elderly, the question is if the risk–benefit ratio seen in RCTs is applicable to this population.

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For AC treatment, many models are available to estimate the risk of embolic ischemic events137 and hemorrhage138. Here, observational studies show that most patients with AF seem to benefit from AC treatment, and that with an increased risk of hemorrhage, the risk of embolic events increases even more139. A recent study shows an increased use of AC, especially among elderly, with a decreased rate of IS but an unchanged rate of serious hemorrhage140. In a RCT with a mean age of 82 years, including a small subgroup with IS and TIA patients, AC seems beneficial also in elderly compared with AP141.

S2TOP-BLEED142 represents one attempt to develop a prediction model for major bleeding in IS and TIA patients on AP. The model includes factors associated with increased risk of hemorrhage in papers I and II, such as impaired functional status, hypertension, prior hemorrhage or stroke, and male sex. In a validation of the scale, the authors could confirm that the risk of hemorrhage was associated with risk of new ischemic events, and despite diminishing, the benefit outweighed the risk143. In contrast, Li et al found that in patients aged >85 years, the risks and benefits of AP could possibly be equal76. In a recent study on data from all RCTs on ASA, Rothwell et al reported on data from all randomized trials on ASA that the main effect comes within the first weeks and that all ages benefit from it, but that there is no certain effect after 12 weeks144. The result from this study, together with the aforementioned observational studies raise the question of what the tipping point is at which risk outweighs benefit and what the timing for withdrawal in older and fragile patients should be, if any. More studies are needed.

Some steps are possible to reduce serious hemorrhage. In short-term use, proton pump inhibitors (PPI) could reduce the risk of upper GI hemorrhage with 70%–90%145 and the numbers needed to treat to prevent an upper GI hemorrhage decrease markedly with age76, but more studies on risks and benefits of long-term use of PPI are needed.

Also, better BP control could reduce the risk of serious hemorrhage. Hypertension is a risk factor for serious hemorrhage in IS and TIA patients135, 142,

146, 147 and in the multivariable analysis in paper II, a diagnosis of hypertension prior to IS or TIA was associated with an increased risk of serious hemorrhage. Hypertension is common: approximately 60% in papers I and II had a diagnosis of hypertension prior to their stroke or TIA, and 68%–78% were discharged with antihypertensive treatment. Improved BP control is important to reduce the risk of ICrH147. A BP >140 mmHg increases the risk of ICH after IS148-150 as well as of recurrent ICH151. Still, many patients do not reach the treatment target93-97, and measurements to improve BP control are further discussed below.

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In paper I, prior ICrH/ICH is strongly associated with a new ICrH/ICH after IS. Patients with prior ICH are at increased risk of new events, both IS and ICH39, 44, complicating decisions about AT treatment and the risk–benefit assessment. Observational studies suggests that restart of AC might be beneficial152-155, while the risk–benefit ratio is more uncertain in restarting AP153, 156 in observational studies. The results of ongoing RCTs are needed that assess the risk–benefit of restarting AC157 and AP158 in patients with ICH.

Interestingly, AT was not associated with an increased risk of serious hemorrhage or ICrH in the multivariable Cox regression analyses. Also, in contrast to the higher incidence of ICH the intervention group in the SPARCL trial83 we found no association of statins with increased risk of hemorrhage in papers I and II but rather an association with a decreased risk of ICrH/ICH. However, we know only the medication on discharge and nothing about its use during the follow-up. There is also, of course, a risk of selection bias, and because ours is an observational study, we cannot draw conclusions on causality.

Time trends In paper I, there is a decrease in ICrH day 31-365, despite an increased proportion of patients being discharged with AT the same period. Although we only can speculate, there is also a trend to a larger proportion being discharged with antihypertensives that might have contributed to the decrease in ICrH in the same period.

In paper I, during the 2000s, there was an increase of ICrH in the acute phase. This increase coincided with the introduction of thrombolysis, which is strongly associated with ICrH in the multivariable analysis in paper I. Patients over age 75 years are represented in RCTs on thrombolysis. Thrombolysis has been analysed in both RCTs and observational studies, and the benefit outweighs the known risk of ICrH, including in older patients159, 160.

Mortality ICrH is the most feared hemorrhagic complication75. In papers I and II, the 30-day fatality rates of ICrH, ICH, and GI hemorrhage were 24%–32%, 36%–42%, and 12%, similar to those described in previous studies19, 34, 74. In the group with mRS 0–2, 8 of 11 of patients with a hemorrhage who died within 30 days had a ICrH. A serious hemorrhage decreased the chance of 5-year survival in patients with mRS 0–2. In the group with mRS 3–5 at discharge, a serious hemorrhage did not affect survival at the group level, probably because of the high mortality, with 31% dead within the first year after discharge compared with 4.2% in patients with mRS 0–2. With the high mortality in the group with mRS 3–5, it is uncertain if secondary prevention might improve survival. On the other hand, the rates might have been even higher without secondary prevention.

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NAILED Papers III and IV showed that the nurse-led, telephone-based follow-up including medication titration was more efficient than usual care in improving BP and LDL-C levels and proportions reaching treatment target. The effect was significant at 12 months, and for BP, the effect increased with time. At 36 months, the difference between groups was 6.1/3.4 mmHg. Paper III showed that the effect was derived from the intervention with an interaction between group allocation and baseline values for both SBP and LDL-C; there were no significant differences between groups for participants already below treatment target at baseline. Among participants above target at baseline for SBP in paper III, the difference between the groups was 8.0 mmHg. In patients above target for SBP at baseline in the intervention group in paper IV, the SBP decreased by 20.9 mmHg, down to 130.8 mmHg at 36 months. Patients above target in the control group had a decrease to 140.0 mmHg, a difference between the groups of 9.2 mmHg. This outcome could be compared with the PROGRESS trial that showed a 9/4 mmHg lower BP in the intervention group compared with the control group, that rendered a RRR for a new stroke of 28%78.

Many efforts have targeted finding strategies to improve modifiable risk factors in patients after stroke. A recent update of the Cochrane review, “Interventions for improving modifiable risk factor control in the secondary prevention of stroke”, including results from paper III in this thesis, states that educational interventions alone seem to have no effect but that organizational interventions (including the NAILED stroke trial) might be associated with an improvement in achieving BP targets161. The interventions studied, however, are heterogeneous in design, outcomes, and duration. There is, for example, significant heterogeneity in the pooled results on BP in studies with organizational interventions. Dissection of the interventions in attempt to identify key components are not uncomplicated, but could improve conclusions about what seems to be successful. Four components characterizing the NAILED stroke trial are that it 1) was telephone-based), 2) was nurse-led, 3) offered the possibility of medicine titration, and 4) had a follow-up period of 3 years (paper IV). These components are discussed below.

Several studies have used telephone partly or completely in an intervention102, 106,

162, 163, including some with promising results on BP, as in papers III and IV105, 106, demonstrating its feasibility. Telephone-based follow-up can be useful for several reasons. It can be a low-resource tool, facilitate a hospital-based follow-up in regions where many patients live far from the hospital, and facilitate follow-up for patients with a low functional level.

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Primary contact with a nurse instead of a physician is also a possible resource-saving alternative. Several studies that have assessed nurse-led follow-up have indicated succes104, 161, 163, but as with other interventions, they vary in design and method, so distinguishing the useful elements might be complex. However, the combination of a nurse-led intervention with the possibility of adjusting medication within the trial105, 108, 163, 164, instead of recommending that the patient seek or be referred to the GP 97, 101, 106, seems to be positive.

We see in paper IV that most of the participants have the possibility of reaching the treatment target. The proportions of the intervention and control groups reaching their targets are quite different, with almost none in the intervention group with measurement above target in all four follow-ups. The strict study protocol instructs the study nurse to contact the study physician when a treatment target is not reached. In addition, the study physician must adjust the medical treatment as long as there is no medical contraindication. These factors might help explain the effect seen in the intervention group. The instruction to always act on measurements above treatment target minimizes therapeutic inertia, defined as: “providers’ failure to increase therapy when treatment goals are unmet”165. Factors associated with this inertia include the primary care setting, male sex, older age, SBP and/or DBP values close to normal and treatment with more than one antihypertensive drug166. Several of these factors could be applied to participants in the control group.

Paper IV shows that between titration and next follow-up, some participants go from under to above treatment target and some patients not in need of titration at one follow-up will need it the next. This change might be explained by one of several reasons, including 1) measurement errors (discussed above), 2) lack of persistence, and 3) BP variability.

Persistence declines soon after a stroke91, 92. In studies on BP, it is often various and low for antihypertensive and lipid-lowering treatments167-172. Lack of persistence is also associated with increased risk of recurrent stroke170, 171. Factors associated with decreased persistence include beliefs about the treatment, the necessity for the treatment, potential side-effects, and fear of over prescription. Support of next of-kin, institutional living, or a scheduled follow-up are associated with improved adherence in previous studies91, 92, 172-176.

The NAILED intervention included opportunity for the patient of discussing risks and benefits and understanding the indication for treatment might address some of the factors associated with lack of persistence. However, most interventions to improve persistence in a stroke/TIA population have failed to show positive results alone but might be beneficial together with other elements of follow-up161. The trend during the follow-up was that the proportion reaching treatment target

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increased for BP but remained the same for LDL-C after 12 months. Lack of persistence to statins could be one explanation, but persistence within NAILED has not yet been analysed, so no further conclusions can be drawn.

BP variability is well described in a stroke TIA population177, is reproducible178, and increases the risk of stroke179. Due to visit-to-visit variability, measuring BP on one occasion each year might be insufficient to capture all patients who could benefit from adjusted hypertensive treatment, and continued follow-up is needed also in participants below treatment target. For practical reasons and to reflect the clinical setting of usual follow-up, the BP measurements were taken at one visit in the nearest health-station. Ambulatory measurement or home measurement could be a way to capture more patients at risk106 but is outside the frame of the NAILED stroke trial and would need a different and possibly more resource-demanding set-up.

In paper IV, the follow-up period was at 36 months. Few studies on intervention of modifiable risk factors after stroke or TIA have had follow-up beyond 12 months99, 110, 180, and only one implemented intervention99 after 12 months. None of these trials with long-time follow-up have shown any significant effect on risk factor levels. In that sense the NAILED trial make a unique contribution. We showed that positive results with the intervention both during short-term and long-term follow-up and that the difference in mean BP and proportion reaching BP target increased over time. Only about 5% of participants in both the intervention and control groups had BP and LDL-C values within target at all follow-ups. This indicates that patients benefit from continuous follow-up, which is true for all patients, not only those who have values above treatment target at baseline.

43

Conclusions

• The risk of an ICrH was 1.97% per year at risk, within the first year after IS, 0.85% excluding the first 30 days.

• From 1998 to 2009 , the cumulative incidence of ICrH/ICH increased the first 30 days after IS. The cumulative incidence decreased day 31–365 after IS, despite an increased use of AT.

• The risk of a serious bleeding was 2.5% per year at risk, after discharge from an IS or TIA. The incidence of serious hemorrhage in patients discharged with AP was higher than in RCTs.

• Fragile patients such as the elderly and/or those with impaired functional status have higher incidence rates of hemorrhage. This together with a very high mortality makes secondary prevention challenging in these patients.

• A serious hemorrhage seems to increase the risk of mortality in patients with no or slight disability but not in patients with impaired functional status.

• Male sex and prior ICrH/ICH are associated with increased risk of ICrH/ICH after IS, and a prior diagnosis of hypertension is associated with a higher risk of all serious hemorrhages.

• The nurse-led, telephone-based intervention including titration of medication used in the NAILED stroke trial improved BP and LDL-C levels with larger proportions reaching treatment targets, both during short- and long-term follow-up.

• The effect of the NAILED trial intervention increased over time. There is a need for continuous, long-term follow-up to maintain control of risk factors after stroke and TIA.

44

Future perspectives In Sweden, incidence rates of stroke are declining, and mortality after a stroke is decreasing. However, the population is aging, and with less case fatality, the number of stroke survivors will increase. These patients have a high risk of new vascular events and need the best possible secondary prevention.

This thesis shows that a more active follow-up of patients after stroke or TIA is needed to improve secondary prevention.

More survivors result in a patient cohort with older average age and more comorbidities, a group that is usually underrepresented in RCTs. In these patients, with other risk profiles and prognosis, observational studies such as papers I and II are important because they complement RCTs. The observational studies showed an increased risk of serious hemorrhage in patients discharged with AP compared with RCTs. The risk–benefit ratio is uncertain in older patients and patients with more comorbidities, and it is reasonable to assess on regular basis the risk of hemorrhage and ischemic events and if any changes in medication should be made in these patients.

The incidence of ICrH was investigated in the Riksstroke population during 1998–2009, and the incidence of all serious hemorrhages in the NAILED population during 2010-2013. Since the start periods of these trials, NOACs have become the standard choice for preventing stroke in patients with AF. NOACs are associated with a decreased risk of ICrH compared with warfarin in the RCTs but there might be an increased risk of GI hemorrhage58-60. Observational studies show a safety profile in clinical setting similar to the RCTs131. A short period with DAPT after a minor stroke or high-risk TIA may be beneficial according to two recent RCTs and will possibly be prescribed to more patients55, 56. Whether use of NOAC and DAPT will affect future rates of hemorrhage in stroke and TIA patients needs to be analysed in unselected stroke and TIA populations. Rates in different categories of patients with different age and functional levels also need to be considered. With more than 40% of patients being over age 80 years, trials that focus on this patient group are warranted.

In the NAILED trial, we showed that a simple but systematic follow-up can improve modifiable risk factors. It was designed to be implemented in clinical practice and to include a large proportion of the target population. The results should therefore be generalizable, at least in Sweden and other high-income countries. The present results from the NAILED trial show that an intervention of short duration is not enough in a target population that suffers from a long-term increased risk of new events40, 181. The effect of our intervention increased

45

over time. Very few participants were below targeting all measurements, including patients below target at baseline. A lifelong follow-up, similar to the practice in people with diabetes, regardless of initial risk factor levels, seems necessary to reach an acceptable quality of secondary prevention after stroke and TIA.

With increasing numbers of stroke patients in low-and middle-income countries, strategies are needed to improve secondary treatment. The NAILED strategy may be possible, but any approach must be adapted to available resources.

Long-term persistence to medication as well as any effect of the intervention on clinical events will be evaluated in coming studies within the NAILED project.

46

Acknowledgements Although many times a lonely work, the work of this thesis would never been made without the contribution from many people involved in different ways. In particular, I would like to thank:

Participants in Riksstroke and NAILED stroke trial.

The study nurses of the NAILED stroke trial, for all your hard work. Without you there would be no N in NAILED.

The health care personnel working with Riksstroke.

Region Jämtland-Härjedalen, for founding the NAILED study and making research in Östersund possible.

Thomas Mooe, supervisor and father of the NAILED stroke trial, who introduced me to clinical research, gave me the trust to work with NAILED and who do not know how to shut down his computer.

Anna-Lotta Irewall, co-author, PhD colleague, future stroke colleague, for your critical eye in discussions over results, manuscripts and good advices. Looking forward to future co-work.

Lisa Bergström, co-author, PhD colleague, for thinking of me as a future co-worker in research in 2013.

Lars Söderström, statistician, for advice and support in the statistician jungle.

Magnus Gibson, Korosh Taheri and everyone in the stroke team, for your enthusiasm and great work, always with focus on the patient. It will be a pleasure to work with you all.

My family, Robert, Margareta, Henrik, and Marlene for always being supportive and convinced that I will manage anything and everything.

Helene, for making life fun, rich and interesting and for showing how to use every aspect of the brain. I love you.

Ebba and Alvar, who maybe not helped with this thesis but certainly made life better. You are my future. I love you.

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48

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