Signild Åsberg

Statin Therapy and Outcome After Ischemic Stroke Systematic Review and Meta-Analysis of Observational Studies and Randomized Trials

Background and Purpose— Although experimental data suggest that statin therapy may improve neurological outcome after acute cerebral ischemia, the results from clinical studies are conflicting. We performed a systematic review and meta-analysis investigating the relationship between statin therapy and outcome after ischemic stroke. Methods— The primary analysis investigated statin therapy at stroke onset (prestroke statin use) and good functional outcome (modified Rankin score 0 to 2) and death. Secondary analyses included the following: (1) acute poststroke statin therapy (⩽72 hours after stroke), and (2) thrombolysis-treated patients. Results— The primary analysis included 113 148 subjects (27 studies). Among observational studies, statin treatment at stroke onset was associated with good functional outcome at 90 days (pooled odds ratio [OR], 1.41; 95% confidence interval [CI], 1.29–1.56; P<0.001), but not 1 year (OR, 1.12; 95% CI, 0.9–1.4; P=0.31), and with reduced fatality at 90 days (pooled OR, 0.71; 95% CI, 0.62–0.82; P<0.001) and 1 year (OR, 0.80; 95% CI, 0.67–0.95; P=0.01). In the single randomized controlled trial reporting 90-day functional outcome, statin treatment was associated with good outcome (OR, 1.5; 95% CI, 1.0–2.24; P=0.05). No reduction in fatality was observed on meta-analysis of data from 3 randomized controlled trials (P=0.9). In studies restricted to of thrombolysis-treated patients, an association between statins and increased fatality at 90 days was observed (pooled OR, 1.25; 95% CI, 1.02–1.52; P=0.03, 3 studies, 4339 patients). However, this association was no longer present after adjusting for age and stroke severity in the largest study (adjusted OR, 1.14; 95% CI, 0.90–1.44; 4012 patients). Conclusion— In the largest meta-analysis to date, statin therapy at stroke onset was associated with improved outcome, a finding not observed in studies restricted to thrombolysis-treated patients. Randomized trials of statin therapy in acute ischemic stroke are needed.

Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients With Atrial Fibrillation Insights From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial

Background—Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. Methods and Results—The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment,...Background— Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. Methods and Results— The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977–2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and of mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. Conclusions— GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Growth Differentiation Factor 15, a Marker of Oxidative Stress and Inflammation, for Risk Assessment in Patients with Atrial Fibrillation: Insights from the ARISTOTLE Trial

Background—Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. Methods and Results—The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment,...Background— Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation. Methods and Results— The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977–2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and of mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels. Conclusions— GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Ischemic Stroke and Secondary Prevention in Clinical Practice A Cohort Study of 14 529 Patients in the Swedish Stroke Register

Background and Purpose— Secondary prevention is recommended after stroke, but adherence to guidelines is unknown. We studied the prescription of antiplatelet drugs, angiotensin-converting enzyme inhibitors, statins, and anticoagulant drugs and their relation to risk of death. Methods— Patients with first-ever ischemic stroke in 2005 were registered in the Swedish Stroke Register. Odds ratios, hazard ratios, and 95% CIs were calculated using logistic and Cox proportional hazard regression models. Adjustments were performed for age, sex, cardiovascular risk factors, other drug therapies, and activities of daily living function. Results— In total, 14 529 patients with a mean age of 75.0 (±11.6) years were included. They were followed for 1.4 (±0.5) years: 52% had hypertension, 26% atrial fibrillation, 19% diabetes, and 15% were smokers. The odds ratio for prescription of antiplatelet was 2.20 (95% CI, 1.86 to 2.60) among the oldest patients (≥85 years of age) compared with the youngest (18 to 64 years of age). The corresponding odds ratio was 0.38 (0.32 to 0.45) for prescriptions of angiotensin-converting enzyme inhibitors, 0.09 (0.08 to 0.11) for statins, and 0.07 (0.05 to 0.09) for anticoagulant therapy. Prescription of statin and anticoagulant therapy was associated with reduced risk of death (hazard ratio, 0.78 [0.65 to 0.91] and hazard ratio, 0.58 [0.44 to 0.76], respectively) but not the prescription of antiplatelet drugs or angiotensin-converting enzyme inhibitors. Conclusions— The prescription of antiplatelet, angiotensin-converting enzyme inhibitors, statins, and anticoagulant therapy was strongly age related. Statin and anticoagulant therapy was associated with reduced risk of death and seemed to be underused among elderly patients. These findings should encourage physicians to follow todays guidelines for stroke care.

Trends in Stroke Treatment and Outcome between 1995 and 2010: Observations from Riks-Stroke, the Swedish Stroke Register

Background: Continuous changes in stroke treatment and care, as well as changes in stroke characteristics, may alter stroke outcome over time. The aim of this paper is to describe time trends for treatment and outcome data, and to discuss if any such changes could be attributed to quality changes in stroke care. Methods: Data from Riks-Stroke, the Swedish stroke register, were analyzed for the time period of 1995 through 2010. The total number of patients included was 320,181. The following parameters were included: use of computed tomography (CT), stroke unit care, thrombolysis, medication before and after the stroke, length of stay in hospital, and discharge destination. Three months after stroke, data regarding walking, toileting and dressing ability, as well social situation, were gathered. Survival status after 7, 27 and 90 days was registered. Results: In 1995, 53.9% of stroke patients were treated in stroke units. In 2010 this proportion had increased to 87.5%. Fewer patients were discharged to geriatric or rehabilitation departments in later years (23.6% in 2001 compared with 13.4% in 2010), but more were discharged directly home (44.2 vs. 52.4%) or home with home rehabilitation (0 vs. 10.7%). The need for home help service increased from 18.2% in 1995 to 22.1% in 2010. Regarding prevention, more patients were on warfarin, antihypertensives and statins both before and after the stroke. The functional outcome measures after 3 months did improve from 2001 to 2010. In 2001, 83.8% of patients were walking independently, while 85.6% were independent in 2010. For toileting, independence increased from 81.2 to 84.1%, and for dressing from 78.0 to 80.4%. Case fatality (CF) rates after 3 months increased from 18.7% (2001) to 20.0% (2010). This trend is driven by patients with severe strokes. Conclusions: Stroke outcomes may change over a relatively short time period. In some ways, the quality of care has improved. More stroke patients have CT, more patients are treated in stroke units and more have secondary prevention. Patients with milder strokes may have benefited more from these measures than patients with severe strokes. Increased CF rates for patients with severe stroke may be caused by shorter hospital stays, shorter in-hospital rehabilitation periods and lack of suitable care after discharge from hospital.

Antithrombotic Treatment Following Intracerebral Hemorrhage in Patients With and Without Atrial Fibrillation

Background and Purpose— Patients who survive intracerebral hemorrhage (ICH) often have compelling indications for anticoagulant and antiplatelet medication. This nationwide observational study aimed to determine the extent and predictors of antithrombotic treatment after ICH in Sweden. Methods— Patients with a first-ever ICH in the Swedish Stroke Register (Riksstroke) 2005 to 2012 who survived hospital discharge were included. Riksstroke data were individually linked with other national registers to determine comorbid conditions and dispensed prescriptions of antithrombotic agents. Results— Among the 2777 patients with atrial fibrillation (AF), the proportion with a dispensed prescription of antithrombotic agents was 8.5% (anticoagulants) and 36.6% (antiplatelet agents) within 6 months and 11.1% (anticoagulants) and 43.6% (antiplatelet agents) within 1 year. Among the 11 268 patients without AF, the corresponding figures were 1.6% (anticoagulants) and 13.8% (antiplatelet agents) within 6 months and 2.0% (anticoagulants) and 17.5% (antiplatelet agents) within 1 year. In patients with AF, predictors of anticoagulant treatment were less severe ICH, younger age, previous anticoagulation, valvular disease, and previous ischemic stroke. High CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke [doubled], vascular disease, age, and sex category [female]) scores did not correlate with anticoagulant treatment. There was a positive correlation between high CHA2DS2-VASc and HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol) scores (rs=0.590, P<0.001). Conclusions— In majority of patients who receive antithrombotic agents, treatment is initiated within 6 months of ICH. Still, many patients with compelling indications for antithrombotic treatment are not prescribed antithrombotic agents. Factors other than high risk of embolic stroke by CHA2DS2-VASc in ICH survivors with concurrent AF are used to guide the anticoagulant treatment decision in Swedish clinical practice.

Comparison of cardiovascular risk factors and survival in patients with ischemic or hemorrhagic stroke.

Background Differences in risk factor profiles between patients with ischemic and hemorrhagic stroke may have an impact on subsequent mortality. Aim To explore cardiovascular disease risk factors, including the CHADS2 score, with survival after ischemic or hemorrhagic stroke. Methods Between 2001 and 2005, 87 111 (83%) ischemic stroke, 12 497 (12%) hemorrhagic stroke, and 5435 (5%) patients with unspecified stroke were identified in the Swedish Stroke Register. Data on gender, age, and cardiovascular disease risk factors were linked to the Swedish Hospital Discharge and Cause of Death Registers. Adjusted odds and hazard ratios and 95% confidence interval were calculated using logistic and Cox proportional hazard regression models. Results Hemorrhagic stroke patients were younger than ischemic stroke patients. All cardiovascular disease risk factors studied, alone or combined in the CHADS2 score, were associated with higher odds ratios for ischemic stroke vs. hemorrhagic stroke. Higher CHADS2 scores and all studied risk factors except hypertension were associated with higher odds ratio for death by ischemic stroke than hemorrhagic stroke. Ischemic stroke was associated with lower early mortality (within 30 days) vs. hemorrhagic stroke (hazard ratio = 0·28, confidence interval 0·27 to 0·29). Conclusions Patients with hemorrhagic stroke had a higher risk of dying within the first 30 days after stroke, but the risk of death was similar in the two groups after one-month. Hypertension was the only cardiovascular disease risk factor associated with an increased mortality rate for hemorrhagic stroke as compared to ischemic stroke.

Hemorrhage after ischemic stroke – relation to age and previous hemorrhage in a nationwide cohort of 58 868 patients

Background In randomized controlled trials of secondary prevention after stroke, the risk of hemorrhage varies between 1% and 5% per year in patients with antithrombotic therapy, i.e. anticoagulants and antiplatelets. Aim To explore the rate and the risk of hemorrhage after stroke in a nationwide cohort. Methods We identified 58 868 first ever ischemic stroke patients in the Swedish Stroke Register during 2001 to 2005 (=index stroke) and followed them by record linkage to the National Patient Register. Rates of hemorrhage and hazard ratios, for comparisons of rates between subgroups, were calculated. Results Of the 58 586 ischemic stroke patients identified, 5527 (9·4%) had a history of hemorrhage. During follow-up (mean 2·0 years), 2876 patients endured a hemorrhage, giving an average hemorrhage rate of 2·6 (95% confidence interval 2·5–2·7) per 100 person-years. After index stroke, 11% of the patients were discharged with anticoagulants, and 79% with antiplatelets. Given the differences in baseline characteristics, the hemorrhage rates (per 100 person-years) were 2·5 (95% confidence interval 2·2–2·8), 2·4 (95% confidence interval 2·3–2·5), and 3·8 (95% confidence interval 3·5–4·2) in patients prescribed anticoagulants, antiplatelets, and no antithrombotics, respectively. There was an increased risk of hemorrhage in patients ≥75 years compared with those <75 years (hazard ratio = 1·61, 95% confidence interval 1·49–1·73) and in patients with previous hemorrhages compared with those without (hazard ratio = 1·82, 95% confidence interval 1·64–2·02). Conclusions When antithrombotics were used in large-scale clinical practice, the observed rates of hemorrhage were similar with anticoagulant therapy but increased with antiplatelet therapy compared with rates reported in randomized controlled trials. Old age and previous hemorrhage were associated with an increased risk of hemorrhage after an ischemic stroke.

Statin therapy and the risk of intracerebral haemorrhage: a nationwide observational study:

Background The association between statin therapy and intracerebral haemorrhage is still unclear. The aim was to investigate whether prior use of statin was associated with risk of intracerebral haemorrhage. Methods Between 2006 and 2009, we identified 7696 cases of intracerebral haemorrhage that were first-ever strokes in the Swedish Stroke Register and 14 670 stroke-free controls that were matched on age and gender in the Population Register. Drug therapy at the time of intracerebral haemorrhage was extracted from the Drug Prescription Register. The risk of intracerebral haemorrhage with statins was estimated by conditional logistic regression. Results In cases and controls, the median age was 73 years and 53% were men. Intracerebral haemorrhage cases had higher prevalence of antithrombotic therapy, hypertension, and diabetes than controls. Statins were used by 1276 (16.6%) of the intracerebral haemorrhage cases and by 2552 (17.4%) of the controls. The crude odds ratios of intracerebral haemorrhage did not differ significantly between patients with and without statins, but after adjustment for antithrombotic therapy, hypertension, and diabetes, patients with statins had a decreased risk of intracerebral haemorrhage (odds ratio = 0.68, 95% confidence interval, 0.63-0.74). The highest proportion (>20%) of antecedent statins was seen in the 70-84 age group, for both cases and controls. Conclusions In this matched case-controlled study, statin therapy was associated with a decreased risk of incident intracerebral haemorrhage. Future studies on risk of stroke with statin therapy after intracerebral haemorrhage are needed.

National registry‐based case–control study: comorbidity and stroke in young adults

Stroke is overrepresented in cohorts of young adults with chronic diseases. The prevalence and impact of comorbidity among young stroke patients have not been compared with individuals without stroke. Our aim was to investigate the association between comorbidity and stroke in young adults.