Karsten Bruins Slot

Impact of functional status at six months on long term survival in patients with ischaemic stroke : prospective cohort studies

Objective To estimate the impact on long term survival of functional status at six months after ischaemic stroke. Design Prospective cohort study. Settings Three cohorts: Oxfordshire community stroke project, Lothian stroke register, and the first international stroke trial (in the United Kingdom). Participants 7710 patients with ischaemic stroke registered between 1981 and 2000 and followed up for a maximum of 19 years. Main outcome measures Functional status at six months after stroke assessed with modified Rankin scale or “two simple questions.” Mortality during follow-up. Survival analysis with Kaplan-Meier curves, log rank test, and Cox’s regression model. Results In a combined analysis of all three cohorts, among patients who survived to assessment six months after the index stroke, the subsequent median length of survival among those independent in daily living and those dependent was 9.7 years (95% confidence interval 8.9 to 10.6) and 6.0 years (5.7 to 6.4), respectively. In a combined analysis of the Oxfordshire and Lothian cohorts, subsequent median survival fell progressively from 12.9 years (10.0 to 15.9) for patients with a Rankin score of 0-1 at six months after the stroke to 2.5 years (1.4 to 3.5) for patients with a Rankin score of 5. All previously stated differences in median survival were significant (log rank test P<0.001). The influence of functional outcome on survival remained significant (P<0.05) in each cohort after adjustment for relevant covariates (such as age, presence of atrial fibrillation, visible infarct on computed tomography, subtype of stroke) in a Cox’s regression model. Conclusion Functional status six months after an ischaemic stroke is associated with long term survival. Early interventions that reduce dependency at six months might have positive effects on long term survival.

Risk Factors for Intracranial Hemorrhage in Acute Ischemic Stroke Patients Treated With Recombinant Tissue Plasminogen Activator: A Systematic Review and Meta-Analysis of 55 Studies

Background and Purpose— Recombinant tissue plasminogen activator (rtPA) is an effective treatment for acute ischemic stroke but is associated with an increased risk of intracranial hemorrhage (ICH). We sought to identify the risk factors for ICH with a systematic review of the published literature. Methods— We searched for studies of rtPA-treated stroke patients that reported an association between a variable measured before rtPA infusion and clinically important ICH (parenchymal ICH or ICH associated with clinical deterioration). We calculated associations between baseline variables and ICH with random-effect meta-analyses. Results— We identified 55 studies that measured 43 baseline variables in 65 264 acute ischemic stroke patients. Post-rtPA ICH was associated with higher age (odds ratio, 1.03 per year; 95% confidence interval, 1.01–1.04), higher stroke severity (odds ratio, 1.08 per National Institutes of Health Stroke Scale point; 95% confidence interval, 1.06–1.11), and higher glucose (odds ratio, 1.10 per mmol/L; 95% confidence interval, 1.05–1.14). There was approximately a doubling of the odds of ICH with the presence of atrial fibrillation, congestive heart failure, renal impairment, previous antiplatelet agents, leukoaraiosis, and a visible acute cerebral ischemic lesion on pretreatment brain imaging. Little of the variation in the sizes of the associations among different studies was explained by the source of the cohort, definition of ICH, or degree of adjustment for confounding variables. Conclusions— Individual baseline variables were modestly associated with post-rtPA ICH. Prediction of post-rtPA ICH therefore is likely to be difficult if based on single clinical or imaging factors alone. These observational data do not provide a reliable method for the individualization of treatment according to predicted ICH risk.

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

BackgroundIntravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit.DesignInternational, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics.ResultsThe initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials.ConclusionThe data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials.Trial registrationISRCTN25765518

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health‐related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two‐day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run‐in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.

Factor Xa Inhibitors vs Warfarin for Preventing Stroke and Thromboembolism in Patients With Atrial Fibrillation

CLINICAL QUESTION Is treatment with factor Xa inhibitors associated with better efficacy and safety compared with the vitamin K antagonist warfarin for preventing strokes or other systemic embolic events in patients with atrial fibrillation? BOTTOM LINE Compared with warfarin, factor Xa inhibitors are associated with a lower risk of stroke and other systemic embolic events in patients with atrial fibrillation. Factor Xa inhibitors were associated with lower rates of intracranial hemorrhage and mortality compared with warfarin. Factor Xa inhibitors were associated with a reduction in major bleeding events, but there was heterogeneity between the included studies, and the reduction was not statistically significant in a prespecified sensitivity analysis.

EPITHET--where next?

Comment on EPITHET: failed chance or new hope? Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial.

Haemorrhagic transformation of a recent silent cerebral infarct during thrombolytic stroke treatment.

We present a patient in her 60s who was admitted with a sudden loss of power in her right arm and leg, right sided facial weakness, and difficulties with speaking. An acute ischaemic stroke in the left hemisphere was diagnosed and the patient received intravenous thrombolytic treatment. Treatment was stopped halfway as a cerebral haemorrhage was suspected. A small haemorrhage in the right frontal cortex was thereafter identified on computed tomography (CT) and magnetic resonance imaging scans. Re-examination of the CT scan taken before the start of thrombolytic treatment revealed a recent silent infarct with cortical petechial haemorrhage at this site. A month later the patient still suffered from a partial paralysis in her right arm and leg, but could now walk without help; she did not have any lasting symptoms of the haemorrhage. Our case illustrates that a recent silent infarct can be a cause of a haemorrhage at an unexpected site during thrombolytic treatment.

New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk

The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals and who could benefit from additional LDL-C-lowering therapy or experience side effects of statins. Fresh approaches are needed to identify promising drug targets early and develop them efficiently. The Cardiovascular Round Table of the European Society of Cardiology (ESC) convened a workshop to discuss new lipid-lowering strategies for cardiovascular risk reduction. Opportunities to improve treatment approaches and the efficient study of new therapies were explored. Circulating biomarkers may not be fully reliable proxy indicators of the relationship between treatment effect and clinical outcome. Mendelian randomization studies may better inform development strategies and refine treatment targets before Phase 3. Trials should match the drug to appropriate lipid and patient profile, and guidelines may move towards a precision-based approach to individual patient management. Stakeholder collaboration is needed to ensure continued innovation and better international coordination of both regulatory aspects and guidelines. It should be noted that risk may also be addressed through increased attention to other risk factors such as smoking, hypertension, overweight, and inactivity.