Tenecteplase and alteplase in acute ischaemic stroke thrombolysis: clinical and imaging study

Introduction: Intravenous thrombolysis in acute ischaemic stroke with alteplase improves clinical outcomes, but it has limited efficacy and is associated with increased risk of intracranial haemorrhage. An improved tissue plasminogen activator, tenecteplase, was evidenced to be at least equally effective with lower risk of haemorrhage in acute myocardial infarction thrombolysis. To date, two completed phase II randomised controlled studies comparing tenecteplase and alteplase in acute ischaemic strokes showed variable results. Methods: A literature review of thrombolytic agents used in myocardial infarction and acute ischaemic stroke was performed, followed by a retrospective investigation of the bolus-to- infusion delay of alteplase administration. The main focus of this thesis is the report of our single centre phase II randomised controlled trial that compared tenecteplase (0.25mg/kg, maximum 25mg) and alteplase (0.9mg/kg, maximum 90mg, 10% as the initial bolus, following by one hour infusion with the rest of the dose) in acute ischaemic stroke thrombolysis using advanced imaging as biomarkers. Imaging comprised baseline computed tomography (CT), CT perfusion (CTP) and CT angiography (CTA), and CT+CTA at 24-48 hours. The primary end-point was penumbral salvage (CTP-defined penumbra volume minus follow-up CT infarct volume). A sub-study of coagulation and fibrinolysis analysis of the two agents was performed by comparing a group of coagulation variables measured pre-treatment, 3-12 hours, and 24±3 hours post thrombolysis. An individual patient data (IPD) meta-analysis was carried out using all three completed tenecteplase/alteplase comparison studies in stroke thrombolysis. We compared clinical outcomes including modified Rankin scale at 3 months, early neurological improvement at 24 hours, intracerebral haemorrhage rate and mortality at 3 months between all three tenecteplase doses (0.1mg/kg, 0.25 mg/kg, and 0.4mg/kg) examined and standard alteplase. Imaging outcomes including penumbra salvage, recanalisation rates were also compared using the data from the two studies that had advance imaging carried out. Results: Delay between the initial bolus and the subsequent infusion in administration of alteplase is common. This may reduce the likelihood of achieving a good functional outcome. Among the 104 patients recruited in ATTEST trial, 71 contributed to the imaging primary outcome. No significant differences were observed for penumbral salvage [68 (SD 28) % tenecteplase vs 68 (SD 23) % alteplase], mean difference 1% (95% confidence interval -10%, 12%, p=0·81) or for any secondary end-point. The SICH incidence (1/52, 2% vs 2/51, 4%, by SITS-MOST definition, p=0·55; by ECASS-2 definition, 3/52, 6% tenecteplase vs 4/51, 8% alteplase, p=0.59) did not differed significantly. There was a trend towards lower ICH risk in the tenecteplase group (8/52 tenecteplase, 15% vs 14/51 alteplase, 29%, p=0·091). Compared to baseline, alteplase caused significant hypofibrinogenaemia (p=0.002), prolonged Prothrombin Time (PT) (p=0.011), hypoplasminogenaemia (p=0.001) and lower Factor V (p=0.002) at 3-12 hours after administration with persistent hypofibrinogenaemia at 24h (p=0.011), while only minor hypoplasminogenaemia (P=0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen (p<0.001) and fibrinogen (p=0.002) compared with alteplase. In a pooled analysis, tenecteplase 0.25mg/kg had the greatest odds to achieve early neurological improvement (OR [95%CI] 3.3 [1.5, 7.2], p=0.093), excellent functional outcome (mRS 0-1) at three months (OR [95%CI] 1.9 [0.8, 4.4], p= 0.28), with reduced odds of ICH (OR [95%CI] 0.6 [0.2, 1.8], P=0.43) compared with alteplase. Only 19 patients were treated with tenecteplase 0.4mg/kg, which showed increased odds of SICH compared with alteplase (OR [95% CI] 6.2 [0.7, 56.3]). In the two studies where advanced imaging was performed, the imaging outcomes did not differ in the IPD analysis. Conclusion: Tenecteplase 0.25 mg/kg has the potential to be a better alternative to alteplase. It can be given as a single bolus, does not cause disruption to systemic coagulation, and is possibly safer and more effective in clot lysis. Further phase III study to compare tenecteplase and alteplase in acute ischaemic stroke is warranted.

Pressure ulcer management in Oman: nurses’ knowledge and views

Background: Pressure ulcers (PrUs) have a significant impact on health system expenditure and patient’s quality of life. It is a global problem. Many studies were undertaken in regard to PrU prevention and management. In Oman, no studies have been conducted to investigate nurses’ knowledge on prevention and management of PrUs. The purpose of this descriptive sequential explanatory mixed-method study was to explore the nurses’ level of knowledge in relation to prevention and management of PrUs in Oman. Methods: A mixed method design was used and the study was conducted over two Phases. In Phase I, a questionnaire was developed to explore nurses’ knowledge on PrU, policy, and resources. The main section of the questionnaire was the Pieper-Zulkowski Pressure Ulcer knowledge test (PZ-PUKT) which tests the knowledge on PrU. Another two sections were developed including questions about wound policy and resources available for PrU prevention and management in Oman. The questionnaire was distributed to nurses who were working in surgical, medical, orthopaedic, CCU, and ICU wards/units in seven hospitals. In Phase II study, semi-structured qualitative interviews were conducted with 16 of the questionnaire respondents. Interviews took approximately 30 minutes, were recorded and transcribed verbatim. Qualitative data were analysed using the Knowledge, Attitudes and Practice (KAP) model as the a priori framework. Results: In Phase I, 478 questionnaires were analysed. The knowledge test results showed the overall mean percent score for correctly answered questions was 51% suggesting a low level of knowledge. There was a significant relationship between nurses’ knowledge and age (P=0.001) and between knowledge and years of experience (P=0.001) with knowledge increasing with age and years of experience. In Phase II, four themes were identified from the interviews: knowledge, attitude, and practice (framework themes) and perception of role. Findings indicated positive and negative attitudes towards the care of PrUs. Some nurses stated feeling rewarded when they see wounds improving while others said they could not work with patients independently because they lacked the knowledge and the skills needed. There was variation in the management of PrU between hospitals. Both studies indicated that the wound management policy did not include enough information to guide nurses. Conclusion: Overall the nurses’ level of knowledge on PrU was relatively low. Most nurses were not familiar with wound management policy or different PrU prevention and management strategies. Nurses are aware of the risk of PrUs and try their best to manage them with the available resources however more training is required.