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Desmoteplase for Acute Ischaemic Stroke

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Desmoteplase for Acute Ischaemic Stroke Desmoteplase for acute ischaemic stroke September 2011 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research September 2011 Desmoteplase for acute ischaemic stroke Target group • Acute ischaemic stroke – within 3 to 9 hours of the onset of symptoms. Technology description Desmoteplase (LU-AE-03329) is a recombinant fibrin-specific plasminogen activator derived from the saliva of the vampire bat, Desmodus rotundus. It catalyses the conversion of plasminogen to plasmin, the enzyme responsible for breaking down fibrin blood clots. Structurally, desmoteplase is very similar to human tissue-type plasminogen activator (tPA), but its activity is 200 times more fibrin-specific than tPA. It therefore does not cause systemic plasminogen activation and fibrinogen depletion. Desmoteplase is intended to be used for the treatment of patients with acute ischaemic stroke in the extended time window of 3 to 9 hours after the onset of symptoms. It is administered as an IV bolus at 90µg/kg (dose used in ongoing phase III clinical trials). Innovation and/or advantages If licensed, desmoteplase would extend the time window for thrombolysis in acute stroke from 3 hours to 9 hours. In addition, because it is highly fibrin-specific it may not have some of the negative effects of tPA (like systemic plasminogen activation and neurotoxicity). Developer Lundbeck. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government priority area This topic is relevant to Equity and Excellence: Liberating the NHS (2010); The National Stroke Strategy (2007); The National Service Framework for Older People (2001) and The National Service Framework for Coronary Heart Disease (2000). Relevant guidance • NICE technology appraisal. Alteplase for the treatment of acute ischaemic stroke. 2007 (review April 2010)1. • NICE clinical guideline in development. Rehabilitation after stroke. Expected April 20122. • NICE clinical guideline. Stroke: the diagnosis and acute management of stroke and transient ischaemic attacks (TIA). 20083. • University of Warwick and Joint Royal Colleges Ambulance Liaison Committee care guideline. Stroke/transient ischaemic attack (TIA) - updated guidance. 20094. • SIGN. Management of patients with stroke or TIA: assessment, investigation, immediate management and secondary prevention. 20085. • The Royal College of Physicians. National clinical guideline for stroke, 3rd edition. 20086. • American College of Chest Physicians Evidence-Based clinical practice guideline. Antithrombotic and thrombolytic therapy for ischemic stroke. 20087. 2 September 2011 • American Heart Association/American Stroke Association Stroke Council. Guidelines for the early management of adults with ischemic stroke. 20078. Clinical need and burden of disease Acute ischaemic stroke is usually caused by cerebral artery thrombosis or embolism, and accounts for 85% of all strokes9, with the remaining 15% being due to intracranial haemorrhage4. Men are at greater risk of stroke than women, and 75% of strokes occur in people aged 65 or over9. Stroke is the third most common cause of death in England and Wales, and the leading cause of severe disability10. Each year in England and Wales, approximately 130,000 people have a first or recurrent stroke11. The risk of recurrent stroke within five years of a first stroke is between 30% and 43%6. In 2009-10, there were 90,822 emergency cases of stroke (ICD10 I60-I64) and 182,944 finished consultant episodes recorded in England12. Following a stroke, approximately 23% of people die within 30 days3, and of initial stroke survivors only 30%-40% are alive after 3 years13. Stroke accounted for 31,613 deaths in England and Wales in 2009 (ICD10 I60-I64)14. More than 900,000 people in England are living with the effects of stroke, with half of these being dependent on other people for help with everyday activities3. A UK study found that 37% of stroke patients presented to hospital within 3 hours of symptom onset15. The median time from stroke to first brain imaging (required to exclude intracranial haemorrhage) is 27 hours in the UK, with fewer than half of patients undergoing brain imaging within 24 hours of symptom onset, and only 15% of patients are admitted to a specialist stroke unit on the same day as their stroke occurs16. The annual cost of stroke in the England has been estimated at around £7 billion3. This comprises direct costs to the NHS of £2.8 billion, costs of informal care of £2.4 billion, and costs because of lost productivity and disability of £1.8 billion3. Existing comparators and treatments Standard pharmacological treatment for acute ischaemic stroke include thrombolytic therapy with alteplase within 3 hours of symptom onset and anti-platelet treatment with aspirin, as soon as possible and within 24 hours of symptom onset1,3. Alternative antiplatelet agents, such as clopidrogel or modified-release dipyridamole, are given if the person with acute ischaemic stroke is allergic or intolerant to aspirin3,13. Alteplase is not indicated for children under 18 years, or adults over 80 years1 and thrombolytic therapy is associated with a risk of bleeding complications, the most important of which being haemorrhagic stroke (occurring in 0.5 to 6.0% of patients3,17), resulting in high mortality and long-term disability among survivors. Efficacy and safety Trial DIAS-4, NCT00856661, 12649A; DIAS-3, NCT00790920, 12402A; desmoteplase or placebo; phase III. desmoteplase or placebo; phase III. Sponsor H. Lundbeck A/S. H. Lundbeck A/S. Status Ongoing. Ongoing. Source of Trial registry18. Trial registry19. information Location EU (inc UK), USA, Canada and other EU, South East Asia and Western Pacific. countries. 3 September 2011 Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=400 (planned); adults; acute ischaemic n=400 (planned); adults; acute ischaemic and schedule stroke; NIHSS scorea 4-24; treatment stroke; NIHSS score 4-24; treatment within 3-9 hrs of symptom onset; vessel within 3-9 hrs of symptom onset; vessel occlusion or high grade stenosis in occlusion or high grade stenosis in proximal cerebral arteries; not treated proximal cerebral arteries; not treated with thrombolytic agent, heparin or with thrombolytic agent, heparin or inhibitors of glycoprotein IIb-IIa (except inhibitors of glycoprotein IIb-IIa (except single oral platelet inhibitors like aspirin) single oral platelet inhibitors like aspirin) in the past 72, 48 and 72 hrs respectively; in the past 72, 48 and 72 hrs respectively; not on treatment with oral anticoagulants; not on treatment with oral anticoagulants; normal prothrombin and/or partial normal prothrombin and/or partial thromboplastin time. thromboplastin time. Randomised to desmoteplase 90µg/kg or Randomised to desmoteplase 90µg/kg or placebo. placebo. Follow-up Received treatment within 3-9 hrs of onset Received treatment within 3-9 hrs of onset of stroke symptoms, then 90 days follow of stroke symptoms, then 90 days follow up. up. Primary Modified Rankin Scale (mRS) score. mRS score. outcome/s Secondary NIHSS score. NIHSS score. outcome/s Expected Study expected to complete July 2012. Study expected to complete September reporting date 2011. Trial DIAS-2, NCT00111852, DSP-MD-01; DIAS, NCT00638781, PN01-CLD- desmoteplase or placebo; phase III. 000001/01; desmoteplase or placebo; phase II. Sponsor Forest Laboratories. PAION Deutschland GmbH. Status Published. Published. Source of Publication20, trial registry21. Publication22, trial registry23. information Location EU, USA, Canada, Australia and EU (inc UK), Australia and Singapore. Singapore. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=193; adults; acute ischaemic stroke; n=104 (47 in part 1, 57 in part 2); adults; and schedule NIHSS score 4-24; treatment within 3-9 acute ischaemic stroke; NIHSS score 4- hrs of symptom onset; clinical signs of 20; treatment within 3-9 hrs of symptom cerebral hemispheric infarction; ≥ 20% onset; ≥ 20% perfusion/diffusion penumbra; received study medication mismatch involving hemispheric grey within 60 mins of diagnostic imaging; not matter; treated within 30 mins of MRI; treated with heparin (except low dose SC not on treatment with inhibitors of platelet heparin) or inhibitors of glycoprotein IIb- function. IIa (except single oral platelet inhibitors Part 1: randomised to desmoteplase at like aspirin) in the past 48 and 72 hrs 25mg, 37.5mg, 50mg or placebo. After respectively; not on treatment with oral enrolment of 30th patient, 37.5 and 50mg anticoagulants; normal prothrombin arms discontinued due to occurrence of and/or partial thromboplastin time. symptomatic ICH. Trial halted after Randomised to desmoteplase 90µg/kg, recruitment of 47th patient due to high 125µg/kg or placebo. symptomatic ICH rates in 25mg arm. Part 2: randomised to desmoteplase a NIHSS – National Institute of Health stroke scale, a 15-item neurologic examination scale used to evaluate the effect of acute cerebral infarction on levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. 4 September 2011 62.5µg/kg,
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