Naftidrofuryl for acute stroke
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of naftidrofuryl in patients in the acute phase of stroke.
Background
Stroke is the third most common cause of death and the commonest cause of disability in the western world. Stroke greatly adds to the burden on patients, carers, medical practitioners and health resources. Enormous efforts have focused on the development of drugs to limit brain damage caused by stroke. The development of drugs to limit brain damage caused by stroke continues but no routine effective treatment has yet been identified.
Ischaemia occurs where the blood supply falls below the requirement of local metabolic demand. This is the normal cause of cerebral infarction. The severity of neuronal tissue damage caused by ischaemia depends on the spatial depth and duration of reduced blood flow. One of the first biological responses to a decrease in local blood flow is the rapid development of collateral circulations. However, these collateral circulations may be slow in developing or may be incomplete in patients with arterial disease. The boundary between the normally perfused area and the ischaemic core is not clear cut but the area between these two regions is called the ischaemic penumbra where moderate blood flow exists. Reperfusion of the penumbra within a given time allows neurons to recover; however, as time goes by damage to this area becomes irreversible. The outcome in the ischaemic area depends on a balance between cells dying where their metabolic needs have not been met and this in turn reduces the overall metabolic demand. Various attempts have been made in the past to modify this situation. One approach could be to improve the efficiency of substrate use. One candidate agent, naftidrofuryl, has been shown to promote glucose consumption, increase the supply of adenosine triphosphate (ATP) and reduce levels of lactate in normal animal brain (Meynaud 1973) and in an animal model of total cerebral ischaemia (Meynaud 1975). If this occurs in human ischaemic brains then naftidrofuryl could offer protection against the harmful metabolic effects of cerebral ischaemia.
Naftidrofuryl is the acid oxalate of N‐diethylaminoethyl‐beta‐(naphthyl‐1)‐beta‐tetra‐hydrofuryl‐isobutyrate. It has been shown in the past to be non‐toxic in animals and man (Robinson 1972). Naftidrofuryl is a 5‐HT2 serotonergic antagonist that prevents platelet aggregation and enhances metabolism without increasing oxygen consumption in damaged brain tissue in vitro, in animal experiments and in humans (Davis 1988; Leponcin 1982; Maloteaux 1986; Yesavage 1982).
Rationale for undertaking this review
Naftidrofuryl has been removed from the market for use in acute stroke in the UK though there is some evidence in the literature to support the safe use of naftidrofuryl in acute stroke. However, no systematic review of the literature has been performed. Therefore, we aim to systematically review all of the available evidence to assess whether naftidrofuryl in the acute phase of stroke (defined as within seven days post ictus) can impact on the risk of early death and late death or disability.
Objectives
To assess the effects of naftidrofuryl in patients in the acute phase of stroke.
Methods
Criteria for considering studies for this review
Types of studies
All published and unpublished randomised controlled trials that evaluate the efficacy of naftidrofuryl or its analogues in acute stroke patients (within seven days post ictus) will be considered in this review. Studies of patients with subarachnoid haemorrhage will be excluded.
Types of participants
Any individual with acute ischaemic or haemorrhagic stroke (defined as within seven days post ictus) that has been diagnosed by a medical practitioner, or confirmed by a computerised tomography (CT) scan, will be considered eligible for inclusion.
Types of interventions
All doses of naftidrofuryl or its analogues (defined as praxilene, dusodril, LS121, artocoron, EU1806, gevatran, iridus, sodipryl, di‐actane, and Vascuprax) for acute stroke will be considered such as:
(1) any oral or intravenous treatment versus no treatment or placebo;
(2) any oral or intravenous treatment in combination with a second agent versus second agent alone;
(3) any oral or intravenous treatment versus any other treatment (these studies will be analysed separately from the other studies).
Types of outcome measures
Primary outcome measures
(1) Late death (at end of scheduled follow up)
(2) Late death or disability or dependency (at end of scheduled follow up)
Secondary outcome measures
(1) Early death (within one month of randomisation)
(2) Early death or deterioration (within one month of randomisation)
(3) Quality of life (at end of scheduled follow up)
(4) Length of stay
(5) Stroke recurrence (at any time during scheduled follow up)
(6) Discharge site (death, institution, home)
(7) Blood pressure
(8) Serious adverse events (requiring withdrawal of the treatment)
(9) Minor adverse events (not requiring withdrawal of the treatment)
Search methods for identification of studies
Electronic databases
We will conduct searches of the following bibliographic databases and ongoing trials and research registers:
(1) the Cochrane Stroke Group Specialised Register;
(2) the Cochrane Central Register of Controlled Clinical Trials (CENTRAL), (TheCochrane Library, latest issue);
(3) the Cochrane Database of Systematic Reviews (TheCochrane Library, latest issue);
(4) the Database of Abstracts of Reviews of Effects (TheCochrane Library, latest issue);
(5) MEDLINE (1966 to 2005);
(6) EMBASE (1980 to 2005);
(7) Science Citation Index (1981 to 2005);
(8) National Research Register (including MRC Clinical Trials Directory), (latest issue);
(9) LILACS Database (Latin American and Caribbean Health Science Literature) (1982 to 2005);
(10) meta Register of Controlled Trials (m RCT) (http://www.controlled‐trials.com/);
(11) SUMsearch, which will search the Internet for medical evidence (http://sumsearch.uthscsa.edu/).
We will use the following search strategy, employing a combination of controlled vocabulary (/) and free text terms (tw), for MEDLINE (Ovid) and we will adapt it to suit the other databases. Due to the specific nature of the intervention under investigation for this review, we anticipate that relatively few references will be retrieved; therefore, we will not use the Cochrane search strategy for locating randomised controlled trials.
Search strategy for MEDLINE (OVID)
1. Cerebrovascular disorders/
2. exp Brain ischemia/
3. Carotid artery diseases/ or Carotid artery thrombosis/
4. exp Cerebrovascular accident/
5. exp Hypoxia‐ischemia, brain/
6. Cerebral arterial diseases/ or Intracranial arterial diseases/
7. exp "Intracranial embolism and thrombosis"/
8. exp basal ganglia cerebrovascular disease/
9. exp intracranial hemorrhages/
10. (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or transient isch?emic attack$ or tia$).tw.
11. (brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation).tw.
12. (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$).tw.
13. 11 and 12
14. (brain or cerebral or intracranial or subarachnoid).tw.
15. (haemorrhage or hemorrhage or haematoma or hematoma or aneurysm or bleed$).tw.
16. 14 and 15
17. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 13 or 16
18. nafronyl/ or furans/
19. (naftidrofur$ or nafronyl$ or naftifurin or naftirofuryl or naphthydrofur$ or naphthohydrofur$).tw.
20. (praxilene or dusodril or LS 121 or LS121 or artocoron or EU 1806 or EU1806 or gevatran or iridus or sodipryl or di‐actane or vascuprax).tw.
21. 18 or 19 or 20
22. 17 and 21
23. limit 22 to human
This is a draft search strategy that we will adapt to include additional search terms where necessary.
References from published studies
We will scan the bibliographies of the identified studies and previous reviews of acute stroke management for possible references to randomised controlled trials.
Unpublished material
We will obtain details of unpublished and ongoing trials through correspondence with authors of identified studies and with pharmaceutical companies, and through searching the metaRegister of Controlled Trials.
Conference proceedings
We will scan the abstracts from major stroke conference proceedings over the past five years to identify further randomised controlled trials. To avoid duplication, we will only handsearch conference proceedings not already searched by the Cochrane Stroke Group.
Adverse events
We will scan all papers identified from searching the bibliographic databases and ongoing trials and research registers for adverse events or side effects.
Language
We will not impose any language restrictions throughout this systematic review and we will seek translations of non‐English language papers where necessary.
Data collection and analysis
Study selection
Two authors (JL‐B & FB‐H) will independently screen the titles and abstracts of all publications obtained by the search to assess the eligibility of the article. If it is clear that thearticle does not refer to a randomised controlled trial on naftidrofuryl, it will be excluded. For all articles that could be an eligible trial the complete article will be obtained, either by accessing the full text through the Internet or by placing a request through interlibrary loans. These full‐text articles will then be inspected to assess their relevance to this systematic review. Any disagreements will be resolved through discussion with the review team. Excluded studies and reasons for exclusion will be reported in the 'Characteristics of excluded studies' table.
Assessment of methodological quality
The quality assessment will include an evaluation of the following component for each included trial, since there is some evidence that these are associated with biased estimates of treatment effect (Juni 2001):
(1) the method of generation of the randomisation sequence;
(2) the method of allocation concealment (it will be considered adequate if the assignment cannot be foreseen);
(3) who was blinded or not blinded (participants, clinicians, outcome assessors);
(4) how many participants were lost to follow up in each arm (split into post‐randomisation exclusions and later losses if possible);
(5) whether the participants were analysed in the groups to which they were originally randomised (intention to treat).
In addition, the quality assessment will also include:
(6) sample size calculation declared;
(7) inclusion and exclusion criteria defined;
(8) time to follow up;
(9) baseline comparability of severity of age, gender, and time since ictus;
(10) conflict of interest;
(11) appropriateness of statistical analyses (this criterion will be considered if the original data cannot be extracted from the publication).
We will record this information in the 'Characteristics of included studies' table and a description of the quality of each study will be given based on these components.
Data extraction
Two authors (JL‐B and FB‐H) will perform data extraction independently and any differences will be resolved through discussion with the review team. Where possible, we will obtain any missing data from the trial authors. We will use a data collection form in order to summarise the information from the trials. One author (JL‐B) will enter and check the data. Where available, we will seek individual patient data from the original trialists, which will be re‐analysed and the resulting group data used in preference to the published data.
Analysis
For studies with a similar type of intervention, for example oral naftidrofuryl, we will perform a meta‐analysis to calculate a weighted treatment effect across trials using a random‐effects model (DerSimonian and Laird model). The results will be expressed as odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes, and mean differences (WMD) with 95% CI for continuous outcomes. The results will also be expressed as the number needed to treat, where appropriate, for a range of plausible control event rates. Where it is not possible to perform a meta‐analysis, either due to too much heterogeneity or where there is a lack of evidence, we will summarise the data for each trial.
We will assess heterogeneity between the trials using I2 (Higgins 2002). If substantial heterogeneity (I2 greater than 50%) exists between studies for the primary outcome, we will explore reasons for the heterogeneity, such as disease severity, dosage and duration of treatment, type of stroke (ischaemia or haemorrhage). We may also conduct sensitivity analyses to examine the effects of excluding studies with lower reported methodological quality.
We will perform further adjusted analyses using the individual patient data, where adequate information is given. Multivariate logistic regression models will be built and augmented to assess the effects of the ages of participants examined, stroke type (ischaemia or haemorrhage), route of administration (oral, intravenous), timing and length of follow up as described by the trialists, on the efficacy of naftidrofuryl in acute stroke. Data will be expressed as OR with 95% CI for dichotomous outcomes.
Data relating to disability or dependency will be dichotomised irrespective of scale used, (e.g. Barthel Index 0 to 55; modified Rankin score 3 to 5). Where non‐consistent cut offs have been used across trials, the raw individual patient data will be used to create consistent categories. Where more than one disability or dependency measurement scale has been used within a trial, the most frequently used measurement scale across trials will be used for the primary analysis. We will then conduct sensitivity analyses to examine the effects of the individual measurement scales. Deterioration is defined as any worsening in severity of stroke within seven days post ictus, as measured using a recognised and validated assessment (for example, the Scandinavian Neurological Stroke Scale).
Quasi‐randomised and non‐randomised controlled studies will be listed, but not discussed further. Studies relating to adverse events will be described qualitatively.
Other
Where there is uncertainty, we will contact trial authors for clarification.
