Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform an assessment of the manufacturer's submission on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The ERG report for this technology appraisal was prepared by the School of Health and Related Research (ScHARR), the University of Sheffield (see the "Availability of Companion Documents" field).
Clinical Effectiveness
Description of Manufacturer's Search Strategy and Comment on whether the Search Strategy Was Appropriate
The searches undertaken by the manufacturer to identify relevant clinical trials were conducted in September 2006, using search strategies which were noticeably simpler than those used in the Cochrane review. They obviously differed from the latter inasmuch as they were intended only to identify studies of alteplase, not all thrombolytic drugs. However, they also differed in that they were designed to be considerably less sensitive in identifying either randomised controlled trials or studies relating to stroke. Consequently, whilst the manufacturer's Medline search strategy identified the key publication relating to each of the included trials, it did not identify the important reanalysis of the NINDS study, two supplementary analyses which the submission identified as relevant, or the Cochrane review on which the submission draws heavily.
The submission also draws on evidence from a number of observational studies. It is not clear how these studies were identified. Supplementary data provided by the manufacturer stated that a systematic search was undertaken for these, but did not provide a relevant search strategy. The main submission implies that the same search strategies were used to identify both clinical trials and studies investigating or evaluating service delivery or provision of technology. However, both the Embase and Medline searches contained a term limiting the search to clinical trials, and therefore neither would identify observational studies. It has not been possible, within the time available, for the ERG to conduct supplementary searches to ensure that relevant studies were not missed as a consequence.
The publicly available databases searched by the manufacturer were Medline, Embase, EBM reviews, and the Cochrane database of systematic reviews; the Cochrane Central Register of Controlled Trials does not seem to have been searched. Language restrictions do not appear to have been applied.
Statement of the Inclusion/Exclusion Criteria Used in the Study Selection and Comment on whether They Were Appropriate
The inclusion/exclusion criteria used in selecting studies of clinical effectiveness are not set out clearly in any one place. The manufacturer's submission states that the inclusion criteria were as follows:
- Randomized controlled trials (RCTs) of alteplase in acute ischaemic stroke
- Large observational cohort studies of thrombolysis in acute ischaemic stroke
- Evaluation studies of service delivery of thrombolysis in acute ischaemic stroke
- Any United Kingdom (UK)-based thrombolysis study (by which is presumably meant any UK-based study of thrombolysis for acute ischaemic stroke).
It is further specifies that the searches sought to identify:
- RCTs which randomised more than 50 patients
- Reviews, editorials, and "studies investigating/evaluating service delivery/provision of the technology"
- Any study undertaken in the UK in relation to the technology.
The exclusion of RCTs simply because they randomised fewer than 50 patients is an arbitrary criterion, which requires further explanation.
The manufacturer's submission clarifies that studies of alteplase given intra-arterially were excluded, since this is not a licensed form of administration. However, no exclusion criteria were applied to exclude studies which used intravenous alteplase at an unlicensed dose, or outside the licensed time-window.
The inclusion and exclusion criteria for the observational studies are summarised in Table 2 of the Assessment Report (see the "Availability of Companion Documents" field).
Refer to Section 4.1.3 and 4.1.4 of the ERG Report (see "Availability of Companion Documents" field) for more information.