Alteplase for the treatment of acute ischaemic stroke: NICE technology appraisal guidance

Abstract

This NICE technology appraisal guidance considers the clinical and cost effectiveness of the use of alteplase for acute ischaemic stroke

Guidance

This was published in the NICE technology appraisal guidance in June 2007.¹

Alteplase is recommended for the treatment of acute ischaemic stroke when used by doctors trained and experienced in the management of acute stroke. It should only be administered in centres with facilities that enable it to be used in full accordance with its marketing authorisation.

Development of the guidance

The Appraisal Committee recognised the high clinical and social burden associated with acute ischaemic stroke and understood the potential for these to be reduced through the thrombolytic action of alteplase. It was also conscious of the crucial role in successful stroke management of prompt assessment, supportive care and careful monitoring given in stroke units. While acknowledging the potential role of a thrombolytic treatment in resolving a stroke episode, the Appraisal Committee was also aware of its time‐dependent efficacy and of the safety concerns around the use of alteplase, which mainly related to the incidence of potentially fatal intracranial haemorrhage.

The Appraisal Committee considered the evidence base for the clinical effectiveness of alteplase in acute ischaemic stroke from the five placebo‐controlled, randomised clinical trials (NINDS I and II, ATLANTIS A and B and ECASS II) that assessed the efficacy of alteplase in this indication within its marketing authorisation. The Committee noted that the licensed dose of alteplase had to be given within 3 hours of onset of stroke symptoms after prior exclusion of symptomatic intracranial haemorrhage by appropriate imaging techniques.²,³,⁴ Meta‐analysis of the trial data indicated that alteplase used in this way is associated with a statistically significant reduction in the risk of death or dependency at 3 months when compared with placebo.⁵ In addition, despite a statistically significant increase in the incidence of symptomatic intracranial haemorrhage in the alteplase arm in the first 7–10 days, the meta‐analysis showed that there was no statistically significant difference between alteplase and placebo in all‐cause mortality at 3 months.

The Appraisal Committee understood there were concerns about the National Institute of Neurological Disorders and Stroke (NINDS) Trials' protocols, which did not prevent a considerable imbalance in baseline stroke severity between treatment and control arms, and thus might influence the validity of conclusions drawn from these trials. Moreover, it appreciated that the meta‐analysis results used in the appraisal were heavily influenced by these trial data. However, the Committee also took note of the discussion in an FDA review and in an independent study that further analysed the NINDS Trial data.⁶,⁷ It was aware of randomised controlled trial evidence of the use of alteplase beyond the 3‐hour window and also took into account the results of a large pan‐European observational study (SITS‐MOST),which supported the conclusions drawn from the NINDS Trials.

An economic model was developed to estimate the lifetime cost effectiveness of alteplase in addition to best supportive care in comparison with best supportive care and medical management without thrombolytic agents. This showed that alteplase is more effective and less costly than the comparator and appeared robust to reasonable changes of the inputs used of costs or clinical effectiveness estimates. It further demonstrated that the probability that the incremental cost effectiveness ratio for alteplase is highly likely to be less than £20 000 per quality‐adjusted life year gained.

The Appraisal Committee discussed the relevance to the economic analysis of the cost of reorganising stroke services to enable the wide use of alteplase in accordance with its marketing authorisation, in particular the need for 24‐hour access CT scanning and availability of doctors with specialist interest in acute stroke care. The Committee concluded that it would not be appropriate to include in its considerations the costs incurred in optimising services to enable the use of thrombolysis as it learnt that reorganisation of stroke services is already taking place through the National Stroke Strategy which include recommendations covering the set up of stroke centres with facilities suitable for treatment with alteplase.

The Appraisal Committee further considered the possibility that alteplase may be particularly effective and thus more cost effective when used in a specific subgroup of patients with acute stroke—for example, if administered in a shorter time frame. However, it considered that there was insufficient evidence from the trials to substantiate the subgroup analysis and therefore concluded that alteplase had not been clearly shown to be any more or less cost effective in particular subgroups of patients.

The Appraisal Committee concluded that the available evidence supported a positive recommendation of alteplase for the treatment of ischaemic stroke within its marketing authorisation. The evidence base indicated that the administration of alteplase together with the provision of best supportive care would not only be more clinically effective than best supportive care alone but might also result in long‐term cost savings for the NHS. The Appraisal Committee emphasised, however, that alteplase should only be initiated by doctors trained and experienced in the management of acute stroke and in centres with facilities that enable it to be used in full accordance with its marketing authorisation.

The Appraisal Committee was aware that research is currently continuing to evaluate the safety and clinical effectiveness of alteplase beyond 3 hours after the onset of stroke symptoms. These studies, together with any potential studies in patients older than 80 years, would enable the assessment of the clinical and cost effectiveness of alteplase in these important groups, which represent a significant proportion of the patients who experience acute ischaemic stroke and are not currently included in the marketing authorisation.