The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of alteplase, having considered evidence on the nature of acute ischaemic stroke and the value placed on the benefits of alteplase by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.
The Committee discussed the place of alteplase in the clinical pathway for people who have had an acute ischaemic stroke. The Committee heard from the clinical specialists that alteplase is routinely used in the NHS in England and Wales in patients aged 18 to 80 years within 4.5 hours of onset of symptoms. The Committee was aware of the recently published third International Stroke Trial (IST-3), an open-label trial comparing alteplase with standard care. However, the Committee noted that the manufacturer had excluded this trial from its submission because it provided data that were not restricted to alteplase within its current UK marketing authorisation; specifically, the trial included patients aged above 80 years and patients who were treated up to 6 hours after the onset of symptoms.
The Committee heard from clinical specialists that alteplase is more effective the earlier it is given to patients. The clinical specialists commented that, while extending the treatment window to 4.5 hours would enable more patients to be treated with alteplase, this might result in some patients who present early receiving delayed treatment and therefore not benefiting from alteplase to the extent that they might otherwise have. The clinical specialists and patient experts emphasised the importance of treating patients with acute ischaemic stroke as early as possible.
The Committee heard from the patient experts that an important benefit of alteplase was its potential to reduce long-term disability caused by stroke, which can affect the quality of life of the patient and their families, carers and friends, and can also increase the need to adjust the patient's lifestyle and living conditions. The Committee was aware that brain imaging must be carried out to confirm the absence of intracranial bleeding before treatment with alteplase can be started. However, the Committee heard from 1 patient expert that some people with acute ischaemic stroke may not have immediate access to brain-imaging facilities. The Committee recognised the importance of this issue, and noted the NICE Quality Standard for Stroke, which recommends that patients with acute stroke receive brain imaging within 1 hour of arrival at hospital. The Committee also heard from clinical specialists that Accident and Emergency departments of all acute-care hospitals in England and Wales should have access to 24-hour, 7 days a week brain-imaging facilities. The Committee recognised that patients outside the licensed indication for alteplase (under 18 years and over 80 years of age) in England and Wales may have the potential to benefit from treatment with the technology. However, consistent with NICE methods, the Committee was aware that it can only make recommendations based on the current marketing authorisation for alteplase.
The Committee considered the evidence submitted by the manufacturer on the clinical effectiveness of alteplase. The Committee noted that no clinical-effectiveness data for the 0- to 3-hour treatment window additional to those included in NICE technology appraisal guidance 122 were available, and that clinical-effectiveness data for the 3- to 4.5-hour treatment window were derived primarily from the ECASS 3 trial. The Committee heard from clinical specialists that, although the trial included only a small proportion of patients from the UK, the results of the trial were generalisable to patients receiving alteplase treatment in England and Wales. The Committee also heard from the clinical specialists that it was reasonable for the manufacturer to measure the effectiveness of alteplase from analyses that adjusted for baseline differences in potential confounding variables between the 2 treatment groups. In addition, the clinical specialists noted that the modified Rankin scale was widely used as a measure of disability in stroke patients in England and Wales. The Committee concluded that the ECASS 3 trial was of good methodological quality and provided robust evidence of the clinical efficacy of alteplase for the 3- to 4.5-hour treatment window.
The Committee considered the clinical effectiveness of alteplase for the 3- to 4.5-hour treatment window. The Committee noted that no statistically significant differences in mortality, or in the composite outcome of death or dependence, between patients randomised to alteplase or standard care were observed at 90-day follow-up. However, the Committee also noted that a statistically significantly higher proportion of patients in the alteplase treatment arm achieved a favourable outcome without significant disability (modified Rankin scale score of 0 or 1) at 90-day follow-up. The Committee therefore concluded that alteplase administered between 3 and 4.5 hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of disability.
The Committee considered the manufacturer's meta-analyses, which generated alternative estimates of alteplase's effect on all-cause mortality and also on death or dependence (modified Rankin scale score of 3 to 6) at 90 days for each of the 3 treatment windows (0 to 3 hours, 3 to 4.5 hours, and 0 to 4.5 hours), and which were used for the clinical-effectiveness parameters in the manufacturer's economic model. The Committee noted that the trials included in the meta-analyses for the 0- to 4.5-hour treatment window were of good methodological quality and were sufficiently similar in terms of study design and results. The Committee noted that there were no statistically significant differences in all-cause mortality reported at 90 days between alteplase and placebo for any of the 3 treatment windows. Therefore, the Committee agreed that an effect of alteplase on improving survival has currently not been proven. The Committee noted that a statistically significant difference in favour of alteplase was reported for the composite outcome of death or dependence for the 0- to 3-hour and 0- to 4.5-hour treatment windows in the manufacturer's meta-analyses. The Committee therefore concluded that alteplase administered between 0 and 4.5 hours after onset of stroke symptoms was an effective treatment for acute ischaemic stroke because it decreased the probability of death or dependence.
The Committee considered the evidence on adverse reactions associated with alteplase. The Committee noted that a significantly higher proportion of patients in the alteplase arm had symptomatic intracranial haemorrhage within 10 days compared with the placebo arm for the 3- to 4.5-hour window in the ECASS 3 trial and for the 0- to 4.5-hour window in the manufacturer's meta-analyses. However, the Committee noted that while alteplase increased the risk of symptomatic intracranial haemorrhage, the absolute number of patients in the ECASS 3 trial who had a symptomatic intracranial haemorrhage was small. The Committee heard from the clinical specialists that symptomatic intracranial haemorrhage is the primary cause of death within 7 days for patients receiving alteplase treatment, and that clinicians have difficulty predicting which patients are at high risk. The Committee also noted that the proportion of other reported serious adverse reactions and fatal adverse reactions in the ECASS 3 trial up to 90 days was similar across the 2 treatment arms. The Committee concluded that, although the increased risk of symptomatic intracranial haemorrhage associated with alteplase is offset by significant improvements in favourable outcomes at 90 days, symptomatic intracranial haemorrhage is an adverse event that needs to be included in modelling of the cost effectiveness of alteplase.
The Committee considered the manufacturer's economic model, the assumptions on which the parameters were based, and the critique and exploratory analyses conducted by the ERG. The Committee noted that the model structure and many of the input parameters were identical to those used in the economic model for NICE technology appraisal guidance 122 (0- to 3-hour window) and agreed that this approach was appropriate. With regard to the clinical-effectiveness parameters used in the model, the Committee acknowledged that the survival benefit associated with alteplase compared with standard care, which resulted from a point estimate for the relative risk for alteplase treatment and death of less than 1, was appropriately reflected in the economic model. However, the Committee noted that the manufacturer had assumed that the relative treatment effect of alteplase was maintained beyond 90 days up to 6 months in the model with no longer-term survival benefit beyond this point. The Committee considered that this may have been a conservative approach if alteplase offers a survival advantage compared with placebo beyond 6 months, a proposition the Committee found plausible, although not currently proven statistically, given that alteplase was associated with a reduction in death or dependence at 90 days. The Committee was aware that the utility values were not adjusted over time in the model, which may have overestimated the QALYs accrued by people in the independent health state and therefore biased the results in favour of alteplase. However, the Committee considered that this was not a crucial limitation of the model because the ICERs were not sensitive to changes in the utility values in the manufacturer's sensitivity analyses, and therefore any downward adjustment over time would have had a small impact on the ICERs. The Committee was also aware that the manufacturer assumed that people who had a symptomatic intracranial haemorrhage in the economic model incurred the additional one-off cost of a CT scan but experienced no further disutility beyond that captured in the dependent or independent health states. The Committee heard from the clinical specialists that this assumption was reasonable. Overall, the Committee concluded that the economic model adhered to the NICE reference case for economic analysis and the modelling approach was reasonable.
The Committee considered the most plausible ICERs presented by the manufacturer and also by the ERG in its exploratory analyses. It agreed that alteplase either dominated standard care or had an ICER below £10,000 per QALY gained depending on the time-to-treatment window considered. The Committee noted that the results were robust for most of the deterministic sensitivity analyses conducted by the manufacturer. The Committee also noted that none of the additional exploratory analyses undertaken by the ERG resulted in ICERs that varied substantially from those presented in the manufacturer's submission. The Committee considered that patients with acute ischaemic stroke who are admitted to hospital later (beyond 3 hours after onset of symptoms) may have less severe stroke and so any absolute benefit of treatment with alteplase compared with standard care may be diminished, resulting in a higher ICER. However, the Committee noted that the ICER for the 3- to 4.5-hour treatment window was low and therefore concluded that treating acute ischaemic stroke with alteplase within 0 to 4.5 hours of onset of stroke symptoms was a cost-effective use of NHS resources. The Committee also agreed with the clinical specialists that extending the time window for treatment should not diminish the urgency with which people suspected of having an acute ischaemic stroke should be treated.
The Committee discussed whether any equality issues required consideration in this appraisal. The Committee was aware that extension of the licence to 4.5 hours after symptom onset may enable increased access to treatment with alteplase for patients in remote or rural locations.