Impact case study database

Impact on regulatory authority

By REF2014, many national and international stroke guidelines had been revised to recommend thrombolysis with alteplase as a response to Edinburgh Neuroscience’s IST-3 trial results ( REF2014/4/J). Clinical questions, however, remained about the treatment of patients over the age of 80, with severe or mild stroke, early ischaemic signs on imaging, and the latest time to treatment. In 2015, the MHRA therefore ordered an independent review of the effects of alteplase on acute ischaemic stroke. Evidence from both the IST-3 [3.1-3.3] and the Stroke Thrombolysis Treatment Collaboration [3.5] was vital to the conclusions of the review.

Following the review, the MHRA fully endorsed the conclusions and recommendations of the expert working group that the benefits of alteplase outweighed any risk when used in accordance with the product licence. “It was considered that the effectiveness of alteplase when given within 4.5 hours of stroke onset did not vary according to stroke severity or age (<80 or ≥80 years).” [p.2; 5.1]. The European regulatory authorities removed the upper age limit on the use of alteplase in acute ischemic stroke in 2018 based on the combined body of evidence from randomized controlled trials and post-marketing registries [5.2].

Impact on policy and guidelines

Further impact from research reported in REF2014

Since July 2019, alteplase has been listed in the 21^st edition of the WHO’s Essential Medicines List [5.3a] to be used in specialised diagnostic or monitoring facilities and with specialist medical care [5.3b]. This marks a major step forward to better stroke treatment internationally. Sandercock was 1 of 13 stroke experts assembled by the World Stroke Organization to make the case for submission, and the IST-3 trial is cited repeatedly in the application [5.3c].

Impact from new research since REF2014

Since the last REF submission, Italy [5.4; 2015], the UK [5.5; 2016] and the US (American Heart Association; AHA) [5.6; 2018] have all removed the upper age limit recommendation for thrombolysis treatment, all citing Edinburgh Neuroscience trial data. The Royal College of Physicians (RCP), for example, states: “Research has established that the current licensed indications for alteplase treatment should be widened. The IST-3 trial and the updated Cochrane systematic review and individual patient meta-analysis published by the Stroke Thrombolysis Trialists’ Collaborative Group have added significantly to our understanding of when and to whom intravenous thrombolysis (IVT) should be offered” [p.40; 5.5]. An independent Evidence Review Group on behalf of the UK’s National Institute for Health and Care Excellence (NICE) determined that costs for treatment with alteplase up to 4.5 hours were well below accepted willingness-to-pay thresholds and that alteplase was cost-effective compared with standard treatment [5.7].

In addition, as a result of Edinburgh Neuroscience’s s novel imaging work, the previous advice, that patients with early ischaemic changes should avoid alteplase, has now been removed from guidelines. In fact, updated recommendations since REF2014 in national and international guidelines now include alteplase use in patients with early infarct signs (e.g. RCP 2016; AHA 2018; NICE 2019) [p.40 in 5.5; p. 5 in 5.6; Recommendation 1.4.1 in 5.7]. Significantly, this affects the 25-33% of patients with early ischaemic changes who were being denied alteplase treatment in the belief that they were at increased risk of haemorrhage or would not benefit from treatment since it was too late.

Impact on clinical practice

The Safe Implementation of Thrombolysis in Stroke (SITS) registry audit (2018), which collates thrombolysis use in 1,200 stroke centres in 75 countries, reported that cumulative use of alteplase has gone from 80,000 patients in 2013 to more than 190,000 patients in 2019, i.e. more than doubled the rate of usage since the publication of IST-3 ( Figure 1) [5.8]. The SITS audit also showed that the median age of alteplase treatment rose from 69 in 2012, to 72 in 2013 and 73 years in 2018, reflecting more patients over the age of 80 receiving alteplase [5.8a]. Indeed, while in 2013 22% of patients over the age of 80 received alteplase, in 2020 29% of them did, reflecting practice change from Edinburgh Neuroscience research since REF2014 [5.8c].

Figure 1. Cumulative and annual registration of patients using IV thrombolysis protocols

In the UK, up to 20% of stroke patients are eligible for thrombolysis. The percentage of eligible patients receiving thrombolysis increased from 74.3% in April 2013 to 89.1% in March 2020 in England, Wales and Northern Ireland [Table 1; 5.9]. The median time between clock start and thrombolysis fell from 58 minutes in 2013 to 52 minutes in 2020 ( Table 1).

Table 1: Results for all teams for all measures collected in SSNAP for England, Wales and NI. This report covers all admissions and discharges between April 2013 and March 2020 [5.9]

¹according to the RCP guideline minimum threshold

In Scotland, the thrombolysis rate increased from 13 per 100,000 of population in 2012 to 19 per 100,000 in 2018 [5.10]. In 2018, 1,033 (12.4%) of all patients with ischaemic stroke received thrombolysis and 60% were thrombolysed within one hour, compared with 915 (11.4%) and 55% in 2016 [5.10]. These rates compare favourably with the rest of the UK and other European countries.

In Germany, the thrombolysis rate for all stroke patients increased from an average of 12.4% in 2013 to 15.9% in 2017, including a 1.5-fold increase in the number of patients older than 80 treated with thrombolysis [5.11]. In Sweden, the number of patients treated with alteplase increased from 2,226 patients to 2,500 between 2013 and 2018 [Riksstroke pers comm]. In Austria, alteplase use continuously increased from 9.9% in 2006 to 17.1% in 2010 – 2013 and 21.8% in 2018, with a pronounced increase in alteplase treatments over time in patients older than 80 years, particularly after 2013 [ Figure 1; 5.12].