Intravenous thrombolysis after ischaemic stroke: When in doubt, leave it out?

Results of the MR CLEAN-NO IV trial failed to show superiority (or non-inferiority) of direct endovascular treatment (EVT) compared with the combination of intravenous thrombolysis (IVT) and EVT. Does this imply guidelines need to be revised?

The publication of the original MR CLEAN trial established mechanical thrombectomy as a safe and effective treatment for acute ischaemic stroke caused by large-vessel occlusion [1]. IVT in eligible patients prior to EVT is still recommended, most notably in the guidelines of the European Stroke Organisation (ESO)–European Society for Minimally Invasive Neurological Therapy (ESMINT) [2]. This may however not be necessary. To bring more certainty, MR CLEAN-NO IV was carried out in 20 centres (16 in the Netherlands) capable of providing EVT. Dr Natalie LeCouffe (Amsterdam University Medical Centre, the Netherlands) presented the results [3,4].

The phase 3 MR CLEAN-NO IV study randomised 539 patients with acute ischaemic stroke to receive EVT alone (n=273) or EVT preceded by alteplase (n=266; standard of care). Median age was 71 years; 56.6% were men. Primary outcome was distribution on the modified Rankin Scale, on a scale of 0 (no complaints) to 6 (death). The results showed no significant difference, with an adjusted common odds ratio (acOR) of 0.84 (95% CI 0.62–1.14). “This difference was not statistically significant, nor was the combined treatment not inferior,” Dr LeCouffe noted.

Recanalisation was successful after 24 hours in 83.1% of the combined treatment group and 78.7% of the EVT-only group (aOR 0.73; 95% CI 0.47–1.13), a non-significant difference. Functional outcomes did not differ between groups. Mortality rate was numerically higher in the EVT-only group, but again the difference was not significant (20.5% vs 15.8%; OR 1.39; 95% CI 0.84–2.30). No difference in risk of any intracranial haemorrhage (35.9% vs 36.4%; OR 0.99; 95% CI 0.70–1.41) or symptomatic intracranial haemorrhage (5.9% vs 5.3%; OR 1.31; 95% CI 0.61–2.84) was present. Dr LeCouffe said the latter finding was the most surprising one and contrary to what was expected.

Dr LeCouffe went on to present some preliminary results of a study-level meta-analysis on behalf of a new collaboration: Improving Reperfusion strategies in Ischemic Stroke (IRIS). Included were 6 similar trials: DIRECT MT, DEVT, DIRECT-SAFE, SKIP, SWIFT-DIRECT, and MR CLEAN-NO IV. The results showed a “suggestion of non-inferiority.” There seems to be a trade-off between successful reperfusion and symptomatic intracranial haemorrhage. A patient-level meta-analysis is called for to identify subgroups (e.g. based on occlusion location) that might benefit or not from pre-treatment with IVT. Dr LeCouffe concluded that recommendations on adding IVT in recent stroke guidelines may have been premature and that the following maxim may apply instead: “When in doubt, leave it out.”

1. Fransen PSS, et al. Trials. 2014;15:343.
2. Turc G, et al. J Neurointerv Surg. 2022;14(3):209.
3. LeCouffe N. MR CLEAN-NO IV: Intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion. Clinical Trials plenary session, AAN 2022, 02–07 April, Seattle, USA.
4. Treurniet KM, et al. Trials. 2021;22(1):141.

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Posted on 2 June 202228 March 2024