DAWN trial: solution or problem?

Key point:

The main results of the “magnificent seven” (MR-CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, THRACE, THERAPY) regarding stroke therapy showed that endovascular thrombectomy had a clinical benefit when it was performed within 6 hours after the onset of stroke symptoms and that there is an inverse relation between time and the benefit of the treatment. We are talking about "relative time" which depends on the effectiveness of collateral circulation; this is the reason why there is limited information on the effect of thrombectomy that is performed more than 6 hours after the symptoms onset, particularly among patients with a small ischemic core and a big ischemic penumbra. Patients with brain tissue that may be salvaged with reperfusion have a clinical-DWI mismatch (defined as NIHSS score of ≥8 and ischemic volume on DWI of ≤25 mL on admission). In this paper, published November 11, 2017, on The New England Journal of Medicine, Authors compared endovascular thrombectomy (ET) plus standard medical care (SMC) with standard medical care alone for the treatment of patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a clinical-DWI mismatch. R.G. Nogueira et al. did a multicenter, prospective, randomized, open-label trial with a Bayesian adaptive-enrichment design and with blinded assessment of end points, enrolling 206 patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume,from September 2014 through February 2017. Infarct volume was assessed with the use of diffusion-weighted magnetic resonance imaging (MRI) or perfusion CT and was measured with the use of automated software (RAPID, iSchemiaView). Based on the mismatch between NIHSS and ischemic core volume, they divided patients population in 3 groups, randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). Patients either did not meet the usual criteria for treatment with intravenous alteplase because of a late presentation or received treatment with intravenous alteplase and had persistent occlusion of the vessel at the time that they were eligible for enrollment in the trial. Inclusion criteria in the following table.

Inclusion criteria and population groups

This trials showed that the mean score for disability on the utility-weighted mRS at 90 days was 5.5 in the thrombectomy group vs. 3.4 in the control group and the rate of functional independence (mRS≤2) at 90 days was 49% in the thrombectomy group vs. 13% in the control group. Authors demonstrated that the rate of a mRS≤2 in the thrombectomy group in selected patients treated 6 to 24 hours after stroke onset, was similar to the rate reported in a pooled analysis of five trials of thrombectomy, in which patients predominantly received treatment within 6 hours after stroke onset (49% vs. 46% respectively).

In contrast, the rate of a mRS≤2 in the control group in this trial was lower than the rate in the pooled analysis (13% vs. 26%), probably due to the lower rate of treatment with intravenous alteplase (only 14% of patients).

Outcome

Our question is

Is this trial a real milestone for stroke treatment? 

The DAWN trial included patients with occlusion of a large cerebral vessel who presented between 6 and 24 hours after the onset of stroke. Approximately 60% of the patients had had their first stroke symptoms when they woke up, which meant that the time of stroke onset was not known, and all patients were selected specifically because they had a region of brain that was poorly perfused but not yet infarcted. In essence, the "time window" for stroke treatment must be replace with a “tissue window”, an already existing idea.

The concept of a time window suggests that a certain stroke treatment has a clearly defined time window between stroke onset and initiation of therapy. Therapy is expected to be futile if a patient is treated at a later time point. It is important to understand that the decreasing therapy benefit is inversely related to the average increase in infarct volume. However, there are considerable interindividual differences in the actual course of ischemic core expansion.

The time-reset effect

For the matter of simplicity, let us assume we talk about the next five patients with proximal occlusion of the middle cerebral artery (MCA). At 3 h after symptom onset, all patients have the same chance of good outcome. One hour later, one of the patient’s collaterals broke down resulting in MCA territory infarct. Assuming that each hour there is a patient that develops an MCA infarction, the chance of good outcome for all five patients decreases and it is time-dependent. But if we look at the three remaining patients, time does not matter, because they still have the same chance of good outcome after 3, 4 or 5 h and for them the time is virtually reset by imaging. This is the time-reset effect that depends on the development of strict selection criteria and that is present in this trial; however for the entire unselected patient population time is crucial. 

In the real world the main problem is to define the aim of the imaging selection for acute stroke patients; we should select all patients that could underwent stroke treatment or we should select only patients that would have a very high benefit from endovascular thrombectomy. The development of strict selection criteria could increase the rate of patients that could have a good outcome, but could reduce the therapy effect of the treatment. To understand this concept see the following table.

Good outcome vs. Therapeutic effect

 

In conclusion:

  • Despite DAWN trial results, time is "still" brain. We need to treat as early as possible as we do not know when the patient in front of us will deteriorate.
  • Time windows derived from studies are influenced by patient selection. A treatment effect can be expected even in patients far beyond the time windows as long as there is brain tissue left to rescue.
  • Extending the time window increases the need for Stroke Centers with high performance imaging tools to select patients that would have a very high benefit from endovascular thrombectomy. 

Reference

  • Raul G. Nogueira, M.D., Ashutosh P. Jadhav, M.D., Ph.D., Diogo C. Haussen, M.D., Alain Bonafe, M.D., Ronald F. Budzik, M.D., Parita Bhuva, M.D., Dileep R. Yavagal, M.D., Marc Ribo, M.D., Christophe Cognard, M.D., Ricardo A. Hanel, M.D., Cathy A. Sila, M.D., Ameer E. Hassan, D.O., Monica Millan, M.D., Elad I. Levy, M.D., Peter Mitchell, M.D., Michael Chen, M.D., Joey D. English, M.D., Qaisar A. Shah, M.D., Frank L. Silver, M.D., Vitor M. Pereira, M.D., Brijesh P. Mehta, M.D., Blaise W. Baxter, M.D., Michael G. Abraham, M.D., Pedro Cardona, M.D., Erol Veznedaroglu, M.D., Frank R. Hellinger, M.D., Lei Feng, M.D., Jawad F. Kirmani, M.D., Demetrius K. Lopes, M.D., Brian T. Jankowitz, M.D., Michael R. Frankel, M.D., Vincent Costalat, M.D., Nirav A. Vora, M.D., Albert J. Yoo, M.D., Ph.D., Amer M. Malik, M.D., Anthony J. Furlan, M.D., Marta Rubiera, M.D., Amin Aghaebrahim, M.D., Jean-Marc Olivot, M.D., Wondwossen G. Tekle, M.D., Ryan Shields, M.Sc., Todd Graves, Ph.D., Roger J. Lewis, M.D., Ph.D., Wade S. Smith, M.D., Ph.D., David S. Liebeskind, M.D., Jeffrey L. Saver, M.D., and Tudor G. Jovin, M.D., for the DAWN Trial Investigators. Thrombectomy 6 to 24 h after stroke with a mismatch  between deficit and infarct. The New England Journal of Medicine. 2017 Nov 11. DOI: 10.1056/NEJMoa1706442.
  • Fiehler J. The time-reset effect: thrombectomy trials challenge the existence of a time windowClin Neuroradiol. 2017 Mar;27(1):3-5. doi: 10.1007/s00062-017-0561-4. Epub 2017 Jan 25.

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