Fig. 2

Flow of patients in the CONTRAST consortium. MR ASAP, Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch; ER, emergency room; DUTCH ICH pilot, a prospective, multicenter, randomized open, blinded end-point clinical trial of minimally invasive surgery, steroids or both in patients with spontaneous, non-traumatic supratentorial ICH in The Netherlands; MR CLEAN-MED,: Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands. The effect of periprocedural MEDication: antiplatelet agents, heparin, both or neither; MR CLEAN-NO IV, Intravenous treatment followed by intra-arterial treatment vs direct intra-arterial treatment for acute ischemic stroke caused by a proximal intracranial occlusion; IVT, intravenous thrombolysis with alteplase; MR CLEAN-LATE, Multicenter Randomized Clinical Trial of Endovascular Stroke treatment in The Netherlands for Late arrivals. Considerations: (1) The CONTRAST studies are independent RCT’s. Patients who have been included in MR ASAP may also be included in one of the intervention trials for ischemic or for hemorrhagic stroke. Being eligible for two trials at the same time raises questions whether the trials influence each other’s results. Therefore, we will perform pre-specified subgroup analyses to test for the interaction between the different performed treatments. Further, part of the potential treatment effect in MR ASAP will be represented in the baseline characteristics measured at inclusion in the second trial, such as collaterals, blood pressure, and NIHSS, which we will adjust for in all analyses. (2) At the first ER (either a primary stroke center or a participating intervention center), all patients with a probable diagnosis of acute stroke will undergo non-contrast CT to differentiate between acute cerebral infarction or acute intracranial hemorrhage. When the first ER is a primary stroke center and the patient could be eligible for the DUTCH ICH TRIAL, MR CLEAN-MED, or MR CLEAN-LATE study, the patient should be transferred to a participating intervention center (where inclusion in one of these studies, randomization, and treatment takes place). (3) Patients arriving first at a primary stroke center will generally not be eligible for the MR CLEAN-NO IV, since intravenous thrombolysis with alteplase (IVT) cannot be withheld until after patient transfer to the participating intervention center, unless the perceived contraindications for alteplase are not present anymore upon arrival at the intervention center. Then, inclusion in MR CLEAN-NO IV will have priority over inclusion in other trials. Patients who are eligible for inclusion in MR CLEAN-NO IV (primary presentation at intervention center, < 4.5 h + eligible for IVT) will not be included in MR CLEAN-MED. Patients presenting at the primary stroke center within 6 h (both eligible or not eligible for IVT) could be eligible for the MR CLEAN-MED. Importantly by this scheme, competition between the intervention trials will not occur.