Intravenous thrombolytic therapy (IV) with recombinant tissue-plasminogen activator (alteplase; 0.9 mg/kg over 1h) is beneficial for acute ischaemic stroke patients with potentially disabling neurological deficits, and without contraindications, when started =4.5h of onset. Benefit is time-dependent: among 1000 patients, IVT =3h lessen long-term disability in 178 patients, between 3-4.5h in 66. IVT under 4.5h is associated with an increase in symptomatic haemorrhage, but not an increase in death or severe disability. Based on trial evidence, IVT =3h is strongly endorsed, and between 3-4.5 hours moderately endorsed, by guidelines on 5 continents. Benefit is evident in patients under and over age 80, and in patients with up to moderate, but not extensive (more than 100 cc), early ischaemic changes on initial CT or MRI. IVT is also beneficial for patients =4.5h after onset with substantial salvageable tissue on penumbral CT or MR imaging. Systems of care should be optimized to start IVT =60m, and optimally =30m, after ED arrival. Large-scale trials are needed to further enhance IVT, testing: faster treatment start in mobile stroke units (mobile CT ambulances): fibrinolytic agent and concomitant lytic-enhancing combinations; bridging neuroprotection and collateral enhancement; and the optimal way to combine intravenous thrombolytic therapy and endovascular mechanical thrombectomy.

Aspirin 160–300 mg daily started within 48 h of onset of acute ischaemic stroke is associated with a small beneficial reduction in recurrent ischaemic stroke (6 fewer per 1000 patients treated) and pulmonary embolism (1.5 fewer per 1000) that outweighs increased risk of bleeding (2 extra symptomatic ICHs and 4 extra major extracranial haemorrhages). The net effect is that, for every 1000 patients treated early with aspirin, 22 have reduced long-term disability, including 11 more achieving full recovery. Only two single antiplatelet regimens have been compared head to head against aspirin alone: cilostazol (a phosphodiesterase inhibitor) performed similarly to aspirin; ticagrelor (a GP IIa/IIIb receptor antagonist) showed tended to reduce ischaemic events but increased minor bleeding and dyspnea. In minor, non-cardioembolic ischaemic stroke or TIA, early dual antiplatelet therapy (DAPT) has shown advantages over early monotherapy. Most well-studied is clopidogrel and aspirin, with similar findings for dipyridamole and aspirin. DAPT reduces all-type (ischaemic and haemorrhagic) recurrent stroke (27 fewer per 1000 treated patients), but minimally increases major extracranial bleedings (3 more per 1000). Confining DAPT to the first 3 w maximizes the benefit to harm ratio. Anticoagulants alone and arterial-dose anticoagulants added to antiplatelet agents offer no net advantages over antiplatelet drugs alone. Venous prophylaxis-dose anticoagulants and aspirin, compared with aspirin alone, reduced recurrent ischaemic stroke more than it tend increased major extracranial haemorrhage.

Endovascular thrombectomy (EVT) with highly effective reperfusion devices is beneficial for: 1) relatively broadly selected acute ischaemic stroke patients with anterior circulation large vessel occlusions (LVOs) who have failed or are ineligible for intravenous fibrinolysis, up to 7 h after onset; and 2) imaging-selected patients with a favorable penumbral profile (small core and substantial salvageable tissue) 6–24h after onset. Among early-presenting patients, benefit is strongly time-dependent; for every 4 m delay in door-to-reperfusion time, 1 of every 100 patients has a worse disability outcome. Based on the trial evidence, EVT is strongly endorsed by guidelines worldwide. Within the first 7h, benefit is evident in patients under and over age 80, and in patients with up to moderate early ischaemic changes on imaging (ASPECTS 6-10). Systems of care should be optimized to deliver likely LVO patients to endovascular-capable stroke centers, and for procedure start (arterial puncture) within 75m, and optimally within 45m, after ED arrival. Large-scale trials are testing: best prehospital recognition and routing protocols: novel device designs to increase reperfusion rates in large and also medium vessel occlusions; bridging neuroprotection and collateral enhancement; potential benefit in patients with large cores; and best concomitant therapies, including sedation mode and post-procedure blood pressure management.