Thrombolytic medicines are approved for the emergency treatment of stroke and heart attack. The most commonly used drug for thrombolytic therapy is tissue plasminogen activator (tPA), but other drugs can do the same thing.
Ideally, you should receive thrombolytic medicines within the first 30 minutes after arriving at the hospital for treatment.
HEART ATTACKS
A blood clot can block the arteries to the heart. This can cause a heart attack, when part of the heart muscle dies due to a lack of oxygen being delivered by the blood.
Thrombolytics work by dissolving a major clot quickly. This helps restart blood flow to the heart and helps prevent damage to the heart muscle. Thrombolytics can stop a heart attack that would otherwise be larger or potentially deadly. Outcomes are better if you receive a thrombolytic drug within 12 hours after the heart attack starts. But the sooner treatment begins, the better the results.
The drug restores some blood flow to the heart in most people. However, the blood flow may not be completely normal and there may still be a small amount of muscle damaged. Further therapy, such as cardiac catheterization with angioplasty and stenting, may be needed.
Your health care provider will base the decisions about whether to give you a thrombolytic medicine for a heart attack on many factors. These factors include your history of chest pain and the results of an ECG test.
Other factors used to determine if you are a good candidate for thrombolytics include:
- Age (older people are at increased risk of complications)
- Sex
- Medical history (including your history of a previous heart attack, diabetes, low blood pressure, or increased heart rate)
Generally, thrombolytics may not be given if you have:
- A recent head injury
- Bleeding problems
- Bleeding ulcers
- Pregnancy
- Recent surgery
- Taken blood thinning medicines such as Coumadin
- Trauma
- Uncontrolled (severe) high blood pressure
STROKES
Most strokes are caused when blood clots move to a blood vessel in the brain and block blood flow to that area. For such strokes (ischemic strokes), thrombolytics can be used to help dissolve the clot quickly. Giving thrombolytics within 3 hours of the first stroke symptoms can help limit stroke damage and disability.
The decision to give the drug is based upon:
- A brain CT scan to make sure there has not been any bleeding
- A physical exam that shows a significant stroke
- Your medical history
As in heart attacks, a clot-dissolving drug isn't usually given if you have one of the other medical problems listed above.
Thrombolytics are not given to someone who is having a stroke that involves bleeding in the brain. They could worsen the stroke by causing increased bleeding.
RISKS
Bleeding is the most common risk. It can be life threatening.
Minor bleeding from the gums or nose can occur in approximately 25% of people who receive the drug. Bleeding into the brain occurs approximately 1% of the time. This risk is the same for both stroke and heart attack patients.
If thrombolytics are felt to be too dangerous, other possible treatments for clots causing a stroke or heart attack include:
- Removal of the clot (thrombectomy)
- A procedure to open narrowed or blocked blood vessels that supply blood to the heart or the brain
CONTACT A HEALTH CARE PROVIDER OR CALL 911
Heart attacks and strokes are medical emergencies. The sooner treatment with thrombolytics begins, the better the chance for a good outcome.
Evidence Table A and Reference List
Evidence Table B and Reference List
Intravenous Thrombolysis The weight of evidence from many large, international trials over a time frame of 20 years, clearly indicate that treatment with intravenous alteplase reduces the risk of death or disability following ischemic stroke, at 3 to 6 months post treatment. The NINDS trial (1995) was one of the earliest, large trials, which was conducted in the USA. Patients were randomized to receive alteplase or placebo within 3 hours of symptom onset. At 3 months, significantly more patients in the rt-PA group had experienced a good outcome (using any one of the study’s 4 metrics), with no difference in 90-day mortality between groups. In contrast, patients who received alteplase within 3 to 5 hours in the ATLANTIS trial (1999) were no more likely to have a good neurological or functional outcome at 90 days than patients in the placebo group. In the first ECASS trial (1995) 620 patients received alteplase or placebo within 6 hours of event. Using intention-to-treat analysis and including the data from 109 patients with major protocol violations, the authors did not report a significant benefit of treatment. The median Barthel Index and modified Rankin scores at 90 days did not differ between groups. In an analysis restricted to patients in the target population, there were differences favouring patients in the alteplase group. In the ECASS II trial (1998), there was again no significant difference on any of the primary outcomes. The percentages of patients with a good outcome at day 90 (mRS<2) treated with alteplase and placebo were 40.3% vs. 36.6%, respectively, absolute difference =3.7%, p=0.277. In subgroup analysis of patients treated < 3 hours and 3-6 hours, there were no between-group differences on any of the outcomes. The authors suggested that the reason for the null result may have been that the study was underpowered, since it was powered to detect a 10% difference in the primary outcome, but the observed difference between groups in previous trials was only 8.3%. Finally, in the ECASS III trial (2008) 821 patients were randomized within 3 and 4.5 hours of symptom onset. In this trial, a higher percentage of patients in the alteplase group experienced a favourable outcome, defined as mRS scores <2 (52.4% vs. 45.2%, adjusted OR=1.34, 95% CI 1.02 to 1.76, p=0.04). A higher percentage of patients in the alteplase group also had NIHSS scores of 0 or 1, (50.2% vs. 43.2%, adjusted OR=1.33, 95% CI 1.01 to 1.75, p=0.04). Secondary outcomes of the ECASS III trial were reported by Bluhmki et al. (2009). At 90 days, there were no between-group differences in the percentages of patients with mRS score of 0-2 (59% vs. 53%, p=0.097) or BI score ≥85 (60% vs. 56%, p=0.249, but a significantly greater percentage of patients had improved NIHSS scores of ≥8 points (58% vs. 51%, p=0.031). In all of the trials described above there was an increased risk of symptomatic ICH associated with treatment with alteplase and in some cases, increased short-term mortality; however, there were no differences between treatment and placebo groups in 90-day mortality. The Third International Stroke Trial (2012), is the largest (n=3,035) and most recent trial of alteplase, in which patients were randomized to receive a standard dose of alteplase (0.9 mg/kg) or placebo. Investigators aimed to assess the risks and benefits of treatment among a broader group of patients, and to determine if particular subgroups of patients might benefit preferentially from treatment. In this trial, 95% of patients did not meet the strict licensing criteria, due to advance age or time to treatment. Unlike all previous, large trials, which excluded them, IST-3 included patients >80 years. In fact, the majority of patients (53%) were >80 years. Approximately one-third of all patients were treated within 0-3 hours, 3.0-4.5 hours and 4.5-6.0 hours of onset of symptoms. Overall, there was an increase in the risk of death within 7 days in patients who had received alteplase, although there was no difference in 6-month mortality in both crude and adjusted analyses. There was no significant difference in the percentage of patients who were treated with alteplase who were alive and independent (defined as an Oxford Handicap Score of 0-1) at 6 months (37% vs. 35%, adjusted OR=1.13, 95% CI 0.95 to 1.35, p=0.181, although a secondary ordinal analysis suggested a significant, favourable shift in the distribution of OHS scores at 6 months. Significantly improved odds of a good outcome at 6 months were associated with the sub groups of older patients (≥80 years), higher NIHSS scores, higher baseline probability of good outcome and treatment within 3 hours. Fatal or non-fatal symptomatic intracranial hemorrhage within 7 days occurred more frequently in patients in the t-PA group (7% vs. 1%, adjusted OR=6.94, 95% CI 4.07 to 11.8, p<0.0001). The 3-year risk of mortality (2016) was similar between groups (47% vs. 47%, 95% CI 3.6%, 95% CI -0.8 to 8.1); however, patients who received rt-PA had a significantly lower risk of death between 8 days and 3 years (41% vs. 47%; HR= 0.78, 95% CI 0·68–0·90, p=0·007). Although it is known that the optimal timing of administration of intravenous alteplase is <3 hours, debate continues as to the safety and efficacy of treatment provided between 3 and 6 hours post stroke. The results from a few studies suggest that treatment is still beneficial if provided beyond the 3-hour window. The Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) includes patients who were treated with intravenous alteplase under strict licensing criteria and also those who were thought to be good candidates based on clinical/imaging assessment of the treating facility. Wahlgren et al. (2008) used data from a cohort of patients collected from 2002-2007 to compare the outcomes of patients who had been treated with alteplase within 3 hour of symptom onset (n=11,865) and those treated from 3-4.5 hours (n=644). The primary focus of this analysis was to assess treatment safety beyond the 3-hour treatment window. Patients in the <3-hour group had significantly lower initial median NIHSS scores (11 vs. 12, p<0.0001). There were no significant between group differences on any of the outcomes (symptomatic ICH within 24-36 hours, mortality within 3 months, or percentage of patients who were independent at 3 months); however, there was a trend towards increased number of patients treated from 3 to 4.5 hours who died (12.7% vs. 12.2%, adjusted OR=1.15, 95% CI 1.00-1.33, p=0.053) and who experienced symptomatic ICH (2.2% vs. 1.6%, adjusted OR=1.32, 95% CI 1.00-1.75, p=0.052). Additional analysis from the SITS-ISTR cohort was conducted to further explore the timing of alteplase treatment (Ahmed et al. 2010). In this study, patients treated within 3 hours (n=21,566) and 3-4.5 hours (n=2,376) of symptom onset between 2007 and 2010, were again compared. Significantly more patients treated from 3-4.5 hours experienced a symptomatic ICH (2.2% vs.1.7%, adjusted OR=1.44, 95% CI 1.05-1.97, p=0.02), and were dead at 3 months (12.0% vs. 12.3%, adjusted OR=1.26, 95% CI 1.07-1.49, p=0.005). Significantly fewer patients treated from 3-4.5 hours were independent at 3 months: (57.5% vs. 60.3%, adjusted OR=0.84, 95% CI 0.75-0.95, p=0.005). Emberson et al. (2014) used data from 6,756 patients from 9 major t-PA trials (NINDs a/b, ECASS I/II, III, ATLANTIS a/b, EPITHET, IST-3) to more closely examine the effect of timing of administration. Earlier treatment was associated with the increased odds of a good outcome, defined as an (mRS score of 0-1 (≤3.0 h: OR=1.75, 95% CI 1.35-2.27 vs. >3 to ≤4.5 h: OR=1.26, 95% CI 1.05-1051 vs. >4.5 h: OR=1.15, 95% CI 0.95-1.40). Framed slightly differently, when patient-level data from the same 9 major RCTs were recently pooled, Lees et al. (2016) reported that for each patient treated within 3 hours, significantly more would have a better outcome (122/1,000, 95% CI 16-171), whereas for each patient treated >4.5 hours, only 20 patients/1,000 (95% CI -31-75, p=0.45) would have a better outcome. Wardlaw et al. (2013), including the results from 12 RCTs (7,012 patients), concluded that for every 1,000 patients treated up to 6 hours following stroke, 42 more patients were alive and independent (mRS<2) at the end of follow-up, despite an increase in early ICH and mortality. The authors also suggested that patients who did not meet strict licensing criteria due to age and timing of treatment (i.e., patients from the IST-3) trial were just as likely to benefit; however, early treatment, within 3 hours of stroke onset, was more effective. Most recently, the results from the Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke (WAKE-Up) trial (Thomalla et al. 2018) suggest that highly-selected patients with mild to moderate ischemic strokes and an unknown time of symptom onset, treated with alteplase may also benefit from treatment. Patients in this trial were not eligible for treatment with mechanical thrombectomy and were selected based on a pattern of "DWI-FLAIR-mismatch. A significantly higher proportion of patients in the alteplase group had a favourable clinical outcome (mRS 0-1) at 90 days (53.3% vs. 41.8%, adj OR=1.61, 95% CI 1.06-2.36, p=0.02), although the risk of parenchymal hemorrhage type 2 was significantly higher compared with placebo (4% vs. 0.4%, adj OR=10.46, 95% CI 1.32 to 82.77, p=0.03). The standard treatment dose of rt-PA is established to be 0.9 mg/kg, with a maximum dose of 90 mg. The non-inferiority of a lower dose (0.6 mg/kg) was recently examined in the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial (Anderson et al. 2016). The primary outcome (death or disability at 90 days) occurred in 53.2% of low-dose patients and 51.1% in standard dose patients (OR=1.09, 95% CI 0.95-1.25, p for non-inferiority=0.51), which exceeded the upper boundary set for non-inferiority of 1.14. The risks of death within 90 days or serious adverse events did not differ significantly between groups (low dose vs. standard dose: 8.5% vs. 10.3%; OR=0.80, 95% CI 0.63-1.01, p=0.07 and 25.1% vs. 27.3%; OR=0.89, 95% CI 0.76-1.04, p=0.16, respectively), although the risk of symptomatic ICH was significantly higher in patients that received the standard dose of rt-PA. Although not yet approved in Canada for the use in stroke, results from several recent studies, indicate that tenecteplase, which has some pharmacokinetic advantages over alteplase, may be non-inferior to alteplase. In the NOR-TEST Logallo et al. (2017) recruited 1,100 patients from 13 stroke units. Patients were randomized to receive intravenous tenecteplase 0.4 mg/kg (maximum of 40 mg) or alteplase 0.9 mg/kg (maximum of 90 mg). At 90 days, a similar proportion of patients had an excellent outcome (mRS 0-1, 64% vs. 63%). Similar percentages of patients in each group experienced an ICH within 24-48 hours (9%) and had died by 90 days (5%). Results from the phase II ATTEST Trial, (Huang et al. 2015) also suggest that tenecteplase is non-inferior to alteplase. In this trail, 104 patients were randomized to receive tenecteplase (0.25 mg/kg, 25 mg max) or alteplase (0.9 mg/kg, 90 mg max) within 4.5 hours of ischemic stroke. Safety and efficacy outcomes were non-significantly different between groups. The use of mobile stroke units, ambulances which are equipped with specialized equipment, such as on-site laboratories and CT scanners, and are staffed with additional personnel with stroke expertise, are now appearing in large, urban cities. The feasibility and effectiveness of these vehicles has yet to be established. Kunz et al. (2016) compared the outcomes of patients who received thrombolysis therapy using the mobile stroke unit, STEMO from 2011-2015 with patients who received thrombolysis, but arrived at hospital via traditional emergency medical services. A significantly higher proportion of patients in the STEMO group were treated ≤ 90 minutes of stroke (62% vs. 35%, p<0.0005) and were living without severe disability at 3 months (83% vs. 74%, p=0.004). The 3-month mortality was also significantly lower in the STEMO group (6% vs. 10%, p=0.022). However, there was no significant difference in the primary outcome, the number of patients who achieved an excellent outcome (mRS 0-1) at 3 months (53% STEMO vs. 47% conventional, p=0.14). There were no significant differences in the safety outcomes between the 2 groups (sICH 3% vs. 5%, p=0.27 and 7-day mortality 2% vs. 4%, p=0.23). Adjusting for baseline characteristics, STEMO was an independent predictor of living without severe disability at 3 months (OR=1.86, 95% CI 1.20-2.88, p=0.006), but not for the primary outcome (OR=1.40, 95% CI 1.00-1.97, p=0.052). In an earlier study examining the use of STEMO, (Ebinger et al. 2014), among patients for whom STEMO was deployed, the mean alarm-to-treatment time for patients who received thrombolysis was reduced by 25 minutes, compared with control weeks. Of the eligible patients, t-PA was used in 32.6% of STEMO deployment cases, 29% during STEMO weeks, and 21.1% during control weeks. The use of thrombolytic therapy in patients who are younger than 18 years and in women at any stage of pregnancy has not been evaluated empirically. The evidence base for the safety and effectiveness of the use of thrombolysis during pregnancy and the puerperium is derived from a series of case reports. The results from a total of 15 previous cases (10 intravenous and 5 intra-arterial), in addition to the presentation of their own case were summarized by Tversky et al. (2016). The neurological outcomes of these women were described as similar to (non-pregnant) patients who met the eligibility criteria. Most of the women who experienced significant recovery went on to deliver healthy babies. The evidence in terms of thrombolytic treatment for patients <18 years comes primarily from the International Pediatric Stroke Study, (IPSS) an observational study (n=687) in which the outcomes of 15 children, aged 2 months to 18 years who received thrombolytic therapy (9 with intravenous Alteplase, 6 with intra-arterial Alteplase). Overall, at the time of hospital discharge, 7 patients were reported having no or mild neurological deficits, 2 had died and the remainder had moderate or severe neurological deficits. The Thrombolysis in Pediatric Stroke (TIPS) study (Amlie-Lefond et al. 2009) is currently recruiting subjects for 5-year, prospective cohort, open-label, dose-finding trial of the safety and feasibility of intravenous and intra-arterial t-PA to treat acute childhood stroke (within 4.5 hours of symptoms). The TIPS investigators are aiming to include 48 subjects.
Endovascular Therapy
Re-vascularization can also be achieved through mechanical dislodgement with specialized devices (+/- intra-arterial and/or intravenous rt-PA). To date, 10 major RCTs have been completed for which results have been published, in which endovascular therapies were compared with best medical management. Several trials are still ongoing, or have yet to report their findings. The recent results from most of these trials indicate that rapid endovascular therapy may be a safe and more effective treatment than intravenous rt-PA alone, for patients with anterior circulation ischemic strokes in selected regions, when performed within 6-12 hours of symptom onset. In the largest trial, MR CLEAN (Berkhemer et al. 2014), included 500 patients who were ≥18 years, with a baseline NIHSS score of 2 or greater, and were treatable within 6 hours of stroke onset. Patients were randomized to receive endovascular treatment with rt-PA or urokinase, and/or mechanical treatment with retrievable stents, which were used in 81.5% of patients, or other available devices, versus best medical management. The median time from stroke onset to groin puncture was 260 minutes. The majority of patients in both groups were treated with intravenous t-PA (87.1% intervention group, 90.6% control group). There was a significant shift in the distribution towards more favourable mRS scores among patients in the intervention group at 90 days (adj common OR=1.67, 95% CI 1.21-2.30). The odds of both a good (mRS 0-2) and excellent (mRS 0-1) recovery at day 90 were also significantly higher among patients in the intervention group (adj OR=2.07, 95% CI 1.07-4.02 and adj OR=2.16, 95% CIU 1.39-3.38, respectively). Patients in the intervention group were more likely to show no evidence of intracranial occlusion on follow-up CTA (adj OR=6.88, 95% CI 4.34-10.94, n=394) and to have a lower median final infarct volume (-19 mL, 95% CI 3-34, n=298). At two-year follow-up (van den Berg et al. 2017), the odds of an mRS score of 0-2 remained significantly higher in the intervention group (37.1% vs. 23.9%, adj OR= 2.21, 95% CI 1.30−3.73, p=0.003). The ESCAPE trial (Goyal et al. 2015) enrolled 316 patients ≥18 years, with stroke onset less than 12 hours, a baseline NIHSS score of > 5 and moderate-to-good collateral circulation. Patients were randomized to receive endovascular mechanical thrombectomy, using available devices or best medical management. The median time from stroke onset to first reperfusion was 241 minutes. 72.7% of patients in the intervention group and 78.7% of those in the control group received intravenous t-PA. The odds of improvement in mRS scores by 1 point at 90 days were significantly higher among patients in the intervention group (adj OR=3.2, 95% CI 2.0-4.7). The odds of good outcome (mRS score 0-2) at 90 days were also higher in the intervention group (adj OR=1.7, 95% CI 1.3-2.2), as were the odds of a NIHSS score of 0-2 and a Barthel Index score of 95-100 (adj OR=2.1, 95% CI 1.5-3.0 and 1.7, 95% CI 1.3-2.22, respectively). The risk of death was significantly lower in the intervention group (adj RR=0.5, 95% CI 0.-0.8). In neither MR CLEAN nor ESCAPE, was there an increased risk of symptomatic ICH associated with endovascular therapy. No interaction effects were found in subgroup analyses of age, stroke severity, time to randomization, or baseline ASPECTS in either of the trials. The THRACE trial (Bracard et al. 2016) had broader eligibility criteria and included 414 patients aged 18-80 years with an occlusion in the intracranial carotid, the MCA (M1) or the upper third of the basilar artery with onset of symptoms <4 hours and NIHSS score of 10-25 at randomization. Patients were randomized to receive dual intravenous rt-PA therapy + intra-arterial mechanical clot retrieval with the Merci, Penumbra, Catch or Solitaire devices or treatment with IV rt-PA only. The median time from symptom onset to thrombectomy was 250 minutes. The odds of achieving mRS score of 0-2 at 90 days were increased significantly in the thrombectomy group (53% vs. 42.1%, OR=1.55, 95% CI 1.05-2.3, p=0.028, NNT=10). There were no significant differences between groups in the number of patients with symptomatic or asymptomatic hemorrhages at 24 hours. Three trials evaluated the efficacy of the use of a specific retriever device (Solitaire FR Revascularization Device). In the EXTEND IA trial (Campbell et al. 2015), there were no inclusion criteria related to stroke severity. Seventy patients ≥18 years, with good premorbid function and an anterior circulation acute ischemic stroke, with criteria for mismatch, who could receive intra-arterial treatment within 6 hours of stroke onset, were included. All patients received intravenous rt-PA, while 35 also underwent intra-arterial mechanical clot retrieval. A significantly greater proportion of patients in the endovascular group experienced early neurological improvement (80% vs. 37%, p<0.001), >90% reperfusion without ICH at 24 hours (89% vs. 34%, p<0.001) and were functionally independent at day 90 (71% vs. 40%, p=0.009). The SWIFT-PRIME trial (Saver et al. 2015) randomized 196 patients, aged 18-80 years with NIHSS scores of 8-29 with a confirmed infarction located in the intracranial internal carotid artery, MCA, or carotid terminus who could be treated within 6 hours of onset of stroke symptom, to receive intravenous rt-PA therapy + intra-arterial mechanical clot retrieval, or rt-PA only. The likelihood of successful reperfusion (>90%) at 27 hours was significantly higher in the endovascular therapy group (82.8% vs. 40.4%, RR=2.05, 95% CI 1.45-2.91, p<0.001) and a significantly higher percentage of patients were independent at day 90 (mRS 0-2) (60.2% vs. 35.5%, RR=1.70, 95% CI 1.23-2.33, p=0.001). Finally, in the REVASCAT trial (Jovin et al. 2015), 206 patients with NIHSS scores of 6 or greater who could be treated within 8 hours of stroke onset were randomized to receive mechanical embolectomy + best medical management or best medical management only, which could include intravenous t-PA (78%). The odds of dramatic neurological improvement at 24 hours were increased significantly in the intervention group (adj OR=5.8, 95% CI 3.0-11.1). The odds for improvement by 1 mRS point at 90 days were increased significantly in the intervention group (adj OR=1.7, 95% CI 1.05-2.8), as were the odds of achieving an mRS score of 0-2 at 90 days (adj OR=2.1, 95% CI 1.1-4.0). At one-year follow-up (Davalos et al. 2017), the proportion of patients who were functionally independent (mRS score 0–2) was significantly higher for patients in the thrombectomy group (44% vs. 30%; OR=1.86, 95% CI 95% CI 1.01-3.44). No treatment effects were noted based on sub group analyses in either SWIFT-PRIME or REVASCAT, based on age, baseline NIHSS score, site of occlusion, time to randomization, or ASPECTS score. There was no increased risk of symptomatic ICH in any of these trials. Two trials (THERAPY and PISTE) halted recruitment prematurely following the presentation of the MR CLEAN trial, resulting in much smaller sample sized than planned. These trials generally reported improved outcomes for patients undergoing mechanical thrombectomy, although the smaller sample sizes were not powered to meet the primary endpoints. As a result, statistical significance was not always achieved. The results of the DAWN (Nogueira et al. 2017) and DEFUSE-3 (Albers et al. 2018) trials suggest that the treatment window for mechanical thrombectomy is wider than previously thought. The DAWN trial included 206 patients, last been known to be well 6 to 24 hours earlier, with no previous disability (mRS 0-1) and who met clinical mismatch criteria who had either failed intravenous t-PA therapy, or for whom its administration was contraindicated, because of late presentation. Patients were randomized to treatment with thrombectomy with Trevo device + medical management or medical management alone. The trial was terminated early after interim analysis when efficacy of thrombectomy was established. The median intervals between the time that a patient was last known to be well and randomization was 12.2 hours in the thrombectomy group and 13.3 hours in the control group. The mean utility weighted mRS score was significantly higher in the thrombectomy group (5.5 vs. 3.4, adj difference =2.0, 95% Cr I 1.1-3.0, prob of superiority >0.999). There were no interactions in sub group analysis (mismatch criteria, sex, age, baseline NIHSS score, occlusion site, interval between time that patient was last known to be well and randomization and type of stroke onset). A significantly higher proportion of patients in the thrombectomy group experienced an early response to treatment, had achieved recanalization at 24 hours and were independent (mRS 0-2) at 90 days (49% vs. 13%, NNT=3). The admission criteria for the DEFUSE-3 trial were broader and included those who had remaining ischemic brain tissue that was not yet infarcted. The median time from stroke onset to randomization was just under 11 hours for patients in the endovascular group. A significantly higher proportion of patients in the endovascular group were independent (mRS 0-2) at 90 days (45% vs. 17%, OR=2.67, 95% CI 1.60–4.48, p<0.001, NNT=4). The positive results from these 7 trials contrast with those of 3 earlier RCTs examining endovascular therapy using first generation devices, which are no longer on the market or in use in Canada. In the SYNTHESIS trial, Ciccone et al. (2013) randomized 362 patients to receive either pharmacological or mechanical thrombolysis, or a combination of these approaches or intravenous rt-PA within 4.5 hours of symptom onset. At 90 days, the percentages of patients alive, living without disability were similar between groups (30.4% vs. 34.8%, adjusted OR=0.71, 95% CI 0.44 to 1.14, p=0.16). The IMS III trial (Broderick et al. 2013), which also randomized patients to receive mechanical or pharmacological endovascular treatment, or intravenous t-PA was stopped early due to a lack of efficacy. Finally, the MR RESCUE trial (Kidwell et al. 2013). randomized 188 patients, within 8 hours of symptom onset to undergo mechanical embolectomy with the Merci Retriever or Penumbra System or standard care, grouped according to penumbra pattern vs. nonpenumbra pattern. At 90 days, there were no significant differences between groups (embolectomy vs. standard care) in the mean mRS score, the proportion of patients with a good outcome (mRS 0-2) or death among patients with penumbral or nonpenumbral patterns. The results from several meta-analyses, indicated the odds of a favourable outcome were all significantly increased with mechanical thrombectomy. Goyal et al. (2016) included the results from 5 trials, using second generation devices. The odds of achieving a mRS score of 0-1 or 0-2 at 90 days were significantly higher for patients in the endovascular group. The NNT for a one-point reduction in mRS was 2.6. Using data from these same trials, Saver et al. (2017) conducted pooled analysis to examine the timeframe in which endovascular treatment is associated with benefit. Compared with medical therapy, the odds of better disability outcomes at 90 days associated with endovascular therapy declined with longer time from symptom onset to arterial puncture. The point at which endovascular therapy was not associated with a significantly better outcome was 7 hours and 18 minutes. Campbell et al. (2016), included the results of 4 trials in which the Solitaire device was used. Treatment with Solitaire device was associated with both a significantly greater likelihood of independence, and of excellent functional outcome at 90 days compared with best medical management. Flynn et al. (2017) included the results from 8 trials and reported that mechanical thrombectomy was associated with significantly higher odds of functional independence (unadjusted OR=2.07, 95% CI 1.70-2.51, p<0.0001). Time series analysis demonstrated robust evidence for a 30% relative benefit for mechanical thrombectomy for this outcome. While there was no evidence that mechanical thrombectomy was associated with increased risks of mortality or symptomatic ICH, robust evidence to demonstrate a 30% relative risk reduction was lacking. Evidence from several trials and meta-analyses have examined the outcomes of patients undergoing mechanical thrombectomy using general anesthesia versus conscious sedation. Generally, the findings indicate that conscious sedation is preferred. Using the results from 7 RCTs including MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, PISTE and THRACE, Campbell et al. (2018) performed a patient-level meta-analysis comparing the outcomes of patients randomized to the mechanical thrombectomy groups who had received general anesthesia or non-general anesthesia. The odds of improved outcome using non-general anesthesia were significantly higher in ordinal analysis of mRS scores. The authors estimated for every 100 patients treated under general anesthesia (compared with non-general anesthesia), 18 patients would have worse functional outcome, including 10 who would not achieve functional independence. There was no increased risk of 90-day mortality associated with general anesthesia. The results from a meta-analysis including the results of 22 studies (Brinjikiji et al. 2017), also indicated that conscious sedation (i.e., non-general anesthesia) was associated with better outcomes. The odds of a favorable functional outcome at 90 days were significantly lower for patients who received general anesthesia (OR=0.58; 95% CI, 0.48–0.64), while the odds of 90-day mortality were significantly increased (OR=2.02, 95% CI 1.66–2.45). In contrast to these findings, Löwhagen Hendén et al. (2017) reported no significant differences between groups (general anesthesia vs conscious sedation) in the proportion of patients with a good outcome at 3 months (42% vs. 40%, p=1.00), or in the distribution of mRS scores at 90 days. In the SIESTA trial (Schönenberger et al. 2016), a significantly higher percentage of patients in the general anesthesia group had a good outcome (mRS 0-2) at 3 months (37% vs. 18.2%, p=0.01), compared with conscious sedation.Many hospitals do not have the in-house expertise to perform endovascular procedures. As a result, patients who are potential candidates for treatment will need to be transported from receiving hospitals to a centre that provides interventional neuroradiologic services. Although the additional transportation involved will inevitably cause treatment delays, particularly the time from symptom onset to groin puncture, results from several recent studies suggest that patient outcomes may not be worse. Gerschenfeld et al. (2017) compared the outcomes of 159 patients who received mechanical thrombectomy following t-PA, using a drip and ship model and those who received the same procedure at the mother ship. Although the median process times from patients in the mothership group were all significantly shorter, there were no significant differences between groups in the proportion of patients with a favourable outcome (mRS 0-2) at 3 months, or who experienced a symptomatic ICH, and discharge NIHSS scores were similar. Weber et al. (2016) reported similar results in a study involving 643 patients consecutively admitted to 17 stroke units, 8 of which offered in-house endovascular procedures. Compared with stroke units which did not offer this service and were required to transfer patients to one that did, the frequency of in-hospital and 3-month mortality were similar. Median periprocedural times were significantly shorter for in-house group.