Ziad Shaman, M.D., Director

Reviewed by Prashanth Thalanayar Muthukrishnan

The current standard of care and practice patterns for management of acute ischemic stroke vary geographically and institutionally (2). Although systemic thrombolysis is used routinely, a narrow therapeutic time window and modest efficacy in opening proximal intracerebral occlusions have inspired a search for endovascular techniques (3). Although the PROACT-II (Prolyse in Acute Cerebral Thromboembolism II) trial in 1999 was suggestive of positive results with endovascular thrombolysis over systemic tissue plasminogen activator (tPA), subsequent studies have not shown much clinical benefit (4–6). Lessons learned from these past trials include the need for proof of proximal vessel occlusion and rapid imaging methods to exclude patients with a large infarct core. Other deficiencies noted were the lack of workflow efficiency, better second- and third-generation stent retrievers, and high reperfusion rates (7). Five recent randomized controlled trials (MR CLEAN [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], ESCAPE [Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke], REVASCAT [Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset], EXTEND-IA [Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial], and SWIFT PRIME [Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment]) have been conducted to better evaluate the efficacy of mechanical endovascular therapy in stroke (7–11).

Saver and colleagues conducted a meta-analysis of previously reported randomized controlled studies to evaluate the benefit of using medical therapy with time-sensitive endovascular stent retrievers over medical therapy alone in acute proximal large-vessel stroke (1). The impetus to undertake this pooled individual-patient data analysis by the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration was the need to delineate the time period in which endovascular thrombectomy is associated with benefit. The pooled data from 1,287 adults (634 randomized to the intervention group and 653 to the control group) revealed that intravenous tPA followed by mechanical thrombectomy up to approximately 7 hours was associated with improved primary outcome compared with intravenous tPA alone within 4.5 hours of symptom onset (modified Rankin disability score [mRS] at 90 days with 95% confidence interval [CI], 2.9 [2.7–3.1] vs. 3.6 [3.5–3.8], respectively). The odds of better disability outcomes in the thrombectomy group compared with the systemic tPA group nominally declined with longer time from symptom onset to arterial puncture (common odds ratio for mRS [95% CI], 2.79 [1.96–3.98] at 3 h vs. 1.98 [1.30–3.00] at 6 h; absolute risk difference for mRS at 3 h vs. 6 h, 39.2% vs. 30.2%, respectively). Rates of functional independence after thrombectomy were 64% with reperfusion at 3 hours versus 46% with reperfusion at 8 hours. Time-by-treatment group interactions were also observed for mortality and mRS change for the interval from emergency department arrival to randomization (P = 0.049 and P < 0.001, respectively), but not from symptom onset to emergency department arrival (P = 0.21 and P = 0.79, respectively). This supports early treatment of patients with endovascular thrombectomy after stroke. Safety outcomes included 90-day mortality, symptomatic intracranial hemorrhage, and radiological major intracerebral parenchymal hematoma within 36 hours, which did not change significantly with longer delay to reperfusion (1).

There are many potential advantages to this meticulous pooled data meta-analysis over aggregate data meta-analysis. These include standardization of criteria and analyses across studies as well as reduction of publication bias and selective reporting. The researchers in the individual trials have explored the in-hospital workflow processes and could direct quality improvement initiatives toward future time targets for time to imaging, puncture, and reperfusion standards in stroke care. The ESCAPE trial has shown that picture-to-puncture time of less than 60 minutes and picture-to-perfusion time of less than 90 minutes are achievable with efficient workflow (8).

One of the important limitations of the study by Saver and colleagues (1) is the potential for confounding when studying time-by-treatment group interactions resulting from differences in the entry criteria of individual trials. The HERMES group addressed this in their statistical analysis. In addition, functional assessment at 3 months after stroke may be considered by some as too short, but the majority of reports in the stroke literature have used this cutoff. Last, eliminating patients with extremes of ischemic injury may affect the generalizability of the study to patients who do not meet the entry criteria of this study.

In summary, Saver and colleagues quantified the diminishing returns of adding thrombectomy to intravenous tPA compared with intravenous tPA alone as time from symptom onset to arterial puncture increases. Hospitals should undertake continuous and parallel, rather than serial, workflow improvements in stroke care by involving personnel simultaneously across paramedics, emergency departments, stroke alert and rapid response teams, ICUs, and interventional radiology departments. A study by Kawano and colleagues suggested that the extent of penumbra salvage visualized by imaging may correlate with the reduction in disability scores associated with ischemic stroke, which reinforces the need for prompt imaging and intervention in ischemic stroke (12). The 2015 American Heart Association/American Stroke Association update to guidelines for ischemic stroke regarding endovascular treatment highlights how these studies have reinforced guideline recommendations to pursue endovascular treatment when arterial puncture can be initiated within 6 hours of symptom onset (13).

Reviewed by Mohammed S. Siddiqui

The overall healthcare burden of acute ischemic stroke continues to be substantial. In 2013 alone, 6.9 million individuals around the world had acute ischemic stroke and another 3.4 million had hemorrhagic stroke (15). Current guidelines recommend a standard dose of 0.9 mg/kg intravenous alteplase (a tPA) for acute ischemic stroke (16); however, the Japanese Pharmaceuticals and Medical Devices Agency has approved the use of 0.6 mg/kg alteplase on the basis of a study that showed similar clinical outcomes and lower risk of intracerebral hemorrhage (ICH) (17). The ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study) was conducted to elucidate this clinical issue.

ENCHANTED was a randomized, prospective, open-label, international noninferiority study with blinded outcomes (14). The study authors conducted a two-by-two quasifactorial study comparing standard-dose tPA (0.9 mg/kg) with lower-dose tPA (0.6 mg/kg). The primary endpoint of the study was the combined outcome of death or disability at 90 days, using the mRS. Among the many secondary outcomes, the key safety outcome was the risk of symptomatic ICH.

A total of 3,310 subjects underwent randomization from March 2012 to August 2015. Of these, 1,654 patients were randomized into the lower-dose tPA (0.6 mg/kg) group, and 1,643 were assigned to the standard-dose tPA (0.9 mg/kg) group. There were minimal baseline differences (including pre-tPA NIH Stroke Scale score) between the groups, which were not significant in either group. The subjects’ median age was 67 years, with 38% women and about two-thirds from Asian countries. The average time of administration was 170 minutes from onset of stroke symptoms, with the mean doses being 35.5 mg in the lower-dose arm and 56.0 mg in the standard-dose arm (P < 0.001). The primary outcome of death or disability (mRS score of 2–5) occurred in 855 of 1,607 participants (53.2%) in the lower-dose group and 817 of 1,599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% CI, 0.95–1.25; P = 0.51). The key secondary outcome of symptomatic ICH occurred in 1.0% of the lower-dose group versus 2.1% in the standard-dose group (P = 0.01). Mortality at 90 days did not differ significantly between groups (8.5% and 10.3%, respectively; P = 0.07); however, mortality at 7 days was lower in the lower-dose arm of the study (3.6% vs. 5.3%; P = 0.02). The trial authors concluded that outcomes with lower-dose tPA were similar to those with standard-dose tPA, except for a lower incidence of symptomatic ICH in the lower-dose tPA group.

A few limitations of this study included its open-label design and recruitment of predominately Asian patients; however, similar clinical outcomes were observed in the non-Asian patient population. Although the study did include non-Asian patients from the United Kingdom and Australia, there was no mention of the racial demographics of these patient populations. The racial demographics in the United States, where a substantial proportion of the population is African American or Hispanic, may limit the generalization of the ENCHANTED results to the U.S. population. The study authors mentioned follow-up mRS assessment being done primarily by telephone as a limitation, possibly altering treatment effects because of interobserver variability.

Alteplase has revolutionized stroke care, but there is always the caveat of devastating ICH. Without question, tPA therapy is the standard of care for eligible stroke patients, and its benefits outweigh the risks, but the question of adequate dose for clot lysis versus a safe dose remains. The rate of ICH was halved, which raises an intriguing question for physicians when presented with a patient with an elevated bleed risk. In the past, these patients would likely have been excluded from consideration for systemic tPA. Coutinho and colleagues recently published a pooled analysis of the SWIFT (Should We Intervene Following Thrombolysis) and STAR (Solitaire Flow Restoration Thrombectomy for Acute Revascularization) studies and reported that adding intravenous tPA to mechanical thrombectomy did not show any significant benefit (18). It is conceivable that adding lower-dose tPA may have a better ICH risk profile but be less likely to lead to improved clinical outcomes. Despite the major findings of the ENCHANTED study, further American studies are needed before current standard of care changes, owing to the diverse racial demographics of the U.S. population.

Reviewed by Ridhwan Y. Baba

Acute ICH affects more than 1 million people worldwide yearly. Elevated blood pressure (BP) is very common in acute ICH, and it is associated with greater hematoma expansion, neurological deterioration, and death or dependency after ICH (20–22). Based on the results of the INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage) trial, current guidelines suggest that early intensive BP lowering (to a systolic BP target of 140 mm Hg) is safe in patients similar to those enrolled in INTERACT2 (23, 24).

From March 2011 to September 2015, the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage II) trial investigators randomized 1,000 adult patients (aged >18 yr) with spontaneous supratentorial ICH to either intensive (systolic BP, 110–139 mm Hg; n = 500) or standard treatment (systolic BP, 140–179 mm Hg; n = 500) (19). The baseline demographic and clinical characteristics were similar between the two groups; however, the majority of patients were Asian (56.2%). No significant difference was noted in the primary outcome (i.e., death or moderately severe or severe disability) (mRS score, 4–6) at 3 months in unadjusted (relative risk [RR], 1.02; 95% CI, 0.83 to 1.25; P = 0.84) and adjusted models (RR, 1.04; 95% CI, 0.85 to 1.27; P = 0.72). There were no differences in the ordinal distribution of the mRS score at 3 months. Similarly, no significant differences were noted in the secondary outcomes of hematoma expansion (adjusted RR, 0.78; 95% CI, 0.58 to 1.03; P = 0.08), European Quality of Life-5 Dimensions Questionnaire Utility Index (adjusted RR, −0.02; 95% CI, −0.05 to 0.02; P = 0.29), and visual analogue scale score at 3 months (adjusted RR, −1.32; 95% CI, −5.25 to 2.60; P = 0.51). Regarding safety outcomes, there were no reported differences in neurological deterioration, treatment-related serious adverse events occurring within 72 hours after randomization, or death within 3 months after randomization. However, post hoc analysis showed a significantly higher proportion of any renal adverse event within 7 days in the intensive treatment group (9.0% vs. 4.0%; adjusted RR, 2.32; 95% CI, 1.37–3.94; P = 0.0018).

In this trial, Qureshi and colleagues demonstrated no meaningful improvement in functional outcomes or mortality with intensive BP lowering in patients with spontaneous ICH, and they reported a significant increase in renal adverse outcomes when intensive BP lowering was attempted. An important distinction between the ATACH-2 and INTERACT2 studies is the actual reported systolic BP that was achieved in the two treatment arms of these studies. The early systolic BP in the intensive treatment group in INTERACT2 was similar to that of the standard treatment group in ATACH-2. It is plausible that even though data from INTERACT2 suggest that intensive systolic BP lowering to a target of 140 mm Hg after spontaneous ICH is clinically feasible and potentially safe, INTERACT2 was underpowered to detect any meaningful differences in mortality and functional outcomes with intensive systolic BP treatment to a target less than 140 mm Hg. This potentially explains the contradictory findings of the two studies.

A detailed analysis of ATACH-2 is important before its findings are integrated into standard guidelines. Primary and secondary treatment failures were more commonly observed in the intensive treatment group. Whether the treatment effect would have been greater if the treatment goals had been met in a higher proportion of participants is unclear. Interestingly, a mean ± SD systolic BP of 141.1 ± 14.8 mm Hg in the standard treatment group compared with 128.9 ± 16 mm Hg in the intensive treatment group at 2 hours was observed. This lack of a significant difference in the mean systolic BP between the intensive and standard treatment arms of the trial persisted for the first 24 hours. It is still unclear if a greater effect of intensive antihypertensive therapy would have been observed at higher systolic BP in the standard treatment group (e.g., systolic BP of 160–180 mm Hg). Another important concern is the primary use of nicardipine in this trial, which potentially limits the generalizability of these results to centers where this drug is available. Finally, the results of ATACH-2 cannot be generalized to patients with large-volume ICH, intracranial pressure elevation, or compromised cerebral perfusion pressure, and the possibility of precipitating global or regional cerebral hypoperfusion with the intensive reduction of systolic blood pressure in such patients may still be a concern. Although ATACH-2 presents important data to clarify the systolic BP thresholds in patients with spontaneous ICH, the rate and/or duration of BP lowering and the effects of BP variability after these events remains unclear.