Historical note and nomenclature

Since the United States Food and Drug Administration approval of intravenous tissue plasminogen activator (tPA) for use in acute ischemic stroke in June 1996, the approach to stroke treatment has changed dramatically. Acute ischemic stroke is now categorized as an emergency and requires rapid assessment and intervention in order to reduce the degree of brain injury and subsequent functional impairment. In addition to acute therapeutic interventions, a number of medical and surgical strategies have been devised to prevent the occurrence of stroke. By identifying patients at high risk and initiating appropriate therapy, up to 80% of strokes can be prevented.

Because most acute ischemic strokes are caused by a thromboembolic occlusion of an intracranial artery (29), the use of thrombolytic agents was a natural choice for acute therapy. The goal of thrombolytic treatment is to promote the dissolution of thrombus and restore blood flow. The basic mechanism of action entails converting plasminogen into plasmin, resulting in the degradation of fibrin and subsequent recanalization of the vessel. The first use of thrombolytic agents for acute stroke occurred in the late 1950s. The early attempts were unsuccessful for a variety of reasons, including lack of CT imaging that invariably led to the treatment of patients with intracerebral hemorrhage. In the early clinical trials, treatment with agents such as streptokinase and urokinase resulted in a high rate of intracerebral hemorrhage without any significant clinical benefit. The enthusiasm over the use of thrombolytic agents in acute stroke was renewed with the publication of certain animal stroke experiments. One study demonstrated significant improvement in the neurologic function of rabbits treated with intravenous tPA after small blood clots were injected into the carotid circulation (84). Data from another study demonstrated the successful recanalization of occluded middle cerebral arteries in primates using intra-arterial urokinase (22). Such results set the stage for further investigation into the efficacy of thrombolysis in acute ischemic stroke.

Scientific basis

The infarction of brain tissue is the result of a series of pathophysiologic events. The disturbance in blood flow reduces the availability of nutrients leading to the production of acidic end products and, ultimately, the reduction in intracellular pH. Other factors may play a role in the severity of the injury produced, including the inflammatory response, the breakdown of the blood-brain barrier, and release of free radicals. There is a finite amount of time available before ischemia produces an irreversible injury. Permanent focal damage begins within several minutes after a significant reduction in cerebral blood flow and is complete within approximately 6 hours. There is a brief period of time when the injury is completely reversible if adequate blood flow is restored; after prolonged ischemia, though, the injury becomes permanent, and no intervention will produce recovery. With the disruption in blood flow, an ischemic core is produced surrounded by a region of potentially viable tissue. This region has been referred to as the ischemic penumbra (09). Prompt restoration of adequate blood flow to this area may prevent further injury and diminish the degree of subsequent neurologic dysfunction. The size and duration of the penumbra are unknown for any individual patient. The dissolution of the thrombus is largely mediated by fibrinolysis localized within the thrombus and degradation of fibrin by plasmin. The recanalization rate is dependent on a variety of factors, including the age, composition, and size of the thrombus, as well as the site of occlusion.

Thrombolytic therapy

NINDS study. At present, tissue plasminogen activator is the only drug approved for use in the treatment of acute ischemic stroke by the United States Food and Drug Administration. Data obtained from the National Institute of Neurological Disorders and Stroke (NINDS) trial demonstrated that tPA given within 3 hours of stroke onset improved the functional outcome at 3 months (79). The study was a randomized, multicenter, placebo-controlled trial. The benefit of tPA was shown across all ischemic stroke subtypes and was not affected by age, sex, or ethnicity. Although the rate of symptomatic intracerebral hemorrhage was significantly higher in patients treated with tPA (6.4% tPA, 0.6% placebo), the mortality rates were similar between the 2 groups.

Additional evidence suggested earlier treatment within the 3-hour window is more effective than delayed therapy. The results of an analysis of the NINDS data showed that individuals treated 0 to 90 minutes from stroke onset achieved a more favorable outcome at 3 months than patients treated later than 90 minutes (57). The analysis stressed the importance of adhering to the NINDS protocol. Moreover, further clinical investigation demonstrated the benefit achieved with intravenous tPA administration extends up to 1 year and beyond (49).

ECASS III. The results of the European Cooperative Acute Stroke Study III were published in The New England Journal of Medicine in September 2008 (38). ECASS III was a double-blind, parallel-group trial that enrolled individuals aged 18 to 80 years of age with a clinical diagnosis of acute ischemic stroke from multiple clinical centers across Europe. In a 1:1 double-blind fashion, random assignments were made with patients receiving either intravenous alteplase (0.9 mg/kg of body weight) or placebo. The primary endpoint was disability at 90 days, dichotomized as a favorable (score of 0 or 1) or unfavorable outcome (score of 2 to 6) assessed by the modified Rankin scale (0=no symptoms, 6=death).

The results of the study revealed that the group given intravenous alteplase 3 to 4.5 hours after symptom onset benefited from the therapy. More patients exhibited a favorable outcome with alteplase when compared to placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval, 1.02 to 1.76; P=0.04). The median time for treatment with alteplase was 3 hours and 59 minutes. Mortality did not differ significantly between the 2 groups (7.7% alteplase; 8.4% placebo, P=0.68), but the overall rate of symptomatic intracranial hemorrhage was increased in the alteplase group (27.0% vs. 17.6%; P=0.001).

The take home message from the ECASS III study was although acute ischemic stroke patients treated with intravenous alteplase 3 to 4.5 hours after symptom onset showed a modest but significant improvement in the clinical outcomes, the maximum benefit of treatment is still seen when patients are treated as early as possible. Many stroke centers in the United States have adopted the ECASS III protocol in treating selected patients within the 3- to 4.5-hour treatment window who meet the eligibility requirements.

ECASS-4: ExTEND Trial. The study was a double-blind, phase 3, randomized clinical trial that assessed the safety and efficacy of intravenous thrombolytic therapy in selected patients who presented between 4.5 to 9 hours after stroke onset or upon awakening (wake up stroke) with evidence of a significant penumbral mismatch on MR-imaging (ECASS-4). The results of the trial were presented at the European Stroke Organization Conference in 2018 (67). The patient enrollment closed prematurely with a total of 119 patients. The results revealed the lack of efficacy of the treatment during the study period with a potential increase in the mortality rate of the intravenous thrombolytic therapy group.

IST-3 Trial (International Stroke Trial). The findings of the third International Stroke Trial (IST-3) revealed that treatment with intravenous t-PA in patients with acute ischemic stroke resulted in less disability and improvement in quality of life measurements over at least 18 months (42).

The IST-3 trial was an international, multicenter, prospective, randomized, open-label study. In total, 3035 patients with acute ischemic stroke were randomly assigned to receive treatment (1515 received 0.9 mg/kg intravenous t-PA vs. the 1520 who received standard therapy) within 6 hours of symptom onset. The primary outcome was the proportion of patents alive and independent with an Oxford Handicap Scale (OHS) score of 0 to 2 at 6 months, whereas the secondary endpoints at 18 months included survival, Oxford Handicap Scale score, health-related quality of life, overall functioning, and living circumstances.

Although the findings did not demonstrate an effect on survival, the results showed that patients treated with intravenous t-PA had clinically relevant improvement in their functional outcomes and health related quality of life issues for at least 18 months. An ordinal analysis of the Oxford Handicap Scale rank revealed a favorable shift in the group who received intravenous t-PA versus the control group (adjusted common odds ratio of 1.27; 95% confidence interval [CI], 1.10, 1.47; P=.001).

Interestingly, several years after the United States FDA approval of intravenous t-PA for the treatment of acute ischemic stroke, studies continue to show the potential benefit of the therapy weeks to months after its administration.

Alternative to alteplase.

Alternative to IV t-PA. Tenecteplase has been heralded as an alternative to intravenous t-PA (alteplase) for the treatment of selected patients with acute ischemic stroke. Tenecteplase is a new generation fibrinolytic agent created as a genetically modified variant of alteplase. It has several advantages over alteplase including a higher specificity for fibrin, a longer half-life, and reduced binding to plasminogen activator inhibitor-1 (PAI-1), which leads to greater resistance to inactivation by PAI-1. Notably, tenecteplase is administered as a single bolus, which should improve the ease of administration and ability to transport the patient for intervention and/or additional tests.

A formal metaanalysis was performed according to PRISMA guideline (Preferred Reporting Items for Systemic Review and Meta-Analyses) adapted to noninferiority analysis (16). The primary outcome measure was freedom from disability (modified Rankin score, 0-1) outcome at 3 months.

In total, 5 trials were reviewed that enrolled 1585 patients (828 tenecteplase, 757 alteplase) (16). The majority of patients were men (58.5%) with a mean age of 70.8 years. The baseline National Institutes of Health Stroke Scale mean was 7.0 and time from last known well to treatment start mean was 148 minutes. Standard dosing of 0.9 mg/kg was used for the patients who received alteplase whereas dosing in the tenecteplase group was 0.1 mg/kg in 6.8%, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%.

For the primary end point freedom from disability (modified Rankin Scale score, 0-1 at 3 months), the crude cumulative rates of disability free outcome were 57.9% for the tenecteplase group compared to 55.4% for alteplase. In informal, random-effects metaanalysis, the risk difference was 4% (95% CI, −1% to 8%). Similar findings were identified for other efficacy end points including functional independence (modified Rankin Scale score, 0-2): crude tenecteplase 71.9% versus alteplase 70.5%, risk difference 2% (95% CI, −3% to 6%) and modified Rankin Scale shift analysis, common odds ratio 1.21 (95% CI, 0.93-1.57).

The results of the analysis revealed tenecteplase is noninferior to alteplase in the treatment of acute ischemic stroke. Based on the findings, many stroke centers are considering a change in their protocols to include the option for the administration of tenecteplase in selected acute ischemic stroke cases.

PROACT II. The PROlase in Acute Cerebral Thromboembolism II evaluated the use of intra-arterial recombinant prourokinase in patients with arteriogram-proven middle cerebral artery occlusions within 6 hours of stroke onset (32). The study was a randomized, controlled, multicenter, open-label clinical trial that enrolled 180 patients. The participants were randomized to receive heparin alone or 9 mg of intra-arterial prourokinase plus heparin. The results demonstrated a significant difference favoring prourokinase over placebo (prourokinase 40%, placebo 25%) using the modified Rankin scale as a measure of functional status. Despite the higher rate of symptomatic hemorrhage in the prourokinase group, the mortality rates were similar for the 2 groups at 90 days. The results of the study demonstrated the efficacy and safety of prourokinase in selected patients with middle cerebral artery occlusions of less than 6-hours duration.

Time window for acute treatment of ischemic stroke. Many analyses have demonstrated that the best clinical outcomes occur with early administration of intravenous tPA in patients with acute ischemic stroke. An article published in Lancet in May 2010 highlighted the benefit of early treatment and concerns over the potential for risks outweighing the benefits in selected patients treated with intravenous thrombolysis over 4.5. hours (52). Data from ECASS III (821 patients) and EPITHET (100 patients) were pooled together with common data elements from 6 additional trials using alteplase for the acute ischemic stroke treatment (61). A multivariate logistic regression analysis was used to examine the relation of stroke onset to start of treatment (OTT). A favorable 3-month outcome was defined as a modified Rankin score of 0-1. All of the patients with a confirmed OTT within 360 minutes were included in the analysis. The analysis revealed odds of a favorable 3-month outcome increased as OTT decreased (p=0.0269). In addition, no benefit was noted with intravenous alteplase treatment after 270 minutes.

Patients with mild, nondisabling strokes. The PRISMS Trial collaborators sought to assess the safety and efficacy of alteplase in patients with ischemic stroke and nondisabling neurologic deficits (NIHSS 0-5) (47). The study was designed as a phase 3b, double-blind, double-placebo, multicenter trial scheduled to enroll 948 patients. The patients were randomized to receive intravenous alteplase (standard dose; 0.9 mg/kg) with an oral placebo (n = 156) or oral aspirin (325 mg) with intravenous placebo (n = 157) within 3 hours of symptom onset. The original primary outcome was the difference in favorable functional outcome measured by the mRS score of 0 or 1 at 90 days (assessed by the Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment). Once the trial was halted early due to slow recruitment, and prior to the unblinding or interim analysis, the plan was changed to analyze the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracerebral hemorrhage development within 36 hours of the intravenous study medication administration.

The results of the trial did not show a significant benefit of alteplase in patients with minor nondisabling acute ischemic stroke. The proportion of patients who had a favorable functional outcome at 90 days was 78.2% in the intravenous alteplase group versus 81.5% in the oral aspirin group (adjusted risk difference, -1.1%; 95%CI, -9.4% to 7.3%). In total, 5 patients (3.2%) treated with intravenous alteplase developed symptomatic intracerebral hemorrhage compared to zero in the aspirin arm.

Notably, the investigators pointed out that the study was underpowered (enrolling only a third of the planned number), precluding any definitive conclusions. Nevertheless, based on the post hoc analysis, it appeared unlikely the benefits of intravenous tPA extended to ischemic stroke patients without clearly disabling deficits upon presentation.

Combined intravenous and intra-arterial tissue plasminogen activator therapy. Despite the success noted with intravenous tPA in the NINDS trial, the prognosis of patients who presented with signs of a severe ischemic stroke due to a large vessel occlusion and treated with intravenous tPA therapy was relatively poor. In fact, among the patients who presented with a National Institutes of Health Stroke Scale score greater than 20 who were treated with intravenous tPA in the NINDS trial, 48% were dead at 3 months, and an additional 21% had a moderate or severe impairment of function (modified Rankin scale 4 or 5) (62). Due to the low rates of recanalization of proximal arterial occlusions with intravenous tPA alone, attention was directed toward different treatment strategies including local intraarterial thrombolytic therapy and/or acute endovascular intervention (mechanical thrombectomy) in the hopes of extending the therapeutic window to achieve better recanalization rates and clinical outcomes. Reestablishing blood flow with the removal of clots by mechanical thrombectomy became another tool in the arsenal for the treatment of acute ischemic stroke.

Historical trials leading to the use of combination therapy for acute ischemic stroke. The following studies paved the way for the use of combination therapy in acute ischemic stroke. The trials highlighted the key ingredients needed to improve clinical outcomes, which included improved technology to allow for faster recanalization times, better neuroimaging techniques, refined criteria to select appropriate patients, and a concerted effort to institute treatment as soon as possible to improve clinical outcomes.

Emergency management of stroke bridging trial. The Emergency Management of Stroke Bridging trial demonstrated that combined intravenous-intraarterial tPA was feasible and resulted in better recanalization rates but did not demonstrate improved patient outcomes (54). Subsequently, a retrospective analysis was conducted on 20 consecutive patients who presented with signs of severe, acute ischemic stroke (median National Institutes of Health Stroke Scale 21, range 11 to 31) and who were treated with combined intravenous-intra-arterial tPA therapy within 3 hours of symptom onset (26). The median time from stroke onset to intravenous treatment was 2 hours and 2 minutes, and the median time to the initiation of intra-arterial therapy was 3 hours and 30 minutes. In total, 50% recovered to a modified Rankin Scale of 0 or 1, 15% to a modified Rankin Scale of 2, and 25% to a modified Rankin Scale of 4 or 5. Two deaths occurred (1 patient developed a symptomatic intracerebral hemorrhage and expired; 1 patient died from complications of the stroke).

Interventional management of stroke (IMS) studies. In the Interventional Management of Stroke (IMS) study, patients aged 18 to 80 years with National Institutes of Health Stroke Scale scores of 10 or greater at baseline were given intravenous rt-PA (0.6 mg/kg, 60 mg maximum over 30 minutes) within 3 hours of onset (40). In addition, intra-arterial rt-PA was administered at the site of the thrombus (up to a total dose of 22 mg over 2 hours or until thrombolysis occurred). After the initial treatment with intravenous rt-PA, only approximately 5% of the cases demonstrated partial or complete recanalization; compared to 62 patients who subsequently received intra-arterial therapy for major arterial occlusions and demonstrated recanalization (TIMI 2 or 3 flow) in 56% of the patients. Because there was no placebo arm, comparisons were made to the results of the patients in the NINDS tPA trial. The Interventional Management of Stroke study patients had a significantly better outcome at 3 months than the NINDSD placebo-treated subjects for all outcome measures (odds ratio 2 or greater). The 90-day mortality rate for the Interventional Management of Stroke group was 16%, which was lower, but not statistically different, than the mortality demonstrated by the NINDS trial for the placebo arm (24%) and tPA-treated patients (21%).

The results of the Interventional Management of Stroke (IMS-II) pilot study revealed improved outcomes in patients with acute ischemic stroke who were treated with a combination of intravenous and intra-arterial tPA in addition to ultrasound therapy to break up stroke-related blood clots (41). In total, 73 patients (aged 18 to 80 years) were given a lower than standard dose of tPA intravenously during a 30-minute period within the 3-hour window after the stroke onset. Subsequently the patients were taken for cerebral angiography and 21 were found not to have a visible/treatable clot. The remaining patients were given intra-arterial therapy and 34 received low-energy ultrasound treatment at the site of the clot. The results of the study demonstrated that of the patients who received intra-arterial thrombolysis in conjunction with ultrasound therapy, 69% exhibited partial or complete recanalization compared with 55% of the patients from the previous trial (IMS-I) who were treated with intra-arterial therapy alone. Notably, although both trials had the same mortality rate (16%), nearly twice as many patients had an intracerebral hemorrhage in IMS-II (11%) when compared to IMS-I (6%).

A publication from the investigators at the University of Cincinnati outlined the results of 62 nonrandomized patients with acute ischemic stroke (NIHSS scores 10 or greater) treated with combination intravenous/intra-arterial therapy after the Emergency Management of Stroke Bridging trial, but before the Interventional Management of Stroke study (30). The results demonstrated 3-month modified Rankin scores of 0 to 2 for 50% of the patients with a mortality rate of 18% and a symptomatic intracerebral hemorrhage rate of 8%. Further research is ongoing to determine the optimal timing and dose of treatment. In addition, efforts are being made to create criteria to assist with the selection of appropriate patients.

One reason the approach of intra-arterial thrombolytic therapy has been supported in the treatment of acute ischemic stroke is that the intervention allows for high concentrations of thrombolytic agents to be delivered into the thrombus. In April 2007, the American Heart Association and American Stroke Association released guidelines for early acute ischemic stroke treatment (01). In regards to intra-arterial thrombolytic therapy, the guidelines stated the administration of at least 1 specific thrombolytic agent appeared to have some benefit in selected individuals with acute ischemic stroke secondary to occlusion of the middle cerebral artery. In addition, new evidence suggested that the use of intra-arterial urokinase within 24 hours of symptom onset in patients with vertebrobasilar occlusions may be beneficial. Lastly, patients who presented within 6 hours of symptom onset, but who were deemed ineligible to receive intravenous thrombolysis due to recent surgery or other procedures, may be considered for intra-arterial thrombolysis.

IMS-III Trial (Interventional Management of Stroke). The IMS III study was a phase 3, randomized, open-label, international trial designed to examine whether a combined approach (intravenous tPA with endovascular intervention) was more effective than treatment with intravenous tPA alone in patients with moderate to severe acute ischemic strokes (13). The target for patient enrollment was 900 patients randomly assigned in a 2:1 ratio to combination or standard therapy within 3 hours of stroke symptom onset. The endovascular treatment arm included a choice of catheters and devices or intraarterial tPA based on the lesion characteristics and discretion of the investigator. A modified Rankin scale of 2 or less (indicating functional independence) at 90 days was used as the primary outcome measure.

In April 2012, the trial was terminated early (434 patients received endovascular therapy, and 222 were administered intravenous tPA alone) after an interim analysis demonstrated futility. The results showed no significant difference in functional outcomes between the 2 groups using the modified Rankin score of 2 or less at 90 days (40.8% with endovascular therapy and 38.7% with intravenous tPA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], - 6.1 to 9.1). In addition, the proportion of patients with symptomatic intracerebral hemorrhage within 30 days after initiation of tPA (6.2% endovascular group and 5.9% intravenous tPA alone, P=0.83) and mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) was similar in both treatment arms. Notably, there was a significant increase in the number of asymptomatic intracerebral hemorrhage cases identified in the endovascular group (27.4% vs. 18.9%; P=.01). Going forward, many clinicians feel future trials should minimize delays in the initiation of endovascular therapy in order to see the potential benefits of the treatment in acute ischemic stroke.

MERCI clot retrieval device. Another advancement in the field of endovascular therapy for acute stroke treatment came with the U.S. Food and Drug Administration approval of the Merci clot retrieval device. The Merci retriever is a tapered wire with 5 helical loops of decreasing diameter (from 2.8 to 1.1 mm) at its distal end. It is advanced through the microcatheter in its straight configuration and resumes its pre-imposed helical shape once it is delivered into the occluded intracranial artery in order to ensnare the thrombus. In Phase 1 of the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial 30 patients were enrolled into the study (33). The inclusion criteria included: (1) an acute ischemic stroke with a NIHSS equal or greater than 10; (2) presented after the 3-hour time window for intravenous thrombolysis and could be treated within 8 hours of symptom onset; (3) presented within 3 hours of symptom onset with a contraindication to intravenous thrombolysis; (4) were older than age 18; and (5) had a normal CT scan or a CT scan showing a region of hypodensity less than one third of the middle cerebral artery territory. Patients were then selected for embolectomy if the diagnostic angiogram showed an occlusion of the internal carotid artery, M1 segment of the middle cerebral artery, basilar artery, or vertebral artery. The primary outcome was defined as arterial recanalization thrombolysis in myocardial infarction (TIMI; grade 2 or 3) without the occurrence of major complications defined as vessel perforation, arterial dissection, or embolization in a previously uninvolved territory. The secondary outcomes included the incidence of hemorrhage revealed by a head CT scan at 24 hours. The hemorrhage was deemed symptomatic if it was associated with a clinical deterioration of greater than 4 points on the NIHSS, and NIHSS and modified Rankin score at 24 hours, 5 days, and 30 days after ictus. A significant recovery was defined as a 30-day modified Rankin score of 0 to 2 in patients with a baseline NIHSS of 10 to 20, and a 30-day modified Rankin score of 0 to 3 in patients with a baseline NIHSS greater than 20.

Out of the 30 patients enrolled in the study, 28 were treated. The remaining 2 were not treated because: (1) the Merci retriever could not get to the site of the thrombus due to the tortuous anatomy, and (2) the thrombus extended into the M2 segment of the middle cerebral artery. The study group consisted of 14 men and 14 women with a mean age of 68 years (range, 28 to 93 years). The median baseline NIHSS was 22 (range, 12 to 39) and the median time from onset to completion of treatment was 6 hours and 15 minutes. Successful recanalization (TIMI 2 to 3) was achieved in 12 (43%) patients with the Merci retriever only. The total recanalization rate, including those patients successfully revascularized with intra-arterial thrombolytics, was 64%. Among the 18 patients who were revascularized, 50% (9 of 18) made a significant recovery (defined as 30-day modified Rankin score 0 to 2 in patients with baseline NIHSS 10 to 20 and 30-day modified Rankin score 0 to 3 in patients with baseline NIHSS greater 20). Notably, of the 10 patients not revascularized, none made a significant recovery. In regards to CNS hemorrhages, no symptomatic hemorrhages were documented, but 12 asymptomatic hemorrhages occurred. The results of the study demonstrated that the embolectomy procedure with the Merci retriever device was safe. There was no angiographic or clinical evidence of vascular injury or emboli into previously uninvolved arteries. Notably, the U.S. Food and Drug Administration approved the device for clot removal in acute ischemic stroke treatment.

The results of the phase 2 MERCI study demonstrated successful revascularization in 46% of patients on intention-to-treat analysis and in 48% of patients in whom the device was deployed (75). The primary outcomes included recanalization and safety; the secondary outcomes were neurologic outcomes at 90 days in recanalized versus nonrecanalized patients. Clinically significant procedural complications developed in 10 of 141 (7.1%) patients, whereas symptomatic intracranial hemorrhages were reported in 11 of 141 (7.8%). Modified Rankin scores of 2 or lower, signifying a good neurologic outcome, were more frequent at 90 days with patients who achieved successful recanalization compared to those with unsuccessful recanalization (46% vs. 10%; relative risk 4.4; 95% confidence interval, 2.1 to 9.3; P< 0.0001). In addition, mortality rates were less for patients with successful recanalization versus unsuccessful recanalization (32% vs. 54%; relative risk, 0.59; 95% confidence interval, 0.39 to 0.89; P=0.01). The study results demonstrated the ability to achieve successful recanalization during the acute ischemic stroke period (within 8 hours of symptom onset).

In 2007, the pooled results of the MERCI and Multi MERCI Part I Trials were published (31). The authors sought to examine the success rate of the MERCI retriever mechanical thrombectomy device in recanalization of intracranial internal carotid artery occlusions and determine whether internal carotid artery recanalization with the device resulted in better outcomes.

In total, 80 patients with acute stroke from an intracranial internal carotid artery occlusion were identified from the MERCI and Multi MERCI Part I Trials. Successful internal carotid artery recanalization with the MERCI device as solo therapy was noted in 53%; 63% had intracranial internal carotid artery recanalization with the MERCI device and adjunctive endovascular therapy. Good clinical outcome (modified Rankin Scale of 0 to 2 at 90 days) was found in 39% of patients with intracranial internal carotid artery recanalization (n=19 of 49) and in 3% of patients without intracranial internal carotid artery recanalization (n=1 of 30). The 90-day mortality rate was 30% (n=15 of 50) in the recanalized group and 73% (n=22 of 30) in the nonrecanalized group (P< 0.001). Multivariable logistic regression analysis identified intracranial internal carotid artery recanalization (OR=28.4, 95% CI=2.6 to > 99.9) and lack of history of hypertension (OR=0.15, 95% CI=0.04 to 0.57) as significant predictors of a good 90-day outcome. The 2 significant predictors of mortality at 90 days were found to be failure to recanalize the intracranial internal carotid artery (OR=0.16, 95% CI=0.05 to 0.51) and age (per decade, OR=1.07, 95% CI=1.03 to 1.13).

Wingspan stent. Intracranial atherosclerosis is a difficult disease to treat successfully and is felt to be the underlying pathology in up to 15% of patients with ischemic stroke. An investigation into the effectiveness of the Wingspan stent in medically refractory patients with high-grade, symptomatic intracranial atherosclerotic stenoses was devised, and the results of a multicenter, prospective, single-arm trial were published in 2007 (12).

The Wingspan stent system is a self-expanding nitinol stent. The endovascular protocol included predilation of the target lesion with an undersized Gateway balloon catheter at nominal pressure with slow inflation. The predilatation would be followed by the deployment of the self-expanding Wingspan stent system to further remodel the target vessel to maintain patency and eliminate the need for postdilation.

Patients were included in the study if they were medically refractory to treatment, had a modified Rankin score of 3 or less, and experienced recurrent symptoms referable to an angiographically demonstrated intracranial stenosis 50% or greater in a vessel 2.5 to 4.5 mm in diameter. Out of the 45 patients enrolled, the degree of stenosis was reduced from a baseline of 74.9±9.8% to 31.9±13.6% after stenting and 28±23.2% at the 6-month follow-up. The 30-day composite ipsilateral stroke/death rate was 4.5% (2 out of 44 patients) and at the 6-month follow-up, the ipsilateral stroke/death rate was 7.0%. The rate for all strokes was 9.7%, and the all-cause mortality was 2.3%. The results of the Wingspan Stent Study opened the door to the use of endovascular therapy for intracranial stenosis, suggesting a possible alternative therapeutic option in the treatment of this difficult disease process. In 2005, the FDA approved the Wingspan stent for use under a Humanitarian Device Exemption. After the approval, the NIH funded the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial to compare the results of aggressive medical management of patients with intracranial arterial stenosis to treatment with percutaneous transluminal angioplasty and stenting (PTAS) (19). In total, 451 patients were randomized to PTAS plus medical management or medical management alone. All of the patients had a history of a recent stroke or transient ischemic attack attributed to significant stenosis (70% to 95%) of a major intracranial artery. The primary endpoint was stroke or death within 30 days after enrollment or after the revascularization intervention for the target vascular lesion during the follow-up period or the development of a stroke in the vascular territory of the target arterial lesion beyond 30 days. The study was halted after enrollment of 451 patients. A review of the results revealed the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) compared to 5.8% in the medical management arm (nonfatal stroke, 5.3%; nonstroke related death, 0.4%; P=0.002). In addition, the 1-year rate of death or stroke was shown to be 20% in the PTAS group compared to 12.5% in the medical arm (P=0.009). The authors of the study concluded aggressive medical management of patients with intracranial arterial stenosis was superior to PTAS with the Wingspan system due to the high risk of early stroke after PTAS and lower than expected risk of stroke with patients receiving aggressive medical therapy.

Solitaire™ With the Intention for Thrombectomy (SWIFT) Trial. The SWIFT Trial was designed to examine the effectiveness of the Solitaire™ flow restoration device, a self-expanding retrievable stent, in the treatment of patients with acute ischemic stroke (71). The patients were enrolled into a multicenter, randomized, active comparator, noninferiority study that compared Solitaire™ as the initial device to the MERCI retriever in 21 sites (20 United States; 1 Europe).

The primary efficacy endpoint was designated as successful recanalization with the study device without the development of symptomatic intracranial hemorrhage. Successful recanalization was defined as TIMI 2 or 3 flow in all treated vessels. The inclusion criteria included patients aged 22 to 85 years, treatment instituted within 8 hours of symptom onset, a NIHSS between 8 and 30, and the presence of clinical signs of an acute ischemic infarct. Eligible patients required evidence of TIMI 0 or 1 flow in the M1 or M2 middle cerebral artery segments, internal carotid artery, or basilar or vertebral arteries confirmed by angiography and accessible to the Solitaire or MERCI devices. Patients could be enrolled in the study if they failed or were ineligible for intravenous tPA therapy. The exclusion criteria were standard for neurothrombectomy studies.

The assigned device (Solitaire™ or MERCI) was used for up to 3 passes followed by an outcome angiogram. Depending on the results, rescue devices could be used but were considered a failure of the proposed treatment. A follow-up brain imaging study was performed at 24 hours with clinical assessments at 3 months.

The first patient was enrolled in February 2010. Notably, the trial was stopped prematurely in July 2011 due to evidence suggesting overwhelming efficacy of 1 of the devices. When the trial was halted, 144 patients had been enrolled at 8 sites (31 roll in, 113 randomized, 55 MERCI, 58 Solitaire). The randomized groups were fairly well matched regarding their clinical features and medical history.

The results of the study revealed the primary measure of successful recanalization with the study device, without the development of symptomatic intracranial hemorrhage, occurred in more patients treated with the Solitaire device (60.7%) compared to the MERCI group (24.1%; noninferiority P value < 0.0001; superiority P value 0.0001). Good neurologic outcomes at 90 days were achieved in 58.2% of the Solitaire™ patients compared to 33.3% in the MERCI arm (noninferiority P value 0.0001, superiority P value 0.017). The mortality rate at 90 days was 17.2% with Solitaire-treated patients and 38.2% in the MERCI group (noninferiority P value 0.0001, superiority P value 0.020).

The symptomatic hemorrhage rate was 1.7% with Solitaire™ and 10.9% with MERCI (noninferiority P value < 0.0001, superiority P value 0.057). Review of all of the intracranial hemorrhages revealed 17.2% occurred with the Solitaire device compared to 38.2% with MERCI. Adverse events were equal in both arms.

In summary, the results of the SWIFT trial revealed the Solitaire™ flow restoration device was superior to the MERCI device in achieving successful recanalization of treated arteries without the development of symptomatic hemorrhage. The question of whether to intervene with a clot retrieval device in the study population examined during the SWIFT trial is still unanswered. Many clinicians await the results of ongoing trials comparing conventional medical therapy to endovascular treatment (ie, MR-Rescue and IMS III) to help answer the question.

MR RESCUE (Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy). MR RESCUE was a phase 2b, multicenter, controlled, blinded outcome study designed to examine whether advanced multimodal penumbral imaging could identify patients who might benefit from late endovascular therapy. In addition, the trial examined whether the treatment improved clinical outcomes (48).

In total, 118 patients with large vessel, anterior circulation strokes, within 8 hours of symptom onset, were randomly assigned to undergo mechanical embolectomy (Merci Retriever or Penumbra System) or standard care. All of the patients had brain imaging (CT or MRI) before treatment. The randomization was stratified based on whether the patient’s results exhibited a favorable penumbral pattern (significant salvageable tissue with a small infarct core) or a nonpenumbral pattern (large core with small or absent penumbra). The patients who received intravenous thrombolysis were eligible for the trial if the vessel imaging after treatment revealed a persistent target occlusion. The modified Rankin scale (mRs) was used to assess clinical outcomes.

Out of the 118 patients, the mean age was 65.5 years with a mean time to enrollment of 5.5 hours. In total, 58% had a favorable penumbral pattern, and recanalization in the embolectomy group was achieved in 67% of the patients.

The trial failed to demonstrate that penumbral imaging could identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke. In addition, endovascular intervention (embolectomy) provided no advantage to either group (favorable penumbral pattern; mean score, 3.9 vs. 3.4; P=0.23 vs. nonpenumbral pattern; mean score, 4.0 vs. 4.4; P=0.32). The rate of all-cause 90-day mortality was 21%, whereas the rate of symptomatic hemorrhage was 4%. The rate of asymptomatic hemorrhage was 58%. Notably, the outcome rates were similar across the groups.

Several questions were prompted by the study, including whether the penumbral pattern can truly identify durable tissue viability and if patients with a favorable penumbral pattern have an advantage for a good outcome because the pattern may indicate the presence of sufficient collaterals capable of helping to limit infarct size.

A significant shift in the treatment of acute ischemic stroke. Starting January 2015, the tide shifted in the approach toward patients with acute ischemic stroke due to a large vessel occlusion. Five clinical studies demonstrated the effectiveness of acute endovascular therapy in selected patients. Notably, this evidence came after 3 trials in 2013 appeared to show the therapy was not more effective than the administration of intravenous tPA alone.

After the publication of the 5 pivotal studies in 2015, more clinical evidence in support of the effectiveness of acute endovascular intervention (mechanical thrombectomy) was released. The Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration published a metaanalysis based on the pooled analysis of 1287 patients. The analysis revealed the combination of best medical therapy with acute endovascular intervention (mechanical thrombectomy) more than doubled the odds of a higher rate of functional independence mRS score of 0 to 2 at 90 days (46% to 27%, odds ratio 2.35, 95% CI 1.85-2.98) (02). In addition, the combination therapy resulted in significantly reduced disability with an improvement of at least 1 point on the mRS at 90 days (adjusted OR 2.49, 95% CI 1.76-3.53) when compared to solo medical treatment in selected patients with stroke due to large vessel occlusions involving the anterior circulation. Notably, there were no significant differences between the rates of symptomatic intracerebral hemorrhage between the 2 groups (36). Interestingly, another metaanalysis from the HERMES collaboration suggested endovascular thrombectomy in combination with best medical therapy was beneficial up to 7.3 hours after stroke onset (72).

Safety and efficacy shown for rapid endovascular treatment of acute ischemic stroke.

MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). At the start of 2015, a new era dawned in acute stroke treatment with the success of several trials showing the safety and efficacy of rapid endovascular intervention for acute ischemic stroke. The first study to demonstrate a clinically significant increase in the functional outcome of patients with an anterior artery circulation occlusion who received endovascular therapy versus intravenous tPA alone was the MR CLEAN trial (11).

MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) was a prospective, randomized trial of endovascular intervention plus intravenous recombinant tissue plasminogen activator (rt-PA) versus conventional therapy with intravenous tPA in patients with acute ischemic stroke due to a proximal intracranial occlusion of the anterior circulation. The initiation of intraarterial thrombolysis had to be feasible within 6 hours of stroke symptom onset. The primary outcome was the modified Rankin scale score at 90 days, which measures functional outcome (0, no symptoms; 6 death). The results were published in the New England Journal of Medicine on January 1, 2015 providing a landmark shift in the treatment of acute ischemic stroke.

In total, 500 patients (N=233 to intraarterial treatment; N=267 intravenous tPA), at 16 medical centers in the Netherlands, were randomized to 2 groups: intravenous tPA versus interventional group plus intravenous tPA. The majority of both groups received intravenous tPA within 4.5 hours. Following the intravenous tPA administration, the interventional group was assigned to receive intraarterial therapy. Notably, retrieveable stents were used in the majority of patients (190 of the 233 patients; 81.5%) assigned to the interventional arm.

The mean age of the study participants was 65 years (range 23 to 96), and 292 (58.4%) were men. No significant differences were noted between the 2 groups regarding risk factors and time to treatment.

The results of the trial showed a shift in the distribution of the primary outcome scores in favor of the interventional group. Notably, the number of patients who attained functional independence (modified Rankin score, 0 to 2) at 90 days was greater in the interventional group (32.6%) compared to the intravenous tPA group (19.1%). No significant differences were seen in mortality or symptomatic intracerebral hemorrhages between the 2 groups.

ESCAPE (Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times). The ESCAPE trial was a multicenter, prospective, randomized, open-label, controlled study with blinded outcome evaluations (35). Three hundred and sixteen patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients were excluded if they had a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography. The participants were randomized to receive intravenous tPA alone or intravenous tPA plus endovascular treatment. The majority of patients in the endovascular arm were treated with retrievable stents (86%). The primary outcome was the modified Rankin score at 90 days (0, no symptoms; 6, death).

The trial was halted early due to the demonstration of efficacy in the endovascular group. Review of the results showed a shift in the functional independence measure in favor of the endovascular arm (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P< 0.001). In addition, the mortality rate in the endovascular group was significantly lower (10.4% vs. 19.0% in the intravenous tPA group; P=0.04), whereas symptomatic intracerebral hemorrhage was reported in 3.6% of the endovascular group versus 2.7% for the intravenous tPA group (P=0.75).

EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-arterial). The results of the EXTEND-IA trial added more evidence to support the use of endovascular therapy in patients with acute ischemic stroke due to an internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion (17). EXTEND-IA was an investigator-initiated, multicenter, prospective, randomized, open-label, blinded-end-point study designed to compare the results of patients randomly assigned to receive intravenous tPA alone versus intravenous tPA plus endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever within 4.5 hours of symptom onset. All of the patients had an internal carotid artery or middle cerebral artery occlusion and evidence of salvageable brain tissue and ischemic core of less than 70 mL on computed tomography perfusion imaging. The co-primary outcomes were reperfusion at 24 hours and early neurologic improvement (≥ 8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3).

After the enrollment of 70 patients (35 patients in each group), the trial was stopped because of the significant benefit seen in the endovascular arm. Review of results revealed improved reperfusion and early neurologic recovery in the endovascular group. Examination of the percentage of ischemic territory showed patients treated with endovascular therapy exhibited increase reperfusion at 24 hours (P< 0.001) and a probability of reperfusion of more than 90% without symptomatic intracerebral hemorrhage when compared to the intravenous tPA group (89% vs. 34%, P< 0.001). In addition, the patients treated with endovascular therapy, (started at a median of 210 minutes after the onset of symptoms), showed greater early neurologic recovery at 3 days (80% vs. 37%, P=0.002). No significant differences were seen between the 2 groups in mortality or rates of symptomatic intracerebral hemorrhage.

SWIFT PRIME (Solitaire PR With the Intention For Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke). The SWIFT PRIME study was another trial stopped early due to the efficacy demonstrated in the endovascular group. The trial was conducted at 39 hospitals in the United States and Europe. In total, 196 patients (98 in each group) were randomized to receive intravenous tPA alone or intravenous tPA plus endovascular thrombectomy with a stent retriever within 6 hours of symptom onset. Confirmation of proximal anterior intracranial occlusions and absence of large ischemic core lesions were required for enrollment. The primary outcome was measured by the severity of global disability at 90 days shown by the modified Rankin scale (0, no symptoms; 6 death).

The trial was halted in November 2014 after review of the results demonstrated compelling differences between the 2 groups in favor of the endovascular arm. The endovascular group showed a significant shift to lower disability levels on the modified Rankin scale. Reduced disability at 90 days was seen over the entire range of scores on the modified Rankin scale (P< 0.001) for the endovascular group and the rate of functional independence (modified Rankin scale score, 0 to 2) was higher in the endovascular group compared to patients who only received intravenous tPA (60% vs. 35%, P< 0.001). No significant differences were seen in the 90-day mortality rates (9% vs. 12%, P=0.50) or symptomatic intracerebral hemorrhage (0% vs. 3%, P=0.12).

REVASCAT (Randomized trial of reVascularization with Solitaire device vs. best medical therapy in the treatment of Acute stroke due to anTerior circulation large vessel occlusion presenting within 8 hours of symptom onset). The results of the REVASCAT trial supported the benefit of endovascular therapy seen with other studies (46). Over a 2-year period, 206 patients were randomly assigned to receive intravenous tPA or intravenous t-PA (when eligible) plus endovascular treatment (Solitaire stent retriever) within 8 hours of stroke symptom onset. All of the patients had strokes attributed to a confirmed proximal anterior circulation occlusion and absence of a large infarct on imaging. The primary outcome measure was the severity of global disability at 90 days demonstrated by the modified Rankin scale (0, no symptoms; 6 death).

The trial was stopped after 206 patients had been enrolled (maximum planned sample size was 690), following the positive results for thrombectomy demonstrated in other studies. The results of the endovascular group showed reduced severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval, 1.05 to 2.8). In addition, higher rates of functional independence scores (mRS 0 to 2) were seen at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). The rates of symptomatic intracerebral hemorrhage at 90 days were the same for both groups (1.9%, P=1.00), whereas the rates of mortality were 18.4% for the endovascular arm and 15.5% for the intravenous t-PA group (P=0.60).

DAWN and DEFUSE-3 Trials. Further fuel in support of combination therapy and extending the therapeutic time window for treating patients with acute ischemic stroke due to large vessel occlusions came in the form of the DAWN and DEFUSE Trials. The DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) trial examined patients who presented with strokes from large vessel occlusions after 6 hours from symptom onset (63). The trial was a multicenter, prospective, randomized, open-label study that compared best medical therapy (control group) to acute endovascular thrombectomy plus best medical treatment in patients with acute ischemic stroke from a large vessel occlusion during an extended time window. Eligible patients presented within 6 to 24 hours of symptom onset with evidence of salvageable brain tissue. Notably, the presence of salvageable brain tissue was assessed by a mismatch between the severity of the neurologic deficits and volume of infarcted brain tissue (mismatch criteria defined according to age; < 80 years or ≥ 80 years). In addition, eligible patients were required to have a good prestroke baseline (mRS 0 to 1).

The patients were randomly assigned to the 2 treatment groups. The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (ranged 0 [death] to 10 [no symptoms]) and rate of functional independence on the modified Rankin scale at 90 days.

In total, 206 patients were enrolled in the study (99 controls and 107 endovascular thrombectomy plus medical therapy). The study showed the benefit of the combination treatment in the extended time window (6-24 hours) for selected patients with salvageable brain tissue. The trial was terminated early once the interim analysis showed a significantly higher rate of functional independence at 90 days when compared to the control group (best medical therapy).

The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 for the endovascular thrombectomy plus medical therapy group compared to 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, > 0.999) and the rate of the functional independence at 90 days was 49% in the endovascular thrombectomy plus medical therapy group compared 13% in the control arm (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, > 0.999). Notably, the rate of symptomatic intracerebral hemorrhage and mortality was not significantly different between the 2 groups (SICH; 6% endovascular thrombectomy plus medical therapy group and 3% control group, P = 0.50; mortality 19% and 18%, respectively; P = 1.00).

The use of the utility-weighted modified Rankin scale and assessment of salvageable brain tissue by considering clinical deficits with the volume of infarcted brain in the DAWN study helped advance the selection process for appropriate patients in the extended time window.

The DEFUSE-3 trial was designed to examine the efficacy of thrombectomy for patients with acute ischemic stroke due to large vessel occlusion in an extended time window based on magnetic resonance imaging criteria (03). The study was conducted as a multicenter, randomized, open-label trial, with a blinded outcome assessment of thrombectomy in patients with an acute ischemic stroke due to a large vessel occlusion within 6 to 16 hours of symptom onset. The eligibility criteria included individuals between 18 to 90 years of age with a large vessel occlusion from a proximal middle cerebral artery or internal carotid artery occlusion, initial infarct volume less than 70 ml, ratio of ischemic volume to initial infarct volume of at least 1.8, and a volume of potentially reversible ischemia (penumbra) of at least 15 ml. The assessment of the ischemic core and penumbra volumes were determined using the RAPID software, which evaluated either computed axial tomography perfusion imaging or MRI diffusion and perfusion studies. The primary outcome was the ordinal score on the modified Rankin scale (0-6) at day 90.

The trial was halted early after randomization of 182 patients (92 endovascular plus medical therapy vs. 90 medical therapy). The results were significantly in favor of the endovascular plus medical therapy group. A positive shift was seen in the distribution of functional outcomes on the modified Rankin scale at 90 days in the endovascular plus medical therapy arm (odds ratio, 2.77; P < 0.001) in addition to a higher percentage of functional independent patients (mRS score of 0-2; 45% vs.17%, P < 0.001). No significant difference was seen between the 2 groups regarding symptomatic intracerebral hemorrhage or serious adverse effects (7% and 4%, respectively; P = 0.75 and 43% and 53%, respectively; P = 0.18). The 90-day mortality rate was 14% in the endovascular plus medical therapy group compared to 26% in the medical therapy arm (P = 0.75).

The results of all of the studies provided strong evidence to support the efficacy of endovascular therapy with intravenous thrombolytic treatment in patients with acute ischemic strokes due to large vessel occlusions. Notably, speed of delivery, multidisciplinary care, and access to specialized teams with endovascular capability is required to achieve similar results seen in the trials. Based on the results of a series of randomized, controlled trials, the current AHA guidelines for acute ischemic stroke support endovascular thrombectomy in selected patients presenting within the 6-hour time window (class IIb).

Sonothrombolysis. Alexandrov and colleagues conducted a randomized, phase 2, multicenter study, The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial (06). The study was designed to determine whether ultrasonography could safely enhance the thrombolytic activity of tPA. Patients who presented with an acute ischemic stroke due to an occlusion of the middle cerebral artery and were treated with Intravenous tPA within 3 hours of symptom onset were eligible for the study. The patients were randomized to continuous 2 MHz transcranial Doppler ultrasonography (study group) or placebo (control group). The primary combined end point was complete recanalization (measured by transcranial Doppler ultrasonography) or dramatic clinical recovery. The results of the study demonstrated that in selected patients with acute ischemic stroke continuous transcranial Doppler appeared to enhance tPA-induced arterial recanalization with a trend (non-significant) toward an increased rate of recovery when compared to placebo.

The promise of neuroprotection. The potential use of neuroprotection in acute stroke is linked to the concept of the ischemic penumbra. In the area surrounding the densely ischemic core, there is a zone of potentially viable tissue. The neuronal tissue injury may be reversible if adequate blood flow is restored to this area. This region is the target of neuroprotective strategies. Despite the success in animal models, the lack of success in humans is probably due to a variety of factors including delay in drug administration, inadequate dosing, and heterozygous stroke population. Two negative neuroprotectant trials were reported in 2005. The first study evaluated repinotan, a serotonin receptor agonist, in the treatment of acute ischemic stroke within a 4.5-hour time window (41). The results of the phase 3 trial did not reveal any efficacy of the drug. The second trial examined the astrocyte activation inhibitor, ONO-2506, in the treatment of acute ischemic stroke (41). Futility analysis in May 2005 led to the early termination of the phase 3 study.

Some promise in the neuroprotective arena came with the results of the Stroke-Acute Ischemic NXY Treatment (SAINT I) trial (53). SAINT I demonstrated that the administration of a free radial trapping agent, NXY-059, within 6 hours of stroke onset in conjunction with intravenous tPA (presenting within 3 hours of stroke onset) resulted in reduced disability at 90 days. The patients who received the experimental agent were 20% more likely to be less disabled 3 months after the stroke when compared to the placebo group. In addition, the patients who received NXY-059 were less likely to develop hemorrhagic conversion of the pre-existing ischemic stroke (15.4%) when compared to the patients on standard therapy (27.3%). The results of the NXY-059 group appeared to be associated with a reduction in the risk of symptomatic intracerebral hemorrhage (6.4% to 2.5%). Notably, although the drug was able to show a reduction in disability at 90 days (the primary endpoint), it did not significantly improve other outcome measures such as neurologic function.

Unfortunately, the promising results of the SAINT I study could not be duplicated with the follow-up SAINT II trial (74). The distribution of the scores on the modified Rankin scale did not differ between the group treated with NXY-059 (1588 patients) compared to the placebo group (1607 patients; P=0.33 by the Cochran-Mantel-Haenszel test; odds ratio for limiting disability, 0.94; 95% confidence interval, 0.83 to 1.06). The authors of the study concluded that NXY-059 was ineffective for the treatment of acute ischemic stroke within 6 hours after the onset of symptoms.

CHOICE trial. Despite the success of mechanical thrombectomy, data have demonstrated approximately 27% of patients with acute ischemic stroke, due to large vessel occlusions, are disability free at 90 days. Incomplete or partial microcirculatory reperfusion may play a role in the less than ideal clinical outcomes.

The Chemical Optimization of Cerebral Embolectomy (CHOICE) study was designed to examine whether treatment with intra-arterial alteplase after thrombectomy resulted in improved outcomes after reperfusion (66). CHOICE was a multicenter, phase 2b, randomized, double-blind, placebo-controlled trial performed in Catalonia, Spain. In total, 121 patients were included in the trial. Patients with acute ischemic stroke attributed to large vessel occlusions who underwent thrombectomy within 24 hours after stroke onset were randomized to receive intra-arterial alteplase (0.225mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n=61) or placebo (n=52). Treatment with thrombectomy resulting in angiographic success was defined as a Treatment in Cerebral Ischemia (TICI) angiographic score or 2b50 to 3.

The primary efficacy outcome measure was defined as the proportion of patients who achieved a 90-day modified Rankin Scale score of 0 or 1. A score of 1 or less demonstrated an excellent functional outcome.

Notably, the study was stopped early due to the inability to maintain placebo availability and enrollment because of the COVID 19 outbreak.

From December 2018 through May 2021, 1825 patients with acute ischemic stroke underwent thrombectomy at 7 study sites. The data showed 748 (41%) fulfilled the angiographic criteria. In total, 121 (7%) were randomized (mean age 70.6 years [SD, 13.7]; 57 women [47%]), and 113 (6%) were treated as randomized. The percentage of patients with a modified Rankin score of 0 to 1 at 90 days was 59.0% with alteplase and 40.4% with placebo. Notably, symptomatic intracranial hemorrhage within 24 hours was not demonstrated in the alteplase group (0%), whereas it was noted in 3.8% of the placebo group (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). The 90-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%).

Although the trial had to be stopped early, the results demonstrated the use of adjunct intra-arterial alteplase compared to placebo in the selected study population resulted in a greater likelihood of a favorable neurologic outcome at 90 days.

IV t-PA administration.

Indications and patient selection. The administration of tPA should be considered in every patient with acute ischemic stroke that arrives to the emergency department. A strict protocol needs to be followed that includes several inclusion and exclusion criteria. The inclusion criteria, derived from the NINDS study, include age (10), signs of a neurologic deficit from an ischemic stroke on examination, and time of onset within 3 hours. Some of the exclusion criteria include (1) evidence of intracranial hemorrhage on CT, (2) elevated blood pressure values (systolic blood pressure greater than 185 mm Hg or diastolic blood pressure greater than 110 mm Hg) on repeated measurements despite intervention known platelet diathesis, and (3) the recent use of an oral anticoagulant with an elevated prothrombin time (greater than 15 seconds). A CT scan should be obtained prior to the administration of tPA to exclude the possibility of tumor or intracranial hemorrhage. A trained professional should review the results of the imaging study. The extent of early infarct signs may influence the risk of intracerebral hemorrhage, but patients with early infarct signs still do better with tPA than placebo. In addition to the imaging study, several laboratory tests should be ordered including chemistries, complete blood count with platelets, and coagulation studies. To complete the evaluation, a 12-lead EKG is needed to investigate the possibility of a myocardial infarction, and serial blood pressure measurements are essential. The dose of intravenous tPA is 0.9 mg/kg (maximum dose 90 mg). The total dose is administered as a bolus (10%) over 1 minute, followed by an intravenous infusion (remainder of the dose) over 1 hour.

Table 1. Administration of tPA (Protocol Guidelines)

I. Inclusion criteria
	• Age 18 years or older • Signs of a measurable neurologic deficit from an ischemic stroke on examination • Time of onset 3 or fewer hours
II. Exclusion criteria
	• Evidence of intracerebral hemorrhage on pretreatment CT • Minor or rapidly improving symptoms • Clinical presentation suggestive of subarachnoid hemorrhage • Active internal bleeding • Known platelet diathesis including, but not limited to:
		- platelet count less than 100,000/mm3 - heparin administration within 48 hours with elevated aPTT - current or recent use of oral anticoagulants with an elevated PT longer than 15 seconds
	• Major surgery or serious trauma in previous 14 days • History of gastrointestinal or urinary tract hemorrhage within 21 days • Recent arterial pressure puncture at noncompressible site or lumbar puncture • Uncontrolled hypertension (systolic blood pressure greater than 185 mm HG or diastolic greater than 110 mm HG) on repeated measurements at time of treatment • History of intracranial hemorrhage • Abnormal blood glucose (less than 50 or greater than 400 mg/dL) • Post myocardial infarction • Seizure at time of stroke onset • Known arteriovenous malformation or aneurysm

Adverse effects

The major risk associated with the administration of thrombolytic therapy is the possibility of a hemorrhagic complication. In the NINDS study, the percentage of symptomatic intracranial hemorrhage was 0.6% with placebo, compared to 6.4% with tPA. Despite the increased rate of intracranial hemorrhage with tPA, there was no difference in mortality rates between the 2 groups at 3 months. The American Academy of Neurology and the American Heart Association have both recommended treatment with tPA in selected individuals with acute ischemic stroke within 3 hours of symptom onset.

Stroke units

Acute care of stroke patients requires a multidisciplinary approach to improve the clinical outcome. Compared to the traditional treatment of stroke patients on general wards, organized inpatient management in a stroke unit reduces the odds of death or dependency at final follow up by 22% (95% confidence interval 11-32) (78). In June 2000, the Brain Attack Coalition, a group of representatives from major professional and advocacy organizations involved in stroke care, published recommendations for primary stroke centers (05). The guidelines included the key elements necessary for the establishment of a primary stroke center. The required elements included acute stroke teams, stroke units, written care protocols, and an integrated emergency response system. In addition, rapid laboratory testing and 24-hour CT scanning with interpretation was mandatory.

Prevention strategies

NASCET/ECST. The results from the North American symptomatic carotid endarterectomy (NASCET) trial and the European carotid surgery (ECST) trial showed the beneficial effects of carotid endarterectomy in individuals with high-grade carotid stenosis (70% to 99%). The inclusion criteria included patients with transient hemispheric or retinal ischemic events or nondisabling strokes referable to an atherosclerotic carotid stenosis. The patients were randomized to receive either optimal medical therapy or medical treatment in combination with surgery.

The NASCET results demonstrated that the cumulative risk of any ipsilateral stroke at 2 years was 26% in the medical group and 9% in the surgical arm, with an absolute risk reduction of 17% + 3.5% (P< 0.001) (64). For a major or fatal stroke, the results were 13.1% for patients who received medical therapy and 2.5% for the surgical group. The absolute risk reduction was 10.6% + 2.6% (P< 0.001). In ECST, the risk of ipsilateral stroke at 3 years was 16.8% for the medical group and 2.8% for the surgical group (27). The absolute risk reduction was 14%. For disabling or fatal stroke or surgical death, the results were 11% for the medical group and 6% for the surgical arm. The disparity in results between the 2 studies was attributed to the different measurements used to assess the degree of stenosis (10). Both studies were unable to demonstrate the benefit of surgery in patients with less than 70% stenosis.

ACAS. The asymptomatic carotid atherosclerosis study (ACAS) was a prospective, randomized, multicenter trial designed to evaluate the effectiveness of carotid endarterectomy in association with aggressive medical therapy in reducing the incidence of stroke in patients with asymptomatic carotid artery stenosis. The results revealed a reduced 5-year risk of ipsilateral stroke in asymptomatic individuals, with 60% carotid artery stenosis if the associated perioperative risk was less than 3% (28). Over 5 years, the estimated risk for ipsilateral stroke and any perioperative stroke or death was 5.1% for the surgery group and 11% for the medical arm. The results translated into an estimated annual absolute difference of approximately 1.2% (P=0.004). At present, there is no general consensus on appropriate treatment for an individual who presents with asymptomatic carotid artery stenosis of 60%. The possible benefit of the surgery relies on the expertise of the individual surgeon and the associated perioperative morbidity and mortality. Perioperative risks greater than 3% can eliminate any benefit from surgery.

Table 2. Summary of Carotid Endarterectomy Trials

Trial	Results
NASCET Degree of stenosis: • 70% to 90% • 30% to 69% Conclusions: CEA is beneficial for symptomatic patients with 70% to 90% high-grade stenosis. The efficacy of CEA still remains unclear in symptomatic patients with 30% to 69% carotid artery sclerosis.	70% to 90% stenosis Estimated cumulative risk of any ipsilateral stroke at 2 years: • 26% (medical n=331) • 9% (surgical n=328) • ARR 17% + 3.5% • P< 0.001
ECST Degree of stenosis: 70% to 99% 30% to 69% 0% to 20% Conclusions: CEA is beneficial for symptomatic patients with 70% to 99% high-grade stenosis. The benefits derived from CEA (over 3 years) outweighed the early risks of surgery (within 30 days). The efficacy of CEA still remains unclear in symptomatic patients with 30% to 99% carotid artery stenosis. There is no evidence to support carotid artery surgery in patients with mild carotid stenosis (0% to 20%).	16.8% (medical n=323) 2.8% (surgical n=455) abs. diff. 14% 2P<0.0001 Estimated 3-year risk of any disabling or fatal stroke (or surgical death): • 11% (medical) • 6% (surgical) • abs difference 5% • 2P<0.0001
ACAS Degree of stenosis: 60% Conclusions: Surgery plus medical therapy was associated with a reduced 5-year risk of ipsilateral stroke in asymptomatic individuals with 60% carotid artery stenosis if the associated perioperative risk was less than 3%.	Over 5 years, the estimated risk for ipsilateral stroke and any perioperative stroke or death: • 5.1% (surgery) • 11.0% (medical)

The value of transcranial ultrasonography in the evaluation of carotid artery stenosis. Since its inception in 1954 the concept of surgical revascularization of the carotid artery for carotid arterial occlusive disease has become the standard of care. The efficacy and durability of carotid endarterectomy for stroke prophylaxis was demonstrated by the results of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Study (ACAS). If there were a way to accurately identify patients at high-risk for stroke from large artery atherosclerotic disease it would be an invaluable tool. Markus and MacKinnon conducted a single-center study and recruited consecutive patients with recently symptomatic carotid artery stenosis to evaluate whether embolic signals detected by transcranial Doppler ultrasound predicted subsequent short-term stroke risk (56).

The results of the study demonstrated asymptomatic embolization in carotid stenosis predicted short-term ipsilateral stroke risk. In total, 226 consecutive patients who presented with equal to or greater than 50% symptomatic carotid artery stenosis by duplex ultrasonography and without evidence of a cardiac embolic source were prospectively recruited into the study. Out of the 226 patients examined, successful insonation of the ipsilateral middle cerebral artery was achieved in 200 patients. A symptomatic status was defined as an ipsilateral stroke, transient ischemic attack, or amaurosis fugax within the past 3 months. For a 1-hour interval, transcranial Doppler was used to record signals from the ipsilateral middle cerebral artery. The Doppler audio signal was analyzed at a later time by clinicians blinded to the clinical data. The patients were followed prospectively until surgical intervention, stroke, or study end at 90 days. Embolic signals were detected in 44.5% of the patients (N=89) and during follow-up 31 patients developed recurrent ipsilateral ischemic events: 7 strokes and 24 transient ischemic attacks. The presence of embolic signals predicted stroke alone (P=0.001) and the combined endpoint of stroke and transient ischemic attack (P=0.00001). Notably, the absence of embolic signals identified a group of patients at low risk for stroke alone and stroke and transient ischemic attack during follow-up: 0% and 7.5%, respectively, versus 3.5% and 15.5% in all 200 patients.

Carotid angioplasty and stenting. Carotid angioplasty and stenting has received a lot of attention as an alternative to carotid endarterectomy in selected patients for the treatment of carotid stenosis. The WALLSTENT trial was the first American randomized study directly comparing carotid angioplasty and stenting to carotid endarterectomy (04). Patients were randomized to receive either angioplasty and stenting with the Schneider WALLSTENT endoprosthesis or carotid endarterectomy. The study was halted early after enrollment of 223 patients because of a statistically significant difference favoring carotid endarterectomy. With respect to the primary endpoint of ipsilateral stroke, procedure-related death or vascular death at 1 year, the event rates were 12.1% in the stent group and 4.5% in the endarterectomy group (P=0.022). Some clinicians attributed the poor outcome in the stent group to inexperienced endovascular interventionalists.

Yadav and colleagues conducted a randomized trial to compare carotid artery stenting with embolic-protection devices to endarterectomy in high-risk patients with symptomatic carotid artery stenoses (at least 50% of the luminal diameter) or asymptomatic stenoses (at least 80%). The Stenting and Angioplasty With Protection in Patient at High Risk for CEA (SAPPHIRE) trial was designed to test the hypothesis that stenting was not inferior to endarterectomy (82). The primary end point was the cumulative incidence of a major cardiovascular event at 1 year; a composite of death, stroke, or myocardial infarction within 30 days after the intervention, or death or ipsilateral stroke between 31 days and 1 year. All of the patients were required to have at least 1 coexisting condition that potentially increased the risk of surgery. The high-risk criteria included: clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, previous radical neck surgery or radiation therapy to the neck, recurrent stenosis after carotid endarterectomy, and age greater than 80 years. The results of the study demonstrated that carotid stenting with emboli-protection devices was not inferior to carotid endarterectomy in patients with severe carotid artery stenosis and coexisting conditions. The primary end point occurred in 20 patients randomly assigned to undergo carotid artery stenting with an emboli-protection device (cumulative incidence, 12.2%) and in 32 patients randomly assigned to undergo endarterectomy (cumulative incidence, 20.1%; absolute difference, -7.9% points; 95% confidence interval, -16.4% to 0.7% points; P=0.004 for noninferiority, and P=0.053 for superiority). At 1 year, a carotid revascularization procedure was required in fewer patients who had received stents than in those who had undergone endarterectomy (cumulative incidence, 0.6% vs. 4.3%; P=0.04).

Preliminary 3-year data from the SAPPHIRE, and final 3-year data from the United States Carotid Feasibility Study (USFS) were presented at the 2005 Transcatheter Cardiovascular Therapeutics meeting. The results showed the long-term durability of carotid artery stenting for the prevention of stroke compared to carotid endarterectomy in high-risk patients. In total, 334 patients in the SAPPHIRE trial were randomized to either carotid artery stenting or carotid endarterectomy. At 36 months in the SAPPHIRE trial, the incidence of stroke was similar for both groups (7.1% for carotid artery stenting and 6.7% for carotid endarterectomy, P=0.945). The 3-year incidence of stroke across the randomized and nonrandomized carotid artery stenting treatment groups in SAPPHIRE and USFS had only an average increase of 4.0% over the 30-day stroke rate.

Conflicting information regarding the efficacy of angioplasty and stenting compared to endarterectomy was published in a New England Journal of Medicine article in 2006. The Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial showed that in patients with symptomatic carotid stenosis of 60% or more, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting (58). The study was stopped abruptly after the enrollment of 527 patients due to concerns of safety and futility. The 30-day incidence of any stroke or death was 3.9% after endarterectomy (95% confidence interval, 2.0 to 7.2) and 9.6% after stenting (95% confidence interval, 6.4 to 14.0) with a relative risk of any stroke or death after stenting compared to endarterectomy of 2.5 (95% confidence interval, 1.2 to 5.1). At 6 months, the incidence of any stroke or death was 6.1% after endarterectomy compared to 11.7% after stenting (P=0.02). In general, more systemic complications (mainly pulmonary) were reported after endarterectomy whereas stenting had more major local complications, but the differences were not significant.

CREST. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) was the largest, prospective, randomized study to date designed to compare carotid artery stenting and carotid endarterectomy for the treatment of carotid artery stenosis (14). The trial included 1321 symptomatic and 1181 asymptomatic patients who were randomized to receive stenting (Acculink and Accunet devices) or carotid endarterectomy. Initially enrollment began with only symptomatic patients, but with slow recruitment, asymptomatic patients were added midway during the study. The primary composite end point was stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization.

The results of the study revealed no significant difference between the 2 treatment groups regarding the primary endpoint (carotid artery stenting 7.2% vs. carotid endarterectomy 6.8%) and Kaplan-Meier curves showed most events were periprocedural. Notably, individual risks varied. The rate of stroke at 30 days was significantly higher in the carotid artery stenting group (4.1%) compared to the carotid endarterectomy group (2.3%), but no difference was seen regarding major stroke risk in both groups (less than 1%). The opposite findings were found in regards to myocardial infarction, where the risk was found to be higher in the carotid endarterectomy group (2.3%) compared to the carotid artery stenting group (1.1%). During the mean follow-up of 2.5 years, the rates of ipsilateral stroke were equal between the 2 groups (carotid artery stenting 2.0% versus carotid endarterectomy 2.4%). The results seemed to suggest an effect of age on the outcome, with younger patients having slightly fewer events with carotid artery stenting whereas older patients had fewer events with carotid endarterectomy.

A presentation at the International Stroke Conference in 2012 showed results from the 2-year follow-up of the CREST Trial (50). Notably, the rate of re-stenosis of the treated carotid artery was similar between the 2 groups and relatively infrequent. A hemodynamically significant re-stenosis (70% or greater diameter reduction) was characterized by a peak systolic velocity of 3 or more m/second on standardized duplex ultrasonography whereas an occlusion was defined by an absence of flow within the treated artery. The rate of re-stenosis and occlusion was 6.0% (n=58) in the CAS group and 6.3% (n=62) in the CEA arm. The difference was not statistically significant. The monitoring of the patient outcomes will continue for the remainder of the 10-year follow-up period.

Long-term CREST results. The results of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) showed no significant difference between the CEA versus stenting group regarding the primary composite end point of stroke, myocardial infarction, or death during the periprocedural period or any subsequent ipsilateral stroke during the 4-year follow-up period. In addition, a review of the 10-year follow-up did not find a significant difference between the stenting group compared to the endarterectomy arm in regards to risk of periprocedural stroke, myocardial infarction, or death and subsequent ipsilateral stroke (15). There was no difference in the postprocedural ipsilateral strokes between the 2 groups.

CREST-2. The CREST-2 trial was designed to address the longstanding question regarding the best treatment of patients with asymptomatic, severe carotid artery stenosis. Estimates of 100,000 vascular interventions (carotid endarterectomy or stenting) are performed in the United States annually, with a major proportion focused on asymptomatic patients. To date, it is unclear what treatment option is the most effective. CREST-2 is being conducted as 2 parallel, multicenter, randomized, observer-blinded endpoint clinical trials. One trial focuses on treatment differences between intensive medical management alone compared to carotid endarterectomy plus intensive medical management. The parallel trial will examine treatment differences between intensive medical management alone compared to carotid artery stenosis plus intensive medical management.

Antiplatelet therapy.

Aspirin. Aspirin has been shown to diminish the risk of myocardial infarction, stroke, and vascular death (07). Aspirin promotes vasoconstriction and reduces platelet aggregation by inhibiting the antithrombotic prostacyclin derived from endothelial cells and restricting thromboxane A2 production. Both mechanisms rely on the inhibition of the cyclooxygenase enzyme. The “right” dose of aspirin for stroke prevention has been the topic of fierce debate for many years and centers around the desire to achieve the antiplatelet effect while minimizing the side effects, particularly gastrointestinal bleeding. Presumably, the bleeding is produced from the erosive effect on the mucosa coupled with the antithrombotic action of aspirin.

Several studies have attempted to evaluate the efficacy of ‘low dose’ aspirin in stroke prevention. The trials examined patients with histories of transient ischemic stroke and minor stroke. Results from The Swedish Aspirin Low-dose Trial [SALT] (70) found that 75 mg/day of aspirin was the most effective dose. The Dutch TIA trial compared 2 doses of aspirin: 30 mg and 283 mg/day (there was no control group). The study group concluded that 30 mg of aspirin was more effective than 283 mg/day (25). In 1996, The European Stroke Prevention Study 2 (ESPS2) was published (24). The data obtained demonstrated that 50 mg/day produced a greater risk reduction than placebo. Given the abundance of different recommendations, it is easy to see why controversy still exists surrounding aspirin dosage in stroke prevention. Although many physicians in clinical practice prescribe 81 mg or 325 mg/day, the jury is still out on the ‘appropriate’ dose for stroke prevention.

Clopidogrel. Clopidogrel is a thienopyridine derivative related to ticlopidine. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study provided information regarding the efficacy of clopidogrel compared to aspirin in individuals with atherosclerotic vascular disease (18). Seventy-five mg of clopidogrel daily was compared to 325 mg/day of aspirin to determine which agent was more effective in reducing the risk of ischemic stroke, vascular death, and myocardial infarction. A 9.78% risk-reduction was found in the clopidogrel group compared to 10.64% in the placebo arm. The relative risk-reduction was 8.7% favoring clopidogrel.

Many clinicians have favored the use of combination antiplatelet therapy (aspirin and clopidogrel) citing the belief that the combined antiplatelet effect of the 2 agents may be better than monotherapy and noting the success of the combination therapy in patients with unstable angina and after coronary artery stenting. The results of the MATCH trial challenged this belief. The MATCH trial was a randomized, double-blind, placebo-controlled study that was designed to examine whether the addition of aspirin (75 mg daily) to clopidogrel would result in a greater benefit than clopidogrel alone in the prevention of vascular events (23). In total, 7599 high-risk patients (individuals with a recent stroke or transient ischemic attack and at least 1 additional vascular risk factor) were enrolled into the study and randomized to clopidogrel and aspirin (N=3797) or clopidogrel and placebo (N=3802). The primary endpoint was a composite of ischemic stroke, myocardial infarction, vascular death, or re-hospitalization for acute ischemia. The duration of treatment and follow-up was 18 months. The results of the study demonstrated that the addition of aspirin to clopidogrel in high-risk patients with ischemic stroke or transient ischemic attack was associated with a nonsignificant difference in reducing major vascular events but an increased risk of life-threatening or major bleeding events. Life-threatening bleeds were higher in the group given aspirin and clopidogrel compared to clopidogrel alone (96 [2.6%] versus 49 [1.3%]) with an absolute risk increase of 1.3% (95% confidence interval 0.6 to 1.9). Further investigation is ongoing to examine the risk/benefit profile associated with the use of combination antiplatelet therapy (aspirin and clopidogrel) in stroke prevention.

Another trial (CARESS) sought to examine the efficacy of combination antiplatelet therapy with clopidogrel and aspirin compared to aspirin alone on asymptomatic embolization in patients with recently symptomatic carotid artery stenosis. The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial was a randomized, double-blind study of patients with recently symptomatic carotid stenosis (50% or greater) who were screened with transcranial Doppler ultrasound (55). If microembolic signals were detected the patients were randomized to clopidogrel and aspirin or aspirin monotherapy. The inclusion criteria included patients aged more than 18 years, with equal to or greater than 50% carotid stenosis who had experienced ipsilateral carotid territory transient ischemic attack (including amaurosis fugax) or stroke within the prior 3 months. The prespecified primary end point was the proportion of patients who were microembolic signals positive on the 1-hour recording performed on day 7. Repeated transcranial Doppler ultrasound recordings were performed on days 2 and 7. In total, 230 patients were screened with transcranial Doppler ultrasound. Microembolic signal was detected in 110 (47.8%) during the initial screening online analysis and 107 were randomized. The results of the study demonstrated combination therapy with clopidogrel and aspirin in patients with recently symptomatic carotid stenosis was more effective than aspirin monotherapy in reducing asymptomatic embolization. The intention-to-treat analysis showed a significant reduction in the primary end point. Of the dual therapy patients, 43.8% were microembolic signals positive on day 7 compared to 72.7% of the monotherapy patients (relative risk reduction 39.8%; 95% confidence interval, 13.8 to 58.0; P=0.0046). In regards to the secondary end point (on the ITT analysis), microembolic signals frequency per hour was reduced by 61.4% (95% confidence interval, 31.6 to 78.2; P=0.0013) in the dual-therapy group at day 7 and by 61.6% (95% confidence interval, 34.9 to 77.4; P=0.0005) at day 2. During the 1-week follow-up, 4 monotherapy patients developed recurrent ipsilateral ischemic stroke; none were reported in the dual-therapy group. Recurrent ipsilateral treatment emergent transient ischemic attacks were noted in 7 monotherapy patients compared to 4 transient ischemic attacks in the dual therapy group. In addition, 2 dual therapy patients developed recurrent ipsilateral transient ischemic attacks before therapy was started. No hemorrhage was reported in any of the cases. Microembolic signals frequency was greater in the 17 patients with recurrent ipsilateral events compared to the 90 without (mean ± SD: 24.4±27.7 vs. 8.9±11.5 per hour; P=0.0003).

Dipyridamole. Dipyridamole is a platelet aggregation inhibitor that acts through the reduction of cyclic adenosine monophosphate. Several trials investigated the efficacy of dipyridamole in stroke prevention, but were unable to show any benefit until the publication of the European Stroke Prevention Study 2 (ESPS2). In ESPS2, 200 mg twice a day of dipyridamole (modified release form) was found as effective as 50 mg (25 mg twice a day) of aspirin for secondary stroke prevention (24). The combination (aspirin plus dipyridamole) was superior to either agent alone. The relative risk-reduction for stroke was 16% for dipyridamole, 18% for aspirin, and 37% for the combination (dipyridamole and aspirin). The relative risk-reduction for stroke or death was 15% for dipyridamole, 13% for aspirin, and 24% for the combination. The most common side effect reported in patients treated with dipyridamole was headache. Gastrointestinal hemorrhage and bleeding were seen more often in the aspirin group than the placebo or dipyridamole arm.

Sacco and colleagues conducted post hoc analyses of the ESPS-2 trial to examine the degree of risk reduction of recurrent stroke in various risk factor subgroups and in subgroups at high risk for recurrent stroke estimated from externally validated measurement scores (69). Post hoc analyses with external stroke models from the Framingham Study and the Stroke Prognostic Instrument II (SPI-2) were used to compute estimated risk categories based on the ESPS-2 baseline variables. Rates of annual strokes and vascular events were determined for the aspirin-only group (n=1649) and the aspirin plus extended-release dipyridamole group (n=1650) and were stratified by risk subgroup and univariate risk factors. The results of the analyses demonstrated aspirin plus extended-release dipyridamole was more effective than aspirin alone in preventing stroke with a more pronounced effect for high-risk groups (individuals younger than 70 years, with hypertension, prior stroke, transient ischemic attack, current smokers, and in individuals with any prior cardiovascular disease). The relative hazard reductions favored the combination antiplatelet regimen and were greatest for the high-risk Framingham Study group and the moderate-risk Stroke Prognostic Instrument II subgroup.

Although there are limitations with any post hoc analysis, the results of the study demonstrated the efficacy of aspirin plus extended-release dipyridamole compared to aspirin-alone in preventing stroke. Notably, the effect became more pronounced in the reduction of stroke for high-risk groups. Presently, there are several antiplatelet choices available for the prevention of stroke and clinicians are faced with the decision of which one to choose for individual cases. It appears that an important variable to consider before making a final decision is the baseline vascular risk of each patient.

Warfarin. The rate of ischemic stroke among individuals with atrial fibrillation is about 5% per year, which is approximately 6 times the rate found in patients without atrial fibrillation. If transient ischemic attacks are included, the rate of cerebral ischemic events associated with nonvalvular atrial fibrillation exceeds 7% per year. Warfarin has been shown effective in preventing cardioembolic stroke in the setting of nonvalvular atrial fibrillation, prosthetic heart valves, and acute myocardial infarction. The Stroke Prevention Atrial Fibrillation III (SPAF III) trial compared the efficacy of dose-adjusted warfarin to aspirin for stroke prevention in high-risk individuals with nonvalvular atrial fibrillation (77). The results showed that warfarin with an INR between 2 to 3 was superior to aspirin and mini-dose warfarin (international normalized ratio less than 1.5).

The Warfarin-Aspirin Recurrent Stroke Study (WARSS). The primary goal of stroke prevention therapy is to reduce the risk of subsequent stroke. Although warfarin has been shown to be effective in preventing cardioembolic stroke in the setting of nonvalvular atrial fibrillation, prosthetic heart valves, and acute myocardial infarction, there is considerable debate about its potential superiority over antiplatelet therapy for the prevention of recurrent ischemic stroke in patients with previous noncardioembolic ischemic stroke. In such patients, antiplatelet treatment reduces the rate of stroke recurrence by approximately 30%, but clearly there is room for improvement. The Warfarin-Aspirin Recurrent Stroke Study (WARSS) was a multicenter, double-blind, randomized trial designed to compare aspirin to warfarin therapy for the prevention of recurrent ischemic stroke in patients with a recent history of noncardioembolic ischemic stroke (60). The primary end point of the study was death from any cause or recurrent ischemic stroke. The patients were followed for 2 years + 1 month (up to a maximum of 761 days).

The participants were randomized to active aspirin (325 mg tablet daily) and warfarin placebo or active warfarin (one 2 mg scored tablet daily) and aspirin placebo. The warfarin doses were adjusted to achieve and maintain an international normalized ratio in the range of 1.4 to 2.8. In order to maintain blinding, the international normalized ratio values obtained from patients receiving active aspirin and warfarin placebo were replaced by the statistical-analysis center with fabricated values considered plausible for the dose and duration of warfarin therapy.

In total, 2206 patients were enrolled in the study. The 2 groups were similar with respect to their baseline risk factors. Overall, the patients taking warfarin were maintained close to the desired goal with 70.7% of daily international normalized ratio values (determined 28 or more days after randomization) within the target range of 1.4 to 2.8.

In the primary intention-to-treat analysis, there were no significant differences between the 2 groups (warfarin vs. aspirin) in the time to the primary end point. The primary end point of recurrent ischemic stroke or death was reached by 17.8% of the patients given warfarin and 16.0% of the patients treated with aspirin (P=0.25; hazard ratio comparing warfarin with aspirin, 1.13; 95% confidence interval, 0.92 to 1.38). Notably, not only did warfarin therapy fall short of the anticipated 30% reduction in the risk of recurrent stroke, the treatment was associated with a 13% higher increase in risk over aspirin (although this finding did not reach the level of significance). Interestingly, the rates of major hemorrhage were low for the 2 groups, with annual rates of 2.22 per 100 patient-years for the warfarin group and 1.49 per 100 patient-years for the aspirin arm (rate ratio, 1.48; P=0.10). The warfarin group had significantly more minor hemorrhages than the aspirin group. There were no significant differences in the time to a primary end point between patients of different sexes, different racial or ethnic groups, or different types of prior stroke. Although some clinicians have suggested warfarin’s protective effect may have been undermined by international normalized ratio values that were too low, the authors pointed out the success of previous stroke prevention trials that used the same range of international normalized ratio values in patients with atrial fibrillation. The results of the study revealed no additional benefit of warfarin over aspirin in preventing recurrent ischemic stroke in the population studied. Nevertheless, this finding does not exclude the possibility that certain subgroups may still attain a greater benefit from warfarin.

Further analyses of the WARSS data revealed some interesting findings regarding the issue of aspirin failure. The results demonstrated that the patients with a history of stroke who were taking aspirin on entry into the study and were subsequently randomized to aspirin therapy had worse outcomes than patients who received aspirin for the first event at the time of randomization into WARSS (59). The difference was not explained by traditional risk factors or newer risk factors including patent foramen ovale, anticardiolipin antibody status, stroke subtype, or sociodemographic status.

The Antiphospholipid Antibodies in Stroke Study (APASS). A substudy of the WARSS trial was the Antiphospholipid Antibodies in Stroke Study (APASS). The objective of the trial was to examine the effect of antiphospholipid antibodies on stroke recurrence and systemic embolization (08). Among the 1770 patients studied with ischemic stroke and tested for antiphospholipid antibodies, 13.4% demonstrated the lupus anticoagulant, 20.5% showed anticardiolipin antibodies, 6.7% demonstrated both types, and 59.3% failed to demonstrate either type. Notably, only patients with both anticardiolipin antibodies and lupus anticoagulant showed a higher thrombotic event rate (35.9% vs. 26.2%). The patients with 1 type alone (anticardiolipin antibody or lupus anticoagulant) had no increase in recurrent thrombotic events when compared to patients without antiphospholipid antibodies.

The Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS). PICSS is another substudy of the WARSS trial (39). The objective was to evaluate transesophageal echocardiographic risk factors in relation to stroke and examine the effectiveness of anticoagulation versus antiplatelet therapy in preventing recurrent stroke. In total, 601 patients with cryptogenic stroke were evaluated with a transesophageal echocardiogram. The results revealed 34% had a patent foramen ovale. Interestingly, the recurrent stroke rate was not higher in the patients who were found to have a patent foramen ovale compared to those without one (19.7% vs. 19.4%). Examination of the patients with a patent foramen ovale and ischemic stroke revealed no difference in events by treatment assignment, and point estimates favored aspirin (16.5% vs. 13.2%, P = .49). In addition, in the group of patients with presumed embolic cryptogenic ischemic stroke and patent foramen ovale, no difference in events by treatment was documented, but estimates favored warfarin (9.5% vs. 17.9%, P= .28). Further investigation may reveal that certain subgroups require more aggressive therapy to produce better clinical outcomes than other subgroups.

African-American Antiplatelet Stroke Prevention Study (AAASPS). AAASPS was designed to compare the results of ticlopidine versus aspirin in the prevention of recurrent stroke in the African-American population (34). Not only did the results of the study fail to demonstrate a significant difference in efficacy, but the data revealed a trend toward the superiority of aspirin therapy.

Warfarin-Aspirin Symptomatic Intracranial Disease (WASID). The WASID trial was a prospective, randomized, placebo-controlled, multi-center study designed to compare warfarin (target international normalized ratio 2 to 3) to aspirin (1300 mg daily) for the prevention of stroke (ischemic and hemorrhagic) and vascular death in patients with symptomatic stenosis of a major intracranial vessel (20). Patients with transient ischemic stroke or stroke caused by an angiographically proven intracranial atherosclerotic stenotic vessel (50% or greater stenosis) were randomized to aspirin (1300 mg/day) or warfarin therapy (target international normalized ratio of 2.0 to 3.0). The primary analysis was designed to compare the rates of stroke (ischemic and hemorrhagic) and vascular death in the 2 treatment groups. The mean duration of follow-up was 1.8 years. In total, 13 patients (2.3%) were lost to follow-up (n=6) or withdrew consent (n=7) and study medications were permanently discontinued in 128 patients (22.5%). Interestingly, there was a significantly higher rate of discontinuation among patients assigned to warfarin therapy (28.4%) compared to patients treated with aspirin (16.4%; P< 0.001). After 569 patients were randomized, the study was terminated early due to the rates of increased systemic bleeding events noted in the warfarin arm. During a mean follow-up period of 1.8 years, adverse events in the 2 groups included death (4.3%in the aspirin arm compared to 9.7% in the warfarin group; hazard ratio (HR) for aspirin relative to warfarin, 0.46; 95% confidence interval, 0.23 to 0.90;P=0.02), major hemorrhage (3.2% vs. 8.3%, respectively; HR,0.39; 95% CI, 0.18 to 0.84; P=0.01), and myocardial infarction or sudden death (2.9% vs. 7.3%, respectively; HR, 0.40; 95% CI, 0.18 to 0.91; P=0.02). The primary end point occurred in 22.1% of the patients in the aspirin group and 21.8% from the warfarin arm (HR, 1.04; 95% CI, 0.73 to 1.48; P=0.83).

The final analysis of the data did not reveal any clear difference between the aspirin group compared to the warfarin arm for the prevention of stroke, transient ischemic attack, or vascular death. Warfarin was associated with significantly higher rates of adverse events and the authors concluded aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis.

Dabigatran, rivaroxaban, and apixaban. Since the 1950s, warfarin has been the first-line treatment for patients with atrial fibrillation to reduce the risk of stroke. These newer agents have increased the available treatment options.

Dabigatran etexilate is an oral anticoagulant (prodrug) in the class of direct thrombin inhibitors. In October 2011, it received FDA approval for risk reduction in stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Because dabigatran has demonstrated predictable anticoagulation responses, it does not require routine blood monitoring as seen with warfarin treatment. In addition, it is not affected by diet changes and appears to have less drug interactions when compared to warfarin.

The results of The Randomized Evaluation of Long-Term Anticoagulation Therapy (Re-ly) trial were published in the New England Journal of Medicine in 2009 (21). It was a large randomized trial (18,113 patients) that compared dabigatran (110 mg twice daily and 150 mg twice daily) to warfarin in patients who had atrial fibrillation with an increased risk of stroke. The median duration of the follow-up period was 2 years. The primary study outcome was stroke or systemic embolism whereas the primary safety outcome was major hemorrhage. The results of the study revealed dabigatran, at a dose of 110 mg, was noninferior to warfarin for the primary endpoint of stroke or systemic embolism whereas dabigatran, at a dose of 150 mg, was significantly more effective than warfarin and the 110 mg dose of dabigatran. Notably, the major bleeding events occurred significantly less often in patients treated with 110 mg of dabigatran compared to warfarin whereas patients who received warfarin and dabigatran at doses of 150 mg had similar bleeding events.

Rivaroxaban is an orally active direct Factor Xa inhibitor. On November 4, 2011, the FDA approved rivaroxaban for stroke risk reduction in patients with nonvalvular atrial fibrillation.

The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) was a large, multi-center, randomized, double-blind, double-dummy, event-driven study that compared once-daily oral rivaroxaban to dose-adjusted warfarin for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation at risk for stroke (65). In total, 14,264 patients were given rivaroxaban (20 or 15 mg daily in patients with a creatinine clearance of 30 to 49 ml per minute) or dose-adjusted warfarin (target international normalized ratio, 2.0 or 3.0). The primary efficacy endpoint was the composite of stroke (ischemic or hemorrhagic) and systemic embolism.

The results of the study revealed rivaroxaban was noninferior to warfarin in the prevention of stroke or systemic embolism. Notably, no significant differences were seen between the 2 groups in regards to major and clinically relevant non-major bleeding, but intracranial and fatal bleeding occurred less frequently in the rivaroxaban arm. Apixiban is a direct Factor Xa inhibitor. The results of a double-blind study, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, were published in The New England Journal of Medicine in 2011 (37). The trial examined 18,201 patients with atrial fibrillation and at least 1 additional risk factor for stroke. The patients were treated with apixaban (5 mg twice daily) or warfarin (target international normalized ratio, 2.0 to 3.0). The primary outcome measure was stroke (ischemic or hemorrhagic) or systemic embolism. The mean duration of follow-up was 1.8 years. The results of the trial revealed apixaban was superior to warfarin in preventing stroke or systemic embolism. In addition, the risk of major bleeding was reduced by 31% in patients given apixaban whereas death was reduced by 11% when compared with the warfarin group.

The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS). PRoFESS was a 2x2 factorial, double-blind, event-driven, active and placebo-controlled trial of aspirin/extended-release dipyridamole versus clopidogrel, and the angiotensin receptor blocker, telmisartan, versus placebo (68). The study included 20,332 patients from 695 centers in 35 countries. All of the patients had a noncardioembolic ischemic stroke within the previous 120 days. The study participants were randomized in a factorial design to receive aspirin (25 mg) plus extended-release dipyridamole (200 mg) twice daily or clopidogrel (75 mg daily). In addition, they were randomized to receive telmisartan (80 mg daily) or placebo.

No clear winner was identified. There was no evidence that either of the 2 therapies (aspirin/extended-release dipyridamole vs. clopidogrel) was superior to the other in the prevention of recurrent ischemic stroke. Recurrent stroke occurred in 916 patients (9.0%) receiving aspirin/extended-release dipyridamole and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval, 0.92 to 1.11). Notably, increased risks of nonfatal hemorrhagic stroke and side effects leading to the discontinuation of therapy were seen with the aspirin/extended-release dipyridamole group.

In a separate article, the results of the telmisartan-placebo data were published (83). The primary outcome of the trial was recurrent stroke and the secondary outcome included major cardiovascular events. The median interval from stroke to randomization was 15 days with a mean follow-up of 2.5 years.

Despite a mean blood pressure difference between the groups of 3.8/2.0 mm Hg, in favor of telmisartan, there was no difference regarding the primary endpoint of recurrent stroke, secondary outcomes (major cardiovascular events), or new-onset diabetes.

The Secondary Prevention of Small Subcortical Strokes (SPS3) Trial. The SPS3 Trial was a randomized, multicenter, international study designed to examine the effectiveness of administering dual antiplatelet therapy (clopidogrel and aspirin) versus solo antiplatlelet treatment (aspirin alone) in selected patients with subcortical infarcts for the prevention of recurrent stroke (76). Eligible patients included individuals with lacunar stroke randomized within 180 days. Patients with cortical strokes, carotid stenosis, or cardioembolic infarcts were excluded. The patients were randomized to 2 interventions in a factorial design: antiplatelet treatment (double blind; aspirin (ASA) 325 mg + placebo vs. ASA 325 mg + clopidogrel 75 mg) and target levels of blood pressure control (open label; usual BP treatment of 130 to 149 mm Hg systolic levels vs. intensive BP treatment of < 130 mm Hg systolic levels).

The primary outcome of the trial was the development of recurrent stroke (ischemic or hemorrhagic) whereas the secondary outcomes included the occurrence of major vascular events, cognitive decline, or death. In total, 3,020 patients were randomized to receive 325 mg of aspirin plus placebo (n=1503) or 325 mg of aspirin plus 75 mg of clopidogrel (n=1517). The antiplatelet arm of the trial was stopped prematurely in October 2011 when review of the data revealed an increased risk of bleeding with the dual antiplatelet therapy. A futility analysis demonstrated low probability of benefit.

After a mean follow-up of 3.5 years, the distribution of recurrent ischemic and hemorrhagic strokes between the 2 groups was similar (hazard ratio, 0.92; 95% confidence interval, 0.73 - 1.2, P = .52). Dual antiplatelet treatment was not more effective than solo antiplatelet therapy. Notably, the patients who received the dual antiplatelet therapy had more major hemorrhages than the aspirin-treated group, with a rate of 2.1% compared to 1.1% per patient-year, respectively. In addition, the investigators identified an unanticipated significant difference in all-cause mortality. In total, 77 deaths were reported in the aspirin group compared to 113 in the dual antiplatlelet arm (hazard ratio, 1.5; 95% confidence interval, 1.1 - 2.0; P = .005). The results of the trial do not support use of dual antiplatelet therapy as secondary stroke prevention treatment for patients with lacunar strokes. Data from the blood pressure management arm of the study are anticipated during the summer of 2012.

Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study. The CHANCE trial was a randomized, double-blind, placebo-controlled study conducted in China (114 centers). The objective of the trial was to investigate whether combination antiplatelet therapy (aspirin and clopidogrel) could provide greater protection against stroke than solo aspirin therapy (81).

In total, 5170 patients with minor ischemic stroke or high-risk transient ischemic attack were randomly assigned to combination therapy (aspirin 75 mg daily for 21 days plus clopidogrel at 300 mg initially, followed by 75 mg per day for 90 days) or solo aspirin therapy (placebo with aspirin 75 mg daily for 90 days). The patients were enrolled within 24 hours of symptom onset. The primary outcome measure was stroke (ischemic or hemorrhagic) within the 90 days of follow-up in an intention-to-treat analysis.

The results revealed a 3.5 % absolute reduction in the occurrence of stroke at 90 days in the combination therapy group. Stroke occurred in 8.2% of the patients in the combination therapy arm compared to 11.7% in the solo aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P< 0.001). The rate of moderate or severe hemorrhage was similar in both groups; 7 patients (0.3%) in the combination group and 8 patients (0.3%) in the solo aspirin group (P=0.73). The rate of hemorrhagic stroke was 0.3% in both groups.

Some clinicians suggested that the results of the CHANCE study do not translate easily into the general population because the trial did not include different ethnic groups and the investigators had to screen more than 40,000 patients to identify 5000 patients for inclusion.

Nevertheless, the findings suggest that short-term treatment with aspirin and clopidogrel, in selected patients during the acute phase after transient ischemic attack or minor stroke, can reduce the risk of stroke within the first 90 days and does not increase the risk of hemorrhage. Interestingly, combination antiplatelet therapy has been found to be beneficial in the treatment of unstable angina, but until the CHANCE study the benefit had not been shown definitely in stroke patients.

Clopidogrel with aspirin in high-risk patients with acute nondisabling cerebrovascular events II (CHANCE - 2) trial. Although recent trials have demonstrated the effectiveness of dual antiplatelet therapy (clopidogrel and aspirin or ticagrelor and aspirin) in selected patients with mild ischemic stroke or TIA, the two combination therapies had not been directly assessed. The CHANCE 2 trial was a randomized, double-blind, placebo-controlled, multicenter study (202 centers) designed to compare the two dual antiplatelet therapy regimens in patients who were CYP2C19 LOF allele carriers with minor stroke or transient ischemic attack (80). The loss of function single nucleotide polymorphism of cytochrome P450 family 2 subfamily C member 19 enzyme (CYP2C19) is a known cause of antiplatelet resistance when using clopidogrel.

Within 24 hours of symptom onset, the patients were randomized to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 to 90) and placebo clopidogrel or clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 to 90) and placebo ticagrelor. Both groups received aspirin for 21 days. The primary efficacy outcome was new stroke, and the primary safety outcome was moderate or severe bleeding (both measures within 90 days). In total, 6412 patients were enrolled into the trial with 3205 treated with ticagrelor/aspirin and 3207 given clopidogrel/aspirin.

The results of the study revealed the risk of stroke at 90 days was moderately lower with ticagrelor (6.0%, N=191) than with clopidogrel (7.6%, N=243, hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P=0.008). Although no significant difference was seen in the risk of severe or moderate bleeding when comparing the ticagrelor treatment arm (N=9 patients, 0.3%) to the clopidogrel group (N=11 patients, 0.3%), more total bleeding events were seen in the patients treated with clopidogrel.

Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial. The study was a prospective, randomized, double-blind, multicenter trial designed to assess combination antiplatelet therapy (clopidogrel plus aspirin) in patients with minor stroke or high-risk transient ischemic attack (45). Notably, an earlier study examined combination antiplatelet therapy in a Chinese population and demonstrated the treatment may be beneficial when given for 21 days after stroke or transient ischemic attack (81).

In total, 4881 patients with minor stroke or high-risk transient ischemic attack were randomized to receive clopidogrel plus aspirin (n = 2432) or aspirin alone (n = 2449). The clopidogrel therapy was given as a loading dose of 600 mg followed by 75 mg daily whereas the aspirin dose ranged from 50 to 325 mg daily.

The trial was stopped after enrolling 84% of the anticipated number of patients once the safety monitoring committee determined the dual antiplatelet therapy was associated with a lower risk of major ischemic events while demonstrating a higher risk of major hemorrhage at 90 days. When compared to aspirin alone, dual antiplatelet therapy reduced the incidence of a major ischemic event by a relative 25%, but more than doubled the rate of major hemorrhage. Major ischemic events occurred in 121 of 2432 patients (5.0%) who received dual antiplatelet therapy and in 160 of 2449 (6.5%) who were given aspirin alone (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P = 0.02). Interestingly, most of the events occurred during the first week after the initial event. Major hemorrhage was seen in 23 patients (0.9%) who received dual antiplatelet therapy compared to 10 patients (0.4%) who were given aspirin alone (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P = 0.02).

Notably, the weekly outcomes were analyzed over the course of the 90-day treatment. During the first 21 days, the rate of major ischemic events was 3.6% in the dual antiplatelet group compared to 5.6% in the aspirin arm, which translated into a 35% relative reduction in adverse outcomes with dual antiplatelet therapy (significantly significant finding). During the following 69 days, the incidence of major ischemic events was generally 1% in both groups, suggesting a loss of the incremental benefit from dual antiplatelet therapy after 21 days. The authors estimated for every 100 patients treated with the regimen, 15 ischemic events would be prevented at a cost of 5 excess major hemorrhages.

THALES—Acute STroke or Transient IscHaemic Attack Treated With TicAgreLor and ASA for PrEvention of Stroke and Death. Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation; therefore, it works as a direct-acting antiplatelet agent. Although a trial of ticagrelor alone in patients with acute ischemic stroke or transient ischemic attack did not demonstrate a benefit in the prevention of cardiovascular and/or cerebrovascular events over patients treated with aspirin (ASA) alone, there was evidence to suggest the combination of aspirin and ticagrelor could be beneficial (43). The THALES Trial was designed to examine the hypothesis that a 30-day regimen of ticagrelor and aspirin would demonstrate superiority over aspirin alone in reducing the risk of a subsequent stroke or death among patients with acute noncardioembolic stroke (44).

THALES was a randomized, placebo-controlled, double-blind study consisting of patients with mild-moderate acute noncardioembolic strokes (designated by a National Institutes of Health Stroke Scale; NIHSS, score of 5 or less) or transient ischemic attack. The patients did not receive intravenous thrombolytic therapy and/or thrombectomy and were assigned to a 30-day treatment regimen within 24 hours of symptom onset. The treatment arms consisted of ticagrelor (180 mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days with severe bleeding as a primary safety outcome. The secondary outcomes included first subsequent ischemic stroke and incidence of disability within 30 days. In total, 11,016 patients were randomized to receive ticagrelor and aspirin (N=5523) or aspirin alone (N=5493).

The results of the trial demonstrated the risk of the composite of stroke or death within 30 days was lower in the patients treated with ticagrelor and aspirin (5.5%, N=303) compared to aspirin alone (6.6%, N=362; hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.02). Notably, the incidence of disability did not differ significantly between the 2 treatment groups, and severe bleeding was more frequent with the patients who received ticagrelor.

PREMIERS study. The PeRiodontal Treatment to Eliminate Minority Inequality and Rural Disparities in Stroke (PREMIERS) trial examined 280 patients with periodontal disease who had experienced a recent stroke or transient ischemic attack to determine if treatment of the periodontal disease reduced the risk of a recurrent stroke and/or cardiovascular events (73). One group received standard periodontal treatment, which consisted of regular hand toothbrushing and removal or plaque typically performed at routine dental visits. The second group received intensive periodontal treatment described as 2 plaque removals, extractions of hopeless teeth, antibiotics and use of mouthwash with an electric toothbrush, and air flosser. Both groups received comprehensive, conventional stroke risk factor management.

An adaptive randomization design was used to ensure both groups were balanced regarding demographics, race, age, cerebrovascular risk factors, stroke etiologies, and social economic status.

After 1 year follow-up, the primary outcome (stroke/myocardial infarction/death) had occurred in 7.7% of the intensive group compared to 12.3% of the standard group (hazard ratio 0.65, 95%CI, 0.30-1.38; P= .26). Notably, both groups (intensive and standard) demonstrated a much lower rate of recurrent events compared with a historical control group that showed a 1-year rate of stroke, myocardial infarction, or death of 24%.

Although the results of the study did not show a statistically significant difference between the intense and standard treatment groups regarding the rate of recurrent stroke, myocardial infarction, and/or death in 1 year follow-up, there was a strong trend towards benefit in the intensive group, which supports the importance of appropriate periodontal care in cerebrovascular risk factor management.

Treatment guidelines

Guidelines for antithrombotic therapy in the prevention of ischemic stroke were outlined by a statement from the American College of Chest Physicians (51).

In patients with a history of noncardioembolic ischemic stroke or transient ischemic attack, the recommendation was for long-term treatment with 1 of the following over no antiplatelet therapy (grade 1A):
	• aspirin (75-100 mg once daily) • clopidogrel (75 mg once daily) • aspirin/extended release dipyridamole (25 mg/200 mg bid) or cilostazol (100 mg bid)
Grade 1B recommendations:
	• oral anticoagulants • combination of clopidogrel plus aspirin
Grade 2B recommendations:
	• triflusal (grade 2B)
Recommendations regarding antiplatelet regimens:
	• clopidogrel or aspirin/extended-release dipyridamole over aspirin (grade 2B) or cilostazol (grade 2C)
Recommendations for patients with a history of stroke or transient ischemic attack and atrial fibrillation include:
	• oral anticoagulation over no antithrombotic therapy (grade 1A) aspirin (grade 1B) or combination therapy with aspirin and clopidogrel (grade 1B)
Recommendations for patients with a history of ischemic stroke or transient ischemic attack and atrial fibrillation, including paroxysmal atrial fibrillation consist of:
	• oral anticoagulation with dabigatran 150 mg bid over adjusted-dose VKA therapy (target international normalized ratio range, 2.0-3.0) (grade 2B)
Recommendations for patients with a history of ischemic stroke or transient ischemic attack and atrial fibrillation, including paroxysmal atrial fibrillation, who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns about major bleeding) include:
	• combination therapy with aspirin and clopidogrel over aspirin (grade 1B).
Aspirin
	Inhibits platelet aggregation
		• Acetylates the enzyme cyclooxygenase and inhibits formation of cyclic endoperoxides and thromboxanes • Inhibits formation of prostacyclin derived from vascular endothelium • Enzyme inactivated for lifetime of platelet
Ticlopidine
	Inhibits platelet aggregation
		• Irreversibly inhibits adenosine diphosphate-induced platelet-fibrinogen binding
Clopidogrel
	Inhibits platelet aggregation
		• Direct inhibition of ADP-receptor binding and inhibition of ADP-mediated activation of glycoprotein IIb/IIIa complex
Dipyridamole
	Inhibits platelet aggregation
		• Induces platelet aggregation by the reduction of cyclic adenosine monophosphate (cAMP)
Warfarin
	Promotes anticoagulation
		• Interferes with synthesis of vitamin K-dependent clotting factors II, VII, IX, and X