Table 5-2 outlines the results of notable pharmacologic and device trials in acute ischemic stroke. Glycoprotein IIb/IIIa (GPIIb-IIIa) inhibitors have been an attractive target for pharmacologic treatment beyond thrombolysis. In a phase II dose-escalation study enrolling 74 patients, investigators found that the administration of abciximab was associated with a trend toward improved disability, with no significant increase in the rate of sICH.98 The Abciximab in Emergency Treatment of Stroke Trial (AbESST), a phase II study using 400 patients, found similar results in terms of safety and a nonsignificant modest trend toward improvement in mRS at 3 months.99 The phase III AbESST II study planned to enroll 1800 patients, with randomization to abciximab or placebo within 5 hours of stroke onset in those who did not receive thrombolysis. The phase III study failed to replicate these findings, as the study was stopped prematurely after 808 patients were enrolled by the data safety monitoring board. There was a significant increase in the rate of sICH in the treatment arm (5.5% versus 0.5%), with no difference in the prespecified primary outcome.100 GPIIb-IIIa inhibitors have also been examined in combination with thrombolysis with the intent to improve recanalization rates based on experience with acute myocardial infarction.
Table 5-2.Summary of Completed Acute Stroke Clinical Trials ||Download (.pdf) Table 5-2. Summary of Completed Acute Stroke Clinical Trials
|Trial and reference no. ||Agent tested ||Time window ||Primary outcome ||Positive? Effect size |
|NINDS tPA trial19 Phase III ||r-tPA (0.9 mg/kg) vs placebo ||Under 3 h from onset ||3-mo composite outcome of BI, NIHSS, mRS, and GOS ||Yes. 39% vs 26% |
|CLOTBUST27 Phase II ||High-frequency ultrasound vs placebo in patients receiving IV r-tPA ||Under 3 h from onset ||Complete recan- alization or dramatic neurologic improvement ||Yes. 49% vs 30% |
|ATLANTIS77 Phase III ||r-tPA (0.9 mg/kg) vs placebo ||3-5 h from stroke onset ||NIHSS ≤ 1; composite of BI, NIHSS, mRS, and GOS ||No for primary or secondary outcome. Significant increase in sICH rates |
|ECASS78 Phase III ||r-tPA (1.1 mg/kg) vs placebo ||Up to 6 h from stroke onset ||BI and mRS at 90 d ||No |
|ECASS II79 Phase III ||r-tPA (0.9 mg/kg) vs placebo ||Up to 6 h from stroke onset, and stratified at 0-3 h and 3-6 h ||mRS at 90 d ||No for the overall group |
|ECASS III82 ||r-tPA (0.9 mg/kg) vs placebo ||3.0-4.5 h from stroke onset ||mRS at 90 d ||Yes. 52.4% vs 45.2% |
|DIAS86 Phase II ||Fixed (part 1) and then weight-based dosing (part 2) of desmoteplase ||3-9 h from stroke onset with evidence of perfusion- diffusion mismatch ||sICH. Secondary: MRI reperfusion and 90-d good outcome ||Yes. 71.4% vs 19.2 % reperfusion for the highest weight-based dose; 60.0% vs 22.2% good clinical outcome for the highest weight-based dose compared to placebo |
|DEDAS87 Phase II ||Escalating dose 90-125 μg/kg desmoteplase vs placebo ||3-9 h from stroke onset with evidence of perfusion- diffusion mismatch ||sICH. Secondary: MRI reperfusion and 90-d good outcome ||sICH not noted. Improvements in recanalization and clinical outcomes in the 125-μg/kg dose |
|DIAS-288 Phase II ||90 μg/kg desmoteplase, 125 μg/kg desmoteplase, or placebo ||3-9 h from stroke onset with evidence of perfusion- diffusion mismatch ||90-d clinical composite outcome ||No. 47% for lower dose and 36% for higher dose desmoteplase; 46% for placebo |
|EPITHET92 Phase II ||r-tPA (0.9 mg/kg) ||3-6 h from stroke onset with evidence of perfusion- diffusion mismatch ||Infarct growth ||No siginificant change in volume of infarct, trend toward beneficial outcomes |
|AbESTT-II100 Phase III ||Abciximab ||Within 5 h, and in wake-up stroke ||mRS ||No. Stopped early due to lack of benefit and significant increase in hemorrhage |
|PROACT-II109 Phase II ||9 mg IA prourokinase and heparin vs heparin ||Within 6 h of onset with angiographic documented MCA occlusion ||mRS and recan-alization ||Yes. 40% vs 25% favorable outcome; 66% vs 18% recanalization; sICH in 10% |
|IMS-II114 Phase II ||0.6 mg/kg of r-tPA followed by IA treatment with further r-tPA or placebo ||Within 3 h who received IV r-tPA ||mRS, global outcome, and sICH ||Similar sICH rates to PROACT II, with improvement in functional outcomes in the IA-treated patients |
|Multi-MERCI121 Phase II ||Merci device (multiple generations of devices), single arm ||Within 8 h of stroke onset ||Recanalization of the partner vessel ||69.5% achieved recanalization, and 36% achieved a favorable mRS |
|Penumbra Pivotal Stroke Trial122 Phase II ||Penumbra device ||Within 8 h of stroke onset ||Safety profile ||81.6% successful recanalization. 11.4 % sICH |
|CAST101 ||Aspirin 162 mg daily vs placebo ||Within 48 h of stroke ||Death or dependence at 4 weeks ||Yes. 3.3% vs 3.9% mortality, and 1.6% vs 2.1% recurrent stroke |
|IST102 ||Heparin (5000 or 12,500 units bid), vs avoid heparin. The latter group randomized to aspirin 300 mg daily or placebo ||As soon as possible ||Death within 14 d, or death/dependency at 6 months ||Yes. No difference in outcomes in heparin allocation. Aspirin had fewer recurrent strokes (2.8% vs 3.9%) |
|TOAST103 ||Heparinoid vs placebo in noncardioembolic stroke ||Within 24 h of stroke ||GOS and BI at 3 mo ||No |
|HAEST104 ||Low-molecular- weight heparin vs aspirin in atrial fibrillation–related stroke ||Within 30 h of stroke onset ||Recurrent stroke at 14 d ||No. 8.5% vs 7.5% in the heparinoid vs aspirin (nonsignificant) |
|Decompressive hemicraniectomy142 ||Hemicraniectomy in space- occupying MCA infarction vs medical management ||Within 48 h of stroke onset ||mRS favorable (0-4); mortality ||Yes. 75% vs 24% for the favorable mRS. Mortality 78% vs 29% favoring surgery |
Antithrombotic agents remain the most commonly used pharmacologic agent for acute stroke prevention. In the Chinese Acute Stroke Trial,101 aspirin showed a modest absolute benefit over placebo in mortality and recurrent stroke risk. In the International Stroke Trial (IST),102 aspirin again had a mild benefit over placebo in preventing stroke and improving mortality rate, while the heparin arm showed a trend toward a mild benefit in the 12,500 arm versus the 5000-unit arm that was offset by the hemorrhage risk. Danaparoid, a heparinoid, was found to be ineffective in grouping the acute setting for noncardioembolic stroke,103 while low-molecular-weight heparin showed a similar lack of effectiveness in acute cardioembolic stroke.104 Pilot data from the LOAD (Loading of Aspirin and Clopidogrel in acute ischemic stroke and transient ischemic attack) trial indicated a favorable safety profile in the acute setting for the combination of aspirin and clopidogrel, with a trend of reduced clinical worsening.105 In the larger FASTER (Fast Assessment of Stroke and Transient ischemic attack to prevent Early Recurrence) trials, there was a reduction in clinical worsening with a combination of the two antiplatelet agents, which offset the slight increase in hemorrhage.106 Currently, there are no phase III clinical trials proving the effectiveness of aspirin and clopidogrel in combination after acute ischemic stroke, although caution is warranted given the lack of clinical effectiveness in secondary prevention studies.107 Heparin may be considered in the acute setting in the post–cardiac surgery stroke population, in selected cases of carotid dissection, and in patients with a mechanical heart valve.
Given the poor outcomes associated with not recanalizing the middle cerebral artery in particular, endovascular treatment has emerged as another option for acute stroke treatment. In the PROACT (Prolyse in Acute Cerebral Thromboembolism) study, 40 patients were randomized to intra-arterial (IA) infusion of prourokinase versus placebo. Treatment with prourokinase was associated with a statistically significant increase in the rate of recanalization, although there was a concomitant increase in the rate of sICH in the medication arm (15.4% versus 7.1%).108 Much of the sICH could be attributed to the use of IV heparin.
Publication of the PROACT II study in 1999 significantly altered the paradigm for acute stroke care, and in specialized stroke centers throughout the country, treatment up to 6 hours from stroke onset became possible, if not part of routine clinical care. In PROACT II,109 180 patients were randomized to receive 9 mg of IA prourokinase plus heparin versus heparin alone. The main outcome was an mRS of 0 to 2, which was achieved in 40% of the treated patients versus 25% in the control group, with a 66% versus 18% success rate at recanalization with IA treatment. There was a statistically significant increase in the rate of sICH (10% versus 2%), although the investigators concluded that the benefits of the treatment outweighed the risks. The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial confirmed improved functional (mRS 0 to 1) and neurologic (NIHSS 0 to 1) outcomes at 90 days with intra-arterial urokinase, although the study's primary outcome of mRS 0 to 2 was not reached.110 In PROACT II age, NIHSS, and initial head CT were all associated with a greater likelihood of clinical benefit from intra-arterial treatment, while experience at the University of Houston has identified age, NIHSS, and admission glucose as predictive of a poor outcome independently of recanalization.111
The Interventional Management of Stroke (IMS) trials further tested the hypothesis of combining intravenous and intra-arterial thrombolysis for patients who had major intracranial artery occlusions under the premise that these patients are unlikely to recanalize with intravenous treatment alone. The phase I Emergency Management of Stroke (EMS) bridging trial showed that this treatment paradigm was feasible and appeared to be safe.112 In IMS I, 80 patients were treated with 0.6 mg/kg of IV r-tPA followed by intra-arterial r-tPA and were compared to historical controls.113 The rates of sICH were similar to the treatment arm of the NINDS r-tPA trial (6.3%).
IMS II assigned 81 patients who received IV r-tPA (0.6 mg/kg) within 3 hours to intra-arterial r-tPA up to 22 mg or when recanalization was achieved, as well as the use of an intravascular sonothrombolysis device. Twenty-six patients were treated with IV r-tPA only, while the rest were treated with a combination of intra-arterial sonothrombolysis or microcatheter injections. Despite a nonsignificant trend toward a higher rate of sICH in the treatment arm compared to the NINDS tPA trial (9.9% versus 6.4%), there was a higher likelihood of achieving global outcomes in the endovascular treated group compared to the historical controls. There was an additional trend toward improvement in some of the outcomes in the endovascular treatment arm compared to the NINDS r-tPA–treated patients.114
IMS III is currently enrolling patients using IV r-tPA at a reduced dose (0.6 mg/kg) IV followed by the rest of the infusion in an IA fashion. A criticism of IMS III has been that patients are not receiving the optimal dose of IV r-tPA up front, although in one small clinical trial, patients also had a benefit from treatment with 0.6 mg/kg of r-tPA.115 The optimal dose of IV r-tPA to be given before IA treatment remains controversial, although in at least one case series giving full-dose 0.9 mg/kg of IV r-tPA was safe and associated with successful recanalization.116 The results are eagerly anticipated as there are reports that the combination of IV and IA r-tPA may increase the risk of sICH.117 The risk factors for sICH remain the same for IV and IA r-tPA in many observational studies, with elevated serum glucose remaining a particularly important factor118 and the number of microinjections during IA treatment being an additional factor.119 Intra-arterial thrombolysis up to 6 hours from onset has class I, level B evidence for selected patients with MCA occlusion and class IIa, level C evidence for treatment in patients who cannot receive thrombolysis.20
In the meantime, industry has spearheaded the development of several devices for the endovascular treatment of acute ischemic stroke. These devices have used a combination of clot extraction, clot suctioning, and ultrasound-assisted thrombolysis. There are two currently approved devices by the US Food and Drug Administration for the mechanical clot extraction in an intracerebral artery—the Merci Retrieval System (Concentric Medical Inc, Mountain View, CA) and the Penumbra System (Penumbra, Inc, Alameda, CA). It is important to note that neither one of these devices has been approved to date to benefit patients but rather to recanalize the vessel. In the MERCI and Multi-MERCI studies, a corkscrew-type device was tested up to 8 hours from stroke onset in a nonrandomized fashion in 151 patients. Recanalization was achieved in up to 69.5% of patients, which is higher than in historical controls, with a comparable sICH rate (9.8%). Favorable clinical outcomes, defined as mRS of 0 to 2 at 90 days, were achieved more often in the patients who had successful recanalization.120,121
The Penumbra device uses continuous suction locally and was tested in 125 patients with an NIHSS greater than 8 and occlusion of a large intracerebral artery in a single-arm fashion. Recanalization was achieved in approximately 83% of participants, which the investigators mentioned was higher than with the Merci device, but there was a 12.8% procedural complication rate of which 2.4% was considered serious. The proportion of patients who had an asymptomatic ICH was 28%, while 11.2% had sICH; 90-day mortality was 32.8%, and 25% of individuals attained an mRS of 0 to 2.122
The window for treatment has been expanded by clinicians for patients who are neurologically devastated from basilar artery thrombosis up to 24 hours with the understanding that the patient's outcome is uniformally dismal, while the risk of hemorrhagic transformation is smaller in the brainstem. One recent research reported superior recanalization success and improved outcomes in patients with acute basilar artery occlusion who were treated with IA thrombolysis in combination with IV abciximab versus IA thrombolysis in a nonprospective manner, and these results cannot be generalized to non–basilar artery involvement.123 A large international registry of patients with acute basilar artery occlusion that examined outcomes after IV r-tPA, antithrombotic treatment alone, and endovascular treatment has provided additional guidance.124 In patients with a mild-moderate deficit, IV r-tPA appeared to be superior, while in a severe deficit, IV r-tPA in combination with IA treatment was a promising treatment modality. The investigators could not conclude on the optimal timing for when not to treat patients with IA modalities, although none of the patients treated after 9 hours from stroke onset had a good outcome.
Stenting for acute ischemic stroke, even in the setting of nonatherosclerotic strokes, has also received recent attention. In a 2009 published pilot trial, stenting performed less than 8 hours from stroke onset had an acceptable safety profile compared to other trials, with comparable recanalization rates to other modalities.125 Further trials are required with this technology or other emerging modalities such as a retrievable stent.126
In patients with internal carotid artery, M1 or M2 segments of the middle cerebral artery, or vertebrobasilar artery occlusions, we will routinely perform catheter angiography after thrombolysis for endovascular treatment, and will consider it for patients up to 8 hours from stroke onset if there is no evidence of large cerebral infarction (more than one-third of the MCA distribution) (see Figure 5-7). In the case of intra-arterial treatment, informed consent is part of our routine clinical protocol, and we will explain thoroughly to the family the risks and benefits, as well as the quality of evidence available.
Nonthrombolytic Acute Stroke Treatment
Statins have shown a clear benefit in secondary stroke prevention, an effect that appears to be independent of the serum lipid panel. The cholesterol-independent effects of statins have been an attractive target in the acute stroke setting. Statins have the potential for being neuroprotectants independently of their effect on modification of dyslipidemia. Animal models have indicated that statins are associated with a reduction in infarct size, a result that was mediated in part by endothelial nitric oxide synthetase expression. Statins also appear to reduce inflammation and may increase angiogenesis, synaptogenesis, and neurogenesis. Lastly statins reduce membrane cholesterol synthesis in neurons, thereby rendering them more resistant to glutamate n-methyl-d-aspartate receptor–mediated excitotoxic effects, one of the principal mechanisms of neuronal death in ischemic brain.127 Patients who were taking a statin in the Northern Manhattan Study at the time of their stroke were more likely to have a favorable outcome,127 while withdrawal of a statin in the acute stroke setting is associated with worsening outcomes.128 There are currently no phase III clinical trials that have enrolled patients in the acute stroke setting. Phase II studies of high doses of statins are currently ongoing.129
The American Heart Association (AHA) guidelines recommend that in patients not receiving thrombolysis the blood pressure should be allowed to remain as elevated as 220/120 mm Hg unless there is another medical reason not to do this. The rationale remains that autohypertension may maintain CBF in the face of impaired autoregulation after stroke, particularly in the penumbra. There is the associated belief that lowering the blood pressure could expand the size of the present infarct. The specific clinical trials that have demonstrated this are scant. Investigators have begun to examine this finding in rigorous clinical trials, though in the recently completed Scandinavian Candesartan Acute Stroke Study, treatment with candesartan was associated with a trend toward worse outcomes, primarily because of worsening neurologic status.131 In phase II trials that enrolled both ICH and ischemic stroke patients, lowering of the blood pressure was not associated with worsening clinical deterioration.130
Salvaging the penumbra by improving blood flow to the region has been the rationale for many of the acute stroke trials. An alternative approach has been to reverse the biochemical pathways in the ischemic penumbra so as to prevent the progression to infarction, and thereby salvage more tissue than just with thrombolysis. Many of the agents have been successful in animal models. In specific GM1 calcium channel antagonists, anti–intercellular adhesion molecule 1 antibodies, GM1 ganglioside, γ-aminobutyric acid agonists, and sodium channel antagonists have all been tried unsuccessfully.131 Preventing glutamate excitotoxicity at the level of the NMDA receptor has been a particularly attractive target, as has targeting free radicals. Gavistenel, a glycine antagonist of the NMDA receptor that reduces glutamate receptor depolarization, was not associated with improvement in clinical outcomes in two separate trials.132,133 In the SAINT (Stroke Acute Ischemic NXY-059 Trial) I trial, patients were randomized to NXY-059 (a free radical scavenger) versus placebo, and there appeared to be a trend toward improvement in mRS at 3 months.134 These findings were, however, not replicated in the SAINT II trial.135 The reason for the failures of all these clinical trials points in part to the imperfect animal models for ischemic stroke.