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Abstract

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References

We review recent advances in the treatment and prevention of acute ischemic stroke, including the current state of endovascular therapy, in light of 5 randomized controlled trials published this past year. Although no benefit of endovascular therapy over intravenous (IV) recombinant tissue plasminogen activator (rt-PA) has been demonstrated, endovascular therapy is an appropriate treatment for acute ischemic stroke patients within the t-PA window who are ineligible for IV t-PA but have a large vascular occlusion. These trials reveal promises and current limitations of endovascular therapy, and comparison of reperfusion therapies remains an important area of research. One common theme is the strong association between a faster time to reperfusion, improved outcome, and reduced mortality. Primary and secondary stroke prevention trials emphasize the importance of aggressive management of medical risk factors as part of any preventative strategy. New oral anticoagulants, for example, offer cost-effective risk reduction in patients with atrial fibrillation, and may represent an opportunity for those with cryptogenic stroke. We highlight areas of unmet need and promising research in stroke, including the need to deliver proven therapies to more patients, and the need to recruit patients into clinical trials that better define the role of endovascular and other stroke therapies. Finally, improvement in strategies to recover speech, cognition, and motor function has the potential to benefit far more stroke patients than any acute stroke therapy, and represents the greatest opportunity for research in the coming century. Ann Neurol 2013;74:363–372

Stroke is the fourth leading cause of death in the United States and second leading cause globally. More than 795,000 individuals per year are diagnosed with acute stroke in the United States; 87% have ischemic stroke, and nearly a quarter have recurrent strokes.[1] Overall stroke incidence and mortality rates in the United States have declined over the past 50 years, although trends vary by age and race.[2] The projected cost of stroke for 2015 including lost wages and other indirect costs is $60 Billion per year.[3]

Modern Understanding of Biology

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References

Causes of ischemic stroke are broadly differentiated as small and large artery occlusion, cardioembolic, cryptogenic, and other. Although some overlap exists, the pathophysiology underlying each cause appears to differ. Occlusion of intra- and extracranial large vessels is thought to involve endothelial injury and platelet aggregation in the setting of atherosclerotic plaque instability, which can occlude the artery locally or as an initial step in artery-to-artery embolism. Occlusion of smaller perforator vessels is associated with arteriosclerosis due to common vascular risk factors of hypertension, diabetes, and hypercholesterolemia, and with formation of platelet-predominant clots. Clot formation in cardioembolic disease is thought to be fibrin-rich and more amenable to anticoagulants.

Acute arterial occlusion is followed quickly by cerebral ischemia, resulting in dysfunction of cellular organelles and disruption of cell membrane homeostasis, which leads to excitotoxicity, oxidative stress, and initiation of apoptotic cascades.[4] In primate models of large vessel occlusion and reperfusion, the benefit of reperfusion is lost after approximately 6 hours.[5]

Currently Available Therapies

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References

Acute Stroke Therapy

Therapy for acute ischemic stroke (AIS) centers first around rapid revascularization of arterial territories, with additional focus on management of blood pressure and cerebral edema; thereafter, the focus shifts to risk factor reduction and secondary prevention.

Intravenous Thrombolysis

Thrombolysis with intravenous (IV) tissue plasminogen activator (t-PA) has been the mainstay of acute stroke therapy since the publication of the National Institute of Neurological Diseases and Stroke (NINDS) trial and subsequent US Food and Drug Administration (FDA) approval in 1996.[6] Numerous analyses have demonstrated the cost-effectiveness of IV t-PA, but its benefit is highly time-dependent, with loss of benefit in pooled analyses beyond 4.5 hours from when the patient was last seen well.[7-9] In 2012, the FDA elected not to extend approval of IV t-PA beyond 3 hours in the United States, although the newest American Heart Association guidelines recommend treating some patients with IV t-PA up to 4.5 hours based on data from European Cooperative Acute Stroke Study (ECASS) III and pooled analyses of prior trials (class I recommendation, level of evidence B).[8, 10] The American College of Emergency Physicians recently recommended that IV t-PA be “offered” to AIS patients meeting NINDS criteria within 3 hours, and “be considered” in patients meeting ECASS III criteria between 3 and 4.5 hours.[11]

Endovascular Therapy

For AIS patients with a large proximal occlusion, revascularization rates achieved by IV t-PA alone are lower than in patients with a smaller arterial occlusion.[12] Targeted endovascular revascularization therefore holds great promise to improve patient outcomes. Two randomized noninferiority trials, SWIFT and TREVO-2, compared newer stent-retriever technology to older Merci retriever technology in AIS patients with major arterial occlusion treated within 8 hours.[13, 14] These trials demonstrated superior reperfusion and better functional outcomes for patients treated with stent-retriever technology, but did not compare stent-retrievers against IV t-PA alone.

Three other AIS trials (IMS-III, SYNTHESIS, and MR RESCUE) were subsequently published that did not demonstrate an overall added benefit for endovascular therapy over IV t-PA alone, or over standard medical therapy beyond the time window for t-PA. IMS-III compared IV t-PA followed by endovascular therapy to IV t-PA alone in patients with moderate to severe AIS.[15] Enrollment was halted early by the data and safety monitoring board after a planned interim analysis predicted futility. The proportion of participants with a modified Rankin score (mRS) of ≤2 at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with IV t-PA; absolute adjusted difference = 1.5%; 95% confidence interval = −6.1 to 9.1). There were no significant differences in predefined subgroups, including age, NIH Stroke Scale (NIHSS) strata, time to treatment, Alberta Stroke Program Early CT Score, or pretreatment evidence of an internal carotid artery (ICA), M1 (major trunk of middle cerebral artery [MCA]), or basilar occlusion on computed tomography (CT) angiography. However, there were nonsignificant trends toward benefit for endovascular therapy in patients with NIHSS ≥ 20 and those treated most rapidly. In addition, post hoc analyses demonstrated better outcomes in patients with ICA terminus occlusion but little difference in those with M1 occlusion.[16]

SYNTHESIS, an Italian trial of endovascular therapy alone versus IV t-PA alone for AIS patients, also failed to observe benefit of endovascular therapy with respect to patients who achieved mRSs of ≤1 at 90 days.[17] Results would not have been significant even if the authors had defined good outcome as achieving mRS of ≤2. Subgroup analyses based on stroke severity, arterial territory, and risk factors also showed no benefit.

A promising approach to patient selection for endovascular therapy was evaluated in MR RESCUE.[18] The authors randomized AIS patients who were ineligible for IV t-PA or were IV t-PA nonresponders to endovascular therapy versus no additional acute therapy, then stratified patients based on favorable or unfavorable penumbral pattern using multimodal (CT or magnetic resonance) perfusion imaging. A favorable penumbral pattern was a predicted infarct core of ≤90cm3, which must be <70% of the tissue at risk. No benefit of endovascular therapy was observed in functional outcome at 90 days, even in those patients with favorable penumbral imaging.

In all 3 trials, safety outcomes of mortality and symptomatic hemorrhage were not different between the 2 groups. Given that endovascular therapy appears at least equivalent to IV t-PA with similar safety, it is an appropriate treatment for AIS patients within the t-PA window who are ineligible for t-PA but have a large vascular occlusion. It is essential to minimize time to reperfusion, as pooled data from endovascular studies including IMS III clearly demonstrate that faster reperfusion is associated with improved functional outcome and reduced mortality.[19, 20]

To better define the role of endovascular therapy in AIS, we strongly recommend enrollment of patients into new randomized trials (Table). For those patients who cannot be enrolled, endovascular therapy is probably best justified in patients within the t-PA window who cannot be treated with IV t-PA, and in those patients who have intracranial ICA occlusion without improvement after IV t-PA, although the data from the IMS III trial for the latter group are limited. Use of endovascular therapy in other patients, including those beyond the time window for IV t-PA, remains a matter of clinical judgment, with insufficient data from randomized trials. However, we must consider data from primate models, in which reperfusion beyond 6 hours is not helpful, and the known time-dependence of endovascular reperfusion, whereby outcomes in patients with reperfusion beyond 6 to 7 hours are similar to subjects who never reperfuse.[5, 19, 20] The usefulness of parenchymal imaging in later time windows to select patients for treatment who have potentially salvageable brain continues to be an area of intense study.

Table 1. Ongoing or Planned Prospective, Randomized Trials of Mechanical Embolectomy versus Medical Therapy with Clinical Endpoints.
TrialDesignand Hypothesis[81]Patient SelectionEndovascular Device(s)Target EnrollmentPrimary OutcomeLocationReference
  1. ReVive SE: Codman, Johnson & Johnson, New Brunswick, NJ; Trevo: Concentric Medical, Mountain View, CA; Solitaire and Solitaire FR:Covidien, Boulder, CO; Penumbra Aspiration System and Separator 3D: Penumbra, Alameda, CA; Catch: Balt Extrusion, Montmorency, France; Merci: Concentric Medical.

  2. A1/A2 = proximal 2 segments of anterior cerebral artery; CT = computed tomography; CTA = CT angiogram; DSA = digital subtraction angiogram; IA = intra-arterial; ICA = internal carotid artery; IV = intravenous; M1/M2 = proximal 2 segments of middle cerebral artery; MR = magnetic resonance; MRA = MR angiogram; mRS = modified Rankin score; NCT = www.clinicaltrials.gov; NIHSS = NIH Stroke Scale; NTR = www.trialregister.nl; PROBE = prospective, randomized, open-label, blinded endpoint design; TCD = transcranial Doppler; t-PA = tissue plasminogen activator.

MR-CLEANMulticenter, PROBE, noninferiority; IA t-PA or urokinase and/or mechanical embolectomy vs standard medical management (IV t-PA allowed)NIHSS ≥ 2 with ICA, M1/M2, or A1/A2 occlusion on CTA/MRA/DSA/TCD, within 6 hoursAny locally approved500mRS at 90 daysNetherlandsNTR1804
THRACEMulticenter, PROBE, superiority; IV t-PA followed by mechanical embolectomy vs IV t-PA aloneNIHSS ≥ 10 but ≤ 25 with ICA, M1, or upper ⅓ of basilarMerci, Penumbra system, Catch, Solitaire480mRS at 90 daysFranceNCT01062698
REVASCATPhase III, multicenter, PROBE, superiority; mechanical embolectomy vs medical therapy aloneNIHSS ≥6 with ICA or M1 occlusion on CTA/MRA/DSA in IV t-PA ineligible or nonresponders, within 8 hoursSolitaire FR690mRS at 90 daysSpainNCT01692379
THERAPYPhase III, multicenter, PROBE, superiority; IV t-PA followed by mechanical embolectomy vs IV t-PA alone.NIHSS ≥8 with large vessel, anterior circulation occlusion ≥8mm on thin-cut noncontrast CT, within 8 hoursPenumbra aspiration system + Separator 3D692mRS 0–2 at 90 daysUSANCT01429350
SWIFT-PRIMEPhase III,multicenter, PROBE, superiority; IV t-PA followed by mechanical embolectomy vs IV t-PA aloneNIHSS ≥8 but ≤30 with occlusion of intracranial ICA, carotid terminus, or M1 on CTA/MRA, within 6 hoursSolitaire FR833mRS at 90 daysUSANCT01657461
EXTEND-IAPhase II, multicenter, PROBE, safety; IV t-PA followed by mechanical embolectomy vs IV t-PA aloneAnterior circulation stroke with ICA, M1, or M2 occlusion on CTA or MRA, and CT or MR perfusion mismatch, within 6 hoursSolitaire100Reperfusion at 24hours (CT or MR perfusion imaging); reduction in NIHSS by ≥8points or achievement of NIHSS 0–1 by 3 daysAustralia & New ZealandNCT01492725
BASICSPhase III, multicenter, PROBE, superiority;NIHSS ≥10 with basilar artery occlusion on CTA/MRA, within 6 hoursAny locally approved750mRS 0–3 at 90 daysAustralia, Brazil, Canada, Israel, Europe, USANTR2617
IV t-PA followed by mechanical embolectomy vs IV t-PA alone
ESCAPE (planned)Phase III, multicenter, PROBE, superiority; IV t-PA followed by mechanical embolectomy/IA t-PA vs IV t-PA aloneNIHSS ≥5 with occlusion in carotid terminus, M1 or 2 M2s on CTA, within 12 hoursAny locally approved250mRS 0–2at 90 daysCanada, USA, and EuropeNCT01778335
NIHSS 0–2 at 90 days
PISTE (planned)Multicenter, PROBE, superiority; IV t-PA followed by mechanical embolectomy/IA t-PA vs IV t-PA aloneSupratentorial stroke, NIHSS ≥6 with occlusion of carotid terminus, M1, or proximal M2 on CTA/MRA/DSA, within 6 hoursAny locally approved800mRS 0–2 at 90 daysUnited KingdomNCT01745692
Early Surgical Decompression

Perhaps the most effective therapy in reducing stroke mortality, with a number needed to treat of 2, is early decompressive hemicraniectomy in patients younger than 60 years with malignant MCA strokes.[21-24] Recently, preliminary results were reported for DESTINY II, a similarly designed trial of decompressive hemicraniectomy for malignant MCA stroke, which included patients age 60 years and older.[25] As in the <60-year age group, decompressive hemicraniectomy appears to reduce mortality and improve patient outcome in older patients, although the authors emphasized that therapy decisions should be made on an individual basis, weighing patient and family perceptions of mortality and dependence.

Stroke Prevention

Stroke Prevention in Patients with Intracranial and Extracranial Atherosclerosis

The SAMMPRIS trial revealed that angioplasty and stenting of intracranial stenosis with the Wingspan self-expanding stent did not reduce the risk of secondary stroke beyond that achieved with aggressive medical management.[26] The lack of a positive significant effect on good outcome appears to have been due to higher rates of periprocedural intracranial hemorrhage and other complications, as well as lower than expected event rates in subjects treated with aggressive medical therapy.

Given the low rates of recurrent stroke with aggressive risk factor modification seen in SAMMPRIS, one wonders how carotid endarterectomy or stenting would fare if landmark trials of these therapies were redone.[27, 28] The proposed CREST-2, SPACE-2, and ECST-2 trials, for example, are designed to address whether either stenting or carotid endarterectomy can reduce the risk of vascular outcomes below rates that can be achieved with aggressive medical therapy.[29-31]

Stroke Prevention in Patients with Atrial Fibrillation

Treatment options for stroke prevention in patients with atrial fibrillation have broadened with the advent of novel oral anticoagulants (NOACs). Direct factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran, were compared with warfarin in patients with nonvalvular atrial fibrillation. Rivaroxaban was not significantly different from warfarin with respect to AIS or systemic embolism, or with respect to major hemorrhage, although intracranial and fatal hemorrhage occurred less often in patients taking rivaroxaban.[32] Apixaban also did not significantly reduce the risk of AIS compared with warfarin among patients with atrial fibrillation, but significantly lower rates of major and intracranial hemorrhage were seen with apixaban than with warfarin.[33] At lower doses, dabigatran was associated with lower rates of major hemorrhage than warfarin without decreasing stroke risk. At higher doses, dabigatran was superior to warfarin with respect to AIS reduction, at the expense of higher rates of major hemorrhage.[34] Taking into account the relatively higher costs of NOACs, rates of AIS and hemorrhagic complication, and warfarin-related expenses (physician visits and international normalized ratio testing), NOACs were still found to be a cost-effective alternative to warfarin in the treatment of atrial fibrillation.[35-37]

For warfarin-ineligible patients with atrial fibrillation, percutaneous closure of the left atrial appendage may offer an alternative. This procedure was shown to be noninferior to warfarin for stroke prevention, but had higher complication rates.[38]

Prevention of Recurrence in Patients with Cryptogenic Stroke

In cryptogenic stroke, accurate determination of stroke etiology guides treatment. Many of these patients have a patent foramen ovale (PFO), common in nonstroke patients as well. Three recent trials failed to demonstrate that percutaneous PFO closure is superior to medical management with antiplatelets or anticoagulants in preventing recurrent stroke, although per-protocol analysis of 1 trial did suggest a benefit of closure.[39-41]

Atrial fibrillation may be diagnosed in a delayed fashion after cryptogenic stroke. Outpatient Holter or event monitors prolong cardiac monitoring, which can increase detection, but event rates after cryptogenic stroke are low and patient compliance is poor.[42, 43] Implantable loop recorders, which facilitate long-term monitoring for atrial fibrillation, promise to improve this sensitivity.[44] It remains to be seen, however, whether these devices are cost-effective in reducing the incidence and burden of recurrent stroke. Use of NOACs in cryptogenic stroke is another avenue for future research.

Overall Secondary Prevention in Patients with Transient Ischemic Attack or Minor Stroke

Neurologists, emergency physicians, and primary care clinicians use a simple risk stratification tool (ABCD2 score) to estimate stroke risk in patients with transient ischemic attack (TIA).[45] A substantial proportion of that risk occurs in the first week after TIA or minor stroke.[46] The recently reported Chinese CHANCE trial (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events) compared clopidogrel plus aspirin to aspirin alone in patients with high-risk TIA or minor stroke who did not have a cardioembolic source for stroke.[47, 48] Adding clopidogrel to aspirin within 24 hours after stroke achieved a 30% relative risk reduction of subsequent AIS by 90 days (11.4% vs 7.9%) without significantly increasing the incidence of intracranial or systemic hemorrhage. Most secondary strokes occurred within the first 2 weeks, where the greatest risk reduction was also observed; the curves remained essentially parallel thereafter. POINT (Platelet-Oriented Inhibition in New TIA), a similar trial in the United States in which patients are randomized to 90 days of clopidogrel plus aspirin compared with aspirin alone (as opposed to only 21 days of dual antiplatelet therapy in CHANCE), is nearing its midpoint data safety and monitoring board review. This analysis will evaluate whether findings in CHANCE are replicated or whether additional recruitment is required to address the study question.

Therapeutic Pipeline in 2013

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References

Alternative or Adjunctive Thrombolytic Agents for Acute Stroke

Several recent trials have evaluated the safety and efficacy of alternative thrombolytic agents administered alone or with IV t-PA. For example, CLEAR-ER is a phase II randomized trial evaluating addition of eptifibatide with medium-dose IV t-PA as compared to standard-dose t-PA, potentially addressing both fibrin and platelet components of the thrombus. The results of this pilot trial regarding potential safety and efficacy are promising, and plans for a phase III trial are in progress.[49, 50] Infusion of the direct thrombin inhibitor argatroban for 48 hours after full-dose IV t-PA can achieve recanalization rates similar to or better than historical controls who received IV t-PA only, with rates of symptomatic hemorrhage no higher than those of historical controls.[51] A small phase IIB/III trial of IV tenecteplase (TNK) versus IV-tPA determined the highest studied dose of TNK to be unsafe, but did not establish benefit over IV t-PA at either of the lower doses.[52] Better outcomes with TNK, however, were demonstrated in a small randomized phase IIB study of AIS patients selected by CT angiography/perfusion imaging.[53] Two ongoing phase III trials are evaluating desmoteplase in patients beyond the approved t-PA window, selected by neuroimaging.[54]

Neuroprotection and Adjunctive Therapies for Cerebral Reperfusion

During routine evaluation of AIS patients with transcranial Doppler ultrasound, recanalization rates of proximal arterial occlusion after IV t-PA were found to exceed rates expected from IV t-PA alone.[55] In CLOTBUSTER, a multicenter phase III trial of ultrasound-enhanced thrombolysis, a SonoLysis Headframe System will direct ultrasound energy at the proximal MCA (Cerevast Therapeutics, Redmond, WA).[56] Other novel therapies, including attempts to augment cerebral perfusion with a device similar to an aortic balloon pump, have proven less effective.[57]

Neuroprotective strategies in the setting of reperfusion continue to be studied in animal models and clinical trials despite a disappointing track record. Hypothermia is known to improve outcome in the setting of reperfusion of global ischemia and is currently under study in several trials of AIS. Agents that uncouple neurotoxic signaling pathways show promise in primate models.[58] If clinical benefit of neuroprotection is demonstrated, it will likely be heavily dependent on time to treatment, as studied in the ongoing phase III trial of prehospital delivery of magnesium neuroprotective therapy (FAST-MAG).[59]

Improved Devices for Endovascular Treatment of Stroke

Revascularization rates for modern stent-retrievers are higher than for older clot retrieval systems.[13, 14] Would the IMS III and SYNTHESIS trials have shown significant improvements in functional outcome with endovascular therapy using newer devices, especially if patients with proximal arterial occlusion were selected? Several randomized trials of new stent-retrievers and embolectomy technologies are ongoing in the United States and other countries, focusing on patient selection by vascular and parenchymal imaging as well as minimizing the time from stroke onset to start of therapy (see Table 1).

Medication Combinations for Prevention of Stroke

A polypill including a statin, aspirin, and 1 or more antihypertensives provides an opportunity for primary and secondary stroke prevention, while theoretically improving medication adherence. By multiplying relative risk reductions achieved by treating each risk factor, Wald and Law initially proposed that a polypill could reduce the relative risk of stroke by 80%.[60] Three recently published trials outside the United States followed patients at low cardiovascular risk who took a once-daily polypill.[61-63] Each trial observed more modest reductions in blood pressure and low-density lipoprotein levels than initially expected, perhaps owing to reduced bioavailability of individual components in this combined preparation. Extrapolated to the US population, a polypill could provide a relative risk reduction for stroke of 37% over 10 years.[64] A multifaceted approach including prevention clinics remains of great value, as does research to determine whether the polypill is cost-effective overall.[65, 66]

Emerging Strategies for Stroke Recovery

Whereas a small subset of stroke patients is eligible for acute revascularization therapy, most may benefit from stroke rehabilitation. Improving effectiveness, timing of, and access to these therapies has enormous potential to improve stroke outcomes. The time-dependence of restorative therapies is likely influenced by “sensitive periods” of mechanisms of cortical reorganization after injury.[67, 68] The most promising research in this field focuses on understanding mechanisms of neurogenesis, expression of genes and growth factors, expansion of axonal and dendritic arbors, and synaptic plasticity, including synaptogenesis as well as structural and physiologic plasticity of individual synapses. Designing randomized, controlled trials in the field of stroke recovery has proven challenging due to variability in stroke characteristics and severity, availability of agreed-upon metrics to quantify recovery, and ethical implications of including a control (no-therapy) group. Despite these challenges, benefit has been established with class 1 evidence for use of fluoxetine as well as constraint-induced movement therapy after stroke.[69, 70] When paired with traditional physical and occupational therapy, noninvasive transcranial magnetic stimulation also facilitates motor recovery, although extending persistence of these benefits awaits refinement of stimulation protocols.[71] Further research in stroke recovery may be focused on optimizing timing and intensity of therapy, use of robotics, and stem cell technologies.[72-75]

Unmet Needs

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References

In addition to the development of new therapies, current unmet needs in stroke treatment and prevention include (1) better methods to deliver proven therapies to more patients, (2) better monitoring and treatments for adverse outcomes associated with current therapies, (3) better recruitment into ongoing trials of new therapies to accelerate progress, and (4) demonstration of which therapies are most cost-effective. Examples of the first need include exploring the potential benefit of t-PA in patients outside of current eligibility requirements (eg, wake-up strokes) and improving public education about stroke warning signs to increase the likelihood of patients arriving within the current t-PA time window. Novel oral anticoagulants promise improved stroke prevention in atrial fibrillation, but we need better treatments to reverse their effects in the setting of hemorrhagic complications. Recruitment of patients into US stroke trials, particularly those with acute stroke, has been frustrating. Hopefully, the institution of a centralized NINDS-funded stroke network will improve subject recruitment. Finally, the evolving health–economic landscape mandates establishing cost-effectiveness for potential acute and prevention therapies.

Possible New Directions for Research

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References

As health care systems consolidate and focus on cost containment, research into effective use of electronic medical records (EMR) to optimize testing and improve medication adherence may modify stroke risk factors in large populations, as has been shown with diabetes by the Kaiser Permanente system.[76] EMR-based initiatives such as Kaiser's ALL/PHASE program remind clinicians to start at-risk patients on an aspirin, antihypertensive, and lipid-lowering agent. Over the long term, multidisciplinary teams including pharmacists within these integrated care delivery networks may help reduce the risk of cardiovascular disease and stroke.[77]

The use of genetic testing to personalize management of medications for stroke has yet to demonstrate the promise seen in other areas of medicine such as cancer and epilepsy. Genetic testing in warfarin and clopidogrel therapy exemplifies the pharmacogenomic approach, yet it has not been widely accepted.[78, 79] With additional research into genetics of stroke etiology, recovery, and therapeutics, these data will likely become incorporated into clinical decision making.

Today's efforts to minimize time to reperfusion may soon reach their limit; such a ceiling effect has been seen already in cardiology, where identifying major improvements in treatment of acute myocardial infarction in the past few years has been challenging. Tomorrow's efforts must be focused on improving stroke education, risk factor modification, and secondary prevention, longer-term goals that will require lifestyle changes of stroke patients and their families. The timeline for advances in neurorecovery is even longer, as we are just beginning to learn how the brain recovers and adapts after injury, and randomized trials in this area are newer and less developed.[80] However, improvement in strategies to recover speech, cognition, and motor function has the potential to benefit far more stroke patients than any acute stroke therapy, and represents the greatest opportunity for research in the coming century.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References

Supported by U01 NS052220, J.P.B. (PI) 9/15/2005 –12/31/2013, NINDS and P50 NS44283 J.P.B. (PPG Director), 8/01/2008 – 4/30/2014. Ekos Corporation supplied catheter devices for the IMS III clinical trial. Schering-Plough supplied drugs for the NINDS-funded CLEAR-ER trial.

We thank Dr P. Khatri for reviewing drafts of the manuscript and Dr S. Cramer for helpful contributions.

Potential Conflicts of Interest

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References

J.P.B.: grants/grants pending, Genentech; data safety monitoring board membership, PhotoThera; consultation, Pfizer.

References

  1. Top of page
  2. Abstract
  3. Modern Understanding of Biology
  4. Currently Available Therapies
  5. Therapeutic Pipeline in 2013
  6. Unmet Needs
  7. Possible New Directions for Research
  8. Acknowledgment
  9. Potential Conflicts of Interest
  10. References