Acute ischemic stroke

Acute Ischemic Stroke Following Transcatheter Aortic Valve Implantation: Current Management Strategies

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Introduction

The safety and efficacy of transcatheter aortic valve replacement (TAVR) as a curative management technique for patients with severe, surgically exempt aortic stenosis has been established in several randomized controlled trials.1-6 Since the Food and Drug Administration’s approval of TAVR in 2012, technological advancements in interventional cardiology and increasing operator experience have made the procedure safer than surgical aortic valve replacement.1-7 Despite such improvements, thromboembolism remains a risk related to TAVR procedures, with periprocedural acute ischemic stroke (AIS) being associated with a short-term reduction in quality of life and increased intervention-related mortality.7-10 A comprehensive meta-analysis of 29,000 patients with aortic stenosis treated with TAVR reported rates of periprocedural AIS and AIS-related mortality of 3.1% and 12%, respectively.10 Moreover, patients who suffer a periprocedural acute neurologic event are shown to have a 3.5-fold increased risk of 30-day mortality, indicating worse short- and long-term outcomes.9 With the expansion of TAVR to include intermediate-risk patients, these rates are expected to rise.

Data regarding the assessment and management of AIS secondary to TAVR and other interventional cardiology procedures are lacking. Levia et al11 present a well-written multicenter study with a large sample size and adequate follow-up that aimed to explore not only the incidence but also the characteristics and management of TAVR-related AIS. The reported AIS rate of 2.3% reflects the current literature. Although most AIS events were managed conservatively (89.9%), those authors treated a considerable number of cases with neurointervention (10.1%) with either mechanical thrombectomy (MT) or thrombolytic therapy. A comparison was performed between these 2 treatment modalities; however, the sample sizes (MT, n = 26 vs thrombolytics, n = 13) became too small for conclusive findings. Nevertheless, neurointervention was shown to be associated with 3-fold odds (95% CI: 1.15-7.88; P = 0.03) of disability-free survival at 90 days. It is safe to say that these real-world findings are useful to fill the gap in the literature regarding the management of moderate to severe TAVR-related AIS events. Subsequent to the major randomized AIS trials in 2015 (MR CLEAN [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], ESCAPE [Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Time], EXTEND-IA [Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-arterial], SWIFT PRIME [Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke], and REVASCAT [Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset]) and 2018 (DAWN [Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo] and DEFUSE-3 [Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3]), MT is the gold standard treatment for most patients suffering an AIS caused by anterior circulation large-vessel occlusion with a salvageable ischemic penumbra.12-14 In light of this overwhelming evidence regarding the benefit of MT in this population, patients presenting with neurologic deficits after any cardiology and peripheral endovascular procedures should undergo a stroke work-up to identify those who might be candidates for MT.

This is especially true, as pointed out by Levia et al,11 when extensive endovascular manipulations are performed in heavily calcified valves and a severely atherosclerotic abdominal and thoracic aorta. Fragments of such calcified or atherosclerotic lesions are notoriously resistant to pharmacologic therapy alone, and MT should be promptly considered in these cases. In the current study, the authors unfortunately did not report a few crucial metrics. Because the benefit of neurointervention is highly dependent on the time from the onset of symptoms (ie, “time is brain”), information on the timing of the administration of thrombolytics or puncture for MT would have been valuable. Additionally, baseline neurologic status measured using the prehospital modified Rankin Scale score as well as the Alberta Stroke Program Early Computed Tomography Score at the time of stroke were not reported for the majority of patients. These limitations, although not major, should be considered when interpreting the results and outcomes of this study and can serve as a suggestion for future similar studies.

Endovascular interventions undoubtedly carry an inherent risk of vascular injury and distal embolization of fragments that can potentially result in AIS.1 Other than apparent neurologic deficits, clinically silent embolic infarcts have also been reported in the literature.15,16 In a study by Kahlert et al,17 diffusion-weighted magnetic resonance Imaging was performed immediately after TAVR procedures, and hyperintensities were noted in as many as 84% of cases. The clinical relevance of these findings remains of debate; however, the long-term implications may be similar to those for traumatic brain injury.17 To minimize the risks related to endovascular manipulations, advancements in interventional technology and newer techniques are expected to further improve the overall safety of such procedures. Cerebral protection devices are 1 specific advancement relevant to TAVR. These devices have shown significant benefit in terms of reduced AIS incidence and other neurologic deficits noted in the periprocedural period.18 With increased use of these devices, it would be interesting to highlight the differences in outcomes after neurointervention for patients undergoing TAVR with and without cerebral protection devices.

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke.

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Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. Methods Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. Results The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). Conclusions This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase.

Tintinalli Reviews ACEP’s Revised tPA Policy

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A review of the revised ACEP Clinical Policy – IV tPA downgraded to Level B evidence

Nothing seems to stir the emotions of an emergency physician more than a discussion of tPA for stroke: who, why, and when. Skeptics cite problems in the data, and conflicts of interest of the authors. Supporters trust the literature that passed peer review and became policy of emergency medicine and neurology professional societies around the world.

2012 and 2015
The 2012 ACEP Clinical Policy  on the use of tissue plasminogen activator for acute ischemic stroke [1] raised plenty of questions. It resulted in concerns about the effectiveness of the drug, the magnitude of its effectiveness, the risks of cerebral hemorrhage, effects of the drug on stroke mimics, legal implications of the policy, the policy’s impact in different practice settings, hospital differences in resources for stroke diagnosis and emergency care, and the lack of  tools for patient/family shared decision making [2,3,4,5]. The key question asked was ‘Is IV tPA safe and effective for acute ischemic stroke if given within 3, and within 3-4.5 hours after symptom onset? The level A recommendation stated: IVtPA should be offered …to patients who meet …(NINDS) inclusion/exclusion criteria and can be treated within 3 hours after symptom onset. The level B recommendation stated: IVtPA should be considered in patients who meet…(ECASS III) inclusion/exclusion criteria and can be treated between 3 to 4.5 hours after symptom onset.

Criticism of this policy was swift, in these pages and elsewhere. Level A recommendations imply generally accepted principles of care and as such seemed to ignore or shut down years of well-intentioned, well-reasoned debate on tPA’s safety and efficacy. Subsequently, ACEP took the unprecedented step of reconsidering their policy, which had been co-authored with the American Academy of Neurology.

In June 2015, the ACEP Board approved a revised clinical policy  on the use of tPA for ischemic stroke [6].  The question asked was the same as in 2012 – whether IV tPA is safe and effective within 3 hours of symptom onset, and within 3-4.5 hours of symptom onset.

2015 Recommendations
Is IV tPA safe and effective for patients with acute ischemic stroke if given within 3 hours, and within 3-4.5 hours  of symptom onset? Recommendations for ❤ and 3-4.5 hours are combined below for simplicity.

  • Level A recommendation: None.
    Note that the 2015 policy no longer provides level A recommendations for IVtPA.
  • Level B recommendation for ❤ hr administration: IV tPA should be offered and may be given …within 3 hours after symptom onset at institutions where systems are in place to safely administer the medication. Consider the increased risk of sICH.
  • Level B recommendation for 3-4.5 hr administration: despite the known risk of sICH and the variability in the degree of benefit in functional outcomes, IV tPA may be offered and may be given to carefully selected patients…within 3-4.5 hours after symptom onset at institutions where systems are in place to safely administer the medication.
  • Level C recommendation: When feasible, shared decisionmaking…should include a discussion of potential benefits and harms…

Risks and Benefits
Here are selected comments from Appendix D and text, using the most robust analyses that  were provided for risk-benefit analysis:

IVtPA given < 3 hrs

  • NNT = 8 (95% CI 4-31)  NINDS
  • NNH=17 (95% CI 12-34)  NINDS
  • sICH 5-7% sICH overall  (could be lower with adherence to protocol; sICH definitions also vary with study)
  • Proportion who improved: 13% achieving Rankin Scale 0-1 (NINDS 39% IVtPA vs 26% control)

IVtPA given 3-4.5 hrs

  • NNT = 14  (95% CI 7-244) ECASS III
  • NNH= 23 (95%  31-78)  ECASS III
  • sICH 3-8% and 2-6% depending on NINDS definition of sICH
  • Proportion who improved: 7% achieving Rankin Scale 0-1, ECASS III, 52% for IVtPA vs 45% for control)

Who benefits and when?
Published data is somewhat population-based and not at all individual-based, so we are still in the dark about the patients most likely to benefit from IVtPA. If only 13% benefit from IVtPA if given within 3 hours, or 7% in 3-4.5 hours, what about the rest? What about the cost and resources used?   Who exactly are the ‘carefully-selected’ patients who may receive IVtPA at 3-4.5 hours? The benefits of giving tPA in ❤ hours, or  ≤90 minutes also needs discussion [8].

Who is most at risk for sICH?
Several scoring systems for assessing the likelihood of sICH after IVtPA have been developed [9]. Predictive variables and scoring methods vary with the tool, but typically include early infarct signs on non-contrast CT scan; prestroke Rankin scale score; age;  antithrombotic therapy; hyperglycemia; and NIHSS on admission.

What about the ED, the hospital and the hospital system?
Stroke diagnosis and emergency management is not a one-man emergency physician show. It requires a team to make what is often a difficult diagnosis and treatment plan. All members of the team should use the same unified protocol: indications for activating Code Stroke; NIHSS reporting; imaging protocols; scoring systems for risk-benefit analysis; and well-articulated and well-presented information and consent forms.

What about tools for shared decision-making?
Involving patients and family in decision-making is more complex than asking ‘do you want the clot-buster’? Patients who elect a treatment, whether a stent for STEMI, or IVtPA for stroke, assume they will personally benefit from the treatment. This is not the case with IVtPA where most do not benefit. Only a few do. And a small number are harmed. Graphs and pictorial images are an excellent way to communicate a risk-benefit analysis, but are in various stages of development [10,11]. The challenge for tool developers is to convey information simply, clearly, and quickly given a variety of clinical scenarios.

Summary
The 2015 ACEP clinical policy discussion is detailed. Study deficiencies are noted, the discussion uses updated data, and methodology, case definitions, heterogeneity and outcome differences are noted. IVtPA was lowered from a level A to level B recommendation, and qualifications on the proper environment for drug administration were added. However, these qualifications were not spelled out in any detail and key issues relative to decision-making remain unaddressed. The revised policy reminds us that data on risks and  benefits are still a moving target. What is clear is that the pressure is on for emergency physicians who must be the initiators and leaders of the emergency stroke care team.

REFERENCES

  1. Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department . Annals of Emergency Medicine, 61:2, February 2013, 225- 243
  2. Ellison D, ‘The Lytic Lottery’ Annals of Emergency Medicine, 62:5, October 2013, 432-33
  3. Newman, David, ‘Thrombolytics for Acute Ischemic Stroke’ ,theNNT.com, March 25, 2013 accessed Aug 7, 2015
  4. Hoffman JR and Schriger DL ‘A Graphic Reanalysis of the NINDS Trial’ Annals of Emergency Medicine 54:3 September 2009, 329-336
  5. Klauer, K ‘tPA and the Problems of ‘Indication Creep. Emergency Physicians Monthly, May 29, 2013.
  6. Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department. http://www.acep.org/workarea/DownloadAsset.aspx?id=102373
  7. Zinsser, William. On Writing Well. The Classic Guide to Writing Nonfiction’. 7e, 2006, HarperCollins, New York.
  8. Miller JB, Heitsch L, Siket M, et al ‘The Emergency Medicine Debate on tPA for Stroke: What is Best for our Patients? Efficacy in the First Three Hours’ Acad Emerg Med 2015 July; 22(7):852-5
  9. Asuzu D, Nystrom K, Amin H et al ‘Comparison of 8 scores for predicting symptomatic intracerebral hemorhage after IV thrombolysis’ NeurocritCare 2015 Apr; 22 (2):229-33. PMID 25168743
  10. Gadhia J, Starkman S, Ovbiagele B, et al ‘Assessment and Immprovement of Figures to Visually Convey Benefit and Risk of Stroke Thrombolysis’ Stroke 2010 February; 41 (2): 300-306
  11. Flynn D, Ford GA, Stobbart L et al ‘A review of decision support, risk communication and patient information tools for thrombolytic treatment in acute stroke: lessons for tool developers. BMC Health Services Research 2013, 13:225

Acute Stroke Intervention :A Systematic Review

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Importance  Acute ischemic stroke is a major cause of mortality and morbidity in the United States. We review the latest data and evidence supporting catheter-directed treatment for proximal artery occlusion as an adjunct to intravenous thrombolysis in patients with acute stroke.

Objective  To review the pathophysiology of acute brain ischemia and infarction and the evidence supporting various stroke reperfusion treatments.

Evidence Review  Systematic literature search of MEDLINE databases published between January 1, 1990, and February 11, 2015, was performed to identify studies addressing the role of thrombolysis and mechanical thrombectomy in acute stroke management. Studies included randomized clinical trials, observational studies, guideline statements, and review articles. Sixty-eight articles (N = 108 082 patients) were selected for review.

Findings  Intravenous thrombolysis is the mainstay of acute ischemic stroke management for any patient with disabling deficits presenting within 4.5 hours from symptom onset. Randomized trials have demonstrated that more patients return to having good function (defined by being independent and having slight disability or less) when treated within 4.5 hours after symptom onset with intravenous recombinant tissue plasminogen activator (IV rtPA) therapy. Mechanical thrombectomy in select patients with acute ischemic stroke and proximal artery occlusions has demonstrated substantial rates of partial or complete arterial recanalization and improved outcomes compared with IV rtPA or best medical treatment alone in multiple randomized clinical trials. Regardless of mode of reperfusion, earlier reperfusion is associated with better clinical outcomes.

Conclusions and Relevance  Intravenous rtPA remains the standard of care for patients with moderate to severe neurological deficits who present within 4.5 hours of symptom onset. Outcomes for some patients with acute ischemic stroke and moderate to severe neurological deficits due to proximal artery occlusion are improved with endovascular reperfusion therapy. Efforts to hasten reperfusion therapy, regardless of the mode, should be undertaken within organized stroke systems of care.

Acute Stroke Intervention :A Systematic Review

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Importance  Acute ischemic stroke is a major cause of mortality and morbidity in the United States. We review the latest data and evidence supporting catheter-directed treatment for proximal artery occlusion as an adjunct to intravenous thrombolysis in patients with acute stroke.

Objective  To review the pathophysiology of acute brain ischemia and infarction and the evidence supporting various stroke reperfusion treatments.

Evidence Review  Systematic literature search of MEDLINE databases published between January 1, 1990, and February 11, 2015, was performed to identify studies addressing the role of thrombolysis and mechanical thrombectomy in acute stroke management. Studies included randomized clinical trials, observational studies, guideline statements, and review articles. Sixty-eight articles (N = 108 082 patients) were selected for review.

Findings  Intravenous thrombolysis is the mainstay of acute ischemic stroke management for any patient with disabling deficits presenting within 4.5 hours from symptom onset. Randomized trials have demonstrated that more patients return to having good function (defined by being independent and having slight disability or less) when treated within 4.5 hours after symptom onset with intravenous recombinant tissue plasminogen activator (IV rtPA) therapy. Mechanical thrombectomy in select patients with acute ischemic stroke and proximal artery occlusions has demonstrated substantial rates of partial or complete arterial recanalization and improved outcomes compared with IV rtPA or best medical treatment alone in multiple randomized clinical trials. Regardless of mode of reperfusion, earlier reperfusion is associated with better clinical outcomes.

Conclusions and Relevance  Intravenous rtPA remains the standard of care for patients with moderate to severe neurological deficits who present within 4.5 hours of symptom onset. Outcomes for some patients with acute ischemic stroke and moderate to severe neurological deficits due to proximal artery occlusion are improved with endovascular reperfusion therapy. Efforts to hasten reperfusion therapy, regardless of the mode, should be undertaken within organized stroke systems of care.