The relationship between plasma D-dimer concentrations and acute ischemic stroke subtypes

Section Editors: Marc Fisher MD Antoni Davalos MD The Food and Drug Administration (FDA) evaluates applications for new human drugs, biologics, and complex medical devices. Companies must obtain FDA approval to legally market these products. In August, the FDA gave Concentric Medical clearance to market its Merci Retriever system to “remove blood clots from the brain in patients experiencing an ischemic stroke.” Given that the FDA is charged with “protecting the public health by assuring the safety, efficacy, and security of… biological products and medical devices…, ” “advancing public health by helping to speed innovations that make medicines … more effective, safer, and more affordable,” and “helping the public get the accurate, science-based information they need to use medicines … to improve their health,”1 the FDA’s decision to approve the Merci Retriever system is of concern. The pathways to approval are reviewed by Felten et al in the accompanying article and are outlined in Figure 1. Figure 1. Potential pathways for device approval. The decision to approve the Merci Retriever was based on data from the MERCI (Mechanical Embolus Removal in Cerebral Ischemia) Trial; the approval was granted through the 510(k) process. The Merci Retriever system includes a flexible nickel titanium (nitinol) wire that obtains a helical shape once it is passed through the tip of the guidance catheter. In practice, the catheter/wire is passed distal to the thrombus, the catheter is removed, and the helical configuration assumed by the wire; the clot is then trapped in the helix and withdrawn from the vasculature (Figure 2). The 510(k) clearance means that the Merci Retriever was felt to be substantially equivalent to a predicate device. In this case, the predicate device was the Concentric Retriever, which itself received 510(k) clearance by the FDA in May 2001 for “use in …

Seven low-density lipoprotein (LDL) subclasses are identified, and smaller LDL particles are associated with an increased risk for cardiovascular events. However, there is limited data about the relationship between the acute ischemic stroke (AIS) subtypes and LDL subclasses. The aim of our study is to investigate the relationship between AIS subtypes and LDL subclasses. This study consisted of 110 AIS patients and 60 healthy controls. Stroke patients were classified according to the TOAST classification system as cardioembolic infarct (CI), large artery atherosclerosis (LAA), and lacunar infarct (LI). LDL subclasses were distributed as seven bands (LDL-1 and-2 defined as large, and LDL-3 to-7 defined as small-LDL particle), using the LipoPrintª System. Control group and AIS subtypes were compared in terms of LDL subclasses; p<0.05 was considered statistically significant. AIS patients had higher LDL-2, LDL-3 and LDL-4 subclasses compared to the control groups, while LDL-1 was similar in two groups. In addition, LDL-2 and LDL-3 subclasses were significantly higher in each AIS subtype when compared to the control group. LDL-4 subclasses were significantly higher in LAA and LI subtypes than in the control group, but there was no relationship for CI subtypes. Smaller subclasses LDL-5 to LDL-7 were undetectable in both AIS patients and controls. Using regression analysis; age, LDL-2, LDL-3 and LDL-4 were found to be independent predictors of AIS development. Our study showed that examination of LDL subclasses may be important in management of AIS patients. LDL-2, LDL-3, and LDL-4 are independent predictors of AIS development. These findings should be supported by further large studies.

Stroke is a leading cause of death and disability and continues to have a great public health impact worldwide. Management of patients with acute ischaemic stroke (IS) has been, until recently, primarily supportive care. A better understanding of the mechanisms of stroke has stimulated a far more aggressive and active treatment strategy, and stroke is now considered a state of medical emergency. Evidence-based protocols for the management of patients with stroke should be implemented in all hospital departments involved in the diagnosis and treatment of such individuals. These protocols should include assessment, investigation, immediate treatment and rehabilitation, as well as secondary prevention and risk factor management strategies. Specialised stroke units are well documented initiatives for optimising the management of patients with stroke and are central to the future of acute stroke management. Establishment of stroke units should receive top priority in strategic planning within the area of stroke management. Immediate and precise evaluation of patients with assumed stroke, including a computerised tomography scan of the brain followed by close monitoring, are essential for preventing medical and neurological complications and for achieving the optimal outcome. Primary treatment of acute IS with thrombolysis is a therapy with substantial risks, but at present is essentially the only available therapy for reversing or reducing effects of acute IS. Antiplatelet therapy with aspirin (acetylsalicylic acid) in the acute phase of IS also has a small but significant effect. Anticoagulant therapy with heparin has not yet proven any net long term benefit in the treatment of acute IS. Likewise, there are currently no convincing data on the efficacy of neuroprotective drugs in a clinical setting. Every patient should have disability needs assessed as soon as possible and a well conceived rehabilitation plan should be made based on the patients’s own goals. To reduce the incidence of a subsequent stroke, secondary prevention is essential. Prevention should primarily focus on detection and management of risk factors for stroke, which in many cases influence both the risk of ischaemic and haemorrhagic stroke. These risk factors include hypertension, atrial fibrillation, smoking, diabetes mellitus, alcohol abuse and hyperlipidaemia. In patients with IS, secondary prevention also includes antiplatelet therapy with aspirin and dipyridamole or clopidogrel and the possibility of carotid endarterectomy.

A multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke caused by proximal arterial occlusion in the anterior circulation.

Objective To investigate the regularity in and risk factors for perioperative deep venous thrombosis (DVT) and the changes in plasma D-dimer in patients with tibiofibular fracture. Methods A retrospective analysis was done of the 180 patients with tibiofibular fracture who had been treated at Department of Orthopaedics and Trauma, Xi'an Honghui Hospital from September 2014 to February 2018. They were 114 males and 66 females, aged from 16 to 83 years (average, 47.6 years). The levels of plasma D-dimer were detected at admission, one day preoperation, and 1, 3, 5 days postoperation. B-ultrasound examination of both lower extremities was performed before and after surgery. According to the results of B-ultrasound, the patients were divided into a DVT group and a non-DVT group. The 2 groups were compared in the plasma D-dimer levels measured at different time points. DVT risk factors were screened by univariate analysis, and multivariate logistic regression analysis was used to determine independent risk factors. Results Of this cohort, 54 cases (30%) developed DVT and 39 cases (21.7%) did preoperation. Of the 39 cases (mixed DVT in one and distal DVT in 38 ones), DVT disappeared in 14 postoperation. Of the 40 cases (22.2%) of postoperative DVT (proximal DVT in one, mixed DVT in one and distal DVT in 38 ones), 15 developed newly postoperation. Multivariate logistic regression analysis showed that age, time from injury to operation, pre-operative and postoperative D-dimer elevation were independent risk factors for DVT in the patients. The D-dimer levels in the DVT group were significantly higher than in the non-DVT group at one day preoperation, and 1, 3, 5 days postoperation (P<0.05). The area under the receiver operating characteristic curve was 0.704. When the critical value of D-dimer was 1.4 mg/L, its sensitivity for DVT diagnosis was 0.944 and its specificity 0.246 (poor). When the concentration of D-dimer was 4.45 mg/L, its sensitivity for DVT diagnosis was 0.574 and its specificity 0.817 (the highest). Conclusions Perioperative DVT may happen in patients with tibiofibular fracture, mostly at the distal end beyond the popliteal vein. Clinically, patients who are advanced in age, have plasma D-dimer elevation at admission and after operation, and have waited long for operation should be alert to the occurrence of DVT. The plasma D-dimer level with a recommended threshold of 4.45 mg/L may have a certain diagnostic value for patients with tibiofibular fracture. Key words: Tibia; Fibula; Fractures, bone; Deep vein thrombosis; Risk factors; D-dimer

Objective Here, we aim to investigate whether D-dimer (DD)/fibrinogen (FIB) ratio or combination of DD and FIB contribute to the prognosis of stroke and stroke subtypes. Methods 1413 patients with acute ischemic stroke (AIS) were recruited. We measured DD and FIB levels on admission and followed up with patients at discharge and 90-day following discharge. We analyzed the association between DD/FIB ratio and poor function outcome of AIS and different AIS subtypes. Similarly, logistic regression model was used to estimate the combined effect of DD level and FIB level on the poor outcomes of stroke and stroke subtypes. Results The patients with DD+FIB+ or high DD/FIB ratio tended to have the high risk of severe neurological deficits at both discharge and 90-day following discharge. In the subgroup analysis, high DD/FIB ratio was significantly associated with the poor function outcome in cardioembolism (CE) and large-artery atherosclerosis (LAA) subtypes. DD+FIB+ was strongly associated with the poor function outcome in CE subtype at discharge and 90-day. Conclusion DD/FIB ratio and combination of DD and FIB may have more significant prognostic value of stroke and stroke subtypes than either index of DD or FIB alone in AIS patients.

Marc Fisher MD Kennedy Lees MD Section Editors: Hypertension is the most important modifiable risk factor for stroke.1,2 It is estimated that 25% or more of strokes may be attributable to hypertension. Because many patients with stroke have mild hypertension or prehypertension, we have shifted our focus and now think of stroke on a continuum of risk based on blood pressure (BP) level rather than on a threshold effect.3 Because high BP may not exist in isolation, a wider definition of hypertension has been proposed that also takes into account the absolute risk of cardiovascular events and associated metabolic factors or early disease markers.3 Lowering BP reduces the risk of stroke. Epidemiological studies have shown that for each 10 mm Hg lower systolic blood pressure (SBP), there is a decrease in risk of stroke of approximately one third in persons aged 60 to 79 years. This association is continuous down to levels of at least 115/75 mm Hg and is consistent across sexes, regions, stroke subtypes, and for fatal and nonfatal events.4 Lowering diastolic blood pressure (DBP) was once the main target to achieve stroke and other cardiovascular event reduction, but SBP has now become the target.3 As recently shown, even the elderly with sustained SBP elevation may gain from BP reduction in relation to less fatal or nonfatal stroke, death, and heart failure.5 Although the role of longer-term BP control to improve outcomes in patients with stroke is undisputed, BP management immediately after a stroke remains controversial. In an effort to resolve this controversy, several pilot clinical trials have been initiated. In this review, we discuss the results of some of these trials and available evidence-based guidelines for BP control in the settings of acute ischemic and hemorrhagic stroke (excluding subarachnoid hemorrhage) and …

Background Reduced baroreflex sensitivity (BRS) has been reported in patients with acute cardiovascular events. We tested the hypothesis that BRS varies in different subtypes of acute ischemic stroke (AIS) and that BRS is a predictor of clinical outcomes. Methods We examined autonomic parameters in 34 patients with AIS, including the small deep hemisphere infarction, the large hemisphere infarction, and the brainstem infarction groups on Day 1, Day 7, and Day 30 after AIS. Autonomic parameters were also evaluated in 18 age- and sex-matched healthy volunteers as a control group. The clinical outcomes were analyzed using the modified Rankin scale at 30 days after stroke. Results The BRS, Valsalva ratio, and heart rate response to deep breathing (HR-DB) were significantly lower in patients after AIS on admission than in controls (p<0.01). The frequency domain of HRV (LF/HF ratio) was significantly increased in patients after AIS compared to controls (p<0.05). BRS was significantly reduced in patients with large hemisphere infarction or brainstem infarction compared to patients with small deep hemisphere infarction on Day 1 after AIS (p<0.01). Stepwise logistic regression showed that the levels of BRS and NIHSS are prognostic factors of 1-month outcomes in patients with AIS. Conclusion Beside NIHSS score on admission, BRS is a potential prognostic factor of 1-month outcomes in patients with AIS. Patients with large hemisphere infarction or brainstem infarction have more blunting BRS than do those with lacunar infarction, which provides some insight into which patients may be expected to have a poor outcome.

To the Editor: We read with great interest the review from H.P. Adams1 who critically re-evaluates individual aspects of well-known and often-discussed studies on anticoagulation in acute stroke. These studies do not exhibit a net benefit of anticoagulant use with regard to the criteria safety, mortality, morbidity, prevention of stroke recurrence and late outcome. The author emphasized the differences among the individual studies with regard to sample sizes, time-to-start of therapy (extending up to 48 hours after stroke onset), protocols for dosages and controls of anticoagulants used and the route of administration leading to a distinct criticism of major meta-analysis published. In addition, prominent shortcomings such as the missing baseline brain imaging studies in the dominating IST and CAST trials and the lack of any efforts to differentiate among stroke subtypes with gross under representation of embolic mechanisms are mentioned. However, despite these shortcomings, H.P. Adams concludes that he sees no indication for anticoagulation in acute stroke and suggests the future role of anticoagulants will be very limited. In our view this conclusion is premature and not accepted by many “stroke experts” in institutions where advanced diagnostic techniques and neuro-monitoring are available. So far the albeit limited data available from these trials reveals statistically significant advantages of anticoagulation in the prevention of deep venous thrombosis, pulmonary …

IntroductionEndovascular treatment’s (EVT) safety and efficacy have been proven in treating acute ischemic stroke (AIS) due to large vessel occlusion (LVO). However, limited data exist in different stroke subtypes. We aimed to investigate the differences in efficacy and safety of EVT for acute LVO according to different stroke subtypes.MethodsA total of 1635 AIS patients with LVO undergoing EVT from a prospective cohort of the Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke (ANGEL-ACT) registry were classified into three types according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. We compared the primary outcome: 90-day modified Rankin Scale (mRS) score, the secondary outcomes: 90-day mRS (0–1, 0–2, and 0–3), successful recanalization (mTICI 2b/3), and complete recanalization (mTICI 3), and the safety outcomes: death within 90 days, parenchymal hemorrhage (PH), and symptomatic intracranial hemorrhage (SICH) among the three subtypes of stroke patients. Then, multivariable logistic regression models adjusting for potential baseline-confounding variables to determine the associations between stroke subtypes and safety and efficacy endpoints were performed. Finally, we performed subgroup analyses to explore discrepancies in the relationships.ResultsEVT of cardioembolic LVO (CE-LVO) had a higher rate of mTICI 3 (71.7% vs. 65.9% and 63.2%; P = 0.024) and a higher rate of PH (13.8% vs. 5.4% and 6.7%; P < 0.001) when compared to other stroke subtypes. Even multivariable analysis demonstrated that CE-LVO was associated with mTICI 3 [adjusted odds ratio (OR), 1.50 (95% CI 1.04–2.17)] and PH [adjusted OR, 1.97 (95% CI 1.09–3.55)]. However, the 90-day mRS distribution and 90-day mRS (0–1, 0–2, and 0–3) did not differ among the stroke subtypes, and nor did the SICH (P > 0.05).ConclusionsFunctional outcomes were similar among different stroke subtypes. Despite a higher rate of complete recanalization, there is an increased risk of parenchymal hemorrhage in CE-LVO.Trial RegistrationClinical trial registration number: NCT03370939.

Early recanalization of occluded vessels in acute ischemic stroke (AIS) either by intravenous thrombolysis or endovascular revascularization has been shown to be associated with improved clinical outcome and reduced mortality.1 Initial works on endovascular treatment (EVT) of AIS was published in the 1980s.2,3 Since then, the endovascular techniques for AIS treatment have tremendously improved, advancing from intra-arterial administration of thrombolytic drugs to first-generation mechanical thrombectomy devices (Merci clot retriever and Penumbra clot aspiration) and more recently to second-generation mechanical thrombectomy devices (stent-retrievers; Figure 1). Introduction of various tools and techniques in EVT for AIS will, for obvious reasons, affect the efficacy and safety. Figure 1. Evolution of endovascular techniques for acute ischemic stroke and clinical trials. IMS indicates Interventional Management of Stroke; MERCI, Mechanical Embolus Removal in Cerebral Ischemia; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; PROACT, Prolyse in Acute Cerebral Thromboembolism; SWIFT, Solitaire With the Intention for Thrombectomy; and TREVO, Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischemic Stroke. On the other hand, intravenous thrombolysis was evaluated in several large randomized trials and was shown to improve clinical outcome at 90 days if treatment was initiated within 3 hours of stroke onset.4 Subsequently, the European Cooperative Acute Stroke Study (ECASS) III showed the benefit of intravenous thrombolysis between 3 and 4.5 hours.5 After establishing the efficacy of intravenous recombinant tissue-type plasminogen activator (r-tPA) in the treatment of AIS, EVT had to be evaluated against intravenous treatment. A long time elapsed before the results of the first randomized controlled trials were published in 2013 demonstrating no major difference between intravenous r-tPA treatment and EVT for AIS.6–8 Noteworthy, these trials had several limitations including the fact that all EVT were approved for use.9 …

Essential Workflow and Performance Measures for Optimizing Acute Ischemic Stroke Treatment in India.

Various endovascular intraarterial approaches are available for treating patients with acute ischemic stroke who present with severe neurological deficits. Three recent randomized trials-Interventional Management of Stroke (IMS) III, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS Expansion)-evaluated the efficacy of endovascular treatment of acute ischemic stroke and, after failing to demonstrate any significant clinical benefit of endovascular therapies, raised concerns and questions in the medical community regarding the future of endovascular treatment for acute ischemic stroke. In this paper, the authors review the evolution of endovascular treatment strategies for the treatment of acute stroke and provide their interpretation of findings and potential limitations of the three recently published randomized trials. The authors discuss the advantage of stent-retriever technology over earlier endovascular approaches and review the current status and future directions of endovascular acute stroke studies based on lessons learned from previous trials.

Coronary evaluation in patients with stroke: Recognizing the risk

Objective To investigate the effect of rivaroxaban in the treatment of deep vein thrombosis (DVT) after total hip replacement (THR) in elderly patients with diabetes mellitus and its influence on plasma D-dimer level. Methods 25 elderly patients with diabetes undergoing elective hip replacement (group B) and 25 elderly patients without diabetes mellitus (group A) were enrolled in this study.The two groups were orally given rivaroxaban for 2 weeks after operation.The results of color Doppler diagnosis of DVT were compared between the two groups, and the content of D-dimer in plasma was detected. Results Before and after operation, the INR between the two groups had no statistically significant differences (P>0.05). The D-dimer levels of the two groups before operation were obviously lower than those postoperative 2 and 7 days (t=3.145, P 0.05), the value of postoperative 2 days was significantly higher than those postoperative 7 and 14 days (t=3.763, P<0.05), the value of postoperative 7 days was significantly higher than those postoperative 14 days (t=2.876, P<0.05). There was no DVT in the two groups of A and B, and no severe bleeding occurred in the two groups. Conclusion Rivaroxaban in the treatment of elderly diabetic patients with THR surgery, can effectively reduce the formation of lower extremity DVT.At the same time, through detection of plasma D-dimer content can accurately judge the occurrence of DVT, which has guiding significance for prevention and treatment of DVT. Key words: hip replacement; diabetes mellitus; Shaaban; deep vein thrombosis