Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Atrial Fibrillation In Patients With Stroke Attributed to Large- or Small-Vessel Disease: 3-Year Results From the STROKE AF Randomized Clinical Trial.

Importance: The STROKE AF study found that in patients with prior ischemic stroke attributed to large-artery atherosclerotic disease (LAD) or small-vessel occlusive disease (SVD), 12% developed AF over 1 year when monitored with an insertable cardiac monitor (ICM). The occurrence over subsequent years is unknown. Objectives: To compare the rates of AF detection through 3 years of follow-up between an ICM vs site-specific usual care in patients with prior ischemic stroke attributed to LAD or SVD. Design, Setting, and Participants: This multicenter, randomized (1:1) clinical trial took place at 33 sites in the US with enrollment between April 2016 and July 2019 and 3-year follow-up through July 2022. Eligible patients were aged 60 years or older, or aged 50 to 59 years with at least 1 additional stroke risk factor and had an index ischemic stroke attributed to LAD or SVD within 10 days prior to ICM insertion. Of the 496 patients enrolled, 492 were randomized and 4 were excluded. Interventions: ICM monitoring vs site-specific usual care. Main Outcomes and Measures: The prespecified long-term outcome of the trial was AF detection through study follow-up (up to 3 years). AF was defined as an episode lasting more than 30 seconds, adjudicated by an expert committee. Results: In total, 492 patients were randomized and included in the analyses (median [IQR] age, 66 [60-74] years; 307 men [62.4%] and 185 women [37.6%]), of whom 314 completed 3-year follow-up (63.8%). The incidence rate of AF at 3 years was 21.7% (46 patients) in the ICM group vs 2.4% (5 patients) in the control group (hazard ratio, 10.0; 95% CI, 4.0-25.2; P < .001). Conclusions and Relevance: Patients with ischemic stroke attributed to LAD or SVD face an increasing risk of AF over time and most of the AF occurrences are not reliably detected by standard medical monitoring methods. One year of negative monitoring should not reassure clinicians that patients who have experienced stroke will not develop AF over the next 2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT02700945.

Cutaneous Paraneoplastic Syndrome Affecting the Hand in a Case of Underlying Waldenström Macroglobulinemia.

Paraneoplastic syndromes represent the body's immune response to an underlying malignancy. The autoimmune response to cancer can manifest itself in multiple ways, including swelling, thickening, and changes in the hand. We report the case of a 65-year-old man who presented with hand swelling that was initially attributed to a work-related finger laceration. The patient developed edema and stiffness in the hand, which was subsequently diagnosed as Waldenström macroglobulinemia. Hand surgeons should be aware that atypical hand and wrist symptoms should raise the suspicion for the potential of a paraneoplastic syndrome and an underlying malignancy.

Predictors of Atrial Fibrillation in Patients With Stroke Attributed to Large- or Small-Vessel Disease: A Prespecified Secondary Analysis of the STROKE AF Randomized Clinical Trial.

Importance: The Stroke of Known Cause and Underlying Atrial Fibrillation (STROKE AF) trial found that approximately 1 in 8 patients with recent ischemic stroke attributed to large- or small-vessel disease had poststroke atrial fibrillation (AF) detected by an insertable cardiac monitor (ICM) at 12 months. Identifying predictors of AF could be useful when considering an ICM in routine poststroke clinical care. Objective: To determine the association between commonly assessed risk factors and poststroke detection of new AF in the STROKE AF cohort monitored by ICM. Design, Setting, and Participants: This was a prespecified analysis of a randomized (1:1) clinical trial that enrolled patients between April 1, 2016, and July 12, 2019, with primary follow-up through 2020 and mean (SD) duration of 11.0 (3.0) months. Eligible patients were selected from 33 clinical research sites in the US. Patients had an index stroke attributed to large- or small-vessel disease and were 60 years or older or aged 50 to 59 years with at least 1 additional stroke risk factor. A total of 496 patients were enrolled, and 492 were randomly assigned to study groups (3 did not meet inclusion criteria, and 1 withdrew consent). Patients in the ICM group had the index stroke within 10 days before insertion. Data were analyzed from October 8, 2021, to January 28, 2022. Interventions: ICM monitoring vs site-specific usual care (short-duration external cardiac monitoring). Main Outcomes and Measures: The ICM device automatically detects AF episodes 2 or more minutes in length; episodes were adjudicated by an expert committee. Cox regression multivariable modeling included all parameters identified in the univariate analysis having P values <.10. AF detection rates were calculated using Kaplan-Meier survival estimates. Results: The analysis included the 242 participants randomly assigned to the ICM group in the STROKE AF study. Among 242 patients monitored with ICM, 27 developed AF (mean [SD] age, 66.6 [9.3] years; 144 men [60.0%]; 96 [40.0%] women). Two patients had missing baseline data and exited the study early. Univariate predictors of AF detection included age (per 1-year increments: hazard ratio [HR], 1.05; 95% CI, 1.01-1.09; P = .02), CHA2DS2-VASc score (per point: HR, 1.54; 95% CI, 1.15-2.06; P = .004), chronic obstructive pulmonary disease (HR, 2.49; 95% CI, 0.86-7.20; P = .09), congestive heart failure (CHF; with preserved or reduced ejection fraction: HR, 6.64; 95% CI, 2.29-19.24; P < .001), left atrial enlargement (LAE; HR, 3.63; 95% CI, 1.55-8.47; P = .003), QRS duration (HR, 1.02; 95% CI, 1.00-1.04; P = .04), and kidney dysfunction (HR, 3.58; 95% CI, 1.35-9.46; P = .01). In multivariable modeling (n = 197), only CHF (HR, 5.06; 95% CI, 1.45-17.64; P = .05) and LAE (HR, 3.32; 1.34-8.19; P = .009) remained significant predictors of AF. At 12 months, patients with CHF and/or LAE (40 of 142 patients) had an AF detection rate of 23.4% vs 5.0% for patients with neither (HR, 5.1; 95% CI, 2.0-12.8; P < .001). Conclusions and Relevance: Among patients with ischemic stroke attributed to large- or small-vessel disease, CHF and LAE were associated with a significantly increased risk of poststroke AF detection. These patients may benefit most from the use of ICMs as part of a secondary stroke prevention strategy. However, the study was not powered for clinical predictors of AF, and therefore, other clinical characteristics may not have reached statistical significance. Trial Registration: ClinicalTrials.gov Identifier: NCT02700945.

Monitoring for atrial fibrillation prior to patent foramen ovale closure after cryptogenic stroke.

BACKGROUND: Patients who had a cryptogenic stroke (CS) suspected to be causally related to a patent foramen ovale (PFO) are candidates for percutaneous PFO closure. In such patients, it is important to screen for atrial fibrillation (AF). Limited guidance is available regarding AF monitoring strategies in CS patients with PFO addressing optimal monitoring technology and duration. AIM: To provide a narrative review of cardiac rhythm monitoring in CS patients considered for PFO closure, including current practices, stroke recurrences after CS, findings from monitoring studies in CS patients, and predictors for AF detection published in the literature. To propose a personalized strategy for cardiac monitoring in CS patients, accounting for aspects predicting AF detection. SUMMARY OF REVIEW: AF detection in CS patients is predicted by age, left atrial enlargement, prolonged PR interval, frequent premature atrial contractions, interatrial conduction block, diabetes, prior brain infarctions, leukoaraiosis, elevated B-type natriuretic peptide (BNP)/N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and a family history of AF, as well as composed scores (e.g. CHA2DS2-VASc, atrial fibrillation in embolic stroke of undetermined source (AF-ESUS)). The causal role of the PFO may be accounted for by the risk of paradoxical embolism (RoPE) score and/or the PFO-Associated Stroke Causal Likelihood (PASCAL) classification. CONCLUSION: A personalized approach to AF detection in CS patients is proposed, accounting for the likelihood of AF detection and aimed at obtaining sufficient confidence regarding the absence of AF in patients considered for PFO closure. In addition, the impact of high-risk PFO features on the monitoring strategy is discussed.

Effect of Long-term Continuous Cardiac Monitoring vs Usual Care on Detection of Atrial Fibrillation in Patients With Stroke Attributed to Large- or Small-Vessel Disease: The STROKE-AF Randomized Clinical Trial.

Importance: Patients with ischemic stroke attributed to large- or small-vessel disease are not considered at high risk for atrial fibrillation (AF), and the AF incidence rate in this population is unknown. Objectives: To determine whether long-term cardiac monitoring is more effective than usual care for AF detection in patients with stroke attributed to large- or small-vessel disease through 12 months of follow-up. Design, Setting, and Participants: The STROKE-AF trial was a randomized (1:1), multicenter (33 sites in the US) clinical trial that enrolled 496 patients between April 2016 and July 2019, with primary end point follow-up through August 2020. Eligible patients were aged 60 years or older or aged 50 to 59 years with at least 1 additional stroke risk factor and had an index stroke attributed to large- or small-vessel disease within 10 days prior to insertable cardiac monitor (ICM) insertion. Interventions: Patients randomized to the intervention group (n = 242) received ICM insertion within 10 days of the index stroke; patients in the control group (n = 250) received site-specific usual care consisting of external cardiac monitoring, such as 12-lead electrocardiograms, Holter monitoring, telemetry, or event recorders. Main Outcomes and Measures: Incident AF lasting more than 30 seconds through 12 months. Results: Among 492 patients who were randomized (mean [SD] age, 67.1 [9.4] years; 185 [37.6%] women), 417 (84.8%) completed 12 months of follow-up. The median (interquartile range) CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score was 5 (4-6). AF detection at 12 months was significantly higher in the ICM group vs the control group (27 patients [12.1%] vs 4 patients [1.8%]; hazard ratio, 7.4 [95% CI, 2.6-21.3]; P < .001). Among the 221 patients in the ICM group who received an ICM, 4 (1.8%) had ICM procedure-related adverse events (1 site infection, 2 incision site hemorrhages, and 1 implant site pain). Conclusions and Relevance: Among patients with stroke attributed to large- or small-vessel disease, monitoring with an ICM compared with usual care detected significantly more AF over 12 months. However, further research is needed to understand whether identifying AF in these patients is of clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT02700945.

Antithrombotic Treatment of Embolic Stroke of Undetermined Source: RE-SPECT ESUS Elderly and Renally Impaired Subgroups.

Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the impact of age, renal function (both predefined), and dabigatran dose (post hoc) on the rates of recurrent stroke and major bleeding. Methods- RE-SPECT ESUS was a multicenter, randomized, double-blind trial of dabigatran 150 or 110 mg (for patients aged ≥75 years and/or with creatinine clearance 30 to <50 mL/minute) twice daily compared with aspirin 100 mg once daily. The primary outcome was recurrent stroke. Results- The trial, which enrolled 5390 patients from December 2014 to January 2018, did not demonstrate superiority of dabigatran versus aspirin for prevention of recurrent stroke in patients with embolic stroke of undetermined source. However, among the population qualifying for the lower dabigatran dose, the rate of recurrent stroke was reduced with dabigatran versus aspirin (7.4% versus 13.0%; hazard ratio, 0.57 [95% CI, 0.39-0.82]; interaction P=0.01). This was driven mainly by the subgroup aged ≥75 years (7.8% versus 12.4%; hazard ratio, 0.63 [95% CI, 0.43-0.94]; interaction P=0.10). Stroke rates tended to be lower with dabigatran versus aspirin with declining renal function. Risks for major bleeding were similar between treatments, irrespective of renal function, but with a trend for lower bleeding rates with dabigatran versus aspirin in older patients. Conclusions- In subgroup analyses of RE-SPECT ESUS, dabigatran reduced the rate of recurrent stroke compared with aspirin in patients qualifying for the lower dose of dabigatran. These results are hypothesis-generating. Aspirin remains the standard antithrombotic treatment for patients with embolic stroke of undetermined source. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

The safety of oral anticoagulants registry (SOAR): A national, ED-based study of the evaluation and management of bleeding and bleeding concerns due to the use of oral anticoagulants.

OBJECTIVE: The Safety of Oral Anticoagulants Registry (SOAR) was designed to describe the evaluation and management of patients with oral anticoagulant (OAC)-related major bleeding or bleeding concerns who present to the emergency department (ED) with acute illness or injury. Patients in the ED are increasingly taking anticoagulants, which can cause bleeding-related complications as well as impact the acute management of related or unrelated clinical issues that prompt presentation. Modifications of emergency evaluation and management due to anticoagulation have not previously been studied. METHODS: This was a multicenter observational in-hospital study of patients who were judged to be experiencing an active OAC effect and had (a) an obvious bleeding event or (b) were deemed at risk for serious bleeding spontaneously, after injury, or during an indicated invasive procedure. Diagnostic testing, therapies employed, and clinical outcomes were collected. RESULTS: Thirty-one US hospitals contributed data to SOAR. Of 1513 subjects, acute hemorrhage (AH) qualified 78%, while 22% had a bleeding concern (BC). Warfarin was the index OAC in 37.3%, dabigatran in 13.3%, and an anti-Factor Xa in 49.4%. The most common sites of AH were gastrointestinal (51.0%) and intracranial (26.8%). In warfarin-treated patients, the mean (IQR) presenting INR was 3.1 (2.2, 4.8) in AH patients and 3.9 (2.4, 7.2) in BC patients. Three-fifths of SOAR patients were treated with factor repletion or specific reversal agents, and those patients had a longer length of stay. In addition, seven (0.76%) of the treated patients experienced an in-hospital thrombotic complication; two of these seven died on the index admission, both of fatal pulmonary embolism. Vitamin K was used and dosed inconsistently in both warfarin and NOAC cohorts. CONCLUSION: Care of anticoagulated patients in the acute care setting is inconsistent, reflecting the diversity of presentation. As the prevalence of OAC use increases with the aging of the US population, further study and targeted educational efforts are needed to drive more evidence-based care of these patients.

Assessment of the End Point Adjudication Process on the Results of the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial: A Secondary Analysis.

Importance: Debate continues about the value of event adjudication in clinical trials and whether independent centralized assessments improve reliability and validity of study results in masked randomized trials compared with local, investigator-assessed end points. Objective: To assess the results of the adjudicated end point process in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial by comparing end points assessed by local site investigators with centrally adjudicated end points. Design, Setting, and Participants: This is an ad hoc secondary analysis of a randomized, double-blind clinical trial comparing safety and effectiveness of clopidogrel bisulphate plus aspirin vs placebo plus aspirin. Patients received either 600 mg of clopidogrel bisulphate on day 1, then 75 mg per day through day 90 plus 50 to 325 mg of aspirin per day, or the same range of dosages of placebo plus aspirin. Investigators reported all potential end points; independent masked adjudicators were randomly assigned to review using definitions specified in the study protocol. This was a multicenter study; 269 international sites in 10 countries enrolled from May 28, 2010, to December 19, 2017. The study enrolled 4881 patients 18 years or older with transient ischemic attack or minor acute ischemic stroke within 12 hours of symptom onset and followed for 90 days from randomization; last follow-up was completed in March 2018. Main Outcomes and Measures: Independent adjudicators external to the study and masked to study treatment assignment adjudicated 467 primary and secondary effectiveness outcomes and major and minor bleeding events, including the primary composite end point, which was the risk of a composite of major ischemic events at 90 days, defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event. The primary safety end point was major hemorrhage. All components of the primary and safety outcomes were adjudicated. Results: In this secondary analysis of an international randomized clinical trial, a total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years; interquartile range, 55-74 years); 55.0% were male. The primary results have been published previously. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary composite end point were 0.75 (95% CI, 0.59-0.95) for adjudicator-assessed events and 0.76 (95% CI, 0.60-0.95) for investigator-assessed events. Agreement between adjudicator and investigator assessments was 90.7%. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary safety end point were 2.32 (95% CI, 1.10-4.87) for adjudicator-assessed events and 2.58 (95% CI, 1.19-5.58) for investigator-assessed events, with an agreement rate of 77.5%. Conclusions and Relevance: Independent end point adjudication did not substantially alter estimates of the primary treatment effectiveness in the POINT trial. Trial Registration: ClinicalTrials.gov identifier: NCT00991029.

Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source.

BACKGROUND: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. METHODS: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. RESULTS: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. CONCLUSIONS: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).

Stroke of Known Cause and Underlying Atrial Fibrillation (STROKE-AF) randomized trial: Design and rationale.

BACKGROUND: Approximately 20% of ischemic strokes are associated with clinically apparent atrial fibrillation (AF). Regardless of stroke etiology, detection of AF in patients with ischemic strokes often changes antithrombotic treatment from anti-platelet to oral anticoagulation therapy. The role and the optimum duration of cardiac monitoring to detect AF in patients with strokes presumed due to large vessel atherosclerosis or small vessel disease is unknown. This manuscript describes the design and rationale of the STROKE-AF trial. STUDY DESIGN: STROKE-AF is a randomized, controlled, open-label, post-market clinical trial. Detection of AF will be evaluated using continuous arrhythmia monitoring with an insertable cardiac monitor (ICM) compared with standard of care follow-up in patients with stroke (within the prior 10 days) that is presumed due to large vessel cervical or intracranial atherosclerosis, or to small vessel disease. Approximately 500 patients will be enrolled at approximately 40 centers in the United States. Patients will be randomized 1:1 to arrhythmia monitoring with an ICM (continuous monitoring arm) or standard of care follow-up (control arm). Subjects will be followed for ≥12 months and up to 3 years. OUTCOMES: The primary objective is to compare the incidence rate of detected AF through 12 months of follow-up between the two arms. CONCLUSION: This trial will provide information on the value of ICMs to detect subclinical AF in patients with stroke presumed due to large vessel atherosclerosis or small vessel disease, which will have implications for guiding treatment with oral anticoagulation for secondary stroke prevention.

The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors.

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti-hyperglycaemic medications have been associated with a concern for worse HF outcomes. More recently, the results of the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 38% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease [Correction added on 8 September 2017, after first online publication: "32%" in the previous sentence was corrected to "38%"]. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate.

A resident boot camp for reducing door-to-needle times at academic medical centers.

BACKGROUND: We sought to determine if a structured educational program for neurology residents can lower door-to-needle (DTN) times at an academic institution. METHODS: A neurology resident educational stroke boot camp was developed and implemented in April 2013. Using a prospective database of 170 consecutive acute ischemic stroke (AIS) patients treated with IV tissue plasminogen activator (tPA) in our emergency department (ED), we evaluated the effect of the intervention on DTN times. We compared DTN times and other process measures preintervention and postintervention. p Values < 0.05 were considered significant. RESULTS: The proportion of AIS patients treated with tPA within 60 minutes of arrival to our ED tripled from 18.1% preintervention to 61.2% postintervention (p < 0.001) with concomitant reduction in DTN time (median 79 minutes vs 58 minutes, p < 0.001). The resident-delegated task (stroke code to tPA) was reduced (75 minutes vs 44 minutes, p < 0.001), while there was no difference in ED-delegated tasks (door to stroke code [7 minutes vs 6 minutes, p = 0.631], door to CT [18 minutes in both groups, p = 0.547]). There was an increase in stroke mimics treated (6.9% vs 18.4%, p = 0.031), which did not lead to an increase in adverse outcomes. CONCLUSIONS: DTN times were reduced after the implementation of a stroke boot camp and were driven primarily by efficient resident stroke code management. Educational programs should be developed for health care providers involved in acute stroke patient care to improve rapid access to IV tPA at academic institutions.

Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .).

Management of Hand Fractures: Simple to Complex.

Hand fractures are among the most common skeletal injuries. Approximately 150,000 hand fractures occur in the United States each year. The management of hand fractures consists of reduction, immobilization, and rehabilitation to return patients to their preinjury status. Hand fractures are managed by restoring articular congruity, reducing malrotation and angulation of the fracture, and maintaining the reduction, all of which should be accomplished with minimal surgical intervention. Surgeons must assess concomitant soft-tissue injuries and respect the soft tissues during the surgical management of hand fractures. Fractures through the metaphyseal bone at the base and neck will heal more quickly than fractures through the diaphyseal bone of the shaft, which makes provisional fixation of metaphyseal fractures more practical compared with provisional fixation of diaphyseal fractures. The fracture pattern determines the most practical type of fixation. Patterns of angulation should be anticipated and corrected during reduction. More rigid fixation is required if substantial comminution and bone loss are present. Bone loss also indicates a high-energy injury, which likely indicates more substantial soft-tissue injury. As the number of injured structures increases, the likelihood of full function after rehabilitation decreases.

Cryptogenic Stroke: Research and Practice.

BACKGROUND: Cryptogenic stroke accounts for 30% to 40% of ischemic stroke. It is essential to determine the possible culprit because this will improve secondary stroke prevention strategies. METHODS: We performed a narrative nonsystematic review of the literature that included randomized trials, exploratory comparative studies, and case series on cryptogenic stroke. RESULTS: There are several possible mechanisms implicated in cryptogenic stroke, including occult paroxysmal atrial fibrillation, patent foramen ovale, aortic arch atherosclerosis, atrial cardiopathy, and substenotic atherosclerosis. The heterogeneity of these mechanisms leads to differences in stroke prevention strategies among cryptogenic stroke patients. CONCLUSIONS: A thorough diagnostic evaluation is essential to determine the pathogenesis in cryptogenic stroke. This approach, in addition to risk factor management and lifestyle modifications, will lead to improved stroke prevention strategies in patients with cryptogenic stroke. This will allow for targeted clinical trials to improve stroke prevention strategies in this patient population.