M. Fernanda Bellolio

Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation

Background The introduction of non–vitamin K antagonist oral anticoagulants has been a major advance for stroke prevention in atrial fibrillation; however, outcomes achieved in clinical trials may not translate to routine practice. We aimed to evaluate the effectiveness and safety of dabigatran, rivaroxaban, and apixaban by comparing each agent with warfarin. Methods and Results Using a large US insurance database, we identified privately insured and Medicare Advantage patients with nonvalvular atrial fibrillation who were users of apixaban, dabigatran, rivaroxaban, or warfarin between October 1, 2010, and June 30, 2015. We created 3 matched cohorts using 1:1 propensity score matching: apixaban versus warfarin (n=15 390), dabigatran versus warfarin (n=28 614), and rivaroxaban versus warfarin (n=32 350). Using Cox proportional hazards regression, we found that for stroke or systemic embolism, apixaban was associated with lower risk (hazard ratio [HR] 0.67, 95% CI 0.46–0.98, P=0.04), but dabigatran and rivaroxaban were associated with a similar risk (dabigatran: HR 0.98, 95% CI 0.76–1.26, P=0.98; rivaroxaban: HR 0.93, 95% CI 0.72–1.19, P=0.56). For major bleeding, apixaban and dabigatran were associated with lower risk (apixaban: HR 0.45, 95% CI 0.34–0.59, P<0.001; dabigatran: HR 0.79, 95% CI 0.67–0.94, P<0.01), and rivaroxaban was associated with a similar risk (HR 1.04, 95% CI 0.90–1.20], P=0.60). All non–vitamin K antagonist oral anticoagulants were associated with a lower risk of intracranial bleeding. Conclusions In patients with nonvalvular atrial fibrillation, apixaban was associated with lower risks of both stroke and major bleeding, dabigatran was associated with similar risk of stroke but lower risk of major bleeding, and rivaroxaban was associated with similar risks of both stroke and major bleeding in comparison to warfarin.

Matrix Metalloproteinase-9 as a Marker for Acute Ischemic Stroke: A Systematic Review

Matrix metalloproteinase-9 (MMP-9) is a possible marker for acute ischemic stroke (AIS). In animal models of cerebral ischemia, MMP expression was significantly increased and was related to blood-brain barrier disruption, vasogenic edema formation, and hemorrhagic transformation. The definition of the exact role of MMPs after ischemic stroke will have important diagnostic implications for stroke and for the development of therapeutic strategies aimed at modulating MMPs. The objectives of the present study were to determine (1) whether MMP-9 is a possible marker for AIS; (2) whether MMP-9 levels correlate with infarct volume, stroke severity, or functional outcome; and (3) whether MMP-9 levels correlate with the development of hemorrhagic transformation after tissue plasminogen activator (t-PA) administration. The literature was searched using MEDLINE and EMBASE with no year restriction. All relevant reports were included. A total of 22 studies (3,289 patients) satisfied the inclusion criteria. Our review revealed that higher MMP-9 values were significantly correlated with larger infarct volume, severity of stroke, and worse functional outcome. There were significant differences in MMP-9 levels between patients with AIS and healthy control subjects. Moreover, MMP-9 was a predictor of the development of intracerebral hemorrhage in patients treated with thrombolytic therapy. MMP-9 level was significantly increased after stroke onset, with the level correlating with infarct volume, stroke severity, and functional outcome. MMP-9 is a possible marker for ongoing brain ischemia, as well as a predictor of hemorrhage in patients treated with t-PA.

Accuracy and Quality of Clinical Decision Rules for Syncope in the Emergency Department: A Systematic Review and Meta-analysis

STUDY OBJECTIVE We assess the methodological quality and prognostic accuracy of clinical decision rules in emergency department (ED) syncope patients. METHODS We searched 6 electronic databases, reviewed reference lists of included studies, and contacted content experts to identify articles for review. Studies that derived or validated clinical decision rules in ED syncope patients were included. Two reviewers independently screened records for relevance, selected studies for inclusion, assessed study quality, and abstracted data. Random-effects meta-analysis was used to pool diagnostic performance estimates across studies that derived or validated the same clinical decision rule. Between-study heterogeneity was assessed with the I(2) statistic, and subgroup hypotheses were tested with a test of interaction. RESULTS We identified 18 eligible studies. Deficiencies in outcome (blinding) and interrater reliability assessment were the most common methodological weaknesses. Meta-analysis of the San Francisco Syncope Rule (sensitivity 86% [95% confidence interval {CI} 83% to 89%]; specificity 49% [95% CI 48% to 51%]) and the Osservatorio Epidemiologico sulla Sincope nel Lazio risk score (sensitivity 95% [95% CI 88% to 98%]; specificity 31% [95% CI 29% to 34%]). Subgroup analysis identified study design (prospective, diagnostic odds ratio 8.82 [95% CI 3.5 to 22] versus retrospective, diagnostic odds ratio 2.45 [95% CI 0.96 to 6.21]) and ECG determination (by evaluating physician, diagnostic odds ratio 25.5 [95% CI 4.41 to 148] versus researcher or cardiologist, diagnostic odds ratio 4 [95% CI 2.15 to 7.55]) as potential explanations for the variability in San Francisco Syncope Rule performance. CONCLUSION The methodological quality and prognostic accuracy of clinical decision rules for syncope are limited. Differences in study design and ECG interpretation may account for the variable prognostic performance of the San Francisco Syncope Rule when validated in different practice settings.

Epinephrine in Anaphylaxis: Higher Risk of Cardiovascular Complications and Overdose After Administration of Intravenous Bolus Epinephrine Compared with Intramuscular Epinephrine

BACKGROUND Epinephrine is the drug of choice for the management of anaphylaxis, and fatal anaphylaxis is associated with delayed epinephrine administration. Data on adverse cardiovascular (CV) complications and epinephrine overdose are limited. OBJECTIVE To compare rates of CV adverse events and epinephrine overdoses associated with anaphylaxis management between various routes of epinephrine administration among patients with anaphylaxis in the emergency department. METHODS This was an observational cohort study from April 2008 to July 2012. Patients in the emergency department who met diagnostic criteria for anaphylaxis were included. We collected demographics; route of epinephrine administration; trigger; overdose; and adverse CV events, including arrhythmia, cardiac ischemia, stroke, angina, and hypertension. RESULTS The study cohort included 573 patients, of whom, 301 (57.6%) received at least 1 dose of epinephrine. A total of 362 doses of epinephrine were administered to 301 patients: 67.7% intramuscular (IM) autoinjector, 19.6% IM injection, 8.3% subcutaneous injection, 3.3% intravenous (IV) bolus, and 1.1% IV continuous infusion. There were 8 CV adverse events and 4 overdoses with 8 different patients. All the overdoses occurred when epinephrine was administered IV bolus. Adverse CV events were associated with 3 of 30 doses of IV bolus epinephrine compared with 4 of 316 doses of IM epinephrine (10% vs 1.3%; odds ratio 8.7 [95% CI, 1.8-40.7], P = .006). Similarly, overdose occurred with 4 of 30 doses of IV bolus epinephrine compared with 0 of 316 doses of IM epinephrine (13.3% vs 0%; odds ratio 61.3 [95% CI, 7.5 to infinity], P < .001). CONCLUSION The risk of overdose and adverse CV events is significantly higher with IV bolus epinephrine administration. Analysis of the data supports the safety of IM epinephrine and a need for extreme caution and further education about IV bolus epinephrine in anaphylaxis.

Antihypertensive medication use is associated with increased organ system involvement and hospitalization in emergency department patients with anaphylaxis

BACKGROUND Risk factors for increased anaphylaxis severity are poorly understood. Angiotensin-converting enzyme (ACE) inhibitors have been associated with severe anaphylactic reactions in patients with hymenoptera venom allergy. Studies evaluating the association between beta-blockers and severe anaphylaxis have been conflicting. OBJECTIVE To evaluate the association between antihypertensive medication use and increased anaphylaxis severity. METHODS We included emergency department anaphylaxis patients aged 18 years and older. Markers of severe anaphylaxis were defined as (1) syncope, hypotension, or hypoxia; (2) signs and symptoms involving 3 or more organ systems; and (3) hospitalization. Antihypertensive medications evaluated included beta-blockers, ACE inhibitors, calcium channel blockers, angiotensin receptor blockers, and diuretics. Simple and multiple logistic regression analyses were conducted to estimate the association between antihypertensive medication use and markers of increased anaphylaxis severity. RESULTS Among 302 patients with anaphylaxis, 55 (18%) had syncope, hypoxia, or hypotension, 57 (19%) required hospitalization, and 139 (46%) had 3 or more organ system involvement. After adjusting for age, gender, suspected trigger, and preexisting lung disease, beta-blocker, ACE-inhibitor, diuretic, or antihypertensive medication use in aggregate remained associated with both 3 or more organ system involvement and need for hospital admission. The adjusted associations between antihypertensive medication use in aggregate and 3 or more organ system involvement yielded an odds ratio of 2.8 (95% CI, 1.5-5.2; P=.0008) and with hospitalization an odds ratio of 4.0 (95% CI, 1.9-8.4; P=.0001). CONCLUSIONS In emergency department anaphylaxis patients, antihypertensive medication use is associated with increased organ system involvement and increased odds of hospital admission, independent of age, gender, suspected trigger, or preexisting lung disease.

Factors associated with repeated use of epinephrine for the treatment of anaphylaxis

BACKGROUND Studies looking at the use of repeated doses of epinephrine in patients experiencing anaphylaxis are limited. OBJECTIVE To determine which patients are most likely to receive repeated doses of epinephrine during anaphylaxis management. METHODS A population-based study with medical record review was conducted. All patients seen during the study period who met the criteria for the diagnosis of anaphylaxis were included. RESULTS The cohort included 208 patients (55.8% female). Anaphylaxis treatment included epinephrine in 104 patients (50.0%). Repeated doses were used in 27 patients (13.0%), 13 (48.1%) of them female. The median age of those who received repeated doses was 18.9 (interquartile range, 10-34) years vs 31.1 (interquartile range, 15-41) years for those who did not receive repeated doses (P = .06). The inciting agents were food (29.6%), insects (11.1%), medications (22.2%), others (7.4%), and unknown (29.6%). Patients who received repeated doses were more likely to have wheezing (P = .03), cyanosis (P = .001), hypotension and shock (P = .03), stridor and laryngeal edema (P = .007), nausea and emesis (P = .04), arrhythmias (P < .01), and cough (P = .04) and less likely to have urticaria (P = .049). They were more likely to be admitted to the hospital than patients who did not receive repeated doses (48.2% vs 15.6%; P < .001). There was no significant difference in the history of asthma between patients who received repeated doses and those who did not (P = .17). CONCLUSIONS Of the patients, 13.0% received repeated epinephrine doses. Patients were younger and were likely to present with wheezing, cyanosis, arrhythmias, hypotension and shock, stridor, laryngeal edema, cough, nausea, and emesis and less likely to have urticaria. A history of asthma did not predict use of repeated doses of epinephrine. Our results help identify high-risk patients who may benefit from carrying more than 1 dose of epinephrine.

Percutaneous Clot Removal Devices in Acute Ischemic Stroke: A Systematic Review and Meta-analysis

We conducted a systematic review and meta-analysis of mechanical thrombectomy in the treatment of ischemic stroke and assessed factors for technical and clinical success and survival. We searched the literature using MEDLINE and EMBASE for January 1, 2000, through March 1, 2006. Studies were limited to those in human beings; there were no language or study design restrictions. Validity assessment was performed using the Newcastle-Ottawa Scale. The pooled cohort was compared with a historical cohort matched for sex, age, and National Institutes of Health Stroke Survey score. The search yielded 114 publications. Two authors determined inclusibility (interrater agreement, kappa = 0.94). Mean preprocedure National Institutes of Health Stroke Survey score was 20.4. The middle cerebral artery (36%) and the posterior circulation (38%) were the most frequently occluded areas. The clot was accessible in 85% of the patients. Hemorrhage occurred in 22% of the patients. Of 81 patients with concurrent thrombolysis, 18.5% had hemorrhage compared with 27.3% of 66 patients without thrombolysis (P = .21). Of the 126 patients with accessible clots, 36% had a good modified Rankin score (<or=2) and 29% died; in patients with inaccessible clots, 24% had a good modified Rankin score and 38% died. Factors associated with clinical success were younger age (P = .001) and lower National Institutes of Health Stroke Survey score at admission to the hospital (P = .001). Compared with a matched cohort, patients who received mechanical intervention were 14.8 times more likely to have a good modified Rankin score (95% confidence interval, 4.4-50.0; P < .001). Percutaneous mechanical embolectomy in the treatment of acute ischemic stroke is feasible and seems to provide an option for some patients seen after the interval for administration of intravenous tissue plasminogen activator therapy has elapsed.

Anaphylaxis in emergency department patients 50 or 65 years or older

BACKGROUND Anaphylaxis is a potentially life-threatening allergic reaction commonly managed in the emergency department (ED). Data describing patients 50 or 65 years or older with anaphylaxis are limited. OBJECTIVE To describe the presentation and management of patients with anaphylaxis who were 50 or 65 years or older and to compare these findings with those of younger patients. METHODS A consecutive cohort study of patients presenting to an ED with approximately 80,000 visits per year was conducted. Patients who met diagnostic criteria for anaphylaxis from April 2008 to June 2010 were included. Data were collected on suspected causes, signs and symptoms, management, ED disposition, and follow-up. RESULTS The study included 220 patients. Food was the most common suspected cause of anaphylaxis for patients younger than 50 (42.2%) or 65 years (38.5%) but was much less common in patients 50 (14.8%, P < .001) or 65 years or older (14.3%, P = .01). Cardiovascular symptoms were more likely to occur in older patients (≥50 years old, 55.6% vs 30.1%, P < .001; ≥65 years old, 64.3% vs 32.3%, P = .002). Patients 50 or 65 years or older were less likely to be dismissed home directly from the ED (≥50 years old, 35.2% vs 56.6%, P = .006; ≥65 years old, 32.1% vs 54.2%, P = .03) and were less likely to be prescribed self-injectable epinephrine (≥50 years old, 40.7% vs 63.3%, P = .004; ≥65 years old, 32.1% vs 61.5%, P = .003). CONCLUSIONS In ED patients presenting with anaphylaxis, age of 50 or 65 years or older is associated with a decreased likelihood of food-induced anaphylaxis, increased likelihood of experiencing cardiovascular symptoms, decreased dismissal to home directly from the ED, and decreased prescriptions for self-injectable epinephrine.

Worse Outcome after Stroke in Patients with Obstructive Sleep Apnea: An Observational Cohort Study

To evaluate the risk and presence of obstructive sleep apnea (OSA) in patients presenting with acute ischemic stroke, and examine the correlation of OSA with age, sex, ischemic stroke subtype, disability, and death, a prospective cohort study was conducted in all consecutive patients presenting with acute ischemic stroke between June 2007 and March 2008. Exclusion criteria were age < 18 years, refusal of consent for the study, and incomplete questionnaire. The Berlin Sleep Questionnaire was used to identify patients at high risk for OSA. A total of 174 patients with acute ischemic stroke were included; 130 (74.7%) had a modified Rankin Scale (mRS) score ≥ 3 at dismissal, and 11 patients (6.3%) died within 1 month. The Berlin Sleep Questionnaire identified 105 patients (60.4%) at high risk for OSA, along with 7 patients (4%) with a previous diagnosis of OSA. Those with a previous diagnosis of OSA were more likely to die within the first month after stroke (relative risk, 5.3; 95% confidence interval, 1.4-20.1) compared with those without OSA. Patients at high risk for OSA did not demonstrate increased mortality at 30 days (P = 1.0). In multivariate analysis, after adjusting for age and National Institutes of Health Stroke Scale score, previous diagnosis of OSA was an independent predictor of worse functional outcome, that is, worse mRS score at hospital discharge (P = .004). The mRS score was 1.2 points higher (adjusted R², 40%) in those with OSA. Our findings suggest that patients considered at high risk for ischemic stroke should be screened for OSA, the prevalence of which may be as high as 60%. Those with definitive diagnosis of OSA before stroke are at increased risk of death within the first month after an acute ischemic stroke.

Effect of anticoagulant and antiplatelet therapy in patients with spontaneous intra-cerebral hemorrhage: Does medication use predict worse outcome?

OBJECTIVES To assess the impact of anticoagulants and antiplatelet agents on the severity and outcome of spontaneous non-traumatic intra-cerebral hemorrhage (ICH). To evaluate associations between reversal of anticoagulation and mortality/morbidity in these patients. METHODS Data was collected on a consecutive cohort of adults presenting with ICH to an academic Emergency Department over a 3-year period starting January 2006. RESULTS The final cohort of 245 patients consisted of 125 females (51.1%). The median age of the cohort was 73 years [inter-quartile (IQR) range of 59-82 years]. Antiplatelet (AP) use was seen in 32.6%, 18.4% were using anticoagulant (AC) and 8.9% patients were on both drugs (AC+AP). Patients on AC had significantly higher INR (median 2.3) and aPTT (median 31 s) when compared to patients not on AP/AC (median INR 1.0, median aPTT 24s; p<0.001). Similarly patients on AC+AP also had higher INR (median 1.9) and aPTT (median 30s) when compared to those not on AC/AP (p<0.001). Hemorrhage volumes were significantly higher for patients on AC alone (median 64.7 cm(3)) when compared to those not on either AC/AP (median 27.2 cm(3); p=0.05). The same was not found for patients using AP (median volume 20.5 cm(3); p=0.813), or both AC+AP (median volume 27.7 cm(3); p=0.619). Patients on AC were 1.43 times higher at risk to have intra-ventricular extension of hemorrhage (IVE) as compared to patients not on AC/AP (95% CI 1.04-1.98; p=0.035). There was no relationship between the use of AC/AP/AC+AP and functional outcome of patients. Patients on AC were 1.74 times more likely to die within 7 days (95% CI 1.0-3.03; p=0.05). No relationship was found between use of AP or AC+AP use and mortality. Of the 82 patients with INR>1.0, 52 patients were given reversal (minimum INR 1.4, median 2.3). Therapy was heterogeneous, with fresh frozen plasma (FFP) being the most commonly used agent (86.5% patients, median dose 4U). Vitamin K, activated factor VIIa and platelets were the other agents used. Post reversal, INR normalized within 24h (median 1.2, IQR 1.1-1.3). There was no association between reversal and volume of hemorrhage, IVE, early mortality (death<7 days) or functional outcome. CONCLUSIONS Anticoagulated patients were at 1.7 times higher risk of early mortality after ICH. Reversal of INR to normal did not influence mortality or functional outcome.