Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study.

BACKGROUND: Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal. METHODS AND RESULTS: In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (≤1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8-20.0) for the 4F-PCC group and 3.60 (1.9-38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, -5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event. CONCLUSIONS: 4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00708435.

Real-World Safety and Effectiveness of a 4-Factor Prothrombin Complex Concentrate in Japanese Patients Experiencing Major Bleeding: A Post-marketing Surveillance Study.

INTRODUCTION: Limited data are available regarding the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) in patients experiencing major hemorrhage or requiring expeditious surgical intervention, both globally and within Japan. METHODS: We executed a prospective, observational post-marketing surveillance study of patients receiving 4F-PCC for the first time between September 19, 2017 and August 15, 2018 in Japan. Patients were subjected to a comprehensive follow-up for a duration of 4 weeks. RESULTS: Of 1381 eligible patients, 1271 (92%) received a vitamin K antagonist. Among these, 58% were aged ≥ 75 years, 49% manifested atrial fibrillation, 17% presented with valvular heart disease, and 6% exhibited venous thromboembolism. The median (range) international normalized ratio was 2.67 (0.96-27.11) at baseline and 1.21 (0.45-6.61) at first measurement post-administration of 4F-PCC. The most common reason for 4F-PCC administration was intracranial hemorrhage (59.6%), followed by gastrointestinal bleeding (6.6%). Hemostatic effectiveness was achieved in 85.8% of patients. The incidences of adverse drug reactions (ADRs) and serious ADRs were 3.9% and 2.8%, respectively. Thromboembolic events (TEEs) occurred in 20 (1.5%) patients, with a mean onset of 10 days. The majority of TEEs were classified as nervous system disorders (55%). At the time of TEE, only 13% of patients resumed anticoagulant therapy. CONCLUSION: The incidence of TEEs following treatment with 4F-PCC did not surpass those observed in phase 3 trials. No novel safety signals were identified. The safety and effectiveness of 4F-PCC in Japanese real-world practice were in harmony with the observations of prior studies.

A randomized controlled trial comparing intravenous ferric carboxymaltose with oral iron for treatment of iron deficiency anaemia of non-dialysis-dependent chronic kidney disease patients.

BACKGROUND: Iron deficiency is a common cause of anaemia and hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in non-dialysis-dependent chronic kidney disease (ND-CKD) patients. Current intravenous iron agents cannot be administered in a single high dose because of adverse effects. Ferric carboxymaltose, a non-dextran parenteral iron preparation, can be rapidly administered in high doses. METHODS: This open-label trial randomized 255 subjects with glomerular filtration rates ≤ 45 mL/min/1.73 m(2), haemoglobin ≤ 11 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL, and stable ESA dose to either intravenous ferric carboxymaltose 1000 mg over 15 min (with up to two additional doses of 500 mg at 2-week intervals) or oral ferrous sulphate 325 mg thrice daily for a total of 195 mg elemental iron daily for 56 days. RESULTS: In the modified intent-to-treat population, the proportion of subjects achieving a haemoglobin increase ≥ 1 g/dL at any time was 60.4% with ferric carboxymaltose and 34.7% with oral iron (P < 0.001). At Day 42, mean increase in haemoglobin was 0.95 ± 1.12 vs 0.50 ± 1.23 g/dL (P = 0.005), mean increase in ferritin was 432 ± 189 ng/mL vs 18 ± 45 ng/mL (P < 0.001) and mean increase in transferrin saturation was 13.6 ± 11.9% vs 6.1 ± 8.1% (P < 0.001). Treatment-related adverse events were significantly fewer with ferric carboxymaltose than with oral iron (2.7% and 26.2%, respectively; P < 0.0001). CONCLUSIONS: We conclude that 1000 mg ferric carboxymaltose can be rapidly administered, is more effective and is better tolerated than oral iron for treatment of iron deficiency in ND-CKD patients.

Pharmacometric modeling to explore 4F-PCC dosing strategies for VKA reversal in patients with INR below 2.

The indicated dose of 4-factor prothrombin complex concentrate (4F-PCC) for urgent vitamin K antagonist (VKA) reversal in patients with an international normalized ratio (INR) of 2 to 4 is 25 IU/kg, but there is no indicated dose for INR <2. We explored 4F-PCC dosing strategies for baseline INR <2. Clinical trial data were used to develop pharmacometric models for Factor X (FX) and FII, accounting for covariates including baseline INR. FX and FII levels over time were simulated for mean baseline INR levels of the clinical trial participants plus baseline INRs 3.1, 1.9, and 1.6. For each INR, 200 virtual male patients were simulated to evaluate 4F-PCC doses of 35, 25, 20, 15, 12.5, and 10 IU/kg. Given an elevated bleeding risk with VKA therapy in Japanese vs Western populations, results were stratified by Japanese and non-Japanese patients. Target levels of FX and FII were ≥50% activity at 30 minutes after dosing in ≥80% of patients. FX- and FII-time models were developed with 1088 FX observations from 193 patients and 1074 FII observations from 192 patients. Model-based simulations indicated that at baseline INR 3.1, ≥80% of patients achieved ≥50% FX and FII activity with 25 IU/kg and 20 IU/kg 4F-PCC, respectively; at baseline INR 1.9, corresponding doses were 20 IU/kg and 15 IU/kg 4F-PCC, and at baseline INR 1.6, corresponding doses were 15 IU/kg, and 10 IU/kg 4F-PCC. Trends in Japanese and non-Japanese patients were similar. In conclusion, low 4F-PCC doses (15-20 IU/kg) may be sufficient to achieve hemostatic levels of FX and FII in Japanese and non-Japanese patients with baseline INR <2.

Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial.

BACKGROUND: The objective was to evaluate efficacy and safety of rapid, large-dose intravenous (IV) administration of ferric carboxymaltose compared to oral iron in correcting iron deficiency anemia due to heavy uterine bleeding. STUDY DESIGN AND METHODS: In a randomized, controlled trial, 477 women with anemia, iron deficiency, and heavy uterine bleeding were assigned to receive either IV ferric carboxymaltose (or= 12 g/dL) of anemia (73% vs. 50%, p < 0.001). Patients treated with ferric carboxymaltose compared to those prescribed ferrous sulfate reported greater gains in vitality and physical function and experienced greater improvement in symptoms of fatigue (p < 0.05). There were no serious adverse drug events. CONCLUSIONS: In patients with iron deficiency anemia due to heavy uterine bleeding, rapid IV administration of large doses of a new iron agent, ferric carboxymaltose, is more effective than oral iron therapy in correcting anemia, replenishing iron stores, and improving quality of life.

Assessment of the prevalence and impact of anemia on women hospitalized for gynecologic conditions associated with heavy uterine bleeding.

OBJECTIVE: Women with heavy uterine bleeding often are untreated or inadequately treated for anemia. This study was conducted to estimate the prevalence and impact of anemia in women hospitalized for gynecologic conditions associated with heavy uterine bleeding. STUDY DESIGN: The largest all-payer inpatient care database, the Healthcare Cost and Utilization Project's 2003 Nationwide Inpatient Sample, was queried using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify and group women with gynecologic diagnoses associated with heavy uterine bleeding into 2 categories: those with or without anemia. Groups were evaluated for demographic characteristics, medical resource utilization and hospitalization costs using descriptive statistics. RESULTS: More than 25% of the estimated 300,589 women in the study had a diagnosis of anemia. Compared to patients without a diagnosis of anemia, those with an anemia diagnosis were more likely to have a blood transfusion (24% vs. 0.7%, p<0.0001), an emergency department admission (26.8% vs. 3.2%, p<0.0001) and higher hospitalization costs ($5,631 vs. $5,101, p <0.0001). CONCLUSIONS: Anemia and blood transfusions are common in women hospitalized for gynecologic conditions associated with heavy uterine bleeding. Greater patient and provider awareness of the prevalence and burden associated with anemia may increase opportunities to reduce blood transfusions and improve general health status and quality of life in this patient population.

Intravenous ferric carboxymaltose compared with oral iron in the treatment of postpartum anemia: a randomized controlled trial.

OBJECTIVE: To estimate efficacy of rapid, large-dose intravenous (IV) administration of ferric carboxymaltose compared with oral iron therapy in anemic postpartum women. METHODS: In a randomized, controlled trial, we assigned anemic women (hemoglobin [Hb] less than or equal to 10 g/dL) within 10 days postpartum to receive either IV ferric carboxymaltose (less than or equal to 1,000 mg over 15 minutes, repeated weekly to achieve a total calculated replacement dose) or ferrous sulfate (FeSO(4)) 325 mg orally thrice daily for 6 weeks. RESULTS: One hundred seventy-four patients received 350 IV doses of ferric carboxymaltose (mean total dose 1,403.1 mg) in 3, 2, or 1 injection (10.9%, 79.3%, or 9.8% of patients, respectively); 178 received FeSO(4). Patients assigned to IV ferric carboxymaltose compared with those assigned to oral iron achieved a Hb rise greater than or equal to 2.0 g/dL earlier (7.0 compared with 14.0 days, P<.001), were more likely to achieve a Hb rise greater than or equal to 3.0 g/dL at any time (86.3% compared with 60.4%, P<.001), and were more likely to achieve a Hb greater than 12.0 g/dL (90.5% compared with 68.6%, P<.001). A similar proportion of patients achieved a Hb rise greater than or equal to 2.0 g/dL (96.4% compared with 94.1%, IV compared with oral, P=.443). There were no serious adverse drug reactions. CONCLUSION: Large-dose IV ferric carboxymaltose administration is a new iron agent that is effective for the treatment of postpartum anemia. When compared with oral ferrous sulfate, IV ferric carboxymaltose is better tolerated, prompts a more rapid Hb response, and corrects anemia more reliably. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00396292 LEVEL OF EVIDENCE: I.

Safety of a Four-factor Prothrombin Complex Concentrate Versus Plasma for Vitamin K Antagonist Reversal: An Integrated Analysis of Two Phase IIIb Clinical Trials.

OBJECTIVES: Clinicians often need to rapidly reverse vitamin K antagonists (VKAs) in the setting of major hemorrhage or urgent need for surgery. Little is known about the safety profile of the traditional reversal agent, plasma, or the newly approved agent, four-factor prothrombin complex concentrate (4F-PCC), in a randomized setting. This is an integrated analysis of safety data from two clinical trials that evaluated 4F-PCC versus plasma for the treatment of patients requiring rapid VKA reversal for acute major bleeding or prior to an urgent surgical/invasive procedure. METHODS: This descriptive analysis comprised adverse event (AE) data from two phase IIIb, randomized, controlled trials. The bleeding and surgical studies were performed across 36 and 33 sites, respectively, in nine countries, with the integrated analysis comprising 388 patients (4F-PCC, n = 191; plasma, n = 197) aged ≥ 18 years, who required VKA reversal due to major bleeding or prior to an urgent surgical/invasive procedure. Patients received either 4F-PCC, containing nonactivated factors II, VII, IX, and X and proteins C and S (Beriplex/Kcentra, CSL Behring) or plasma, both dosed according to baseline international normalized ratio and body weight. Patients were also to receive vitamin K1. AEs and serious AEs (SAEs) were assessed up to days 10 and 45, respectively. RESULTS: The proportion of patients with AEs (4F-PCC, 115/191 [60.2%]; plasma, 124/197 [62.9%]) and SAEs (4F-PCC, 54/191 [28.3%]; plasma, 49/197 [24.9%]) was similar between groups. The proportion of patients with thromboembolic events was also similar between groups (4F-PCC, 14/191 [7.3%]; plasma, 14/197 [7.1%]). There were 13 (6.8%) deaths in the 4F-PCC group and 13 (6.6%) in the plasma group. Fluid overload events occurred in more patients in the plasma group than the 4F-PCC group (25 [12.7%] and 9 [4.7%], respectively). CONCLUSIONS: These safety data represent the largest controlled assessment of a 4F-PCC to date. For patients requiring urgent VKA reversal, 4F-PCC had a safety profile similar to that of plasma (AEs, SAEs, thromboembolic events, and deaths), but was associated with fewer fluid overload events.

Biochemical and clinical predictors of long-term outcome in patients with nonspecific chest pain and nondiagnostic electrocardiograms.

BACKGROUND: There are few data assessing the relative value of clinical factors and sensitive cardiac markers in determining the long-term prognosis of patients with chest pain. Likewise, little information exists about the long-term outcome of patients with chest pain who have negative markers of myocardial cell necrosis. This study addresses these issues in a cohort of patients with nonspecific chest pain and nondiagnostic electrocardiograms (ECGs). METHODS: Eligible subjects (n = 501) had experienced >15 minutes chest pain at rest during the previous 24 hours, but were found to be at low-risk for acute myocardial infarction (AMI) by means of a well-validated clinical algorithm. Cardiac troponin I, creatine kinase MB(mass), myoglobin, and myosin light chain-1 were collected at presentation and 3, 6, and 12 hours later. Patients were observed for a median of 31 months. The composite end point was death or AMI subsequent to the index admission. RESULTS: Cardiac troponin I was the best single biochemical predictor of outcome (risk ratio 2.34, 95% CI 1.31-4.17, P =.004), but was of less independent prognostic value than age and an abnormal presenting ECG. It was also inferior to a combination strategy, using all 4 markers tested (risk ratio 2.37, 95% CI 1.44-3.91, P <.001). Fifty of 428 patients (12%) with a cardiac troponin I level < or =0.2 ng/mL and 25 of 287 patients (9%) without elevation of any marker tested sustained an adverse event during follow-up. CONCLUSIONS: Cardiac troponin I is the most useful single biochemical predictor of long-term outcome, but the best determinants are age, an abnormal presenting ECG, and an "any marker positive" strategy. Patients without elevated cardiac markers have an adverse event rate of approximately 10% in the subsequent 31 months.

Elevated soluble P-selectin levels are associated with an increased risk of early adverse events in patients with presumed myocardial ischemia.

BACKGROUND: Cell adhesion molecules (CAMs) play a pivotal role in the interactions between leukocytes, platelets, and vascular endothelium. Soluble CAMs (sCAMs) are shed from cell surfaces and reflect cellular activation. Elevated levels of sCAMs have been reported in the acute coronary syndromes. We hypothesized, therefore, that sCAMs might prove of prognostic value in patients with acute chest pain presumed to be the result of myocardial ischemia. METHODS: One hundred twenty-six consecutive patients with chest pain, thought clinically to represent myocardial ischemia, were studied prospectively. Soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin) and P-selectin (sP-selectin) levels were assayed at presentation, as were cardiac troponin I (cTnI) and creatine kinase-MB(mass) (CK-MB(mass)). The primary study end point was the occurrence of a serious cardiac event (SCE) during the index admission or the subsequent 3 months. RESULTS: sP-selectin and cTnI levels were significantly higher among patients who had an early SCE (P =.006 and P <.001, respectively). Both remained independently predictive (P <.001) in a multivariate regression equation. The other independent predictor was a history of vascular disease (P <.05). No other markers were significant predictors of early outcome. CONCLUSION: Elevated sP-selectin levels, but not those of other sCAMs, are predictors of early adverse events in patients with chest pain presumed caused by myocardial ischemia. Their utility in predicting the outcome of individual patients is, however, limited.

Treatment of chronic low back pain with etoricoxib, a new cyclo-oxygenase-2 selective inhibitor: improvement in pain and disability--a randomized, placebo-controlled, 3-month trial.

We evaluated etoricoxib, a novel COX-2-specific inhibitor, in 319 patients with chronic low back pain (LBP) in this double-blind, placebo-controlled trial. Patients were randomized to a 60 mg dose (n = 103) or 90 mg dose (n = 107) of etoricoxib, or placebo (n = 109), daily for 12 weeks. The primary endpoint was low back pain intensity scale (Visual Analog Scale of 0- to 100-mm) time-weighted average change from baseline over 4 weeks. Other endpoints included evaluation over 3 months of low back pain intensity scale, Roland-Morris Disability Questionnaire (RMDQ), low back pain bothersomeness scale, patient- and investigator-global assessments, Patient Health Survey (MOS SF-12), rescue acetaminophen use, and discontinuation due to lack of efficacy. Etoricoxib provided significant improvement from baseline versus placebo in pain intensity (4 weeks: 12.9 mm and 10.3 mm for 60-mg and 90-mg doses, P <.001 for each; 12 weeks: 10.5 mm and 7.5 mm for 60-mg and 90-mg doses, P =.001 and.018, respectively). Etoricoxib at either dose led to significant improvement in other endpoints, including RMDQ scores, bothersomeness scores and global assessments. Etoricoxib given once daily provided significant relief of symptoms, and disability associated with chronic LBP that was observed 1 week after initiating therapy, was maximal at 4 weeks, and was maintained over 3 months.

The relative utility of cardiac troponin I, creatine kinase-MBmass, and myosin light chain-1 in the long-term risk stratification of patients with chest pain.

BACKGROUND: Sensitive and specific cardiac markers convey important short-term prognostic information about patients with an acute coronary syndrome. There are, however, few data assessing their value as long-term predictors. HYPOTHESIS: The aim of the current study was to assess the relative value of three such markers and clinical characteristics in determining the long-term prognosis of patients with chest pain. METHODS: Cardiac troponin I (cTnI), myosin light chain-(MLC-1), and creatine kinase-MBmass levels were obtained on admission (0 h) and at 4, 8, 16, and 24 h in 208 patients with chest pain. Eligible subjects were determined, at the time of hospital admission, to be at >7% risk of acute myocardial infarction (MI), but without new ST-segment elevation on their presenting electrocardiogram. Follow-up was performed a median of 28 (range 1-46) months later. The primary study endpoint was death or nonfatal MI, subsequent to the index admission. RESULTS: Cardiac TnI levels > or = 0.2 ng/ml (odds ratio [OR] 1.93, 95% confidence interval [CI] 1.09-3.40) and MLC-1 levels > or = 1 ng/ml (OR 3.24, 95% CI 1.83-5.73) were both significant predictors of death or MI during long-term follow-up; MLC-1 was, however, the only independent biochemical predictor (OR 2.11,95% CI 1.14-3.93). CONCLUSIONS: Both cTnl and MLC-1 predict the long-term outcome of patients with chest pain, but, in this cohort, MLC-1 proved to be a better predictor of mortality and nonfatal acute MI.

Comparison of linear-stochastic and nonlinear-deterministic algorithms in the analysis of 15-minute clinical ECGs to predict risk of arrhythmic death.

OBJECTIVE: Comparative algorithmic evaluation of heartbeat series in low-to-high risk cardiac patients for the prospective prediction of risk of arrhythmic death (AD). BACKGROUND: Heartbeat variation reflects cardiac autonomic function and risk of AD. Indices based on linear stochastic models are independent risk factors for AD in post-myocardial infarction (post-MI) cohorts. Indices based on nonlinear deterministic models have superior predictability in retrospective data. METHODS: Patients were enrolled (N = 397) in three emergency departments upon presenting with chest pain and were determined to be at low-to-high risk of acute MI (>7%). Brief ECGs were recorded (15 min) and R-R intervals assessed by three nonlinear algorithms (PD2i, DFA, and ApEn) and four conventional linear-stochastic measures (SDNN, MNN, 1/f-Slope, LF/HF). Out-of-hospital AD was determined by modified Hinkle-Thaler criteria. RESULTS: All-cause mortality at one-year follow-up was 10.3%, with 7.7% adjudicated to be AD. The sensitivity and relative risk for predicting AD was highest at all time-points for the nonlinear PD2i algorithm (p 100 (p 11.4 (p

An assessment of medical resource utilization and hospitalization cost associated with a diagnosis of anemia in women with obstetrical bleeding in the United States.

OBJECTIVE: Anemia during pregnancy has been associated with adverse maternal and fetal outcomes. Although women with obstetrical bleeding are at increased risk for developing anemia, little is known about the prevalence and burden associated with anemia in hospitalized women with this condition. This study was conducted to estimate the prevalence, demographic characteristics, medical resource utilization, and hospitalization cost associated with a diagnosis of anemia in hospitalized women with obstetrical bleeding in the United States. METHODS: The Healthcare Cost and Utilization Project Nationwide Inpatient Sample (2003) was queried using ICD-9-CM codes to identify all pregnancy-related discharges as well as discharges with diagnosis codes for conditions associated with obstetrical bleeding. Descriptive statistics were used to evaluate demographic characteristics, medical resource utilization components and hospitalization cost for two groups: patients with a diagnosis of anemia and patients without a diagnosis of anemia. RESULTS: Of the estimated 4,525,714 pregnancy-related discharges in the United States in 2003, more than 250,000 recorded diagnosis codes associated with obstetrical bleeding. Nearly 1 in 5 of these women had an anemia diagnosis. A diagnosis of anemia in hospitalized women with obstetrical bleeding was associated with a 9-fold increase in blood transfusion (p < 0.0001), 33% longer average length of stay (p < 0.0001), and 50% higher average total cost per hospitalization (p < 0.0001). CONCLUSIONS: Anemia and blood transfusion are frequently observed in hospitalized women with obstetrical bleeding. To improve outcomes in these patients and alleviate the adverse impact of anemia on postpartum health status, greater provider awareness of the prevalence and burden of illness associated with a diagnosis of anemia in hospitalized women with obstetrical bleeding is warranted.

Risk stratification for arrhythmic death in an emergency department cohort: a new method of nonlinear PD2i analysis of the ECG.

Heart rate variability (HRV) reflects both cardiac autonomic function and risk of sudden arrhythmic death (AD). Indices of HRV based on linear stochastic models are independent risk factors for AD in postmyocardial infarction (MI) cohorts. Indices based on nonlinear deterministic models have a higher sensitivity and specificity for predicting AD in retrospective data. A new nonlinear deterministic model, the automated Point Correlation Dimension (PD2i), was prospectively evaluated for prediction of AD. Patients were enrolled (N = 918) in 6 emergency departments (EDs) upon presentation with chest pain and being determined to be at risk of acute MI (AMI) >7%. Brief digital ECGs (>1000 heartbeats, approximately 15 min) were recorded and automated PD2i results obtained. Out-of-hospital AD was determined by modified Hinkle-Thaler criteria. All-cause mortality at 1 year was 6.2%, with 3.5% being ADs. Of the AD fatalities, 34% were without previous history of MI or diagnosis of AMI. The PD2i prediction of AD had sensitivity = 96%, specificity = 85%, negative predictive value = 99%, and relative risk >24.2 (p ≤ 0.001). HRV analysis by the time-dependent nonlinear PD2i algorithm can accurately predict risk of AD in an ED cohort and may have both life-saving and resource-saving implications for individual risk assessment.

Inflammatory cytokines provide limited early prognostic information in emergency department patients with suspected myocardial ischemia.

STUDY OBJECTIVE: The aim of this study was to assess the early prognostic value of the inflammatory cytokines interleukin 6, interleukin 8, and tumor necrosis factor alpha in a cohort of emergency department (ED) patients with chest pain who have suspected myocardial ischemia. METHODS: One hundred eighteen patients with chest pain presenting to 2 urban EDs were studied. Interleukin 6, interleukin 8, and tumor necrosis factor alpha levels were assayed at presentation. The end point was the occurrence of a serious cardiac event (death, nonfatal acute myocardial infarction, myocardial revascularization, or readmission with an acute coronary syndrome) during the index admission or subsequent 3 months. RESULTS: Mean levels of all 3 cytokines were higher among patients experiencing a serious cardiac event, with the greatest differences observed in levels of interleukin 6 (mean 2.5 pg/mL [95% confidence interval (CI) 1.2 to 3.7 pg/mL] versus mean 9.8 pg/mL [95% CI 2.4 to 17.2 pg/mL]). Interleukin 6 had a sensitivity of 35% (95% CI 20% to 54%), a specificity of 86% (95% CI 76% to 92%), and an overall prognostic accuracy of 71% (95% CI 63% to 79%) for predicting serious cardiac events. However, logistic regression analysis revealed that the only independent predictor of an adverse outcome was an ECG suggestive of ischemia at presentation. CONCLUSION: Among patients presenting to the ED with suspected myocardial ischemia, higher levels of inflammatory cytokines are associated with an increased risk of a serious cardiac event during the subsequent 3 months. There is, however, considerable overlap in levels among patients who do and do not have a serious cardiac event, limiting their utility as predictors of outcome in individual patients.