Efficacy and safety of dilpacimab (ABT-165) versus bevacizumab plus FOLFIRI in metastatic colorectal cancer: a phase II study.

Aim: This phase II study investigated safety and efficacy of dilpacimab or bevacizumab plus FOLFIRI in patients with previously treated metastatic colorectal cancer (mCRC). Materials & methods: Overall, 66 patients were treated (n = 34 dilpacimab + FOLFIRI; n = 32 bevacizumab + FOLFIRI). Progression-free survival, overall survival, response rates and tolerability were assessed. Results: Median progression-free survival for dilpacimab + FOLFIRI compared with bevacizumab + FOLFIRI was 3.78 months (95% CI: 2.07-7.20) versus 7.36 months (95% CI: 5.68-10.55) (hazard ratio: 3.57; 95% CI: 1.57-8.11; stratified). Median overall survival: 7.95 months for dilpacimab + FOLFIRI; not reached for bevacizumab + FOLFIRI. Objective response rates: 5.6% for dilpacimab + FOLFIRI and 14.7% for bevacizumab + FOLFIRI. Patients treated with dilpacimab + FOLFIRI experienced serious treatment-related adverse events (n = 4; 11.8%), including one case of intestinal perforation leading to death; none were reported for bevacizumab + FOLFIRI. Conclusion: Treatment with dilpacimab + FOLFIRI was not well tolerated and did not provide clinical benefit to patients with mCRC compared with bevacizumab + FOLFIRI. Clinical Trial Registration: NCT03368859 (Clinicaltrials.gov).

Tenecteplase for the improvement of blood flow rate in dysfunctional hemodialysis catheters.

BACKGROUND: We evaluated the efficacy and safety of the thrombolytic agent tenecteplase for the treatment of dysfunctional hemodialysis (HD) catheters. METHODS: Data were pooled from 2 Phase III clinical studies: the randomized, placebo-controlled TROPICS 3 trial and the open-label TROPICS 4 trial. Eligible patients received either an initial dose of tenecteplase (2 mg/lumen) or placebo (TROPICS 3 only) for a 1-h intracatheter dwell. Treatment success was defined as blood flow rate (BFR) ≥ 300 ml/min and a ≥ 25 ml/min increase from baseline BFR, without line reversal, 30 min before and at the end of HD. All TROPICS 4 patients and the TROPICS 3 patients enrolled after the final protocol amendment without treatment success received an instillation of tenecteplase at the end of the initial visit for an extended dwell of up to 72 h. RESULTS: A total of 372 patients with dysfunctional catheters were enrolled in the 2 studies. Of the 297 patients treated with tenecteplase at the initial visit, 31% achieved treatment success, with a mean (SD) change from baseline BFR of 73 (120) ml/min. Among the 179 patients who received a 1-h dwell of study drug followed by extended-dwell tenecteplase, 46% had treatment success at the end of the next HD session. Six catheter-related bloodstream infections and 2 thromboses were reported in patients following tenecteplase exposure. CONCLUSION: Tenecteplase, administered as a 1-h dwell or a 1-h dwell followed by an extended dwell, was associated with improved BFR in dysfunctional HD catheters in the TROPICS 3 and 4 clinical trials.

A phase III, open-label, single-arm study of tenecteplase for restoration of function in dysfunctional central venous catheters.

PURPOSE: To evaluate, in a phase III, single-arm study, the safety and efficacy of the thrombolytic agent tenecteplase in restoring function to dysfunctional central venous catheters (CVCs). MATERIALS AND METHODS: Pediatric and adult patients with dysfunctional CVCs were eligible to receive as much as 2 mL (2 mg) of intraluminal tenecteplase, which was left to dwell in the CVC lumen for a maximum of 120 minutes. If CVC function was not restored at 120 minutes, a second dose was instilled for an additional 120 minutes. RESULTS: Tenecteplase was administered to 246 patients. Mean patient age was 44 years (range, 0-92 y); 72 patients (29%) were younger than 17 years of age. Chemotherapy was the most common reason for catheter insertion. Restoration of CVC function was achieved in 177 patients (72%) within 120 minutes after the first dose. After instillation of a maximum of two doses of tenecteplase, CVC function was restored in 200 patients (81%), with similar frequencies in pediatric (83%) and adult (80%) patients. Adverse events (AEs) were reported in 31 patients (13%); fever (2%), neutropenia (1%), and nausea (0.8%) were most common. One serious AE, an allergic hypersensitivity reaction, was judged to be related to tenecteplase and/or a chemotherapeutic agent that the patient was receiving concurrently. CONCLUSIONS: Consecutive administration of one or two doses of tenecteplase into CVCs showed efficacy in the restoration of catheter function in patients with dysfunctional CVCs.

Improvement of hemodialysis catheter function with tenecteplase: a phase III, open-label study: TROPICS 4.

Hemodialysis (HD) catheters are prone to thrombotic occlusion. We evaluated tenecteplase, a thrombolytic, for the treatment of dysfunctional HD catheters. Patients with tunneled HD catheters and blood flow rate (BFR) <300 mL/min received open-label tenecteplase (2 mg/lumen) for a 1 h intracatheter dwell. Treatment success was defined as BFR ≥ 300 mL/min and a ≥ 25 mL/min increase from baseline BFR, 30 min before and at the end of HD. Patients without treatment success at the end of the initial visit received another 2 mg dose of tenecteplase for an up to 72 h extended dwell. Of 223 enrolled patients, 34% (95% confidence interval [CI], 28-40%) had treatment success after a 1 h dwell. Mean (standard deviation [SD]) BFR change from baseline was 82 (124) mL/min. Treatment success in those who received extended-dwell tenecteplase (n = 116) was 49% (95% CI, 40-58%), with mean (SD) BFR change from baseline of 117 (140) mL/min. Reported targeted adverse events included five catheter-related bloodstream infections and one thrombosis. No intracranial hemorrhage, major bleeding, embolic events, or catheter-related complications were reported. Tenecteplase administered as a 1 h or 1 h plus extended dwell was associated with improved HD catheter function in the TROPICS 4 trial.

Phase I Open-Label Study Evaluating the Safety, Pharmacokinetics, and Preliminary Efficacy of Dilpacimab in Patients with Advanced Solid Tumors.

Dilpacimab (formerly ABT-165), a novel dual-variable domain immunoglobulin, targets both delta-like ligand 4 (DLL4) and VEGF pathways. Here, we present safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data from a phase I study (trial registration ID: NCT01946074) of dilpacimab in patients with advanced solid tumors. Eligible patients (≥18 years) received dilpacimab intravenously on days 1 and 15 in 28-day cycles at escalating dose levels (range, 1.25-7.5 mg/kg) until progressive disease or unacceptable toxicity. As of August 2018, 55 patients with solid tumors were enrolled in the dilpacimab monotherapy dose-escalation and dose-expansion cohorts. The most common treatment-related adverse events (TRAE) included hypertension (60.0%), headache (30.9%), and fatigue (21.8%). A TRAE of special interest was gastrointestinal perforation, occurring in 2 patients (3.6%; 1 with ovarian and 1 with prostate cancer) and resulting in 1 death. The PK of dilpacimab showed a half-life ranging from 4.9 to 9.5 days, and biomarker analysis demonstrated that the drug bound to both VEGF and DLL4 targets. The recommended phase II dose for dilpacimab monotherapy was established as 3.75 mg/kg, primarily on the basis of tolerability through multiple cycles. A partial response was achieved in 10.9% of patients (including 4 of 16 patients with ovarian cancer). The remaining patients had either stable disease (52.7%), progressive disease (23.6%), or were deemed unevaluable (12.7%). These results demonstrate that dilpacimab monotherapy has an acceptable safety profile, with clinical activity observed in patients with advanced solid tumors.

TROPICS 1: a phase III, randomized, double-blind, placebo-controlled study of tenecteplase for restoration of function in dysfunctional central venous catheters.

PURPOSE: To evaluate the efficacy and safety of the thrombolytic tenecteplase, a fibrin-specific recombinant tissue plasminogen activator, for restoring function to dysfunctional central venous catheters (CVCs). MATERIALS AND METHODS: In this double-blind, placebo-controlled study, eligible patients with dysfunctional nonhemodialysis CVCs were randomly assigned to two treatment arms. In the first arm (TNK-TNK-PBO), patients received an initial dose of intraluminal tenecteplase (TNK) (up to 2 mg), a second dose of tenecteplase if indicated, and a third placebo (PBO) dose. In the PBO-TNK-TNK arm, placebo was instilled first followed by up to two doses of tenecteplase, if needed, for restoration of catheter function. After administration of each dose, CVC function was assessed at 15, 30, and 120 minutes. RESULTS: There were 97 patients who received either TNK-TNK-PBO (n = 50) or PBO-TNK-TNK (n = 47). Within 120 minutes of initial study drug instillation, catheter function was restored to 30 patients (60%) in the TNK-TNK-PBO arm and 11 patients (23%) in the PBO-TNK-TNK arm, for a treatment difference of 37 percentage points (95% confidence interval 18-55; P = .0002). Cumulative restoration rates for CVC function increased to 87% after the second dose of tenecteplase in both study arms combined. Two patients developed a deep vein thrombosis (DVT) after exposure to tenecteplase; one DVT was considered to be drug related. No cases of intracranial hemorrhage, major bleeding, embolic events, catheter-related bloodstream infections, or catheter-related complications were reported. CONCLUSIONS: Tenecteplase was efficacious for restoration of catheter function in these study patients with dysfunctional CVCs.

Clinical characteristics of dialysis patients with acute myocardial infarction in the United States: a collaborative project of the United States Renal Data System and the National Registry of Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) is catastrophic for dialysis patients. This study set out to determine the clinical characteristics of dialysis patients hospitalized for AMI in the United States. METHODS AND RESULTS: This retrospective cohort study used data from the US Renal Data System (USRDS) database (n=1,285,177) and the third National Registry of Myocardial Infarction (NRMI 3) (n=537,444). AMI hospitalizations from April 1, 1998, through June 30, 2000, were identified using International Classification of Diseases, 9th edition, clinical modification, codes 410, 410.x, 410.x0, and 410.x1. The 9418 unique dialysis patients identified with AMI hospitalizations in the USRDS database were cross-matched with the NRMI registry, creating a cohort for analysis that consisted of 3049 matching patients. Clinical characteristics of dialysis and nondialysis (n=534,395) AMI patients were compared by use of the chi2 test. Of clinical significance, 44.8% of dialysis patients were diagnosed as not having acute coronary syndrome on admission, versus 21.2% of nondialysis patients; 44.4% presented with chest pain, versus 68.3% of nondialysis patients; and 19.1% had ST elevation, versus 35.9% of nondialysis patients. Cardiac arrest was twice as frequent for dialysis patients (11.0% versus 5.0%), and in-hospital death was nearly so (21.3% versus 11.7%). In a logistic regression model, the odds ratio for in-hospital death for dialysis versus nondialysis patients was 1.498 (95% CI, 1.340 to 1.674). CONCLUSIONS: Dialysis patients hospitalized for AMI differ strikingly from nondialysis patients, which possibly explains their poor outcomes. Intensive efforts for early, accurate recognition of AMI in dialysis patients are warranted.

Impact of delay in door-to-needle time on mortality in patients with ST-segment elevation myocardial infarction.

Fibrinolytic therapy is the most common reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI), particularly in smaller centers. Previous studies evaluated the relation between time to treatment and outcomes when few patients were treated within 30 minutes of hospital arrival and many did not receive modern adjunctive medications. To quantify the impact of a delay in door-to-needle time on mortality in a recent and representative cohort of patients with STEMI, a cohort of 62,470 patients with STEMI treated using fibrinolytic therapy at 973 hospitals that participated in the National Registry of Myocardial Infarction from 1999 to 2002 was analyzed. Hierarchical models were used to evaluate the independent effect of door-to-needle time on in-hospital mortality. In-hospital mortality was lower with shorter door-to-needle times (2.9% for < or =30 minutes, 4.1% for 31 to 45 minutes, and 6.2% for >45 minutes; p <0.001 for trend). Compared with those experiencing door-to-needle times < or =30 minutes, adjusted odd ratios (ORs) of dying were 1.17 (95% confidence interval [CI] 1.04 to 1.31) and 1.37 (95% CI 1.23 to 1.52; p for trend <0.001) for patients with door-to-needle times of 31 to 45 and >45 minutes, respectively. This relation was particularly pronounced in those presenting within 1 hour of symptom onset to presentation time (OR 1.25, 95% CI 1.01 to 1.54; OR 1.54, 95% CI 1.27 to 1.87, respectively; p for trend <0.001). In conclusion, timely administration of fibrinolytic therapy continues to significantly impact on mortality in the modern era, particularly in patients presenting early after symptom onset.

A Phase I/Ib Study of Enzalutamide Alone and in Combination with Endocrine Therapies in Women with Advanced Breast Cancer.

Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor-positive/progesterone receptor-positive (ER+/PgR+) breast cancer.Results: Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer. Clin Cancer Res; 23(15); 4046-54. ©2017 AACR.

Early coronary revascularization diminishes the risk of ischemic stroke with acute myocardial infarction.

BACKGROUND AND PURPOSE: Ischemic stroke is an uncommon but devastating complication of myocardial infarction (MI). It is possible that delay in the acute revascularization of these patients influences the risk of peri-MI ischemic stroke independent of size of infarction or residual ventricular function. The influence of the timing and type of revascularization on risk of ischemic stroke in the patient with MI has not previously been assessed. METHODS: We used the National Registry of Myocardial Infarction 3 and 4 databases to identify 45,997 subjects who received thrombolytic therapy and 47,876 patients who were treated with primary percutaneous transluminal coronary angioplasty for MI. In-hospital ischemic stroke occurred in 248 (0.54%) and 150 (0.31%) patients in the two groups, respectively. Patients were stratified based on time from presentation to initial therapy. RESULTS: A statistically significant linear relationship between time to revascularization therapy and risk of in-hospital ischemic stroke was seen on univariate analysis. A multivariate model incorporating 26 other variables showed thrombolytic therapy within 15 minutes was associated with a lower risk of ischemic stroke (odds ratio, 0.58; 95% CI, 0.36-0.94). Primary angioplasty within 90 minutes of arrival was associated with a nonsignificant trend toward lower stroke risk (odds ratio, 0.68; 95% CI, 0.41-1.12). Interestingly, his benefit of early reperfusion therapy did not appear to be related to improvements in left ventricular function. CONCLUSIONS: Risk of in-hospital ischemic stroke with MI is closely tied to the time to revascularization with both thrombolytic and percutaneous transluminal coronary angioplasty therapies. Early revascularization is independently predictive of a lower risk of ischemic stroke, but the mechanism of this does not appear to be related to improved cardiac function. The records of 45,997 subjects who received thrombolytic therapy and 47,876 patients who were treated with primary percutaneous transluminal coronary angioplasty for myocardial infarction were analyzed to determine the relationship between time to revascularization and the occurrence of ischemic stroke. A statistically significant linear relationship between time to revascularization therapy and risk of in-hospital ischemic stroke was seen on univariate analysis. A multivariate model incorporating 26 other variables showed thrombolytic therapy within 15 minutes of presentation was associated with a lower risk of ischemic stroke, and angioplasty within 90 minutes was similarly associated with a nonsignificant trend toward lower stroke risk.

Door-to-drug and door-to-balloon times: where can we improve? Time to reperfusion therapy in patients with ST-segment elevation myocardial infarction (STEMI).

BACKGROUND: To better understand hospital performance in door-to-drug and door-to-balloon times for patients with STEMI, we examined hospital-level variation in key subintervals of door-to-drug time (door-to-electrocardiogram [ECG] and ECG-to-drug) and of door-to-balloon time (door-to-ECG, ECG-to-lab, lab-to-balloon). We sought to identify achievable subinterval times based on the experience of top performing hospitals. METHODS: We conducted a cross-sectional analysis, using data from the National Registry of Myocardial Infarction, of admissions between January 1, 2001, and December 31, 2002 (20435 patients receiving fibrinolytic therapy in 693 hospitals, and 13387 patients receiving percutaneous coronary intervention in 340 hospitals). Using hierarchical regression modeling, we estimated hospital-level geometric means of each subinterval, adjusted for patient clinical characteristics. We ranked hospitals based on the proportion of patients treated within 30 minutes for door-to-drug time and 90 minutes for door-to-balloon times and compared adjusted subinterval times across these groups. RESULTS: The higher performing hospitals (top 20%) in door-to-drug time and door-to-balloon times had significantly shorter times in nearly all subintervals compared with other hospitals, adjusted for patient clinical characteristics. Adjusted mean subinterval times in higher performing hospitals in door-to-drug time were 6.8 minutes (SD = 1.7) for door-to-ECG and 18.7 minutes (SD = 3.5) for ECG-to-drug. Adjusted mean subinterval times in higher performing hospitals in door-to-balloon time were 7.9 minutes (SD = 1.7) for door-to-ECG, 47.8 minutes (SD = 7.1) for ECG-to-lab, and 29.0 minutes (5.4) for lab-to-balloon, adjusted for patient clinical characteristics. CONCLUSIONS: Substantial national attention is being directed at improving time to treatment of patients with STEMI. These data suggest achievable subinterval times for hospitals seeking to improve performance in this important quality indicator.

Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction.

CONTEXT: Understanding how door-to-drug and door-to-balloon times vary by time of day and day of week can inform the design of interventions to improve the timeliness of reperfusion therapy. OBJECTIVE: To determine the pattern of door-to-drug and door-to-balloon times by time of day and day of week and whether this pattern may affect mortality. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 68,439 patients with ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy and 33,647 treated with percutaneous coronary intervention (PCI) from 1999 through 2002. We classified patient hospital arrival period into regular hours (weekdays, 7 am-5 pm) and off-hours (weekdays 5 pm-7 am and weekends). MAIN OUTCOME MEASURES: Geometric mean door-to-drug time for fibrinolytic therapy and door-to-balloon time for PCI and all-cause in-hospital mortality. All outcomes were adjusted for patient and hospital characteristics. RESULTS: Most fibrinolytic therapy (67.9%) and PCI patients (54.2%) were treated during off-hours. Door-to-drug times were slightly longer during off-hours (34.3 minutes) than regular hours (33.2 minutes; difference, 1.0 minute; 95% confidence interval [CI], 0.7-1.4; P<.001). In contrast, door-to-balloon times were substantially longer during off-hours (116.1 minutes) than regular hours (94.8 minutes; difference, 21.3 minutes; 95% CI, 20.5-22.2; P<.001). A lower percentage of patients met guideline recommended times for door-to-balloon during off-hours (25.7%) than regular hours (47%; P<.001). Door-to-balloon times exceeding 120 minutes occurred much more commonly during off-hours (41.5%) than regular hours (27.7%; P<.001). Longer off-hours door-to-balloon times were primarily due to a longer interval between obtaining the electrocardiogram and patient arrival at the catheterization laboratory (off-hours, 69.8 minutes vs regular hours, 49.1 minutes; P<.001). This pattern was consistent across all hospital subgroups examined. Furthermore, patients presenting during off-hours had significantly higher adjusted in-hospital mortality than patients presenting during regular hours (odds ratio, 1.07; 95% CI, 1.01-1.14; P = .02). CONCLUSIONS: Presentation during off-hours was common and was associated with substantially longer times to treatment for PCI but not for fibrinolytic therapy. To achieve the best outcomes, hospitals providing PCI during off-hours should commit to doing so in a timely manner.

Racial and ethnic differences in time to acute reperfusion therapy for patients hospitalized with myocardial infarction.

CONTEXT: Nonwhite patients experience significantly longer times to fibrinolytic therapy (door-to-drug times) and percutaneous coronary intervention (door-to-balloon times) than white patients, raising concerns of health care disparities, but the reasons for these patterns are poorly understood. OBJECTIVES: To estimate race/ethnicity differences in door-to-drug and door-to-balloon times for patients receiving primary reperfusion for ST-segment elevation myocardial infarction; to examine how sociodemographic factors, insurance status, clinical characteristics, and hospital features mediate racial/ethnic differences. DESIGN, SETTING, AND PATIENTS: Retrospective, observational study using admission and treatment data from the National Registry of Myocardial Infarction (NRMI) for a US cohort of patients with ST-segment elevation myocardial infarction or left bundle-branch block and receiving reperfusion therapy. Patients (73,032 receiving fibrinolytic therapy; 37,143 receiving primary percutaneous coronary intervention) were admitted from January 1, 1999, through December 31, 2002, to hospitals participating in NRMI 3 and 4. MAIN OUTCOME MEASURE: Minutes between hospital arrival and acute reperfusion therapy. RESULTS: Door-to-drug times were significantly longer for patients identified as African American/black (41.1 minutes), Hispanic (36.1 minutes), and Asian/Pacific Islander (37.4 minutes), compared with patients identified as white (33.8 minutes) (P<.01 for all). Door-to-balloon times for patients identified as African American/black (122.3 minutes) or Hispanic (114.8 minutes) were significantly longer than for patients identified as white (103.4 minutes) (P<.001 for both). Racial/ethnic differences were still significant but were substantially reduced after accounting for differences in mean times to treatment for the hospitals in which patients were treated; significant racial/ethnic differences persisted after further adjustment for sociodemographic characteristics, insurance status, and clinical and hospital characteristics (P<.01 for all). CONCLUSION: A substantial portion of the racial/ethnic disparity in time to treatment was accounted for by the specific hospital to which patients were admitted, in contrast to differential treatment by race/ethnicity inside the hospital.

A phase III, randomized, double-blind, placebo-controlled study of tenecteplase for improvement of hemodialysis catheter function: TROPICS 3.

BACKGROUND AND OBJECTIVES: Despite widespread use of tunneled hemodialysis (HD) catheters, their utility is limited by the development of thrombotic complications. To address this problem, this study investigated whether the thrombolytic agent tenecteplase can restore blood flow rates (BFRs) in dysfunctional HD catheters. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this randomized, double-blind study, patients with dysfunctional tunneled HD catheters, defined as a BFR <300 ml/min at -250 mmHg pressure in the arterial line, received 1-hour intracatheter dwell with tenecteplase (2 mg) or placebo. The primary endpoint was the percentage of patients with BFR > or =300 ml/min and an increase of > or =25 ml/min above baseline 30 minutes before and at the end of HD. Safety endpoints included the incidence of hemorrhagic, thrombotic, and infectious complications. RESULTS: Eligible patients (n = 149) were treated with tenecteplase (n = 74) or placebo (n = 75). Mean baseline BFR was similar for the tenecteplase and placebo groups at 151 and 137 ml/min, respectively. After a 1-hour dwell, 22% of patients in the tenecteplase group had functional catheters compared with 5% among placebo controls (P = 0.004). At the end of dialysis, mean change in BFR was 47 ml/min in the tenecteplase group versus 12 ml/min in the placebo group (P = 0.008). Four catheter-related bloodstream infections (one tenecteplase, three placebo) and one thrombosis (tenecteplase) were observed. There were no reports of intracranial hemorrhage, major bleeding, embolic events, or catheter-related complications. CONCLUSIONS: Tenecteplase improved HD catheter function and had a favorable safety profile compared with placebo.

Acute reperfusion therapy in ST-elevation myocardial infarction from 1994-2003.

BACKGROUND: Appropriate utilization of acute reperfusion therapy is not a national performance measure for ST-elevation myocardial infarction at this time, and the extent of its contemporary use among ideal patients is unknown. METHODS: From the National Registry of Myocardial Infarction, we identified 238,291 patients enrolled from June 1994 to May 2003 who were ideally suited for acute reperfusion therapy with fibrinolytic therapy or primary percutaneous coronary intervention. We determined rates of not receiving therapy across 3 time periods (June 1994-May 1997, June 1997-May 2000, June 2000-May 2003) and evaluated factors associated with underutilization. RESULTS: The proportion of ideal patients not receiving acute reperfusion therapy decreased by one half throughout the past decade (time period 1: 20.6%; time period 2: 11.4%; time period 3: 11.6%; P <.001). Utilization remained significantly lower in key subgroups in the most recent time period: those without chest pain (odds ratio [OR] 0.29; 95% confidence interval [CI], 0.27-0.32); those presenting 6 to 12 hours after symptom onset (OR 0.57; 95% CI, 0.52-0.61); those 75 years or older (OR 0.63 compared with patients <55 years old; 95% CI, 0.58-0.68); women (OR 0.88; 95% CI, 0.84-0.93); and non-whites (OR 0.90; 95% CI, 0.83-0.97). CONCLUSIONS: Utilization of acute reperfusion therapy in ideal patients has improved over the last decade, but more than 10% remain untreated. Measuring and improving its use in this cohort represents an important opportunity to improve care.

Alteplase for the treatment of central venous catheter occlusion in children: results of a prospective, open-label, single-arm study (The Cathflo Activase Pediatric Study).

PURPOSE: Alteplase is approved for use in the restoration of function to occluded central venous access devices (CVADs); however, there are few prospective studies in children. This study was undertaken to evaluate the safety and efficacy of alteplase in the treatment of CVAD occlusions in a pediatric population. MATERIALS AND METHODS: A prospective, multicenter, open-label, single-arm study evaluating a maximum of two doses (< or =2 mg per dose) of alteplase was performed in pediatric patients. Inclusion criteria included patient age less than 17 years with an occluded CVAD (single-, double-, and triple-lumen catheter or implanted port). Patients with hemodialysis catheters, those with known mechanical occlusion, or those considered at high risk for bleeding or embolization were excluded. Assessment of function was made 30 and 120 minutes (if required) after each dose. The primary objective of the study was to evaluate the safety of alteplase as measured by the incidence of intracranial hemorrhage (ICH); secondary objectives included the evaluation of specific targeted serious adverse events and efficacy of alteplase in the restoration of catheter function. RESULTS: A total of 310 patients (174 male patients, 136 female patients; mean age, 7.2 years; range, 0.04-18.3 y) were treated; 55 of the patients (17.7%) were younger than 2 years of age. No patients experienced ICH (95% CI, 0%-1.2%). Nine serious adverse events were noted in eight patients (2.6% incidence), two of which were attributed by the investigator to study drug administration (one case of sepsis and one case of a ruptured catheter lumen). The cumulative rate of restoration of CVAD function after serial administration of a maximum of two instillations of alteplase, each with a maximum dwell time of 120 minutes, was 82.9% (95% CI, 78.2%-86.9%). Similar rates of catheter function restoration were seen among all catheter types studied; there were no clinically meaningful differences among age or sex subgroups. CONCLUSION: The administration of alteplase is safe and effective for the restoration of function to CVADs in pediatric patients.

Hospital improvement in time to reperfusion in patients with acute myocardial infarction, 1999 to 2002.

OBJECTIVES: The purpose of this study was to analyze recent trends in door-to-reperfusion time and to identify hospital characteristics associated with improved performance. BACKGROUND: Rapid reperfusion improves survival for patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: In this retrospective observational study from the National Registry of Myocardial Infarction (NRMI)-3 and -4, between 1999 and 2002, we analyzed door-to-needle and door-to-balloon times in patients admitted with STEMI and receiving fibrinolytic therapy (n = 68,439 patients in 1,015 hospitals) or percutaneous coronary intervention (n = 33,647 patients in 421 hospitals) within 6 h of hospital arrival. RESULTS: In 1999, only 46% of the patients in the fibrinolytic therapy cohort were treated within the recommended 30-min door-to-needle time; only 35% of the patients in the percutaneous coronary intervention cohort were treated within the recommended 90-min door-to-balloon time. Improvement in these times to reperfusion over the four-year study period was not statistically significant (door-to-needle: -0.01 min/year, 95% confidence interval [CI] -0.24 to +0.23, p > 0.9; door-to-balloon: -0.57 min/year, 95% CI -1.24 to +0.10, p = 0.09). Only 33% (337 of 1,015) of hospitals improved door-to-needle time by more than one min/year, and 26% (110 of 421) improved door-to-balloon time by more than three min/year. No hospital characteristic was significantly associated with improvement in door-to-needle time. Only high annual percutaneous coronary intervention volume and location in New England were significantly associated with greater improvement in door-to-balloon time. CONCLUSIONS: Fewer than one-half of patients with STEMI receive reperfusion in the recommended door-to-needle or door-to-balloon time, and mean time to reperfusion has not decreased significantly in recent years. Relatively few hospitals have shown substantial improvement.

The pre-hospital electrocardiogram and time to reperfusion in patients with acute myocardial infarction, 2000-2002: findings from the National Registry of Myocardial Infarction-4.

OBJECTIVES: The aim of this study was to determine the use of pre-hospital electrocardiogram (ECG) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing reperfusion therapy, and evaluate the effect of pre-hospital ECG on door-to-reperfusion times. BACKGROUND: Although national guidelines recommend the use of pre-hospital ECG, there is limited contemporary information about its current use and effectiveness. METHODS: Using data from the National Registry of Myocardial Infarction-4, we studied patients with STEMI or left bundle branch block who received acute reperfusion with either fibrinolytic therapy (n = 35,370) or primary percutaneous coronary intervention (PCI) (n = 21,277) within 6 h of admission. We determined the prevalence of pre-hospital ECG use, evaluated the association between pre-hospital ECG and door-to-reperfusion time, and estimated the incremental reduction in time to reperfusion using hierarchical models to adjust for differences in patient and hospital characteristics. RESULTS: A pre-hospital ECG was performed in 4.5% of the fibrinolytic therapy cohort and in 8.0% of the PCI cohort. After adjusting for patient and hospital characteristics, the use of pre-hospital ECG was associated with a significantly shorter geometric mean door-to-drug time: 24.6 min (95% confidence interval [CI]: 23.7 to 25.5) vs. 34.7 min (95% CI: 34.2 to 35.3; p < 0.0001), and a significantly shorter geometric mean door-to-balloon time (94.0 min [95% CI: 91.8 to 96.3] vs. 110.3 min [95% CI: 108.7 to 112.0]; p < 0.0001). CONCLUSIONS: The national use of pre-hospital ECG to diagnose and facilitate the treatment of STEMI remains low. When used, however, pre-hospital ECG is associated with a significantly shorter time to reperfusion.

Effect of door-to-balloon time on mortality in patients with ST-segment elevation myocardial infarction.

OBJECTIVES: We sought to determine the effect of door-to-balloon time on mortality for patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). BACKGROUND: Studies have found conflicting results regarding this relationship. METHODS: We conducted a cohort study of 29,222 STEMI patients treated with PCI within 6 h of presentation at 395 hospitals that participated in the National Registry of Myocardial Infarction (NRMI)-3 and -4 from 1999 to 2002. We used hierarchical models to evaluate the effect of door-to-balloon time on in-hospital mortality adjusted for patient characteristics in the entire cohort and in different subgroups of patients based on symptom onset-to-door time and baseline risk status. RESULTS: Longer door-to-balloon time was associated with increased in-hospital mortality (mortality rate of 3.0%, 4.2%, 5.7%, and 7.4% for door-to-balloon times of < or =90 min, 91 to 120 min, 121 to 150 min, and >150 min, respectively; p for trend <0.01). Adjusted for patient characteristics, patients with door-to-balloon time >90 min had increased mortality (odds ratio 1.42; 95% confidence interval [CI] 1.24 to 1.62) compared with those who had door-to-balloon time < or =90 min. In subgroup analyses, increasing mortality with increasing door-to-balloon time was seen regardless of symptom onset-to-door time (< or =1 h, >1 to 2 h, >2 h) and regardless of the presence or absence of high-risk factors. CONCLUSIONS: Time to primary PCI is strongly associated with mortality risk and is important regardless of time from symptom onset to presentation and regardless of baseline risk of mortality. Efforts to shorten door-to-balloon time should apply to all patients.

Achieving door-to-balloon times that meet quality guidelines: how do successful hospitals do it?

OBJECTIVES: We sought to recommend an approach for minimizing preventable delays in door-to-balloon time on the basis of experiences in top-performing hospitals nationally. BACKGROUND: Prompt percutaneous coronary intervention (PCI) for patients with ST-segment elevation myocardial infarction (STEMI) significantly reduces mortality and morbidity; however, door-to-balloon times often exceed the 90-min guideline set forth by the American College of Cardiology (ACC) and the American Heart Association (AHA). METHODS: We conducted a qualitative study using in-depth interviews (n = 122) of hospital staff at hospitals (n = 11) selected as top performers based on data from the National Registry of Myocardial Infarction from January 2001 to December 2002. We used the constant comparative method of qualitative data analysis to synthesize best practices across the hospitals. RESULTS: Top performers were those with median door-to-balloon times of < or =90 min for their most recent 50 PCI cases through December 2002 and the greatest improvement in median door-to-balloon times during the preceding four-year period 1999 to 2002. Several critical innovations are described, including use of pre-hospital electrocardiograms (ECGs) to activate the catheterization laboratory, allowing emergency physicians to activate the catheterization laboratory, and substantial interdisciplinary collaboration throughout the process. In the ideal approach, door-to-balloon time is 60 min for patients transported by paramedics with a pre-hospital ECG and 80 min for patients who arrive without paramedic transport and a pre-hospital ECG. CONCLUSIONS: Hospitals can achieve the recommended ACC/AHA guidelines for door-to-balloon time with specific process design efforts. However, the recommended best practices involve extensive interdisciplinary collaboration and will likely require explicit strategies for overcoming barriers to organizational change.