Susan M. Begelman

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.

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.

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.

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.

Previous Myocardial Infarction as a Risk Factor for In-Hospital Cardiovascular Outcomes (from the National Registry of Myocardial Infarction 4 and 5)

Patients with acute coronary syndromes have a substantial disease burden and are at continued risk of future cardiovascular events. In this setting, the relation between previous myocardial infarction (MI) and the risk of subsequent in-hospital adverse cardiovascular outcomes has not been definitively established. The data were analyzed from 427,778 hospitalized patients presenting with acute MI from July 2002 to December 2006, who were enrolled in the National Registry of Myocardial Infarction 4-5 study. Multivariate logistic regression models were developed to examine the association between a history of MI and in-hospital all-cause mortality, recurrent MI, and congestive heart failure/pulmonary edema. Covariate adjustments were made for demographic characteristics, co-morbidities, prearrival medications, and health status at presentation. Similarly, multivariate linear regression models were used to evaluate the length of stay. Of the 232,927 patients with acute MI included in the present study after exclusions, 24.7% reported a history of MI. In-hospital mortality was not significantly different between the patients with and without a history of MI (adjusted odds ratio 0.99, 95% confidence interval 0.95 to 1.04, p = 0.75). However, patients with a previous MI had a small increased risk of in-hospital recurrent MI (adjusted odds ratio 1.18, 95% confidence interval 1.08 to 1.29, p <0.001) and congestive heart failure/pulmonary edema (adjusted odds ratio 1.23, 95% confidence interval1.19 to 1.28, p <0.001) compared with patients with no history of MI. In conclusion, a history of MI did not significantly affect in-hospital mortality after admission for an acute MI.

Patient-centered assessment on disease burden, quality of life, and treatment satisfaction associated with acromegaly

The study aimed to assess the economic burden, health-related quality of life (HRQoL), and acromegaly treatment satisfaction in the USA. A web-based, cross-sectional survey was distributed to members of Acromegaly Community. Data related to comorbidities, treatment patterns, and treatment satisfaction were collected. The costs over the past 3 months included out-of-pocket cost, sick leave, leave of absence, direct loss of job due to acromegaly, unemployment, assistance to perform household chores, and family member loss of income. The HRQoL was assessed by Acromegaly Quality of Life (AcroQoL) and EQ-5D-3L questionnaires. Among 106 patients who completed the survey (mean age: 46 years, female: 76.4%), 44.3% presented with ≥5 comorbidities, and 90.6% reporting acromegaly-related symptoms. Compared with the low-symptom group 0–3 (n=41), the 4+ symptoms group (n=65) was more likely to have depression (OR=2.3, 95% CI 1.1 to 5.2) and cardiovascular disease (OR=5.8, 95% CI 2.0 to 16.7), and experienced higher costs (loss of job:

Incidence of catheter-related complications in patients with central venous or hemodialysis catheters: a health care claims database analysis

8874 vs

Presence of carotid and peripheral arterial disease in patients with left main disease.

1717, P=0.02; unemployment disability:

Heparin-induced thrombocytopenia: Principles for early recognition and management

17,102 vs

Relationship Between Serum Low-Density Lipoprotein Cholesterol and In-hospital Mortality Following Acute Myocardial Infarction (The Lipid Paradox)

429, P=0.003; household chores: