Bowel Preparations for Colonoscopy: A Regulatory Perspective.

Agents indicated for cleansing of the colon as a preparation for colonoscopy (bowel preps) are among the most frequently prescribed drugs for otherwise healthy patients. Better bowel preparation has been shown to translate into higher adenoma detection rates. Therefore, safety and efficacy standards need to be high. Clinical trials can be designed to show superiority or non-inferiority, and there are 3 different types of relevant New Drug Applications. Current endpoint instruments rely on clinician reporting, and more than 1 endpoint instrument may be required to ensure a valid appraisal of efficacy. Future trials that study hard-to-prepare patients and populations who are potentially at higher risk for adverse events (eg, those with renal dysfunction) would be of interest. Orthostatic hemodynamic changes with bowel preps as a drug class occur more frequently than previously recognized, and this also deserves further study.

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.

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, 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.

Mortality, kidney disease and cardiac procedures following acute coronary syndrome.

BACKGROUND: Cardiac interventions are underutilized in patients with chronic kidney disease (CKD) following acute coronary syndrome (ACS) partly due to nephrotoxicity concerns. METHODS: We analyzed outcomes of 4631 subjects with ACS enrolled in the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion trial, including time to death, time to reduced renal function (50% reduction in estimated glomerular filtration rate (eGFR) or development of end-stage renal disease (ESRD)) and percent change in eGFR from baseline. RESULTS: Subjects with a lower baseline eGFR were more likely to be older, female and have diabetes, hypertension, congestive heart failure or peripheral vascular disease (all P < 0.0001); they were less likely to be taking aspirin > or = 162 mg or to have undergone a percutaneous coronary intervention (PCI) prior to enrollment (P < 0.0001). As eGFR declined, the proportion of subjects experiencing death versus reduced eGFR or ESRD qualitatively increased. In adjusted analyses, every 10 ml/min/1.73 m(2) decrease in eGFR < or = 90 was associated with a 15% increased hazard of death (HR 1.15, P = 0.01). In adjusted analyses of predictors of percent change in eGFR, catheterization (cath) with or without PCI compared to medical therapy during follow-up was not associated with significant differences in long-term eGFR (P = 0.09). CONCLUSIONS: Among CKD subjects in this study, the risk of death greatly outweighed the risk of reduced eGFR or development of ESRD following ACS and the occurrence of cath +/- PCI was not associated with significant differences in long-term renal function. The presence of CKD should not preclude potentially beneficial interventions and research should focus on reducing the high cardiovascular burden in this population.

Risk for cardiovascular outcomes among subjects with atherosclerotic cardiovascular disease and greater-than-normal estimated glomerular filtration rate.

BACKGROUND AND OBJECTIVES: Estimating equations for calculating glomerular filtration rate (eGFR) occasionally identify patients with elevated eGFR, yet the prognostic significance remains to be determined. This study sought to define the association of an elevated eGFR on the risk for death and cardiovascular outcomes among subjects with atherosclerotic cardiovascular disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 8941 subjects who had a history of atherosclerotic vascular disease and were enrolled in the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion trial were analyzed. Time to the composite end point of death, congestive heart failure, myocardial infarction, or stroke was modeled using Cox proportion hazards regression. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease and Cockcroft-Gault formulas. RESULTS: Compared with subjects with eGFR of 100 to 125 ml/min per 1.73 m2, subjects with eGFR > or = 125 (n = 462) were younger, female, and nonwhite. In addition, subjects with an elevated eGFR were more likely to have diabetes and congestive heart failure. In adjusted analyses, every 10-ml/min per 1.73 m2 decrease in eGFR < 100 was associated with a 13% increased hazard for the composite end point. In addition, every 10-ml/min per 1.73 m2 increase in eGFR > or = 100 was associated with a 9% increased hazard for the composite end point. CONCLUSIONS: In individuals with a history of vascular disease, the relationship between eGFR and cardiovascular outcomes may be parabolic, with increased risk among patients with both reduced and elevated eGFR.

Relationship between interdialytic weight gain and blood pressure among prevalent hemodialysis patients.

BACKGROUND: Hypertension is common in hemodialysis patients; however, the relationship between interdialytic weight gain (IDWG) and blood pressure (BP) is incompletely characterized. This study seeks to define the relationship between IDWG and BP in prevalent hemodialysis subjects. STUDY DESIGN, SETTING, & PARTICIPANTS: This study used data from 32,295 dialysis sessions in 442 subjects followed up for 6 months in the Crit-Line Intradialytic Monitoring Benefit (CLIMB) Study. OUTCOMES & MEASUREMENTS: Mixed linear regression was used to analyze the relationship between percentage of IDWG (IDWG [%] = [current predialysis weight - previous postdialysis weight]/dry weight * 100) as the independent variable and systolic BP (SBP) and predialysis - postdialysis SBP (deltaSBP) as dependent variables. RESULTS: In unadjusted analyses, every 1% increase in percentage of IDWG was associated with a 1.00 mm Hg (95% confidence interval [CI], +/-0.24) increase in predialysis SBP (P < 0.0001), 0.65 mm Hg (95% CI, +/-0.24) decrease in postdialysis SBP (P < 0.0001), and 1.66 mm Hg (95% CI, +/-0.25) increase in deltaSBP (P < 0.0001). After controlling for other significant predictors of SBP, every 1% increase in percentage of IDWG was associated with a 1.00 mm Hg (95% CI, +/-0.24) increase in predialysis SBP (P < 0.0001) and a 1.08 mm Hg (95% CI, +/-0.22) increase in deltaSBP with hemodialysis (P < 0.0001). However, in subjects with diabetes as the cause of end-stage renal disease, subjects with lower creatinine levels, and older subjects, the magnitude of the association between percentage of IDWG and predialysis SBP was less pronounced. The magnitude of percentage of IDWG on deltaSBP was less pronounced in younger subjects and subjects with lower dry weights. Results were similar with diastolic BP. LIMITATIONS: Hemodialysis BP measurements are imprecise estimates of BP and true hemodynamic burden in dialysis subjects. CONCLUSIONS: In prevalent hemodialysis subjects, increasing percentage of IDWG is associated with increases in predialysis BP and BP changes with hemodialysis; however, the magnitude of the relationship is modest and modified by other clinical factors. Thus, although overall volume status may impact on BP to a greater extent, day-to-day variations in weight gain have a modest role in BP increases in prevalent subjects with end-stage renal disease.

Anemia management in chronic kidney disease.

Anemia is common in chronic kidney disease (CKD) due to a state of erythropoietin deficiency. Erythropoietin therapy has been used for approximately 20 years to correct anemia in CKD and to improve both subjective and objective outcomes. Guidelines that establish a hemoglobin (Hb) goal for anemia correction in CKD patients are largely based on observational data. Controversy still exists, however, because outcomes have not been consistent with various degrees of anemia correction. The number of prospective randomized trials investigating the effects of anemia correction on cardiovascular (CV) morbidity and mortality in CKD patients, an already high-risk group, is limited. With respect to improving CV outcomes in the CKD population, the currently available trial data caution against raising Hb levels in CKD patients to approach more "normal" physiologic ranges. The disappointing experience with the trial data must be weighed against the beneficial associations of erythropoietin therapy that have been generated from observational data. Establishing the ideal target Hb ranges for anemia correction in CKD patients remains a dynamic process and leaves many gray areas to be further elucidated. Here, we present a case that underscores the need to consider the study design when reviewing the data at a population level in order to determine what is most appropriate for our patient.