Drug-induced QT-interval prolongation: considerations for clinicians.

Drug-induced proarrhythmia is a frequently encountered clinical problem and a leading cause for withdrawal or relabeling of prescription drugs. Suppression of the rapid component of the delayed rectifier potassium current, I(Kr), represents the principal pharmacodynamic mechanism leading to heterogeneous prolongation of the ventricular action potential and prolongation of the QT interval clinically. However, the risk of proarrhythmia by QT-interval-prolonging drugs is variable and critically dependent on several factors leading to multiple reductions in the cardiac repolarization reserve. As antiarrhythmic drugs that prolong the QT interval are usually aggressively managed with continuous electrocardiogram monitoring and screening for drug interactions when administered to patients who have a high risk of sudden cardiac death, their risk of mortality is not increased. However, noncardiovascular QT-interval-prolonging drugs, which often produce less QT-interval prolongation compared with antiarrhythmic drugs, are found to be associated with increased rates of death in patients who have a markedly lower de novo risk of sudden cardiac death. Thus, it is important for clinicians, particularly pharmacists, to be cognizant of the levels of risk associated with varying degrees of QT-interval prolongation caused by drugs so that they can develop strategies to either prevent or reduce the risk of proarrhythmias.

Effect of clinical characteristics on neutropenia-related inpatient costs among newly diagnosed non-Hodgkin's lymphoma cases during first-course chemotherapy.

STUDY OBJECTIVE: To estimate the costs of hospitalization for neutropenia among chemotherapy-treated patients with newly diagnosed non-Hodgkin's lymphoma and to assess baseline patient factors associated with these costs. DESIGN: Retrospective cohort study. DATA SOURCE: Linked Surveillance, Epidemiology, and End Results Program-Healthcare Cost and Utilization Project databases for Iowa from 1993-1998. PATIENTS: Patients with newly diagnosed non-Hodgkin's lymphoma who received all inpatient care at Iowa hospitals during their first course of chemotherapy. MEASUREMENTS AND MAIN RESULTS: Neutropenia-related hospitalization costs were estimated from discharge abstracts found within the earliest of the following: 6 months after the diagnosis month, the date of bone marrow transplantation, or date of death. We performed univariate tests of differences in neutropenia-related hospitalization costs in all patients in the sample, as well as tests for neutropenia-related hospitalization costs, length-of-stay, and cost/inpatient day for patients with at least one hospitalization for neutropenia. We modeled total inpatient charges over the period for patients with at least one neutropenia-related hospitalization (multiple regression). A total of 1636 patients with non-Hodgkin's lymphoma had chemotherapy in Iowa and met inclusion criteria; of these, 316 had at least one hospitalization for neutropenia. The 316 patients had 418 stays. Patients with advanced stage (vs limited stage), previous anemia (vs no anemia), positive Charlson comorbidity score (vs score of 0), and diffuse large cell histology (vs follicular) had higher mean neutropenia-related hospitalization cost/patient with non-Hodgkin's lymphoma (p<0.05). Among those with neutropenia-related hospitalizations, a longer length of stay was associated with nonfollicular histologies, previous anemia, and positive Charlson score (p<0.05). CONCLUSION: When estimating expected payments for neutropenia-related hospitalization in patients with non-Hodgkin's lymphoma, payers need to be aware of the distribution of clinical characteristics in these patients.

Days of prophylactic filgrastim use to reduce febrile neutropenia in patients with non-Hodgkin's lymphoma treated with chemotherapy.

BACKGROUND: Filgrastim prophylaxis lessens the occurrence of febrile neutropenia in patients with non-Hodgkin.s lymphoma (NHL) treated with chemotherapy, but differences in days of therapy and mode (primary or secondary) of prophylaxis may affect clinical outcomes. OBJECTIVE: To describe the patterns of use of filgrastim prophylaxis, especially days of therapy and mode, and the possible associated incidence of febrile neutropenia in patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. METHODS: Using medical records from the Oncology Practice Pattern Study in patients treated between 1991 and 1999 at 12 sites in the United States, we studied patients with intermediate-grade NHL treated with first-line CHOP chemotherapy and prophylactic filgrastim. The number of days of prophylactic filgrastim use, mode of prophylaxis, and incidence of febrile neutropenia were evaluated. The cycles were stratified into 2 groups based on days of filgrastim prophylaxis (<7 days [Group 1] and > or = 7 days [Group 2]). RESULTS: One hundred seventy patients were treated with 652 cycles of CHOP chemotherapy with filgrastim prophylaxis. The mean days of filgrastim prophylaxis was 9.5 days (95% confidence interval [CI], 9.3-9.7 days) across all cycles, 4.7 days (95% CI, 4.5-5.0 days) across Group 1 cycles (n=73), and 10.1 days (95% CI, 9.9-10.3 days) across Group 2 cycles (n=579). Thirty-seven percent of patients were treated with primary prophylaxis; 94% of these patients. cycles were Group 2 cycles. The incidence of febrile neutropenia was 3.6% and 7.7% across cycles in patients receiving primary versus secondary prophylaxis, respectively. In patients treated with secondary prophylaxis, the incidence was 16.7% and 6.1% in Group 1 and Group 2 cycles, respectively. Multiple logistic regression modeling indicated that a lower risk of febrile neutropenia was associated with primary prophylaxis (mainly Group 2) (odds ratio [OR] 0.3; 95% CI, 0.1-0.6) and secondary prophylaxis in Group 2 (OR 0.4; 95% CI, 0.2-0.8), and lower body surface area was associated with a greater risk of febrile neutropenia (OR 1.8; 95% CI, 1.1-3.0). CONCLUSION: Primary prophylaxis with filgrastim (mainly Group 2) and secondary prophylaxis in Group 2 (mean 10.1 days) may be associated with a lower incidence of febrile neutropenia than secondary prophylaxis in Group 1.

Factors associated with early termination of CHOP therapy and the impact on survival among patients with chemosensitive intermediate-grade non-Hodgkin's lymphoma.

BACKGROUND: Six to eight cycles of CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) is standard for intermediate-grade non-Hodgkin's lymphoma (NHL) but is associated with toxicity that may cause premature termination of therapy. METHODS: We studied factors associated with premature termination of CHOP therapy (receiving fewer than 6 cycles) and the relationship of premature termination with survival. Subjects consisted of a population-based sample of Iowa residents with intermediate-grade NHL who were planned to receive > or = 6 or more cycles of CHOP and who were chemosensitive (ie, achieved a documented partial or complete response to CHOP). RESULTS: In a comparison with patients 18-59 years of age, the odds of premature termination of CHOP therapy was 2.6 (95% CI, 0.7-9.2) for those aged 60-74 and 6.2 (95% CI, 1.7-23.3) for those aged > or = 75. Patients with cycle 1 febrile neutropenia hospitalization (FNH) were 4.4 times (95% CI, 1.4-13.8) more likely to terminate CHOP prematurely than those without cycle 1 FNH. Among patients aged 60-74, but not those aged > or = 75, premature termination appeared to be associated with decreased 5-year survival (hazard ratio [HR] = 6.0; 95% CI, 2.4-15.2) compared with those completing CHOP therapy (HR = 2.1; 95% CI, 1.0-4.2). Findings for overall survival were similar. CONCLUSIONS: First-cycle FNH and age > or = 60 years were associated with premature termination of CHOP therapy. The association of premature termination with survival among chemosensitive patients differed by age.

Anticholinergic agents for the treatment of "death rattle" in patients with myasthenia gravis.

Difficulty clearing upper airway secretions (death rattle) is a frequent problem at the end of life. Treatment often includes the use of anticholinergic drugs. Myasthenia gravis is a disease characterized by muscle weakness and fatigue caused by an immune-mediated deficiency of acetylcholine receptors at the neuromuscular junction, and it is treated with anticholinesterase agents. We report the case of a patient dying of myasthenia gravis who had problems with the "death rattle" and who presented a dilemma as to whether the use of anticholinergics would be helpful or would cause deterioration of her myasthenia. This is accompanied by a review of the relevant literature.

Was breast conserving surgery underutilized for early stage breast cancer? Instrumental variables evidence for stage II patients from Iowa.

OBJECTIVE: To estimate the average survival effects of breast conserving surgery plus irradiation relative to mastectomy for marginal stage II breast cancer patients in Iowa from 1989-1994. DATA SOURCES/DATA SETTING: Secondary linked Iowa SEER Cancer Registry--Iowa Hospital Association discharge abstract data for women in Iowa with stage II breast cancer from 1989-1994. STUDY DESIGN: Observational instrumental variables (IV) analysis. DATA COLLECTION/EXTRACTION METHODS: Women with stage II breast cancer from the Iowa SEER Cancer Registry 1989-1994 who received all of their inpatient care in Iowa were linked with their respective hospital discharge abstracts. PRINCIPAL FINDINGS: Breast conserving surgery plus irradiation decreased survival relative to mastectomy for marginal stage II breast cancer patients in Iowa during the early 1990s. In this study marginal patients were those whose surgery choices were affected by differences in area treatment rates and access to radiation facilities. CONCLUSIONS: If marginal patients are representative of patients whose treatment choices would be affected by changes in treatment rates, an increase in the breast conserving surgery plus irradiation rate for stage II early stage breast cancer patients would have decreased survival in Iowa during the early 1990s. Further research with newer data and broader samples is needed to make more current and specific assessments.

Dose conversion from recombinant human erythropoietin to darbepoetin alfa: recommendations from clinical studies.

Recombinant human erythropoietin (r-HuEPO, epoetin alfa), is an established and effective treatment for anemia associated with both chronic kidney disease (CKD) and cancer and has improved the management of anemia over alternatives such as transfusion. Darbepoetin alfa is a new erythropoietic agent with a 3-fold longer half-life and increased in vivo potency relative to r-HuEPO. These properties allow patients to be treated with longer dosing intervals than with r-HuEPO. Relative potency between r-HuEPO and darbepoetin alfa is not a fixed relationship but is dependent on several factors. Clinical study results suggest that greater relative potency differences are seen between r-HuEPO and darbepoetin alfa when the dosing intervals are longer and when r-HuEPO dose requirements are higher. Although 200 U of r-HuEPO contains the same peptide mass as 1 microg of darbepoetin alfa, a fixed ratio of 200:1 does not necessarily predict an appropriate dose conversion between the two drugs across the entire spectrum of dose ranges. When converting patients with CKD from r-HuEPO to darbepoetin alfa, dosing should be based on relevant clinical data. Appropriate guidance for conversion of patients with CKD from r-HuEPO to darbepoetin alfa is provided in the approved United States package insert for darbepoetin alfa. In patients who are prescribed darbepoetin alfa, either by conversion from r-HuEPO or as de novo treatment, therapy should begin according to recommendations in the package insert, after which, doses should be titrated individually according to each patient's hemoglobin response. Dosing data from oncology clinical studies, although not necessarily applicable to CKD, indicate similar potency ratios between r-HuEPO and darbepoetin alfa, and in addition affirm the finding that, as the interval between doses of darbepoetin alfa is increased, hemoglobin response is maintained.