Anidulafungin compared with fluconazole for treatment of candidemia and other forms of invasive candidiasis caused by Candida albicans: a multivariate analysis of factors associated with improved outcome

<p>Abstract</p> <p>Background</p> <p><it>Candida albicans </it>is the most common cause of candidemia and other forms of invasive candidiasis. Systemic infections due to <it>C. albicans </it>exhibit good susceptibility to fluconazole and echinocandins. However, the echinocandin anidulafungin was recently demonstrated to be more effective than fluconazole for systemic <it>Candida </it>infections in a randomized, double-blind trial among 245 patients. In that trial, most infections were caused by <it>C. albicans</it>, and all respective isolates were susceptible to randomized study drug. We sought to better understand the factors associated with the enhanced efficacy of anidulafungin and hypothesized that intrinsic properties of the antifungal agents contributed to the treatment differences.</p> <p>Methods</p> <p>Global responses at end of intravenous study treatment in patients with <it>C. albicans </it>infection were compared post-hoc. Multivariate logistic regression analyses were performed to predict response and to adjust for differences in independent baseline characteristics. Analyses focused on time to negative blood cultures, persistent infection at end of intravenous study treatment, and 6-week survival.</p> <p>Results</p> <p>In total, 135 patients with <it>C. albicans </it>infections were identified. Among these, baseline APACHE II scores were similar between treatment arms. In these patients, global response was significantly better for anidulafungin than fluconazole (81.1% vs 62.3%; 95% confidence interval [CI] for difference, 3.7-33.9). After adjusting for baseline characteristics, the odds ratio for global response was 2.36 (95% CI, 1.06-5.25). Study treatment and APACHE II score were significant predictors of outcome. The most predictive logistic regression model found that the odds ratio for study treatment was 2.60 (95% CI, 1.14-5.91) in favor of anidulafungin, and the odds ratio for APACHE II score was 0.935 (95% CI, 0.885-0.987), with poorer responses associated with higher baseline APACHE II scores. Anidulafungin was associated with significantly faster clearance of blood cultures (log-rank <it>p </it>< 0.05) and significantly fewer persistent infections (2.7% vs 13.1%; <it>p </it>< 0.05). Survival through 6 weeks did not differ between treatment groups.</p> <p>Conclusions</p> <p>In patients with <it>C. albicans </it>infection, anidulafungin was more effective than fluconazole, with more rapid clearance of positive blood cultures. This suggests that the fungicidal activity of echinocandins may have important clinical implications.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00058682">NCT00058682</a></p

Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer

Purpose Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. Patients and methods PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients’ tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13. Results: 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life. Conclusion: The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066 patients with ALK-positive NSCLC are consistent with previous reports. Trial registration number Phase 2 trial (NCT00932451); Results

Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA)

BACKGROUND: In patients receiving oral anticoagulation, improved control can reduce adverse outcomes such as stroke and major hemorrhage. However, little is known about patient-level predictors of anticoagulation control. OBJECTIVES: To identify patient-level predictors of oral anticoagulation control in the outpatient setting. PATIENTS/METHODS: We studied 124,619 patients who received oral anticoagulation from the Veterans Health Administration from October 2006 to September 2008. The outcome was anticoagulation control, summarized using percentage of time in therapeutic International Normalized Ratio range (TTR). Data were divided into inception (first 6 months of therapy; 39,447 patients) and experienced (any time thereafter; 104,505 patients). Patient-level predictors of TTR were examined by multivariable regression. RESULTS: Mean TTRs were 48% for inception management and 61% for experienced management. During inception, important predictors of TTR included hospitalizations (the expected TTR was 7.3% lower for those with two or more hospitalizations than for the non-hospitalized), receipt of more medications (16 or more medications predicted a 4.3% lower than for patients with 0-7 medications), alcohol abuse (-4.6%), cancer (-3.1%), and bipolar disorder (-2.9%). During the experienced period, important predictors of TTR included hospitalizations (four or more hospitalizations predicted 9.4% lower TTR), more medications (16 or more medications predicted 5.1% lower TTR), alcohol abuse (-5.4%), female sex (- 2.9%), cancer (-2.7%), dementia (-2.6%), non-alcohol substance abuse (-2.4%), and chronic liver disease (-2.3%). CONCLUSIONS: Some patients receiving oral anticoagulation therapy are more challenging to maintain within the therapeutic range than others. Our findings can be used to identify patients who require closer attention or innovative management strategies to maximize benefit and minimize harm from oral anticoagulation therapy

Risk-Adjusted Percent Time in Therapeutic Range as a Quality Indicator for Outpatient Oral Anticoagulation: Results of the Veterans Affairs Study To Improve Anticoagulation (VARIA)

Background- Oral anticoagulation is safer and more effective when patients receive high-quality care. However, there have been no prior efforts to measure quality of oral anticoagulation care or to risk adjust it to ensure credible comparisons. Our objective was to profile site performance in the Veterans Health Administration (VA) using risk-adjusted percent time in therapeutic range (TTR). Methods and Results- We included 124 551 patients who received outpatient oral anticoagulation from 100 VA sites of care for indications other than valvular heart disease from October 1, 2006, to September 30, 2008. We calculated TTR for each patient and mean TTR for each site of care. Expected TTR was calculated for each patient and each site based on the variables in the risk adjustment model, which included demographics, comorbid conditions, medications, and hospitalizations. Mean TTR for the entire sample was 58%. Site-observed TTR varied from 38% to 69% or from poor to excellent. Site-expected TTR varied from 54% to 62%. Site risk-adjusted performance ranged from 18% below expected to 12% above expected. Risk adjustment did not alter performance rankings for many sites, but for other sites, it made an important difference. For example, the site ranked 27th of 100 before risk adjustment was one of the best (risk-adjusted rank, 7). Risk-adjusted site rankings were consistent from year to year (correlation between years, 0.89). Conclusions- Risk-adjusted TTR can be used to profile the quality of outpatient oral anticoagulation in a large, integrated health system. This measure can serve as the basis for quality measurement and quality improvement efforts

Re-Examining the Recommended Follow-Up Interval after an In-Range INR Value: Results from the Veterans AffaiRs Study to Improve Anticoagulation (VARIA)

BACKGROUND: Patients receiving oral anticoagulation should be tested often enough to optimize control, but excessive testing increases burden and cost. We examined the relationship between the follow-up interval after an in-range (2.0-3.0) INR and anticoagulation control. METHODS: We studied 104,451 patients receiving anticoagulation from 100 anticoagulation clinics in the Veterans Health Administration (VA). Most patients (98,877) recorded at least one in-range INR followed by another INR within 56 days. For each such patient, we selected the last in-range INR and characterized the interval between this index value and the next INR. The independent variable was site mean follow-up interval after an in-range INR. The dependent variable was site mean risk-adjusted percent time in therapeutic range (TTR). RESULTS: Site mean interval varied from 25-38 days. As the mean site follow-up interval became longer, risk-adjusted TTR was worse (-0.51% per day, p = 0.004). This relationship persisted when the index value was the first consecutive in-range INR (-0.63%, p \u3c 0.001), or the second (-0.58%, p \u3c 0.001), but not the third or greater (-0.12%, p = 0.46). CONCLUSIONS: Sites varied widely regarding follow-up intervals after in-range INR (25-38 days). Shorter intervals were generally associated with better anticoagulation control, but after a third consecutive in-range value, this relationship was greatly attenuated and no longer statistically significant. Our results suggest that a maximum interval of 28 days after the first or second in-range value and consideration of a longer interval after the third or greater consecutive in-range value may be appropriate

Prompt Repeat Testing After Out-of-Range INR Values: A Quality Indicator for Anticoagulation Care

Background- Improved control of oral anticoagulation reduces adverse events. A program of quality measurement is needed for oral anticoagulation. The interval until the next test after an out-of-range International Normalized Ratio (INR) value (the follow-up interval ) could serve as a process of care measure. Methods and Results- We studied 104,451 patients cared for by 100 anticoagulation clinics in the Veterans Health Administration (VA). For each site, we computed the average follow-up interval after low (≤1.5) or or high (≥4.0) INR. Our outcome was each site\u27s average anticoagulation control, measured by percent time in therapeutic range (TTR); 59 837 patients (57%) contributed to the low INR analysis, 37 697 (36%) contributed to the high INR analysis, and all patients contributed to the dependent variable (mean site TTR). After a low INR, site mean follow-up interval ranged from 10 to 24 days. Longer follow-up intervals were associated with worse site-level control (1.04% lower for each additional day, P\u3c0.001). After a high INR, site mean follow-up interval ranged from 6 to 18 days, with longer follow-up intervals associated with worse site-level control (1.12% lower for each additional day, P\u3c0.001). These relationships were somewhat attenuated but still highly statistically significant when the proportion of INR values in-range was used as the dependent variable rather than TTR. Conclusions- Prompt repeat testing after out-of-range INR values is associated with better anticoagulation control at the site level and could be an important part of a quality improvement effort for oral anticoagulation

Relationship between molecular response and quality of life with bosutinib or imatinib for chronic myeloid leukemia

Patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) can be effectively treated with tyrosine kinase inhibitors (TKIs) and achieve a lifespan similar to the general population. The success of TKIs, however, requires long-term and sometimes lifelong treatment; thus, patient-assessed health-related quality of life (HRQoL) has become an increasingly important parameter for treatment selection. Bosutinib is a TKI approved for CP CML in newly diagnosed adults and in those resistant or intolerant to prior therapy. In the Bosutinib Trial in First-Line Chronic Myelogenous Leukemia Treatment (BFORE), bosutinib demonstrated a significantly higher major molecular response rate compared with imatinib, with maintenance of HRQoL (measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire), after 12 months of first-line treatment. We examined relationships between molecular response (MR) and HRQoL. MR values were represented by a log-reduction scale (MRLR; a continuous variable). A repeated-measures longitudinal model was used to estimate the relationships between MRLR as a predictor and each FACT-Leu domain as an outcome. Effect sizes were calculated to determine strength of effects and allow comparisons across domains. The majority of FACT-Leu domains (with the exception of social well-being and physical well-being) demonstrated a significant relationship with MRLR (p &amp;lt; 0.05). Our results showed variable impact of clinical improvement on different dimensions of HRQoL. For patients who achieved M