Received Augmentation Therapy Research Articles

Healthcare resource utilization and costs among patients with alpha-1 antitrypsin deficiency with liver and/or lung disease: a longitudinal retrospective study in the USA.

Aim: To evaluate all-cause and liver-associated healthcare resource utilization (HCRU) and costs among patients with alpha-1 antitrypsin deficiency (AATD) with liver disease (LD) and/or lung disease (LgD). Materials & methods: This was a retrospective analysis of linked administrative claims data from the IQVIA PharMetrics® Plus and the IQVIA Ambulatory Electronic Medical Records (AEMR) databases from 1July2021 to 31January 2022. Patients with AATD in the IQVIA PharMetrics Plus database were included with ≥1 inpatient or ≥2 outpatient medical claims ≥90days apart with a diagnosis of AATD, or with records indicating a protease inhibitor (Pi)*ZZ/Pi*MZ genotype in the IQVIA AEMR database with linkage to IQVIA PharMetrics Plus. For a patient's identified continuous enrollment period, patient time was assigned to health states based on the initial encounter with an LD/LgD diagnosis. A unique index date was defined for each health state, and HCRU and costs were calculated per person-year (PPY). Results: Overall, 5136 adult and pediatric patients from the IQVIA PharMetrics Plus and IQVIA AEMR databases were analyzed. All-cause and liver-associated HCRU and costs were substantially higher following onset of LD/LgD. All-cause cost PPY ranged from US $11,877 in the absence of either LD/LgD to US $74,015 in the presence of both LD and LgD. Among liver transplant recipients in the AATD with LD health state, liver-associated total costs PPY were US $87,329 1-year pre-transplantation and US $461,752 1-year post-transplantation. In the AATD with LgD and AATD with LD and LgD health states, patients who received augmentation therapy were associated with higher all-cause total costs PPY and lower liver-associated total costs PPY than their counterparts who did not receive augmentation therapy. Conclusion: Patients with AATD had increased HCRU and healthcare costs in the presence of LD and/or LgD. HCRU and healthcare costs were highest in the AATD with LD and LgD health state.

Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ)

α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P= .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P= .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Augmentation Therapy Modulates Systemic Inflammation in Individuals with Alpha-1 Antitrypsin Deficiency and Chronic Obstructive Pulmonary Disease.

Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder that leads to chronic obstructive pulmonary disease (COPD) and lower circulating levels of AAT, which is a protease inhibitor with potent anti-inflammatory effects. In order to better understand the presence of systemic inflammation in AAT-deficient individuals with COPD, we investigatedthe plasma levels of C-reactive protein (CRP). AAT-deficient individuals and a matched cohort with a normal AAT genotype were recruited from the Alpha-1 Foundation DNA and Tissue Bank. AAT genotypes were determined by a combination of a Taqman-based assay. AAT and CRP levels were determined by nephelometry. Comparisons were determined by unpaired t-test and standard Pearson's correlation. Our study included 40 control participants and 742 AAT-deficient participants, of which 498 received augmentation therapy. In the AAT-deficient participants, the plasma AAT was 20.2±11.6µM and 4.5±1.3µM (P<0.0001) with and without augmentation therapy, respectively, and the CRP was 0.32±0.53mg/dL and 0.69±1.97mg/dL (P=0.0169), respectively. There was a negative correlation between the percentage predicted of forced expiratory volume in 1 second and CRP in the group not receiving augmentation therapy (r=-0.2528, P<0.05), and there was no correlation in participants receiving augmentation therapy. Compared to healthy individuals, AAT-deficient individuals with COPD have higher levels of circulating CRP, suggesting increased systemic inflammation. However, AAT-deficient individuals receiving augmentation therapy had lower plasma CRP levels compared to those who are not.

Demographic and clinical characteristics of patients with α1-antitrypsin deficiency genotypes PI*ZZ and PI*SZ in the Spanish registry of EARCO.

BackgroundThe Spanish registry of α1-antitrypsin deficiency (AATD) integrated in the European Alpha-1 Research Collaboration (EARCO) provides information about the characteristics of patients, in particular those with the PI*SZ genotype, which is frequent in Spain.MethodIndividuals with severe AATD defined as proteinase inhibitor (PI) genotypes PI*ZZ, PI*SZ and other rare deficient variants were included from February 1, 2020, to February 1, 2022. The analysis focused on a comparison of the characteristics of PI*ZZ and PI*SZ patients.Results409 patients were included (53.8% men) with a mean±sd age of 53.5±15.9 years. Genotypes were PI*ZZ in 181 (44.7%), PI*SZ in 163 (40.2%), PI*SS in 29 (7.2%) and other in 32 (7.9%). 271 (67.4%) had lung disease: 175 chronic obstructive pulmonary disease (43.5%), 163 emphysema (40.5%) and 83 bronchiectasis (20.6%). Patients with the PI*SZ genotype were younger, more frequently non-index cases and had a lower frequency of respiratory diseases except asthma compared with PI*ZZ patients. Among patients with respiratory diseases, PI*SZ individuals were significantly older both at onset of symptoms and at diagnosis; only asthma was more frequent in PI*SZ than in PI*ZZ individuals. Twelve PI*SZ patients (15.4%) received augmentation therapy compared with 94 PI*ZZ patients (66.2%; p<0.001).ConclusionsThere is a high prevalence of PI*SZ in Spain. Patients with the PI*SZ genotype were older at symptom onset and diagnosis and had less severe lung disease compared with PI*ZZ patients. The prevalence of asthma was higher in PI*SZ, and up to 15% of PI*SZ patients received augmentation therapy.

Long-term effect of α1-antitrypsin augmentation therapy on the decline of FEV1 in deficient patients: an analysis of the AIR database.

BackgroundPatients with ZZ (Glu342Lys) α-1-antitrypsin deficiency (ZZ-AATD) who received augmentation therapy with α-1-antitrypsin (AAT) in randomised controlled trials over 2–3 years failed to show a significant reduction of the annual decline of forced expiratory volume in 1 s (FEV1).MethodsTo compare the trajectory of FEV1 change during 4 or more years in ZZ-AATD patients with emphysema receiving or not receiving intravenous augmentation therapy, a retrospective analysis of FEV1 values entered in the Alpha-1 International Registry (AIR) of ZZ-AATD patients from five different European countries (Germany, UK, Spain, Italy and the Netherlands) was performed. The post-bronchodilator FEV1 % predicted values for baseline and follow-up over time from patients were analysed using linear mixed effects models.ResultsData of 374 patients were analysed: 246 untreated and 128 treated with intravenous AAT augmentation therapy. The mean±sd follow-up duration of the untreated group was 8.60±3.34 years and 8.59±2.62 years for the treated group. The mixed effects model analysis showed a mean FEV1 decline of −0.931% predicted per year (95% CI −1.144 to −0.718) in the untreated group and a decline of −1.016% predicted per year (95% CI −1.319 to −0.7145) in the treated group. The likelihood ratio test showed no difference between the two groups (p=0.71).ConclusionIn our study population, we could not detect a significant difference in the annual decline of FEV1 by AAT augmentation treatment over a mean period of 8.6 years. Other approaches are needed to validate any benefit of augmentation therapy.

Epidemiology and current treatment patterns of treatment-resistant depression in Scotland: a CPRD study

AimsTo assess the incidence and treatments currently used in clinical practice for the treatment of treatment-resistant depression (TRD) in Scotland.BackgroundPatients with major depressive disorder (MDD) who have not responded to at least two successive antidepressant (AD) treatments in a single episode are described as having Treatment-Resistant Depression (TRD). Epidemiological data on TRD in Scotland is lacking. Furthermore, there is no data to our knowledge on therapies prescribed in Scottish clinical practice to treat TRD.MethodA retrospective, longitudinal cohort study was conducted using Clinical Practice Research Datalink (CPRD) medical records. Adult patients were indexed on AD prescription, requiring MDD diagnosis within 90 days, from Jan 2011-May 2018 with 360-day baseline and 180-day minimum follow-up periods. Failure of ≥2 adequate oral AD regimens following indexing constituted TRD classification. Incidence rates of MDD and TRD (within the MDD cohort) and treatment lines following TRD classification were derived.ResultThe analysis included 20,059 patients with MDD (mean age 44 years, 63% female, median follow-up 59 months); 1,374 (6.8%) were classified as TRD. Median time-to-TRD classification was 25 months. The incidence rate of MDD was 15.9 per 1,000 patient-years and for TRD was 14.7 per 1,000 MDD-patient-years. For all first four post-TRD treatment lines, SSRI monotherapy was the most commonly prescribed therapy, followed by combination (dual/triple) therapy and augmentation therapy (at least one oral AD supplemented with lithium, an antipsychotic or an anticonvulsant therapy). At first-line of TRD treatment, 1,050 (76.4%) patients received monotherapy AD, 212 (15.4%) received combination AD therapy and 112 (8.2%) received augmentation therapy. The most common monotherapy treatments at first-line TRD were sertraline (15.6%), mirtazapine (13.8%), fluoxetine (12.2%) and venlafaxine (11.6%). Among combination therapies, mirtazapine, venlafaxine, sertraline and amitriptyline were frequently used. Among the TRD and MDD cohort, no somatic treatments were coded in CPRD, although the use of these treatments was likely underestimated.ConclusionMonotherapy AD treatment was the most common therapy type for all four post-TRD treatment lines. These data support the need for new treatments that can achieve and maintain therapeutic response, and avoid continuous cycling through similar AD therapies.This study was sponsored by Janssen Cilag Ltd.

Relationship Between UGT1A4 and UGT2B7 Polymorphisms and the Steady-State Plasma Concentrations of Lamotrigine in Patients With Treatment-Resistant Depressive Disorder Receiving Lamotrigine as Augmentation Therapy.

In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy. The subjects were 103 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses. There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication. This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

BRONCHIECTASIS IN ALPHA-1 ANTITRYPSIN DEFICIENCY: A SINGLE-CENTER REVIEW

SESSION TITLE: Asthma and Comorbid Disease SESSION TYPE: Original Investigations PRESENTED ON: 10/10/2018 08:45 AM - 09:45 AM PURPOSE: Alpha-1 Antitrypsin Deficiency (A1ATD) is a genetic disease that results in abnormal alpha-1 antitrypsin protein polymers which cannot be released from hepatocytes. This results in low circulating alpha-1 antitrypsin and hepatotoxicity. Alpha-1 antitrypsin has a protective effect in the lungs by neutralizing pro-inflammatory enzymes, such as neutrophil elastase, and sufficiently low levels can result in emphysema.1 Bronchiectasis has also been associated with A1ATD since the original description of the disease.2 Augmentation therapy has been shown to have beneficial pulmonary effects in patients with emphysema, but outcome data in patients with bronchiectasis and the effects of augmentation therapy is lacking. METHODS: Patients with A1ATD and alpha-1 carrier status evaluated at Mayo Clinic Rochester from January 1, 2000 to October 1, 2016 were included in this retrospective review. Data relating to demographics, exacerbations, spirometry, and other causes of bronchiectasis were extracted. Patients with fewer than 12 months of augmentation therapy were excluded from outcome comparisons. RESULTS: 122 patients were included in the final analysis, of which 47 (38.5%) had bronchiectasis. 10 patients with bronchiectasis had MZ or MS genotypes. Compared to those without bronchiectasis, patients with bronchiectasis had a higher mean baseline rate of pulmonary exacerbations (0.73/year vs. 0.28/year, p=0.003). 34 patients received augmentation therapy, including 18 patients with bronchiectasis. Compared to patients without bronchiectasis who also received augmentation, those with bronchiectasis had a faster mean rate of decline in DLCO (-0.56 vs. +0.51 mL/min/mmHg/year, p=0.010), and a higher mean rate of post-treatment exacerbations (+1.28/year vs +0.5/year, p=0.011). Comparing patients with bronchiectasis and emphysema who did and did not receive augmentation, those who received augmentation therapy had more exacerbations compared to their baseline (+0.53/year vs. -0.31/year, p=0.019) and lower mean baseline percent predicted forced expiratory volume in one second (FEV1%) (46.5% vs. 67.8%, p=0.006) and DLCO (12.9 vs. 18.9 mL/min/mmHg, p=0.015), although the change over time was not significantly different. CONCLUSIONS: Bronchiectasis is a common finding in A1ATD, and is not exclusive to patients with ZZ genotypes. Patients with bronchiectasis in this cohort had higher rates of pulmonary exacerbations, regardless of treatment with augmentation therapy. CLINICAL IMPLICATIONS: The role of augmentation therapy for patients with bronchiectasis in the absence of emphysema is unclear and warrants additional studies. DISCLOSURES: No relevant relationships by Megan Dulohery Scrodin, source=Web Response No relevant relationships by Gregory Stroh, source=Web Response

Prediction of an Optimal Dose of Lamotrigine for Augmentation Therapy in Treatment-Resistant Depressive Disorder From Plasma Lamotrigine Concentration at Week 2

The authors have previously shown that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder. The present study investigated whether or not an optimal dose of lamotrigine could be predicted from plasma lamotrigine concentration at week 2. The subjects were 37 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 15), bipolar I disorder (n = 6), and bipolar II disorder (n = 16). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 16 subjects who were not taking valproate and 75 mg/d for 21 subjects taking valproate, respectively. Blood sampling was performed at weeks 2 and 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. There were significant linear relationships between the plasma lamotrigine concentrations at week 2 (x) and those at week 8 (y) for subjects who were not taking valproate (P < 0.01) and those taking valproate (P < 0.01). Regression equations were y = 2.032x + 2.549 for the former and y = 3.599x + 5.752 for the latter, respectively. Based on the equations, a nomogram to estimate an optimal dose of lamotrigine could be calculated. The present study suggests that an optimal dose of lamotrigine for augmentation therapy in treatment-resistant depressive disorder can be predicted from a plasma lamotrigine concentration at week 2.

Spanish Registry of Patients With Alpha-1 Antitrypsin Deficiency; Comparison of the Characteristics of PISZ and PIZZ Individuals

Alpha-1 antitrypsin deficiency (AATD) is associated with an increased risk of pulmonary emphysema and liver disease. The growing interest in this deficiency in Spain led to the development of the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency (REDAAT) in 1993. At present, the REDAAT is a network of more than 350 health care professionals and the database includes a total of 511 individuals. The adult population included consists of 469 individuals (91.8% of the total) and their phenotype distribution is: 348 Pi*ZZ (74.2%), 100 Pi*SZ (21.3%) and 21 carriers of rare variants (4.5%). The most frequent diagnosis is lung disease (74.6%). Patients with chronic obstructive pulmonary disease (COPD) registered in the REDAAT constitute approximately 15% of the expected cases of AATD-related COPD in Spain. Pi*ZZ showed more severe impairment in lung function and younger age at baseline compared with Pi*SZ. The mean decline in FEV1 in the Pi*ZZ subgroup was –23 ml/year (SD:142.8), being –18 ml/year (SD:108.8) in Pi*SZ. Forty-five percent of the Pi*ZZ individuals received augmentation therapy. A total of 61 deaths was recorded.The characteristics of the REDAAT population demonstrate some differential trends compared to other series: distribution of phenotypes, inclusion of children and patients treated with replacement therapy. Patients with the Pi*SZ phenotype were older and had milder lung function impairment. The most important challenge of this registry is to collect good quality long-term data that will allow better understanding of the natural history of the disease in real life.

Alpha-1-antitrypsin augmentation therapy in deficient individuals enrolled in the Alpha-1 Foundation DNA and Tissue Bank

Intravenous augmentation therapy with purified intravenous alpha-1 antitrypsin replaces the deficient protein and is the only currently approved treatment for alpha-1 antitrypsin deficiency (AATD) related lung disease. While augmentation therapy has been available for more than 20 years, there are a limited number of studies evaluating the effect of augmentation on lung function. We examined the decline in forced expiratory volume in one second (FEV(1)) in patients enrolled in the Alpha-1 Foundation DNA and Tissue Bank in relation to the use or not of alpha-1 antitrypsin augmentation therapy. For the purpose of our analysis we included 164 patients with AATD and PI ZZ genotype. Mean age of the patients was 60 years, 52% were females, 94% were white and 78% ex-smokers. The mean FEV(1) at baseline was 1.7 L and the mean FEV(1) % of predicted was 51.3%. The mean follow-up time was 41.7 months. A total of 124 (76%) patients received augmentation therapy (augmented group) while 40 patients (24%) did not received it (non-augmented group). When adjusted by age at baseline, sex, smoking status, baseline FEV(1) % of predicted, the mean overall change in FEV(1) was 47.6 mL/year, favoring the augmented group (DeltaFEV(1) 10.6 +/- 21.4 mL/year) in comparison with the non-augmented group (DeltaFEV(1) -36.96 +/- 12.1 mL/year) (P = 0.05). Beneficial DeltaFEV(1) were observed in ex-smokers and the group with initial FEV(1) % of predicted of <50%. No differences were observed in mortality. In conclusion, augmentation therapy improves lung function in subjects with AATD when adjusted by age, gender, smoking status and baseline FEV(1) % of predicted. The beneficial effects were noted in ex-smoker subjects with FEV(1) below 50% of predicted.

Exacerbations in subjects with alpha-1 antitrypsin deficiency receiving augmentation therapy

The frequency, characteristics and impact of acute exacerbations in patients with alpha-1 antitrypsin deficiency (AATD) and COPD who are on intravenous alpha-1 antitrypsin augmentation therapy have not been described. 922 subjects with AATD and COPD on augmentation therapy (mean age 54.5 years) were followed with monthly telephone surveys to record exacerbation characteristics, as well as healthcare resource utilization and health-related quality of life (HRQoL). Exacerbations were defined by symptom-based and healthcare resource utilization (HRU) criteria. During the 1-year follow-up, 91.5% of participants experienced at least one exacerbation (mean 2.4 exacerbations per subject, median 2, and mean duration 17 days per episode, regardless of the definition used). Most exacerbations were categorized as severe by symptoms and moderate by HRU criteria. Subjects who had 3 or more exacerbations (48.6%) were younger, had higher medication use and had higher tobacco consumption compared with subjects with less exacerbations. Subjects with frequent exacerbations had the worst baseline HRQoL scores, as well as more physician visits, emergency room visits, and hospitalizations. Although most subjects received augmentation therapy on a weekly basis, other infusion schedules were more commonly observed in subjects with fewer exacerbations. COPD exacerbations occur frequently and are associated with significant disease burden in subjects with AATD receiving augmentation therapy.

Caractéristiques des patients inclus dans la cohorte française de patients emphysémateux déficitaires en alpha-1 antitrypsine

Alpha-1 antitrypsin deficiency is associated with the occurrence of pulmonary emphysema. The aim of this study is to describe the characteristics of patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema. We describe a prospective cohort study including adult patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema confirmed by CT scan living in France. Patients' clinical and functional characteristics, quality of life measures and management were recorded every 6 months during a five-year period. 201 patients were included from 56 centres between 2005 and 2008. The characteristics of 110 patients have been analysed. Mean age was 50 years (SD:11.8), 62.7% were males, 90% were tobacco smokers. The main functional results (% predicted) were: FEV1: 42.8 (19.6), CPT: 128.3 (21.7), CRF: 167.0 (46.0), 6 minute walking distance (meters): 413 (130). 51 (46.4%) patients received augmentation therapy. Augmentation therapy was administered weekly (37.5%), twice a month (35.4%) or monthly (25.5%). Study centre was the only factor associated with the likelihood to received augmentation therapy. The clinical and functional characteristics as well as management of these patients varied markedly. There is a need for a standardization of the management of patients with alpha-1 antitrypsin deficiency associated pulmonary emphysema.

Augmentation Therapy With α1-Antitrypsin: Patterns of Use and Adverse Events

To describe patterns of prescribing augmentation therapy, and types and rates of adverse events in the National Heart, Lung, and Blood Institute Registry for Individuals with Severe Deficiency of Alpha(1)-Antitrypsin. Observational cohort study with follow-up visits every 6 to 12 months for up to 7 years. The rate and dosing frequency with which Registry participants were prescribed to receive augmentation therapy by their managing physicians, and the type and frequency of adverse events, classified in two ways: severity of self-reported symptoms, and actions taken as a consequence of the symptom. Over the course of Registry follow-up, 66% (n = 747) of the participants received augmentation therapy at some time. In keeping with recommendations made in the 1989 American Thoracic Society (ATS) statement, 75% of participants with airflow obstruction at first visit (defined as FEV(1) < 80% predicted) received augmentation therapy within 3 years, though some participants with FEV(1) > or = 80% predicted (14%) also received augmentation therapy. Among those with COPD for whom augmentation therapy was not prescribed, financial constraints were the reported cause in 30%. Observed patterns also varied from approved practice, in that dosing frequencies other than the US Food and Drug Administration-approved, once-weekly regimen were frequently prescribed. The overall rate of reported adverse events was 0.02 per patient-month, with 83% of participants reporting no events. This overall rate was composed of 16% considered mild events, 76% moderate events, and 9% severe events. We conclude that augmentation therapy was generally well tolerated and, consistent with ATS guidelines, physicians generally did not prescribe augmentation therapy for subjects with FEV(1) > or = 80% predicted. However, the large percentage of subjects with FEV(1) <80% predicted not receiving augmentation therapy and the frequent use of 2- to 3-week or monthly dosing reflects variation of practice from suggested treatment guidelines.

Risk Factors for Falls During Treatment of Late-Life Depression

Prior studies have found that antidepressant medications are associated with an increased risk of falling in elderly persons. However, little is known about the prevention of falls during treatment for depression in elderly persons. This study evaluated the time course and potential risk factors for falls in a treatment protocol for late-life depression to identify specific at-risk periods and risk factors for falls in this population. One hundred four subjects aged 69 years and over were treated in a protocolized manner using paroxetine and interpersonal psychotherapy. Those who did not respond received augmentation therapy with bupropion, nortriptyline, or lithium. Subjects were assessed at baseline and weekly during treatment; demographic and clinical characteristics of those who experienced a fall during treatment were compared with those who did not fall. Cox proportional hazards models were used to define risk factors for falls in univariate and multivariate models. During a mean of 21 weeks of treatment, 40 subjects (38%) fell. About half (53%) of the subjects fell during the first 6 weeks of treatment. In the multivariate model, memory impairment and orthostatic changes in blood pressure during treatment were risk factors for falling. Additionally, augmentation with bupropion appeared to be a risk factor for falls in univariate analysis, but this result is preliminary due to the small number of subjects who took bupropion. Increased monitoring for falls is warranted during the acute treatment of late-life depression. When treating such patients, clinicians should be especially watchful of those with memory impairments or those who develop orthostatic blood pressure changes; orthostatic blood pressure should be measured throughout acute treatment. Additionally, augmenting paroxetine with bupropion may also increase the risk of falls, and this medication combination should be used with caution in elderly patients.

High-dose cytosine arabinoside: clinical response to therapy in acute leukemia.

High dose cytosine arabinoside (HD-AraC) was evaluated 1) as remission induction therapy for refractory acute leukemia and high risk AML, 2) as augmentation therapy for acute leukemia, and 3) as conditioning therapy prior to allogeneic bone marrow transplantation for acute leukemia. Seven of 10 patients with refractory AML achieved complete remission with a median time to response of 32 days. Four of 8 patients with previously untreated, high risk AML had a favorable therapeutic outcome with 3 patients achieving complete remission and 1 patient converting to a chronic myeloproliferative disorder. Median time to response was 36 days. Three of 8 patients with refractory ALL achieved partial remission with response also demonstrated for 5 of 6 patients with meningeal leukemia. Seven patients with previously untreated AML, predicted to be at high risk of failing conventional remission induction therapy because of persistent marrow hypercellularity after 6 days, received augmentation therapy with HD-AraC. Four patients achieved complete remission with a median time to response of 36 days. Augmentation therapy was also employed for refractory AML and refractory ALL. HD-AraC was included as part of a conditioning regimen for allogeneic bone marrow transplantation to provide initial cytoreductive/cytoablative therapy and to provide therapy directed at leukemic sanctuary sites. Treatment was well tolerated with the major toxicities being myelosuppression, nausea, vomiting and diarrhea. Neurologic toxicity, manifested as confusion and/or cerebellar ataxia occured in 13% of patients and was reversible in all but one instance. Other toxicities were conjunctivitis and/or photophobia (22%), hepatic enzyme abnormalities (13%), rash (17%), and drug-related fever (2%).