George Tomlinson

Influence of obstructive sleep apnea on mortality in patients with heart failure.

OBJECTIVES This study sought to determine, in patients with heart failure (HF), whether untreated moderate to severe obstructive sleep apnea (OSA) is associated with a higher mortality rate than in patients with mild to no sleep apnea (M-NSA). BACKGROUND Obstructive sleep apnea is common in patients with HF and exposes the heart and circulation to adverse mechanical and autonomic effects. However, its effect on mortality rates of patients with HF has not been reported. METHODS In a prospective study involving 164 HF patients with left ventricular ejection fractions (LVEFs) < or =45%, we performed polysomnography and compared death rates between those with M-NSA (apnea-hypopnea index [AHI] <15/h of sleep) and those with untreated OSA (AHI > or =15/h of sleep). RESULTS During a mean (+/- SD) of 2.9 +/- 2.2 and a maximum of 7.3 years of follow-up, the death rate was significantly greater in the 37 untreated OSA patients than in the 113 M-NSA patients after controlling for confounding factors (8.7 vs. 4.2 deaths per 100 patient-years, p = 0.029). Although there were no deaths among the 14 patients whose OSA was treated by continuous positive airway pressure (CPAP), the mortality rate was not significantly different from the untreated OSA patients (p = 0.070). CONCLUSIONS In patients with HF, untreated OSA is associated with an increased risk of death independently of confounding factors.

Socio-economic, gender and health services factors affecting diagnostic delay for tuberculosis patients in urban Zambia

In‐depth interviews regarding health seeking behaviour were conducted with 202 adults registered with pulmonary tuberculosis at the centralized Chest Clinic in Lusaka, Zambia. The median (mean) diagnostic delay was 8.6 (9) weeks, and was significantly associated with the following factors: female sex, lower education, more than six instances of health‐seeking encounters, outpatient diagnosis of tuberculosis, and visiting a private doctor or traditional healer. More effective tuberculosis control interventions require novel methods of accessing women and less educated people. Decentralization of public tuberculosis care and improved integration with private sector health providers may also reduce diagnostic delay.

Comparative Effectiveness of Immunosuppressants and Biologics for Inducing and Maintaining Remission in Crohn's Disease: A Network Meta-analysis

BACKGROUND & AIMS There is controversy regarding the best treatment for patients with Crohns disease because of the lack of direct comparative trials. We compared therapies for induction and maintenance of remission in patients with Crohns disease, based on direct and indirect evidence. METHODS We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Central databases, through June 2014. We identified randomized controlled trials (N = 39) comparing methotrexate, azathioprine/6-mercaptopurine, infliximab, adalimumab, certolizumab, vedolizumab, or combined therapies with placebo or an active agent for induction and maintenance of remission in adult patients with Crohns disease. Pairwise treatment effects were estimated through a Bayesian random-effects network meta-analysis and reported as odds ratios (OR) with a 95% credible interval (CrI). RESULTS Infliximab, the combination of infliximab and azathioprine (infliximab + azathioprine), adalimumab, and vedolizumab were superior to placebo for induction of remission. In pair-wise comparisons of anti-tumor necrosis factor agents, infliximab + azathioprine (OR, 3.1; 95% CrI, 1.4-7.7) and adalimumab (OR, 2.1; 95% CrI, 1.0-4.6) were superior to certolizumab for induction of remission. All treatments were superior to placebo for maintaining remission, except for the combination of infliximab and methotrexate. Adalimumab, infliximab, and infliximab + azathioprine were superior to azathioprine/6-mercaptopurine: adalimumab (OR, 2.9; 95% CrI, 1.6-5.1), infliximab (OR, 1.6; 95% CrI, 1.0-2.5), infliximab + azathioprine (OR, 3.0; 95% CrI, 1.7-5.5) for maintenance of remission. Adalimumab and infliximab + azathioprine were superior to certolizumab: adalimumab (OR, 2.5; 95% CrI, 1.4-4.6) and infliximab + azathioprine (OR, 2.6; 95% CrI, 1.3-6.0). Adalimumab was superior to vedolizumab (OR, 2.4; 95% CrI, 1.2-4.6). CONCLUSIONS Based on a network meta-analysis, adalimumab and infliximab + azathioprine are the most effective therapies for induction and maintenance of remission of Crohns disease.

Quality of life in early Parkinson's disease: Impact of dyskinesias and motor fluctuations

The impact of dyskinesias and motor fluctuations on quality of life (QOL) at various stages in the course of Parkinsons disease (PD) is not well understood. In 301 subjects with early PD enrolled in a clinical trial (CALM‐PD), we quantified the impact of motor complications on QOL and investigated how this changes over time. We also compared QOL related to demographic and treatment characteristics. The presence of dyskinesias was associated with visual analogue scale (VAS) scores 3.0 of 100 points higher (better) than those without dyskinesias in years 1 to 2, even when adjusting for Unified Parkinsons Disease Rating Scale (UPDRS) motor scores. The positive association between dyskinesias and QOL scores was more marked in older patients. In years 3 to 4, dyskinesias no longer had a significant relationship with QOL. Younger subjects had higher VAS scores. Gender, motor fluctuations, and treatment regimen had no significant association with QOL, although a trend was found toward a small negative effect of motor fluctuations on QOL. We conclude that motor complications that occur within the first 4 years of treatment of PD do not have a significant negative effect on quality of life as measured by a visual analogue scale for most patients.

Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial

BACKGROUND Exemestane can prevent breast cancer in postmenopausal women. Because of potential widespread use, we examined the safety of exemestane on bone health. METHODS In this nested safety substudy of the MAP.3 trial (a randomised, placebo-controlled, double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer), we included postmenopausal women from five centres who were eligible to participate in MAP.3, not osteoporotic, not receiving drugs for bone-related disorders, with baseline lumbar spine, total hip, and femoral neck T-scores above -2·0. The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density (BMD) at the distal radius by high-resolution peripheral quantitative CT. The primary analysis was per protocol using a non-inferiority margin. This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT01144468, and has been extended to 5 years of unmasked follow-up. FINDINGS 351 women (176 given exemestane, 175 given placebo; median age 61·3 years [IQR 59·2-64·9]) met our inclusion criteria and completed baseline assessment. At the time of clinical cutoff, 242 women had completed 2-year follow-up (124 given exemestane, 118 given placebo). From baseline to 2 years, the mean percent change in total volumetric BMD at the distal radius was -6·1% (95% CI -7·0 to -5·2) in the exemestane group and -1·8% (-2·4 to -1·2) in the placebo group (difference -4·3%, 95% CI -5·3 to -3·2; p<0·0001). The lower limit of the 95% CI was lower than our non-inferiority margin of negative 4% (one-sided test for non-inferiority p=0·70), meaning the hypothesis that exemestane was inferior could not be rejected. At the distal tibia, the mean percent change in total volumetric BMD from baseline to 2 years was -5·0% (95% CI -5·5 to -4·4) in the exemestane group and -1·3% (-1·7 to -1·0) in the placebo group (difference -3·7%, 95% CI -4·3 to -3·0; p<0·0001). The mean percent change in cortical thickness was -7·9% (SD 7·3) in the exemestane group and -1·1% (5·7) in the placebo group at the distal radius (difference -6·8%, 95% CI -8·5 to -5·0; p<0·0001) and -7·6% (SD 5·9) in the exemestane group and -0·7% (4·9) in the placebo group at the distal tibia (difference -6·9%, -8·4 to -5·5; p<0·0001). Decline in areal BMD, as measured by dual-energy x-ray absorptiometry, in the exemestane group compared with the placebo group occurred at the lumbar spine (-2·4% [95% CI -3·1 to -1·7] exemestane vs -0·5% [-1·1 to 0·2] placebo; difference -1·9%, 95% CI -2·9 to -1·0; p<0·0001), total hip (-1·8% [-2·3 to -1·2] exemestane vs -0·6% [-1·1 to -0·1] placebo; difference -1·2%, -1·9 to -0·4; p=0·004), and femoral neck (-2·4% [-3·2 to -1·7] exemestane vs -0·8% [-1·5 to 0·1] placebo; difference -1·6%, -2·7 to -0·6; p=0·002). INTERPRETATION 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation. Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits. For women taking exemestane, regular bone monitoring plus adequate calcium and vitamin D supplementation are important. To assess the effect of our findings on fracture risk, long-term follow-up is needed. FUNDING Canadian Breast Cancer Research Alliance (Canadian Institutes of Health Research/Canadian Cancer Society).

A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue

Fatigue is common in primary biliary cirrhosis (PBC). Altered central serotonergic neurotransmission may be involved in its pathogenesis. This multicenter, randomized, double‐blind, placebo‐controlled, crossover trial evaluated the efficacy of ondansetron, a selective 5‐HT3 receptor subtype antagonist, for treating fatigue in PBC. A crossover design was chosen, allowing subjects to serve as their own controls—appropriate to evaluate fatigue, a subjective symptom. Sixty patients with clinically stable PBC, a Fatigue Severity Score (FSS) > 4, and no other identifiable cause for fatigue were enrolled. Subjects were randomized to receive ondansetron (4 mg) or placebo orally 3 times daily for 4 weeks (period 1). Subjects then crossed over, after a minimum 1‐week washout period, for a further 4 weeks of ondansetron or placebo (period 2). Fatigue was measured at the beginning and end of each period by using the FSS and Fatigue Impact Scale (FIS). Six patients withdrew; the remaining 54 subjects had a mean baseline FSS of 5.55 (±0.1). Response to study medication in period 1 versus period 2 was not uniform; thus, it was necessary to analyze the trial periods separately. In period 1, there was no significant additional fatigue reduction on ondansetron over placebo. During period 2, FSS and FIS decreased significantly on ondansetron versus placebo (P = .001). However, period 2 results were invalidated because drug side effects unblinded subjects (constipation affected 63.0% of patients taking ondansetron, versus 13.3% on placebo). In conclusion, ondansetron administration did not confer clinically significant fatigue reduction when compared with placebo in our study population. (HEPATOLOGY 2005;41:1305–1312.)

Management of decreased bone mineral density in men starting androgen‐deprivation therapy for prostate cancer

To determine whether clinicians discuss bone‐specific side‐effects with patients on androgen‐deprivation therapy (ADT) for prostate cancer, or prescribe lifestyle and pharmacological interventions for low bone mineral density (BMD), as decreased BMD is a common side‐effect of ADT, leading to increased risk of fracture.

Fatigue in older adults with acute myeloid leukemia : predictors and associations with quality of life and functional status

Fatigue in older adults with acute myeloid leukemia: predictors and associations with quality of life and functional status

The proportion of variation in perioperative transfusion decisions in Canada attributable to the hospital.

PurposeHospital variation in transfusion practices has been described previously but the proportion of variation attributable to the hospital has not. The objective of this report was to quantify hospital variation in red cell transfusion decisions perioperatively for patients undergoing coronary artery bypass surgery (CABG).MethodsWe used a cross-sectional study design using pretestedself-administered mailed questionnaires sent to all anesthesiologists and cardiac surgeons involved in CABG in Canada.ResultsResponses were received from anesthesiologists from all 32 hospital sites and from cardiac surgeons from 30/32 sites (94%). There was variation attributable to the hospital in transfusion triggers selected (P < 0.0001). For patients who had uncomplicated CABG surgery, the range of transfusion triggers among hospitals for the intraoperative and postoperative case scenarios were 61 to 80 g·L-1 and 64 to 80 g·L-1, respectively. The hospital accounted for 20% of the variation in the transfusion practice intraoperatively and postoperatively. The remainder of the variation was attributable to the individual physician. Academic affiliation and the number of surgical cases performed at the hospital were not significant factors impacting on the transfusion triggers selectedConclusionThis is the first study to quantify the variation in red cell transfusion practices according to individual physicians and the hospital. The variation attributed to the hospital is significant. The explanation for the variation in transfusion decisions that relate to the hospital needs to be explored further in order to help optimize transfusion practice.RésuméObjectifLa variation entre les hôpitaux en ce qui touche aux pratiques transfusionnelles a été précédemment décrite, mais la proportion de cette variation imputable aux hôpitaux ne l’a pas encore été. L’objectif de ce compte-rendu était de quantifier la variation entre les hôpitaux dans les pratiques transfusionnelles périopératoires de globules rouges chez les patients subissant un pontage aortocoronarien (PAC).MéthodeNous avons utilisé un concept d’étude transversale en nous basant sur des questionnaires pré-testés et auto-administrés envoyés à tous les anesthésiologistes et les chirurgiens cardiaques pratiquant des PAC au Canada.RésultatsDes réponses ont été reçues d’anesthésiologistes des 32 centres hospitaliers et de chirurgiens cardiaques de 30/32 sites (94 %). Une variation imputable à l’hôpital a été observée dans les seuils d’amorce de transfusion choisis (P < 0,0001). Chez les patients ayant une chirurgie PAC sans complication, la gamme de seuils transfusionnels entre les hôpitaux pour les scénarios de cas peropératoire et postopératoire allait de 61 à 80 g·L-1 et de 64 à 80 g·L-1, respectivement. L’hôpital était responsable de 20 % de la variation dans la pratique transfusionnelle peropératoire et postopératoire. Le reste de la variation était imputable au médecin lui-même. L’affiliation universitaire et le nombre de cas chirurgicaux effectués à l’hôpital n’ont pas constitué de facteurs significatifs ayant un impact sur les seuils de transfusion choisis.ConclusionCette étude est la première à quantifier la variation dans les pratiques de transfusion de globules rouges selon les médecins eux-mêmes et l’hôpital. La variation attribuée à l’hôpital est significative. L’explication pour la variation dans les décisions de transfusion liées à l’hôpital doit être approfondie afin d’améliorer la pratique de la transfusion.

Non-biologic remission maintenance therapy in adult patients with ANCA-associated vasculitis: A systematic review and network meta-analysis

OBJECTIVE To determine the comparative efficacy of non-biologic treatments for remission maintenance in ANCA-associated vasculitis. METHODS We identified all randomized trials comparing leflunomide, azathioprine, methotrexate or mycophenolate mofetil in adult patients with granulomatosis with polyangiitis or microscopic polyangiitis. Relapse-free survival was compared through hazard ratios (HR) using a Bayesian fixed-effects network meta-analysis. Multiple sensitivity analyses were performed to explore biases identified in one trial using original trial data. RESULTS Three trials were available (leflunomide-methotrexate, methotrexate- azathioprine, azathioprine-mycophenolate). Mycophenolate was inferior to all treatments, although the 95% credible interval (CrI) of the HR relative to methotrexate crossed 1. Leflunomide was superior to azathioprine (HR 0.43 [95% CrI: 0.14-1.3]) and methotrexate (HR 0.47 [95% CrI: 0.18-1.2]), although the 95% CrI also crossed 1. There was a 90% probability that leflunomide was the best treatment. After down weighting the effect of leflunomide vs. methotrexate for early trial termination and slow MTX dose escalation, there remained a 55% probability leflunomide was best. CONCLUSION Based on indirect evidence, leflunomide is effective in maintaining remission in granulomatosis with polyangiitis or microscopic polyangiitis relative to other non-biologic treatments. Further randomized trials of leflunomide are needed for confirmation.