Nazir Lone

Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis

Background: Roflumilast, a phosphodiesterase 4 inhibitor, has been shown to improve lung function and reduce exacerbation rates, but is associated with adverse events (AEs). The purpose of this study was to systematically review the clinical effectiveness and safety of roflumilast. Methods: A systematic search was made of MEDLINE, Cochrane trials database, DARE and CINAHL. Randomized, controlled trials of more than 12 weeks’ duration comparing roflumilast with placebo were reviewed. Studies were pooled to yield relative risk (RR), incident rate difference or weighted mean differences with 95% confidence intervals (CIs). Results: Eight trials (8698 patients) met the inclusion criteria. Roflumilast significantly reduced moderate to severe exacerbations (RR 0.85; 95% CI 0.80−0.91) compared with placebo, but not severe exacerbations (RR 0.83; 95% CI 0.68–1.01) or mortality (RR 0.90; 95% CI 0.63–1.28). Roflumilast significantly improved lung function relative to placebo, but not quality of life measures. AEs (RR 1.11; 95% CI 1.03–1.19) and discontinuations of treatment due to AEs (RR 1.63; 95% CI 1.45–1.84) were significantly more frequent with roflumilast than placebo. In the chronic obstructive pulmonary disease (COPD) Safety Pool (12,054 patients), the overall incidence of serious AEs did not differ between groups. However, atrial fibrillation (0.4% versus 0.2%; p = 0.02) and suicidality (0.08% versus 0%) were more frequent with roflumilast than placebo. Conclusions: The efficacy of roflumilast appears modest compared with other available therapies for COPD. Further studies are needed to investigate the risk–benefit ratio and long-term safety of roflumilast before its wider use.

Mortality benefit of vasopressor and inotropic agents in septic shock: A Bayesian network meta-analysis of randomized controlled trials

OBJECTIVE The choice of vasopressor in septic shock has been a matter of debate. The purpose of this study was to systematically review overall evidence of vasopressor and inotropic agents in septic shock using a Bayesian network meta-analysis. METHODS Databases, including Medline, Scopus, CINAHL, and Google Scholar were searched to identify relevant studies. Eligible studies were randomized controlled trials that reported mortality rates on the use of vasopressors and inotropes in patients with septic shock. We chose to use 28-day mortality as the outcome assessment criterion. RESULTS Fourteen studies with a total of 2811 patients were included in the analysis. Norepinephrine (NE) and NE + low-dose vasopressin but not epinephrine (EPI) were associated with significantly reduced mortality compared with dopamine. (Odds ratio, 0.80 [95% credibility interval, 0.65-0.99], 0.69 [0.48-0.98], and 0.56 [0.26-1.18], respectively). The addition of an inotropic agent such as dobutamine or dopexamine did not reduce mortality compared with EPI or NE alone. CONCLUSIONS Our results support the use of NE with or without low-dose vasopressin as the first-line vasopressor therapy in septic shock. No concrete evidence exists to support the use of EPI over dopamine as the second-line agent or the addition of an inotropic agent.

Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis.

Background A combination therapy with inhaled corticosteroid (ICS) and a long-acting beta agonist (LABA) is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations. Currently, there are five ICS/LABA combination products available on the market. The purpose of this study was to systematically review the efficacy of various ICS/LABA combinations with a network meta-analysis. Methods Several databases and manufacturer’s websites were searched for relevant clinical trials. Randomized control trials, at least 12 weeks duration, comparing an ICS/LABA combination with active control or placebo were included. Moderate and severe exacerbations were chosen as the outcome assessment criteria. The primary analyses were conducted with a Bayesian Markov chain Monte Carlo method. Results Most of the ICS/LABA combinations reduced moderate-to-severe exacerbations as compared with placebo and LABA, but none of them reduced severe exacerbations. However, many studies excluded patients receiving long-term oxygen therapy. Moderate-dose ICS was as effective as high-dose ICS in reducing exacerbations when combined with LABA. Conclusion ICS/LABA combinations had a class effect with regard to the prevention of COPD exacerbations. Moderate-dose ICS/LABA combination therapy would be sufficient for COPD patients when indicated. The efficacy of ICS/LABA combination therapy appeared modest and had no impact in reducing severe exacerbations. Further studies are needed to evaluate the efficacy of ICS/LABA combination therapy in severely affected COPD patients requiring long-term oxygen therapy.

Comparative efficacy of long-acting muscarinic antagonists in preventing COPD exacerbations: a network meta-analysis and meta-regression

Background: We hypothesized a class effect of currently available long-acting muscarinic antagonists (LAMAs; i.e. tiotropium as a dry powder inhaler or a soft mist inhaler, aclidinium bromide, and glycopyrronium) in preventing chronic obstructive pulmonary disease (COPD) exacerbations. The hypothesis was tested with a network meta-analysis. Methods: Several databases and manufacturer’s websites were searched for relevant clinical trials. Randomized, controlled trials, of at least 12 weeks duration, comparing a LAMA with placebo or another LAMA were included. Moderate-to-severe and severe exacerbations were chosen as the outcome assessment criteria. The data were pooled using network meta-analysis. Results: A total of 27 studies with 48,140 subjects were included. All LAMAs reduced moderate-to-severe exacerbations compared with placebo. However, there were no statistically significant differences in preventing moderate-to-severe or severe exacerbations among LABAs. In a subgroup analysis restricting studies to those that had a minimum of 6 months of treatment, glycopyrronium was associated with the least-effective strategy and aclidinium was associated with the greatest probability of being the best therapy in preventing severe exacerbations. Our meta-regression analysis suggested that the prevention of COPD exacerbations were less effective in studies which allowed concomitant use of a long-acting beta agonist (LABA). Conclusion: All LAMAs were equally effective in preventing moderate-to-severe exacerbations. Aclidinium was associated with the lowest risk for severe exacerbations when treatment duration was 6 months or longer. The concomitant use of LABA may not enhance the efficacy of LAMAs in preventing COPD exacerbations. More studies are needed to further examine above findings.

Multiloculated pleural effusion detected by ultrasound only in a critically-ill patient

Summary Background: Multiloculated pleural effusion is a life-threatening condition that needs early recognition. Drainage by chest tube might be difficult which necessitates a surgical intervention. While x-ray typically does not show loculations, CT scan might not also identify the loculations. Ultrasound has a high sensitivity in detecting pleural diseases including multiloculated pleural effusion. Case Report: A 55-year-old female presented with dyspnea, cough and yellowish sputum for 3 days. Her heart rate was 136 bpm ,O2 saturation 88%, and WBC 21,000/mcL. Chest x-ray showed complete opacification of right lung. A chest tube insertion was unsuccessful. CT scan of the chest showed large pleural effusion occupying the right hemithorax with collapse of the right lung. Bedside ultra-sound showed a multiloculated pleural effusion with septations of different thickness. The patient subsequently underwent thoracotomy which showed multiple, fluid-filled loculations with significant adhesions. The loculations were dissected along with decortications of thick a pleural rind. Blood and pleural fluid cultures grew Streptococcus pneumoniae and the patient was treated successfully with Penicillin G. Conclusions: We advocate bedside ultrasound in patients with complete or near complete opacification of a hemithorax on chest x-ray. CT scan is less likely to show septations within pleural effusions compared to ultrasounnd. Therefore, CT scan and ultrasound are complementary for the diagnosis of empyema and multiloculated pleural effusion.

Roflumilast: a green signal is yet to come

Chronic obstructive pulmonary disease (COPD) is a disabling disease and prevalent across nations with a huge economic impact. COPD is the third leading cause of death in the United States and will become the third leading cause of death worldwide by 2030. The increasing morbidity and mortality of COPD are a major threat to public health (1,2). Epidemiological evidence has shown that a substantial proportion of COPD mortality and morbidity is related to cardiovascular disease (3-5). Multiple studies have demonstrated that systemic inflammation and release of inflammatory mediators in COPD may potentially mediate its cardiovascular complications (6).

Hodgkin’s Lymphoma presenting as an obstructing endobronchial mass—A rare presentation

We report a case of Hodgkin’s lymphoma presenting as an endobronchial mass in a 40-year-old man with history of 8 months of non-specific symptoms like cough, fatigue and weight loss. Initially he was treated with broad-spectrum antibiotics for suspicion of pneumonia without recovery. Radiographic work-up showed cavitary consolidation of the upper lobe of the left lung, followed by bronchoscopy which showed obstructing mass of the upper lobe of the left lung mimicking primary lung carcinoma. Immunohistochemical staining of the specimen was suggestive of Hodgkin’s lymphoma. The patient responded well to the chemotherapy regimen.

Spontaneous thyroid hemorrhage on chronic anticoagulation therapy

Even though highly vascularized, the thyroid gland rarely has spontaneous bleeding. Bleeding into the thyroid gland can result in potentially lethal acute airway compromise. This case report describes an elderly patient on warfarin for atrial fibrillation, who presented with swelling on the right side of her neck causing acute airway obstruction. An urgent computed tomography of the neck showed an enlarging hemorrhage into the right lobe of the thyroid gland. She was initially intubated for airway protection and her anticoagulation was reversed to stop the bleeding. She was closely monitored in the intensive care unit. After an uncomplicated tracheal extubation and recovery, she was discharged and scheduled for an elective total thyroidectomy. We desire that physicians be aware of this rare, potentially lethal bleeding complication.

Aripiprazole-induced hypersensitivity pneumonitis

Aripiprazole is an atypical antipsychotic agent commonly used in the management of schizophrenia. Aripiprazole has not been reported to have an association with interstitial lung disease. We describe a case of a 36-year-old woman who began to experience respiratory issues shortly after starting aripiprazole and presented to us 4 years later with progressive exertional shortness of breath. High-resolution CT of the chest showed a bilateral ground glass pattern. Video-assisted thoracoscopy with biopsy revealed alveolar septal thickening and an inflammatory infiltrate composed mainly of lymphocytes, suggestive of chronic hypersensitivity pneumonitis. After discontinuing aripiprazole and initiating prednisolone therapy, the patient’s pulmonary symptoms improved. This case highlights that aripiprazole can cause hypersensitivity pneumonitis in susceptible individuals.

Cardiovascular Safety of Roflumilast

In this issue of CHEST (see page 758), White et al 1 report signifi cantly lower major adverse cardiovascular events (MACEs) for rofl umilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P 5 .019) from data in 12,054 patients with COPD. In addition to the studies analyzed not being designed or powered to examine cardiovascular outcomes, we would like to point out other limitations of the study. First, the incidence of nonfatal stroke was the only component of MACEs that showed a statistically signifi cant difference. It may not be appropriate to use a composite outcome if the magnitude of treatment effects is not comparable across the outcome components. 2 It may be fair to say that rofl umilast could decrease cerebrovascular events but not cardiovascular events or mortality because rofl umilast was not associated with a lower incidence of such MACE components compared with placebo. Second, the incidence of atrial fi brillation was not included in the study. Our recent meta-analysis showed that atrial fi brillation was signifi cantly more frequent with rofl umilast than with placebo (0.4% vs 0.2%; P 5 .02). 3 The COPD safety pool White et al 1 used included this information, and they should have incorporated it into the study. Third, the discontinuation rate because of adverse effects was signifi cantly more frequent with rofl umilast than with placebo (15% vs 9.2%, P , .0001). 3 The imbalance of dropout rates between the two groups may have affected the study results. The results may have been quite different if all patients recruited for rofl umilast continued to take the drug during the entire study period. Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts: Dr MacNee has acted in an advisory capacity for GlaxoSmithKline plc; Pfi zer, Inc; Novartis AG; and Almirall, SA. He has received payment from GlaxoSmithKline plc and Pfi zer, Inc for research programs and clinical activities and has also received payments from Boehringer-Ingelheim GmbH, GlaxoSmithKline, AstraZeneca, Novartis AG, and Janssen Pharmaceuticals to travel to meetings and/or present at conferences. Dr Maclay has reported no potential confl icts of interest exist with any companies/organi zations whose products or services may be dis cussed in this article . Correspondence to: John D. Maclay, MBChB MD, University of Edinburgh, Centre for Infl ammation Research, 47 Little France Crescent, Edinburgh EH16 4SB, Scotland; e-mail: johnmaclay@ gmail.com