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69.7 months ( 95 % CI 49.4 - not reached ), for an HR of 0.52 ( 95 % CI 0.34-0.92 ; p = 0.03 ).

However , in this subgroup analysis , the authors observed no statistically significant difference in PFS between those originally treated with BR ( 72.1 months ; 95 % CI 52.7-not reached ) and FR ( 93.6 months ; 95 % CI 45-not reached ; HR = 1.02 ; 95 % CI 0.42- 2.50 ; p = 0.96 ).

The authors noted that the post-hoc design of this analysis was a limitation of the study . Since the study began in 2003 and patients had received their first treatment prior to enrollment , fewer than half ( 42 %; n = 91 ) had previously received rituximab , Prof . Rummel and coauthors explained . “ Because most patients now receive rituximabbased chemotherapy in the first-line setting , results might not be fully generalizable to these patients ,” they wrote . “ Results from the subset of patients given rituximab maintenance must be interpreted with caution , given that this was a post-hoc analysis , included a small sample size , and patients were not randomly assigned between groups .” Other study limitations include investigators not being blinded to treatments patients received , and assessing the relative contribution of rituximab maintenance to study results .

REFERENCE

Rummel M , Kaiser U , Balser C , et al . Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas : a multicentre , randomised , open-label , non-inferiority phase 3 trial . Lancet Oncol . 2016 ; 17:57-66 .

— PROF . MATTHIAS RUMMEL

Patients with chronic inflammatory diseases , such as chronic obstructive pulmonary disease and asthma , are already at an increased risk for developing a first pulmonary embolism ( PE ) and , according to a case-control study published in Thrombosis Research , the use of oral or inhaled corticosteroids to treat these chronic diseases puts patients at an increased risk for recurrent PE .

“ A significant proportion of patients suffer from recurrent PE , in particular after discontinuation of anticoagulant therapy ,” the authors , led by Marlous M . S . Sneeboer , MD , from the Department of Respiratory Medicine at the Academic Medical Center in Amsterdam , the Netherlands , wrote . “ Since most of these patients require treatment with inhaled or oral corticosteroids for control of their disease , it is important to know whether the use of these drugs also predisposes [ them ] for recurrent events .”

Dr . Sneeboer and colleagues analyzed data from 1,414 adult patients with a primary diagnosis of PE and a prescription for vitamin K antagonists ( VKAs ) registered in the Dutch PHARMO database from 1998 to 2008 . Of these , 384 patients experienced a recurrent PE ; these cases were matched with 1,030 patients without recurrent PE .

The majority of patients in both case and control groups had been hospitalized for cancer :

• Ever hospitalized for cancer : 12 ( 3.1 %) cases and 52 ( 5.0 %) controls

• For asthma or COPD : 6 ( 1.6 %) and 21 ( 2.0 %)

• For Crohn ’ s disease or ulcerative colitis : 1 ( 0.3 %) and 2 ( 0.2 %)

• For systemic lupus erythematosus or rheumatoid arthritis : 4 ( 1.0 %) and 3 ( 0.3 %)

The median time from initial to recurrent PE was 14 months ( interquartile range [ IQR ] = 7.0-33.8 months ) and , in all patients , the median duration of VKA treatment after the first PE episode was 9.6 months ( IQR 6.5-24.8 months ).

All odds ratios ( ORs ) for the risk of recurrent PE were adjusted for the use of VKA in the last month prior to the PE ; use of acetylsalicylic acid , clopidogrel , and carbasalate calcium ; and patients ’ underlying diseases .

Use of corticosteroids was categorized as non-use , current use (< 1 month prior to recurrent PE ), recent use ( 1-6 months prior to recurrent PE ), and past use (> 6 months prior to recurrent PE ). Investigators found no difference between oral or inhaled corticosteroid use between patients with or without recurrent PE ( TABLE 2 ).

Current use of oral corticosteroids increased the risk of recurrent PE ( odds ratio [ OR ] = 3.74 ; 95 % CI 2.04- 6.87 ; p = 0.02 ), compared with those who did not use oral corticosteroids .

This increased risk was not seen among patients who were considered recent users of oral corticosteroids ( OR = 1.07 ; 95 % CI 0.60-1.91 ), and past users actually had a lower risk of recurrent PE ( OR = 0.46 ; 95 % CI 0.28 – 0.74 ) compared with patients who did not use oral corticosteroids .

There was no relationship between dose of oral corticosteroids and the risk of recurrent PE , the authors added .

Similar patterns were observed among patients who used inhaled corticosteroids ( compared with nonusers ) with respect to recurrent PE :

• Current use ( defined as < 1 month prior to recurrent PE ; OR = 1.55 ; 95 % CI 0.90-2.67 )

• Recent use ( defined as 1 to 6 months prior to recurrent PE ; OR = 1.01 ; 95 % CI 0.61-1.68 )

• Past use ( defined as > 6 months prior to recurrent PE ; OR = 0.52 ; 95 % CI 0.30-0.90 ; p = 0.10 for all )

When patients used a combination of oral and inhaled corticosteroids , the risk of recurrent PE increased substantially ( OR = 4.60 ; 95 % CI 1.54- 13.76 ), compared with non-users .

Dr . Sneeboer and colleagues proposed several possible mechanisms that could explain the association between the use of corticosteroids and the development of recurrent PE , including that these medications have been shown to lead to a pro-coagulant state in healthy volunteers . However , the authors noted that the study ’ s results were limited by “ whether this increased risk was caused by corticosteroids themselves or by the underlying inflammatory diseases , or both , could not be established .” Other study limitations include the data deriving from a fixed database , which may not include all factors contributing to PE ; and the selection of control patients .

“ Given the frequent use of this type of medication in patients with chronic inflammatory diseases , the clinical impact may be substantial ,” the authors concluded , recommending that clinicians “ be rather restrictive ” in prescribing corticosteroids to patients who already have experienced a first PE – particularly those who have frequent disease exacerbations . “[ In these cases ] novel anti-inflammatory treatments with less adverse effects might be more appropriate .”

REFERENCE

Sneeboer MMS , Hutten BA , Majoor CJ , et al . Oral and inhaled corticosteroid use and risk of recurrent pulmonary embolism . Thromb Res . 2016 ; 140:46-50 .

TABLE 2 . Corticosteroid Use Among All Patients

Patients With Recurrent PE ( n = 384 )

Patients Without Recurrent PE ( n = 1,030 )

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