Corticosteroids Increase the Risk of Recurrent Thrombotic Events

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).

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 non-users) 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.