Even Low-Dose Steroids Increase the Risk of CVD

The use of oral glucocorticoids for a range of immune-mediated inflammatory diseases, even at low doses, is associated with an increased risk of adverse cardiovascular events, according to a new analysis of patients treated in primary care clinics in the United Kingdom.

After 1 year of treatment, patients taking less than 5 mg of prednisone had a twofold higher absolute risk of fatal and nonfatal CVD, including MI, heart failure, atrial fibrillation, cerebrovascular disease, PAD, and abdominal aortic aneurysm, when compared with individuals not taking oral glucocorticoids. For those taking more than 25 mg of prednisolone, the absolute risk of CVD events was sixfold greater than for nonusers.

“Most physicians would think that at doses of less than 5 mg, the risk of toxicity is minimal, but what we’re seeing more and more is that this is not true and the risk remains high,” lead investigator Mar Pujades-Rodriguez, PhD (University of Leeds, England), told TCTMD. “Because patients are taking these doses for quite a long time, this risk accumulates.”

It’s widely accepted that high-dose steroid use increases the risk of CVD, with numerous studies showing that current glucocorticoid users are at an increased risk of MI, heart failure, stroke, and atrial fibrillation. Some of those studies, say the researchers, highlight a risk only in patients taking daily doses greater than 5 or 10 mg per day, and as such, the toxicity of low-dose steroid therapy is less clear.

Risk Consistent Across Inflammatory Conditions 

The new analysis, published today in PLoS Medicine, focused on 87,794 patients included in the Clinical Practice Research Datalink (CPRD) with immune-mediated inflammatory disease, such as giant cell arteritis and/or polymyalgia rheumatica, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and/or vasculitis, and without preexisting CVD. Median follow-up was 5.0 years, and mean duration since diagnosis of the immune-mediated disease was 9.6 years. Incident CVD occurred in 13,426 patients, including 6,013 who developed atrial fibrillation, 7,727 who developed heart failure, and 2,809 who had an acute MI.

To account for the variation in the relative anti-inflammatory effects of different glucocorticoids, the researchers converted the daily dosage in milligrams for each prescription to an equivalent dose of prednisolone. They also converted the proportion of patient-years spent at each level of daily exposure to various dosages. Overall, 80% of person-years were spent not exposed to glucocorticoids, while 6.0% of person-years were exposed to less than 5.0 mg and 11.2% person-years exposed to 5.0 to 14.9 mg. For dosages of 15.0 to 24.9 mg and 25 mg or more, the person-years of exposure were 1.6% and 1.2%, respectively.

The incidence of all-cause CVD increased from 18.5 per 1,000 person-years during periods of nonuse to 45.6 per 1,000 person-years for patients exposed to ≥ 25 mg daily of prednisolone-equivalent. The cumulative incidence of all-cause CVD at 1 year increased from 1.4% for periods of nonexposure to 3.8% for those treated with less than 5 mg and 8.9% for those treated with more than 25 mg. Compared with nonusers, those treated with less than 5 mg per day had a relative 74% higher risk of all-cause CVD, with the hazard ratios ranging from 1.52 among those with polymyalgia rheumatic and/or giant cell arteritis to 2.82 for systemic lupus erythematosus.   

For each 5-mg increase in the daily dose of oral glucocorticoids in the overall cohort, the risk of all-cause CVD increased 9% (HR 1.09; 95% CI 1.07-1.11 per 5 mg/day).

In their analysis, the researchers also assessed risk based on the patient’s total cumulative exposure in the year prior to the start of follow-up and again observed a dose-dependent increased risk of CVD. Compared with those not treated, the largest cumulative exposure (≥ 7,300 mg) in patients with all types of immune-mediated disease was associated with a relative 76% increased risk of CVD. The risk was highest for those with systemic lupus erythematosus (HR 2.09; 95% CI 1.53-2.85).    

Importantly, the risk of CVD with low-dose prednisolone was observed across all types of inflammatory disease. While estimations of risk were quite similar in all six conditions, Pujades-Rodriguez said, the guidelines only emphasize the higher risk of cardiovascular disease with steroid therapy in those inflammatory arthritis and lupus erythematosus.

“It’s not only those conditions,” she said. “For any inflammatory disease treated with a steroid in the medium-to-long term, the risk [of CVD] needs to be taken into account.”   

Pujades-Rodriguez recommended that patients with inflammatory disease requiring oral glucocorticoids be treated with the minimal dose required while being closely monitored for cardiovascular risk. If a higher dose of steroid is required to treat a flare-up, she said the dose should be reduced as soon as possible, although the specific treatment course will be dependent on the patient’s needs. She noted that many patients in the CPRD with inflammatory disease had modifiable risk factors, including one-quarter with obesity and another 25% with hypertension.

“Physicians need to keep this in mind, as well,” she said. “It’s not only a question of monitoring their inflammatory condition but [also] at the same time looking at whether there are other risk factors for cardiovascular disease, such as hypertension or diabetes or obesity. . . . Any of the traditional risk factors will need to be assessed and monitored accordingly as it will help reduce their risk.”

COVID-19 and Steroid Therapy

In COVID-19, dexamethasone, an anti-inflammatory steroid, is used for patients requiring ventilation for oxygen therapy based on the strength of the RECOVERY trial. To TCTMD, Pujades-Rodriguez said these patients are dramatically different from those studied in their analysis, and that their results can’t be extrapolated to this setting.

However, for patients being treated with steroids prior to becoming infected with COVID-19, there might be a need for higher drug doses as a result of the infection. Here, the United Kingdom’s Society for Endocrinology has provided some recommendations, with the dose adapted depending on the patient’s status, length of prior steroid treatment, and so on. However, in this setting, as well as in general, patients should never abruptly stop their steroids, said Pujades-Rodriguez.

“This needs to be carefully assessed by the treating physician to ensure that the patient receives the minimal necessary dose to achieve an appropriate risk-benefit balance,” she said. “What our study highlights is the importance that, for any patient, the minimal dose required is provided and that the dose and requirements are closely monitored by physicians in order to reduce the dose as quickly as possible and safely to prevent any risks that are not outweighed by the benefits of using the medication.”