This large nested case–control study addressed specifically the risk of cardiovascular and cerebrovascular disease associated with oral glucocorticoid treatment. This study shows that, in a cohort of patients receiving glucocorticoid by some route, those receiving prescriptions for oral glucocorticoid have a 25% higher risk of cardiovascular disease than patients with non-oral, non-systemic glucocorticoids after adjusting for confounders. The OR was higher among current users of oral glucocorticoids and patients taking the highest dose. The increased use of oral corticosteroids was greatest for patients with heart failure, was less obvious for patients with ischaemic heart disease, and was not apparent for patients with cerebrovascular disease. Moreover, the increased proportion of current oral glucocorticoid use among patients with cardiovascular disease was observed in patients with different underlying disease indications for glucocorticoid treatment, although it was greater among patients with COPD than among patients with RA or other diseases. Therefore, we found a relatively small but significant increase in risk of cardiovascular events among patients at a high baseline risk. Given the high prevalence of glucocorticoid use in the general population, the number needed to harm—that is, the number of patients needed to be treated with glucocorticoids for one additional outcome event to occur—is clinically relevant.
The way cases and controls were identified means that some caution is required in the interpretation of the magnitude of these associations. To ensure active registration of each case in the GPRD and hence to ensure complete outcome data, all participants had to have received at least one prescription during the study period. To minimise bias we chose to compare patients receiving oral glucocorticoids with patients receiving topical glucocorticoids. This means that the estimates in this study reflect a comparison of oral glucocorticoid use with glucocorticoid use by another route, not with non-use of glucocorticoids. Since topical (when frequently used) and inhaled glucocorticoids may also exhibit systemic effects, this approach may slightly underestimate associations with glucocorticoid treatment. Estimation of glucocorticoid exposure is not straightforward, however, since glucocorticoid treatment for chronic disease is typically intermittent over many years. Cumulative dose in intermittent users is difficult to estimate because prescriptions may not always be recorded—for example, if short courses of drugs are issued during hospital admissions—and because the average time between start of follow up and the index date was only about three years. We therefore believe that the best indicator of exposure is the current dose being prescribed to patients who are current users in the three months leading up to their index date; these patients are most likely to be receiving chronic glucocorticoid treatment. Indeed, we found that current users were those patients with the highest number of prescriptions during follow up and who had the highest cumulative dose compared with non-current users of glucocorticoids. In the group of current users we found the strongest associations with cardiovascular disease together with evidence of a dose–response relation.
The ascertainment of cases and controls is also subject to misclassification. All outcome events are related to incident diagnoses. There could have been misclassification with respect to diagnoses of study outcomes but this is likely to be non-differential between cases and controls for cardiovascular and cerebrovascular events. As fluid retention is a known side effect of glucocorticoid use, we cannot exclude the possibility that diagnostic suspicion bias accounts for part of the observed effect for heart failure.
Further, risk factors for cardiovascular disease may be identified and treated more readily among patients being prescribed glucocorticoids. Finally, smoking is more common among patients with COPD and RA and may explain an apparent association between glucocorticoid treatment and cardiovascular disease. To account for these potential confounders, ORs were adjusted for all relevant drug prescriptions and for BMI and smoking. These adjustments had only modest effects on the estimates, suggesting that the associations between cardiovascular disease and oral glucocorticoid use are independent of these confounders in this study.
A major methodological concern in observational studies arises from the lack of random allocation of patients to use oral glucocorticoids and hence the potential for confounding by indication.27
As both RA and COPD are associated with cardiovascular morbidity and mortality, the underlying disease, rather than exposure to glucocorticoids, may explain the observed association. To address this issue, we examined the consistency of the association between oral glucocorticoid use and cardiovascular disease among patients with different underlying diseases: cases and controls were matched according to the presence of RA, COPD, or the absence of either condition.
The results may also be biased due to confounding by disease severity, as patients using oral glucocorticoids are likely to be more severely affected by the underlying disease. Thus, we adjusted for use of other disease modifying drugs that reflect, at least in part, disease activity in RA. Duration of disease was not a confounder in this study.
Finally, the use of glucocorticoids in RA, COPD, and other conditions may be different. The most frequent indications for oral glucocorticoid treatment besides RA and COPD are skin, neurological, and gastrointestinal tract diseases,1
in which patterns of prescription may differ from those in RA and COPD.
Despite these limitations, the results in table 4 show associations between oral glucocorticoid prescription and cardiovascular disease in all groups and show interesting differences between groups. Among patients with COPD, use of oral glucocorticoids was associated more strongly with heart failure than with ischaemic heart disease. Among patients with RA, heart failure and ischaemic heart disease were similarly associated with oral glucocorticoid use. Among patients with neither RA nor COPD, only heart failure was significantly associated with oral glucocorticoid treatment. These data suggest that there is an interaction between the associations of cardiovascular outcome and the underlying disease indication or oral glucocorticoid use, but that both have independent effects.
In all of our analyses, use of oral glucocorticoids was most strongly associated with heart failure. Associations with ischaemic heart disease events were relatively weak and there were no associations with cerebrovascular disease. Sodium retention and increase in extracellular fluid are well known side effects of glucocorticoids and may be responsible for precipitating diagnosis, particularly in patients with cor pulmonale caused by COPD. However, the association between oral glucocorticoid treatment and heart failure was also present among patients with as well as those without COPD who had not received a recorded prescription for glucocorticoids for more than a year before diagnosis, long after any sodium retaining effect would have corrected itself. We can only speculate on the mechanism for this, although it may involve actions of corticosteroids on cardiac remodelling and fibrosis.
Our hypothesis a priori was that oral glucocorticoid use would predict ischaemic heart disease events and strokes because glucocorticoids adversely affect long term risk factors including obesity, blood pressure, plasma lipids, and glucose. However, adjustment for body mass index and antihypertensive, lipid lowering, and hypoglycaemic medications did not substantially attenuate the association between oral glucocorticoid treatment and cardiovascular outcomes. It may be that the risk factors mediating adverse effects of glucocorticoids were not adequately treated in many patients or that subtle changes in risk factors occurred that were insufficient to cause practitioners to initiate treatment but were sufficient to adversely affect outcome. These explanations do not, however, explain the discrepancy between associations of oral glucocorticoid use and occlusive disease in the coronary and cerebrovascular circulation. For patients with stroke and transient ischaemic attack, oral glucocorticoid treatment was associated with a protective effect (table 3). This suggests that the mechanisms linking glucocorticoid use and cardiovascular outcome are complex, perhaps reflecting a balance between adverse and potentially protective effects. However, there is also evidence suggesting that patients cured of Cushing’s disease still have an increased prevalence of atherosclerosis and maintain cardiovascular risk factors of the active disease, possibly due to residual obesity, insulin resistance syndrome, or both.28,29
Our results raise the possibility that general practitioners avoid prescribing oral glucocorticoids to patients with established cardiovascular risk factors. There were no striking differences between users and non-users of oral glucocorticoids, except that patients with diabetes were less likely to have been prescribed oral glucocorticoids. However, diabetes was adjusted for in the multivariate analyses.
This large study identified oral glucocorticoid use as a risk factor for heart failure and ischaemic heart disease. Physicians should be aware of the negative vascular effect of glucocorticoids and add this knowledge in balancing positive and negative effects for the individual patient when considering to prescribe glucocorticoids, especially to patients with cardiovascular risk factors. However, this evidence remains observational and only a randomised controlled trial of glucocorticoid treatment versus other disease modifying agents is likely to distinguish the importance of the underlying disease activity from its treatment in predicting cardiovascular outcome.