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Taking Glucocorticoids by Prescription Is Associated with Subsequent Cardiovascular Disease

Li Wei, MB, MSc; Thomas M. MacDonald, MD, FRCPE; and Brian R. Walker, MD, FRCPE
[+] Article, Author, and Disclosure Information

From Ninewells Hospital and Medical School, Dundee, Scotland, and University of Edinburgh School of Molecular and Clinical Medicine and Western General Hospital, Edinburgh, Scotland, United Kingdom.

Acknowledgments: The MEMO database is part of the U.K. Medical Research Council Health Services Research Collaboration.

Grant Support: By the Chief Scientist Office of the Scottish Executive (research grant CZG/4/1/36). Dr. Walker is a British Heart Foundation Senior Research Fellow.

Potential Financial Conflicts of Interest: Expert testimony: T.M. MacDonald (U.K. Committee on Safety of Medicines).

Requests for Single Reprints: Thomas M. MacDonald, MD, FRCPE, Medicines Monitoring Unit, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, United Kingdom; e-mail, t.m.macdonald@dundee.ac.uk.

Current Author Addresses: Drs. Wei and MacDonald: Medicines Monitoring Unit, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, United Kingdom.

Dr. Walker: University of Edinburgh, Endocrinology Unit, School of Molecular and Clinical Medicine, Western General Hospital, Edinburgh, Scotland EH4 2XU, United Kingdom.

Author Contributions: Conception and design: L. Wei, T.M. MacDonald, B.R. Walker.

Analysis and interpretation of the data: L. Wei, T.M. MacDonald, B.R. Walker.

Drafting of the article: L. Wei, T.M. MacDonald, B.R. Walker.

Critical revision of the article for important intellectual content: L. Wei, T.M. MacDonald, B.R. Walker.

Final approval of the article: L. Wei, T.M. MacDonald, B.R. Walker.

Provision of study materials or patients: L. Wei, T.M. MacDonald.

Statistical expertise: L. Wei, T.M. MacDonald.

Obtaining of funding: L. Wei, T.M. MacDonald, B.R. Walker.

Administrative, technical, or logistic support: L. Wei, T.M. MacDonald.

Collection and assembly of data: L. Wei, T.M. MacDonald.

Ann Intern Med. 2004;141(10):764-770. doi:10.7326/0003-4819-141-10-200411160-00007
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We performed this study in the Tayside region in Scotland by using the MEMO record linkage database. The MEMO database covers a geographically compact population and serves about 400 000 patients in the National Health Service (NHS) in Scotland, 97% of whom are white. The NHS in Scotland is tax-funded and free at the point of consumption and covers the entire population. In Tayside, almost no health care is delivered without the NHS. The data collection methods for this database have previously been described (12). In brief, this database contains several data sets, including all dispensed community prescriptions, hospital discharge data, mortality data, biochemistry data, and other data, that are linked by a unique patient identifier, the community health index number. These data are made anonymous for the purposes of research, as approved by the Tayside Caldicott Guardians (a group appointed by the government to protect the confidentiality of medical records). The Tayside committee on research medical ethics also approved the project. We cleaned and validated all data before analysis.

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Glucocorticoid use with different cardiovascular diseases.

TIA = transient ischemic attack.

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A Rheumatology Perspective
Posted on December 16, 2004
Allan C Gelber
Johns Hopkins University School of Medicine
Conflict of Interest: None Declared

The relationship of steroid therapy to risk of cardiovascular disease is of great interest, particularly among rheumatologists. Notably, systemic lupus erythematosus and rheumatoid arthritis are each linked to an increased incidence of heart disease and stroke (1) (2) (3) (4). These observations spark ongoing debate as to whether the offending process is the disease itself or the drug(s), particularly steroids, used to treat the disease.

In this context , the recent paper by Wei, MacDonald and Walker (5) tested the hypothesis that users of exogenous glucocorticoids have an increased risk for cardiovascular disease. The investigators studied this association using an administrative database. All dispensed community prescriptions, in a geographical population in Scotland numbering 400,000 people, were linked with hospital discharge and mortality data.

The number of participants with inflammatory arthritis, however, was relatively small, and constituted only 1.7% of the 68,781 glucocorticoid users. Moreover, the range of steroid doses in the "high" exposure category was ostensibly rather broad. For example, among patients treated for active giant cell arteritis, lupus nephritis or even polymyalgia rheumatica, a common starting dose of prednisone is 1 mg/kg/day. This often corresponds to average steroid exposures during the first year of therapy at substantially higher levels than the cutoff for the high exposure category, of > 7.5 mg of prednisolone per day. Therefore, even though patients with inflammatory arthritis were captured in the dataset, the richness of the data beyond the upper cutoff is seemingly not fully captured. One remains intrigued to know if the observed dose-response relationship would similarly apply, and perhaps be amplified, among those with active rheumatologic disorders.

In the same vein, an important limitation is the lack of clear information regarding inpatient steroid administration. Many patients with severe and life-threatening rheumatic disorders are often treated as inpatients with corticosteroids administered at pulse levels, with 1000 mg of methylprednisolone for several consecutive days. Information regarding exposure to these levels is again not captured.

Finally, the number of Scottish residents in the high level category constituted only 2% of the Exposure Cohort. Interestingly, it was the high dose group among those with Inflammatory Arthritis who experienced a 5- fold increase in cardiovascular risk, the highest risk estimate reported. Yet, it remains plausible that the severity of disease activity in these patients, rather than their therapy, was the causative factor for this high risk, and that steroids may have actually attenuated rather than exacerbated their risk.

Reference List

(1) Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA, Jr., Jansen-McWilliams L et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997; 145(5):408-415.

(2) Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003; 107(9):1303-1307.

(3) Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994; 37(4):481-494.

(4) Sibley JT, Olszynski WP, Decoteau WE, Sundaram MB. The incidence and prognosis of central nervous system disease in systemic lupus erythematosus. J Rheumatol 1992; 19(1):47-52.

(5) Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004; 141(10):764-770.

Conflict of Interest:

None declared

Increase in homocysteine levels: a new atherogenic mechanism of corticosteroids
Posted on January 29, 2005
Victor M Martinez-Taboada
Rheumatology Division. Hospital Universitario Marqu¨¦s de Valdecilla.
Conflict of Interest: None Declared

To the Editor

We read with interest the study recently published in Annals of Internal Medicine by Wei L and co-investigators (1). In this large cohort study, the use of corticosteroids was associated with an increased risk for cardiovascular events, especially in patients treated with high-dose corticosteroids (¡Ý 7.5 mg of prednisone or equivalent). These results are also consistent with another case-control study, which demonstrated that higher doses of corticosteroids were more prevalent in patients with cardiovascular disease (2). After correction for confounder factors such as underlying disease or other well-known vascular risk factors of steroid use (blood pressure, glucose and lipids), the authors found no significant influence of them of the main results of the study.

In 2003, our group described several findings on patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) during corticosteroid treatment (3). First, patients with active PMR and GCA had a significant elevation of homocysteine levels compared with age-matched controls. A non-surprising observation because previous studies have suggested that GCA may share a common pathway with atherosclerosis (4). Second, The increase in homocysteine levels was also not related to the inflammatory process per se. In fact, we found a negative correlation between acute-phase response and homocysteine levels in the GCA group. Third, and more interesting, treatment with corticosteroids induced an increase in homocysteine levels in both groups of patients. However, this increase was only significant in patients with GCA. In our daily practice, PMR patients are usually treated with 10 mg of prednisone, and GCA patients are treated with 45 to 60 mg of prednisone or equivalent. Thus, our results might reflect that the higher increase in homocysteine levels seen in patients with GCA is due to the higher doses of corticosteroids used to treat these patients (3).

In contrast to other risk factors for atherosclerosis, hyperhomocysteinemia is correctable with folic acid and/or vitamin B12 supplementation. In fact, the majority of patients with significant increase in homocysteine levels responded adequately to vitaminic supplementation.

As suggested by Wei and co-investigators high¨Cdose corticosteroids seemed to be associated with a higher risk for cardiovascular disease. Our data suggests that corticosteroid therapy induced a significant, and to some extend dose-related, increase in homocysteine levels, and suggests a new atherogenic and treatable mechanism of corticosteroids.

References 1.- Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004; 141: 764-770. 2.- Souverain PC, Berard A, van Staa TP, Cooper C, Leufkens HGM, Walker BR. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population-based case-control study. Heart 2004; 90: 859-65. 3.- Martinez-Taboada VM, Bartoloma MJ, Fernandez-Gonzalez MD, Blanco, R, Rodriguez-Valverde V, Lopez-Hoyos M. Homocysteine levels in polymyalgia rheumatica and giant cell arteritis: influence of corticosteroid therapy. Rheumatology 2003; 42: 1055-61. 4.- Duhaut P, Pinede L, Demolonbe-Rague S et al. Giant cell arteritis and cardiovascular risk factors. A multicenter, prospective case-control study. Arthritis Rheum 1998; 41: 1960-5.

Conflict of Interest:

None declared

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Summary for Patients

Glucocorticoid Medications and the Risk for Cardiovascular Disease

The summary below is from the full report titled “Taking Glucocorticoids by Prescription Is Associated with Subsequent Cardiovascular Disease.” It is in the 16 November 2004 issue of Annals of Internal Medicine (volume 141, pages 764-770). The authors are L. Wei, T.M. MacDonald, and B.R. Walker.


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