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Alert Number 57

R plus HDPM

Date: November 16, 2004

The latest Medscape Newsletter contained an article from Reuters, titled "High-Dose Steroid Use Greatly Increases Risk of Cardiovascular Disease".

Editor's note: Unfortunately by mid-2007, Medscape seems to have reorganized this page right out of its website so that the once-live link does not work any more.

The article describes results when researchers compared the cardiovascular events for 68,781 glucocorticoid users and 82,202 non-users who were followed between 1993 and 1996. The huge size of the experimental and control groups makes this a statistically significant study. The rate of cardiovascular events in the non-user group was 17.0 (per 1000 person-years). For patients exposed to the highest doses of glucocorticoids the rate was roughly four times higher, at 76.5. The same general conclusion is also drawn by a very recent article in "Heart" (abstract attached below). Once again, glucocorticoid use and more especially high dose glucocorticoid use had significant increase in risk of stroke and heart disease.

In previous Topics Alerts we raised the possibility of adverse effects with the use of high dose glucocorticoids (methylprednisolone used in the Rituxan + HDMP is an example of a glucocorticoid drug). The point of these Alerts is to provide timely information to our patient community. Please realize that statistical information such as this is based on studies with thousands of patients, but each one of us is unique. Statistics such as this give no more than the odds, they do not guarantee with 100% certainty how any given patient will react to high dose methylprednisolone or similar glucocorticoids or how things will play out in any given patient in the R + HDMP trial.

CLL Topics and these Alerts cater to a large group of CLL patients. We now have more than 650 registered members who get these Alerts. That number keeps growing week by week and we will be doing less than justice to our membership if we pulled our punches in order not to "upset" any single patient or group of patients. The intent is not to cause worry or "post -purchase trauma" to those who have already made their bets. I do not write these Alerts as a way of getting across some subliminal message to a given patient. That is way too subtle for my engineering personality; if I had something to say it would be lot simpler for me to write that patient a personal email!

As they say, fore-warned is fore-armed. The latest I have heard on the subject of R + HDMP trial is that it has now been halted at Ohio State, because a very large percentage (8 out of 9) of the patients who had participated in the trial were subsequently hospitalized with life threatening infections. This information has not been personally confirmed by me - you have to keep that in mind in as you evaluate it. It is also not clear to me whether all of the CLL Consortium Centers who used (or are using) this approach had the exact same protocol, whether any of them had less or more emphasis on preemptive medications to protect patients and whether they had similar time periods for monitoring patients after completion of therapy. Some of the adverse effects of glucocorticoid use discussed in the literature happened quite a while after the completion of the therapy. We will have a better fix on all these details when the full text articles are published regarding this interesting combination. In the meantime, you will have to use your own judgment to make sense of the sometimes conflicting information coming at you.

Be well,



Heart. 2004 Aug;90(8):859-65.

Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study.

Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts AC, Leufkens HG, Walker BR.

Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, PO Box 80082, 3508 TB Utrecht, The Netherlands.

OBJECTIVE: To assess whether use of oral glucocorticoids is associated with cardiovascular and cerebrovascular morbidity.
DESIGN AND SETTING: Nested case-control study within a cohort of patients (> or = 50 years old) with at least one prescription for oral or non-systemic glucocorticoids. Data were from the general practice research database.
PATIENTS: 50 656 patients were identified with a first record for ischaemic heart disease (International classification of diseases, ninth revision (ICD-9) codes 410, 411, 413, and 414), ischaemic stroke or transient ischaemic attack (ICD-9 codes 430-436), or heart failure (ICD-9 code 428) between 1988 and 1998. One control was matched to each case by sex, age, general practice, underlying disease, and calendar time.
MAIN OUTCOME MEASURE: Odds ratio (OR) of cardiovascular or cerebrovascular events in patients using oral glucocorticoids compared with non-users.
RESULTS: There was a significant association between ever use of oral glucocorticoids and any cardiovascular or cerebrovascular outcome (adjusted OR 1.25, 95% confidence interval (CI) 1.21 to 1.29). The association was stronger for current use of oral glucocorticoids than for recent or past use. Among current users, the highest ORs were observed in the group with the highest average daily dose, although the dose-response relation was not continuous. Current use was associated with an increased risk of heart failure (adjusted OR 2.66, 95% CI 2.46 to 2.87), which was consistent between patients with rheumatoid arthritis, patients with chronic obstructive pulmonary disease, and patients without either of the two conditions. Also, current use was associated with a smaller increased risk of ischaemic heart disease (OR 1.20, 95% CI 1.11 to 1.29).
CONCLUSIONS: Oral glucocorticoid use was identified as a risk factor for heart failure. However, the 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 outcomes.

PMID: 15253953

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