ABSTRACT
BACKGROUND: Mitoxantrone is used for aggressive multiple sclerosis (MS), but concerns about safety, including cardiotoxicity and other laboratory measures, prevail. OBJECTIVE: To evaluate the incidence and potential predictors of adverse events associated with mitoxantrone at the MS Clinic, University of British Columbia, Canada. METHODS: Retrospective review of patients treated with mitoxantrone by standard protocol; maximum cumulative dose = 120 mg/m(2). Left ventricular ejection fraction (LVEF) was measured with regular multiple-gated acquisition (MUGA) scans; blood cell counts and biochemical liver tests were performed before infusions. Generalized estimating equations were used to examine potential predictors of adverse events (graded according to the Common Toxicity Criteria, version 4) in patients with normal baseline and > or =1 follow-up MUGA or laboratory assessment. RESULTS: All 163 patients (58% women) treated with mitoxantrone from 1999 to 2007 were reviewed. Mean baseline age was 41.9 (SD 10.8) years, cumulative dose was 59.7 (SD 26.0) mg/m(2), and median follow-up duration was 14 months (maximum 6.5 years). By study end, 14% developed de novo cardiotoxicity (grade > or =2) as measured by decreased LVEF, 27% neutropenia (grade > or =1), 15% anemia (grade > or =1), and 15% liver toxicity (grade > or =1). Possible predictors of adverse events included sex, age, disease duration, and cumulative dose; only women exposed to a higher cumulative dose were at a greater risk of anemia (adjusted odds ratio 1.26, 95% confidence interval 1.08-1.48 per 10 mg/m(2)). CONCLUSIONS: Based on cardiac and laboratory assessments, mitoxantrone was reasonably well tolerated. However, cardiotoxicity was evident after doses well below current maximum recommended levels. A dose-response effect was not apparent. Findings emphasize the importance of monitoring; the long-term effects of mitoxantrone in multiple sclerosis require investigation.
Subject(s)
Analgesics/adverse effects , Liver Diseases/etiology , Mitoxantrone/adverse effects , Neutropenia/chemically induced , Ventricular Dysfunction, Left/chemically induced , Adult , Age Factors , Anemia/chemically induced , Female , Follow-Up Studies , Humans , Male , Middle Aged , Multiple Sclerosis/drug therapy , Retrospective Studies , Sex Factors , Ventricular Dysfunction, Left/diagnosisSubject(s)
Anaphylaxis/chemically induced , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Cyclooxygenase Inhibitors/adverse effects , Diclofenac/adverse effects , Lactones/adverse effects , Misoprostol/adverse effects , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Drug Combinations , Humans , Isoenzymes/antagonists & inhibitors , Male , Membrane Proteins , Middle Aged , Osteoarthritis/drug therapy , Prostaglandin-Endoperoxide Synthases , SulfonesABSTRACT
There is an increasing body of clinical trial evidence to support the use of angiotensin-converting enzyme (ACE) inhibitors in the management of patients following myocardial infarction (MI). Enthusiasm for the use of ACE inhibitors in the acute phase of MI had previously been tempered by the adverse results of an early trial. However, exciting new information is available from several large, randomized studies that has not only quelled those initial concerns but also attests to the efficacy of using this class of medication in the first 24 h after an acute MI. A Canadian National Opinion Leader Symposium was held in November 1995 to review the results of the major ACE inhibitor clinical trials and to discuss key issues and controversies surrounding their use in acute MI. The focus of this paper, the first of two parts, is on the results of the major ACE inhibitor clinical trials.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Myocardial Infarction/drug therapy , Clinical Trials as Topic , Humans , Myocardial Infarction/mortality , Risk FactorsABSTRACT
Over the past 10 years, several clinical studies have concluded that, in patients already receiving conventional therapies, angiotensin-converting enzyme (ACE) inhibitors further reduce the risk of death following myocardial infarction (MI). Post-MI ACE inhibitors have proven to be effective as long term therapy in high risk patients as well as when used for much shorter periods in a broad patient population. However, while considerable mortality data have been collected, the effects of ACE inhibitors post-MI on other cardiovascular outcomes have not been as well documented. In addition, a number of issues regarding the most effective use of these agents remain unresolved. This paper, the second of two parts, focuses on the clinical issues and controversies surrounding the use of ACE inhibitors following acute MI. The effects of ACE inhibitors on the outcomes of sudden death, nonsudden death, recurrent angina, mitral regurgitation and left ventricular dysfunction are reviewed and potential mechanisms of action are proposed. In addition, ACE inhibitor therapy is discussed in terms of patient selection criteria, choice of agent, optimal dosing regimen, concomitant use of other therapies and relative costs of treatment. Finally, potential mechanisms of action of ACE inhibitors are proposed for each of the outcomes examined.
