Definitions of the strength of the recommendations (A, B, C, U) and classification of the evidence (Class I through Class IV) are provided at the end of the "Major Recommendations" field.
Note from the American Academy of Neurology (AAN) and National Guideline Clearinghouse (NGC): This guideline review contains no new efficacy evidence that would change the recommendation from the previous report, so the 2003 recommendations are included as well as the 2010 conclusions.
- On the basis of evidence from a single Class I study and a few Class II or III studies, it appears that mitoxantrone may have a beneficial effect on disease progression in patients with multiple sclerosis (MS) whose clinical condition is deteriorating (Type B recommendation). In general, however, this agent is of limited use and of potentially great toxicity. Therefore, it should be reserved for patients with rapidly advancing disease who have failed other therapies.
- On the basis of several consistent Class II and III studies, mitoxantrone probably reduces the clinical attack rate and reduces attack-related magnetic resonance imaging (MRI) outcomes in patients with relapsing MS (Type B recommendation). The potential toxicity of mitoxantrone, however, considerably limits its use in patients with relapsing forms of MS.
- Because of the potential toxicity of mitoxantrone, it should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapeutic agents (Type A Recommendation). In addition, patients being treated with mitoxantrone should be monitored routinely for cardiac, liver, and kidney function abnormalities (Type A Recommendation).
While the Class III and IV evidence available provides conflicting estimates of both the frequency and severity of mitoxantrone (MX)-related cardiotoxicity, asymptomatic decreased systolic function occurs in approximately 12% of patients treated with MX, and congestive heart failure (CHF) occurs in approximately 0.4%. The literature on therapy-related acute leukemia (TRAL) in MX-treated patients with multiple sclerosis (MS) is also limited to Class III and IV evidence; however, the cumulative incidence appears to be ∼0.8%. Both TRAL and systolic dysfunction can occur at any time after initiation of MX, including early in the treatment course.
The evidence regarding toxicity suggests the risk of systolic dysfunction associated with the use of MX in patients with MS results in an number needed to harm (NNH) of 8, and the risk of TRAL with MX therapy results in an NNH of 123. This demonstrates that the risk of both cardiotoxicity and leukemia is likely higher than earlier estimates.
Recommendations on MX use reflecting the potential for harm would require a risk-benefit analysis and are beyond the scope of an evidence-based guideline. In the absence of such an analysis, it is reasonable for clinicians to follow the recommendations outlined in the product monograph and include ejection fraction assessments before initiating treatment and administering each dose of MX and yearly after discontinuation of treatment. It is not known whether patients treated with MX with asymptomatic decreased left ventricular ejection fraction (LVEF) will experience long-term sequelae. The long-term sequelae of asymptomatic cardiotoxicity are not clear. It is reasonable for clinicians to monitor patients for TRAL after MX therapy with periodic complete blood cell counts, although the optimal timing of such monitoring is not known.
Clinicians contemplating MX administration for an individual patient with MS must weigh the potential or benefit against the potential for harm given the ∼12% risk of systolic dysfunction and ∼0.8% risk of TRAL and the availability of alternative therapies with less severe toxicities (e.g., interferon-β and glatiramer acetate) for patients with relapsing-remitting multiple sclerosis [RRMS]).
American Academy of Neurology (AAN) Classification of Evidence for Therapeutic Articles
Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required:
- Concealed allocation
- Primary outcome(s) clearly defined
- Exclusion/inclusion criteria clearly defined
- Adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.
- For non inferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
- The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority.
- The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
- The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
- The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.
Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a-e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b-e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**
Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion.
* Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.
**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).
AAN Classification of Evidence for Screening Articles
Class I: A statistical, population-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. All patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.
Class II: A statistical, non-referral-clinic-based sample of patients studied at a uniform point in time (usually early) during the course of the condition. Most patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation that is masked to the patients' clinical presentations.
Class III: A sample of patients studied during the course of the condition. Some patients undergo the intervention of interest. The outcome, if not objective, is determined in an evaluation by someone other than the treating physician.
Class IV: Studies not meeting Class I, II or III criteria including consensus, expert opinion or a case report.
Classification of Recommendations
A - Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)
B - Probably effective, ineffective, or harmful for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)
C - Possibly effective, ineffective, or harmful for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
U - Data inadequate or conflicting; given current knowledge, treatment is unproven.