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Although the NNT was originally conceived to be used in RCTs[1], the concept has been used to express treatment differences in comparative studies with other designs, including systematic reviews and meta-analyses, and observational studies cohort and case—control studies [18][19][20][21][22][23]. Number needed to treat NNT in clinical literature: The number needed to treat NNT is an absolute effect measure that has been used to assess beneficial and harmful effects of medical interventions.
Several methods can be used to calculate NNTs, and they should be applied depending on the different study characteristics, such as the design and type of variable used to measure outcomes. Whether or not the most recommended methods have been applied to calculate NNTs in studies published in the medical literature is yet to be determined. The aim of this study is to assess whether the methods used to calculate NNTs in studies published in medical journals are in line with basic methodological recommendations. Studies were categorized according to their design and the type of variables.
NNTs were assessed for completeness baseline risk, time horizon, and confidence intervals [CIs]. The methods used for calculating NNTs in selected studies were compared to basic methodological recommendations published in the literature.
Neuropsychiatr Dis Treat. Apr 23; doi: /NDT. S eCollection New horizons for multiple sclerosis therapeutics. Current and emerging multiple sclerosis therapeutics. Greenberg BM, Khatri BO, Kramer JF. For a disease whose cause remains elusive, there has been a.
Data were analyzed using descriptive statistics. The search returned citations, of which 51 were selected. Basic methodological recommendations to calculate NNTs were not followed in 15 studies A considerable proportion of studies, particularly meta-analyses, applied methods that are not in line with basic methodological recommendations. Despite their usefulness in assisting clinical decisions, NNTs are uninterpretable if incompletely reported, and they may be misleading if calculating methods are inadequate to study designs and variables under evaluation.
Further research is needed to confirm the present findings. Clinicians are expected to select a therapy based on their appraisal of evidence on benefit-to-risk profiles of therapies. In the management of relapsing-remitting multiple sclerosis RRMS , evidence is typically expressed in terms of risk proportion of event, risk reduction, relative and hazard rate reduction, or relative reduction in the mean number of magnetic resonance imaging lesions.
Interpreting treatment effect using these measures from a RRMS clinical trial is fairly reliable; however, this might not be the case when treatment effect is expressed in terms of the number needed to treat NNT. This article presents an overview of the methodological definition and characteristics of NNT as well as the relative merit of NNT use in RRMS controlled clinical trials, where endpoints are typically time-to-event and frequency of recurrent events. The authors caution against using NNT in multiple sclerosis, a clinically heterogeneous disease that can change course and severity unpredictably.
The authors also caution against the use of NNT to interpret results in comparative trials where the absolute risk difference is not statistically significant, computing NNT using the time-to-event endpoint at intermediate time points, computing NNT using the annualized relapse rate, and comparing NNT across trials. However, their results are mainly expressed as relative measures of effect [14,[34][35][36].
The major problem with relative effect measures is that they do not reflect baseline risks i. Using these examples, the ARR of placebo was estimated at 0. A growth of the placebo effect has also been seen in other settings, such as in RCTs conducted with neuropathic pain drugs in the US [44].
The safety analysis was challenging, and some considerations need to be pointed out. A Systematic Review and Meta-Analysis. Conclusions These metrics may be valuable for benefit—risk assessments, as they reflect baseline risks and are easily interpreted. Before making treatment decisions, clinicians must acknowledge that a higher RR reduction with drug A as compared with drug B versus a common comparator in trial A and trial B, respectively does not necessarily mean that the number of patients needed to be treated for one patient to encounter one aditional outcome of interest over a defined period of time is lower with drug A than with drug B.
In addition, the follow-up period of the patients is the longest in any other study that addressed treatment response, giving the opportunity for a better assessment of disability progression and relapse rates in the long-term. Treatment response is a controversial issue and remains a matter of debate [35]. Placebo cohorts of clinical trials have been very diverse regarding ARR, ranging from 1. MS patients show a remarkable heterogeneity in their response to disease modifying treatments.
Given the need for early treatment initiation and the diversity of available options, a predictive marker that indicates good or poor response to treatment is highly desirable. The remaining 8 patients showed a very favorable outcome and remained untreated noRx. Estimating a treatment effect: Choosing between relative and absolute measures.
The size of a treatment effect in clinical trials can be expressed in relative or absolute terms. Commonly used relative treatment effect measures are relative risks, odds ratios, and hazard ratios, while absolute estimate of treatment effect are absolute differences and numbers needed to treat. When making indirect comparisons of treatment effects, which is common in multiple sclerosis MS , having now many drugs tested in independent trials, we can have different figures if we use relative or absolute measures, and a frequently asked question by clinicians is which approach should be used.
In this report, we will try to define these measures, to give numerical examples of their calculation and specify their meaning and their context of use. Reduce the risk of adverse events associated with disease-modifying therapies for multiple sclerosis by following appropriate mitigation strategies. Mar Drugs Ther Perspect. A number of disease-modifying therapy options are available to treat multiple sclerosis.
Careful consideration of the benefits and risks of each agent, as well as the preferences and characteristics of the individual patient, is needed when selecting the most appropriate treatment approach for each patient. Risk migration strategies should be followed to reduce the likelihood and severity of potential adverse effects. Treatment options in relapsing-remitting multiple sclerosis have increased considerably in recent years; currently, a dozen different preparations of disease-modifying therapies are available and some more are expected to be marketed soon. For the treating neurologist this broad therapeutic repertoire not only greatly improves individualized management of the disease, but also makes choices more complex and difficult.
A number of factors must be considered, including disease activity and severity, safety profile, and patient preference. We here discuss the currently existing options and suggest treatment algorithms for managing relapsing-remitting multiple sclerosis. Therapeutic decision making for disease modification in ms: Where are the gaps? Interferon beta-1b mcg, interferon beta-1b mcg and glatiramer acetate: Neurological examinations were done every 3 months. All patients had MRI twice yearly and had monthly scans in the first 9 months of treatment.
Analysis was by intention to treat. The accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group. Longer-term benefits may become clearer with further follow-up and investigation. Recommended diagnostic criteria for multiple sclerosis: Jul Ann Neurol. The focus remains on the objective demonstration of dissemination of lesions in both time and space.
Magnetic resonance imaging is integrated with clinical and other paraclinical diagnostic methods. Disease-modifying therapy in multiple Sclerosis Update and clinical implications. As new therapies become available for the treatment of multiple sclerosis, the relative value of established and newer disease-modifying therapies must be considered. However, comparing the apparent efficacy of different agents across clinical trials is not easy and can be misleading when different therapies have been studied during different time periods.
There has been a shift in current clinical trials toward enrolling patients with less advanced or less active disease compared with trials undertaken when no effective therapies were available.
If early treatment is more effective than late treatment, this practice will produce a bias in favor of newer agents. Head-to-head trials offer the most reliable means of comparing therapies, but these trials are expensive and time consuming. Consequently, cross-trial comparisons are necessary, but a reliable means to make such comparisons is needed.
One useful but imperfect approach is to compute the relative risk of therapy and the number-needed-to-treat, applying both measures to any cross-trial comparison. These measures capture different aspects of the trials relative and absolute differences and, if they agree, this suggests that the cross-trial comparison may be valid. If the two methods disagree, no reliable conclusion about relative efficacy can be made. There are only two valid conclusions from the available head-to-head and cross-trial data. All instructor resources are now available on our Instructor Hub.
The student resources previously accessed via GarlandScience.
For Instructors Request Inspection Copy. Since the publication of the previous edition of this volume, there has been substantial progress in a number of areas of multiple sclerosis MS research. Although immunosuppressive treatments continue to be developed and refined, more targeted immunomodulatory therapies are surfacing as we learn more about how the immune system works in health and disease. Multiple Sclerosis Therapeutics, Third Edition provides a comprehensive review of clinical trial methodology and therapeutic modalities in MS.
This edition reflects current understanding of the pathophysiology of the disease and includes popular and emerging treatments. Within the next several years, we will begin to discover the utility and the limitations of stem cells in the treatment of MS. It is likely that the next edition of this text will include clinical trial data that evaluate early attempts at nervous system regeneration in MS. Until that time occurs, this volume remains an essential resource for neurologists and anyone involved in the treatment of MS.
Aspects of multiple sclerosis that relate to trial design and clinical management. Biological concepts of multiple sclerosis pathogenesis and relationship to treatment. The multiple sclerosis disease process as characterized by magnetic resonance imaging. Measures of neurological impairment and disability in multiple sclerosis.
Assessment of neuropsychological function in multiple sclerosis. Health-related quality of life assessment in multiple sclerosis. Measures of gadolinium enhancement, T1 black holes and T2-hyperintense magnetic resonance imaging in multiple sclerosis. Measures of magnetization transfer in multiple sclerosis.
Measurement of central nervous system atrophy in multiple sclerosis. Axonal pathology in patients with multiple sclerosis: Functional imaging in multiple sclerosis. Magnetic resonance imaging of pathway-specific structure and function in multiple sclerosis. Optical coherence tomography to monitor neuronal integrity in multiple sclerosis.
Biomarkers in multiple sclerosis. Selection and interpretation of end-points in multiple sclerosis clinical trials. The challenge of long-term studies in multiple sclerosis: Alternative designs for multiple sclerosis clinical trials. Ethical considerations in multiple sclerosis clinical trials.
Pharmacogenetics and pharmacogenomics in multiple sclerosis. Interferons in secondary progressive multiple sclerosis. Neutralizing antibodies directed against interferon A. Glatiramer acetate as therapy for multiple sclerosis. Use of mitoxantrone to treat multiple sclerosis. Use of cyclophosphamide and other immunosuppressants to treat multiple sclerosis. Natalizumab in multiple sclerosis. High-dose methylpredisolone in the treatment of multiple sclerosis. Intravenous immunoglobulin in multiple sclerosis. Therapeutic plasma exchange for multiple sclerosis.
Statins in multiple sclerosis.