The concept of ”number needed to treat” (NNT) was introduced in the medical literature by Laupacis et al. in 1988 [1]. NNT is an absolute effect measure which is interpreted as the number of patients needed to be treated with one therapy versus another for one patient to encounter an additional outcome of interest within a defined period of time [1, 2]. The computation of NNT is founded on the cumulative incidence of the outcome per number of patients followed over a given period of time, being classically calculated by inverting absolute risk reduction (ARR) (also called risk difference [RD]) between two treatment options [1, 2].

Some characteristics are inherently associated with the concept of NNT. The resulting value is specific to a single comparison between two treatment options within a single study, rather than an isolated absolute measure of clinical effect of a single intervention. Thus, NNT is specific to the results of a given comparison, not to a particular therapy [3]. In addition, three other factors, beyond the efficacy or safety of the intervention and the comparator, influence NNT: baseline risk (i.e., control event rate [CER]), time frame, and outcomes [3].

The use of NNT has been valuable in daily clinical practice, namely at assisting physicians in selecting therapeutic interventions [4, 5]. Further, this metric has the potential for use as a supportive tool in benefit-risk assessments and in helping regulators make decisions on drug regulation [6–8].

The Consolidated Standards of Reporting Trials (CONSORT) statement recommends the use of both relative and absolute measures of effect for randomized controlled trials (RCTs) with binary and time-to-event outcomes [9, 10]. The British Medical Journal (BMJ) requires that, whenever possible, absolute rather than relative risks and NNTs with 95% confidence intervals (CIs) are to be reported in RCTs [11]. Yet, few authors express their findings in terms of NNT or ARR [12–14]. Relative effect measures, such as relative risk (RR) or odds ratio (OR), are more commonly seen in the scientific literature [14, 15]. Despite the unquestionable usefulness of relative effect measures, they do not reflect baseline risks, making it impracticable to discriminate large from small treatment effects, and leading sometimes to misleading conclusions [15–17].

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) [18–23]. Note that the terms ”number needed to treat to benefit” (NNTB) and ”number needed to treat to be harmed” (NNTH) were proposed to distinguish between beneficial and harmful outcomes, respectively [24]. Furthermore, “number needed to be exposed” (NNE) has been proposed to apply the concept of NNT in observational studies, in which the focus is exposure rather than treatment [22]. NNEB and NNEH can be used to describe the number needed to be exposed for one person to benefit or be harmed [22]. In order to simplify, the term NNT is used throughout this paper.

The calculation of NNT should be based upon the use of methods that align with the characteristics of a given study, such as the research design and the type of variable (e.g., binary, time to event, or continuous) used to express the outcome of interest [19, 22, 25–32]. The use of inadequate methods may lead to erroneous results [12, 29, 30, 33, 34]. A previous research study analyzing articles published in four major medical journals found that NNTs were miscalculated in 60% of RCTs involving varying follow-up times [29]. The authors of another paper concluded that 50% of the RCTs reporting NNTs derived from time-to-event outcomes applied inadequate calculation methods [12]. Moreover, only 34% of RCTs presented the corresponding CIs for point-estimate NNTs [12]. The application of inadequate methods within other research designs, such as using pooled RDs in meta-analyses [35, 36] or unadjusted incidence rates in observational studies [22, 34], has also been pointed out.

The main goal of this study is to assess whether the methods used to calculate NNT in studies published in medical journals are in line with basic methodological recommendations.

The present study provides an overview about the use of the NNT in medical research during the last decade. The adherence of selected studies to basic methodological recommendations was reviewed. This topic is particularly relevant given that the NNT concept has been extended to derive related metrics with potential for use in benefit-risk assessments, namely for clinical decision making or drug regulatory purposes. An example is provided by impact numbers, which give a population perspective to the NNT [45, 46]. Impact numbers are useful to describe the public health burden of a disease and the potential impact of a treatment [6]. Two measures of impact numbers are particularly interesting: the number of events prevented in the population (NEPP) and the population impact number of eliminating a risk factor over time \( t \) (PIN-ER- \( t \)) [6, 47, 48].

Clinicians and other investigators should be aware that the calculation and interpretation of NNTs depend on specific study characteristics, particularly the design and outcome variables. The use of inadequate calculating methods may lead to biased results and misleading conclusions [22, 29, 35, 49].

The majority of studies included in the present review aimed at assessing primarily only the efficacy of medical interventions. The NNT was used more often to assess only benefits (51.9%) rather than only harms (21.2%). This finding was expected, considering what is commonly seen in the medical literature. A previous systematic review including meta-analyses published over a 5-year period found that only 14% of studies were designed to investigate drug safety as primary outcome [38]. In another study comprising systematic reviews with absolute effect estimates, it was found that the NNT was mostly used to assess beneficial outcomes rather than harmful events [14].

Overall, included studies reported more frequently results for binary outcomes than for time-to-event outcomes. This finding contrasts with the results of a previous review in which nearly 55% of included studies reported NNTs for time-to-event outcomes [12]. However, that review included only RCTs [12], while the present study included several research designs.

Relative measures of effect were used to express treatment differences in the majority of included studies (82.4%). These findings are in line with the conclusions of a recent survey of 202 systematic reviews [14]. Of those, the majority included meta-analyses with estimation of relative effects (92.1%), while absolute effect estimates were provided in 36.1% [14].

As previously mentioned, the concept of NNT requires the description of a defined period of time and varies with baseline risk (also called CER). Nevertheless, the time horizon was lacking in more than one fourth (25.5%) of studies. The NNT is uninterpretable if the time of follow-up during which cumulative outcome incidences are measured is not provided [34]. In addition, baseline risks could not be ascertained in nearly 28% of studies. Previous findings indicate that 56.2% of studies reporting absolute risks do not present the source of baseline risk estimates [14]. Lastly, more than one third (37.3%) of studies included in the present review did not report the CI for the point-estimate NNT. This result is in line with previous findings [12]. Thus, a moderately high proportion of papers published in journals with high impact factor in the category of “General and/or Internal Medicine” misuse the NNT metric.

As seen across the articles reviewed here, several approaches have been used to derive NNTs from meta-analyses. However, in 13 out of 23 meta-analyses (56.5%) the approach was considered inadequate. Of these meta-analyses, one calculated the reciprocal of simple proportions (using total numbers of both patients with outcome and exposed patients coming from all included studies). Using simple proportions, i.e., treating the data as if they all come from a single trial, to calculate NNTs is not correct, as this method is prone to bias due to Simpson’s paradox [35, 50]. The other 12 meta-analyses inverted pooled RDs, but this method should also be avoided [19, 31, 36, 51]. Absolute RDs are usually not constant and homogeneous across different baseline event rates; therefore, they are rarely appropriate for calculating NNTs from meta-analyses [19, 31, 36, 51]. Moreover, the effects of secular trends on disease risk and time horizon preclude the use of pooled RDs, as they can result in misleading NNTs [36, 51]. Relative effect measures (such as RR and OR) are usually more stable across risk groups than are absolute differences. Thus, pooled estimates of relative effect measures should be used rather than absolute RDs to derive NNTs from meta-analyses [19, 31, 36]. Clinicians should preferably use fixed effects OR, random effects OR or RR, and the patient expected event rate (PEER) to individualize NNT when applying results from meta-analyses in clinical practice [4, 19].

Most RCTs (94.1%) followed basic methodological recommendations to calculate NNTs. It is noteworthy that the majority of included RCTs (13 out of 17) analyzed binary outcomes. Studies with fixed times of follow-up are usually not prone to miscalculation of NNT because cumulative incidences equal simple proportions at the study end [29]. However, previous studies suggested that NNTs are miscalculated in at least half of RCTs with time-to-event outcomes [12, 29].

In the present review, one out four RCTs with varying follow-up times applied a non-recommended method to calculate NNT (see, e.g., [52]). In that RCT, the effect of two doses of atorvastatin (80 mg or 10 mg daily) was tested, for the first occurrence of a major cardiovascular event (i.e., a time-to-event outcome), in patients with coronary artery disease (CAD) and type 2 diabetes, with and without chronic kidney disease [52]. Patients were followed for varying times (median, 4.8 years). Although Kaplan-Meier curves have been estimated, the authors used simple proportions of patients with the outcome to compute NNT (e.g., for patients with diabetes without CAD, 1/([62/441] – [57/444]) = 82) and concluded that 82 patients were needed to treat with 80 mg/day versus 10 mg/day to prevent one major cardiovascular event over 4.8 years [52]. Using the cumulative incidences provided in Kaplan-Meier curves (12.5% for 80 mg and 13.3% for 10 mg), NNT would have been estimated at 125 over the same time horizon. This example illustrates how the use of simple proportions can lead to misleading values of NNT. Simple proportions should be used only if all patients are followed for the entire study period, as they equal cumulative incidences estimated by the Kaplan-Meier approach [30]. Since follow-up times usually vary in RCTs, simple proportions are not valid estimates of cumulative incidences. In cases where follow-up is short and mostly complete, simple proportions and Kaplan-Meier incidences are almost similar [30].

As the present study assessed results from research published since 2006, two different methodologies were considered adequate for calculating NNT from RCTs where the outcome is time to an event [26, 53, 54]. More recently, however, the authors of a study comparing the risk difference approach (reciprocal of risk differences estimated by survival time methods) and the incidence difference approach (reciprocal of incidence rates differences) concluded that the methods based on incidence rates often lead to misleading NNT estimates and recommended the use of survival time methods to estimate NNTs in RCTs with time-to-event outcomes [28]. The incidence difference approach still can be used in the case of small baseline risks, strong treatment effects, and exponentially distributed survival times [28]. Nevertheless, Girerd et al. argued that the two methods measure different things, but both are valid and provide complementary information regarding the absolute effect of an intervention, highlighting that the incidence rate approach assesses person-years rather than persons [55]. This calculating method estimates the number of person-times (e.g. patient-years), not the absolute number of persons, needed to observe one less (or one more) event in the treatment group than in the control group [28, 29, 54–56]. This estimate is different from the “classical” person-based NNT, and therefore may be difficult to interpret [56]. For example, 100 patient-years do not necessarily mean 100 individual patients treated over 1 year (or 50 patients treated for 2 years). A thorough explanation of person-based NNT, person-time-based NNT, and event-based NNT (for multiple recurrent outcome events) is provided elsewhere [29, 57].

With regard to observational studies, one cohort study did not follow methodological recommendations [58]. In that study, Kaplan-Meier curves and Cox proportional HRs for time to event, adjusted for confounding factors, with pioglitazone as reference, were used to test the effect of rosiglitazone on several cardiovascular adverse events [58]. However, the authors applied unadjusted incidence rate differences to calculate NNTs, instead of using adjusted data. For example, at 1 year of follow-up, the NNT for a composite cardiovascular endpoint would be 92 from Kaplan-Meier curves rather than the 60 person-years obtained by the authors. Further, the authors interpreted person-years as number of persons treated over 1 year, which is not exactly the same. A detailed review and discussion of methods used to calculate NNTs from observational studies is provided elsewhere [21–23].

The present study was not primarily aimed at identifying all papers with methodological recommendations for calculating NNTs. For this reason, a systematic review of literature was not performed to identify such papers. This is a potential limitation of the study. Nevertheless, the literature used as the source of evidence was probably adequate for the complexity of the assessment. The study focused on the adherence of calculating methods to basic methodological recommendations, rather than to more complex methodological and statistical issues. Therefore, estimates of NNT reported by studies that followed basic methodological recommendations are not necessarily correct. There are possibly other reasons that can still lead to biased estimates, but which could not be assessed with an acceptable effort. In addition, the magnitude of error produced in studies that did not follow basic methodological recommendations to calculate NNTs was not tested. Aside from some examples provided in the discussion, the calculation of correct NNTs was not sought for studies that did not follow recommendations. Lastly, the study was limited to the top 25 high-impact factor journals in the “General and/or Internal Medicine” category. Whether or not the results in other fields are likely to show similar results deserves further testing.

The present results illustrate that these metrics have not always been adequately calculated. From the clinicians’ point of view, this may cause some concerns, since these metrics can be used to support clinical decision-making processes, including the prescription of medicines. Therefore, clinicians need to rely on the methodological appropriateness of such calculations.

The NNT helps to quantify the magnitude of effects of medical interventions in an absolute scale, therefore bringing added value to decisions on drug utilization for clinicians, regulators, and other stakeholders. However, they should be aware that the calculation and interpretation of the NNT depend on the characteristics of a given study, namely the design and outcome variables. Moreover, they must acknowledge that an NNT is specific to a given comparison. Therefore, baseline risks, clearly defined outcomes, time horizons, and confidence intervals should be provided. The presentation of an NNT alone, i.e., without its context, would be ambiguous and less useful for decision making.

This study showed that, although the concept of NNT was introduced several years ago, there are basic methodological recommendations still not being followed, particularly in meta-analyses, leading to miscalculated and misinterpreted results. Further research is needed to confirm the present findings and to explore the influence of other methodological aspects that may impact the calculation of the NNT in clinical studies.