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Number Needed to Treat (NNT): Implication in Rheumatology Clinical Practice M Osiri, M E Suarez-Almazor, G a Wells, V Robinson, P Tugwell

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Number Needed to Treat (NNT): Implication in Rheumatology Clinical Practice M Osiri, M E Suarez-Almazor, G a Wells, V Robinson, P Tugwell 316 EXTENDED REPORT Ann Rheum Dis: first published as 10.1136/ard.62.4.316 on 1 April 2003. Downloaded from Number needed to treat (NNT): implication in rheumatology clinical practice M Osiri, M E Suarez-Almazor, G A Wells, V Robinson, P Tugwell ............................................................................................................................. Ann Rheum Dis 2003;62:316–321 Objective: To calculate the number needed to treat (NNT) and number needed to harm (NNH) from the data in rheumatology clinical trials and systematic reviews. Methods: The NNTs for the clinically important outcome measures in the rheumatology systematic reviews from the Cochrane Library, issue 2, 2000 and in the original randomised, double blind, con- trolled trials were calculated. The measure used for calculating the NNT in rheumatoid arthritis (RA) See end of article for interventions was the American College of Rheumatology 20% improvement or Paulus criteria; in authors’ affiliations osteoarthritis (OA) interventions, the improvement of pain; and in systemic sclerosis (SSc) interventions, ....................... the improvement of Raynaud’s phenomenon. The NNH was calculated from the rate of withdrawals Correspondence to: due to adverse events from the treatment. Dr P Tugwell, Center for Results: The data required for the calculation of the NNT were available in 15 systematic reviews and Global Health, University 11 original articles. For RA interventions, etanercept treatment for six months had the smallest NNT of Ottawa, Institute of (1.6; 95% confidence interval (CI) 1.4 to 2.0), whereas leflunomide had the largest NNH (9.6; 95% Population Health, 1 CI 6.8 to 16.7). For OA treatment options, only etodolac and tenoxicam produced significant pain Stewart Street, Room 312, Ottawa, Ontario, Canada, relief compared with placebo (NNT=4.4; 95% CI 2.4 to 24.4 and 3.8; 95% CI 2.5 to 7.3, respec- K1N 6N5; tively). For SSc interventions, none were shown to be efficacious in improving Raynaud’s phenomenon [email protected] because the 95% CI of the NNT was infinite. Accepted 2 September Conclusions: The NNT and NNH are helpful for clinicians, enabling them to translate the results from 2002 clinical trials and systematic reviews to use in routine clinical practice. Both NNT and NNH should be ....................... accompanied by a limited 95% CI and adjusted for the individual subject’s baseline risk. n rheumatology clinical practice, one of the major decisions event) and assumed to be prevented by the active treatment. with which rheumatologists are confronted is the choice of The probability of the event in the treatment group (X) is sup- treatment for their patients. Although there is increasing posed to be less than the probability of the event in the placebo I http://ard.bmj.com/ appreciation of evidence based medicine, the data sources for group (Y). Relative risk is defined as the ratio of the probabil- this are still in their infancy. Guidelines and algorithms have ity of the event in the treatment group and that of the control been developed to help determine the appropriate choices of group (X/Y). RRR is defined as the reduction of the probability treatment, but they are not applicable to every patient. More- of the event in the treatment group in proportion to that in the over, new information from clinical trials is being published at placebo group [(Y−X)/Y] and it can be calculated from relative too fast a rate for textbooks to remain current. The challenge risk as RRR=1−relative risk (1−X/Y). RRR is usually expressed is to translate the clinical research data into a format suitable as a percentage [(1−(X/Y))×100%]. The problem of the RRR is for use by busy clinicians in practice. One key item of that it fails to discriminate between enormous absolute treat- information needed for an informed decision is an easily ment effects and very small effects in absolute numbers. Table on October 1, 2021 by guest. Protected copyright. understood estimate of the magnitude of benefit (and risk of 1 shows an example of this. The relative risk and RRR adverse effects) that can be used by doctors and other care calculated from the trial by Moreland and colleagues2 and a givers.1 Those most commonly used in rheumatology include hypothetical trial were similar. event rates, relative risk, relative risk reduction, absolute risk In contrast, the absolute difference in rates between the reduction or risk difference, and odds ratios. In addition, a experimental and control groups does discriminate between number of rheumatological measures are based on continuous low and high magnitudes of benefit and harm. Absolute risk outcomes—for example, number of tender joints or swollen reduction is the difference in the event rates between the pla- joints. Many of these are difficult for the clinicians to use in cebo and treatment groups (Y−X).1 3–5 The inverse of the abso- clinical practice for reasons that include their complexity, the lute risk reduction applies for estimating the increase in abso- difficulty in assessing the clinical importance of a specific lute risk for a side effect (absolute risk increase). Because the result, and the challenge in comparing benefits with values of relative risk and RRR depend on the probability of risks/adverse effects. One approach that is becoming increas- the event in the control group, they provide less information ingly used in other disciplines is the “number needed to treat” on the clinical benefit. Absolute risk reduction is considered a (NNT). Our review aims at describing the concept, method of better measure of treatment effect than relative risk or RRR calculation, and interpretation of the NNT and its use in deci- sion making of rheumatology clinical practice. ............................................................. Abbreviations: ACR, American College of Rheumatology; CI, CURRENT MEASURES OF TREATMENT EFFECT confidence interval; CsA, cyclosporin A; DMARD, disease modifying The most common measure used in reporting clinical trials is antirheumatic drug; MTX, methotrexate; NNH, number needed to harm; NNT, number needed to treat; NSAIDs, non-steroidal anti-inflammatory the relative risk reduction (RRR). In brief, consider a parallel drugs; OA, osteoarthritis; RA, rheumatoid arthritis; RCT, randomised group, randomised trial comparing an active treatment with controlled trial; RRR, relative risk reduction; SSc, systemic sclerosis; SSZ, placebo; the outcome of interest is dichotomous (event/no sulfasalazine www.annrheumdis.com Number needed to treat 317 Table 1 Measures of treatment efficacy from the randomised controlled trials in rheumatoid arthritis (RA)* Ann Rheum Dis: first published as 10.1136/ard.62.4.316 on 1 April 2003. Downloaded from Etanercept v placebo2 Drug A v placebo (a hypothetical study) Variable Treatment group Placebo group Treatment group Placebo group Group size (n) 78 80 Number not met ACR50 improvement (n) 38 75 Risk for treatment failure 0.487 (X) 0.938 (Y) 0.0026 (X) 0.005 (Y) Relative risk (X/Y) 0.52 0.52 Relative risk reduction ((Y−X)/Y or 1−X/Y) 0.48 0.48 Absolute risk reduction ([|]Y−X[|]) 0.45 0.0024 Number needed to treat (1/[|]Y−X[|]) 2.2 416.7 Number of withdrawals due to AEs 2 3 Risk for withdrawal 0.026 (a) 0.038 (b) Number needed to harm (1/[|]b−a[|]) 83.3 *Adapted from reference 7. AEs, adverse events because it expresses the consequences of giving no useful when an adverse event is caused by the active treatment.13 However, the absolute risk reductions and treatment. The NNH is defined as the number of patients who increases are often <1 and have to be expressed as a decimal receive the active treatment that will lead to one additional fraction, which is difficult to incorporate into clinical practice. patient being harmed compared with those receiving Table 1 shows that the difference between treatment groups is placebo.5 The 95% CI for the NNH is calculated as for the NNT. much larger when looking at absolute risk reductions than the The NNH should be considered together with the NNT because relative risk or RRR. However, it may still be difficult to under- an experimental treatment may help decrease the probability stand the clinical benefit of an absolute reduction of 0.45 of one event, but may increase the probability of another compared with that of 0.0024. adverse event, which might exceed the beneficial effect of the The risk reduction obtained from either of these measures active treatment. The NNH calculation is also shown in table 1. of treatment effect is regarded as a “point estimate” because Among the measures of treatment effect, the NNT seems to the precise value of risk reduction is unknown but lies within be the most helpful tool for therapeutic decision making and a certain extent—that is, confidence intervals (CIs). The point bedside teaching, as it is easier to interpret and can be estimates are usually provided by most clinical trials and the compared among different treatment alternatives.1 The NNT 95% CI is frequently used.3 describes the difference in the outcome of interest achieved The advantages of the absolute risk reduction can be between treatment and control. For therapeutic trials, small retained but made much easier to use by “inverting” it and NNTs (with the numbers close to 1) indicate a favourable taking its reciprocal—this is called the NNT. This is clinically effect of the treatment.7 useful because it is the number of patients who must be The NNT for a certain intervention in an individual patient treated in order to obtain the benefit of interest in one new depends on both the nature of treatment and the baseline risk 3 patient. The point estimates of NNT should be accompanied of that patient—that is, the event rate in the control http://ard.bmj.com/ by the 95% CI, which is simply the reciprocals of the 95% CI of group.3 6–9 If the baseline risk is high, even a small RRR will absolute risk reduction.13The advantage of the NNT over the produce a low NNT.
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