Dissecting clinical trials with ‘number needed to treat’

• An NNT of 100 or more usually means little difference exists between interventions for the outcome of interest.
  
• An NNT of 2 would be hugely important and is rarely encountered.
  

Keep in mind, however, that some NNTs may be clinically important even though they are relatively large. An NNT of 500, for example, could be important if the outcome measured is death. Similarly, relatively small NNTs may be clinically irrelevant, such as an NNT of 5 when the outcome is a mild dry mouth.

Example. We can calculate the NNT (actually, NNH) for risk of new-onset diabetes mellitus attributable to second-generation antipsychotics (SGAs), using data from a study that compared diabetes rates in patients given SGAs versus conventional antipsychotics.⁴ Differences in new-onset diabetes rates across ≤25 months were 2.03%, 0.80%, 0.63%, and 0.05% for clozapine, quetiapine, olanzapine, and risperidone, respectively, versus first-generation antipsychotics (FGAs).

The NNH for clozapine compared with FGAs is 1/0.0203=49. This means you would need to treat 49 patients with clozapine instead of an FGA for up to 25 months to encounter 1 extra case of new-onset diabetes mellitus. NNH calculations for quetiapine, olanzapine, and risperidone compared with FGAs would be 125, 159, and 2,000, respectively.

Applying nnt and nnh to catie

An ongoing controversy in schizophrenia treatment is the relative merit of using the more-expensive SGAs versus FGAs. The National Institute of Mental Health-funded CATIE study addressed this issue.^5-7

In CATIE phase 1, which was double-blinded, 1,493 patients with schizophrenia were randomly assigned to 1 of 5 antipsychotics—perphenazine, olanzapine, quetiapine, risperidone, or ziprasidone—for up to 18 months. Patients who discontinued phase 1 before 18 months could participate in phase 2, where 543 patients were randomly assigned to 1 of 5 SGAs that they did not receive in phase 1. Those who prematurely discontinued phase 2 were offered open-label treatment with one or two antipsychotics. When they enrolled, patients were told these switches were possible.

Nearly one-half of all patients who enrolled finished 18 months of follow-up. What resulted, however, was a morass of percentages and p values that were misinterpreted by various parties—including The New York Times, which published an article headlined, “Little difference found in schizophrenia drugs.”⁸ We can apply NNT and NNH to the CATIE study results, however, and discover that:

• important differences do exist between the drugs tested
  
• these differences are clinically and statistically significant.³
  

Overall effectiveness in the CATIE trial was measured by determining how long patients remained on the medications to which they were randomly assigned. All-cause discontinuation—the primary outcome measure—included discontinuation because of:

• lack of efficacy
  
• poor tolerability
  
• patient decision.
  

Thus, both clinician and patient input—and both efficacy and tolerability—affected all-cause discontinuation. In CATIE phase 1, 74% of patients stopped participating (all-cause discontinuation) before 18 months. The percentage of patients who ended phase 1 early ranged from 64% for olanzapine to 82% for quetiapine. Thus, calculating NNT comparing olanzapine and quetiapine on this measure yields:

• NNT=1/(difference in discontinuation rates)=1/(0.82 - 0.64)=1/0.18=5.6. By convention, we round up to the next whole number, in this case 6. This means that for every 6 patients randomized to olanzapine treatment, 1 extra patient completed phase 1 on his or her initially initial medication, compared with patients randomized to quetiapine treatment.
  

Similarly, we can calculate the NNT for all-cause discontinuation for olanzapine compared with ziprasidone, perphenazine, and risperidone, and find NNT of 7, 9, and 11, respectively. In general, a single-digit NNT is sufficiently small for the result to be clinically relevant in day-to-day patient treatment.

In measuring the number of hospitalizations for exacerbation of schizophrenia symptoms per total person-year of exposure, NNT ranged from 3 to 7 in favor of olanzapine compared with the other antipsychotics. This means that for every 3 to 7 patients treated with olanzapine versus another antipsychotic, 1 hospitalization was avoided.

Tolerability. Calculating NNH can show how often you could expect specific tolerability outcomes when comparing medications. In CATIE, differences in tolerability emerged among the medications, and each antipsychotic had a unique profile of relative strengths and weaknesses that can be expressed in NNT and NNH. For example, in CATIE phase 1:

• For every 5 to 8 patients treated with olanzapine compared to other antipsychotics, 1 additional patient gained >7% in body weight (NNH is 5 to 8; not corrected for duration of exposure to the medication)
  
• For every 13 to 18 patients treated with olanzapine versus another antipsychotic, 1 additional patient discontinued because of weight gain or metabolic effects.
  

Data from phase 2 were largely consistent with those from phase 1, with important advantages noted for clozapine. NNT in favor of clozapine for all-cause discontinuation was 3, 4, and 7 compared with quetiapine, risperidone, and olanzapine, respectively. In phases 1 and 2, ziprasidone presented with the most favorable metabolic profile, whereas risperidone appeared to have the best overall tolerability.