Anticholinergic effects. Another statistically significant disadvantage is seen when clozapine was compared with olanzapine on the occurrence of urinary hesitancy, dry mouth, or constipation, with a NNT for clozapine of –5 (NNH 5). The comparison of clozapine with risperidone on this outcome, which yielded a NNT of –8, was not statistically significant. Clozapine vs quetiapine on this measure also was not statistically significant but showed an advantage for clozapine (disadvantage for quetiapine), with a NNT of 4.
Sialorrhea is a common adverse event attributed to clozapine. Here the NNTs for clozapine compared with olanzapine, risperidone, and quetiapine were –5, –5, and –4, respectively. The comparison with risperidone was not statistically significant.
Table
Using NNTs to compare clozapine’s effects in CATIE phase 2E
| Comparison | Clozapine vs olanzapine | Clozapine vs risperidone | Clozapine vs quetiapine |
|---|---|---|---|
| All cause discontinuation | 7 | 4* | 3* |
| Discontinuation because of poor efficacy | 5 | 4* | 4* |
| Discontinuation because of poor tolerability | –20 | –9* | 10 |
| Urinary hesitancy, dry mouth, constipation | –5* | –8 | 4 |
| Sialorrhea | –5* | –5 | –4* |
| *Statistically significant p<0.05 | |||
Interpreting the CI
The CI width is affected by the variability of the estimate and the sample size, not the true population effect size. This means that a larger sample size might decrease the CI width. Sometimes, narrowing the CI width will change a nonsignificant result to statistically significant. When researchers design a study, a large sample size helps minimize the chance of not finding a statistically significant difference if a true difference exists.
A CI that includes ∞ indicates a NNT that is not statistically significant, but low CI boundaries (close to 1 or –1) can suggest potentially important results and the need for more studies to provide additional data. The study might have been “under-powered” with an inadequate sample size.
NNTs for all-cause discontinuation and their CIs when comparing clozapine with olanzapine, risperidone, or quetiapine in CATIE phase 2E are shown in Figure 1. The figure’s y-axis is centered on zero, but because a NNT must fall between 1 and ∞ (or –1 to –∞), we “grayed out” the interval around zero.
CI is easy to interpret for a statistically significant NNT. For NNT values that are not statistically significant, the CI contains 2 ranges of numbers. For the comparison of clozapine vs olanzapine, the 2 ranges are 3 to ∞ and –10 to –∞. The NNT of 7 falls within the range of 3 to ∞, but the 95% confidence interval also includes the range of –10 to –∞.
It may be easier to visualize and understand the CI by reformatting the figure so that it is centered on ∞ (Figure 2). Any CI that “crosses” ∞ represents a result that is not statistically significant. In Figure 1 and Figure 2 we also can examine the “width” of the CI. The comparison of clozapine vs quetiapine yields a NNT with a narrower CI than the comparison of clozapine vs risperidone. A narrow CI implies greater precision of our estimate of NNT and potentially its clinical importance.
Figure 1
CATIE Phase 2E: What was the advantage for clozapine?
NNTs for all-cause discontinuation and 95% confidence intervals in comparing clozapine with other SGAs. The y-axis is centered on zero, but because a NNT must fall between 1 and infinity (∞) (or –1 to –∞), the interval around zero is ‘grayed out.’
Figure 2
CATIE Phase 2E: What was the advantage for clozapine (revised)?
NNTs for all-cause discontinuation and 95% confidence intervals (CI) in comparing clozapine with other SGAs. Figure 2 shows Figure 1 reformatted to center on infinity (∞). Any CI that ‘crosses’ ∞ represents a result that is not statistically significant.Related Resources
- Confidence interval calculator. www.cebm.utoronto.ca/practise/ca/statscal.
- Guyatt G, Rennie D. Users’ guides to the medical literature: a manual for evidence-based clinical practice. Chicago, IL: AMA Press; 2001.
- Straus SE, Richardson WS, Glasziou P, et al. Evidence-based medicine: how to practice and teach EBM. 3rd ed. Edinburgh, UK: Elsevier/Churchill Livingstone; 2005.
Drug brand names
- Clozapine • Clozaril
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosures
Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca Pharmaceuticals, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceutica, Jazz Pharmaceuticals, and Pfizer Inc.