Number needed to harm in the post-marketing safety evaluation: results for rosiglitazone and pioglitazone

Pharmacoepidemiol Drug Saf. 2015 Dec;24(12):1259-70. doi: 10.1002/pds.3874. Epub 2015 Sep 16.


Purpose: Our aim is to investigate the usefulness of metric indices in post-marketing safety evaluations by estimating number needed to harm (NNH) values for cardiovascular (CV) adverse outcomes for rosiglitazone and pioglitazone.

Methods: Reports from regulatory authorities (RAs) were consulted, and Medline searches were performed to identify studies assessing CV risks [all-cause death, CV death, myocardial infarction (MI), stroke, or congestive heart failure (CHF)] for thiazolidinediones. Meta-analyses were performed to pool evidence from randomized controlled trials (RCTs) and observational studies (OS). NNHs [with 95% confidence intervals (CI)] per year were estimated for CV adverse events.

Results: Reports from RAs included two meta-analyses of short-term RCTs, two long-term RCTs (RECORD and PROACTIVE), and a systematic review of OS (n = 29). The Medline search identified six additional OS. Statistically significant NNH values were obtained for the following: (i) rosiglitazone versus control on MI and CHF in the meta-analysis of RCTs (NNH = 16; 95%CI = 10-255; and NNH = 7; 95%CI = 5-16, respectively) and meta-analysis of OS (NNH = 12; 95%CI = 9-20; and NNH = 5; 95%CI = 32-131, respectively) and on CHF in the RECORD (NNH = 6; 95%CI = 4-14); (ii) pioglitazone versus control on CHF (NNH = 11; 95%CI = 6, 403) in the meta-analysis of RCTs and PROACTIVE (NNH = 12; 95%CI = 8-43); and (iii) rosiglitazone versus pioglitazone on MI (NNH = 69; 95%CI = 32-379), stroke (NNH = 36; 95%CI = 20-225), CHF (NNH = 33; 95%CI = 19-47), and all-cause death (NNH = 63; 95%CI = 49-100) in the meta-analysis of OS.

Conclusion: The NNH values suggested an increased CV risk with rosiglitazone versus pioglitazone across several sources of information. The inclusion of objective metrics in post-marketing drug's benefit-risk assessments could be of increased value and help RAs to make consistent decisions on drug safety.

Keywords: NNH; benefit-risk assessment; cardiovascular diseases; pharmacoepidemiology; pioglitazone; rosiglitazone; safety-based drug withdrawals.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adverse Drug Reaction Reporting Systems / standards*
  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / epidemiology*
  • Female
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Male
  • Patient Selection
  • Pioglitazone
  • Randomized Controlled Trials as Topic
  • Rosiglitazone
  • Thiazolidinediones / adverse effects*
  • United States / epidemiology


  • Hypoglycemic Agents
  • Thiazolidinediones
  • Rosiglitazone
  • Pioglitazone