The return of “negative” trials?
====================================

* Mario L. de Lemos

I was surprised that several important issues were not addressed in the original reports1,2 and editorial3 about rate versus rhythm control in atrial fibrillation published in the *New England Journal of Medicine*, or in the review4 and editorial5 published subsequently in *CMAJ*. 

The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) investigators found no statistically significant difference between rhythm control and rate control.1 However, one cannot rule out the possibility of a type II error, given that a sample size of 5300 was planned6 but only 4060 patients were enrolled in the study.

In the noninferiority study by Van Gelder and associates,2 the efficacy of rate control was within the upper bound of the 95% confidence interval of that of rhythm control. However, 3 concerns must be addressed.

First, it is not clear if the rhythm control strategy is a suitable active comparator. Neither the authors nor the practice guidelines cited7 provided details on any earlier trials that showed rhythm control to be consistently better than placebo. Thus, it is not possible to assess the similarity of the current trial to those earlier trials, the expected effect size of rhythm control relative to placebo8 or the consistent responsiveness to rhythm control of the composite endpoint components9 used in the current trial.

Second, the investigators performed an intention-to-treat analysis only, which gives a conservative estimate of the effect size and hence bias toward a conclusion of noninferiority, when a per-protocol analysis is generally preferred.10

Finally, neither the AFFIRM trial1 nor the noninferiority study2 defined or reported compliance. Poor compliance can create bias toward a conclusion of “no difference” in both cases and would be of particular interest in assessing life-long therapies with recognized adverse effects. 

**Mario L. de Lemos** Provincial Drug Information Coordinator British Columbia Cancer Agency Vancouver, BC

## References

1.  1. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 1825-33.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1056/NEJMoa021328&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=12466506&link_type=MED&atom=%2Fcmaj%2F168%2F11%2F1392.2.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000179596900002&link_type=ISI) 

2.  2. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-40.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1056/NEJMoa021375&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=12466507&link_type=MED&atom=%2Fcmaj%2F168%2F11%2F1392.2.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000179596900003&link_type=ISI) 

3.  3. Cain ME. Atrial fibrillation — rhythm or rate control [editorial]. N Engl J Med 2002;347:1822-3.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1056/NEJMp020134&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=12466505&link_type=MED&atom=%2Fcmaj%2F168%2F11%2F1392.2.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=000179596900001&link_type=ISI) 

4.  4. Kovacs KA. Long-term management of atrial fibrillation: Rhythm or rate control? CMAJ 2003; 168(5):591-2.
    
    [FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czo5OiIxNjgvNS81OTEiO3M6NDoiYXRvbSI7czoyNDoiL2NtYWovMTY4LzExLzEzOTIuMi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

5.  5. Nattel S. Rhythm versus rate control for atrial fibrillation management: what recent randomized clinical trials allow us to affirm [editorial]. CMAJ 2003;168(5):572-3.
    
    [FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY21haiI7czo1OiJyZXNpZCI7czo5OiIxNjgvNS81NzIiO3M6NDoiYXRvbSI7czoyNDoiL2NtYWovMTY4LzExLzEzOTIuMi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

6.  6. Atrial fibrillation follow-up investigation of rhythm management — the AFFIRM study design. The Planning and Steering Committees of the AFFIRM study for the NHLBI AFFIRM investigators. Am J Cardiol 1997;79(9):1198-202.
    
    [CrossRef](http://www.cmaj.ca/lookup/external-ref?access_num=10.1016/S0002-9149(97)00082-9&link_type=DOI) 
    
    [PubMed](http://www.cmaj.ca/lookup/external-ref?access_num=9164885&link_type=MED&atom=%2Fcmaj%2F168%2F11%2F1392.2.atom) 
    
    [Web of Science](http://www.cmaj.ca/lookup/external-ref?access_num=A1997WX17700009&link_type=ISI) 

7.  7. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Circulation 2001;104:2118-50.
    
    [FREE Full Text](http://www.cmaj.ca/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6MTQ6ImNpcmN1bGF0aW9uYWhhIjtzOjU6InJlc2lkIjtzOjExOiIxMDQvMTcvMjExOCI7czo0OiJhdG9tIjtzOjI0OiIvY21hai8xNjgvMTEvMTM5Mi4yLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

8.  8. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH E10. *Choice of control group and related issues in clinical trials.* London: European Agency for the Evaluation of Medicinal Products; 2000 Jul 20.
    
    

9.  9. Committee for Proprietary Medicinal Products. *Points to consider on multiplicity issues in clinical trials.* London: European Agency for the Evaluation of Medicinal Products; 2002.
    
    

10. 10. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). ICH E9. *Statistical principles for clinical trials*. London: European Agency for the Evaluation of Medicinal Products; 1998 Feb 5.