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Aggregating and Disaggregating Patients in Clinical Trials and Their Subgroup Analyses

David M. Kent, MD, MS; and Peter K. Lindenauer, MD, MSc
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From Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA 02111, and Center for Quality of Care Research, Baystate Medical Center, Springfield, MA 01199.


Grant Support: In part by the National Center for Research Resources of the National Institutes of Health (grant UL1RR025752) and the National Institute of Neurological Disorders and Stroke (grant R01 NS062153).

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1096.

Requests for Single Reprints: David M. Kent, MD, MS, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Box 63, 800 Washington Street, Boston, MA 02111; e-mail, dkent1@tuftsmedicalcenter.org.

Current Author Addresses: Dr. Kent: Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Box 63, 800 Washington Street, Boston, MA 02111.

Dr. Lindenauer: Center for Quality of Care Research, Baystate Medical Center, 759 Chestnut Street, Springfield, MA 01199.


Ann Intern Med. 2010;153(1):51-52. doi:10.7326/0003-4819-153-1-201007060-00012
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In this issue, Hull and colleagues (1) report on their trial examining venous thromboembolism (VTE) prophylaxis in medical patients. An interim analysis of this trial, performed after enrollment of more than 3000 patients at 370 sites in 20 countries, found a lower-than-anticipated VTE rate (symptomatic or asymptomatic) in those treated with standard enoxaparin prophylaxis (3.3%). In a different context, one might have expected the trial's sponsor, which markets enoxaparin, to have been pleased. However, because this trial was designed to test extended-duration enoxaparin, these results may not have been a cause for celebration. For new therapies, especially those with risks for serious harms, demonstrating benefit is highly dependent on a sufficiently high control rate (2). Rather than simply conclude that standard enoxaparin is highly effective and that the incremental benefits of prolonged therapy would be unlikely to outweigh the additional bleeding risk, the investigators instead set out to identify a subgroup of patients with a higher VTE rate who might be likely to benefit from extended prophylaxis.

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Figure.
Sample risk distribution.

The risk distribution in the figure is generated from the following assumptions: 3 risk factors (X, Y, and Z), each of which doubles outcome risk, has a prevalence of 50% and assorts independently. The base risk (with no risk factors) is 1%. If treatment were justified for patients with an outcome risk of 4.5% or greater, sequential one-variable-at-a-time subgroup analyses (on risk factor X, or Y, or Z) would suggest that patients with any one of these risk factors might benefit, together comprising seven eighths of patients. Subgrouping based on a multivariable risk score would demonstrate that only one eighth of patients is at sufficiently high risk to warrant therapy.

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