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Original Investigation |

Interpreting Treatment Effects From Clinical Trials in the Context of Real-World Risk Information:  End-Stage Renal Disease Prevention in Older Adults

Ann M. O’Hare, MA, MD1,2,3; John R. Hotchkiss, MD4,5; Manjula Kurella Tamura, MD, MPH6,7; Eric B. Larson, MD, MPH2,3; Brenda R. Hemmelgarn, MD, PhD8; Adam Batten, BA1; Thy P. Do, PhD1,9; Kenneth E. Covinsky, MD, MPH10,11
[+] Author Affiliations
1Department of Medicine, Department of Veterans Affairs Puget Sound Healthcare System, Seattle, Washington
2Department of Medicine, University of Washington, Seattle
3Group Health Research Institute, Seattle, Washington
4Veterans Engineering Resource Center, Department of Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennyslvania
5Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
6Department of Medicine, Department of Veterans Affairs Palo Alto Healthcare System, Palo Alto, California
7Department of Medicine, Stanford University Medical Center, Palo Alto, California
8Department of Medicine, University of Calgary, Calgary, Alberta, Canada
9currently with Amgen, Thousand Oaks, California
10Department of Medicine, Department of Veterans Affairs Medical Center, San Francisco, San Francisco, California
11Department of Medicine, University of California, San Francisco
JAMA Intern Med. 2014;174(3):391-397. doi:10.1001/jamainternmed.2013.13328.
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Importance  Older adults are often excluded from clinical trials. The benefit of preventive interventions tested in younger trial populations may be reduced when applied to older adults in the clinical setting if they are less likely to survive long enough to experience those outcomes targeted by the intervention.

Objective  To extrapolate a treatment effect similar to those reported in major randomized clinical trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for prevention of end-stage renal disease (ESRD) to a real-world population of older patients with chronic kidney disease.

Design, Setting, and Participants  Simulation study in a retrospective cohort conducted in Department of Veterans Affairs medical centers. We included 371 470 patients 70 years or older with chronic kidney disease.

Exposure  Level of estimated glomerular filtration rate (eGFR) and proteinuria.

Main Outcomes and Measures  Among members of this cohort, we evaluated the expected effect of a 30% reduction in relative risk on the number needed to treat (NNT) to prevent 1 case of ESRD over a 3-year period. These limits were selected to mimic the treatment effect achieved in major trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for prevention of ESRD. These trials have reported relative risk reductions of 23% to 56% during observation periods of 2.6 to 3.4 years, yielding NNTs to prevent 1 case of ESRD of 9 to 25.

Results  The NNT to prevent 1 case of ESRD among members of this cohort ranged from 16 in patients with the highest baseline risk (eGFR of 15-29 mL/min/1.73 m2 with a dipstick proteinuria measurement of ≥2+) to 2500 for those with the lowest baseline risk (eGFR of 45-59 mL/min/1.73 m2 with negative or trace proteinuria and eGFR of ≥60 mL/min/1.73 m2 with dipstick proteinuria measurement of 1+). Most patients belonged to groups with an NNT of more than 100, even when the exposure time was extended over 10 years and in all sensitivity analyses.

Conclusions and Relevance  Differences in baseline risk and life expectancy between trial subjects and real-world populations of older adults with CKD may reduce the marginal benefit to individual patients of interventions to prevent ESRD.

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Number Needed to Treat (NNT) to Prevent 1 Case of End-Stage Renal Disease (ESRD) Over 10 Years

The NNT is calculated assuming a 30% reduction in relative risk over 10 years.

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