Popular Drugs Do Little to Prevent ESRD in Older Patients

Diedtra Henderson

January 13, 2014

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) show promise in preventing end-stage renal disease (ESRD) in younger patients, but have marginal benefit for older patients with chronic kidney disease (CKD), according to a simulation study. The new data highlight a possible disconnect between clinical trials and real-world use of the drugs, especially for older. sicker patient populations.

Ann M. O'Hare, MA, MD, from the Department of Medicine, Department of Veterans Affairs Puget Sound Healthcare System; the Department of Medicine, University of Washington; and the Group Health Research Institute, Seattle, Washington, and colleagues report their findings in an article published online January 13 in JAMA Internal Medicine.

According to the Centers for Disease Control and Prevention, 1 in 10 American adults (or more than 20 million people) have some level of CKD, a disease characterized by kidney damage that impairs their ability to properly filter blood. The incidence of CKD is rising most dramatically among people aged 65 years and older and more than doubled from 2000 to 2008, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

Because preventive interventions are typically tested in younger, healthier patients, Dr. O'Hare and colleagues sought to quantify the benefit of such drugs for older, sicker patients. These patients are more representative of the real world, but are less frequently included in clinical trials, and are also less likely to survive long enough to experience the same magnitude of benefit as the younger patients who do enroll in trials.

The authors ran a simulation study that applied the relative risk reduction seen in clinical trials for ACEIs and ARBs to 371,470 patients aged 70 years or older who suffered from CKD.

Both medications showed promise in high-risk younger patients by slowing progression to ESRD. The researchers selected 4 trials that had tested the medicines in at least 350 patients for 2.6 to 3.4 years, finding a relative risk reduction of 23% to 56% and a number needed to treat (NNT) ranging from 9 to 25. They used an observation period of 3 years and relative risk reduction for ESRD of 30% for their simulations.

The study group, selected from 790,342 patients who had been treated at a Department of Veterans Affairs medical center from October 1, 2000, through September 30, 2001, had a mean age of 77.8 years. Of these patients, 9.2% were black, 47.1% had been diagnosed with diabetes, and 37.9% were taking an ACEI or an ARB. Median survival was 6.7 years, with 23.3% of the study participants dying within 3 years and 68.6% dying within 10 years.

"When extrapolated to this real-world cohort of adults 70 years or older with CKD, a treatment effect within this range would be expected to yield NNTs ranging from 16 for those at highest risk for ESRD to 2500 for those at lowest risk, with most patients belonging to groups with an NNT greater than 100," Dr. O'Hare and colleagues write.

"The most effective treatments have NNTs close to 1, indicating that only a few patients must be treated to achieve the desired outcome in a single patient. As the NNT increases, the marginal benefit to the individual patient decreases," they add.

In an accompanying commentary, Mary E. Tinetti, MD, from the Section of Geriatrics, Department of Internal Medicine, Yale School of Medicine, and the Yale School of Public Health, New Haven, Connecticut, write that the results are important because they call into question routine assumptions that guide geriatric care.

"These findings leave one wondering whether the poor translation of the effectiveness of ACEIs and ARBs from younger to older individuals is an isolated situation or whether we are unwittingly subjecting older adults to a wide array of preventive treatments that have no or marginal benefit or even impart unintended harm," Dr. Tinetti writes. "The study by O'Hare et al supports the need to look at this question more systematically and calls into question the prevailing practice of assuming that results extrapolate from young to old and from healthier to sicker populations."

Because clinical practice guidelines take their cues from clinical trials that exclude older patients, clinicians should be more circumspect about which preventive treatments to recommend to older patients. The uncertain benefit/risk balance "mandates shared decision making between clinician and patient," Dr. Tinetti adds.

The study authors conclude, "Differences in baseline risk and life expectancy may substantially modify the benefit of ESRD-preventive interventions when applied to real-world populations of older adults compared with trial populations.... This consideration may be particularly relevant in older adults because they are often underrepresented in clinical trials and their risk for experiencing the outcome of interest during their remaining lifetime may be very different from that for younger trial populations."

Financial support for the study was provided by the National Institute on Aging, Veterans Affairs Health Services Research and Development, and the Roy and Vi Baay Chair in Kidney Research. One coauthor has disclosed having served on a scientific advisory board for Amgen. The other authors and Dr. Tinetti have disclosed no relevant financial relationships.

JAMA Intern Med. Published online January 13, 2014.

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