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Is There a ‘Nonadherence Phenotype?’ (CME/CE)

Action Points

  • A nonadherence behavior profile, marked by nonadherence to cancer screening tests, was associated with increased mortality among middle-age and older adults.
  • The study suggests that the combination of a lifestyle marked by nonadherence to health preventive guidelines and medical tests and treatments may significantly increase mortality risk.

CME Author: Vicki Brower

Study Authors: Dudith Pierre-Victor, Paul F. Pinsky

Target Audience and Goal Statement:

Oncologists, primary care physicians, family medicine specialists, and preventive medicine specialists

The goal was to determine whether individuals who did not adhere to established cancer screenings had higher mortality rates from other, non-cancer causes than those who did adhere to regular cancer screenings.

Questions Addressed:

  • What is the association, if any, between nonadherence to cancer screening tests and mortality from all other causes except cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial?
  • Is there a behavioral pattern of nonadherence to medical tests and treatments, a “nonadherence phenotype,” that is associated with increased overall mortality?

Study Synopsis and Perspective:

Researchers conducted an observational analysis of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial and found at 15 years of follow-up, that forgoing screening was associated with an increased risk for death due to respiratory diseases, digestive diseases, cardiovascular diseases, and other non-screened cancers, compared with rates for patients who fully adhered to the cancer screening protocol.

Authors Dudith Pierre-Victor, PhD, and Paul F. Pinsky, PhD, both of the National Cancer Institute in Bethesda, Md. excluded deaths from the cancers screened for in the trial, controlled for age, sex, and race/ethnicity, and found that participants who were nonadherent to guidelines had a 73% increased risk for death compared with fully adherent participants (HR 1.73, 95% CI 1.60-1.89).

After adjusting the data for medical risk factors for mortality and behavioral-related factors such as marriage and education, the HR for death decreased to 1.46 for nonadherent participants compared with fully adherent participants (95% CI 1.34-1.59). Participants who were partially adherent had a moderately increased risk for death (HR 1.36, 95% CI 1.19-1.54), as reported in JAMA Internal Medicine.

The new analysis from Pierre-Victor and Pinsky included 64,567 of the eligible participants. Based on the number of screening tests they received, participants were classified as fully adherent (85.3%), partially adherent (3.9%), or nonadherent (10.8%) to the screening protocol.

“For each period, rates [for non-related cancers] were lowest for full adherents and highest for non-adherents, with partial adherents intermediate,” researchers wrote. There were no significant interactions with sex or age among participants.

“The most cogent explanation for these findings is that nonadherence to protocol screenings was a marker for a general behavioral profile of nonadherence to medical tests and treatments, and that this behavioral profile was associated with increased mortality,” researchers wrote. “Together, a lifestyle marked by nonadherence to health preventive guidelines and medical tests and treatments may significantly increase mortality risk.”

According to the researchers, this increased risk could be explained by nonadherence to other guidelines for cancer screening, chronic disease prevention, or medical tests and treatment.

Other studies the authors cite appear to confirm their findings: in a Medicare claims data study from 1999 to 2012, nonadherence to cancer screening was associated with mortality after controlling for age and comorbidities. Women who did not have a mammogram screening in the past 2 years had a 52% increase in the multivariate hazard for overall mortality, and men who did not receive a prostate-specific antigen screening in the past year had a 23% increase in the multivariate hazard for overall mortality.

“These findings have implications for the interpretation of screening and other prevention trials with mortality endpoints,” the authors wrote. “Because a nonadherence phenotype is associated with higher mortality for causes that are not related to the trial, that phenotype may also convey higher risk for the cause of interest, irrespective of the effect of the intervention being studied.”

Researchers recommended that future studies be conducted to investigate this association in clinical care settings outside of a research trial context.

Source References:

JAMA Internal Medicine, online Dec. 28, 2018; DOI: 10.001/jamainternmed.2018.5982

Editorial JAMA Internal Medicine, online Dec. 28, 2018; DOI: 10.1001/jamainternmed.2018.6813

Study Highlights: Explanation of Findings

This observational analysis included data from the PLCO Cancer Screening trial, which was conducted at 10 U.S. screening centers from 1993 to 2001. In PLCO, more than 75,000 patients underwent cancer screening interventions that included chest radiographs and flexible sigmoidoscopy for all patients, prostate-specific antigen (PSA) tests, and digital rectal examinations for men, and cancer antigen 125 tests and transvaginal ultrasonography for women.

Researchers found “statistically significant and clinically important differences in all-cause mortality, excluding mortality from cancers studied in the PLCO Cancer Screening trial, by cancer screening adherence status of patients, which remained significant after adjusting for demographic, medical, and behavioral characteristics.”

“Although we believe that such a general nonadherence phenotype explains the preponderance of the increased risk associated with nonadherence observed in this study, it cannot be ruled out that reverse causation bias may explain a portion of the increased risk,” Pierre-Victor and Pinsky wrote. “Specifically, some participants may have had an underlying condition(s) at baseline, perhaps incompletely captured by our comorbidity variables, that both made it harder to comply with screening and predisposed the participants to earlier mortality,” they explained.

The team concluded that “these results imply that observational studies comparing those who undergo screening with those who do not undergo screening have a high likelihood of bias, and that controlling for important demographic, behavioral, and medical history factors may not eliminate this bias.”

Researchers wrote that their research’s prospective design, large size, and long follow-up were study strengths.

One limitation of the study they mentioned is that nonadherents had higher rates of missing data than did full and partial adherents.

In an editorial published along with the study, Deborah Grady, MD, MPH, and Monica Parks, MD, of the University of California San Francisco, observed that “there is no way that nonadherence with cancer screening could cause increased mortality from a range of diseases not associated with screening.” Because the analyses were adjusted for a range of factors including age, sex, race/ethnicity, cigarette smoking, body mass index, major comorbidities, and more, it is unlikely that these health-related variables account for the study results, Grady and Parks noted.

They asked, then what does account for increased risk of death in the nonadherents? They agreed with the study authors that “most likely” a patient’s nonadherence to recommended screening guidelines may be an indication, or “marker,” of behaviors that are associated with increased mortality. “Previous studies have shown that patients who are adherent to recommended medications are more likely to seek out other preventive services such as screenings and vaccinations, while nonadherence [to medication and/or screening regimens] has been associated with increased mortality,” wrote Grady and Parks. “This association has been dubbed adherence bias or compliance bias, but is really a form of unmeasured confounding,” the editorialists asserted.

While they called the study findings “interesting,” they asked whether they have any “real clinical effect.”

Notably, the editorialists proposed a twofold critique of the study. They noted that compliance bias is important for 2 reasons: “First, it highlights the fact that secondary analyses of clinical trial results that compare those who are adherent with intervention with those who are not adherent with the intervention may markedly overestimate the benefit of the intervention. This problem can be dealt with by comparing adherent participants in the intervention group with adherent participants in the control group, if there is an active, placebo or sham control,” Grady and Parks wrote.

They mentioned a different meta-analysis of an observational trial in which there was a placebo group, and adherent patients were found in both groups. In contrast, because there was no “sham screening” in the current study, “there was no way to compare outcomes among the intervention and control group among nonadherent participants,” the editorial writers observed.

Their second reason pointed to a major difference between observational studies and randomized clinical studies. “Compliance bias might explain some of the discrepancies between the findings of observational studies and randomized trials,” they wrote. Grady and Parks contrasted findings in two other observational studies with those in clinical studies, and noted that findings in certain observational studies have been proven to be incorrect once clinical trials were conducted. Examples given were post-menopausal hormone therapy and cardiovascular risk reduction, and the use of beta-carotene and reduction in cancer risk. In both cases the clinical studies negated findings in the observational studies.

“Thus, we should view the findings of observational studies where the risk factor requires adherence to a drug or behavior with some skepticism. This effect is particularly notable in observational studies of preventive interventions in the primary care setting,” the editorialists concluded.

Leah Lawrence wrote the original story for MedPage Today

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
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