’Pioneering’ post-hoc analysis suggests that aspirin does not prevent sepsis-related death

Daily low-dose aspirin was not the answer for reducing deaths associated with sepsis in community-dwelling older adults, researchers reported.

In the ANTISEPSIS trial, among 8,322 (49.8%) patients getting aspirin and 8,381 (50.2%) on placebo, a little over 200 deaths were deemed tied to sepsis, and the rates of death associated with sepsis were similar between the two group (hazard ratio 1.08 for aspirin versus placebo, 95% CI 0.82-1.43, P=0.57), according to Damon P. Eisen, MD, of the College of Medicine and Dentistry at James Cook University in Douglas, Australia, and co-authors.

For the secondary endpoint of hospital admission linked with sepsis, there also was no evidence of a protective effect of aspirin (HR 1.18, 95% CI 0.95-1.46, P=0.13), they wrote in the Lancet Respiratory Medicine.

ANTISEPSIS was a substudy of the ASPREE trial, which was a randomized controlled primary prevention trial of low-dose aspirin (100 mg/day versus placebo in community dwelling older adults (ages ≥70 years) conducted in the U.S. and Australia.

ASPREE showed that among healthy adults who did not have an indication for aspirin use, all-cause mortality seemed higher among those who received daily low-dose aspirin versus those who received placebo, and that cancer was the principal cause of the excess deaths.

ASPREE was stopped prematurely because interim analysis showed no benefit of the intervention for the trial’s primary outcome, so the current post-hoc analysis was also stopped early with 203 recorded sepsis-associated deaths.

Eisen and co-authors explained that “analyzed individuals whose death we classified as associated with sepsis and reanalyzed them stratified according to whether they were classified as death due to cancer in ASPREE. We did this assess the potential effect of aspirin on death due to sepsis, mediated by cancer.”

ANTSEPSIS participants were enrolled from March 2010 through December 2014 and were evenly matched at randomization for age, prevalence of diabetes, smoking history, alcohol use, and history of cancer.

“All ANTISEPSIS endpoint data relied on ASPREE trial processes — i.e., participant diaries, in-person visits and scheduled telephone calls to encourage trial retention and collect additional information, retrieval of hospital records, and death certificates,” the authors stated.

Sepsis was defined as as infection plus at least two of four Systemic Inflammatory Response Syndrome (SIRS) criteria measured in a 24-hour period.

The primary endpoint was met if sepsis contributed to death; the secondary endpoint was reached if a participant was admitted to hospital or an ICU due to non-fatal sepsis, according to the authors, who added that the HR for the primary endpoint was assumed as 0.63. Median follow-up of participants was 4.6 years to the time of study cessation (June 2017).

“Among all primary and secondary endpoint events, sepsis was predominantly due to pneumonia with smaller numbers of urinary tract infections and bacteremia,” the authors noted.

Study limitations included the fact that SIRS sepsis criteria has poor specificity, and that episodes of sepsis that did not lead to hospital or ICU admission were not recorded. Also, participants were predominantly white.

Nonetheless, “ANTISEPSIS is a pioneering study in the field of sepsis suggesting that aspirin probably does not prevent sepsis-related death,” noted Djillali Annane, MD, PhD, of Raymond Poincare University Hospital, in Garches, France, in a comment accompanying the study.

However, the study findings don’t rule out the possibility that other low-dose antiplatelet drugs should be considered for the prevention of sepsis-related death. “Indeed, different antiplatelet agents might have quantitatively and qualitatively variable immune effects,” Annane wrote. “Likewise, it might be worth investigating the benefit and risk of secondary prevention of sepsis with antiplatelet drugs in patients who survived a first episode of sepsis.”

The authors pointed out several limitations to the ANTISEPSIS study, the most obvious of which was its failure to support the hypothesis that aspirin might reduce sepsis-associated death. Other limitations included the study’s reliance on hospital admission associated with sepsis, a small number of non-white individuals among the Australian study participants, and the fact that “[i]nformation on whether aspirin had an acute influence on study endpoints was not available as data relating to drug treatment in hospital could not be reliably extracted due to the absence of drug charts,” they wrote.

  1. Daily low-dose aspirin therapy was not associated with a reduction in deaths or sepsis-associated hospital admissions among community-dwelling adults (ages ≥70 years).

  2. The post-hoc analysis of the ASPREE trial does not support the use of aspirin as a primary prevention strategy to reduce the burden of sepsis in this population.

Shalmali Pal, Contributing Writer, BreakingMED™

The ANTISEPSIS trial was supported by the National Health and Medical Research Council of Australia (NHMRC). The ASPREEtrial was supported by the National Institute on Aging, the National Cancer Institute, NHMRC, Monash University, and the Victorian Cancer Agency. Bayer Pharma (Germany) provided the trial drug and placebo.

Eisen reported no relationships relevant to the contents of this paper to disclose. A co-author reported a relationship with Bayer AG.

Annane reported no relationships relevant to the contents of this paper to disclose.

Cat ID: 494

Topic ID: 398,494,282,494,255,925