Statins Linked to Reduced Postop Adhesions, Bowel Obstruction

Batya Swift Yasgur MA, LSW

February 11, 2021

Statin use is associated with a lower risk for postoperative adhesion-related complications (ARCs) after intra-abdominal surgery, a new observational study suggests.

Investigators retrospectively studied two cohorts of patients who underwent intra-abdominal surgery, comprising more than 1.3 million individuals, and found that statin use was associated with a reduction of up to 20% in rates of ARCs over time, after adjustment for other comorbidities and patient characteristics. The association was not found in individuals using other lipid-lowering or antihypertensive therapies.

"Adhesion formation is the main underlying etiology of small bowl obstruction, and adhesions are responsible for significant morbidity and healthcare expenditures, with limited effective options at this time for preventing adhesion formation," lead author Frank Scott, MD, MSCE, assistant professor of medicine, Crohn's and Colitis Center, Division of Gastroenterology, University of Colorado School of Medicine, Aurora, told theheart.org | Medscape Cardiology.

"If our findings are confirmed in prospective randomized clinical trials, statins may represent an effective prophylactic therapy for preventing adhesion-related complications in those undergoing elective intra-abdominal surgery," said Scott, who is also codirector of the AGI Outcomes Research Group and codirector of clinical research/DART at the University of Colorado School of Medicine.

The study was published online February 3 in JAMA Network Open.

First Step

More than 90% of patients develop adhesions after intra-abdominal surgery, and ARCs occur in up to 5% of patients, the authors write.

Statins have "well-described antifibrotic properties" and have been shown in animal models to potentially reduce adhesion formation, Scott said.

"This class of medication would represent an inexpensive, well-tolerated perioperative adjunct to reduce adhesion-related complications if these findings could be translated to human populations, and we felt that this pharmacoepidemiologic approach would be an important first step in addressing if an association between statins and reduced adhesion-related complications existed in humans," he added.

To investigate the question, the researchers turned to two separate retrospective cohort studies — The Health Improvement Network (THIN) and Optum's Clinformatics Data Mart (Optum) — which compared adults receiving statins at the time of intra-abdominal surgery with individuals not receiving statins.

The THIN cohort consisted of 148,601 individuals (mean [SD] age, 49.6 [17.7] years; 70.1% female) and the Optum cohort consisted of 1,188,216 individuals (mean age, 48.2 [16.4] years; 72.6% female) who met the inclusion criteria. Of these, 4.1% and 4.6%, respectively, experienced an ARC during a median (IQR) follow-up time of 3.8 years (598 - 2632 days).

Statin used was defined as "receipt of two prescriptions for a statin before the surgery," and was categorized as no use, former use, and current use. Indications for statin prescription were not available.

Age at surgery, sex, and whether the index surgery involved the small bowel or colon were used as covariates. Other factors assessed were hypertension, hyperlipidemia, obesity, tobacco use, and malignant tumor.

Statins Inhibit Fibrosis-Related Cytokines

In the THIN cohort, 11.7% of individuals were using a statin at the time of surgery, with a median duration of preoperative statin use of 3.7 (IQR, 1.7 - 6.5) years. A smaller percentage (2.3%) of individuals had used a statin but had stopped taking the medication before surgery.

Fewer patients (0.6%) were taking fibrates at the time of surgery. In contrast, angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) were used by 12.6% of the cohort at the time of surgery.

Statin use at the time of intra-abdominal surgery was associated with a lower hazard of postoperative ARCs (hazard ratio [HR], 0.95; 95% CI, 0.74 - 0.99). Increasing age, bowel surgery, and history of malignant tumors were all associated with a higher risk for ARCs, whereas sex, diabetes, hyperlipidemia, and obesity were not associated with risk.

A second statistical "parsimonious" model similarly found statin use to be statistically associated with a reduced hazard of ARCs (HR, 0.81; 95% CI, 0.73 - 0.96).

In the Optum cohort, 10.8% of individuals were using statins at the time of surgery. As with the THIN cohort, a small percentage (0.4%) of patients were using fibrates. Similar to the findings in the THIN cohort, statin use at the time of surgery was associated with a decreased risk for ARCs (HR, 0.92; 95% CI, 0.90 - 0.95).

Factors associated with increased risk for ARCs were diseases that affect the microvasculature, including hypertension, diabetes, and obesity; bowel operations; a history of malignant tumors; tobacco use; and advanced age (>65 years).

Factors not associated with ARC risk included fibrates and ACEIs or ARBs and former statin use with subsequent discontinuation. By contrast, concurrent use remained associated with ARC risk (HR, 0.84; 95% CI, 0.72 - 0.97) in THIN. Similar findings were obtained in the Optum cohort (HR, 0.92; 95% CI, 0.89 - 0.95).

Statins were associated with a reduced hazard of small bowel obstructions (SBOs) in both the THIN cohort (HR, 0.80; 95% CI, 0.70 - 0.92) and the Optum cohort (HR, 0.88; 95% CI, 0.85 - 0.91). In contrast, no association was found between ACEI or ARB use and ARCs.

Scott addressed the potential mechanism by which statins might be associated with a lower risk for ARCs.

"Statins inhibit cholesterol metabolism," he explained. "One of the downstream molecules in this metabolic pathway is geranylgeranyl pyrophosphate, a key molecule in the modulation of fibrosis-related cytokines, such as PAI-1, tissue plasminogen activator (tPA), IL-6, and TGF-beta."

He noted that in vitro assays "have demonstrated that statins impact the production of each of these cell-signaling molecules, and statin administration had previously been shown to reduce adhesion formation in two in vivo animal models."

Auspicious Solution?

In an accompanying editorial, Sue Fu, MD, and Lisa Knowlton, MD, MPH, both of the Department of Surgery, Stanford University School of Medicine, California, called statins a "promising avenue for reducing the risk of ARCs."

The study "suggests that statins could provide an auspicious solution to ARCs," but they caution that randomized clinical trials are needed "to determine which patient populations are likely to receive maximum benefit from statins in this setting, as well as the optimal dosing and duration of therapy," they write.

The study was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. Scott reports receiving grants from the National Institute of Diabetes and Digestive and Kidney Disorders during the conduct of the study; grants from Janssen Pharmaceuticals Investigator Initiated Study, Takeda Pharmaceuticals Investigator Initiated Study, and Crohn's and Colitis Foundation Investigator Initiated Study unrelated to this work; and personal fees from PRIME Inc, Janssen Pharmaceuticals, Takeda Pharmaceuticals, and Merck Pharmaceuticals outside the submitted work. The other authors' disclosures are listed on the original paper. Fu and Knowlton report no relevant financial relationships.

JAMA Netw Open. 2021;4:e2036315, e2037296. Full text, Editorial

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