Statins may reduce risk of death by 39% for patients with life-threatening sepsis, large study finds

Sepsis is when the immune system overshoots its inflammatory reaction to an infection, so strongly that the vital organs begin to shut down. It is life-threatening: each year in the US alone, approximately 750,000 patients are hospitalized for sepsis, of which approximately 27% die.

In about 15% of cases, sepsis worsens into septic shock, characterized by dangerously low blood pressure and reduced blood flow to tissues. The risk of death from septic shock is even higher, between 30% and 40%.

The earlier patients with sepsis are treated, the better their prospects. Typically, they receive antibiotics, intravenous fluids, and vasopressors to raise blood pressure. But now, a large cohort study in Frontiers in Immunology has shown for the first time that supplementary treatment with statins could boost their chances of survival.

“Our large, matched cohort study found that treatment with statins was associated with a 39% lower death rate for critically ill patients with sepsis, when measured over 28 days after hospital admission,” said Dr. Caifeng Li, the study’s corresponding author and an associate professor at Tianjin Medical University General Hospital in China.

Statins are best known as a protective treatment against cardiovascular disease, which function by lowering ‘bad’ LDL cholesterol and triglycerides, and raising ‘good’ HDL cholesterol. But they have been shown to bring a plethora of further benefits, which explains the burgeoning interest in their use as a supplementary therapy for inflammatory disorders, including sepsis.

Not just lowering cholesterol

“Statins have anti-inflammatory, immunomodulatory, antioxidative, and antithrombotic properties. They may help mitigate excessive inflammatory response, restore endothelial function, and show potential antimicrobial activities,” said Li.

The authors sourced their data from the public Medical Information Mart for Intensive Care-IV (MIMIC-IV) database, which holds the anonymized e-health records of 265,000 patients admitted to the emergency department and the intensive care unit of the Beth Israel Deaconess Medical Center of Boston between 2008 and 2019. Only adults with a diagnosis of sepsis hospitalized for longer than 24 hours were included.

The authors compared outcomes between patients who received or didn’t receive any statins during their stay besides standard of care, regardless of the type of statin.

Unlike in randomized clinical trials—the gold standard among clinical studies—the allocation of treatments is not determined by random in observational studies like the present cohort study. This means that it is in principle hard to rule out that an unknown underlying variable affected allocation, for example if physicians unconsciously or on purpose were prone to give statins to those patients most likely to benefit from them.

However, Li and colleagues used a technique called “propensity score matching” to minimize the risk of such bias: they built a statistical model to determine a likelihood score that a given patient would receive statins, based on their medical records, and then found a matching patient with a similar score, but who didn’t receive statins. In the final sample, 6,070 critical patients received statins while another 6,070 did not.

The primary analysis focused on 28-day all-cause mortality, while supplementary analyses examined outcomes such as the duration of the hospital stay, of mechanical ventilation, and of continuous renal replacement therapy.

The results showed that the 28-day all-cause mortality rate was 14.3% in the statin group and 23.4% in the no statin group, indicating a relative reduction of 39% [9.1 percentage points]. However, the duration of mechanical ventilation (MV) or continuous renal replacement therapy (CRRT) increased by an average of three hours and 26 hours, respectively, in the group receiving statins.

This prolonged duration of MV and CRRT in the statin group may be attributed to a tradeoff between 28-day all-cause mortality and the duration of MV or CRRT.

“These results strongly suggest that statins may provide a protective effect and improve clinical outcomes for patients with sepsis,” concluded Li.

Supplementary analyses confirmed these results separately for patients with a normal, overweight, or obese body mass index, but not for underweight patients.

Larger randomized clinical trial needed

Why haven’t previous randomized controlled trials, which are in theory more powerful, found any benefit of statins? Li and colleagues speculated that this might be due to poor design. Randomized controlled trials are expensive, and hence are often “underpowered,” with too few patients enrolled to show any significant effect.

“Previous randomized controlled trials may not have found a benefit of statins in patients with sepsis due to underreporting of sepsis diagnoses, small sample sizes, and failure to account for the complex interactions between statin use and patient characteristics,” suggested Li.

“An ideal randomized controlled trial to confirm or reject our results should include a large sample size of sepsis patients, with detailed information on statin types, doses, and treatment duration. It should also carefully consider the timing of statin initiation and control for potential confounders,” said Li.