RAS Inhibitors May Hold Potential as Preventive for Acute Chest Syndrome in Sickle Cell Disease

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), both renin-angiotensin system (RAS) blockades, have been shown to mitigate vascular damage in patients with pulmonary fat embolism (PFE) in rat models. A study published in Cureus aimed to determine whether these drugs hold potential for preventing acute chest syndrome (ACS) in those with sickle cell disease (SCD).

ACS, a lung injury syndrome, is one of the most common acute events seen in SCD and accounts for 25% of SCD-related deaths. Potential causes of ACS include pulmonary infection, bone marrow fat embolization, and intravascular pulmonary accumulation of sickled red blood cells. It is currently treated with supplemental oxygen, transfusions, and antibiotics. Hydroxyurea, a standard therapy option for SCD, has been shown to prevent painful crises and reduce ACS incidence in SCD, but it does not treat crises or current ACS.

PFE and ACS are similar in that they both involve vascular obstruction and bone marrow necrosis. In rat models of PFE, which involves pulmonary microvasculature blockages caused by bone marrow fat, ACE inhibitors and ARBs have been shown to improve damage caused by the condition. Therefore, the authors of the current study hypothesized that patients on ACE inhibitors or ARBs would have lower readmission rates for ACS after 1 hospitalization vs patients not reporting ACE inhibitor or ARB use.

The retrospective cohort study included 6972 patients with sickle cell anemia, hemoglobin SCD, sickle cell thalassemia, and ACS identified in the Health Facts database. A total of 667 patients (9.6%) reported taking an ACE inhibitor or ARB. The average age in the overall cohort was 38 years, and those taking ACE inhibitors or ARBs were typically older, at average age of 54 years. Ninety percent were African American, and 16% of the overall cohort reported smoking.

In this cohort, readmission rates were higher at 1 year for patients who reported not taking an ACE inhibitor or ARB compared with patients who reported taking them. At 1 year, the odds ratio (OR) for readmission in patients taking ACE inhibitors or ARBs was 0.28 (95% CI, 0.24-0.31) vs 0.44 (95% CI, 0.43-0.46) in patients who did not. At 2 years, the ORs were 0.33 (95% CI, 0.29-0.37) and 0.56 (95% CI, 0.55-0.58), respectively.

A covariate analysis showed that age had a significant effect on readmission rates, with an adjusted HR of 0.78 (95% CI, 0.68-0.91). Males also had a 32% higher readmission rate vs females, with an adjusted HR of 1.32 (95% CI 1.23-1.42).

The results of the study are in line with evidence from animal models: ACE inhibitors and ARB agents may have beneficial effects for patients with SCD in terms of ACS prevention. Age was also a significant factor, with older patients showing lower readmission rates than younger patients. The study authors note that older patients might have less severe disease vs younger patients with aggressive disease and older patients are more likely to be taking an ACE inhibitor or ARB because hypertension is more common in middle-aged/older patients.

Although the study suggests a correlation between ACE inhibitor or ARB regimens and lower hospital readmission rates, it is retrospective and did not include information on why patients were on these agents to begin with and how long they were taking them. Still, these findings may help make disease management decisions for patients with SCD.

“Further study goals would involve prospective clinical trials comparing ACS readmission in patients who receive ACE inhibitor/ARB/renin inhibitor therapy vs placebo after an initial event to confirm this preventive effect,” study authors wrote. “The possible future therapeutic use of these drugs after symptoms of ACS have developed needs to be investigated.”

Reference

Wamkpah N, Shrestha A, Salzman G, et al. Renin-angiotensin blockade reduces readmission for acute chest syndrome in sickle cell disease. Cureus. Published online March 28, 2022. doi:10.7759/cureus.23567