Frequent Hospitalized VOCs Worsens Mortality Risk in Sickle Cell Disease

Credit: Olga Kononenko/Unsplash

A large, nationwide study of an adult population with sickle cell disease (SCD) in France revealed the likelihood of mortality increased with the number of hospitalized vaso-occlusive crises (HVOCs) experienced one year before death.¹

Patients with SCD endure frequent VOCs and early mortality—SCD-related health complications are known to reduce the quality of life, shorten a patient’s lifespan, and raise healthcare costs.²

These findings, based on the largest European population of patients with SCD, showed a notable association between HVOC and death and multiple hospitalized complications, with the strongest association for acute chest syndrome (ACS), sepsis, acute kidney injury, osteonecrosis, and pulmonary embolism.¹

“Better management of HVOCs is needed not only to improve the patient’s quality of life, but also to prevent premature mortality, and debilitating complications,” wrote the investigative team, led by Jean-Benoît Arlet, department of internal medicine, European Georges Pompidou Hospital.

In this analysis, Arlet and colleagues evaluated the relationship between HVOCs and mortality in patients aged ≥16 years with a diagnostic code for SCD in the French National Health Data System. HVOC was defined as a hospitalization of ≥1 night with a primary diagnosis of SCD with crisis following a visit to the emergency room.

The team identified 28,834 individuals with hospitalizations for SCD between January 2012 and December 2018. Of this population, 8018 patients (56.6% female) met the inclusion criteria and were selected for the analysis. Patients were followed for an average of 5.8 years, for a cumulative time of 46,825 patient-years.

Investigators found the standardized one-year prevalence of adult SCD increased from 14.6 cases per 100,000 person-years (95% CI, 17.4 - 18.3) in 2012 to 17.9 cases per 100,000 person-years (95% CI, 17.4 - 18.3) in 2018. 5341 patients (66.6%) experienced ≥1 HVOC, an average of 0.84 per person-year.

During the study period, the annual proportion of patients experiencing no HVOC declined from 73.0% to 70.0%, while the proportion of patients experiencing 1–2 or ≥3 HVOCs increased from 21.2% to 22.0% and from 6.6% to 8.0%, respectively. The mean survival duration between the first HVOC and second HVOC was 690 days with a median duration of 415 days (95% CI, 386 - 439). A total of 312 deaths occurred, including 327 in-hospital (76%) and 75 out-of-hospital (24%) deaths.

Arlet and colleagues found the hazard ratio (HR) for death increased with the HVOC category in the year before death. Compared with patients without HVOC, the HRs of death in patients with 1–2 or ≥3 HVOCs were 1.67 (95% CI, 1.21 - 2.30) and 3.70 (2.30 - 5.93), respectively.

During the study follow-up, investigators identified an association between the hospitalized VOCs and complications, with the strength of the association varying by complications. Complications associated with category ≥3 HVOCs included:

• ACS: HR, 4.38; 95% CI, 3.95 - 4.87)
• Sepsis: HR, 4.70; 95% CI, 4.13 - 5.34)
• Osteonecrosis: HR, 4.43; 95% CI, 3.62 - 5.41)
• ≥1 dialysis session: HR, 3.40; 95% CI, 3.20 - 3.61)
• acute kidney injury: HR, 3.06; 95% CI, 2.49 - 3.76)
• Pulmonary embolism: HR, 3.07; 95% CI, 2.32 - 4.07

No association was observed between category 3+ HVOCs and stroke (HR, 1.04; 95% CI, 0.67 - 1.62).

Hydroxyurea dispensing regularly increased during the study period across the entire cohort, with the proportion of treated patients with ≥3 HVOCs rising by 11% each year (55.4% in 2012 to 69.8% in 2018; P <.0001). However, in 2018, Arlet and colleagues found that 29.5% of adults with ≥3 HVOCs did not take hydroxyurea, despite its efficacy in lowering VOCs and ACS.

“Our findings imply that, despite the availability of hydroxyurea (free for all patients with sickle cell anemia in France), SCD patients still suffer from HVOCs and that their accumulation is associated with higher mortality,” they wrote.

References

1. _{Arlet JB, Herquelot E, Lamarsalle L, Raguideau F, Bartolucci P. Impact of hospitalized vaso-occlusive crises in the previous calendar year on mortality and complications in adults with sickle cell disease: a French population-based study. Lancet Reg Health Eur. 2024;40:100901. Published 2024 Apr 6. doi:10.1016/j.lanepe.2024.100901}
2. _{GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021 [published correction appears in Lancet Haematol. 2023 Aug;10(8):e574]. Lancet Haematol. 2023;10(8):e585-e599. doi:10.1016/S2352-3026(23)00118-7}