Direct Oral Anticoagulants in Sickle Cell Disease: A Systematic Review and Meta-Analysis

Introduction:

The sickle cell mutation of the β globin gene (HbS) is inherited in an autosomal recessive fashion. When present in the homozygous state (HbSS), the problems of sickle cell anemia (SCA) manifest. In the heterozygous state known as sickle cell trait, and patients are normally asymptomatic. One complication of SCD is a substantially increased risk of venous thromboembolism (VTE), which in turn increases the risk of mortality. VTE among patients with SCD is associated with a 2 to 4 times increase in mortality risk compared with patients with SCD without VTE.

Methods:

We performed a systematic review following the PRISMA guidelines. We searched PubMed and Embase for studies published in English about the use of DOAC for treating thromboembolic disease in patients with SCA until 20 April 2021. Two independent reviewers screened the titles and abstracts of the records independently, and papers unrelated to our inclusion criteria were excluded. Outcomes assessed were recurrent VTE and major bleeding.

Results:

The review included seven articles, comprising four observational studies and three case series, with a total of 236 patients. Of the seven articles, three observational studies directly compared VKAs and DOACs and were included in the meta-analysis. Patel A et al. found that the use of DOACs in comparison to vitamin K antagonists (VKAs) and low molecular weight heparin (LMWH) for the treatment of VTE in SCD among adults was associated with better safety profile in terms of a significant reduction in major bleeding events. In addition to that, Roberts MZ et al. found that the use of DOACs for VTE treatment in SCD compared to VKAs resulted in similar effectiveness in terms of VTE recurrence. With regards to the risk of major hemorrhagic events associated with the use of non-VKAs, Gupta VK et al. showed that among 55 patients with SCD treated with VKAs, DOACs, or injectable anticoagulants, only patients treated with VKAs had major bleeding events.

The meta-analysis included three studies with a combined total of 172 patients, 88 receiving DOACs and 84 receiving VKAs. The results indicated that DOACs were associated with a similar rate of VTE recurrence compared to VKAs (OR = 1.03; 95% CI, 0.5-2.10; I2 = 0%). Furthermore, the use of DOACs was associated with significantly lower odds of major bleeding events compared to VKAs (OR = 0.16; 95% CI, 0.04-0.59; I2 = 0%).

Conclusion:

The results of this systematic review and meta-analysis showed lower major bleeding rates and similar VTE recurrence rates with DOACs use compared with VKA in patients with SCD, making DOACs a reasonable alternative to VKAs for VTE in patients with SCD.

For special SCD populations, including pregnancy, pediatrics, and chronic kidney disease, general recommendations provided by clinical practice guidelines for VTE should be followed. Extending the anticoagulation duration beyond 3 months among patients with SCD should be determined by balancing the risk of recurrent VTE and major bleeding.

No relevant conflicts of interest to declare.