Direct Oral Anticoagulants in Sickle Cell Disease, Where We Stand and Where We Are Heading: A Systematic Review

Abstract Introduction: Sickle Cell Disease (SCD) is a hemolytic disorder with an increased risk of venous thromboembolism (VTE). By the age of 40 years around 11-12% of sickle cell disease patients will have at least one episode of VTE. VTE among patients with SCD is associated with a two to four times increase in mortality compared to SCD patients without VTE. Nevertheless, the evidence guiding VTE management in SCD, specifically in terms of anticoagulant choice, is scarce. Therefore, we conducted a systematic review that evaluates the effectiveness and safety of direct oral anticoagulants (DOACs) in SCD with VTE. Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the English literature (PubMed, SCOPUS, and Google Scholar) for randomized controlled trials, observational studies, reviews, case series, and case reports for patients with SCD treated with DOAC for thromboembolic disease. We used the terms in combination: "Sickle cell disease" or "Sickle cell anemia", and "DOAC", "rivaroxaban", "apixaban", "dabigatran" "edoxaban". The search included all articles published up to 20th April 2021. Quality and risk of bias assessment were done by two independent authors for each included study. Results: A total of 7 articles were included; four observational studies, and three case series addressing this matter. Patel A et al. found that the use of DOACs, including rivaroxaban, dabigatran, and apixaban 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 similar VTE recurrence rate and a better safety profile in terms of a significant reduction in major bleeding events. Similarly, Roberts MZ et al. reported that the use of DOACs for VTE treatment in SCD compared to VKAs resulted in similar effectiveness in terms of VTE recurrence, but the use of DOACs was associated with a similar safety in comparison to VKAs in contrary to the results reported by Patel A et al. in their retrospective study. 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. Discussion: The current data demonstrated that the use of DOACs for VTE in SCD has similar effectiveness in the prevention of VTE recurrence in comparison to other anticoagulants, including VKAs and injectable anticoagulants with a better safety profile. However, given the absence of clinical practice guidelines for the treatment of VTE among patients with SCD, the clinical practice guidelines recommendations for VTE treatment can be applied to patients with SCD. According to the latest CHEST guidelines (2016) for the treatment of VTE, the use of DOACs is recommended in patients with VTE over VKAs. Similarly, the latest American Society of Hematology (2020) guidelines for VTE suggest the use of DOACs over VKAs, except among patients with renal insufficiency (creatinine clearance less than 30 mL/min), moderate to severe liver disease, or those with antiphospholipid syndrome. Conclusion: In view of the current evidence and based on the results observed; using DOACs was associated with lesser bleeding incidence and fewer complications comparing to VKAs. We think it is rational to use DOACs for VTE treatment among patients with SCD rather than use VKAs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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DIRECT ORAL ANTICOAGULANTS IN SICKLE CELL DISEASE, WHERE WE STAND AND WHERE WE ARE HEADING: A SYSTEMATIC REVIEW

Hematology Transfusion and Cell Therapy ◽

10.1016/j.htct.2021.10.977 ◽

2021 ◽

Vol 43 ◽

pp. S19

Author(s):

Waail Rozi ◽

Abdulrahman Al-Mashdali ◽

Elrazi Ali ◽

Alaa Rahhal ◽

Yousef Hailan ◽

...

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Cell Disease

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Efficacy and Safety of Voxelotor in Sickle Cell Disease: A Systematic Review

Blood ◽

10.1182/blood-2020-135960 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-35

Author(s):

Muhammad Ashar Ali ◽

Anam Khan ◽

Sana Irfan Khan ◽

Sobia Aamir ◽

Saad Ur Rahman ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Sickle Cell Disease ◽

Adverse Events ◽

Sickle Cell ◽

Reticulocyte Count ◽

Case Series ◽

Efficacy And Safety ◽

Cell Disease ◽

Grade 3

Introduction: Sickle cell disease (SCD) is caused by mutation of beta-globin chain alleles, with the involvement of at least one sickle mutation. Sickling of red cells leads to hemolytic anemia, vaso-occlusions, and inflammation. Voxelotor (GBT440) is a hemoglobin modulator that prevents polymerization by increasing the affinity of hemoglobin with oxygen. We performed a systematic review to evaluate the efficacy and safety of voxelotor in SCD patients. Methods: PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and clinicaltrials.gov. We used the following keywords, "Voxelotor" OR "Benzaldehydes" OR "GBT440" AND "Sickle Cell Anemia" from the inception of literature till 04/25/2020. Out of 475 articles, we screened and included three clinical trials and a case series measuring the efficacy (i-e, change in Hemoglobin (Hb), Hb modification, etc.) and safety (adverse events) in clinical terms (N=359). We excluded case reports, pre-clinical studies, review articles, and meta-analysis. RESULTS: We included data on 359 patients, with 12-67 years of age. In Blyden et al. 2018, authors presented a case series of 7 patients with advanced SCD treated with 700 mg-1500 mg voxelotor. With treatment, vaso-occlusive episodes related hospitalizations decreased by 67%, hemoglobin levels, and markers of hemolysis improved in all patients. Authors in Hutchaleelaha et al. 2019 randomly assigned 24 participants to a once-daily dose of 900 mg, 600 mg, 300 mg voxelotor, and placebo for 15 days. With treatment, hemoglobin modification was maximum in the 900 mg voxelotor group. Headache and diarrhea were the only adverse events related to voxelotor treatment. No grade 3 adverse events were reported. In phase I/II trial by Howard et al. 2019, (n=54) 38 patients were followed for 28 days, and 16 patients were followed for >90 days. The compliance for study drug was 91%. In the 28-day cohort, treatment with 1000 mg of voxelotor showed maximum improvement in hemoglobin level, reticulocyte count, and unconjugated bilirubin. In >90-day cohort, the improvement in hemoglobin, unconjugated bilirubin, and reticulocyte count were statistically significant in favor of 900 mg voxelotor treatment as compared to placebo (p<0.05). LDH showed variability with treatment. Vaso-occlusive episodes seen in voxelotor groups were reported when the treatment was on hold or after the last dose. No grade ≥3 adverse events were reported. In a randomized placebo-controlled phase III clinical trial by Vichinsky et al. 2019, two doses of voxelotor 1500 mg (N=90) and 900 mg (N=92) were compared with placebo (N=92). 12-65 years old SCD patients were followed for 24 weeks. After treatment, improvement in hemoglobin was statistically significant in favor of 1500 mg voxelotor vs. placebo. Moreover, markers of hemolysis, reticulocyte count, and indirect bilirubin levels were also significantly improved in favor of 1500mg voxelotor treatment vs. placebo. The incidence of vaso-occlusive crisis episodes was similar in 1500 mg, 700 mg, and placebo groups (p>0.05). Treatment-related adverse events were seen in 94%, 93%, and 89% of participants in 1500mg, 700mg, and placebo groups, respectively. (Table 1) There are 6 ongoing clinical trials registered on clinicaltrials.gov (n=665) to determine the efficacy and safety of high doses of voxelotor and its use in children below 12 years. (Table 2) Conclusion: Voxelotor has an acceptable safety profile in sickle cell disease patients of 12 years or older. Voxelotor has shown a dose-dependent improvement in hemoglobin levels and markers of hemolysis, which is associated with a reduction in end-organ damage. Moreover, the increase in hemoglobin was not associated with an increase in vaso-occlusive crisis episodes, in contrast to the other hemoglobin modulator (senicapoc). Additional large prospective multicenter randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

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The Role of Hydroxyurea to Prevent Silent Stroke in Sickle Cell Disease: Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2018-99-112290 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2373-2373

Author(s):

Carla Hasson ◽

Lisa Veling ◽

Juan Felipe Rico ◽

Rahul Mhaskar

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Adverse Events ◽

Sickle Cell ◽

Observational Studies ◽

Assessment Tool ◽

Conflicts Of Interest ◽

Meta Analysis ◽

Blood Transfusions ◽

Cell Disease

Abstract Chronic blood transfusions are standard of care for stroke prevention in sickle cell disease. We evaluated hydroxyurea's efficacy in preventing silent stroke. We searched for randomized controlled trials (RCTs) and observational studies on Pubmed, CENTRAL, Embase, and Web of Science without using language/time limits. Eligible studies compared hydroxyurea with transfusions or observation to prevent silent stroke. This systematic review adheres to the Cochrane guidelines. Data were pooled using random effects model using STATA to perform meta-analysis. Methodological quality of RCTs was investigated using the Cochrane risk of bias assessment tool, while observational studies were assessed using the Downs & Black Checklist for Study Quality. One RCT enrolling 121 participants was included. There were no strokes, silent strokes, or deaths reported in either arm. There was no difference between hydroxyurea versus chronic blood transfusions (RR 1.52, 95% CI 0.57 to 4.02, P = 0.39) for adverse events. We included 10 observational studies, with 361 participants receiving hydroxyurea. There were no deaths attributed to hydroxyurea. Approximately 1% (I2 = 48.67%, 95% CI 0.0 to 0.05, 314 participants, seven comparisons) of patients receiving hydroxyurea had stroke. Approximately 18% (I2 = 91.37%, 95% CI 0.03 to 0.4, 266 participants, six comparisons) of the hydroxyurea patients had silent stroke. Approximately 24% (I2 = 88.54%, 95% CI 0.02 to 0.57, 91 participants, four comparisons) of the hydroxyurea patients had adverse events attributed to hydroxyurea. Our findings suggest that hydroxyurea is safe and may prevent silent stroke and stroke. More high-quality studies are needed. Disclosures No relevant conflicts of interest to declare.

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Decreased Bleeding Incidence with Direct Oral Anticoagulants Compared to Vitamin K Antagonist and Low-Molecular-Weight Heparin in Patients with Sickle Cell Disease and Venous Thromboembolism

Acta Haematologica ◽

10.1159/000500223 ◽

2019 ◽

Vol 142 (4) ◽

pp. 233-238 ◽

Cited By ~ 6

Author(s):

Ameet Patel ◽

Hants Williams ◽

Maria R. Baer ◽

Ann B. Zimrin ◽

Jennie Y. Law

Keyword(s):

Molecular Weight ◽

Venous Thromboembolism ◽

Sickle Cell Disease ◽

Low Molecular Weight Heparin ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Low Molecular Weight ◽

Cell Disease ◽

Bleeding Events

Background: Venous thromboembolism (VTE) is a recognized complication of sickle cell disease (SCD), yet the optimal pharmacologic anticoagulant is unknown. Methods: A retrospective single-institution cohort study of patients with SCD complicated by first VTE from January 2009 through July 2017 was performed using ICD 9/10 codes. Data collected included the anticoagulant used, VTE recurrence, and incidence of bleeding. Results: 109 patients with VTE were identified. SCD genotypes included HbSS in 92 (84%), HbSC in 13 (12%), and HbS-β+ thalassemia in 4 (4%). After the initial VTE event, 32 patients received a vitamin K antagonist (VKA), 34 for low-molecular-weight heparin (LMWH), and 43 for direct oral anticoagulants (DOACs). 16 patients (15%) experienced a clinically significant bleeding event, including 9 on VKA, 5 on LMWH, and 2 on DOACs. At a median follow-up of 11.8 (range, 3.4–60) months, 33 patients had a recurrent VTE, including 10 on VKA, 10 on LMWH, and 13 on DOACs (p = 0.833). Bleeding incidence was least with the DOACs, which were associated with fewer bleeding events (OR 0.22), and greatest with VKA (OR 1.55) (p < 0.05). Conclusion: There was no difference between VTE recurrence and choice of anticoagulation in SCD patients with VTE. Bleeding events were lower for DOACs compared to VKA or LMWH.

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Use of Direct Oral Anticoagulants in Patients with Sickle Cell Disease and Venous Thromboembolism: A Prospective Cohort Study of 12 Patients

Hemoglobin ◽

10.1080/03630269.2019.1689997 ◽

2019 ◽

Vol 43 (4-5) ◽

pp. 296-299 ◽

Cited By ~ 4

Author(s):

Jacques-Robert Christen ◽

Julien Bertolino ◽

Estelle Jean ◽

Laurence Camoin ◽

Mikael Ebbo ◽

...

Keyword(s):

Cohort Study ◽

Venous Thromboembolism ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Cell Disease

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Manifestations of HbSE sickle cell disease: a systematic review

Journal of Translational Medicine ◽

10.1186/s12967-021-02931-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ibrahim Khamees ◽

Fateen Ata ◽

Hassan Choudry ◽

Ashraf T. Soliman ◽

Vincenzo De Sanctis ◽

...

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Case Series ◽

Causative Mutation ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Number Of Patients ◽

The Mean ◽

Marrow Embolism

Abstract Background Sickle cell disease (SCD) is commonly encountered in Africa and Middle Eastern countries. The causative mutation in the gene encoding the hemoglobin subunit β (HBB) leads to various genotypic variants of the disease. This results in varied phenotypes, with a spectrum of complications, from benign to fatal. Hemoglobin SS (HBSS) genotype is associated with most of these complications; hence, it is a severe form of SCD. On the other hand, rare genotypes such as hemoglobin SE (HBSE) are considered benign. There is limited literature about the clinical manifestations and characteristics of patients with HBSE. We pooled all available data describing the phenotypic manifestations of HBSE heterozygote worldwide to perform a systematic review. Methods We performed a systematic review according to PRISMA guidelines using PubMed, SCOPUS, and Google Scholar databases. Two independent reviewers (FA and IK) evaluated studies for eligibility and extracted data. We synthesized data on demographics, manifestations, and management of HBSE disease. PROSPERO Registration Number: CRD42021229877. Results We found 68 HBSE patients reported in the literature. 24 cases were extracted from case reports whereas 44 cases from case series and retrospective studies. Turkey reported the highest number of patients (n = 22). 32 (47%) of the patients were males. The mean age was 20.9 ± 18.26 years. The mean HBS and HBE percentages were 61.1% ± 7.25% and 32.3% ± 5.06%, respectively, whereas the mean hemoglobin was 11.64 ± 1.73 g/dl. Reported manifestations of HBSE disease included acute vaso-occlusive pain crisis (n = 22, 32.3%), splenomegaly (n = 11, 16.1%), hemolytic anemia (n = 10, 14.7%), infections (n = 8. 11.7%), bone infarction (n = 4, 5.8%), gallstones (n = 3, 4.4%), venous thromboembolism (VTE) (n = 2, 2.9%) and stroke (n = 2, 2.9%), and hematuria (n = 2, 2.9%). Death due to HBSE complications was reported in three patients. Conclusion HBSE is a rare genotypic variant of SCD. It has been considered a benign form; however, there are multiple reports of severe complications. Severe complications observed in HBSE disease include vaso-occlusive crisis, acute chest syndrome, stroke, bone marrow embolism, and death.

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