Clinical Care Pathway and Management of Major Bleeding Associated with Nonvitamin K Antagonist Oral Anticoagulants: A Modified Delphi Consensus from Saudi Arabia and UAE.

Background: The nonvitamin K antagonist oral anticoagulants (NOACs) have become the mainstay anticoagulation therapy for patients requiring oral anticoagulants (OACs) in the Gulf Council Cooperation (GCC) countries. The frequency of NOAC-associated major bleeding is expected to increase in the Emergency Department (ED). Nonetheless, we still lack local guidelines and recommendations for bleeding management in the region. The present Delphi-based consensus aims to establish a standardized and evidence-based clinical care pathway for managing NOAC-associated major bleeding in the Kingdom of Saudi Arabia (KSA) and the United Arab Emirates (UAE). Methods: We adopted a three-step modified Delphi method to develop evidence-based recommendations through two voting rounds and an advisory meeting between the two rounds. A panel of 11 experts from the KSA and UAE participated in the consensus development. Results: Twenty-eight statements reached the consensus level. These statements addressed key aspects of managing major bleeding events associated with NOACs, including the increased use of NOAC in clinical practice, clinical care pathways, and treatment options. Conclusion: The present Delphi consensus provides evidence-based recommendations and protocols for the management of NOAC-associated bleeding in the region. Patients with major DOAC-induced bleeding should be referred to a well-equipped ED with standardized management protocols. A multidisciplinary approach is recommended for establishing the association between NOAC use and major bleeding. Treating physicians should have prompt access to specific reversal agents to optimize patient outcomes. Real-world evidence and national guidelines are needed to aid all stakeholders involved in NOAC-induced bleeding management.

A Saudi multicenter experience on therapeutic plasma exchange for patients with thrombotic thrombocytopenic purpura: A call for national registry.

BACKGROUND: The improvement in the clinical care for patients with thrombotic thrombocytopenic purpura (TTP) is evolving, and many efforts are being put to standardize it. Here, we aimed to assess the provided care at a national level and identify deficiencies. METHODS: A national Saudi retrospective descriptive study was carried out at six tertiary referral centers and included all patients who underwent therapeutic plasma exchange (TPE) for the diagnosis of TTP between May 2005, and July 2022. Collected information included demographic data, clinical features on presentation, and the results of laboratory investigations at admission and discharge. In addition, the number of TPE sessions, days till the first session of TPE, usage of immunological agents, and clinical outcomes were all collected. RESULTS: One hundred patients were enrolled, predominantly female (56%). The mean age was 36.8 years. At diagnosis, 53% of patients showed neurological involvement. The mean platelet count at presentation was 21 × 109 /L. All patients had anemia (mean hematocrit 24.2%). Schistocytes were present in the peripheral blood film of all patients. The mean number of TPE rounds was 13 ± 9.3, and the mean days to start TPE since admission for the first episode was 2.5 days. ADAMTS13 level was measured in 48% of patients and was significantly low in 77% of them. Assessing for clinical TTP scores, 83%, 1000%, 64% of eligible patients had an intermediate/high PLASMIC, FRENCH, and Bentley scores, respectively. Caplacizumab was used on only one patient, and rituximab was administered to 37% of patients. A complete response for the first episode was achieved in 78% of patients. The overall mortality rate was 25%. Neither time to TPE, the use of rituximab or steroid affected survival. CONCLUSIONS: Our study shows an excellent response to TPE with a survival rate approximate to the reported international literature. We observed a deficiency in using validated scoring systems in addition to confirming the disease by ADAMTS13 testing. This emphasizes the need for a national registry to facilitate proper diagnosis and management of this rare disorder.

Comparison of a modified pediatric protocol versus a hyper-CVAD protocol in adolescents and young adults with Philadelphia-negative acute lymphoblastic leukemia: A multicenter retrospective analysis.

BACKGROUND: The outcomes of Pediatric acute lymphoblastic leukemia (ALL) have improved dramatically whereas outcomes for ALL amongst adolescents and young adults (AYA) have lagged behind. The introduction of pediatric-like regimens to manage adult ALL has shown promising outcomes across several analyses. MATERIALS AND METHODS: In this analysis, we aimed to retrospectively compare the differences in outcomes among patients aged 14-40 years with Philadelphia-negative ALL treated with a Hyper-CVAD protocol versus a modified pediatric protocol. RESULTS: A total of 103 patients were identified with 58 (56.3%) in the modified ABFM group and 45 (43.7%) in the hyper-CVAD group. The median duration of follow-up for the cohort was 39 months (range 1-93). There were significantly lower rates of MRD persistence after consolidation (10.3% vs. 26.7%, P = 0.031) and transplantation (15.5% vs. 46.6%, P < 0.001) in the modified ABFM group. 5-year OS rates (83.9% vs. 65.3%, P = 0.036) and DFS rates (67.4% vs. 44%, P = 0.014) were higher in the modified ABFM groups. The incidence of grade 3 and 4 hepatotoxicity (24.1% vs. 13.3%, P < 0.001) and osteonecrosis (20.6% vs. 2.2%, P = 0.005) were higher in the modified ABFM group. CONCLUSION: Our analysis demonstrates that the use of a pediatric modified ABFM protocol demonstrated superior outcomes compared to the hyper-CVAD regimen in the treatment of Philadelphia-negative ALL amongst AYA patients. However, the modified ABFM protocol was associated with an increased risk of certain toxicities including high grade liver toxicity and osteonecrosis.

Diagnostic approach and use of CTPA in patients with suspected pulmonary embolism in an emergency department in Saudi Arabia.

Background: In patients with suspected pulmonary embolism (PE), the literature suggests the overuse of computerized tomography pulmonary angiography (CTPA) and underuse of clinical decision rules before imaging request. This study determined the potential for avoidable CTPA using the modified Wells score (mWS) and D-dimer assay in patients with suspected PE. Methods: This hospital-based retrospective study analyzed the clinical data of 661 consecutive patients with suspected PE who underwent CTPA in the emergency department of a tertiary hospital for the use of a clinical prediction rule (mWS) and D-dimer assay. The score was calculated retrospectively from the available data in the files of patients who did not have a documented clinical prediction rule. Overuse (avoidable) CTPA was defined as D-dimer negativity and PE unlikely for this study. Results: Of 661 patients' data examined, clinical prediction rules were documented in 15 (2.3%). In total, 422 patients (63.8%) had required information on modified Wells criteria and D-dimer assays and were included for further analysis. PE on CTPA was present in 22 (5.21%) of PE unlikely (mWS ≤4) and 1 (0.24%) of D-dimer negative patients. Thirty patients (7.11%) met the avoidable CTPA (DD negative+PE unlikely) criteria, and it was significantly associated with dyspnea. The value of sensitivity of avoidable CTPA was 100%, whereas the positive predictive value was 90.3%. Conclusion: Underutilization of clinical prediction rules before prescribing CTPA is common in emergency departments. Therefore, a mandatory policy should be implemented regarding the evaluation of avoidable CTPA imaging to reduce CTPA overuse.

Incidence and Predictors of Recurrence and Mortality Following First Venous Thromboembolism Among the Saudi Population: Single-Center Cohort Study.

Background: Little is written about recurrence and mortality rates after a first episode of venous thromboembolism (VTE) among Saudi population. Aim: Determine incidence rates and assess predictors of recurrence and mortality following the first VTE event. Patients and Methods: A total of 1124 patients aged ≥18 years with symptomatic VTE confirmed by imaging tests were evaluated. The incidence of VTE recurrence and mortality were assessed. The association between patient characteristics, and VTE recurrence and mortality was explored by estimating the hazard ratio (HR) and 95% confidence interval (CI). The difference between cancer-related, provoked and unprovoked VTE in terms of recurrence and mortality was explored using Kaplan-Meier curves. Results: The annual incidence rate of the first VTE was 1.7 per 1000 patients. Of 1124 patients with first VTE, 214 (19%) developed recurrent VTE, and 192 (17%) died with overall incidence rates of 15.8 per 100 person-years (95% CI, 13.8-18.0) and 10.0 per 100 person-years (95% CI, 8.7-11.5). Intensive care unit (ICU) admission (HR, 2.15; 95% CI, 1.67-3.10), presence of active cancer (HR, 2.97; 95% CI, 1.87-3.95), immobilization (HR, 2.52; 95% CI, 1.79-3.67), infection (HR, 2.32; 95% CI, 1.94-3.45), and pulmonary embolism ± deep venous thrombosis (HR, 2.22; 95% CI, 1.56-3.16) were found to be independent predictors of recurrent VTE. Recurrence carries a high hazard of mortality (HR, 5.21; 95% CI, 3.61-7.51). The estimated median time to VTE recurrence was lower in cancer-related VTE (18.7 months) compared with provoked (29.0 months) and unprovoked VTE (28.4 months). The estimated survival median time was lower in cancer-related VTE (21.8 months) compared with provoked (30.5 months) and unprovoked VTE (29.8 months). Conclusion: Immobilization and presence of active cancer, infection, and PE ± DVT were significant predictors of recurrent VTE. Patients who developed recurrent VTE had a 5.2-fold higher hazard of mortality compared with patients with no VTE recurrence.

High rate of bleeding and arterial thrombosis in COVID-19: Saudi multicenter study.

BACKGROUND: Several observational studies have reported the rate of venous and arterial thrombotic events in patients infected with COVID-19, with conflicting results. The aim of this study was to estimate the rate of thrombotic and bleeding events in hospitalized patients diagnosed with Coronavirus disease 2019 (COVID-19). METHODS: This was a multicenter study of 636 patients admitted between 20 March 2020 and 31 May 2020 with confirmed COVID-19 in four hospitals. RESULTS: Over a median length of stay in the non-ICU group of 7 days and of 19 days in the ICU group, twelve patients were diagnosed with Venous thromboembolism (VTE) (1.8 %) (95 % CI, 1.1-3). The rate in the non-ICU group was 0.19 % (95 % CI, 0.04-0.84), and that in the ICU group was 10.3 % (95 % CI, 6.4-16.2). The overall rate of arterial event is 2.2 % (95 % CI, 1.4-3.3). The rates in the non-ICU and ICU groups were 0.94 % (95 % CI, 0.46-0.1.9) and 8.4 % (95 % CI, 5.0-14.0). The overall composite event rate was 2.9 % (95 % CI, 2.0-4.3). The composite event rates in the non-ICU and ICU groups were 0.94 % (95 % CI, 0.46-0.1.9) and 13.2 % (95 % CI, 8.7-19.5). The overall rate of bleeding is 1.7 % (95 % CI, 1.0-2.8). The bleeding rate in the non-ICU group was 0.19 % (95 % CI, 0.04-0.84), and that in the ICU group was 9.4 % (95 % CI, 5.7-15.1). The baseline D-dimer level was a significant risk factor for developing VTE (OR 1.31, 95 % CI, 1.08-1.57, p = 0.005) and composite events (OR 1.32, 95 % CI, 1.12-1.55, p = 0.0007). CONCLUSIONS: In this study, we found that the VTE rates in hospitalized patients with COVID-19 might not be higher than expected. In contrast to the risk of VTE, we found a high rate of arterial and bleeding complications in patients admitted to the ICU. An elevated D-dimer level at baseline could predict thrombotic complications in COVID-19 patients and may assist in the identification of these patients. Given the high rate of bleeding, the current study suggests that the intensification of anticoagulation therapy in COVID-19 patients beyond the standard of care be pursued with caution and would best be evaluated in a randomized controlled study.

Safety and Efficacy of Convalescent Plasma to Treat Severe COVID-19: Protocol for the Saudi Collaborative Multicenter Phase II Study.

BACKGROUND: The COVID-19 pandemic is expected to cause significant morbidity and mortality. The development of an effective vaccine will take several months to become available, and its affordability is unpredictable. Transfusion of convalescent plasma (CP) may provide passive immunity. Based on initial data from China, a group of hematologists, infectious disease specialists, and intensivists drafted this protocol in March 2020. OBJECTIVE: The aim of this study is to test the feasibility, safety, and efficacy of CP in treating patients with COVID-19 across Saudi Arabia. METHODS: Eligible patients with COVID-19 will be recruited for CP infusion according to the inclusion criteria. As COVID-19 has proven to be a moving target as far as its management is concerned, we will use current definitions according to the Ministry of Health (MOH) guidelines for diagnosis, treatment, and recovery. All CP recipients will receive supportive management including all available recommended therapies according to the available MOH guidelines. Eligible CP donors will be patients with COVID-19 who have fully recovered from their disease according to MOH recovery criteria as detailed in the inclusion criteria. CP donors have to qualify as blood donors according to MOH regulations except for the history of COVID-19 in the recent past. We will also test the CP donors for the presence of SARS-CoV-2 antibodies by a rapid test, and aliquots will be archived for future antibody titration. Due to the perceived benefit of CP, randomization was not considered. However, we will compare the outcome of the cohort treated with CP with those who did not receive CP due to a lack of consent or lack of availability. In this national collaborative study, there is a likelihood of not finding exactly matched control group patients. Hence, we plan to perform a propensity score matching of the CP recipients with the comparator group patients for the major characteristics. We plan to collect demographic, clinical, and laboratory characteristics of both groups and compare the outcomes. A total sample size of 575 patients, 115 CP recipients and 460 matched controls (1:4 ratio), will be sufficient to detect a clinically important hospital stay and 30-day mortality difference between the two groups with 80% power and a 5% level of significance. RESULTS: At present, patient recruitment is still ongoing, and the interim analysis of the first 40 patients will be shared soon. CONCLUSIONS: In this paper, we present a protocol for a national collaborative multicenter phase II study in Saudi Arabia for assessing the feasibility, safety, and potential efficacy of CP in treating patients with severe COVID-19. We plan to publish an interim report of the first 40 CP recipients and their matched comparators soon. TRIAL REGISTRATION: ClinicalTrials.gov NCT04347681; https://clinicaltrials.gov/ct2/show/NCT04347681. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/23543.