The effect of anticoagulant choice on venous thromboembolism recurrence and bleeding in sickle cell disease
Authors: Vishal K. Gupta, Rachel Strykowski, Brittany Scarpato, Romy Lawrence, Sarah L. Khan, Jay Patel, S. Mehdi Nouraie, Robyn T. Cohen, J. Mark Sloan, Elizabeth S. Klings
Journal: American Journal of Hematology (2020)

Sickle cell disease (SCD) is a genetic hemoglobinopathy affecting approximately 100 000 people in the United States.1 Patients experience vascular complications leading to frequent hospitalizations, multiorgan complications, and a reduced lifespan. The risk of venous thromboembolism (VTE) is increased in SCD, with 11% to 12% of adults experiencing a VTE by age 40.2 Sickle cell disease creates a hypercoagulable state through alterations in platelet function and the coagulation cascade. The risk for VTE is exacerbated by the increased use of indwelling catheters and frequent hospitalizations in this population.3 So, VTE in SCD is associated with a 2-fold to 4-fold increase in the risk of death compared to those who do not develop VTE.2 Despite the increased incidence of VTE and its related mortality risk in this population, minimal data exists regarding the optimal length of treatment, or the safety and efficacy of heparins, warfarin or direct oral anticoagulants (DOACs) in SCD. Recent guidelines from the American Society of Hematology (ASH) recommend indefinite anticoagulation for unprovoked or recurrent provoked VTE, and short-term (3-6 months) anticoagulation for an initial provoked VTE, however no guidance is given regarding choice of anticoagulant due to a paucity of data. We present safety and efficacy data for different anticoagulants in the treatment of VTE at our institution to begin to address this question. A retrospective chart review was performed on all patients with SCD ≥18 years of age, alive or deceased, who received care at Boston Medical Center (BMC) between 2003 and 2018. All patients were part of the BMC SCD Clinical Database and had SCD confirmed by hemoglobin electrophoresis. Inpatient and ambulatory visit notes were reviewed for VTE occurrence and treatment course. This study was approved by the Boston University School of Medicine Institutional Review Board. Venous thromboembolism was defined as (a) deep venous thrombosis (DVT) diagnosed by duplex ultrasound or (b) pulmonary embolism (PE) diagnosed by either ventilation-perfusion (V/Q) scanning or computed tomography (CT) angiography. The primary efficacy outcome was the number of VTE events that occurred while a patient was receiving anticoagulation. The primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Hemostasis 2005 guidelines.4 Descriptive statistics were used to describe baseline patient characteristics and primary efficacy and safety outcomes. Continuous variables were presented as medians with interquartile ranges (IQR). Analyses were performed using Microsoft Excel (Microsoft Corporation, Redmond, WA). The medical records of 233 patients with SCD were reviewed. Venous thromboembolism was identified in 55 (23.6%) patients. Thirty-six (65%) were female and 34 (62%) had HbSS disease (Figure S1). In the 55 patients, 94 VTE events occurred. These included 55 (58.5%) PE by CT angiogram, six (6.4%) PE by V/Q scan, and 33 (35.1%) DVT by duplex ultrasound. Fifteen (16.0%) were catheter-associated upper extremity DVTs that occurred in 13 (24%) patients. Index VTE cases included 35 (63.6%) PEs and 20 (36.4%) DVTs; 8 (40.0%) of which were catheter-associated. For the initial VTE, outpatient treatment consisted of warfarin in 31 (56.0%), low-molecular-weight heparin (LMWH) in 10 (18.2%), rivaroxaban in five (9.1%), apixaban in three (5.5%), and fondaparinux in two (3.6%). The mean length of treatment was 7.3 (median: 6, IQR: 3-12) months. Information regarding duration of treatment was unavailable for 39 (41%) events. The mean duration of follow-up was 8.3 (median: 8.5; IQR: 4.4-11.2) years. Recurrent VTEs occurred in 27 (49.1%) patients with a total of 39 recurrent events. Among the recurrent events, 13 (33.0%) were treatment failures during anticoagulation (Table 1); seven of 37 (18.9%) patients on warfarin, 2 of 20 (10.0%) on LMWH, and 4 of 15 (26.7%) on rivaroxaban. No recurrences occurred during treatment with apixaban or fondaparinux. In the 15 catheter-associated DVTs, 4 (26.6%) were followed by a subsequent VTE (two PEs, one lower extremity DVT and one catheter-associated DVT). Two of these four recurrences occurred ≥5 years after the initial event. Mortality related to recurrent VTE occurred in two patients; in one case, the patient was therapeutic on warfarin and in the other, the patient was not on anticoagulation. In both cases, the patients developed pulseless electrical activity; one received tissue plasminogen activator with hemodynamic improvement but developed severe anoxic brain injury leading to withdrawal of care, and the other was unable to be resuscitated. Major bleeding (intracranial hemorrhage) occurred in two patients (3.6%) taking warfarin. In this retrospective study of VTE in SCD, efficacy and safety outcomes were determined for oral anticoagulation and injectable agents. In comparing the efficacy and safety of treatments, the most notable finding was the increased frequency of hemorrhage and death in those prescribed warfarin. Only those treated with warfarin experienced major bleeding. This finding is consistent with the only other published study that examined this question.5 Those investigators identified one major bleeding event in a sample of 37 SCD patients, a vitreal hemorrhage which occurred in a patient treated with warfarin. Patients who experienced a catheter-associated DVT had a low recurrence rate; 80% of these patients experienced either no recurrence or a VTE greater than 5 years from the initial event. This finding provides preliminary support for the ASH 2019 guidelines recommending short-term anticoagulation for those with provoked events, specifically those with a catheter-associated VTE.6 Data on recurrence rates of catheter-associated DVT in the general population is lacking, so we cannot comment if our observations diverge from what is commonly observed. Similar to prior work, the current study demonstrated a high incidence of VTE recurrence (49%), higher than what has been previously observed in patients with SCD and up to 20-fold higher than the general population.5, 7 The increased detection of VTE recurrence in our sample was likely due to a longer period of follow-up (up to 15 years in some patients). These data affirm the need for long-term anticoagulation in patients with SCD who develop an unprovoked VTE and is consistent with current ASH guidelines. There are limitations to this study. First, adherence was not completely ascertained due to limited data availability. However, the outcomes from this study represent the real-world situation of prescribing anticoagulation in a patient population that often experience psychosocial barriers, including financial issues and pill burden, that may limit anticoagulant adherence. Based on review of clinic notes, adherence was relatively poor as those taking warfarin often had a sub-therapeutic international normalized ratio. Second, available duration-of-treatment data was limited, as is often the case in retrospective chart reviews. Future multicenter prospective studies are needed to begin to understand prescribing practices and adherence patterns, and we advocate for larger sample sizes to determine relative risk of treatment failure and complications from different therapies. These larger, prospective trials with adherence measures may help clarify the high number of VTE recurrence with rivaroxaban compared to warfarin, which is in contrast to findings in the general population.8 In conclusion, these data support indefinite anticoagulation particularly for unprovoked events and suggest against the use of warfarin as first-line treatment for VTE in patients with SCD due to hemorrhagic concerns. Acknowledging limited data on adherence, treatment failure was highest with warfarin and rivaroxaban. Dr. Elizabeth Klings is funded by NIH/NHLBI 1U01HL128566 and 1UG3 HL143192-01A1. She receives research support from Actelion Pharmaceuticals, Pfizer, Bayer, Reata, Micelle, Novartis and Arena/United Therapeutics. Dr. John Mark Sloan consults for Abbvie and Stemline Pharmaceuticals. The remainder of the authors have no disclosures or conflicts of interest. VKG designed the study, reviewed charts, collected and analyzed data (with MN), analyzed data, and wrote the manuscript. E.S.K., R.T.C. and J.M.S. designed the study, critically reviewed and edited the manuscript. SK, RL, BS, RS reviewed charts and collected data. All authors approved the final version of the manuscript. Figure S1. Patient Demographics Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.