VTE prevention and treatment: Role of fondaparinux in hospitalized patients

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is highly prevalent among hospitalized patients, potentially fatal, yet preventable. In an interview with MIMS Doctor, Dr Andy Sing-Ong Tang, Clinical Haematologist of the Sarawak General Hospital, Kuching, Sarawak, Malaysia, discussed the role of fondaparinux in prevention and treatment of VTE among hospitalized patients, with a particular focus on obese and Muslim patients.

VTE: Leading cause of preventable mortality
VTE is a leading cause of preventable mortality among hospitalized patients, in whom the risk of VTE is 100 times higher than in the general population. Each year in the US, approximately 100,000 people die of VTE. Nearly half of all VTE cases occur during or after hospitalization, with PE accounting for 10 percent of inpatient mortality. [Ann Vasc Dis 2020;13:38-44; Vasc Health Risk Manag 2022 ;18:575-587; www.cdc.gov/blood-clots/data-re­search/facts-stats/index.html]

“VTE risk stratification should be considered for all hospitalized patients, preferably within the first 24 hours after ad­mission. Clinically, I use the IMPROVE-VTE and IMPROVE-BLEED risk scores to stratify risks of VTE and bleeding, respectively, in medically ill hospitalized patients,” said Tang. (Figure 1) The core concept of Virchow’s tri­ad is essential when determining VTE risk. Factors such as circulatory stasis or immo­bility, endothelial damage or inflammation, and overall hypercoagulable state, including prior history of thrombophilia or VTE, can cu­mulatively increase VTE risk. [Ann Vasc Dis 2020;13:38-44]

VTE prophylaxis underused
“In line with evidence-based guide­line recommendations, I support the use of anticoagulation prophylaxis [eg, fondaparinux, low-molecular-weight hepa­rin (LMWH), unfractionated heparin (UFH), direct oral anticoagulants] for eligible pa­tients [VTE score ≥3 and bleeding score <7],” advised Tang. (Figure 1)

“However, adoption of VTE prophylaxis remains low and a standardized approach is lacking in many healthcare systems,” noted Tang. “These may be attributed to factors such as insufficient awareness, time constraints, unfamiliarity with drug-drug interactions [DDIs], and efficacy and safety profiles of different anticoagulants. In 80–90 percent of cases, DVT is asymp­tomatic. The condition therefore remains underdiagnosed.” However, asymptom­atic DVT is associated with approximately 3-fold higher risk of short-term all-cause mortality in acutely ill hospitalized patients. [Thromb Haemost 2018;118:2046-2052]

Fondaparinux: Efficacy and safety
Fondaparinux is a synthetic, once-daily, injectable, selective factor Xa inhibitor with proven efficacy and safety for both prevention and treatment of VTE. [Arixtra Prescribing Information, February 2019]

ARTEMIS: Prevention of VTE
In the multicentre, randomized, pla­cebo-controlled ARTEMIS trial, 849 older medical patients (aged ≥60 years) hospi­talized for congestive heart failure, acute respiratory illness with chronic lung dis­ease, or acute infectious or inflammatory disease who were expected to remain bedridden for ≥4 days were randomized to receive fondaparinux 2.5 mg QD or pla­cebo subcutaneously within 48 hours of admission. [BMJ 2006;332:325-329]

Fondaparinux significantly reduced the risk of VTE by nearly 50 percent vs placebo (5.6 vs 10.5 percent; relative risk reduction [RRR], 46.7 percent; 95 per­cent confidence interval [CI], 7.7–69.3; p=0.0029), while the frequency of ma­jor bleeding was comparable between groups (both 0.2 percent). (Figure 2)

“ARTEMIS showed the importance of starting fondaparinux as VTE prophylaxis as early as possible, preferably within the first 48 hours of hospitalization,” Tang highlighted.

Prevention of VTE in obese patients
Obesity is a common and indepen­dent risk factor associated with a 2- to 3-fold increase in the occurrence of VTE. Patients with VTE and comorbid obesity tend to require longer hospital stays. [Am J Health Syst Pharm 2011;68:1716-1722; Thrombosis J 2019;17:24]

“Many clinicians have misconcep­tions regarding VTE prophylaxis in obese patients. A common belief is that stan­dard doses of anticoagulants are inade­quate for this population, prompting the assumption that higher doses should be used,” Tang said. “However, the height­ened risk of bleeding associated with higher doses is a common concern.” Notably, obese patients were underrep­resented in clinical trials that established the safety and efficacy of VTE preven­tion strategies. [Am J Health Syst Pharm 2011;68:1716-1722]

In a retrospective, cross-sectional study, medical records of 45 morbidly obese (body mass index [BMI], ≥40 kg/m²) hospitalized patients who received ≥4 fondaparinux injections for VTE prophy­laxis were reviewed. Of the 47 anti–factor Xa concentrations evaluated, 53 percent were within or above the target range (≥0.3 mg/L) in these patients. No thrombo­embolic events were documented during hospitalization in the cases evaluated. One patient developed minor bleeding after a muscle biopsy, which resolved without in­tervention.

The randomized, double-blind EFFORT trial evaluated the efficacy of pre­operative enoxaparin (a LMWH) 40 mg BID vs postoperative fondaparinux 5 mg QD for thromboprophylaxis in bariatric surgical patients (BMI, 35–59 kg/m²). Of 198 patients randomized, 177 underwent magnetic resonance venography to detect DVT, and 137 had interpretable anti–factor Xa levels. Almost half (47.4 percent) were found to have inadequate anti–factor Xa activity when evaluated on post­operative day 1 at 3 hours after drug administration. [Surg Obes Relat Dis 2015;11:672-683]

Of note, more patients reached tar­get prophylactic anti–factor Xa levels on fondaparinux than enoxaparin (74.2 vs 32.4 percent; difference, -41.8 percent; 95 percent CI, -57.0 to -26.7; p<0.001). (Figure 3) No symptomatic DVT was re­ported in either treatment arm.

Of the eight patients with minor bleeding, five had intraoperative bleeding (fondaparinux, 2 percent; enoxaparin, 3.1 percent), but none required transfusion. “The binding between fondaparinux and antithrombin is noncovalent and revers­ible, whereas LMWH binds strongly and irreversibly,” explained Tang. “This distinct mechanism explains why fondaparinux does not pose a higher risk of bleeding vs LMWH, despite its longer half-life.”

“These results show that once-daily fondaparinux can reach the target level even in patients with comorbid obesi­ty, without requiring regular monitoring and dose adjustment,” commented Tang. “This simplifies the process of care for both patients and clinicians, eliminating the need for dose calcula­tions and concerns about underdosing or overdosing in obese patients.”

MATISSE: DVT treatment
In the randomized, multicentre, double-blind MATISSE trial, 2,205 pa­tients with symptomatic DVT were ran­domized to receive either fondaparinux 7.5 mg (5 mg QD for body weight <50 kg and 10 mg QD for body weight >100 kg) or enoxaparin 1 mg/kg BID subcutaneously for ≥5 days plus an oral vitamin K antagonist for 3 months. [Ann Intern Med 2004;140:867-873]

Fondaparinux was as effective as enoxaparin in initial treatment of symp­tomatic DVT (recurrent thromboembol­ic events, 3.9 vs 4.1 percent; absolute difference, -0.15 percentage points; 95 percent CI, -1.8 to 1.5), while the rates of major bleeding were comparable be­tween groups (1.1 vs 1.2 percent; abso­lute difference, -0.1 percentage points; 95 percent CI, -1.0 to 0.8).

Optimal patient populations
“I would certainly consider prescrib­ing fondaparinux for overweight or obese patients as it does not require dose ad­justments based on body weight,” rec­ommended Tang. (Table)

“Another group to consider is patients with extremely high thrombosis risk, as fondaparinux's long half-life of 17 hours may offer durable protection, especially during the critical period of 2 weeks post­discharge, without increasing the risk of bleeding,” added Tang. “I would also prefer fondaparinux in Muslim patients who have religious concerns, as fondaparinux is a synthetic medication that does not contain any porcine-derived products.” (Table)

Fondaparinux is a preferred treat­ment in patients with a history of heparin-induced thrombocytopenia (HIT) as it is a synthetic pentasaccharide that selectively binds to antithrombin without interacting with platelet factor 4. (Table) In contrast, both LMWH and UFH are associated with increased risks of HIT – an off-target, immune-mediated, life-threatening ad­verse drug reaction. [Ann Vasc Dis 2020;13:38-44; Pharmacogenet Genom­ics 2022;32:117-124; Proc (Bayl Univ Med Cent) 2012;25:13-15]

DDIs and renal impairment
Fondaparinux has little hepatic me­tabolism and does not inhibit CYP450. “As a result, there is limited concern about potential DDIs with most comedications,” pointed out Tang. [Arixtra Prescribing Infor­mation, February 2019]

Additionally, fondaparinux can be used in patients with mild to moderate renal impairment (creatinine clearance, ≥30 mL/min) without requiring dosage reduction.

Summary
VTE remains underdiagnosed, and thromboprophylaxis is often underused. Fondaparinux is an effective option for both treatment and prevention of VTE, with no markedly increased risk of bleeding. It can be considered in patients with a history of HIT, Muslim patients, as well as those with comorbid obesity or mild to moderate re­nal impairment, without the need for dose adjustments.