|Year : 2016 | Volume
| Issue : 4 | Page : 131-135
Evaluation of bleeding risk in patients with renal impairment treated with Fondaparinux (Arixtra)
Hend H Metwali PharmD 1, Mohammed A Aseeri1, Ahmed Mahmoud2, Ahmad S Alsaeed1, Mona E Albdelwahab1, Abdul Salam3, Rayf Abulezz4
1 King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, MNGHA, King Abdulaziz Medical City, Jeddah, Saudi Arabia
2 Northwestern Memorial Hospital, Chicago, IL, United States
3 King Abdullah International Medical Research Center, Al Hasa, Saudi Arabia
4 Prince Mohamed bin Abdulaziz Hospital, Madinah, Saudi Arabia
|Date of Web Publication||18-Jan-2017|
Dr. Hend H Metwali
Associate Clinical Pharmacist, Pharmaceutical Care Department, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, PO Box 9515, c/o Pharmacy, Jeddah 21423
Source of Support: None, Conflict of Interest: None
Background: Fondaparinux (Arixtra) a synthetic pentasaccharide that causes an antithrombin III-mediated selective inhibition of factor Xa. The clearance of fondaparinux reduces in patients with renal impairment, and there are no dosage adjustments provided in the manufacturer’s labeling. In patients with creatinine clearance rate (CrCl) >50 ml/min, total clearance is reduced by 25% while in case of CrCl 30–50 ml/min, the total clearance could be 40% lower when compared to patients with normal renal function.
Aim of the Study: To evaluate the risk of bleeding in patients with renal impairment treated with fondaparinux.
Materials and Methods: We performed a retrospective chart review study of patients 18 years of age and older who received fondaparinux between 11/10/2003 and 30/12/2009 during their hospital stays, and who had a CrCl of ≤80 ml/min. The patients were classified according to their degree of renal dysfunction as either stage A (CrCl: 80–50 ml/min; mild dysfunction) or stage B (CrCl: <50 ml/min; moderate or severe dysfunction). The HAS-BLED scoring system (HAS-BLED mnemonic stands for: hypertension, abnormal renal and liver function, stroke, bleeding, labile international normalized ratios, elderly, drugs or alcohol) was used to categorize the bleeding risk as mild, moderate, or high. Additionally, the bleeding severity was categorized as either major bleeding or minor bleeding.
Results: A total of 165 patients were included in the study; of which 87 were men. In that 52.7% of the total were classified as stage A and the remainder as stage B. The patients classified as stage B were more frequently classified at high risk of bleeding than stage A patients (48.7%, n = 38 of stage B patients vs. 23.0%, n = 20 of stage A patients). Twenty-three percent (n = 38) of the patients experienced bleeding, and most of which were stage B patients (55.3%, n = 21). The majority of the patients who bled experienced major bleeding (71.0%, n = 27). Ten percent (n = 16) of the total number of patients, whose fondaparinux doses were adjusted as per the drug monograph, were documented to have had a bleeding event during their hospital stay. By contrast, 13% of the total number of patients (n = 22) who required dose adjustments and received fondaparinux without adjustments had bleeding events.
Conclusion: Fondaparinux increases the risk of bleeding in patients with mild-to-moderate renal impairment even with appropriate dose adjustments. The risk of bleeding and the incidence of major bleeding are increased in patients with moderate and severe renal dysfunction.
Keywords: Bleeding risk, fondaparinux, renal impairment
|How to cite this article:|
Metwali HH, Aseeri MA, Mahmoud A, Alsaeed AS, Albdelwahab ME, Salam A, Abulezz R. Evaluation of bleeding risk in patients with renal impairment treated with Fondaparinux (Arixtra). J Appl Hematol 2016;7:131-5
|How to cite this URL:|
Metwali HH, Aseeri MA, Mahmoud A, Alsaeed AS, Albdelwahab ME, Salam A, Abulezz R. Evaluation of bleeding risk in patients with renal impairment treated with Fondaparinux (Arixtra). J Appl Hematol [serial online] 2016 [cited 2020 Jan 22];7:131-5. Available from: http://www.jahjournal.org/text.asp?2016/7/4/131/198518
| Background|| |
Fondaparinux (Arixtra), a synthetic pentasaccharide, indirectly inhibits factor Xa, resulting in the interruption of the blood coagulation cascade and inhibiting thrombin formation and thrombus development. Fondaparinux has been approved in December, 2001 by the U.S. Food and Drug Administration for deep venous thrombosis (DVT) prophylaxis in patients undergoing hip, knee or abdominal surgery, and for DVT and pulmonary embolism treatment in conjunction with warfarin. Following hip, knee or abdominal surgery, fondaparinux is administered as a 2.5 mg subcutaneous (SQ) injection once per day for up to 9 days. In clinical practice, however, the duration of fondaparinux is commonly longer, and clinical trials have demonstrated the safety of the use of fondaparinux a prophylactic agent following hip surgery for up to 33 days.
Fondaparinux is usually cleared from the body unchanged via the urine, so it takes longer to clear in patients with renal dysfunction or impairment. Available data demonstrate that the total clearance of fondaparinux reduced by 25, 40, and 55% in patients with mild (creatinine clearance rate [CrCl]: 50–80 ml/min), moderate (CrCl: 30–50 ml/min), and severe renal impairment (CrCl: <30 ml/min), respectively, compared to patients with normal renal function. On the basis of reduction of fondaparinux in this group of patients as mentioned above, the dose adjustment will be as the following, in patients with CrCl >50 ml/min, no dose adjustment required, while in patients with CrCl 30–50 ml/min, consider to decrease the dose by 50%; however, it is contraindicated in patients with creatinine ClCr <30 ml/min. To better understand the optimal dose of fondaparinux patients with renal impairment, a comprehensive review was conducted by Turpie et al., which focused on the pharmacokinetics of 1.5 mg SQ daily injections of fondaparinux. The authors reviewed data from phase II and III studies that compared the predicted steady-state exposure (area under the plasma concentration–time curve from 0 to 24 h) to fondaparinux between patients with moderate renal impairment (CrCl: 20–50 ml/min) receiving 1.5 mg and patients with normal renal function receiving 2.5 mg was similar. The authors concluded that patients with a mild renal impairment who received exhibited two-fold higher accumulation of fondaparinux compared with patients with normal renal function. In contrast, the patients with mild renal impairment who received fondaparinux at doses that were adjusted to 1.5 mg daily exhibited pharmacokinetic parameters similar to those of patients with normal renal function who received 2.5 mg daily. The authors also reviewed data from a phase II study, in which patients with moderate renal impairment received daily doses of 1.5 mg fondaparinux, and these patients did not exhibit major bleeding events or deaths attributable to fondaparinux.
A double-blind randomized study conducted by Bauer et al. in 2001 compared the efficacies of enoxaparin (low molecular weight heparin) and fondaparinux in terms of the prevention of venous thromboembolisms (VTEs) after knee surgery. A total of 1049 patients underwent major knee surgery and were randomly assigned to receive either fondaparinux (2.5 mg SQ daily) or enoxaparin (30 mg SQ twice daily). They excluded the patients with elevated serum creatinine concentration (>2 mg/dl [177 μmol/l]). The treatments were initiated postoperatively, and the primary efficacy outcome was the development of VTE by postoperative day 11. The primary safety outcome was the incidence of major bleeding by postoperative day 49. The study concluded that the incidences of VTE did not differ significantly between the two treatments (1.0% vs. 1.9% for fondaparinux and enoxaparin, respectively). However, there were 11 major bleeding episodes in the fondaparinux group and only one in the enoxaparin group.
Fox et al. investigated the efficacy (incidence of VTE) and safety (incidence of major bleeding) of the use of fondaparinux (2.5 mg SQ daily) versus those of enoxaparin (1 mg/kg SQ twice daily) in patients with non-ST-segment elevation acute coronary syndrome (ACS) and renal dysfunction at days 9, 30 and 180. On day-9, death, myocardial infarction, and refractory ischemia occurred in 6.7% of patients receiving fondaparinux and in 7.4% of those receiving enoxaparin (hazard ratio, 0.90 [95% confidence interval (CI), 0.73–1.11]); besides, major bleeding occurred in 2.8% and 6.4% in both kind of patients, respectively (hazard ratio, 0.42 [95% CI, 0.32–0.56]). Statistically significant differences in major bleeding persisted at 30 and 180 days. The patients were classified into four groups according to their glomerular filtration rates (GFR). The authors reported that fondaparinux was associated with a lower incidence of major bleeding events than enoxaparin (2.8% vs. 6.4%, respectively), especially in patients with GFR below 58 ml/min per 1.73 m2. The study concluded that the advantage of fondaparinux over enoxaparin when administered for non-ST-segment elevation ACS is most noted among renal dysfunction patients and is largely explained by smaller percentage of major bleeding with fondaparinux.
In Bauer’s study, the authors used enoxaparin and fondaparinux as VTEs prophylaxis after knee surgery which excluded the patients with abnormal renal function. They reported that the episodes of major bleeding in the fondaparinux group are more than in the enoxaparin group. While in Fox et al. the authors used fondaparinux and enoxaparin as therapeutic in patients with non-ST-segment elevation ACS, the incidence of major bleeding was lower with fondaparinux than enoxaparin, especially in patients with low GFR. However, in our study, we included the patients with impaired renal function who received fondaparinux as prophylactic or therapeutic and evaluated the risk of their bleeding.
Fondaparinux was added to our hospital formulary in October 2003, and since then it has been used primarily in patients who present with ACS, postoperative prophylaxis or suspected or confirmed heparin-induced thrombocytopenia. Considering the anecdotal reports of bleeding in our hospital targeting renal impairment patients and the lack of availability of appropriate dosage adjustments for prophylactic dosing in this group of patients, a safety study was proposed. Thus, the aim of the current study was to evaluate the risk of bleeding associated with the use of fondaparinux in patients with renal impairment.
| Materials and Methods|| |
This study was conducted based on the records of patients admitted to the King Khalid National Guard Hospital who received fondaparinux during the study period (11/10/2003 to 30/12/2009). This hospital is a tertiary care hospital with 500 beds. The study received approval from the hospital ethics committee. We performed a retrospective chart review of patients with renal dysfunction (CrCl ≤80 ml/min, the CrCl level that affect the fondaparinux clearance) who were admitted to the hospital and received fondaparinux as an anticoagulant, either as a prophylactic or a treatment therapy. We excluded the patients with CrCl >80 ml/min. Eligible patients were identified from the hospital information system between 11/10/2003 (the date on which fondaparinux was added to the formulary) and 30/12/2009 (when a different document management system was introduced). Renal function was estimated using the Cockcroft–Gault equation, and the renal insufficiency of the patients was then classified as either stage A (CrCl: 80–50 ml/min; mild dysfunction) or stage B (CrCl: <50 ml/min; moderate or severe dysfunction). HAS-BLED score used to categorize the bleeding risk as mild, moderate or high. HAS-BLED is an acronym for hypertension (uncontrolled, >160 mmHg systolic), abnormal renal/liver function (one point for presence of renal or liver impairment, maximum two points), stroke (previous history, particularly lacunar), bleeding history or predisposition (anemia), labile international normalized ratio (i.e., therapeutic time in range, 60%), elderly (65 years), drugs/alcohol concomitantly (antiplatelet agents, nonsteroidal anti-inflammatory drugs; one point for drugs plus one point for alcohol excess, maximum two points), if the total score is 0–1 that means the patient is at low risk of bleeding, if the total score is 2, the patient is intermediate risk of bleeding while if the total score is 3 or more then that means the patient is at high risk of bleeding., We used HAS-BLED score specifically based on Zhu et al. that compared the diagnostic accuracy between the HAS-BLED score and other bleeding score; they found that the HAS-BLED score was the optimal choice to assess major bleeding risk in clinical practice. We choose to evaluate the bleeding risk of included patients to exclude any cause of bleeding except fondaparinux. Bleeding was classified as either major or minor. Major bleeding was defined as a reduction in the hemoglobin (Hgb) level to at least 2 g/dl, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ (intracranial, intra-abdominal, intra-spinal, retro-peritoneal, intra-articular, or deep muscle hematoma). Life-threatening major bleeding events were sub-categorized as follows: fatal bleeding, bleeding with a decrease in the Hgb level of at least 50 g/l or bleeding that required the transfusion of at least 4 units of blood, the administration of inotropic agents, or that necessitated surgery. All other types of bleeding were classified as minor. The Hgb baseline was defined as the Hgb value on the first day of fondaparinux administration. The Hgb values for up to 3 days after the discontinuation of fondaparinux treatment were included in the analysis.
Results are expressed as the means ± the standard deviations and numbers (%). P-values were calculated using the Pearson Chi-square test.
| Results|| |
A total of 487 patients were identified who received fondaparinux during the study period, and their medical records were extracted successfully from the hospital information system. Patients were excluded if they had CrCl >80 ml/min. A total of 165 patients were, therefore, included in this study; in that 87 (52.7%) were men. The mean age was 65.5 ± 12.9 years. The calculated body mass indices ranged from 18.6 to 38.1, with a mean of 24.4 ± 3. Among the study patients, 52% (n = 87) of the patients were classified with stage A renal dysfunction, the majority of them were men (59.8%, n = 52), and the majority of patients with stage B renal insufficiency were women (55.1%, n = 43), although these differences were not statistically significant (P = 0.056). Stage B patients were significantly older (68.85 ± 14.68 years) than stage A patients (62.57 ± 10.22 years; P = 0.003). The most common dose of fondaparinux (95.2, n = 157) was the prophylactic dose of 2.5 mg, and the mean duration of treatment was 11.3 ± 9.9 days [Table 1]. Ten percent (n = 16) of the total number of patients whose fondaparinux doses were adjusted per the drug monograph were documented to have had a bleeding event during their hospital stay. By contrast, 13% of the total number of patients (n = 22) who required dose adjustments and received fondaparinux without adjustments had bleeding events. Two patients from stage B died, so the overall mortality rate was 1.2%.
Risk of bleeding
Fifty-five percent (n = 91) of the patients were categorized as being at a moderate risk of bleeding, as determined using the HAS-BLED scoring system;, nearly one-third (35.2%, n = 58) of the patients were categorized as being at a high risk of bleeding [Table 1].
The risk of bleeding, as calculated using the HAS-BLED scoring system,, was higher for stage B patients than stage A patients; 48.7% stage B patients were classified as at high risk of bleeding compared to 23.0% stage A patients (P < 0.05).
Twenty-tree percent (n = 38) of the patients experienced bleeding events. Major bleeding uncured in (16.4%, n = 27) of the total patients while 6.7% (n = 11) had minor bleeding. In addition, Hgb decreased by more than 2 g/dl from the Hgb baseline level in (14.5%, n = 24) of all patients, and 19% (n = 32) of the patients required blood transfusions. Over half of the patients who required blood transfusions (53.2%, n = 17) received 1 unit of blood, nine patients (28.1%) required 2 units, and two patients (6.3%) required more than 3 units of blood [Table 2].
The frequency of bleeding was higher among stage B patients than stage A patients (13% vs. 10%), and stage B patients were also more likely to experience decreased Hgb levels than stage A patients (17.9% vs. 11.5%; P = 0.240). Moreover, 20% (n = 16) of stage B patients were treated for major bleeding compared to 12% (n = 11) of stage A patients (P = 0.394). It, therefore, follows that the proportion of patients who received blood transfusions was higher among stage B patients (7.7%) than stage A patients (2.3%, P = 0.107). None of these differences, however, were statistically significant.
| Discussion|| |
Patients with renal impairment have an increased risk of bleeding complications. Most of antithrombotic medications undergo renal clearance. For that reason, estimation of renal function is necessary when prescribing these medications to this group of patients. Pharmacokinetic and clinical data in renal impairment patients are limited. The aim of the current study was to evaluate the risk of bleeding associated with the use of fondaparinux in patients with renal impairment. Appropriate dosage adjustments for prophylactic dosing in this group of patients are not clear. In our study, we included patients with CrCl ≤80 ml/min who received fondaparinux as a prophylactic or treatment therapy. The patients were classified into two groups based on their renal function to evaluate their risk of bleeding as assessed by the HAS-BLED scoring system. In addition, the type of bleeding was classified as major or minor bleeding. Using HAS-BLED scores, half of the patients were found to be at moderate risk of bleeding, and almost one-third of the patients were found to be at high risk of bleeding. The risk and the rate of bleeding were higher in stage B patients (the patients with lower CrCl) than in stage A patients, but these differences were not statistically significant that may be because of small sample size. Moreover, the results revealed that the patients with stage B renal insufficiency had higher number of major bleeding than the patients with stage A. We conclude that fondaparinux might increase the bleeding risk of patients with CrCl ≤80 ml/min even with appropriate dose adjustments (either prophylactic or therapeutic doses). As this is the first study to evaluate the bleeding risk associated with fondaparinux in patients with renal impairment, additional studies are needed to evaluate the bleeding risk associated with fondaparinux in similar groups of patients with larger sample size.
This study is limited by the retrospective design, and by the fact that it was conducted in a single center with a small sample size. There was no control group who received no fondaparinux.
| Conclusion|| |
Fondaparinux might increase the risk of bleeding in patients with CrCl ≤80 ml/min even when the dose is adjusted appropriately. The risk of bleeding and the incidence of major bleeding are higher in patients with CrCl <50 ml/min than in those with CrCl 80–50 ml/min.
The statistical analysis of the research data was performed by Oyindamola B. Yusuf, Epidemiologist, King Abdullah International Medical Research Center. The research laboratory results were extracted from the hospital information system by Mr. Mohammad Al-Harbi, Lab Information System Team Leader, King Saud bin Abdulaziz University for Health Sciences/King Abdulaziz Medical City, Jeddah.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Product Information: ARIXTRA (R) Subcutaneous Injection, Fondaparinux Sodium Subcutaneous Injection. Research Triangle Park, NC: GlaxoSmithKline; 2008.
Eriksson BI, Lassen MR; PENTasaccharide in HIp-FRActure Surgery Plus Investigators. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: A multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003;163:1337-42.
Turpie AG, Lensing AW, Fuji T, Boyle DA. Pharmacokinetic and clinical data supporting the use of fondaparinux 1.5 mg once daily in the prevention of venous thromboembolism in renal impaired patients. Blood Coagul Fibrinolysis 2009;20:114-21.
Bauer KA, Eriksson BI, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305-10.
Fox KA, Bassand JP, Mehta SR, Wallentin L, Theroux P, Piegas LS et al.
Influence of renal function on the efficacy and safety of fondaparinux relative to enoxaparin in non ST-segment elevation acute coronary syndromes. Ann Intern Med 2007;147:304-10.
Botev R, Mallié JP, Couchoud C, Schück O, Fauvel JP, Wetzels JF et al.
Estimating glomerular filtration rate: Cockcroft-Gault and modification of diet in renal disease formulas compared to renal inulin clearance. Clin J Am Soc Nephrol 2009;4:899-906.
Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest 2010;138:1093-100.
Lip GY, Frison L, Halperin JL, Lane DA. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: The HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2011;57:173-80.
Zhu W, He W, Guo L, Wang X, Hong K. The HAS-BLED score for predicting major bleeding risk in anticoagulated patients with atrial fibrillation: A systematic review and meta-analysis. Clin Cardiol 2015;38:555-61.
Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692-4.
[Table 1], [Table 2]