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Research Article
Once daily versus twice daily enoxaparin for acute pulmonary embolism in cancer patients
J Oncol Pharm Practice 0(0) 1–6 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215583374 opp.sagepub.com
Amber C King1, Maggie Q Ma1, Gary Chisholm2 and Katy M Toale1
Abstract Background: Venous thromboembolism (VTE) is a condition in which a thrombus occludes the vasculature. The incidence of VTE in cancer patients is three times higher than that of the general population. Enoxaparin 1 mg/kg subcutaneously (SC) twice daily and enoxaparin 1.5 mg/kg SC once daily are both FDA-approved dosing regimens for the treatment of pulmonary embolism (PE). The objectives of this study were to assess outcomes of cancer patients treated with once or twice daily enoxaparin for acute PE. Primary outcomes included recurrent or worsening PE and secondary outcomes included mortality or signs of clinically overt, major bleeding. Methods: This study was a retrospective chart review of adult cancer patients treated at The University of Texas MD Anderson Cancer Center from 2011 to 2013 who received either 1 mg/kg twice daily or 1.5 mg/kg once daily enoxaparin for acute PE upon discharge. Results: Among 48 patients in each the twice daily and once daily group, six recurrent PEs occurred. The incidence of recurrent PE was higher in the once daily group (n ¼ 4) versus twice daily group (n ¼ 2). More major bleeding events occurred in the once daily group than the twice daily group (15% vs. 6%). Mortality at 6 months was higher in the twice daily group versus once daily group (13% vs. 6%). Conclusion: Cancer patients receiving once daily enoxaparin for the treatment of acute PE may be at increased risk of recurrent PE and clinically overt bleeding. Larger randomized trials are needed to confirm the results of this study.
Keywords Pulmonary embolism, enoxaparin, cancer
Introduction Venous thromboembolism (VTE) is a condition in which a thrombus, or blood clot, occludes the vasculature within the body. VTE can manifest as a deep venous thromboembolism (DVT), which is a thrombus in the lower extremities that can propagate into proximal veins or a pulmonary embolism (PE), which is a thrombus that occludes the pulmonary arteries. Overall, the incidence of VTE is estimated to be between 300,000 and 600,000 cases per year in the United States. Approximately, one-third of patients with VTE will present with PE, and 20–25% of these cases result in sudden death.1,2 After a standard course of anticoagulant therapy for VTE, 30% of the general population will experience a
recurrence within 10 years, with the highest risk occurring within the first year of the initial event.1 In cancer patients, thrombogenic chemotherapy, immobility, advanced age, indwelling catheters, and tumor burden contribute to increased VTE risk. Even with therapeutic anticoagulation, the incidence of recurrent
1 Department of Pharmacy, The University of Texas MD Anderson Center, Houston, TX, USA 2 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Corresponding author: Katy M Toale, Department of Pharmacy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 377, Houston, TX 77030, USA. Email: [email protected]
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VTE in cancer patients is three times higher than that of the general population. VTE is the second leading cause of death in hospitalized cancer patients.2,3 In addition, cancer patients generally have a higher risk of bleeding, which is augmented when therapeutic anticoagulation is added. Bleeding risk in cancer patients may be increased due to malnutrition, organ dysfunction affecting anticoagulant clearance, thrombocytopenia secondary to chemotherapy or to cancer itself.3 Enoxaparin 1 mg/kg subcutaneously (SC) twice daily and enoxaparin 1.5 mg/kg SC once daily are both FDA-approved regimens for the treatment of DVT with or without PE. While currently approved for DVT with or without PE, enoxaparin does not have a specific FDA-approval for treatment of VTE in cancer patients. The only medication with an approved indication for cancer-related VTE is dalteparin. Currently, there are no published randomized clinical trials directly comparing the efficacy and safety of enoxaparin twice daily versus once daily for treatment of PE in cancer patients. A subgroup analysis of cancer patients (n ¼ 141) demonstrated a non-statistically significant higher rate of recurrent VTE in patients bridged to warfarin with enoxaparin dosed with 1.5 mg/kg daily versus 1 mg/kg SC twice daily (12.2% vs. 6.4%).4 Conversely, death in the once daily enoxaparin group was 0% versus 8.5% in the twice daily enoxaparin group. The cause of death among the subgroup of patients with cancer was not specifically reported. Current guidelines addressing anticoagulation therapy in cancer patients all recommend low-molecular-weight heparins for treatment of VTE.5–7 However, no consensus for the preferred dosing of enoxaparin in cancer patients exists between the National Comprehensive Cancer Network (NCCN),5 the American Society of Clinical Oncology (ASCO),6 and the American College of Chest Physicians (ACCP)7 guidelines. The NCCN guidelines recommend all of the following agents for treatment of cancer-related VTE: dalteparin 200 units/kg SC daily and enoxaparin 1 mg/kg SC every 12 h are preferred and fondaparinux SC, unfractionated heparin (UFH) intravenously at a dose of 80 units/kg load followed by 18 units/kg/h infusion, and UFH SC at a dose of 333 units/kg load followed by 250 units/kg every 12 h are second-line therapy.5 The ASCO guidelines also prefer treatment with low-molecular-weight heparins over UFH and only recommend fondaparinux in initial treatment, but not for long-term therapy. The ASCO guidelines also recommend the use of tinzaparin 175 units/kg SC daily as a treatment option.6 The ACCP guidelines suggest low-molecular-weight heparin use over vitamin K antagonists for patients with VTE and cancer.7 The objective of our study was to determine whether once daily or twice daily enoxaparin is associated with an increase in recurrent or worsening
pulmonary embolism. Secondary objectives of our study were to determine whether once daily or twice daily enoxaparin is associated with an increase in mortality or signs of any clinically overt major bleeding.
Methods This study was a retrospective chart review of adult patients with acute PE who received treatment at The University of Texas MD Anderson Cancer Center between July 2011 and March 2013. Recurrent pulmonary embolism was defined as a new embolism or extension of a current embolism on computed tomography (CT) pulmonary angiography or ventilation-perfusion (VQ) scan or symptoms requiring anticoagulation medication changes such as an increased strength in dosing, increased frequency of dosing, or a change to an alternative anticoagulant. Mortality was defined as death within 6 months of acute PE. Clinically overt signs of major bleeding were defined as an intracranial, intraspinal, intraocular, retroperitoneal, pericardial, intramuscular with compartment syndrome, or intraarticular bleed, a drop in hemoglobin by 2 g/dL from baseline, a requirement of 2 units of packed red blood cells, or any bleed requiring major medical or surgical intervention. Thrombogenic chemotherapy included the use of lenalidomide, bevacizumab, diethylstilbestrol (DES), or tamoxifen. The time frame evaluated when assessing changes in hemoglobin included the entire follow-up period of 6 months. The protocol was reviewed and approved by the Institutional Review Board. Patients were identified through a pharmacy informatics request for all initial enoxaparin outpatient prescriptions that were filled at our institution during the specified time period, followed by further screening of prescriptions used to treat acute PE. Patients were assigned unique numeric identifiers entered into an electronic random number generating software (www.ran dom.org). Data were collected for the first 50 random patients that met inclusion criteria in the once and twice daily enoxaparin groups. Inclusion criteria were as follows: a documented diagnosis of active cancer, PE confirmed by radiographic findings, an initial enoxaparin prescription filled at our institution, enoxaparin dosing within 20 mg of actual body weight, patients greater than 18 years of age, and a documented follow-up within 6 months. Enoxaparin dosing was based on physician preference. Patients meeting one or more of the following exclusion criteria were omitted from our study: in or transitioning to hospice, pregnant patients, patients weighing above 190 kilograms, patients with 1 enoxaparin dose held prior to completion of 30 days of drug administration, or patients with an estimated creatinine clearance less than 30 mL/min.
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Statistical analysis Patient characteristics, baseline demographics, primary, and secondary outcomes were evaluated using descriptive statistics. The study was not powered to detect differences between treatment groups. Baseline characteristics were compared using the t-test and Fisher’s exact test.
Results Of 359 patients screened, 96 patients were included. Baseline patient demographics and characteristics can be seen in Table 1. Patients were similar among the groups, being predominantly males with a median age of 60–62 years, coagulation assays within normal limits, creatinine clearances >100 mL/min, and baseline platelet counts >100,000/uL. However, notable differences seen were the presence of brain metastases in the twice daily group. Conversely, the once daily group had more central venous catheters (CVC), and thrombogenic chemotherapy. None of these differences were statistically significant. The only statistically significant difference in the baseline characteristics was weight which was higher in the twice daily group. The incidence of recurrent PE was higher in the once daily than the twice daily group (8% vs. 4%). Subsequent management of recurrent PE for each group can be seen in Table 2. Following the recurrent episode, one patient in the once daily group discontinued chemical anticoagulation and received an inferior vena cava (IVC) filter, while another patient in the once daily group was kept on the same regimen with no documented changes. In the twice daily group, one patient discontinued anticoagulation per patient preference. One patient in the once daily group was taking concomitant thrombogenic chemotherapy (bevacizumab). The incidence of clinically overt, major bleeding events was 15% in the once daily group compared to 6% in the twice daily group. Two patients in the once daily group were taking concomitant COX-inhibitors and experienced a drop in hemoglobin of 2 g/dL, while one patient in the once daily taking a concomitant COX-inhibitor experience a new hemorrhagic brain lesion. Mortality at 6 months was more prevalent in the twice daily group than once daily group (13% vs. 6%) (Table 3).
Discussion Our study demonstrated that once daily enoxaparin was associated with increased recurrent PE when compared with twice daily enoxaparin in cancer patients. Regarding the primary objective, results seen for once daily versus twice daily enoxaparin were similar to those reported in the Merli trial subgroup analysis of
cancer patients (12.2% in once daily vs. 6.4% in twice daily). The primary and secondary objectives in this retrospective chart review are entirely collected and analyzed from cancer patients, differing from the patients analyzed in the trial conducted by Merli et al.4 Baseline characteristics of the once daily group may have influenced the increased trend of recurrent PE. Factors with the highest potential to increase recurrent PE were presence of CVCs and thrombogenic therapy. A higher percentage of patients in the once daily group had CVCs at the time of their initial PE compared to the twice daily group (56% vs. 46%). Also, more patients in the once daily group were on bevacizumab, an agent known to increase thromboembolic events, compared to the twice daily group (17% vs. 13%).8 It is also likely that the higher total daily dosage in the twice daily group (2 mg/kg/day vs. 1.5 mg/kg/day) could have resulted in a lower incidence of recurrent PE. Even though there is a lack of data to support benefits of the higher dosage, the current ACCP guidelines suggest the use of once daily dosing but only when the regimen uses the same total daily dose as the twice daily regimen; however, this dosing strategy is not routinely used in clinical practice (2 mg/kg/day).7 Regarding the secondary safety objectives, there was an increase in major bleeding events in the once daily group compared to the twice daily group. More patients in the once daily group were on concurrent aspirin during their PE treatment compared to the twice daily group (29% vs. 21%), which may have affected the results of the secondary objective. Patients in the twice daily group had a higher mortality at six months when compared to the once daily group (13% vs. 6%). These results are similar to those seen in the Merli subgroup analysis of cancer patients, where 0% of patients in the once daily group were documented as deceased within 6 months compared to 8.5% in the twice daily group. Baseline characteristics that may have influenced the increased mortality were the increased presence of brain metastases at baseline in the twice daily group, which has been shown to result in a poorer prognosis in many subsets of cancer.9 Due to the nature of the patient population, it is difficult to confirm PE as cause of mortality in a cancer patient. Many patients that present at our institution are often refractory to frontline treatments and are referred from outside facilities. Autopsies were not performed on any patients who passed away during this trial. There were limitations to this study. Patient data were collected retrospectively by a single party through chart review at single center. There is a reliance on accurate and complete documentation of patient events throughout the course of the study period. Many patients were excluded due to a lack of follow-up.
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Journal of Oncology Pharmacy Practice 0(0) Table 1. Patient demographics.
Age (years) Male sex, no. (%) Height (cm) Weight (kg) Primary cancer Solid tumor, no. (%) Breast Gastrointestinal Genitourinary Gynecology Head and neck Lung Melanoma Sarcoma Other Liquid tumor, no. (%)
Once daily group (n ¼ 48)
Twice daily group (n ¼ 48)
p-Value
62 35 170 80
60 26 171 91
(26–82) (54) (154–198) (56–130)
0.31 0.09 0.20 0.002
(90) (4) (25) (19) (8) (6) (19) (2) (2) (4) (10)
1.00 0.49 0.13 0.79 0.68 0.62 0.23 0.62 0.11 1.00 1.00
44 0 20 7 2 1 4 3 6 1 4
Pulmonary embolism characteristics Massive/Saddle Submassive
(25–88) (73) (150–187) (43–134) (92) (0) (42) (15) (4) (2) (8) (6) (13) (2) (8)
43 2 12 9 4 3 9 1 1 2 5
2 (4) 0 (0)
3 (6) 4 (8)
1.00 0.12
Baseline platelet count, no. (%) 20,000–49,000 50,000–99,000 >100,000
1 (2) 1 (2) 46 (96)
0 (0) 3 (6) 45 (94)
1.00 0.62 1.00
Baseline creatinine clearance, no. (%) 30–49 mL/min 50–99 mL/min >100 mL/min
4 (8) 14 (29) 30 (63)
0 (0) 12 (25) 36 (75)
0.12 0.81 0.27
Baseline aPTT, no. (%) 35.9 s Unknown
1 20 7 20
(2) (42) (15) (42)
1 30 7 10
(2) (63) (15) (21)
1.00 0.18 0.56
1 20 8 19 5 5 27 11
(2) (42) (17) (40) (10) (10) (56) (23)
2 25 11 10 8 5 22 11
(4) (52) (23) (21) (17) (10) (46) (23)
1.00 1.00 1.00 0.55 1.00 0.41 1.00
6 (13) 4 (8)
0.77 1.00
Baseline PT, no. (%) 15 s Unknown Brain metastases at baseline, no. (%) Spinal cord metastases at baseline, no. (%) Presence of CVC, no. (%) Hospitalization in past 30 days, no. (%) Thrombogenic chemotherapy, no. (%) Bevacizumab Hormonal agent
8 (17) 3 (6)
(continued)
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Table 1. Continued. Once daily group (n ¼ 48) Concomitant medications COX inhibitor NSAID P2Y12 inhibitor
14 (29) 1 (2) 1 (2)
Twice daily group (n ¼ 48) 10 (21) 1 (2) 1 (2)
p-Value 0.48 1.00 1.00
Age, gender, height, weight values are reported as median (range) unless otherwise specified. Characteristics of the pulmonary embolism (massive/saddle and submassive) were based on the radiology imaging reports. a PTT: activated partial thromboplastin time; PT: prothrombin time; CVC: central venous catheter; COX: cyclooxygenase; NSAID: nonsteroidal anti-inflammatory drug.
Table 2. Primary endpoint.
Recurrent PE per diagnostic imaging, no. (%) Increased strength of enoxaparin, no. (%) Change in frequency of enoxaparin, no. (%)
Once daily groupa (n ¼ 48)
Twice daily groupb (n ¼ 48)
4 (8)
2 (4)
1 (2)
0 (0)
1 (2)
1 (2)
a One patient in the once daily group discontinued chemical anticoagulation and received an inferior vena cava filter while another patient was kept on the same dose of anticoagulation with no documented changes. b One patient in the twice daily group discontinued anticoagulation per patient preference.
Table 3. Safety endpoints. Once daily Twice daily group (n ¼ 48) group (n ¼ 48) Clinically overt, major bleed, no. Drop in hemoglobin by 2 g/dL Retroperitoneal Intracranial Death within 6 months, no. (%)
(%) 6 (13)
2 (4)
0 (0) 1 (2) 3 (6)
1 (2) 0 (0) 6 (13)
a difference between groups; therefore, we can only hypothesize that there is a higher recurrence of PE with once daily administration of enoxaparin. It is difficult to conclude whether the choice of anticoagulation regimen was the primary factor for outcomes observed. Due to the retrospective nature of the trial, compliance was not able to be assessed and confounding variables cannot be excluded. Therefore, differences may exist among the patients analyzed regarding compliance and other causes may have been present, which could have influenced outcomes.
Conclusion The trend towards a higher recurrence of PE and more bleeding events in the once daily group may support the use of twice daily over once daily dosing of enoxaparin for acute PE in cancer patients. Large, prospective studies are needed to further evaluate superiority of twice daily enoxaparin in cancer patients. This study may provide a foundation for larger, randomized, controlled trials to determine whether once daily or twice daily dosing of enoxaparin should be the preferred PE treatment in cancer patients. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest Outcomes of these patients could potentially impact the trends observed in our study. As previously mentioned, patients who present to our institution are often refractory to many lines of treatment regimens, representing a population with an overall shorter survival compared to the general population. When assessing major bleeding, a drop in hemoglobin of 2 g/dL was used as one of the definitions. Since the entire follow-up period was assessed, gradual drops may have been related to chemotherapy or disease progression rather than bleeding complications. The trial was not powered to detect
None declared.
References 1. Heit JA. The epidemiology of venous thromboembolism in the community: Implications for prevention and management. J Thromb Thrombolysis 2006; 21: 23–29. 2. Beckman MG, Hooper WC and Critchley SE. Venous thromboembolism: A public health concern. Am J Prev Med 2010; 38: S495–S501. 3. Diaz AH, Rodgers GM and Gilreath JA. Enoxaparin once daily vs. twice daily dosing for the treatment of venous
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thromboembolism in cancer patients: A literature summary. J Oncol Pharm Pract 2011; 18: 264–270. 4. Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001; 134: 191–202. 5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Venous Thromboembolic Disease Version 2.19 April 2013, National Comprehensive Cancer Network. 6. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients
with cancer: American Society of Clinical Oncology practice guideline update. J Clin Oncol 2013; 31: 2189–2204. 7. Guyatt GH, Akl EA, Crowther M, et al. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141: 7S–47S. 8. Haddad TC and Greeno EW. Chemotherapy-induced thrombosis. Thromb Res 2006; 118: 555–568. 9. Riihimaki M, Thomsen H, Hemminki A, et al. Comparison of survival of patients with metastases from known versus unknown primaries: Survival in metastatic cancer. BMC Cancer 2013; 13: 1–8.
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Research Article
Once daily versus twice daily enoxaparin for acute pulmonary embolism in cancer patients
J Oncol Pharm Practice 0(0) 1–6 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155215583374 opp.sagepub.com
Amber C King1, Maggie Q Ma1, Gary Chisholm2 and Katy M Toale1
Abstract Background: Venous thromboembolism (VTE) is a condition in which a thrombus occludes the vasculature. The incidence of VTE in cancer patients is three times higher than that of the general population. Enoxaparin 1 mg/kg subcutaneously (SC) twice daily and enoxaparin 1.5 mg/kg SC once daily are both FDA-approved dosing regimens for the treatment of pulmonary embolism (PE). The objectives of this study were to assess outcomes of cancer patients treated with once or twice daily enoxaparin for acute PE. Primary outcomes included recurrent or worsening PE and secondary outcomes included mortality or signs of clinically overt, major bleeding. Methods: This study was a retrospective chart review of adult cancer patients treated at The University of Texas MD Anderson Cancer Center from 2011 to 2013 who received either 1 mg/kg twice daily or 1.5 mg/kg once daily enoxaparin for acute PE upon discharge. Results: Among 48 patients in each the twice daily and once daily group, six recurrent PEs occurred. The incidence of recurrent PE was higher in the once daily group (n ¼ 4) versus twice daily group (n ¼ 2). More major bleeding events occurred in the once daily group than the twice daily group (15% vs. 6%). Mortality at 6 months was higher in the twice daily group versus once daily group (13% vs. 6%). Conclusion: Cancer patients receiving once daily enoxaparin for the treatment of acute PE may be at increased risk of recurrent PE and clinically overt bleeding. Larger randomized trials are needed to confirm the results of this study.
Keywords Pulmonary embolism, enoxaparin, cancer
Introduction Venous thromboembolism (VTE) is a condition in which a thrombus, or blood clot, occludes the vasculature within the body. VTE can manifest as a deep venous thromboembolism (DVT), which is a thrombus in the lower extremities that can propagate into proximal veins or a pulmonary embolism (PE), which is a thrombus that occludes the pulmonary arteries. Overall, the incidence of VTE is estimated to be between 300,000 and 600,000 cases per year in the United States. Approximately, one-third of patients with VTE will present with PE, and 20–25% of these cases result in sudden death.1,2 After a standard course of anticoagulant therapy for VTE, 30% of the general population will experience a
recurrence within 10 years, with the highest risk occurring within the first year of the initial event.1 In cancer patients, thrombogenic chemotherapy, immobility, advanced age, indwelling catheters, and tumor burden contribute to increased VTE risk. Even with therapeutic anticoagulation, the incidence of recurrent
1 Department of Pharmacy, The University of Texas MD Anderson Center, Houston, TX, USA 2 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Corresponding author: Katy M Toale, Department of Pharmacy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 377, Houston, TX 77030, USA. Email: [email protected]
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VTE in cancer patients is three times higher than that of the general population. VTE is the second leading cause of death in hospitalized cancer patients.2,3 In addition, cancer patients generally have a higher risk of bleeding, which is augmented when therapeutic anticoagulation is added. Bleeding risk in cancer patients may be increased due to malnutrition, organ dysfunction affecting anticoagulant clearance, thrombocytopenia secondary to chemotherapy or to cancer itself.3 Enoxaparin 1 mg/kg subcutaneously (SC) twice daily and enoxaparin 1.5 mg/kg SC once daily are both FDA-approved regimens for the treatment of DVT with or without PE. While currently approved for DVT with or without PE, enoxaparin does not have a specific FDA-approval for treatment of VTE in cancer patients. The only medication with an approved indication for cancer-related VTE is dalteparin. Currently, there are no published randomized clinical trials directly comparing the efficacy and safety of enoxaparin twice daily versus once daily for treatment of PE in cancer patients. A subgroup analysis of cancer patients (n ¼ 141) demonstrated a non-statistically significant higher rate of recurrent VTE in patients bridged to warfarin with enoxaparin dosed with 1.5 mg/kg daily versus 1 mg/kg SC twice daily (12.2% vs. 6.4%).4 Conversely, death in the once daily enoxaparin group was 0% versus 8.5% in the twice daily enoxaparin group. The cause of death among the subgroup of patients with cancer was not specifically reported. Current guidelines addressing anticoagulation therapy in cancer patients all recommend low-molecular-weight heparins for treatment of VTE.5–7 However, no consensus for the preferred dosing of enoxaparin in cancer patients exists between the National Comprehensive Cancer Network (NCCN),5 the American Society of Clinical Oncology (ASCO),6 and the American College of Chest Physicians (ACCP)7 guidelines. The NCCN guidelines recommend all of the following agents for treatment of cancer-related VTE: dalteparin 200 units/kg SC daily and enoxaparin 1 mg/kg SC every 12 h are preferred and fondaparinux SC, unfractionated heparin (UFH) intravenously at a dose of 80 units/kg load followed by 18 units/kg/h infusion, and UFH SC at a dose of 333 units/kg load followed by 250 units/kg every 12 h are second-line therapy.5 The ASCO guidelines also prefer treatment with low-molecular-weight heparins over UFH and only recommend fondaparinux in initial treatment, but not for long-term therapy. The ASCO guidelines also recommend the use of tinzaparin 175 units/kg SC daily as a treatment option.6 The ACCP guidelines suggest low-molecular-weight heparin use over vitamin K antagonists for patients with VTE and cancer.7 The objective of our study was to determine whether once daily or twice daily enoxaparin is associated with an increase in recurrent or worsening
pulmonary embolism. Secondary objectives of our study were to determine whether once daily or twice daily enoxaparin is associated with an increase in mortality or signs of any clinically overt major bleeding.
Methods This study was a retrospective chart review of adult patients with acute PE who received treatment at The University of Texas MD Anderson Cancer Center between July 2011 and March 2013. Recurrent pulmonary embolism was defined as a new embolism or extension of a current embolism on computed tomography (CT) pulmonary angiography or ventilation-perfusion (VQ) scan or symptoms requiring anticoagulation medication changes such as an increased strength in dosing, increased frequency of dosing, or a change to an alternative anticoagulant. Mortality was defined as death within 6 months of acute PE. Clinically overt signs of major bleeding were defined as an intracranial, intraspinal, intraocular, retroperitoneal, pericardial, intramuscular with compartment syndrome, or intraarticular bleed, a drop in hemoglobin by 2 g/dL from baseline, a requirement of 2 units of packed red blood cells, or any bleed requiring major medical or surgical intervention. Thrombogenic chemotherapy included the use of lenalidomide, bevacizumab, diethylstilbestrol (DES), or tamoxifen. The time frame evaluated when assessing changes in hemoglobin included the entire follow-up period of 6 months. The protocol was reviewed and approved by the Institutional Review Board. Patients were identified through a pharmacy informatics request for all initial enoxaparin outpatient prescriptions that were filled at our institution during the specified time period, followed by further screening of prescriptions used to treat acute PE. Patients were assigned unique numeric identifiers entered into an electronic random number generating software (www.ran dom.org). Data were collected for the first 50 random patients that met inclusion criteria in the once and twice daily enoxaparin groups. Inclusion criteria were as follows: a documented diagnosis of active cancer, PE confirmed by radiographic findings, an initial enoxaparin prescription filled at our institution, enoxaparin dosing within 20 mg of actual body weight, patients greater than 18 years of age, and a documented follow-up within 6 months. Enoxaparin dosing was based on physician preference. Patients meeting one or more of the following exclusion criteria were omitted from our study: in or transitioning to hospice, pregnant patients, patients weighing above 190 kilograms, patients with 1 enoxaparin dose held prior to completion of 30 days of drug administration, or patients with an estimated creatinine clearance less than 30 mL/min.
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Statistical analysis Patient characteristics, baseline demographics, primary, and secondary outcomes were evaluated using descriptive statistics. The study was not powered to detect differences between treatment groups. Baseline characteristics were compared using the t-test and Fisher’s exact test.
Results Of 359 patients screened, 96 patients were included. Baseline patient demographics and characteristics can be seen in Table 1. Patients were similar among the groups, being predominantly males with a median age of 60–62 years, coagulation assays within normal limits, creatinine clearances >100 mL/min, and baseline platelet counts >100,000/uL. However, notable differences seen were the presence of brain metastases in the twice daily group. Conversely, the once daily group had more central venous catheters (CVC), and thrombogenic chemotherapy. None of these differences were statistically significant. The only statistically significant difference in the baseline characteristics was weight which was higher in the twice daily group. The incidence of recurrent PE was higher in the once daily than the twice daily group (8% vs. 4%). Subsequent management of recurrent PE for each group can be seen in Table 2. Following the recurrent episode, one patient in the once daily group discontinued chemical anticoagulation and received an inferior vena cava (IVC) filter, while another patient in the once daily group was kept on the same regimen with no documented changes. In the twice daily group, one patient discontinued anticoagulation per patient preference. One patient in the once daily group was taking concomitant thrombogenic chemotherapy (bevacizumab). The incidence of clinically overt, major bleeding events was 15% in the once daily group compared to 6% in the twice daily group. Two patients in the once daily group were taking concomitant COX-inhibitors and experienced a drop in hemoglobin of 2 g/dL, while one patient in the once daily taking a concomitant COX-inhibitor experience a new hemorrhagic brain lesion. Mortality at 6 months was more prevalent in the twice daily group than once daily group (13% vs. 6%) (Table 3).
Discussion Our study demonstrated that once daily enoxaparin was associated with increased recurrent PE when compared with twice daily enoxaparin in cancer patients. Regarding the primary objective, results seen for once daily versus twice daily enoxaparin were similar to those reported in the Merli trial subgroup analysis of
cancer patients (12.2% in once daily vs. 6.4% in twice daily). The primary and secondary objectives in this retrospective chart review are entirely collected and analyzed from cancer patients, differing from the patients analyzed in the trial conducted by Merli et al.4 Baseline characteristics of the once daily group may have influenced the increased trend of recurrent PE. Factors with the highest potential to increase recurrent PE were presence of CVCs and thrombogenic therapy. A higher percentage of patients in the once daily group had CVCs at the time of their initial PE compared to the twice daily group (56% vs. 46%). Also, more patients in the once daily group were on bevacizumab, an agent known to increase thromboembolic events, compared to the twice daily group (17% vs. 13%).8 It is also likely that the higher total daily dosage in the twice daily group (2 mg/kg/day vs. 1.5 mg/kg/day) could have resulted in a lower incidence of recurrent PE. Even though there is a lack of data to support benefits of the higher dosage, the current ACCP guidelines suggest the use of once daily dosing but only when the regimen uses the same total daily dose as the twice daily regimen; however, this dosing strategy is not routinely used in clinical practice (2 mg/kg/day).7 Regarding the secondary safety objectives, there was an increase in major bleeding events in the once daily group compared to the twice daily group. More patients in the once daily group were on concurrent aspirin during their PE treatment compared to the twice daily group (29% vs. 21%), which may have affected the results of the secondary objective. Patients in the twice daily group had a higher mortality at six months when compared to the once daily group (13% vs. 6%). These results are similar to those seen in the Merli subgroup analysis of cancer patients, where 0% of patients in the once daily group were documented as deceased within 6 months compared to 8.5% in the twice daily group. Baseline characteristics that may have influenced the increased mortality were the increased presence of brain metastases at baseline in the twice daily group, which has been shown to result in a poorer prognosis in many subsets of cancer.9 Due to the nature of the patient population, it is difficult to confirm PE as cause of mortality in a cancer patient. Many patients that present at our institution are often refractory to frontline treatments and are referred from outside facilities. Autopsies were not performed on any patients who passed away during this trial. There were limitations to this study. Patient data were collected retrospectively by a single party through chart review at single center. There is a reliance on accurate and complete documentation of patient events throughout the course of the study period. Many patients were excluded due to a lack of follow-up.
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Journal of Oncology Pharmacy Practice 0(0) Table 1. Patient demographics.
Age (years) Male sex, no. (%) Height (cm) Weight (kg) Primary cancer Solid tumor, no. (%) Breast Gastrointestinal Genitourinary Gynecology Head and neck Lung Melanoma Sarcoma Other Liquid tumor, no. (%)
Once daily group (n ¼ 48)
Twice daily group (n ¼ 48)
p-Value
62 35 170 80
60 26 171 91
(26–82) (54) (154–198) (56–130)
0.31 0.09 0.20 0.002
(90) (4) (25) (19) (8) (6) (19) (2) (2) (4) (10)
1.00 0.49 0.13 0.79 0.68 0.62 0.23 0.62 0.11 1.00 1.00
44 0 20 7 2 1 4 3 6 1 4
Pulmonary embolism characteristics Massive/Saddle Submassive
(25–88) (73) (150–187) (43–134) (92) (0) (42) (15) (4) (2) (8) (6) (13) (2) (8)
43 2 12 9 4 3 9 1 1 2 5
2 (4) 0 (0)
3 (6) 4 (8)
1.00 0.12
Baseline platelet count, no. (%) 20,000–49,000 50,000–99,000 >100,000
1 (2) 1 (2) 46 (96)
0 (0) 3 (6) 45 (94)
1.00 0.62 1.00
Baseline creatinine clearance, no. (%) 30–49 mL/min 50–99 mL/min >100 mL/min
4 (8) 14 (29) 30 (63)
0 (0) 12 (25) 36 (75)
0.12 0.81 0.27
Baseline aPTT, no. (%) 35.9 s Unknown
1 20 7 20
(2) (42) (15) (42)
1 30 7 10
(2) (63) (15) (21)
1.00 0.18 0.56
1 20 8 19 5 5 27 11
(2) (42) (17) (40) (10) (10) (56) (23)
2 25 11 10 8 5 22 11
(4) (52) (23) (21) (17) (10) (46) (23)
1.00 1.00 1.00 0.55 1.00 0.41 1.00
6 (13) 4 (8)
0.77 1.00
Baseline PT, no. (%) 15 s Unknown Brain metastases at baseline, no. (%) Spinal cord metastases at baseline, no. (%) Presence of CVC, no. (%) Hospitalization in past 30 days, no. (%) Thrombogenic chemotherapy, no. (%) Bevacizumab Hormonal agent
8 (17) 3 (6)
(continued)
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Table 1. Continued. Once daily group (n ¼ 48) Concomitant medications COX inhibitor NSAID P2Y12 inhibitor
14 (29) 1 (2) 1 (2)
Twice daily group (n ¼ 48) 10 (21) 1 (2) 1 (2)
p-Value 0.48 1.00 1.00
Age, gender, height, weight values are reported as median (range) unless otherwise specified. Characteristics of the pulmonary embolism (massive/saddle and submassive) were based on the radiology imaging reports. a PTT: activated partial thromboplastin time; PT: prothrombin time; CVC: central venous catheter; COX: cyclooxygenase; NSAID: nonsteroidal anti-inflammatory drug.
Table 2. Primary endpoint.
Recurrent PE per diagnostic imaging, no. (%) Increased strength of enoxaparin, no. (%) Change in frequency of enoxaparin, no. (%)
Once daily groupa (n ¼ 48)
Twice daily groupb (n ¼ 48)
4 (8)
2 (4)
1 (2)
0 (0)
1 (2)
1 (2)
a One patient in the once daily group discontinued chemical anticoagulation and received an inferior vena cava filter while another patient was kept on the same dose of anticoagulation with no documented changes. b One patient in the twice daily group discontinued anticoagulation per patient preference.
Table 3. Safety endpoints. Once daily Twice daily group (n ¼ 48) group (n ¼ 48) Clinically overt, major bleed, no. Drop in hemoglobin by 2 g/dL Retroperitoneal Intracranial Death within 6 months, no. (%)
(%) 6 (13)
2 (4)
0 (0) 1 (2) 3 (6)
1 (2) 0 (0) 6 (13)
a difference between groups; therefore, we can only hypothesize that there is a higher recurrence of PE with once daily administration of enoxaparin. It is difficult to conclude whether the choice of anticoagulation regimen was the primary factor for outcomes observed. Due to the retrospective nature of the trial, compliance was not able to be assessed and confounding variables cannot be excluded. Therefore, differences may exist among the patients analyzed regarding compliance and other causes may have been present, which could have influenced outcomes.
Conclusion The trend towards a higher recurrence of PE and more bleeding events in the once daily group may support the use of twice daily over once daily dosing of enoxaparin for acute PE in cancer patients. Large, prospective studies are needed to further evaluate superiority of twice daily enoxaparin in cancer patients. This study may provide a foundation for larger, randomized, controlled trials to determine whether once daily or twice daily dosing of enoxaparin should be the preferred PE treatment in cancer patients. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest Outcomes of these patients could potentially impact the trends observed in our study. As previously mentioned, patients who present to our institution are often refractory to many lines of treatment regimens, representing a population with an overall shorter survival compared to the general population. When assessing major bleeding, a drop in hemoglobin of 2 g/dL was used as one of the definitions. Since the entire follow-up period was assessed, gradual drops may have been related to chemotherapy or disease progression rather than bleeding complications. The trial was not powered to detect
None declared.
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