Safety and Efficacy of Low Molecular Weight Heparin Vs. Direct Oral Anticoagulants in Cancer-Associated Venous Thromboembolism

By Samar Minallah¹, Amer Rehman Farooqi¹, Kashif Sajjad¹, Zainab Shakeel¹, Manzoor Khan², Sajjad Ullah³

Affiliations

1. Department of Internal Medicine, Shaukat Khanum Memorial Cancer Hospital, Peshawar, Pakistan
2. Department of Medical Oncology, Shaukat Khanum Memorial Cancer Hospital, Peshawar, Pakistan
3. Department of Pharmacy, Shaukat Khanum Memorial Cancer Hospital, Peshawar, Pakistan

doi: 10.29271/jcpsp.2025.07.875

ABSTRACT
Objective: To compare the safety and efficacy of low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs) in treating venous thromboembolism (VTE) among cancer patients.
Study Design: Descriptive study.
Place and Duration of the Study: Department of General Medicine, Shaukat Khanum Memorial Cancer Hospital, Peshawar, Pakistan, from February to September 2023.
Methodology: This retrospective study included 150 cancer patients treated with either LMWH or DOACs for at least one month. The safety and efficacy were measured in terms of occurrences of major bleeding (assessed through International Society of Thrombosis and Haemostasis (ISTH) score) and recurrent VTE within six months.
Results: Among the 150 patients studied, 99 (66%) received LMWH, while 51 (34%) were treated with DOACs. The mean age in the LMWH group was 45.49 ± 13.48 years, compared to 54.00 ± 12.22 years in the DOAC group. Major bleeding events were more frequent 11 (11.1%) in the LMWH group than 3 (5.9%) in the DOAC group, though this difference was not statistically significant (p = 0.383). Recurrence rates of VTE were higher 8 (16%) in the DOAC group compared to the LMWH group 10 (10.1%), with no statistically significant difference (p = 0.300). The LMWH therapy was associated with a longer median treatment duration (170 days versus 166.5 days for DOACs; p = 0.290) and a statistically significant shorter hospital stay (0-25 days versus 0-30 days for LMWH; p = 0.038).
Conclusion: Both DOACs and LMWH are equally effective for managing VTE. DOACs offer relatively shorter treatment durations and hospital stays, though they have a slightly higher recurrence rate and comparable or lower major bleeding risk.

Key Words: Venous thromboembolism, Low molecular weight heparin, Direct oral anticoagulants, Cancer, Thrombosis.

INTRODUCTION

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major factor in morbidity and mortality among cancer patients. Those with cancer are six times more likely to develop VTE than individuals without cancer, primarily due to the prothrombotic effects of the cancer and the haemostatic changes induced by specific anticancer treatments. VTE is identified as the second leading cause of death in this patient population.^1,2
 

A meta-analysis included 2,245 patients, emphasising that recurrent cancer-associated VTE occurred in 6.7% of patients while on anticoagulation during 6 months.³ The recurrence is linked to a 52% rise in mortality risk, highlighting the substantial effect of recurrent VTE on survival rates among cancer patients.^4,5

The incidence of VTE is highest among patients with solid malignancies (78.6%), most commonly gastrointestinal (28.7%) and lung cancer (25.9%); in haematological cancer, Hodgkin lymphoma accounts for 42% of VTE cases.⁶ This risk can be further increased by systemic chemotherapy, cancer hormonal treatment, supportive measures, such as erythropoietin-stimu  lating medicines, and, more recently, anti-angiogenic and immunomodulatory medicines. Cancer- related thrombosis may interrupt cancer therapy, extend hospitalisation, and strain healthcare resources, making effective preventive an  d treatment strategies critical for reducing morbidity, mortality, and healthcare costs for cancer patients.⁷

VTE in cancer patients is linked to adverse outcomes such as increased recurrence, severe bleeding, and early death.⁸ A secondary analysis of the CANVAS trial was conducted which followed 671 patients with cancer and newly diagnosed VTE, providing valuable insight into the factors that increase these risks. The study concludes that patients with poor performance status, metastatic disease, those receiving Bevacizumab, or those presenting with deep vein thrombosis alone were more likely to experience recurrent VTE. Additionally, low albumin levels and metastatic disease were associated with a higher risk of major bleeding.⁹

A validated VTE risk score is utilised to identify high-risk ambulatory cancer patients for inclusion in the thromboprophylaxis studies.¹⁰ The low molecular weight heparin (LMWH) has traditionally been the preferred treatment for cancer-associated venous thromboembolism (CAVTE). However, factors such as patient preferences, the availability of oral anticoagulants, cost issues, and the potential for thrombocytopenia may make LMWH less suitable for some cancer patients with VTE. Managing VTE in cancer patients is especially challenging due to their increased risk of both bleeding complications and recurrent VTE.^11,5

Randomised controlled trials (RCTs) and meta-analyses have consistently shown that LMWHs significantly reduce VTE incidence in cancer patients. While DOACs were historically avoided due to limited cancer-specific evidence, recent studies have demonstrated that DOACs are more effective in preventing recurrent VTE. However, this increased efficacy comes with a higher risk of major bleeding compared to LMWHs.¹¹ Studies show that DOACs are particularly effective in preventing recurrent VTE within six months. However, their use is associated with a higher risk of major bleeding and a tendency toward increased clinically relevant non-major bleeding (CRNMB). Mortality rates between DOACs and LMWHs are comparable, with only small absolute risk differences (2-3%). These findings suggest that improved patient adherence to DOAC therapy could further enhance its effectiveness.¹² These findings have prompted updates to the clinical guidelines, including those from the American Society of Clinical Oncology (ASCO), which now recommend DOACs as a viable treatment option for managing VTE in cancer patients.¹²

Existing studies about safety and efficacy of DOACs compared to LMWH in high-risk cancer often focus on either efficacy or safety, with limited consideration of other critical factors such as treatment duration and hospital resource utilisation. This study aimed to address these gaps by retrospectively evaluating the safety and efficacy of LMWH versus DOACs in treating VTE among cancer patients.

METHODOLOGY

This was a retrospective descriptive study conducted at the Department of General Medicine, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Peshawar, Pakistan, including patients’ records from February to September 2023. Patients’ records were tracked through the Hospital Management Information System (HMIS). A total of 150 patients were identified during this period, with complete medical and follow-up records for up to six months.

The study included patients of either gender, aged 18 years and above, diagnosed with VTE, and treated with either LMWH or DOACs for at least one month, within one week of the diagnosis of VTE. Additionally, patients with a Khorana score of ≥2, indicating intermediate to high risk of thrombosis, were included. Patients were excluded if they had surgery, received anticoagulants for conditions other than VTE, had unrelated bleeding disorders, had prior anticoagulant therapy, had incomplete records, or were pregnant or non-compliant with treatment.

The International Society on Thrombosis and Haemostasis (ISTH) score was used to classify and assess bleeding events in this study. The ISTH bleeding assessment tool calculates the severity of bleeding based on several parameters, including a decrease in haemoglobin levels of ≥2 g/dL, the need for transfusion of ≥2 units of packed red blood cells, bleeding at critical anatomical sites (such as intracranial, intraspinal, intraocular, retroperitoneal, or pericardial locations), and bleeding that leads to death. If any of these criteria were met, the bleeding event was classified as major bleeding. Minor bleeding, which did not meet the major bleeding criteria, included visible bleeding that required medical attention, unscheduled physician visits, interruption or cessation of anticoagulation therapy, or bleeding that caused discomfort or impairment in daily activities. The study also examined the occurrence of major bleeding and recurrent VTE within six months. Recurrent VTE was identified as a new thrombotic event at a previously unaffected site or a recurrence at the original site, confirmed through imaging, such as the Doppler ultrasound or CT pulmonary angiography, within six months of initial treatment.

Patients included in the study were primarily undergoing chemotherapy, and the Khorana score was used to assess their baseline thrombotic risk. Thromboprophylaxis was administered in accordance with hospital protocols before the diagnosis of VTE for patients deemed at high risk. Creatinine clearance (CrCl) was calculated for all patients to assess renal function, and the doses of anticoagulants were adjusted accordingly for those with poor renal functions. Laboratory monitoring for LMWH was conducted using the anti-Xa activity levels, which measure the anticoagulant effect of LMWH by quantifying the inhibition of Factor Xa, a key enzyme in the coagulation cascade. Anti-Xa testing is performed when clinically indicated, particularly in patients with risk factors such as renal impairment, to ensure appropriate dosing. Differences in treatment duration between LMWH and DOACs were attributed to variations in patient-specific factors such as cancer type, stage, concurrent therapies, and clinical guidelines or physician preferences.

Ethical approval for the use of patient records was obtained from the Institutional Review Board (IRB) and the Ethical Committee of the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Peshawar, Pakistan. Informed consent was not obtained directly from the patients due to the retrospective nature of this study. All patient data were anonymised to ensure confidentiality and was handled in accordance with the hospital’s ethical standards and data protection policies. Data regarding the safety and efficacy of LMWH versus DOACs in treating VTE among cancer patients were collected from the patients' medical records. Eligible patients were identified based on the predefined inclusion criteria, and relevant data, including patient information, medical history, laboratory values, comorbidities, anticoagulation treatment details, and outcomes, were abstracted using a standardised form. The collected data were entered into an Excel sheet, with strict adherence to ethical considerations, including maintaining patients’ confidentiality.

For statistical analysis, the SPSS version 25 was used. Continuous variables such as age, BMI, haemoglobin levels, duration of anticoagulant therapy, and length of hospital stay were compared between the LMWH and DOAC groups using either an independent t-test or Mann-Whitney U test, after verifying the normality of the data using the Kolmogorov-Smirnov test. Categorical variables such as gender, platelet count, CrCl level, cancer type, stage, history of bleeding, history of VTE, ISTH score, type of VTE, anticoagulant started, occurrence of major bleeding, and recurrence of VTE were analysed using Chi-square tests. To control the baseline differences between the groups, binary logistic regression models included clinically relevant covariates. A p-value of ≤0.05 was considered statistically significant.

RESULTS

The study included a cohort of 150 patients diagnosed with VTE to evaluate the safety and efficacy of two anticoagulant treatments: LMWH and DOACs. The mean age of the patients was 48.49 ± 13.624 years, with ages ranging from 14 to 75 years. The gender distribution was nearly balanced, comprising 77 female patients (51%) and 73 male patients (48.7%). The mean body mass index (BMI) was 24.05 ± 6.13 kg/m², indicating that most participants were within the normal BMI range. The median duration of hospital stay was 0 days, with a minimum of 0 days and a maximum of 30 days. The median of 0 days showed that most of the patients were on home medication with zero hospital stay.

Table I: Baseline characteristics of the patients.
 

Baseline characteristics	LMWH n = 99 (66%)	DOAC n = 51 (34%)	p-value
Age (mean ± SD), years	45.49 ± 13.48	54.00 ± 12.22	<0.001
Gender (n, %)	-	-	0.863
Female	50 (50.5%)	27 (52.9%)	-
Male	49 (49.5%)	24 (47.1%)	-
BMI (mean ± SD) kg/m2	23.05 ± 5.98	26.01 ± 5.96	0.005
Crcl Levels (n, %) ml/min	-	-	-
Normal	24 (24.2%)	16 (31.4%)	0.646
Decrease	45 (45.5%)	21 (41.2%)	-
High	30 (30.3%)	14 (27.5%)	-
Haemoglobin (mean ± SD) g/dl	10.57 ± 2.14	11.64 ± 1.78	0.002
Platelet counts (n, %) ml	-	-	-
Normal	74 (74.7%)	38 (76.0%)	0.665
Thrombocytopenia	15 (15.2%)	9 (18.0%)	-
Thrombocytosis	10 (10.1%)	4 (6.0%)	-
Cancer types	-	-	-
Brain	2 (2.0%)	1 (2.0%)	0.003
Lung	6 (6.1%)	3 (5.9%)	-
Breast	12 (12.1%)	14 (27.5%)	-
Ovary	7 (7.1%)	0 (0.0%)	-
GI	37 (37.4%)	17 (33.3%)	-
Prostate	4 (4.0%)	9 (17.6%)	-
Others	31 (31.3%)	7 (13.7%)	-
Stages	-	-	-
I	5 (5.1%)	4 (8.2%)	0.173
II	19 (19.2%)	8 (16.3%)	-
III	42 (42.4%)	13 (26.5%)	-
IV	33 (33.3%)	24 (49%)	-
History of bleeding	-	-	-
Yes	27 (27.3%)	17 (33.3%)	0.454
History of VTE	-	-	-
Yes	15 (15.2%)	18 (35.3%)	0.007
ISTH scores	-	-	-
<5	99 (100%)	50 (98.0%)	0.340
≥5	0 (0.0%)	1 (2.0%)
Types of VTE	-	-	-
DVT	42 (42.4%)	16 (31.4%)	0.049
PE	11 (11.1%)	3 (5.9%)	-
DVT and PE	5 (5.1%)	9 (17.6%)	-
Others	41 (41.4%)	23 (45.1%)	-
Anticoagulant started	-	--	-
Same day	69 (69.7%)	21 (41.2%)	0.005
After 1 day	21 (21.2%)	23 (45.1%)	-
Within 1 week	8 (8.1%)	7 (13.7%)	-
Note: The p-value for age, BMI, and haemoglobin was determined by the independent sample t-test. The p-value for gender, creatinine clearance (CrCl) level, platelet count, cancer type, stage, history of bleeding, VTE, ISTH score, type of VTE, and anticoagulant started by the Chi-square test.

Table II: Safety and efficacy outcomes of anticoagulants.

Outcomes	LMWH n = 99 (66%)	DOAC n = 51 (34%)	p-value
Major Bleeding (n, %)	11 (11.1%)	3 (5.9%)	0.383
Recurrence (n, %)	10 (10.1%)	8 (16.0%)	0.300
Duration of anticoagulant used (median (IQR)) days	170 (90) days	166.5 (120) days	0.290
Length of hospital stay (median (IQR)) days	0 (3) days	0 (0)	0.038
Note: The p-value for major bleeding and recurrence between the two groups was calculated through Chi-square, whereas the p-value for the duration of anticoagulant use and length of hospital stay was calculated through the Mann-Whitney U test.

Table III: Binary logistic regression analysis.

Predictors	Dependent variable: Bleeding event			Dependent variable: Recurrence
	OR	95% CI	p-value	OR	95% CI	p-value
Gender (Female)	0.123	0.024–0.627	0.012	0.546	0.181–1.643	0.282
Age	0.97	0.924–1.019	0.227	0.959	0.918–1.002	0.061
BMI	0.92	0.808–1.047	0.208	1.089	0.986–1.203	0.092
CrCl	0.997	0.985–1.010	0.68	0.99	0.980–1.001	0.079
Haemoglobin	0.848	0.630–1.142	0.278	0.977	0.762–1.253	0.855
AC used (DOAC)	1.126	0.221–5.731	0.886	2.109	0.660–6.739	0.208

Patients who received DOACs were older and had substantially higher BMI and haemoglobin levels than those on LMWH (p <0.001, p = 0.005, and p = 0.002, respectively). The two groups also exhibited a significant difference in cancer type (p = 0.003), with breast and prostate cancers being more prevalent among those taking DOACs. The DOAC group had a significantly higher frequency of VTE (p = 0.007), and VTE type was also distinct, with a higher frequency of combined DVT and PE cases (p = 0.049). Furthermore, patients who were prescribed DOACs were less likely to initiate anticoagulation on the same day, suggesting a delay in treatment initiation (p = 0.005). There were no statistically significant differences between the groups in terms of other factors, including gender, kidney function, platelet count, cancer stage, haemorrhage history, and ISTH score (all p >0.05, Table I).

The safety and efficacy outcomes between patients receiving LMWH and those on DOACs showed no statistically significant differences in major bleeding (p = 0.383), recurrence of VTE (p = 0.300), or duration of anticoagulant use (p = 0.290), suggest-ing comparable profiles in these aspects. However, a significant difference was observed in the length of hospital stay, with patients on LMWH experiencing a slightly longer stay com-pared to those on DOACs (p = 0.038), indicating that DOACs may be associated with shorter hospitalisation (Table II).

The binary logistic regression analyses were performed to identify predictors of both major bleeding events and recurrence among patients receiving anticoagulation therapy. For major bleeding events, the overall model was statistically significant (χ² (6) = 16.202, p = .013). Among the predictors, female gender was significantly associated with reduced odds of major bleeding (OR = 0.123, 95% CI: 0.024-0.627, p = 0.012). No other variables, including age, BMI, creatinine clearance, haemoglobin, or type of anticoagulant, showed statistically significant associations.

For recurrence, the logistic regression model was not statistically significant (χ² (6) = 8.058, p = 0.234). None of the predictors reached statistical significance (Table III).

DISCUSSION

In this study, the safety and efficacy of LMWH were compared with DOACs within a cohort of cancer patients. The findings indicated that both LMWH and DOACs were effective in managing VTE, although significant differences were observed in patient characteristics, treatment duration, and safety outcomes.

The study findings diverge from the existing literature,^13-15 which showed that DOACs were more frequently prescribed to older cancer patients, potentially due to the convenience of oral administration compared to the subcutaneous route required for LMWH. In this study, the mean age of patients receiving DOACs was significantly higher than those receiving LMWH (54.00 ± 12.22 vs. 45.49 ± 13.48 years, p <0.001). This suggests that contrary to some studies, the preference for DOACs in older populations may be influenced by factors such as the ease of administration and patient preference, rather than aligning with the general trend observed in other research.

The efficacy of both anticoagulants was evaluated through recurrence rates, major bleeding in 6 months, and the duration of treatment. Recurrence rates were slightly higher in the DOAC group (8 out of 51 individuals, 16%) compared to the LMWH group (10 out of 99 patients, 10.1%), though this difference was not statistically significant (p = 0.300). Previous studies have shown similar trends. These results align with the findings of a study conducted by Pritchard et al. who demons-trated in their study that VTE recurrence was higher in the DOAC group (6, 18%) compared to the patients receiving LMWH (11, 12%). This suggests that while DOACs provide an effective alternative to LMWH, particularly for longer treatment durations, their efficacy in preventing recurrence might be slightly lower in certain cancer populations.

The safety profiles of the two treatments were a key focus of this study and found that major bleeding events were more common in the LMWH group (11 out of 99 patients, 11.1%) compared to the DOAC group (3 out of 51, 5.9%), though this difference was not statistically significant (p = 0.383). These results are consistent with other research, which suggests that LMWH, particularly in high-risk cancer patients, is linked to a higher risk of major bleeding. In contrast, DOACs have generally been associated with fewer major bleeding compli-cations.^5,16 However, the absence of statistically significant differences makes the two modalities approximately equally effective.¹⁷ The non-significant results may reflect limitations in sample size or reporting accuracy. One possible explanation for the lower bleeding risk observed in the DOAC cohort could be the careful patient selection based on renal function and platelet count, which might have minimised the risk in this population. Renal function and platelet counts were closely monitored, with more DOAC patients having normal CrCl and platelet counts compared to the LMWH group. These factors likely contributed to the safer bleeding profile observed in the DOAC cohort.

A multivariate analysis conducted in this study found that female cancer patients were significantly less likely to experience major bleeding while on the anticoagulant therapy, highlighting gender as an important factor in treatment decisions. This supports findings from the TESEO Registry, which showed that men had nearly twice as many major bleedings as women.¹⁸ While reasons for this difference may include hormones, body size, or how medicines are processed in the body, it underscores the need to consider gender when managing bleeding risk. Other factors such as age, BMI, kidney function, and haemoglobin levels were not strongly linked to bleeding or recurrence, although some showed borderline significance. Overall, these results suggest that no single factor can predict outcomes with certainty, and a more personalised approach to treatment is needed for cancer patients on anticoagulants.

In this study, the median duration of anticoagulant therapy was slightly shorter for the DOAC group (median = 166.5 days) compared to the LMWH group (median = 170 days). However, when the authors examined the minimum and maximum durations of anticoagulant use in both groups, they noted that the LMWH group had an interquartile range (IQR) of 90 days, with a minimum of 6 days and a maximum of 574 days, while the DOAC group had an IQR of 120 days, with a minimum of 22 days and a maximum of 630 days. Although the difference was statistically insignificant, this slightly extended the treatment period for DOACs aligns with their growing acceptance as a long-term therapeutic option for CAVTE, as recommended by the guidelines from organisations such as ASCO.^12,19,20 The guideline also emphasises the importance of considering patient-specific and ease of administration when selecting an anticoagulant, which was reflected in the older average age of the DOAC group in this study.¹²

The shorter length of hospital stays in the DOAC group (median = 0 days, IQR = 0), with (min = 0, max = 25) days compared to the LMWH group (median = 0 days, IQR = 3), with (min = 0, max = 30) days, and a statistically significant difference (p = 0.038), further underscores the potential benefits of DOACs in reducing healthcare burden, likely due to their oral route of administration and lower need for monitoring.

This study is limited by its retrospective design, introducing biases such as selection bias from relying on existing medical records with potentially inconsistent data. Baseline differences between the LMWH and DOAC groups, such as age, cancer type, and renal function, were not fully cont-rolled, leading to residual confounding that influenced the outcomes, however, multivariate logistic regression tech-nique was used to mitigate these biases.

Variations in the treatment protocols and clinician discretion further limit the generalisability. The inability to control all confounding factors, such as cancer severity and comorbidities, and the short follow-up period of six months restricted the evaluation of long-term outcomes. Additionally, the small sample size reduced the statistical power to detect significant differences between LMWH and DOACs.

Future research should involve larger cohorts and RCTs to minimise bias and provide stronger evidence. It should also explore different anticoagulant regimens based on cancer type, renal function, and personalised dosing strategies, using advanced statistical techniques to control for the baseline differences. Longer follow-up periods are needed to assess the full safety and efficacy profiles of LMWH and DOACs in cancer patients.

CONCLUSION

This study demonstrated that both therapies are effective for cancer-associated VTE, however, DOACs offer practical advantages such as shorter treatment duration and reduced hospital stay compared, potentially due to their oral administration and outpatient management flexibility, which may contribute to more efficient treatment delivery. They also showed a slightly higher recurrence rate of VTE while main-taining a comparable or lower incidence of major bleeding. Despite these observations, the differences in efficacy and safety between DOACs and LMWH were not statistically significant.

ETHICAL  APPROVAL:
This study was conducted after obtaining ethical approval from the Institutional Review Board of Shoukat Khanam Memorial Hospital, Peshawar, Pakistan (Approval. No: Ex-05- 01-23-02).

PATIENTS’ CONSENT:
Informed consent was not obtained directly from the patients due to the retrospective nature of this study.

COMPETING INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
SM: Conceptualisation, design of the study, data arrangement, and drafting of the manuscript.
ARF: Data collection and ethical clearance.
KS: Supervision of the project, conception, and design of the study and critical revision of the manuscript.
ZS: Data analysis and interpretation of radiological aspects of the data.
MK: Analysis, interpretation of the statistical aspects of the data, and drafting of the manuscript.
SU: Acquisition of the data.
All authors approved the final version of the manuscript to be published.

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