A retrospective assessment of venous recanalization outcomes for oral anticoagulant treatment in deep vein thrombosis

Abstract

Objective

This study aims to provide effective treatment by comparing the venous recanalization responses of oral anticoagulants in deep vein thrombosis therapy.

Methods

From January 2013 to March 2019, a retrospective analysis was conducted on 109 patients who had been diagnosed with deep vein thrombosis and received treatment with apixaban, rivaroxaban, or warfarin within 1 week of symptom onset. Demographic, clinical data, and venous recanalization responses on Doppler ultrasonography of the patients that were followed-up 1 year from the date of diagnosis were evaluated.

Results

At the end of the 1-year follow-up, 21 (19.3%) patients had delayed recanalization, 39 (35.8%) patients had partial recanalization, and 49 (44.9%) patients had complete recanalization. The mean time to complete recanalization was 9.178 months for apixaban, 8.986 months for rivaroxaban, and 10.641 months for warfarin. Rivaroxaban was found to result in earlier completion of recanalization compared to warfarin (p = .012).

Conclusion

Direct oral anticoagulants might be more effective than vitamin K antagonists in achieving complete recanalization in patients that have deep vein thrombosis. Improving outcomes can be achieved by evaluating current treatment options.

Keywords

Venous thrombosis anticoagulants factor Xa inhibitors

Introduction

The most frequent cause of venous thromboembolism (VTE) is deep vein thrombosis (DVT). DVT is the primary cause of life-threatening pulmonary embolism (PE) in the acute phase and post-thrombotic syndrome (PTS), which results in permanent damage to the lower extremities during the chronic phase.¹ Despite medical treatment, the recurrence rate of VTE within 5 years in patients with proximal DVT is 26.4%, and the incidence of PE is 3.6%.² PTS occurs in 30%–50% of patients.³

Factors that stimulate new thrombus development and factors that restore the venous lumen determine the course of DVT. Recanalization is the restoration of the venous lumen, which includes fibrinolysis, thrombus organization, remodeling, and neovascularization.⁴ The thrombus adheres to the vessel wall; the local inflammatory response of the vessel wall initiates thrombus organization; and endogenous fibrinolysis of areas within the thrombus leads to recanalization.⁵ The process of thrombolysis and recanalization following acute DVT can take several months or years.⁶ This process may provide a complete return of the impaired phasic flow of the venous segment in some patients, while it may be insufficient in others. Residual thrombus and venous wall damage after DVT are risk factors for recurrent DVT. Moreover, patients with residual thrombus have higher mortality rates.⁷ Therefore, early and complete recanalization may lead to fewer complications in patients.

Heparin, fondaparinux, and vitamin K antagonist (VKA) are commonly used drugs for DVT treatment. However, due to their interactions with many other medications and the need for frequent monitoring and dosage adjustment, direct oral anticoagulants (DOACs) have become increasingly used in recent years. These include direct thrombin inhibitors (DTI) and factor Xa inhibitors. The predictability of the effect, no need for monitoring or dose adjustments, and minimal interactions with other drugs make factor Xa inhibitors and oral direct thrombin inhibitors preferred options in treatment.⁸

In this study, venous Doppler ultrasound data were retrospectively evaluated during 1-year follow-ups of patients diagnosed with acute DVT and prescribed warfarin, apixaban, or rivaroxaban therapy. The purpose of this study was to compare the time and efficacy of venous recanalization between warfarin and direct oral anticoagulants. It is aimed to improve the outcomes by determining the correct and appropriate options for the treatment of DVT.

Materials and method

The data of 1053 patients first evaluated with a deep vein thrombosis (DVT) diagnosis at the Trakya University Faculty of Medicine Hospital between January 2013 and March 2018 were reviewed through the hospital automation system. 353 patients who presented within 1 week of the onset of their complaints and were diagnosed with deep vein thrombosis by detecting venous thrombosis on lower extremity Doppler ultrasound (DUSG) were identified. At the time of diagnosis, patients under 18 years old, pregnant patients, oncology patients receiving active chemotherapy or radiotherapy, and patients with primary hematological diseases were not compromised in the study. After applying exclusion criteria, the study included 109 patients evaluated between January 2013 and March 2019 who underwent at least two or more DUSG and biochemical examinations during a 1-year follow-up period and received apixaban, rivaroxaban, or warfarin treatment.

Deep vein thrombosis patients were assessed for age, gender, diabetes, coronary artery disease (CAD), hypertension (HT), history of cerebrovascular disease (CVD), surgical history, and pulmonary embolism (PE). The patients’ oral anticoagulant drug (apixaban, rivaroxaban, or warfarin) treatment applied for DVT treatment and the response of recanalization and thrombus burden in the Doppler ultrasound examinations during follow-up were examined. Patients’ venous thromboembolism (VTE) recurrence and venous recanalization status were evaluated during the 1-year follow-up period since the acute DVT diagnosis.

The localization of venous thrombosis in the lower extremity Doppler ultrasound reports were evaluated in three groups according to the LET (lower extremity thrombosis) classification proposed by Arnoldussen et al.⁹: iliofemoral (LET class III), femoropopliteal (LET class II), and calf veins (LET class I). In our study, no inferior vena cava thrombosis (LET class IV) was detected according to the ultrasound results. Venous recanalization statuses were evaluated based on the lower extremity venous Doppler ultrasound reports during follow-up, as in the studies by Jezovnik et al.⁶ and Zhang et al.¹⁰ The recanalization responses were examined based on the DUSG results applied to the patients at 1, 3, 6, and 12 months. Delayed recanalization (complete occlusion) was defined as the absence of a Doppler signal in the vein; partial recanalization was described as a venous segment with decreased Doppler signal and partially compressible; complete recanalization was defined as the complete dissolution of the thrombus, allowing full compression of the vessel. All patients were evaluated in two groups, those with recanalization and those with complete recanalization, based on the month when the responses were first seen in the DUSG reports during the follow-up period. The recanalization group consisted of those with partial or complete recanalization responses, and the complete recanalization group consisted of those with complete recanalization responses in DUSG. The venous thrombus burden of the patients was examined by modifying the thrombus score proposal in Porter et al.’s study,¹¹ similar to Ramshorst et al.’s study.⁵ The lower extremity tibial-soleal veins, popliteal veins, common femoral or superficial femoral veins, iliac veins, and caval veins were each scored according to the status of the thrombus in the ultrasound report. A patent vein was scored 0 points, a vein with a thrombus but without occlusion was given 1 point, and a vein with total occluded by thrombus was given 2 points. Thus, the thrombus burden score was considered as a maximum score of 10 for each limb.

Following the acute DVT diagnosis, 44 patients in our study received apixaban 5 mg twice daily; 39 patients received rivaroxaban 20 mg once daily. In 26 patients, low molecular weight heparin (LMWH) was administered as a bridging therapy for the first 5–7 days, followed by long-term treatment with warfarin. The warfarin dose in these patients was adjusted with a target international normalized ratio (INR) value of 2 to 3. All patients received anticoagulant treatment for at least 6 months. In addition, seven patients who developed venous thromboembolism recurrence during anticoagulant treatment received extended anticoagulant treatment. Patients followed-up for 1 year were divided into three groups according to the received treatment: apixaban, rivaroxaban, and warfarin.

Statistical analysis

The total sample size was estimated at least 78 patients, considering the means of recanalization times for the treatment groups, with a standard deviation of 0.63, a power of 0.8, and an alpha level of 0.05, using the G*Power software (ver. 3.1.9.7; Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany).¹²

For the analysis of the data, the SPSS v.22 (IBM Corp., Armonk, NY, USA) package program was used. Pearson chi-square test was used to evaluate the significance level of patient groups, recanalization responses, and thrombus localizations; ANOVA test was used to evaluate the significance level of mean value distributions. Since survival analyses can be performed on paired groups, recanalization responses were divided into pairs and analyzed as recanalized and complete recanalized patients. Kaplan–Meier survival analysis was applied to examine the effects of the drugs on recanalization in the followed-up patients, considering the time of first recanalization and complete recanalization development. Data were evaluated with Log Rank (Mantel-Cox), Tarone-Ware, and Breslow (Generalized Wilcoxon) chi-square tests.

Results

A total of 109 patients, 44 using apixaban, 39 using rivaroxaban, and 26 using warfarin, were examined in their follow-up. Of all patients included in the study, 10% (11 patients) also had acute PE at the time of diagnosis of acute DVT. The distribution of patient groups is given in Table 1. During a 1-year follow-up of patients, delayed revascularization was observed in 21 (19.3%) patients, partial revascularization in 39 (35.7%) patients, and complete revascularization in 49 (44.9%) patients. During the 1-year follow-up of the patients, VTE recurrence was evaluated by considering both PE and DVT recurrences together. Recurrence of venous thromboembolism (VTE) was reported in 7 (6.42%) patients. Deep vein thrombosis (DVT) was detected in both legs of 3 (2.7%) patients. No major bleeding events were encountered. The mean INR value of patients in the warfarin group was calculated as 2.5391 (± 0.7005), with a 95% confidence interval of 2.2561–2.8221. According to the ANOVA test, there was no significant difference (p = .145 > 0.05) in the mean INR values of patients in the warfarin group based on their recanalization status during the treatment period (Table 2).

Table 1.

Distribution of patient groups.

Variable	Groups	Apixaban	Rivaroxaban	Warfarin	Total	p
Sex	Male	27	24	17	68	0.937
Sex	Female	17	15	9	41
Age	Mean ± SD	57.59 (±17.235)	60.18 (±15.254)	48.42 (±16.386)	56.33 (±16.833)	0.017
HT	Yes	11	9	4	24	0.631
HT	No	33	30	22	85
CAD	Yes	3	3	2	8	0.985
CAD	No	41	36	24	101
DM	Yes	5	7	1	13	0.226
DM	No	39	32	25	96
CVD	Yes	1	2	2	5	0.566
CVD	No	43	37	24	104
DVT + PE	Yes	1	7	3	11	0.058
DVT + PE	No	43	32	23	98
Surgical history	Yes	6	5	3	14	0.968
Surgical history	No	38	34	23	95

HT: Hypertension, CAD: Coronary artery disease, DM: Diabetes mellitus, CVD: Cerebrovascular disease, DVT + PE: Pulmonary embolism accompanying deep vein thrombosis, SD: Standard deviation, p: Significance level (Pearson chi-square test).

Table 2.

Distribution of INR values of patients taking warfarin according to their recanalization status at the end of 1 year.

Recanalization groups	Number of patients	Average INR	Standard deviation	95% confidence interval
Recanalization groups	Number of patients	Average INR	Standard deviation	Lower	Upper
Delayed recanalization	4	3.0363	0.26961	2.6072	3.4653
Partial recanalization	14	2.3112	0.84078	1.8257	2.7966
Complete recanalization	8	2.6894	0.37139	2.3789	2.9999
Sum	26	2.5391	0.70057	2.2561	2.8221

ANOVA test, p: 0.145 > 0.05.

52 iliofemoral, 47 femoropopliteal, and 10 calf venous segment localization DVT patients were studied. The distribution of DVT localization by drug groups was not statistically significant according to the Pearson chi-square test (p = .182 > 0.05) (Table 3). The initial thrombus burden was calculated as 3.5 (±2.454), with a 95% confidence interval of 2.75–4.25 in the apixaban group, 3.33 (±1.991), with a 95% confidence interval of 2.69–3.98 in the rivaroxaban group, and 4.54 (±2.302), with a 95% confidence interval of 3.61–5.47 in the warfarin group. According to the ANOVA test, there was no statistically significant difference (p = .089 > 0.05) in thrombus burden among patients based on their drug groups.

Table 3.

Distribution of DVT localization by drug groups.

Drug groups	Calf	Femoropopliteal	Iliofemoral	Sum
Apixaban	6	20	18	44
Rivaroxaban	4	18	17	39
Warfarin	0	9	17	26
Sum	10	47	52	109

According to Pearson chi-square test: 0.182 > 0.05.

Complete recanalization responses were observed in 20 patients (45.5%) in the apixaban group, 21 patients (53.9%) in the rivaroxaban group, and 8 (30.8%) patients in the warfarin group at the end of the 1-year follow-up. There was no statistically significant difference in recanalization responses among drug groups (p = .227 > 0.05) (Table 4). All patients were evaluated in two groups: patients with or without recanalization and patients with or without complete recanalization, based on the first response times in the DUSG reports so that survival analyzes could be applied. In the Kaplan–Meier survival analysis applied to the patients with recanalization, taking into account the 1-year follow-up period according to the drug groups, recanalization development time, mean 5.533 ± 0.667 months in the apixaban group, recanalization development interval with 95% probability was 4.224–6.841 months; mean 5.652 ± 0.711 months in the rivaroxaban group, recanalization development interval with 95% probability was 4.258–7.045 months; and mean 6.115 ± 0.958 months in the warfarin group, recanalization development interval with 95% probability was 4.239–7.992 months (Figure 1, Table 5). No statistically significant relationship between recanalization times according to drug groups was found using Log Rank (Mantel-Cox) test (p = .835 > 0.05).

Table 4.

Distribution of recanalization responses by drug groups.

Drug groups	Delayed recanalization		Partial recanalization		Full recanalization		Sum
Drug groups	Number of patients, %		Number of patients, %		Number of patients, %		Number of patients, %
Apixaban	9	20.5	15	34.0	20	45.5	44	100
Rivaroxaban	8	20.5	10	25.6	21	53.9	39	100
Warfarin	4	15.4	14	53.8	8	30.8	26	100
All	21	19.3	39	35.8	49	44.9	109	100

According to Pearson chi-square test: 0.227 > 0.05.

Figure 1.

Kaplan–Meier survival analysis for recanalization time and probability of drug groups.

Table 5.

Recanalization and complete recanalization times by drug groups.

	Recanalization time (months)				Complete recanalization time (months)
Drug groups	Average		95% confidence interval		Average		95% confidence interval
Drug groups	Mean	Standard deviation	Lower	Upper	Mean	Standard deviation	Lower	Upper
Apixaban	5.533	0.667	4.224	6.841	9.178	0.674	7.856	10.500
Rivaroxaban	5.652	0.711	4.258	7.045	8.986	0.741	7.534	10.439
Warfarin	6.115	0.958	4.239	7.992	10.641	0.668	9.331	11.950
Sum	5.732	0.433	4.884	6.58	9.462	0.408	8.661	10.263

In the Kaplan–Meier survival analysis applied to the patients with complete recanalization, taking into account the 1-year follow-up period according to the drug groups, complete recanalization development time, mean 9.178 ± 0.674 months in the apixaban group, complete recanalization development interval with 95% probability was 7.856–10.500 months; mean 8.986 ± 0.741 months in the rivaroxaban group, complete recanalization development interval with 95% probability was 7.534–10.439 months; and mean 10.641 ± 0.668 months in the warfarin group, complete recanalization development interval with 95% probability was 9.318–11.964 months (Figure 2, Table 5). A significant difference between the complete recanalization times according to the drug groups was found using the Pearson chi-square test (p = .040 < 0.05). Since a statistically significant relationship was found between the complete recanalization times according to the drug groups, the drug groups were tested with paired comparison tests. According to Log Rank (Mantel-Cox) test, a significant difference was found between the complete recanalization times of rivaroxaban and warfarin drug groups (p = .012 < 0.05).

Figure 2.

Kaplan–Meier survival analysis for complete recanalization time and probability of drug groups.

ANOVA test revealed a significant difference between the mean age of the patients and the drug groups with a probability of 95% (p = .017) (Table 4). In the Bonferroni multiple comparison test, there was no statistically significant difference between the age distribution of the patients in the apixaban with rivaroxaban (p = 1) and the apixaban with warfarin groups (p = .076). In contrast, a significant difference was found between the age distribution of the patients in the rivaroxaban with warfarin groups (p = .016). Since the Bonferroni multiple comparison test found a significant difference between the age distributions of the patients and the drug groups, the Cox regression test was applied to evaluate whether the age difference between the drug groups affected the statistical results in the Kaplan–Meier survival analysis. In the Cox regression test, the effect of the age of the patients in the drug groups on recanalization Exp (B) = 1.001; p = .834; 95% CI and effect on complete recanalization Exp (B) = 1.002; p = .779; 95% CI, it was found that there was no statistically significant difference.

Discussion

It is partially possible to evaluate whether drugs are effective or not. In our study, patients using warfarin were followed-up primarily with INR values. It was observed that the INR values measured in all recanalization groups using warfarin were in the effective range. However, patients taking warfarin may remain outside the therapeutic range for an average of one-third of the treatment time.¹³ Anticoagulation that has not achieved a therapeutic effect causes continued thrombin production so that clotting is not restricted, clot lysis is reduced, and venous wall damage occurs.¹⁴ Therefore, it is thought that warfarin has a narrow therapeutic range. Furthermore, the antithrombotic effect of DOACs are more stable, resulting in faster recanalization.¹⁵ In addition, rivaroxaban stimulates fibrinolysis with its anti-inflammatory effect, leading to a more efficient recanalization since inflammation induces coagulation and inhibits endogenous fibrinolysis.¹⁴ Apixaban and rivaroxaban have been shown to increase fibrinolysis by activating the tissue plasminogen activator (t-PA) cofactor function of FXaβ in plasma.¹⁶ It has been shown that patients treated with apixaban exhibit a better fibrinolysis profile than those taking warfarin or aspirin.¹⁷ In addition, apixaban has been shown to have an anti-inflammatory effect by reducing the production of free radicals in an in vitro ischemic stress model.¹⁸ It has also been shown that rivaroxaban provides central venous catheter patency by reducing cell proliferation and inflammation in the mouse model.¹⁹

Prandoni et al.¹⁵ reported that the rate of residual thrombus detected by ultrasonography was 54.5% in patients receiving warfarin and 21.1% in those receiving DOACs when 6 months of anticoagulant therapy was administered to patients with proximal DVT. Soares et al.²⁰ calculated the rates of complete venous recanalization in patients with acute DVT after 1 year of follow-up as 40.5% in all patients, 76.1% in patients using rivaroxaban, and 13.2% in patients using warfarin. Residual thrombus in acute DVT increases the incidence of venous reflux.²¹ Early resolution of thrombus in the vein helps to maintain venous valve integrity.²² Damage to venous valves and increased venous pressure due to chronic venous occlusion are the underlying causes of post-thrombotic syndrome (PTS) development.²³ Failure to complete recanalization after DVT increases the risk of PTS.^24,25 In the study by Jeraj et al.,¹⁴ PTS was 25% in patients treated with rivaroxaban and 49% in those treated with warfarin.

In this study, when the patients were grouped according to the drugs they used (apixaban, rivaroxaban, or warfarin), there was no significant difference between the first recanalization times in venous Doppler USG reports. As the initiation of recanalization is a natural response to occlusion of the venous lumen, the initial partial recanalization times reported in the DUSG can be expected to be similar across drug groups. Recanalization started at the same time for all three drugs; however, it was determined that there was a significant difference between the time to complete recanalization. The calculated mean time to complete recanalization was 9.178 months for apixaban, 8.986 months for rivaroxaban, and 10.641 months for warfarin. There was no significant difference between patients using apixaban with rivaroxaban and warfarin, but patients using rivaroxaban had earlier complete recanalization than patients using warfarin. It was observed that the initiation time of recanalization was not dependent on the drug used, and the completion time of recanalization occurred earlier in DOACs than in VKAs. This may be because VKAs are more difficult to stay within therapeutic limits than DOACs^13,15 and DOACs stimulate fibrinolysis.^14,16,17,19

Conclusion

In our study, in the 1-year follow-up of patients using apixaban, rivaroxaban, and warfarin, there was no significant difference between the first recanalization development time observed in DUSG; however, there was a significant difference in the development time of complete recanalization between patients using rivaroxaban and warfarin. It was determined that complete recanalization was earlier in patients using rivaroxaban compared to patients using warfarin.

Study limitations

Patients with DVT diagnosed with PE were included in our study; however, patients with PE were not included by actively screening.

Footnotes

Author contributions

This article is extracted from the first author’s medical specialization thesis entitled “Evaluation of the Efficiency of Novel Oral Anticoagulants and Warfarin in Deep Vein Thrombosis with Simple Blood Parameters” supervised by Canbaz, S (Trakya University, Edirne, Turkey, 2020).

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical statement

ORCID iD

Anil Guzel

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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