1 INTRODUCTION

Cancer induces inflammation and coagulopathy that may result in subsequent venous thromboembolism (VTE) and atrial fibrillation (AF), necessitating the initiation of anticoagulation treatment.^1-4 Non-vitamin K antagonist oral anticoagulants (NOACs), including direct thrombin inhibitor dabigatran and factor Xa inhibitors, are increasingly used in patients with VTE or AF because of their favorable efficacy and safety, replacing traditional vitamin K antagonist (VKA) in the general population wherein there are a small proportion of cancer patients.^5-12 Currently, low-molecular-weight heparins (LMWHs) are the treatment of choice for VTE in cancer patients.^13-16 Because it is not inferior to subcutaneous dalteparin and has no increased risk of major bleeding, the 2021 National Comprehensive Cancer Network guideline incorporated apixaban as a treatment of cancer-associated VTE.¹⁷

It has been debated that anticoagulants have potential anti-cancer actions and could affect survival in patients. Whether different NOACs affect survival and safety in cancer patients is essentially unknown.^18-20 Therefore, we investigated the impact on cancer survival in dabigatran or rivaroxaban-treated patients.

2 METHODS

The Nation Health Institute (NHI) was launched by the national health and welfare administration in 1995 to offer medical insurance to more than 99% of the 23.8 population in Taiwan. The NHI has extensive reimbursements, including hospital admissions, emergency room visits, surgeries, medical exams, and pharmaceutical prescriptions. The Taiwan Cancer Registry (TCR) database has information on cancer sites, histology, diagnosis date, and initial stage from 1979. The Taiwan Death Registry (TDR) has information on the cause of death and the location of the occurrence dated since 1971. De-identified medical and health information can be obtained through the International Classification of Diseases (ICD), Ninth or Tenth Revision, Clinical Modification (ICD-9-CM or ICD-10-CM) linked with the NHI, TCR, and TDR databases. These sources can provide analyzable data through which research can be conducted and informed consent is waived. The current study is approved by the Institutional Review Board (IRB) at Chang Gung Memorial Hospital, Chiayi Branch (IRB No. 201901482B1).

3 RESULTS

There were 202,754 patients who received anticoagulation therapy between 2011 and 2016. Patients who took apixaban and edoxaban were excluded due to the short follow-up period (apixaban, median: 8.8 ± 6.6 months) and small numbers (edoxaban, N = 287), which were insufficient for matching and outcome analysis. There were 3591 patients with active cancer eligible for analysis. Of these, 907 patients took dabigatran (approved in Taiwan on June 1, 2012) and 2684 patients took rivaroxaban (approved on February 1, 2013) (Figure 1). Before IPTW, most dabigatran prescriptions were for patients with coexisting AF or atrial flutter (81%), whereas those for rivaroxaban were for patients with coexisting VTE (61.3%). Compared with patients prescribed rivaroxaban, patients prescribed dabigatran were older (76.0 ± 9.0 vs. 69.7 ± 12.8 y) and had a higher prevalence of comorbidities, such as hypertension (80.9% vs. 62%), ischemic heart disease (32.6% vs. 22.2%), and heart failure (22.1% vs. 12.1%) (Table 1).

Regarding cancer types, dabigatran was prescribed mainly to patients with colorectal (24.3% vs. 17.8%) and male genital cancer (20.2% vs. 10.1%). In contrast, most rivaroxaban was prescribed to patients with lung cancer (13.1% vs. 19.3%) and female genital cancer (2.2% vs. 7.6%). Compared with rivaroxaban, angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) (58.5% vs. 43.3%), calcium channel blockers (38.5% vs. 31.9%), beta-blockers (58.7% vs. 38.7%), and digoxin (22.8 vs. 9.9%) were more commonly prescribed to the dabigatran group. After matching with IPTW, the covariates were similar between the groups with absolute STD values <0.2 (Table 1).

3.1 Cancer-related death and all-cause mortality

During the entire observation period, there was a significantly lower risk of cancer-related death in patients who received dabigatran than those who took rivaroxaban (27.7% vs. 33.6%; hazard ratio [HR] = 0.79, 95% confidence interval [CI] = 0.64–0.98; p = 0.029) (Table 2, Figure 2A). This observed effect on cancer-related death was consistent across cancer stages (P for interaction =0.305; Table S3). The specific types of cancer with dabigatran-associated lower cancer-related death were colorectal (HR = 0.61, 95% CI = 0.41–0.90; p = 0.014), breast (HR = 0.43, 95% CI = 0.20–0.93; p = 0.033), male genital organ (HR = 0.54, 95% CI = 0.32–0.91; p = 0.020), and urinary tract cancers (HR = 0.45, 95% CI = 0.22–0.94; p = 0.034) (Table S4). Subgroup analysis showed that the observed effect was consistent in all variables, except hypertension (P for interaction =0.024; Figure 3A).

TABLE 2. Follow-up outcomes of patients under dabigatran and rivaroxaban treatment after IPTW-adjusted

Follow up length/Outcome	Event rate		Dabigatran vs. Rivaroxaban
	Dabigatran	Rivaroxaban	HR (95% CI)a	p value
3 months follow-up
Cancer related death	7.7%	12.2%	0.61 (0.36–1.02)	0.059
Secondary outcomes
All-cause mortality	8.9%	13.7%	0.63 (0.40–0.99)	0.048
Major bleeding	1.1%	3.9%	0.28 (0.14–0.57)	<0.001
Gastrointestinal bleeding	0.7%	2.9%	0.25 (0.11–0.56)	<0.001
6 months follow-up
Cancer related death	12.8%	19.2%	0.66 (0.45–0.96)	0.028
Secondary outcomes
All-cause mortality	14.5%	21.5%	0.66 (0.47–0.93)	0.018
Major bleeding	2.5%	5.5%	0.45 (0.25–0.81)	0.008
Gastrointestinal bleeding	1.7%	4.2%	0.40 (0.19–0.85)	0.017
9 months follow-up
Cancer related death	16.6%	23.4%	0.70 (0.52–0.95)	0.023
Secondary outcomes
All-cause mortality	18.5%	26.3%	0.70 (0.53–0.92)	0.011
Major bleeding	2.7%	6.1%	0.45 (0.26–0.77)	0.004
Gastrointestinal bleeding	1.7%	4.6%	0.38 (0.19–0.78)	0.009
1-year follow-up
Cancer related death	19.4%	26.9%	0.71 (0.54–0.93)	0.012
Secondary outcomes
All-cause mortality	21.5%	30.2%	0.70 (0.54–0.90)	0.005
Major bleeding	3.5%	6.7%	0.53 (0.33–0.83)	0.006
Gastrointestinal bleeding	2.3%	5.1%	0.46 (0.26–0.83)	0.009
At the end of the follow-up
Cancer related death	27.7%	33.6%	0.79 (0.64–0.98)	0.029
Secondary outcomes
All-cause mortality	32.9%	39.1%	0.81 (0.67–0.97)	0.023
Major bleeding	6.2%	9.6%	0.64 (0.47–0.88)	0.006
Gastrointestinal bleeding	4.3%	7.5%	0.57 (0.39–0.84)	0.004

• Abbreviations: CI, confidence interval; HR, hazard ratio; IPTW, inverse probability of treatment weighting.
• ^a Estimated using the subdistribution hazard model which considered all-cause death as a competing risk.

Regarding all-cause mortality, there was also a significantly lower risk in patients with dabigatran compared to that of patients with rivaroxaban (32.9% vs. 39.1%; HR = 0.81, 95% CI = 0.67–0.97; p = 0.023) (Table 2, Figure 2B). This observed effect on all-cause mortality was consistent across cancer stages (P for interaction =0.425; Table S3). The specific types of cancer that had seemed to have lower cancer-related death associated with dabigatran uses were colorectal (HR = 0.64, 95% CI = 0.45–0.92; p = 0.014), male genital (HR = 0.60, 95% CI = 0.40–0.92; p = 0.019), and urinary tract cancers (HR = 0.40, 95% CI = 0.20–0.81; p = 0.010) (Table S4). However, these statistical results are offered post hoc and as an exploratory analysis. Therefore, we present these results as supplemental information and not as confirmation. Moreover, the subgroup analysis showed that the lower risks of cancer-related death and all-cause mortality associated with dabigatran compared with rivaroxaban were consistent across different levels of the subgroup variables, except for hypertension (P for interaction =0.020; Figure 3B).

4 DISCUSSION

To the best of our understanding, the current investigation on the impact of different classes of NOACs (dabigatran and rivaroxaban) on cancer survival is the first. Preclinical research has shown that coagulation and thrombosis play essential roles in cancer progression and spread at levels of thrombin and factor Xa regulation.^{25, 26} Therefore, thrombin and factor Xa inhibition seem to be critical steps in modulating cancer metastasis and progression.^{25, 26} The improvement of cancer survival has been reported by anticoagulation with LMWH use.²⁷ However, NOACs, such as warfarin or apixaban, do not exhibit survival benefits in cancer patients at the cost of bleeding risk.²⁸ It is hypothesized that the observed effects could result from the differential inhibition of the coagulation pathway, in which dabigatran acts directly on thrombin and avoids prothrombin feedback activation as rivaroxaban does. Besides, the major bleeding risk of rivaroxaban in this study was numerically higher (9.6% vs. 2.0%) than that with the prophylactic dosage (10 mg once daily for 180 days) reported by Khorana et al.,¹⁴ and the major bleeding risk of dabigatran (6.2%). In addition, rivaroxaban was comparable to other factor Xa inhibitors within the therapeutic dosage (1.1%–6.9%).^{13, 15}

The antitumor benefits of anticoagulants have been debated for several decades. Previous studies revealed positive effects on cancer survival in randomized controlled trials. Also, the survival benefits of anti-coagulations in cancer patients without venous thrombosis may be partly explained by the heterogeneity of designs of studies, types, and stages of cancers, therapeutic regimens, and classes, doses, and duration of the anticoagulants.^{29, 30} Our study adopted IPTW to minimize the selection bias between the dabigatran and rivaroxaban arm and showed clinically meaningful survival benefits compared with previous studies.^{29, 30} Patients with colorectal cancer, male genital organ cancers, and urinary tract cancer seemed to have a lower risk of cancer-related death associated with dabigatran use (Table S4), which could be related to the strong expression of thrombin level in these malignancies.³¹ In addition, patients with female and male genital organs who received dabigatran showed differential effects on cancer survival, which could be partly explained by the gender difference in the blood coagulation system.³²

5 LIMITATIONS

There are several limitations when using epidemiologic data from the national insurance database for studies. First, using ICD-9-CM and ICD-10 codes for patient screening may miss certain cases for conditions not coded correctly. Second, the heterogeneity of the selection criteria and management between active cancers receiving standard treatment plus dabigatran and standard treatment plus rivaroxaban may lead to difficulties interpreting the results, especially the imbalance of indication of NOACs, as AF/flutter, venous thromboembolism, and underlying comorbidities. Moreover, a strength of this study is that actions were taken to reduce these potential biases. Indeed, the data on cancer diagnosis, initial cancer stage, corresponding treatment, cancer-related death, and all-cause mortality were extracted from cross-links to a national level data of cancer registry and death with insurance covering 99.7% of the whole population. Also, a propensity score based on the IPTW adjustment was used to reduce the confounding bias and imbalances in covariates, potentially estimating treatment effects similar to randomized trials. Third, regarding bleeding events, minor bleeding events (i.e., gum bleeding) may not require medical attention and would result in undercoded (underreported) information as adverse events. Therefore, in our study, only major bleeding events requiring blood transfusion >2 Units, life-threatening bleeding or vital organ hemorrhage, such as ICH and GI bleeding, which necessitated intervention, treatment in the emergency room, or during hospitalization, were studied as outcomes. Finally, this study was conducted in a primarily ethnic homogenous population, and whether these findings apply to other populations warrants further studies.

6 CONCLUSION

In cancer patients with VTE or AF, the use of dabigatran may be associated with a lower risk of cancer-related death and all-cause mortality compared with rivaroxaban. Further studies are warranted to confirm these findings.

ETHICS STATEMENT

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation by Chang Gung Memorial Hospital, Taiwan, and with the Helsinki Declaration of 1975, as revised in 2000. The de-identified medical and health information can provide analyzable data through which research can be conducted and informed consent is waived. The current study is approved by the Institutional Review Board (IRB) at Chang Gung Memorial Hospital, Chiayi Branch (IRB No. 201901482B1).

CONFLICT OF INTEREST

None.