Sex differences in utilization and outcomes of catheter-directed thrombolysis in patients with proximal lower extremity deep venous thrombosis – Insights from the Nationwide Inpatient Sample

Abstract

Catheter-directed thrombolysis (CDT) is being increasingly used for the treatment of proximal lower extremity (LE) deep venous thrombosis (DVT). However, sex differences in utilization and safety outcomes of CDT in these patients are unknown. The Nationwide Inpatient Sample (NIS) database was used to identify all patients with a principal discharge diagnosis of proximal LE or caval DVT who underwent CDT between January 2005 and December 2011 in the United States. We evaluated the comparative safety outcomes of CDT among a propensity-matched group of 1731 men versus 1731 women. Among 108,243 patients with proximal LE or caval DVT, 4826 patients (4.5%) underwent CDT. Overall, women underwent CDT less often compared to men (4.1% vs 4.9%, p<0.01, respectively). The rates of CDT increased between 2005 and 2011 for both women (2.1% to 5.9%, p<0.01) and men (2.5% to 7.5%, p<0.01). There was no significant difference in in-hospital mortality (1.2% vs 1.3%, p=0.76). Women were noted to have higher rates of blood transfusions (11.7% vs 8.8%, p<0.01), but lower rates of intracranial hemorrhage (0.5% vs 1.2%, p=0.03) and gastrointestinal bleeding (0.9% vs 2.2%, p<0.01) compared with men. Women were more likely to undergo inferior vena cava filter placement (37.0% vs 32.1%, p<0.01). In this large nationwide cohort, women with proximal DVT were less likely to receive CDT compared to men. Although mortality rates were similar, women were noted to have higher blood transfusion rates while men had more episodes of intracranial and gastrointestinal bleeding.

Keywords

administrative data deep vein thrombosis lower extremity sex differences thrombolytic therapy safety outcomes

Introduction

Deep vein thrombosis (DVT) is a major cause of cardiovascular morbidity and mortality. In the United States, its annual incidence is estimated to be between 0.1% and 0.2% among the general population, affecting a total of 300,000–600,000 patients.¹ Lower extremity (LE) DVT accounts for the majority (80%) of these cases² and leads to a debilitating chronic condition known as post-thrombotic syndrome in more than 50% of patients.³ Catheter-directed thrombolysis (CDT), which utilizes localized infusion of a thrombolytic agent directly into the thrombus, has been shown to reduce the incidence of post-thrombotic syndrome.⁴ This has led to increased rates of CDT utilization in the United States.⁵

Female patients have higher rates of bleeding complications, including intracranial hemorrhage (ICH), when treated with systemic thrombolysis for conditions like acute myocardial infarction (AMI) and pulmonary embolism (PE).^6–9 However, sex-based differences in bleeding complications related to CDT for treatment of DVT are currently unknown. In the present study, we sought to describe the sex-based differences in (1) temporal trends of differential CDT utilization and (2) safety outcomes of CDT for treatment of LE or caval DVT in the United States.

Methods

The Nationwide Inpatient Sample (NIS) database was used to identify all patients with a primary discharge diagnosis of proximal LE or caval DVT in the United States. The NIS is the largest publicly available inpatient health care database in the US. It contains all discharge data from a 20% stratified sample from over 1000 US non-federal hospitals.¹⁰ Data are collected from over 7 million hospitalizations each year and can be used to estimate over 35 million hospitalizations nationally through the use of provided weighting algorithms.

Study population

Patients aged 18 years or older with a primary discharge diagnosis of proximal LE or caval DVT from January 2005 to December 2011 were identified using the International Classification of Diseases 9^th Revision (ICD-9-CM) codes for proximal LE DVT (ICD-9-CM code 453.41) and inferior vena caval DVT (ICD-9-CM code 453.2). Within this patient cohort, we identified patients who were treated with thrombolytic therapy (ICD-9-CM code 99.10). Patients with a principal discharge diagnosis of pulmonary embolism (PE) (ICD-9-CM code 415.1) were not included. Since systemic thrombolysis is rarely used in the setting of LE or caval DVT, we hypothesized that the resultant cohort of patients was treated with CDT plus anticoagulation. Comparative sex-stratified analysis was then performed between male and female patients treated with CDT using rigorous propensity matching. The patient selection flow diagram is shown in Figure 1.

Figure 1.

Patient selection flow diagram.

We did not include patients with pregnancy-related DVT (ICD-9-CM codes 671.3, 671.4, and 671.9), isolated distal LE DVT (ICD-9-CM code 453.42), and unspecified LE DVT (ICD-9-CM code 453.40).

Statistical analysis

Given significant differences in the baseline clinical characteristics between men and women treated with CDT, propensity-score matching was used to minimize the effect of selection and indication bias. Propensity scores were calculated using 46 clinical and hospital-related variables (including the Elixhauser comorbidity index)¹¹ (Supplementary Table 1). A nearest neighbor 1:1 variable ratio, parallel, balanced propensity-matching method with a caliper width of 0.01 was then used to generate two matched groups of men and women that were used for comparative analysis. Distribution of propensity scores before and after matching is shown in Supplementary Figure 1.

Trends in CDT utilization were compared using the Cochran–Armitage trend test. In-hospital outcomes (death, shock, acute kidney injury (AKI), inferior vena cava (IVC) filter placement, angioplasty and stenting rates), bleeding complications (ICH, gastrointestinal bleeding, procedure-related hemorrhage, blood transfusion rates) and resource utilization (length-of-stay, hospital charges) were compared between the two groups using an independent sample t-test for continuous variables and the Pearson χ² test for categorical variables. A p-value less than 0.05 was considered statistically significant. We also performed an age-adjusted comparison of the CDT techniques, angioplasty and stenting for both men and women to evaluate the relationship between age and the intensity of therapy.

Most categorical variables had less than 1% missing data and for these variables data were imputed to the most common category. The race variable was missing in 13.3% of the cases. The dummy variable adjustment method was used to preserve the full sample size.¹² The resultant study outcomes were then adjusted for race using multivariate logistic regression. Race-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated. Finally, to further assess for residual confounding, a rule-out approach to sensitivity analysis was used to illustrate how strongly a single unmeasured confounder would need to be associated with patient sex and a significant outcome endpoint to fully explain our findings (Supplementary Figure 2).¹³

Results

Between January 2005 and December 2011, a total of 108,243 patients with a principal discharge diagnosis of proximal LE or caval DVT were identified in the NIS dataset (representing a national estimate of 533,944 patients). Among these patients, 4826 (4.5%) were treated with CDT. Overall utilization of CDT was higher in men (2478, 4.9%) compared to women (2348, 4.1%) (p < 0.01). Over the 7-year study period, CDT use increased for both men (from 2.5% to 7.5%, p < 0.01) and women (from 2.1% to 5.9%,p < 0.01) (Figure 2). Despite lower overall utilization, women were more likely to be treated with CDT compared with men if they were 50 years of age or younger (9.5% vs 7.3%, p < 0.01, respectively) (Figure 3). Key baseline clinical characteristics of the unmatched and matched groups of men and women treated with CDT are shown in Table 1. In the unmatched cohort, women were younger than men and had lower rates of prior VTE, stroke, diabetes, hypertension or malignancy.

Figure 2.

Sex-based trends in utilization of CDT for proximal LE and caval DVT (2005–2011). CDT, catheter-directed thrombosis; LE, lower extremity; DVT, deep vein thrombosis.

Figure 3.

Overall CDT utilization by age category (2005–2011). CDT, catheter-directed thrombosis.

Table 1.

Key unmatched and matched baseline clinical characteristics of patients undergoing catheter-directed thrombolysis (CDT) for proximal lower extremity or caval deep vein thrombosis (DVT).

Unmatched group	Male(n = 2478)	Female(n = 2348)	p-value
Age, years (mean ± SD)	54.1 ± 16.0	52.6 ± 18.3	<0.01
Race			0.02
Caucasian, n (%)	1623 (78.9)	1463 (76.4)
African American, n (%)	213 (10.3)	225 (11.8)
Teaching hospital, n (%)	1259 (50.8)	1218 (51.9)	0.46
Caval DVT, n (%)	406 (16.4)	312 (13.3)	<0.01
History of VTE, n (%)	417 (16.8)	299 (12.7)	<0.01
History of CVA, n (%)	105 (4.2)	57 (2.4)	<0.01
Iron deficiency anemia, n (%)	419 (39.8)	635 (27.0)	<0.01
Chronic blood loss anemia, n (%)	35 (1.4)	81 (3.4)	<0.01
Chronic pulmonary disease, n (%)	287 (11.6)	360 (15.3)	<0.01
Diabetes without complications, n (%)	372 (15.0)	264 (11.2)	<0.01
Diabetes with complications, n (%)	53 (2.1)	48 (2.0)	0.82
Hypertension, n (%)	1047 (42.3)	818 (34.8)	<0.01
Hyperlipidemia, n (%)	604 (24.4)	429 (18.3)	<0.01
Coronary artery disease, n (%)	308 (12.4)	162 (6.9)	<0.01
Any malignancy, n (%)	412 (16.6)	479 (20.4)	<0.01
Metastatic cancer, n (%)	123 (5.0)	154 (6.6)	0.02
Alcohol abuse, n (%)	101 (4.1)	28 (1.2)	<0.01
Active smoking, n (%)	435 (17.6)	295 (12.6)	<0.01
Matched group	Male(n = 1731)	Female(n = 1731)	p-value
Age, years (mean ± SD)	52.8 ± 16.2	52.7 ± 18.5	0.87
Race			0.02
Caucasian, n (%)	1119 (78.4)	1085 (76.2)
African American, n (%)	140 (9.8)	171 (12.0)
Teaching hospital, n (%)	902 (52.1)	912 (52.7)	0.73
Caval DVT, n (%)	249 (14.4)	257 (14.8)	0.70
History of VTE, n (%)	246 (14.2)	245 (14.2)	0.96
History of CVA, n (%)	39 (2.3)	44 (2.5)	0.58
Iron deficiency anemia, n (%)	360 (20.8)	358 (20.7)	0.93
Chronic blood loss anemia, n (%)	33 (1.9)	32 (1.8)	0.90
Chronic pulmonary disease, n (%)	218 (12.6)	224 (12.9)	0.76
Diabetes without complications, n (%)	199 (11.5)	5.9 (11.8)	0.79
Diabetes with complications, n (%)	37 (2.1)	33 (1.9)	0.63
Hypertension, n (%)	621 (35.9)	634 (36.6)	0.65
Hyperlipidemia, n (%)	331 (19.1)	333 (19.2)	0.93
Coronary artery disease, n (%)	133 (7.7)	139 (8.0)	0.71
Any malignancy, n (%)	319 (18.4)	325 (18.8)	0.79
Metastatic cancer, n (%)	106 (6.1)	106 (6.1)	1.0
Alcohol abuse, n (%)	25 (1.4)	27 (1.6)	0.78
Active smoking, n (%)	238 (13.7)	232 (13.4)	0.77

VTE, venous thromboembolism; CVA, cerebral vascular accident.

Matched sex-based outcomes

The propensity-score matching algorithm yielded a total of 3462 patients (1731 males and 1731 females) that were used for comparative analysis (c-statistic 0.696). Propensity-matching resulted in two balanced groups of males and females aside from patient race (p=0.02) (Table 1). Matched in-hospital outcomes are shown in Table 2. Race adjustment did not significantly affect the study outcomes. There was no significant difference between the in-hospital mortality rates in men and women treated with CDT (1.3% vs 1.2%, p=0.76, respectively). Women were more likely to require any blood transfusion (11.7% vs 8.8%, p < 0.01), undergo angioplasty (64.1% vs 54.3%, p < 0.01), stenting (32.2% vs 19.9%, p < 0.01) and IVC filter placement (37.0% vs 32.1%, p < 0.01) compared to men, respectively. Length of stay (7.0 ± 5.7 days vs 7.1 ± 5.5 days, p=0.55) and total hospital charges ($88,837 ± 68,284 vs $91,487 ± 77,129, p=0.28) were not significantly different between the two groups.

Table 2.

Matched outcomes of patients undergoing catheter-directed thrombolysis (CDT) for proximal lower extremity or caval deep vein thrombosis (DVT).

	Male(n = 1731)	Female(n = 1731)	OR (95% CI)	p-value
In-hospital death, n (%)	22 (1.3)	20 (1.2)	1.1 (0.60–2.0)	0.76
Blood transfusion, n (%)	153 (8.8)	202 (11.7)	0.73 (0.59–0.92)	<0.01
Intracranial hemorrhage, n (%)	21 (1.2)	9 (0.5)	2.4 (1.1–5.1)	0.03
Gastrointestinal bleeding, n (%)	38 (2.2)	15 (0.9)	2.6 (1.4–4.7)	<0.01
Procedure-related hemorrhage, n (%)	25 (1.4)	20 (1.2)	1.3 (0.69–2.3)	0.45
Acute kidney injury, n (%)	171 (9.9)	112 (6.5)	1.6 (1.2–2.0)	<0.01
IVC filter placement, n (%)	556 (32.1)	640 (37.0)	0.81 (0.70–0.93)	<0.01
Angioplasty rates, n (%)	940 (54.3)	1110 (64.1)	0.67 (0.58–0.76)	<0.01
Stent placement, n (%)	344 (19.9)	557 (32.2)	0.52 (0.45–0.61)	<0.01
Length of stay (days ± SD)	7.0 ± 5.7	7.1 ± 5.5	–	0.55
Total charges ($ ± SD)	88,837 ± 68,284	91,487 ± 77,129	–	0.28

OR, race adjusted odds ratio; CI, confidence interval; IVC, inferior vena cava.

Angioplasty, stenting and IVC filter placement

The rates of angioplasty and stenting were higher in women every consecutive calendar year throughout the study period (Supplementary Figures 3 and 4). However, the angioplasty and stenting rates were only higher in female patients younger than 75 years of age (Figures 4 and 5). Female patients with proximal LE DVT underwent more stenting procedures compared to female patients with caval DVT (33.7% vs 23.3%, p < 0.01, respectively). There was no significant difference, however, in angioplasty rates between women with proximal LE or caval DVT (64.7% vs 60.7%, p=0.22, respectively). IVC filter placement took place either prior to CDT (27.5% vs 28.2%) or on the day of CDT (62.8% vs 63.7%) in the majority of male and female patients, respectively. Those women who had adjunctive IVC filter placement were more likely to require a blood transfusion compared to women not treated with IVC filters (13.9% vs 10.4%, p=0.026, respectively). Blood transfusion rates were not significantly different in men irrespective of whether they had an IVC filter placed or not (9.5% vs 8.5%, p=0.48).

Figure 4.

Overall angioplasty rates by age category (2005–2011).

Figure 5.

Overall stenting rates by age category (2005–2011).

Major bleeding complications

The rates of ICH (1.2% vs 0.5%, p=0.03) and gastrointestinal bleeding (2.2% vs 0.9%, p < 0.01) were significantly higher in men. This was especially true for patients over the age of 75 (Supplementary Figures 5 and 6). Interestingly, the rates of ICH were only higher among men over the age of 75 and not for the other age categories.

Discussion

In this large nationwide observation study, we found that the utilization of CDT for treatment of proximal LE or caval DVT was lower in women compared with men. Those women who were treated with CDT were more likely to receive adjunctive angioplasty, stenting and IVC filter placement. Men and women had similar in-hospital mortality rates; however, women required more blood transfusions.

The underutilization of CDT among women in this study is a novel but not a surprising finding given that systemic thrombolytic therapy is used less frequently in women presenting with an acute stroke^14,15 and AMI.^16,17 A meta-analysis of 18 stroke studies showed that women were 30% less likely to receive thrombolytic therapy compared to men¹⁴ in spite of the fact that women may derive more benefit from systemic thrombolysis in the setting of acute stroke.¹⁵ Upon presentation with an AMI, women have also been shown to be 30–50% less likely to be treated with systemic thrombolysis compared with male patients.^16,17 Further subgroup analysis of our dataset revealed that CDT rates were only lower in women over the age of 50 years, suggesting that younger women were just as likely to be treated with CDT as men.

Among patients who received CDT, women underwent more angioplasty and stenting procedures. Interestingly, the increased use of these procedures was only seen in women younger than 75 years of age. In essence, although CDT rates are lower in women, once the decision to perform CDT is made, women are more likely to receive aggressive procedures in the interventional suite. This finding stands in contrast to the observed sex differences in the management of coronary artery disease (CAD) in which women are less likely both to be referred for cardiac catheterization^18,19 and to undergo coronary artery revascularization.^20,21 The higher rates of angioplasty and stenting among female patients undergoing CDT may be related to their anatomically smaller vein sizes compared with male patients. The smaller vein diameter in women would result in a lower luminal area for the same degree of residual thrombus as compared with men, thereby potentially resulting in stent implantation. Women have also been shown to have a higher incidence of May–Thurner syndrome, which would necessitate adjunctive stenting at the time of CDT.^22–24

Similarly, this study showed that the overall IVC filter placement rates were higher in women compared to men. Although no prior study specifically evaluated sex differences in IVC filter placement rates in patients undergoing CDT, previous studies that enrolled patients admitted with an acute DVT or PE reported lower IVC filter rates in women.^5,25 Higher IVC filter rates may be a surrogate marker for increased bleeding events in women at the time of CDT. This theory is supported by the fact that women who underwent IVC filter placement were more likely to receive a blood transfusion compared with women without IVC filter placement (13.9% vs 10.4%, p=0.026).

In our study, blood transfusion rates were higher in women than in men, suggesting that women may have higher bleeding rates from treatment with CDT. Although no other study has previously reported on higher bleeding rates in women undergoing CDT, similar sex discrepancy has been described in trials evaluating the role of systemic thrombolysis in the setting of AMI and submassive PE.^6,9 The discrepancy between higher rates of gastrointestinal bleeding in men and higher blood transfusion rates in women described in our study may be related to an increased incidence of other clinically relevant bleeds such as access site bleeding and retroperitoneal hemorrhage, which has been previously described in women.²⁶ Despite the potential of increased bleeding in women, ultimately the in-hospital mortality rates were not significantly different between men and women treated with CDT. It is important to note, however, that sex-based differences in blood transfusion rates may also be related to other factors such as lower baseline pre-procedural hemoglobin levels in women²⁷ which can lower the threshold for blood transfusion.²⁸

One of the most interesting findings of our study is that men were more likely to develop ICH. Sex differences in ICH rates were particularly pronounced in the category of patients over the age of 75. Nevertheless, the overall ICH rate among men undergoing CDT was still lower compared to historical ICH rates in patients undergoing systemic thrombolysis.²⁹ Prior studies that evaluated sex differences in the incidence of secondary ICH among patients undergoing systemic thrombolysis for AMI, PE and stroke have reported significant variability in their results.^7,8,15 Women treated with systemic thrombolysis were more likely to develop ICH when presenting with an AMI and submassive PE, whereas men had a higher incidence of ICH when treated with systemic thrombolysis for an acute ischemic stroke. Our study is the first one to show sex differences in ICH rates among patients treated with CDT.

Finally, the rates of AKI were found to be higher in men treated with CDT despite a similar baseline incidence of chronic kidney disease in men and women. Sex-based differences in the rates of AKI have been previously reported in the surgical literature. Bell et al. found women to be 50% less likely to develop AKI after undergoing orthopedic surgery.³⁰ Similarly, in a study of postoperative general surgery patients, women were noted to be 40% less likely to develop AKI.³¹ Although the complete mechanism is not well understood, animal models suggest that estrogen might be responsible for protecting the kidney from ischemic injury.³²

Limitations

Our study has several limitations. First, there is a possibility that an unmeasured confounder may be responsible for the outcome differences seen between the groups of men and women. However, we believe that our rigorous propensity matching addresses this limitation and therefore significantly reduces the effect of selection bias. Second, ICD-9-CM coding of bleeding complications does not allow us to determine the timing of the bleeding events. It is therefore difficult to determine the exact relationship between the timing of CDT/IVC filter placement and bleeding. Third, the accuracy of our dataset relies on appropriate coding of diagnoses and procedures. It is therefore subject to the limitations of administrative datasets. Fourth, since our data are derived from an entirely inpatient cohort, our results may not be definitively applicable to patients undergoing CDT in an outpatient setting. Finally, the NIS database only contains in-hospital patient data and therefore does not allow for post-discharge longitudinal outcomes analysis.

Conclusions

The results of our study suggest that although female patients are less likely to be treated with CDT for proximal LE or caval DVT, they do experience more bleeding complications requiring blood transfusion. Interestingly ICH, gastrointestinal bleeding and AKI rates were noted to be more common in men compared to women. Nevertheless, mortality rates were similar for both men and women treated with CDT. Finally, women treated with CDT were more likely to undergo angioplasty, stenting and adjunctive IVC filter placement compared with men.

Footnotes

Declaration of conflicting interests

Dr. Bashir is a cofounder of and has equity interest in Thrombolex Inc. The rest of the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Supplementary material

The supplementary material is available at

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Supplementary Material

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