Saddle pulmonary embolism with acute cor pulmonale in contemporary practice: Epidemiological trends and reperfusion strategies

Abstract

Background:

Saddle pulmonary embolism (SPE) is defined as large emboli located at the bifurcation of the main pulmonary artery. The prevalence and optimal intervention for SPE remain unclear. Herein, we focus on contemporary epidemiology and reperfusion strategies for SPE with acute cor pulmonale (SPE-ACP).

Methods:

The National Inpatient Sample of the USA (2016–2022) was analyzed. Diagnoses and procedures were identified by International Classification of Diseases, Tenth Revision (ICD-10) codes. Therapies were classified as conventional therapy (CT), systemic fibrinolysis (SF), catheter-directed thrombolysis (CDTL), and catheter-directed mechanical thrombectomy (CDMT). Outcomes evaluated were bleeding, transfusion, discharge to home, and in-hospital mortality. Statistical analyses included chi-squared tests, Wilcoxon rank-sum tests, propensity score matching, and logistic regression.

Results:

SPE-ACP constituted 1.7% of all PEs (frequency-trend, 2016–2022, p_trend < 0.001); 49.2% of patients received CT. Among advanced reperfusion therapies (ARTs), SF was associated with higher risks of major bleeding and mortality (vs CDTL/CDMT, p < 0.05). CDTL was associated with lower transfusion risk (vs SF/CDMT, p < 0.01) and higher rates of discharge to home (vs SF, p = 0.009). Notably, CDMT showed increasing trends in utilization and discharge to home, and decreasing trends in transfusion and mortality (2016–2022, all p_trend < 0.05). Except for transfusion (p = 0.013), the outcomes became comparable between CDTL and CDMT (2020–2022, all p > 0.10). SPE-ACP with acute popliteal/femoral deep vein thrombosis (DVT) was associated with lower mortality risk (vs no femoropopliteal DVT, all p < 0.05).

Conclusion:

SPE-ACP, an uncommon condition, showed a substantially increased prevalence over time. Among ARTs, favorable outcomes were observed with CDTL during 2016–2022; CDMT may be evolving into an alternative strategy given its relatively comparable outcomes during 2020 to 2022. SPE-ACP with concomitant acute femoral/popliteal DVT may be associated with lower mortality risk.

Keywords

acute cor pulmonale antithrombotic therapy endovascular therapy saddle pulmonary embolism venous thromboembolism (VTE)

Background

Saddle pulmonary embolism (SPE) is an anatomic diagnosis defined as the presence of large emboli located at the bifurcation of the main pulmonary artery.^1,2 SPE presents with a wide spectrum of signs and symptoms, ranging from dyspnea to more severe manifestations, such as right heart failure, syncope, and cardiogenic shock, with catastrophic cases of sudden death before hospital admission.^1,2 SPE has been reported to occur in approximately 2–5% of all pulmonary embolism (PE) cases, a rare subgroup of venous thromboembolism (VTE) stemming from risk factors like major surgery, trauma, active cancer, or cases of idiopathic origin.^2,3

Historically, SPE was identified primarily at autopsy due to limited diagnostic tools and high mortality rates from rapid hemodynamic collapse.^4,5 In the modern era, newer imaging modalities, particularly computed tomography pulmonary angiography, which has become the gold standard for diagnosis, allow for earlier detection and optimal timely intervention.⁴ However, due to the relatively low incidence of SPE in VTE, there are only a few single-center studies investigating SPE, which has limited the development of evidence-based practice guidelines. Currently, clinical practice guidelines for PE, such as those from the European Society of Cardiology (ESC) and American College of Chest Physicians (CHEST), recommend the use of risk stratification to guide advanced reperfusion interventions (e.g., systemic fibrinolysis, catheter-directed thrombolysis, catheter-directed thrombectomy, and surgical embolectomy) beyond anticoagulation, based on hemodynamic status, right ventricular function, cardiac injury, comorbidities, local expertise, and resources.^6,7

There has been a long-standing debate as to whether SPE should be managed similarly to PEs in general, as some patients with SPE may exhibit relatively mild symptoms and no signs of right heart dysfunction despite the fact that the emboli lodge at the main pulmonary artery.^8,9 Some physicians argue that the central location, large clot burden, and instability of the emboli may leave SPE at high risk of rapid hemodynamic collapse and thus warrant consideration of advanced reperfusion therapy, beyond anticoagulation, to prevent adverse events and even death, in selected cases of intermediate-risk PE or borderline hemodynamics.^2,10 These complexities and lack of evidence-based guidance reflect the need for a better understanding of how to treat patients with SPE. In addition to the anatomic diagnosis of SPE identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes prior to 2015, ICD-10-CM codes, available since 2016 in the Nationwide Inpatient Sample (NIS), further differentiate SPE by the functional status of the right heart: namely, SPE with or without acute cor pulmonale. The new functional diagnostic codes, which more accurately indicate the status of acute right heart failure, reflect real-world practice and provide an avenue to address knowledge gaps in SPE population beyond the anatomic diagnosis.

In this study, we utilized publicly available NIS and focused on SPE with acute cor pulmonale (SPE-ACP) from 2016 to 2022, to address: (1) the frequency and prevalence-trend of SPE-ACP over time; (2) the range of therapeutic patterns in current practice and their association with demographics, comorbidities, and clinical outcomes; (3) trends for the utilization, safety, and efficacy outcomes of treatments, and potential optimal reperfusion strategy; and (4) the association between concomitant acute proximal deep vein thrombosis (DVT) and clinical outcomes in patients with SPE-ACP.

Methods

Data sources

NIS data covering the 7-year period spanning January 2016 to December 2022 was analyzed. NIS is a publicly available administrative database sponsored by the Healthcare Cost and Utilization Project (HCUP). The database represents a 20% stratified sample of all inpatient hospitalizations in the USA. The requirements for institutional review board approval and informed consent were waived because the database contains de-identified records under the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule.

Study population

Patients with PE, SPE-ACP, and SPE without acute cor pulmonale were identified by ICD-10-CM diagnostic codes. To evaluate SPE-ACP frequency and prevalence-trend over time in the general population, patients were excluded if they were less than 18 years of age or pregnant (Figure 1). To focus on SPE-ACP-based clinical outcomes and procedures, patients with a nonprimary diagnosis of SPE-ACP, or with acute myocardial infarction, acute ischemic stroke, chronic limb-threatening ischemia (CLTI), or with peripheral arterial embolism were also excluded. To further investigate the effects of therapies, patients receiving tissue plasminogen activator (tPA) prior to treatment at the current facility, or with inferior vena cava filter placement, surgical embolectomy, or with combined advanced reperfusion therapies (ARTs) were also excluded. Patients were classified into conventional therapy (CT) without ART, or those who received ART were classified into systemic fibrinolysis (SF), catheter-directed thrombolysis (CDTL), and catheter-directed mechanical thrombectomy (CDMT) groups (Figure 1). The full inclusion and exclusion list of diagnostic and procedure codes are provided in supplementary Table S1.

Figure 1.

Study flowchart and enrollment. Patients with saddle pulmonary embolism with and without acute cor pulmonale, comorbidities, and procedures were identified by ICD-10-CM and PCS codes.

Definition of variables

Age was stratified into three groups: 18–50 years; 51–75 years; > 75 years. Race and ethnicity comprised three groups: White, Black, and others. Socioeconomic status encompassed four groups (lower, lower middle, upper middle, and upper) according to the percentile of median household income. Based on the National Center for Health Statistics (NCHS) Urban-Rural Classification Scheme, patient location was categorized into urban (NCHS codes 1–4) or rural (NCHS codes 5–6). Hospital location/teaching type was categorized into three groups (rural area, urban nonteaching, and urban teaching) based on the NIS stratum identifier. Based on the HCUP indicator of emergency department (ED) record, ED admission was categorized as no emergency (value 0) or emergency (values 1–4). Based on the HCUP transfer into the hospital indicator, admission was categorized as not transferred (value 0) or transferred in from different facility (values 1–2). Tobacco use was identified by documented history of tobacco or nicotine use. Obesity was identified as body mass index (BMI) ⩾ 30.0 kg/m², or a documented clinical diagnosis of obesity. Acute proximal DVT was stratified into three groups: (1) no femoral or popliteal DVT; (2) popliteal DVT only; and (3) femoral DVT only. Risk factors, comorbidities, and associated conditions (e.g., shock, DVT), and in-hospital advanced revascularization were identified using appropriate ICD-10-CM and Procedure Coding System (PCS) codes (Supplemental Table S1).

Study outcomes

Bleeding, transfusion, routine discharge to home, and in-hospital mortality were the major outcome measures evaluated in this study. Bleeding and transfusion were identified according to the ICD-10-CM and PCS codes (Table S1). Routine discharge to home and in-hospital mortality were identified by the specific NIS indicators for discharge and mortality, respectively.

Statistical analysis

Categorical variables were reported as percentages, and continuous variables were presented as medians with IQRs. All-cause hospitalizations with a diagnosis of SPE-ACP were used to estimate frequency and prevalence-trend. The chi-squared test was applied to evaluate the difference between proportions at two points, and the Wilcoxon rank-sum test with Cuzick’s test was used to assess the overall trend of change from 2016 to 2022.¹¹

One-to-one propensity score matching (PSM) was conducted in each paired cohort for the outcome measures between two types of ART (SF vs CDTL, SF vs CDMT, CDTL vs CDMT).^12,13 Patients were matched 1:1 in each dataset via propensity scores generated by probit regression based on demographics, risk factors, and comorbidities, such as cardiogenic shock and acute femoral DVT (a complete list of covariates is given in Table S3). The nearest neighbor matching method without replacement with a caliper of 0.01 was used. The balance of covariates was checked based on standardized differences with a threshold of 10%.^12,13

After pairwise PSM, the risk of outcomes was evaluated with logistic regression models. In model 1, therapy was included in univariable logistic regression analyses, and no other covariates were included based on each paired PSM cohort. In model 2, to further explore how acute proximal DVT affected the outcomes, the status of acute DVT was added to the therapeutic variable for multivariable logistic regression analyses, with femoral DVT used as the reference. To test the robustness of the findings, subgroup analyses were conducted in urban teaching hospitals, urban hospitals, the years 2020–2022, and the years 2019–2022, respectively. Cell sizes ⩽ 10 are not reported in publications in accordance with HCUP policy. For all the analyses, a two-sided p-value less than 0.05 was considered statistically significant. All statistical analyses were performed with STATA version 18 (StataCorp LLC).

Results

There were 584,719 documented all-cause hospitalizations of PEs in the NIS dataset from 2016 to 2022, and 9717, including patients less than 18 years (n =14) or at pregnancy (n =31) (1.7%) of them were SPE-ACP. Among all the SPEs (n = 35,188), 27.6% presented with acute cor pulmonale and 72.4% presented without acute cor pulmonale (Figure 1). After the exclusion criteria were applied, 6410 patients with a primary diagnosis of SPE-ACP were enrolled. Patients with SPE-ACP underwent the following therapies: CT (n = 3156, 49.2%), SF (n = 832, 13.0%), CDTL (n = 1308, 20.4%), and CDMT (n =1114, 17.4%).

Owing to the small sample size, patients with surgical embolectomy (SURGE) and combined ARTs were excluded from further analyses. The distribution of clinical characteristics is presented in Table S2. Patients with SURGE and combined ARTs showed low rates of discharge to home and high rates of mortality. The discharge-to-home rate was only 24.4% in the SURGE group, and 37.5% in the SF + CDMT group. The mortality rate was up to 12.7% in the SURGE group and 20.3% in the SF + CDMT group.

Saddle pulmonary embolism with acute cor pulmonale (SPE-ACP) frequency and prevalence-trend

There was an increase in the diagnosis of SPE-ACP over time, from 12 cases per 100,000 hospitalizations in 2016, up to 43 cases per 100,000 hospitalizations in 2022 (p < 0.001; Figure 2A). In addition, there appeared to be an increasing prevalence-trend from 2016 to 2022 (p_trend < 0.001). SPE-ACP constituted 0.9% of all PE cases in 2016, rising to 2.3% in 2022 (p_trend < 0.001; Figure 2B).

Figure 2.

Frequency and prevalence-trend of SPE-ACP from 2016 to 2022. (A) Annual SPE-ACP rate analysis revealed 12 cases per 100,000 hospitalizations in 2016, increasing to 43 cases per 100,000 hospitalizations in 2022; ^###p < 0.001, analyzed by chi-squared test. There was an increase in the prevalence-trend from 2016 to 2022; ***p_trend < 0.001, analyzed by the Wilcoxon rank-sum test. (B) Proportion (%) of SPE-ACP among all PEs each year, from 0.9% of all PE cases in 2016 to 2.3% in 2022; ^###p < 0.001, analyzed by chi-squared test. The proportion of SPE-ACP showed an increasing trend from 2016 to 2022; ***p_trend < 0.001, analyzed by Wilcoxon rank-sum test.

Distribution of clinical characteristics before propensity score matching (PSM)

Descriptive results of demographic characteristics, comorbidities, and clinical outcomes are presented in Table 1 prior to PSM (differences between variables were diminished after the pairwise PSM). The highest and lowest rates were based on the level of values in the therapeutic groups.

Table 1.

Distribution of demographic and clinical characteristics of saddle pulmonary embolism with acute cor pulmonale by therapy before propensity score matching.

	All therapies(N = 6410)	Conventional therapy(n = 3156)	Systemic fibrinolysis(n = 832)	Catheter-directed thrombolysis(n = 1308)	Catheter-directed mechanical thrombectomy(n = 1114)
Demographics
Female sex	3080 (48.1)	1546 (49.0)	404 (48.6)	621 (47.5)	509 (45.7)
Male sex	3328 (51.9)	1609 (51.0)	428 (51.4)	686 (52.5)	605 (54.3)
Age
⩽ 50 years	1234 (19.3)	526 (16.7)	191 (23.0)	304 (23.2)	213 (19.1)
51–75 years	3863 (60.3)	1837 (58.2)	520 (62.5)	810 (61.9)	696 (62.5)
> 75 years	1313 (20.5)	793 (25.1)	121 (14.5)	194 (14.8)	205 (18.4)
Race/ethnicity
White	4681 (75.4)	2346 (76.6)	592 (73.5)	959 (76.1)	784 (72.3)
Black	1112 (17.9)	510 (16.7)	147 (18.3)	218 (17.3)	237 (21.9)
Others	419 (6.8)	206 (6.7)	66 (8.2)	84 (6.7)	63 (5.8)
Socioeconomic status
Lower	1583 (25.0)	722 (23.3)	196 (23.9)	365 (28.1)	300 (27.2)
Lower middle	1659 (26.2)	796 (25.6)	215 (26.3)	341 (26.3)	307 (27.8)
Upper middle	1676 (26.5)	834 (26.9)	220 (26.9)	338 (26.0)	284 (25.7)
Upper	1409 (22.3)	754 (24.3)	188 (23.0)	254 (19.6)	213 (19.3)
Rural area resident	1099 (17.2)	546 (17.4)	121 (14.5)	258 (19.8)	174 (15.6)
Hospital location/teaching
Rural area	330 (5.2)	209 (6.6)	42 (5.1)	62 (4.7)	17 (1.5)
Urban nonteaching	1042 (16.3)	505 (16.0)	150 (18.0)	247 (18.9)	140 (12.6)
Urban teaching	5038 (78.6)	2442 (77.4)	640 (76.9)	999 (76.4)	957 (85.9)
ED admission	4983 (77.7)	2493 (79.0)	689 (82.8)	971 (74.2)	830 (74.5)
Transferred-in admission	1464 (22.8)	664 (21.0)	141 (17.0)	341 (26.1)	318 (28.6)
Risk factor and comorbidity
Tobacco use	2220 (34.6)	1110 (35.2)	296 (35.6)	454 (34.7)	360 (32.3)
Obesity	2494 (38.9)	1077 (34.1)	338 (40.6)	601 (46.0)	478 (42.9)
Hyperlipidemia	2565 (40.0)	1280 (40.6)	292 (35.1)	526 (40.2)	467 (41.9)
Diabetes	1686 (26.3)	792 (25.1)	236 (28.4)	320 (24.5)	338 (30.3)
Hypertension	3990 (62.3)	1981 (62.8)	478 (57.5)	824 (63.0)	707 (63.5)
Mental disorder	1373 (21.4)	666 (22.1)	197 (23.7)	285 (21.8)	225 (20.2)
Atherosclerosis	1253 (19.6)	653 (20.7)	133 (16.0)	238 (18.2)	229 (20.6)
Heart failure	1063 (16.6)	530 (16.8)	155 (18.6)	193 (14.8)	185 (16.6)
Atrial fibrillation	696 (10.9)	363 (11.5)	102 (12.3)	230 (9.9)	101 (9.1)
Chronic kidney disease	349 (5.4)	188 (6.0)	43 (5.2)	81 (6.2)	37 (3.3)
COPD	528 (8.2)	289 (9.2)	61 (7.3)	102 (7.8)	76 (6.8)
Anemia	1439 (22.5)	590 (18.7)	221 (26.6)	279 (21.3)	349 (31.3)
Hypothyroidism	735 (11.5)	400 (12.7)	86 (10.3)	133 (10.2)	116 (10.4)
Thrombophilia	369 (5.8)	176 (5.6)	57 (6.9)	68 (5.2)	68 (6.1)
Active cancer	753 (11.8)	454 (14.4)	78 (9.4)	94 (7.2)	127 (11.4)
Femoral deep vein thrombosis	1607 (25.1)	717 (22.7)	209 (25.1)	363 (27.8)	318 (28.6)
Popliteal deep vein thrombosis	2215 (34.6)	1019 (32.3)	258 (31.0)	499 (38.2)	439 (39.4)
Clinical outcome
All shock	647 (10.1)	192 (6.1)	225 (27.0)	94 (7.2)	136 (12.2)
Cardiogenic shock	335 (5.2)	104 (3.3)	111 (13.3)	42 (3.2)	78 (7.0)
Vasopressor use	186 (2.9)	43 (1.4)	78 (9.4)	19 (1.5)	46 (4.1)
ECMO	52 (0.8)	21 (0.7)	⩽ 10	⩽ 10	22 (2.0)
All bleeding	616 (9.6)	258 (8.2)	115 (13.8)	138 (10.6)	105 (9.4)
Major bleeding	106 (1.7)	44 (1.4)	30 (3.6)	14 (1.1)	18 (1.6)
Blood transfusion	198 (3.1)	66 (2.1)	44 (5.3)	26 (2.0)	62 (5.6)
Length of stay, median [IQR], day	4 [3–6]	4 [3–6]	4 [3–7]	4 [3–6]	4 [2–6]
Routine discharge to home	3968 (61.9)	1832 (58.1)	503 (60.5)	945 (72.3)	688 (61.8)
In-hospital mortality	285 (4.5)	117 (3.7)	82 (9.9)	34 (2.6)	52 (4.7)
Total charge, median [IQR], thousands USD	71 [39–112]	41 [25–72]	82 [57–126]	90 [68–127]	112 [84–170]

Values are presented as n (%) for categorical variables and median [IQR] for continuous variables.

Cell sizes less than or equal to 10 are not reported in publications in accordance with HCUP policy.

COPD, chronic obstructive pulmonary disease; ECMO, extracorporeal membrane oxygenation; ED, emergency department; HCUP, healthcare cost and utilization project; PSM, propensity score matching; SPE-ACP, saddle pulmonary embolism with acute cor pulmonale.

Demographic characteristics

Among all the patients, 60.3% were 51–75 years of age and 75.4% were White. The SF group showed the highest rate of ED admission (82.8%) and the lowest rate of transferred-in admission from different facilities (17.0%). The CDMT group showed the lowest rate of hospitalization in rural areas (1.5%) and the highest rate of hospitalization in urban teaching hospitals (85.9%).

Risk factors and comorbidities

The CT group showed the highest rate of active cancer (14.4%). The SF group showed the highest proportion in heart failure (18.6%). The CDTL group showed the highest proportion with obesity (46.0%). The CDMT group showed the highest proportion with acute femoral DVT (28.6%) and popliteal DVT (39.4%).

Shock-related clinical outcomes

Among the ARTs, the SF group showed the highest rate of all shock (27.0%), cardiogenic shock (13.3%), and vasopressor use (9.4%). The CDTL group showed the lowest rate of shock (7.2%), cardiogenic shock (3.2%), and vasopressor use (1.5%). The rates in the CDMT group were 12.2% for all shock, 7.0% for cardiogenic shock, and 4.1% for vasopressor use. The use of extracorporeal membrane oxygenation was 0.8% across all treatments, and the highest utilization rate was in the CDMT group (2.0%).

Bleeding-related clinical outcomes

Among the ARTs, the SF group showed the highest rate of all bleeding (13.8%) and major bleeding (3.6%). The CDTL group showed the lowest rate of major bleeding (1.1%). Notably, the CDMT group showed the lowest rate of all bleeding (9.4%) but had the highest blood transfusion rate (5.6%).

Discharge-related clinical outcomes

The median length of stay was 4 days across all interventions. For in-hospital mortality, the lowest rate was in the CDTL group (2.6%) and the highest rate was in the SF group (9.9%); the rates were 4.7% in the CDMT group and 3.7% in the CT group. For routine discharge to home, the highest rate was in the CDTL group (72.3%) and the lowest rate was in the CT group (58.1%). The median total in-hospital charge was highest in the CDMT group (up to $112,000 USD) and CDTL group ($90,000), followed by the SF and CT groups.

Therapy utilization and related clinical outcomes

We observed a decreasing trend in the utilization of CT (from 51.2% to 41.3%), SF (from 22.5% to 8.8%), and CDTL (from 23.9% to 11.3%), but a substantial increasing trend in CDMT utilization from 2.4% to 38.6% (2016–2022, all p_trend < 0.001; Figure 3A). There were no changes in the trends for all bleeding, major bleeding, blood transfusion, discharge to home, or mortality in the CT, SF, and CDTL groups, respectively (Figures 3B–3F). In the CDMT group, a decreasing trend in blood transfusion from 8.3% in 2016 to 5.1% in 2022 (p_trend < 0.05; Figure 3D), an increasing trend in routine discharge to home from 50.0% in 2016 to 66.4% in 2022 (p_trend < 0.001; Figure 3E), and a decreasing trend in mortality from 8.3% in 2016 to 2.6% in 2022 (p_trend < 0.01; Figure 3F) were observed.

Figure 3.

Trends in intervention utilization and outcomes in patients with SPE-ACP from 2016 to 2022. (A) Utilization trends of therapies. (B) All bleeding trends among therapeutic groups. (C) Major bleeding trends among therapeutic groups. (D) Blood transfusion trends among therapies. (E) Routine discharge-to-home trends among therapies. (F) In-hospital mortality trends among therapeutic groups.

Risk factors associated with clinical outcomes after pairwise PSM in advanced reperfusion therapies (ARTs)

Using PSM, three treatment pairs among ARTs were matched separately: SF (n = 700) vs CDTL (n = 700), SF (n = 673) vs CDMT (n = 673), and CDTL (n = 926) vs CDMT (n = 926). The baseline characteristics of the matched populations are shown in Table S3.

Treatment effect on clinical outcomes

The SF group showed a higher risk of all bleeding (vs CDMT, p = 0.008), and major bleeding (vs CDTL, p = 0.003; vs CDMT, p = 0.041; Table 2). Notably, although no difference in bleeding was observed between the CDTL and CDMT groups, the CDMT group showed a higher risk of blood transfusion (vs CDTL, p = 0.005). The CDTL group showed a significantly higher rate of routine discharge to home compared to SF (p = 0.009) and no significantly higher rate compared to CDMT (p = 0.081); no difference in the rates was observed between the SF and CDMT groups. The SF group showed a higher risk of mortality (vs CDTL, p = 0.002; vs CDMT, p = 0.001).

Table 2.

Treatment effect on clinical outcomes between advanced reperfusion therapies in all patients with saddle pulmonary embolism with acute cor pulmonale after propensity score matching.

	SF^a vs CDTL (n = 700)		SF^a vs CDMT (n = 673)		CDTL^a vs CDMT (n = 926)
	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
Model 1
All bleeding	0.78 (0.56–1.09)	0.137	0.63 (0.44–0.88)^b	0.008	0.91 (0.66–1.23)	0.528
Major bleeding	0.25 (0.10–0.63)^b	0.003	0.47 (0.23–0.97)^b	0.041	1.20 (0.52–2.80)	0.668
Blood transfusion	0.39 (0.20–0.77)^b	0.006	1.32 (0.81–2.15)	0.267	2.15 (1.25–3.70)^c	0.005
Discharge to home	1.35 (1.08–1.69)^b	0.009	1.08 (0.87–1.35)	0.468	0.84 (0.69–1.02)	0.081
In-hospital mortality	0.46 (0.29–0.75)^b	0.002	0.46 (0.30–0.72)^b	0.001	1.14 (0.69–1.90)	0.606
Model 2
All bleeding
Treatment effect	0.86 (0.61–1.23)	0.413	0.65 (0.44–0.94)^b	0.024	0.79 (0.56–1.11)	0.171
DVT effect^d
– No FPDVT	0.80 (0.47–1.35)	0.400	0.93 (0.54–1.60)	0.790	0.61 (0.38–0.98)^b	0.040
– Popliteal DVT	0.96 (0.53–1.75)	0.906	0.76 (0.40–1.45)	0.409	0.59 (0.34–1.02)	0.061
Major bleeding
Treatment effect	0.29 (0.11–0.80)^b	0.016	0.57 (0.26–1.26)	0.166	1.23 (0.48–3.13)	0.668
DVT effect^d
– No FPDVT	0.60 (0.21–1.68)	0.331	1.39 (0.41–4.76)	0.597	1.04 (0.23–4.72)	0.963
– Popliteal DVT	0.37 (0.09–1.57)	0.176	0.89 (0.21–3.80)	0.876	1.15 (0.22–6.00)	0.865
Blood transfusion
Treatment effect	0.34 (0.15–0.78)^b	0.010	1.30 (0.74–2.28)	0.364	2.45 (1.30–4.60)^c	0.005
DVT effect^d
– No FPDVT	0.80 (0.26–2.44)	0.692	1.73 (0.60–4.96)	0.307	0.69 (0.31–1.55)	0.369
– Popliteal DVT	1.74 (0.54–5.61)	0.353	1.73 (0.56–5.37)	0.343	0.62 (0.24–1.57)	0.314
Discharge to home
Treatment effect	1.36 (1.06–1.74)^b	0.014	1.09 (0.86–1.39)	0.464	0.81 (0.65–1.01)	0.057
DVT effect^d
– No FPDVT	1.32 (0.91–1.90)	0.146	0.87 (0.60–1.26)	0.462	0.97 (0.69–1.37)	0.861
– Popliteal DVT	1.76 (1.14–2.73)^b	0.011	1.50 (0.99–2.29)	0.059	1.28 (0.87–1.89)	0.209
In-hospital mortality
Treatment effect	0.41 (0.24–0.68)^b	0.001	0.48 (0.30–0.76)^b	0.002	1.35 (0.78–2.33)	0.278
DVT effect^d
– No FPDVT	3.71 (1.32–10.3)^c	0.013	2.99 (1.28–7.02)^c	0.012	4.74 (1.14–19.7)^c	0.032
– Popliteal DVT	0.15 (0.02–1.34)	0.089	0.44 (0.13–1.49)	0.187	1.15 (0.22–6.00)	0.866

The reference therapy between the ART comparisons.

Indicate results associated with better outcomes.

Indicate results associated with worse outcomes.

In model 2, femoral DVT was used as the reference level; these results are presented in the table. When popliteal DVT was used as the reference, the results were presented in Table S4. The status of acute DVT was categorized as three levels: (1) no femoropopliteal DVT, (2) femoral DVT only, and (3) popliteal DVT only.

Statistically significant p-values are bold.

ART, advanced reperfusion therapy; CDMT, catheter-directed mechanical thrombectomy; CDTL, catheter-directed thrombolysis; DVT, deep vein thrombosis; FPDVT, femoropopliteal DVT; OR, odds ratio; PSM, propensity score matching; SF, systemic fibrinolysis; SPE-ACP, saddle pulmonary embolism with acute cor pulmonale.

Effect of deep vein thrombosis (DVT) location

The presence of acute femoral DVT was associated with a lower mortality risk (compared to those without femoropopliteal DVT), regardless of the type of reperfusion therapy selected (all p < 0.05; Table 2). A similar tendency was observed when popliteal DVT was used as the reference (vs no femoropopliteal DVT, all p < 0.01; Table S4).

Subgroup analyses

Subgroup analyses were performed for patients with SPE-ACP at urban teaching hospitals and urban hospitals, and for study years 2020–2022 and 2019–2022 (Table 3, Table S7). The major results showed similar trends among ARTs and suggest that CDTL was associated with better outcomes. Notably, besides transfusion (p = 0.013), the outcomes became comparable between CDTL and CDMT (2020–2022, all p > 0.10; Table 3).

Table 3.

Treatment effect on clinical outcomes between advanced reperfusion therapies in subgroups of saddle pulmonary embolism with acute cor pulmonale after propensity score matching: hospitalizations at urban teaching hospitals or all hospitalizations from 2020–2022.

A. At urban teaching hospital	SF^a vs CDTL (n = 534)		SF^a vs CDMT (n = 548)		CDTL^a vs CDMT (n = 789)
	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
All bleeding	0.85 (0.59–1.23)	0.395	0.67 (0.46–0.98)^b	0.038	0.76 (0.55–1.06)	0.109
Major bleeding	0.27 (0.10–0.74)^b	0.010	0.44 (0.20–0.98)^b	0.044	1.11 (0.45–2.75)	0.818
Blood transfusion	0.51 (0.25–1.04)	0.063	1.22 (0.70–2.12)	0.482	1.63 (0.92–2.87)	0.094
Discharge to home	1.32 (1.02–1.70)^b	0.033	1.04 (0.81–1.33)	0.756	0.77 (0.63–0.95)^c	0.016
In-hospital mortality	0.34 (0.18–0.64)^b	0.001	0.70 (0.43–1.13)	0.145	1.50 (0.85–2.63)	0.161
B. From 2020 to 2022	SF^a vs CDTL (n = 285)		SF^a vs CDMT (n = 322)		CDTL^a vs CDMT (n = 458)
	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
All bleeding	0.71 (0.42–1.19)	0.192	0.76 (0.47–1.24)	0.270	0.69 (0.44–1.09)	0.111
Major bleeding	0.42 (0.11–1.65)	0.215	1.15 (0.41–3.20)	0.794	1.25 (0.33–4.70)	0.738
Blood transfusion	0.74 (0.26–2.17)	0.590	1.91 (0.96–3.83)	0.066	2.84 (1.25–6.44)^c	0.013
Discharge to home	1.72 (1.20–2.46)^b	0.003	1.12 (0.82–1.54)	0.470	0.80 (0.60–1.08)	0.151
In-hospital mortality	0.32 (0.15–0.71)^b	0.005	0.52 (0.29–0.94)^b	0.031	1.35 (0.63–2.88)	0.444

The reference therapy between the ART comparisons.

Indicates results associated with better outcomes.

Indicates results associated with worse outcomes.

Statistically significant p-values are bold.

ART, advanced reperfusion therapy; CDMT, catheter-directed mechanical thrombectomy; CDTL, catheter-directed thrombolysis; OR, odds ratio; PSM, propensity score matching; SF, systemic fibrinolysis; SPE-ACP, saddle pulmonary embolism with acute cor pulmonale.

Discussion

The present study is one of the first studies to investigate the frequency and prevalence-trend, therapeutic patterns, and outcomes among patients with SPE-ACP. Using the NIS database from 2016 to 2022, we observed a substantial increase in the frequency and prevalence of SPE-ACP over time.

The increasing trend may be due to: (1) recent availability of specific ICD-10 diagnostic codes with status of acute cor pulmonale since 2016; (2) rising awareness of risk-stratified therapy and greater utilization of modalities for the structural and functional diagnosis of acute PE;^6,7 (3) the growing incidence and prevalence of SPE-ACP which may occur in modern times due to a higher burden of risk factors, such as a rise in cancer prevalence or COVID-19;^14–16 and (4) the existence of coding variability or bias, as the increasing utilization of catheter-based interventions for PE may spur the diagnosis of SPE-ACP.^17–19 Additionally, we observed that SPE-ACP with concomitant acute femoral/popliteal DVT may be associated with lower mortality compared to no femoropopliteal DVT. Collectively, our results provide insights and implications for optimal reperfusion strategies in patients with SPE-ACP.

Therapeutic anticoagulation is the cornerstone for VTE management, which primarily prevents clot extension and relies on an individual’s endogenous fibrinolytic system for gradual thrombus resolution.^20,21 Therefore, in cases of greater clinical risk and thrombus burden, adjunctive ARTs (e.g., SF, CDTL, CDMT) are increasingly being evaluated in the clinical setting for their ability to rapidly resolve thrombi.^6,7 At present, there is no evidence-based data demonstrating that ART can improve long-term outcomes for intermediate-high-risk PE compared to anticoagulation alone, although several randomized clinical trials (RCTs) currently investigating this question.^6,7,22–25

In this study, the SF group showed a higher risk of major bleeding and in-hospital mortality compared to CDTL and CDMT (all p < 0.05; Table 2) after PSM. Previous studies reported that SF can improve hemodynamic decompensation in intermediate-risk PE at the cost of increased major bleeding, and did not demonstrate a benefit on short-term mortality compared to anticoagulation alone.^26–28 We found that the clinical outcomes appeared worse for patients with SPE-ACP in the SF group, compared to previously reported studies on intermediate-risk PE.^26–28 This observation may be due to: (1) more severe baseline symptoms, which may limit the time window for optimal diagnostic and therapeutic strategies; and (2) a larger thrombus burden in the central pulmonary artery location and/or fibrinolytic resistance in thrombi that may be resistant to dissolution by standard tPA regimens. Recent studies indicate that blood biomarkers (e.g., plasma fibrinogen, d-dimer) and imaging for thrombus chronicity and inflammatory status may help to identify thrombi that could not be adequately lysed via endogenous and exogenous fibrinolysis.^29–31 Novel types of plasminogen activators and antagonists of fibrinolysis inhibitors are being developed in preclinical studies and early-phase clinical trials. Future studies are needed to confirm whether these therapies would be safer or more efficacious in VTE treatment compared to standard options, and merit further investigation of how blood biomarkers and imaging modalities can enhance the decision-making for VTE management.

The CDTL group showed significant lower risks of blood transfusion (vs SF/CDMT) and higher rates of routine discharge to home (vs SF; Table 2) after PSM. These results align with previous studies showing that CDTL is associated with a lower risk of blood transfusion and in-hospital mortality, and a shorter length of stay in intermediate-high-risk PE (vs anticoagulation, SF, and CDMT).^17,32,33 Based on the current analyses, it is plausible that CDTL could serve as an optimal ART in selected patients with SPE-ACP. Of note, CDMT showed favorable trends in improved outcomes from 2016 to 2022 (Figure 3), and the outcomes were relatively comparable with CDTL at urban teaching hospitals and during the study years 2020–2022 (Table 3). The results are in line with previous studies showing that the safety and efficacy outcomes of CDMT appear to improve with procedural volume, accumulated expertise, and novel devices.^17,32,34 Moreover, major large-bore and CDMT systems were not approved by the FDA until 2018 and 2020. Thus, earlier results may be reflective of rheolytic thrombectomy-related complications, and the results from 2020 to 2022 may better represent current practice with fewer complications.^35–37 It appears that CDMT is evolving as an effective and safe alternative reperfusion strategy for selected patients with SPE-ACP, reflecting advances in device technology and accumulated expertise.^17,26,32 It is important to note that, despite these advancements, the FDA highlights safety concerns and prompts refinement of patient selection if CDMT is planned. The critical cautions involve the removal of fibrous, firmly adherent, or calcified material; excessive clot volume that cannot be removed by one pass; and cases of suspected tumor thrombus.^35–38 Currently, several RCTs comparing catheter-directed reperfusion therapies in addition to anticoagulation for the treatment of intermediate- and high-risk PE are underway.^22–25 The upcoming results are anticipated to further clarify the safety and efficacy of these therapies and inform the development of future RCTs and clinical registries, including SPE-ACP.

Notably, the rate of ED admission was 77.7%, and the rate of transfer from different facilities was 22.8% in patients with SPE-ACP (Table 1). Therefore, the timely and safe implementation of reperfusion therapies is critical, both in tertiary care centers and/or referring institutions.^10,20,39,40 A hospital-based, dedicated multidisciplinary care team for PE operating based on local resources and expertise, such as Pulmonary Embolism Response Teams (PERTs), can be considered when rapid thrombus removal is planned for patients with SPE-ACP. The PERT concept is a well-recognized multidisciplinary care model that aims to bring together various specialists in real time to efficiently and safely implement the best patient-centered care.^39,40 Some studies found that PERT implementation can facilitate risk stratification and transfers when appropriate, and improve short-term outcomes with optimal reperfusion therapy.^10,41,42 Future studies are warranted to explore the effect of hospital-based multidisciplinary care on long-term outcomes (e.g., exercise capacity, chronic thromboembolic pulmonary hypertension, quality of life), and the effect of structured home-based multidisciplinary care (e.g., lifestyle modification, antithrombotic management, and rehabilitation clinics).^20,40,43,44

Importantly, no matter what type of ART was applied, SPE-ACP with concomitant acute femoral/popliteal DVT was associated with a lower mortality risk (vs no femoropopliteal DVT, all p < 0.05; Table 2). The results indicate that the presence and location of DVT could inform SPE-ACP prognosis; this aligned with a previous study showing that PE harboring a concomitant DVT may experience a lower risk of in-hospital adverse events and mortality compared to those with isolated PE.⁴⁵ The origin of emboli—whether from DVT, right heart dysfunction, in situ pulmonary artery thrombosis, or idiopathic sources—can significantly influence clinical outcomes. Emboli originating from the right heart, or in situ, or those that are unprovoked are associated with a poorer prognosis compared with those from DVT.^2,45–48 Saddle emboli originating from acute DVT, but not chronic DVT or mixed/uncertain chronicity, may have distinct characteristics—lower collagen content and less adherence to vessel walls—potentially leading to better responsiveness to antithrombotic treatments.^20,49,50 Other potential reasons for this connection should be considered. For example, in a subset of individuals, the acute proximal DVT with large clot burden may have completely dislodged to the main pulmonary artery. Further, some patients may have been unable to undergo noninvasive imaging due to highly unstable presentations, thus limiting data derived from this subset. Future studies are warranted to investigate how a VTE clot in transit, the different origins of emboli, and thrombus chronicity affect SPE-ACP management and prognosis systemically. Also, research should explore how artificial intelligence can integrate diverse data sources to safely, efficiently, and equitably assist in decision-making to maintain vascular patency and holistic health.

Limitations

Saddle pulmonary embolism with acute cor pulmonale (SPE-ACP) is a rare subtype of PE, making it challenging to recruit a sufficient number of patients for RCTs within a set timeframe. In the absence of RCT data, these results may indicate the optimal use of ARTs in this population. The NIS dataset, due to its large sample size, comprehensive demographics, acceptable diversity, ICD-coded diagnoses, and procedures, is a valuable resource that enables analyses of SPE-ACP in real-world settings. However, the inherent limitations of this administrative dataset should also be noted, including lack of patient-level linkage, longitudinal data, and data granularity, as well as coding variability, missing data, and sampling bias.

This study has additional limitations that should be considered when interpreting the results. First, early initialization and rapid achievement of therapeutic anticoagulation is the cornerstone for PE management. Ideally, anticoagulants should be administered as baseline treatment for patients with SPE-ACP without contraindications. As there is no specific ICD-10-CM or PCS code for in-hospital anticoagulation, the effect of anticoagulation alone compared to ARTs could not be investigated in this study. Therefore, the conventional medical therapy group could serve as an important comparative cohort for routine medical management to better understand the outcome measures against ARTs. Second, patients with SPE are generally diagnosed using computed tomography pulmonary angiography, which does not routinely examine the pelvic or lower-extremity veins. Duplex ultrasound is not optimal for diagnosing pelvic or iliac vein thrombosis, whereas it is widely used to detect femoral and popliteal DVT with high sensitivity and specificity. Therefore, to investigate how DVT presence and location affect SPE-ACP prognosis, femoral and popliteal DVT—but not iliac DVT—were included in this study. Third, comorbidities or adverse events were identified by ICD-10 codes without a temporal profile. It cannot be confirmed whether they occurred before or after treatment. Therefore, the comorbidities (e.g., acute femoral DVT, cardiogenic shock) were included in the PSM models to balance the confounders. Fourth, although pairwise PSM was applied, the sample size was relatively small and potential residual confounders not captured in this study may skew the results. These limitations highlight the need for RCTs evaluating the safety and efficacy between treatment modalities representing current practice. Fifth, acute cor pulmonary is a rapid onset of right heart failure caused by a sudden increase in pressure in the pulmonary artery, most commonly in massive (high-risk) PE. In this study, the overall rates of cardiogenic shock ranged from 3.2% to 13.3% among the therapeutic groups. Therefore, the hemodynamic status could be assumed to be stable in the vast majority of patients with SPE-ACP or at borderline hemodynamics, which may be in the scope of intermediate- or intermediate-high-risk PE, rather than high-risk PE. However, the classification of intermediate- or intermediate-high-risk PE is based on cardiac biomarkers and multimodality imaging, which cannot be identified by ICD-10 codes in NIS. In addition, the definition of acute cor pulmonale may vary across hospitals or physicians. Sixth, due to small cell sizes (n ⩽ 10), more serious SPE-ACP involving SURGE, combined ARTs, or the use of extracorporeal membrane oxygenation only showed the descriptive results, without further comparisons on the outcomes by PSM. Seventh, the NIS is derived from the US healthcare system; therefore, the dataset may have limited applicability and generalizability to minority populations within the USA (e.g., Black, Hispanic, and Asian populations) and in different geographical regions. Taken together, the NIS findings in this study should be interpreted with caution.

Conclusion

Using a large administrative inpatient database, the frequency and prevalence-trend of SPE-ACP increased substantially during the 2016–2022 period. Among patients with a primary diagnosis of SPE-ACP, approximately half received CT and half received ARTs. Among all ARTs, favorable outcomes were observed with CDTL from 2016 to 2022. CDMT showed increasing trends with utilization and improving outcomes from 2016 to 2022, with outcomes that were relatively comparable with those of CDTL from 2020 to 2022. Novel CDMT appears to be evolving as an alternative reperfusion strategy for selected patients with SPE-ACP. In addition, SPE-ACP with concomitant acute femoral/popliteal DVT may be associated with lower mortality risk compared to patients with no femoropopliteal DVT. Further studies are warranted to understand the mechanisms and prognosis of SPE-ACP systemically, as well as the implementation of dedicated, structured hospital- and home-based multidisciplinary care to facilitate optimal, efficient, safe, equitable, and cost-effective patient-centered care in diverse populations.

Supplemental Material

sj-docx-1-vmj-10.1177_1358863X261431264 – Supplemental material for Saddle pulmonary embolism with acute cor pulmonale in contemporary practice: Epidemiological trends and reperfusion strategies

Supplemental material, sj-docx-1-vmj-10.1177_1358863X261431264 for Saddle pulmonary embolism with acute cor pulmonale in contemporary practice: Epidemiological trends and reperfusion strategies by Wenzhu Li, Stavros K Kakkos, Ahmed A Tawakol, Guy L Reed, Peter K Henke, Eric A Secemsky and Rachel P Rosovsky in Vascular Medicine

Footnotes

Declaration of conflicting interests

The authors disclosed the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr Tawakol reports research funding, in part, by NIHHL164337, AR077187, HL109448, HL149516, and the International Atomic Energy Agency (IAEA) Coordinated Research Project E13048; consulting fees from Genentech and Tourmaline; and is supported by Lung Biotechnology, Inc. Dr Reed reports research funding from the NIH (R01NS89707, UG3NS125023) and University of Arizona Institutional funding; and is a founder of Translational Sciences, Inc. Dr. Secemsky is the Principal Investigator for trials for Abbott, BD, Cook, Concept, and R3; he receives consulting fees from Abbott, Asahi, BD, Bayer, Boston Scientific, Conavi, Concept Medical, Cook, Cordis, Endovascular Engineering, Evident Vascular, GE, Gore, Haemonetics, Medtronic, Nipro, Penumbra, Philips, RapidAI, Rampart IC, R3, Regeneron, Shockwave, Siemens, SoniVie, Teleflex, Terumo, Thrombolex, VentureMed, Verve, and Zoll. Dr Rosovsky reports research funding from Bristol Myers Squibb (BMS) and Janssen; consultancy/advisory board participation fees from Abbott, BMS, Dova, Janssen, Inari, Inquis, and Penumbra; is the National Lead Investigator for Penumbra, STORM-PE trial; and is the President of The Pulmonary Embolism Response Team Consortium. The remaining authors report no conflict of interests.

Funding

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

ORCID iDs

Wenzhu Li

Stavros K Kakkos

Ahmed A Tawakol

Peter K Henke

Eric A Secemsky

Rachel P Rosovsky

Supplemental material

Supplemental material for this article is available online.

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