Clinical Surveillance vs Anticoagulation Therapy for Isolated Subsegmental Pulmonary Embolism: A Systematic Review of Clinical Outcomes

Abstract

Background

This systematic review aims to evaluate and compare differences in clinical outcomes for adult patients diagnosed with ISSPE who were managed with anticoagulation vs clinical surveillance.

Methods

PubMed, Embase, ProQuest, Cochrane, and Google Scholar were searched to identify studies evaluating the use of anticoagulation and/or clinical surveillance in patients diagnosed with ISSPE. The search included studies published up to August 3, 2023. Outcomes of interest included 90-day recurrent venous thromboembolism (VTE), major bleeding, and all-cause mortality rates.

Results

Ten studies were included with a total of 1224 patients. Of these patients, 791 were treated with anticoagulation and 433 underwent surveillance. Studies found no difference in recurrent VTE rates, with the majority of studies reporting no recurrence. Of the studies that reported VTE recurrence, rates were .5% to 1.4% for the anticoagulation groups and 3.1% to 3.2% for the surveillance groups. Major bleeding rates were also similar. In anticoagulated patients, major bleeding rates ranged from 1% to 10%. In clinical surveillance patients, the majority found no rate of major bleeding, with 2 studies reporting rates of .8% to 3.2%. Mortality rates ranged widely with no significant differences reported.

Conclusion

Clinical surveillance appears to be a safe and effective alternative to anticoagulation in patients with ISSPE. Ninety-day rates of recurrent VTE, major bleeding, and mortality were comparable between groups. These findings highlight the need for updated practice management guidelines to improve patient outcomes.

Keywords

subsegmental pulmonary embolism venous thromboembolism deep vein thrombosis mortality major bleeding anticoagulation surveillance

Background

The incidence of pulmonary embolism has increased significantly since the introduction of computed tomography pulmonary angiography (CTPA), with some studies demonstrating elevations of up to 81%.¹ Moreover, the rate of subsegmental pulmonary embolism (SSPE) diagnoses has almost doubled when comparing earlier studies using single-row detector CT to more recent studies using multi-row detector CT.² Despite these advances in imaging, there has been only minimal reduction in mortality, raising concerns about diagnostics reliability and existing practice management.¹ Many patients with isolated SSPE (ISSPE) are diagnosed incidentally and have been found to have lower D-dimer levels, fewer deep vein thromboses (DVTs), and less frequent EKG changes.^1,3 Additionally, these patients are less likely to become hypoxic compared to patients with non-subsegmental PE. This suggests that ISSPE may pose lower risks to patients compared to more proximal PE.

The use of anticoagulation vs clinical surveillance for ISSPE is controversial throughout the literature. One review by den Exter et al found that patients with ISSPE have similar risk of recurrent venous thromboembolism (VTE) when compared to those with proximal thrombus, suggesting the need for anticoagulation.⁴ However, other retrospective cohort studies have reported that management of SSPE with anticoagulation did not yield improved outcomes when compared to clinical surveillance.^5,6 Notably, these studies did identify higher rates of major bleeding in the anticoagulated group.

A previous 2018 systematic review by Bariteau et al was unable to recommend anticoagulation or surveillance due to low numbers of patients and heterogeneity among studies.⁷ Furthermore, Yoo et al conducted a systematic review in 2020 with a specific focus on identifying randomized controlled trials for ISSPE, but no eligible studies were identified for inclusion.⁸ Due to this paucity of data, both the European Society of Cardiology (ESC) and the American College of Chest Physicians (ACCP) currently lack strong management guidelines for patients with ISSPE.^9,10 Given the expanding body of literature since the last revision of these guidelines in 2020, an updated systematic review of outcomes in ISSPE patients managed with clinical surveillance vs anticoagulation therapy is warranted. This will ultimately allow for the creation of stronger evidence-based recommendations.

Objectives

This systematic review aims to evaluate and compare differences in clinical outcomes for adult patients diagnosed with single and/or multiple isolated subsegmental pulmonary embolism managed with clinical surveillance or anticoagulation therapy in order to provide more definitive evidence and guidance for future practice management guidelines. Clinical outcomes evaluated for this study include 90-day rates of recurrent VTE (pulmonary embolism or deep vein thrombosis), major bleeding, and all-cause mortality.

Population, Intervention, Comparator, and Outcomes

PICO 1: In adult patients with ISSPE undergoing either clinical surveillance or anticoagulation therapy, is there a difference in 90-day recurrent VTE rates?

PICO 2: In adult patients with ISSPE undergoing either clinical surveillance or anticoagulation therapy, is there a difference in 90-day major bleeding rates?

PICO 3: In adult patients with ISSPE undergoing either clinical surveillance or anticoagulation therapy, is there a difference in 90-day all-cause mortality?

Methods

Data Sources and Search Strategy

This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and has been registered with PROSPERO (identification number: CRD42023452019). A comprehensive search of PubMed, Embase, ProQuest, Google Scholar, and Cochrane databases was performed to identify studies that assessed the outcomes of adult patients with ISSPE who underwent clinical surveillance or anticoagulation therapy. ISSPE was defined as one or multiple PEs limited to the subsegmental pulmonary arteries without evidence of larger artery involvement. The search included all studies published up to August 3, 2023. The Boolean query used for this review can be found in the Supplementary file eTable 1.

Study Selection and Eligibility Criteria

This systematic review included original research articles, such as prospective studies, retrospective studies, and randomized controlled trials. Selected studies included adult patients with single or multiple ISSPE who were treated with anticoagulation or clinical surveillance. Studies were included if they evaluated any of the following outcomes of interest: 90-day recurrent VTE rates (DVT or PE), 90-day major bleeding rates, and 90-day all-cause mortality rates. Only studies written in English were included.

Exclusion criteria included studies that exclusively evaluated high-risk patient populations, such as those with active malignancy. Additionally, studies were excluded if they did not report quantitative data on the outcomes of interest or did not stratify outcomes by anticoagulation and/or clinical surveillance groups. Lastly, review articles, commentaries, case reports, meta-analyses, and other systematic reviews were excluded.

Data Collection

All authors participated in the comprehensive literature search and individually evaluated the articles’ titles and abstracts to determine eligibility based on the inclusion and exclusion criteria. All authors participated in the review of discrepancies and inconsistencies in the screening of selected studies. Any discrepancies and inconsistencies identified in the screening of selected studies were discussed and resolved by all authors. All selected articles underwent an additional screening process to assess their overall relevance. Data was then extracted from full-text articles and incorporated into this systematic review. The extracted data encompassed authors, publication date, study design, patient demographics, and desired outcomes. A PRISMA diagram illustrating the data search process is depicted in Figure 1.

Study Outcomes

The primary study outcome was 90-day recurrent VTE rates in adult patients managed with clinical surveillance or anticoagulation therapy for ISSPE. Secondary outcomes included 90-day major bleeding rates and 90-day mortality rates. Recurrent VTE was defined as a new DVT or PE diagnosed within 3 months of the initial ISSPE diagnosis. The major bleeding definition from the International Society on Thrombosis and Haemostasis was used: fatal or overt bleeding in a critical site, a decrease in hemoglobin of at least 2 g/dL, or bleeding requiring transfusion of 2 or more units of packed red blood cells.¹¹

Risk of Bias Assessment and Quality of Evidence

The Joanna Briggs Institute (JBI) critical appraisal checklist for observational studies was used to evaluate the risk of bias (Supplementary file eTable 2).¹² Additionally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group Criteria were used to assess the quality of evidence (Supplementary file eTable 3).¹³ Quality of evidence was moderate or high in 8 studies^6,14-20 and low in 2 studies.^21,22

Results

Systematic Review

In a comprehensive search across five databases, 4920 studies were identified for possible inclusion. Eliminating duplicate entries resulted in 656 unique articles. After further screening by title and abstract and performing full-text reviews, 10 studies remained with a total of 1224 patients (Figure 1). This included 4 prospective studies^14,18,21,22 and 6 retrospective studies.^{6,15-17,19,20} Seven studies evaluated patients with both single and multiple ISSPE^{6,14,16,17,20-22} and 3 studies evaluated patients with single ISSPE only.^15,18,19 A total of 791 patients received anticoagulation for ISSPE with an average age of 63.1 years old and 59.7% were male.^6,15-22 Among the 433 patients who underwent clinical surveillance, the average age was 58.6 years old and 68.4% were male.^6,14-20 Complete study characteristics and patient demographics for each group can be found in Tables 1 and 2.

Table 1.

Anticoagulation Group Demographics and Study Characteristics.

Study Characteristics and Demographics of Anticoagulation Groups
Author (Year)	Study Design	Country	Patient Population	Total ISSPE Patients (n)	Single SSPE, Multiple SSPE, or Both	Received Anticoagulation, n (%)	Mean Age (years)	Male Gender, n (%)
Castaner et al (2022)	Retrospective	Spain	Medical	59	Single	41 (69.5%)	70.1	31 (52.5%)
Li et al (2022)	Prospective	New Zealand	Medical and surgical	38	Single	7 (18.4%)	72.7	7 (100%)
Mehta et al (2014)	Retrospective	New Zealand	Medical and surgical	32	Single	20 (62.5%)	69.1	5 (25%)
Cambron et al (2020)	Prospective	U.S.	Medical and surgical	220	Both	220 (100%)	61.4	122 (55.5%)
Dahan et al (2022)	Retrospective	Australia	Medical and surgical	166	Both	123 (74.10%)	69	66 (39.8%)
Donato et al (2010)	Retrospective	U.S.	Medical	93	Both	71 (76.34%)	63.5	41 (44.1%)
Eyer et al (2005)	Retrospective	U.S.	Medical and surgical	77	Both	45 (58.44%)	51	39 (50.7%)
Hirao-Try et al (2022)	Prospective	U.S.	Medical and surgical	202	Both	202 (100%)	60.9	124 (61.4%)
Raslan et al (2018)	Retrospective	U.S.	Medical and surgical	71	Both	62 (87%)	67.5	NR

Abbreviations: NR = not reported; ISSPE = isolated subsegmental pulmonary embolism.

Table 2.

Clinical Surveillance Group Demographics and Study Characteristics.

Study Characteristics and Demographics of Clinical Surveillance Groups
Author (Year)	Study Design	Country	Patient Population	Total ISSPE Patients (n)	Single SSPE, Multiple SSPE, or Both	Received Clinical Surveillance, n (%)	Mean Age (years)	Male Gender, n (%)
Castaner et al (2022)	Retrospective	Spain	Medical	59	Single	18 (30.5%)	70.1	31 (52.5%)
Li et al (2022)	Prospective	New Zealand	Medical and surgical	38	Single	31 (82.6%)	69.7	18 (58.1%)
Mehta et al (2014)	Retrospective	New Zealand	Medical and surgical	32	Single	12 (37.5%)	59.8	4 (33.3%)
Dahan et al (2022)	Retrospective	Australia	Medical and surgical	166	Both	43 (26%)	65	21 (48.8%)
Donato et al (2010)	Retrospective	U.S.	Medical	93	Both	22 (23.6%)	63.5	41 (44.1%)
Eyer et al (2005)	Retrospective	U.S.	Medical and surgical	77	Both	32 (42%)	51	39 (50.7%)
Le Gal et al (2021)	Prospective	Canada, France, Netherlands, and Switzerland	Medical	266	Both	266 (100%)	55.6	136 (51.1%)
Raslan et al (2018)	Retrospective	U.S.	Medical and surgical	71	Both	9 (12.7%)	67.5	NR

Abbreviations: NR = not reported; ISSPE = isolated subsegmental pulmonary embolism.

For patients receiving anticoagulation for ISSPE, 8 studies reported 90-day recurrent VTE rates,^{6,15-19,21,22} 6 studies reported major bleeding rates,^{6,15,18,19,21,22} and 9 studies reported all-cause mortality rates (Table 3).^6,15-22 For patients undergoing clinical surveillance, 8 studies reported recurrent VTE rates,^6,14-20 5 reported major bleeding rates,^{6,14,15,18,19} and 8 reported all-cause mortality rates (Table 4).^6,14-20

Table 3.

90-Day Clinical Outcomes for ISSPE Patients Who Received Anticoagulation.

Anticoagulation Group 90-Day Outcomes
	Author (Year)	Recurrent VTE, n (%)	Major Bleeding, n (%)	All-Cause Mortality, n (%)
Patients with single ISSPE only	Castaner et al (2022)	0 (0%)	2 (4.9%)	1 (2.4%)
	Li et al (2022)	0 (0%)	0 (0%)	1 (14.3%)
	Mehta et al (2014)	0 (0%)	2 (10%)	1 (5%)
Patients with single or multiple ISSPE	Cambron et al (2020)	2 (.9%)	3 (1.4%)	2 (.9%)
	Dahan et al (2022)	0%	NR	26 (21.1%)
	Donato et al (2010)	1 (1.4%)	5 (7.0%)	2 (2.8%)
	Eyer et al (2005)	0 (0%)	NR	2 (4.4%)
	Hirao-Try et al (2022)	1 (.5%)	2 (1.0%)	16 (7.9%)
	Raslan et al (2018)	NR	NR	10 (16.1%)

Abbreviations: NR = not reported; VTE = venous thromboembolism; ISSPE = isolated subsegmental pulmonary embolism.

Table 4.

90-Day Outcomes for ISSPE Patients Who Underwent Clinical Surveillance.

Clinical Surveillance Group 90-Day Outcomes
	Author (Year)	Recurrent VTE, n (%)	Major Bleeding, n (%)	All-Cause Mortality, n (%)
Patients with single ISSPE only	Castaner et al (2022)	0 (0%)	0 (0%)	0 (0%)
	Li et al (2022)	1 (3.2%)	1 (3.2%)	3 (9.7%)
	Mehta et al (2014)	0 (0%)	0 (0%)	1 (8.3%)
Patients with single or multiple ISSPE	Dahan et al (2022)	0 (0%)	NR	7 (16.3%)
	Donato et al (2010)	0 (0%)	0 (0%)	0 (0%)
	Eyer et al (2005)	0 (0%)	NR	5 (15.6%)
	Le Gal et al (2021)	8 (3.0%)	2 (.8%)	4 (1.5%)
	Raslan et al (2018)	0 (0%)	NR	4 (44.4%)

Abbreviations: NR = not Reported; VTE = venous thromboembolism; ISSPE = isolated subsegmental pulmonary embolism.

Recurrent VTE Rates: Anticoagulation vs Clinical Surveillance

Eight studies evaluated 90-day recurrent VTE rates in ISSPE patients receiving anticoagulation. One prospective study and 4 retrospective studies found 0% recurrent VTE rates.^15-19 Two prospective studies and 1 retrospective study found rates ranging from .5% to 1.4%.^6,21,22 Eight studies evaluated recurrent VTE rates for patients undergoing clinical surveillance. Six retrospective studies found a 0% recurrent VTE rate^{6,15-17,19,20} and 2 prospective studies found rates of 3.1% to 3.2%.^14,18 Mehta et al and Li et al directly compared recurrent VTE rates between the 2 groups and found no statistically significant differences (P > .05).^18,19

Major Bleeding Rates: Anticoagulation vs Clinical Surveillance

Six studies evaluated 90-day major bleeding rates in ISSPE patients who received anticoagulation. Five of these studies, including 3 retrospective and 2 prospective studies, reported major bleeding rates ranging from 1.0% to 10%,^{6,15,19,21,22} while 1 prospective study by Li et al found a 0% bleeding rate.¹⁸ Five studies evaluated major bleeding rates in ISSPE patients who underwent clinical surveillance. Two prospective studies reported rates of .8% and 3.2%,^14,18 while 3 retrospective studies had no reports of major bleeding.^6,15,19 Mehta et al and Li et al found no significant differences in bleeding rates between groups (P > .05).^18,19

Mortality Rates: Anticoagulation vs Clinical Surveillance

Nine studies investigated mortality in ISSPE patients receiving anticoagulation, with mortality rates ranging from .9% to 21.1%.^6,15-22 Eight studies investigated mortality in ISSPE patients undergoing clinical surveillance. Rates ranged from 1.5% to 16.3% in 5 of these studies.^14,16-19 Two retrospective studies by Castaner et al and Donato et al found 0% mortality rates, while another retrospective study by Raslan et al found a rate of 44.4%.^6,15,20 Dahan et al found no significant differences in 90-day mortality between groups (P = .416).¹⁶ Mehta et al and Li et al also found no significant differences (P > .05).^18,19

Discussion

This systematic review found similar rates of 90-day clinical outcomes for ISSPE patients receiving anticoagulation compared to clinical surveillance. Of the studies that directly compared groups, no significant difference was found for any outcome of interest. The majority of studies reported no recurrent VTE for either group. Among the studies that did have VTE recurrence, rates were low and supported by similar levels of evidence. Likewise, major bleeding rates were comparable, with most studies reporting no major bleeding events for patients undergoing clinical surveillance, whereas nearly all studies documented some degree of major bleeding for patients receiving anticoagulation therapy. Lastly, mortality rates were also similar between groups. Notably, 2 studies found no mortality for clinical surveillance patients, while all studies evaluating anticoagulated patients had some level of mortality.

Recurrent VTE rates were low, with the majority of studies for both treatment modalities reporting no recurrence. Neither of the studies that directly compared rates between groups found statistically significant differences.^18,19 Notably, 4 out of the 5 studies that did report recurrent VTE for the 2 groups were prospective in nature, which is a higher level of evidence than the studies that found no recurrence.^14,18,21,22 Regardless, findings from our study align with those from the 2018 systematic review and meta-analysis by Bariteau et al, who found similar VTE recurrence rates between groups.⁷ In that study, the pooled recurrent VTE rates were lower in the clinical surveillance group compared to the anticoagulation group. Our observations of more recent literature, including 5 studies published since the aforementioned systematic review, further substantiate the safety profile of clinical surveillance in ISSPE patients.

90-Day Major Bleeding Rates

While major bleeding rates were not statistically different between anticoagulation and clinical surveillance groups, bleeding was more commonly reported in studies evaluating anticoagulated patients, with only 1 of 6 studies reporting a 0% bleeding rate.¹⁸ Conversely, 3 out of the 5 studies evaluating clinical surveillance patients had no incidence of major bleeding.^6,15,19 Moreover, the highest rate of major bleeding for anticoagulated patients was over 3 times greater than the highest rate of major bleeding for surveillance patients.^18,19 Therefore, since anticoagulation was not found to reduce risk of VTE recurrence, ISSPE patients receiving anticoagulation may be undertaking an unnecessary risk of bleeding. A review by Shoeb et al found 90-day major bleeding rates to be as high as 13% in older high-risk patients receiving anticoagulation.²³ Findings from our study provide evidence not previously identified by studies such as Bariteau et al, which was unable to find any major bleeding data for clinical surveillance patients. Additionally, the studies included in our review had consistent definitions of major bleeding unlike those in the aforementioned review, allowing for more homogeneity among studies.

Mortality rates were not significantly different between groups and varied widely for both anticoagulation and clinical surveillance groups. Raslan et al was an apparent outlier, finding a surveillance group mortality rate over twice that of any other reported mortality rate; however, the number of patients in this group was very low. Overall, our findings are similar to the previous review by Bariteau et al, who found similar pooled mortality rates between groups.⁷ It is important to note that both our study and Bariteau et al analyzed all-cause mortality and, therefore, includes patients who died from non-VTE-related causes. While we would have liked to evaluate solely VTE-related deaths, the lack of consistency in reported mortality data precluded us from performing such an analysis. Future studies should aim to evaluate this outcome more specifically in order to determine the mortality risks of ISSPE.

Findings from this study have many implications regarding patient care algorithms, patient outcomes, associated costs, and practice management guidelines. A review by Grosse et al in 2015 found that treatment with anticoagulation places a significant burden on patients and hospitals, with the average cost of acute VTE treatment ranging between $12,000 and $15,000 per patient in the first year.²⁴ This cost burden to patients and health care systems would be somewhat alleviated by movement toward treatment of SSPE with surveillance. This treatment strategy would decrease health care utilization, as anticoagulant monitoring is no longer needed, and reduce the cost associated with adverse outcomes of anticoagulation such as bleeding and heparin-induced thrombocytopenia.²⁴

Existing guidelines regarding SSPE management vary significantly across major organizations. The American College of Chest Physicians provides a weak recommendation that low-risk SSPE patients with no proximal PE or DVT should undergo monitoring without anticoagulation.²⁵ Moreover, the American Society of Hematology offers no specific guidelines for ISSPE while the European Society of Cardiology recommends anticoagulation for incidental PE in cancer patients.^9,26 It is noteworthy that these guidelines only consider literature published up until 2020. Given that half of the studies included in our review were published after 2020, we recommend revisiting these guidelines in order to provide more robust, updated practice management guidelines for SSPE patients.

We offer several recommendations based on the findings from this systematic review. Our study supports the safety of surveillance in ISSPE patients when compared to anticoagulation. In order to substantiate these findings, we recommend larger studies be conducted to provide stronger levels of evidence and determine a standardized surveillance protocol. Ongoing randomized controlled clinical trials such as the Surveillance vs Anticoagulation for low-risk patients with isolated subsegmental pulmonary embolism (SAFE-SSPE) aims to investigate the efficacy and safety of surveillance in low-risk SSPE patients. In addition to this, we recommend investigating ISSPE outcomes in higher risk patient populations, such as those with active malignancy, recent surgery, or trauma in order to allow for more comprehensive and specific recommendations. Additionally, studies should aim to stratify outcomes based on the type and timing of anticoagulation used. A retrospective study by Pawar et al found lower rates of recurrent VTE hospitalization for patients receiving apixaban compared to warfarin, highlighting the potential effects of different pharmacologic treatments on outcomes.²⁷ Future research should also stratify outcomes by number of SSPEs, such as single vs multiple, to delineate the risks of these emboli. Lastly, because our study evaluated specifically 90-day outcomes, we recommend future studies evaluate these outcomes at additional time frames such as 12 months.

Limitations of this systematic review include the small sample sizes and single-center data collection among many of the included studies. Despite our exclusion of studies that focused on specific patient populations, some inherent heterogeneity persisted among patient groups across different studies. This includes variations in relevant comorbidities such as cancer, thrombophilia, and prior history of VTE. Moreover, due to the lack of clear and specific guidelines for the management of ISSPE, there was significant variability in the decision to use anticoagulation, as well as in the timing and choice of medication. Lastly, it is important to note that patients may have had asymptomatic, and therefore undocumented, VTE recurrence.

This systematic review provides an updated review of the literature regarding ISSPE treatment and reinforces the apparent safety of clinical surveillance in these patients. Recurrent VTE, major bleeding, and mortality rates were all found to be comparable between anticoagulation and clinical surveillance groups. These findings can serve as valuable input for shaping future guidelines, ultimately leading to stronger recommendations for managing patients with ISSPE.

Conclusion

Findings from this systematic review demonstrate that clinical surveillance in the management of patients with isolated subsegmental pulmonary embolism is likely safe and effective when compared to anticoagulation in terms of recurrent VTE, major bleeding, and mortality rates. Future research should focus on assessing the effects of anticoagulation vs clinical surveillance in more individualized patient populations, thereby providing more robust evidence-based practices.

Supplemental Material

Supplemental Material - Clinical Surveillance vs Anticoagulation Therapy for Isolated Subsegmental Pulmonary Embolism: A Systematic Review of Clinical Outcomes

Supplemental Material for Clinical Surveillance vs Anticoagulation Therapy for Isolated Subsegmental Pulmonary Embolism: A Systematic Review of Clinical Outcomes by Brian Chin, Caitlin Tweedie, Hazem Nasef, Nickolas Hernandez, D-Dre Wright, Muhammad Usman Awan, and Adel Elkbuli in The American Surgeon™

Footnotes

Author Contributions

Study design and conception: AE; data collection, analysis, and interpretations: BC, CT, HN, NH, DW, MA, and AE; manuscript preparation and drafting: BC, CT, HN, NH, DW, MA, and AE; critical revisions of the manuscript: BC, CT, HN, NH, DW, MA, and AE.

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.

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

Please find the following supplemental material available below.

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