Anticoagulant treatment for subsegmental pulmonary embolism

  • Review
  • Intervention

Authors

  • Hugo HB Yoo,

    Corresponding author
    1. Botucatu Medical School, UNESP - Univ Estadual Paulista, Department of Internal Medicine, Botucatu, Sao Paulo, Brazil
    • Hugo HB Yoo, Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista, Distrito de Rubiao Junior, s/n, Campus de Botucatu, Botucatu, Sao Paulo, 18618-970, Brazil. hugo@fmb.unesp.br.

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  • Thais HAT Queluz,

    1. Botucatu Medical School, UNESP - Univ Estadual Paulista, Department of Internal Medicine, Botucatu, Sao Paulo, Brazil
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  • Regina El Dib

    1. Botucatu Medical School, UNESP - Univ Estadual Paulista, Department of Anaesthesiology, Botucatu, São Paulo, Brazil
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Abstract

Background

Acute pulmonary embolism (PE) is a common cause of death, accounting for 50,000 to 200,000 deaths annually. It is the third most common cause of mortality among the cardiovascular diseases, after coronary artery disease and stroke.

The advent of multi-detector computed tomographic pulmonary angiography (CTPA) has allowed better assessment of PE regarding visualisation of the peripheral pulmonary arteries, increasing its rate of diagnosis. More cases of peripheral PEs, such as isolated subsegmental PE (SSPE) and incidental PE, have thereby been identified. These two conditions are usually found in patients with few or none of the classic PE symptoms such as haemoptysis or pleuritic pain, acute dyspnoea or circulatory collapse. However, in patients with reduced cardio-pulmonary (C/P) reserve the classic PE symptoms can be found with isolated SSPEs. Incidental SSPE is found casually in asymptomatic patients, usually by diagnostic imaging performed for other reasons (for example routine CT for cancer staging in oncologic patients).

Traditionally, all PEs are anticoagulated in a similar manner independent of the location, number and size of the thrombi. It has been suggested that many patients with SSPE may be treated without benefit, increasing adverse events by possible unnecessary use of anticoagulants.

Patients with isolated SSPE or incidental PE may have a more benign clinical presentation compared with those with proximal PEs. However, the clinical significance in patients and their prognosis have to be studied to evaluate whether anticoagulation therapy is required.

Objectives

To assess the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE.

Search methods

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched October 2013) and CENTRAL (2013, Issue 9). MEDLINE, EMBASE, LILACS and clinical trials databases were also searched (October 2013).

Selection criteria

Randomised controlled trials of anticoagulation therapy versus no intervention in patients with SSPE or incidental SSPE.

Data collection and analysis

Two review authors inspected all citations to ensure reliable selection. We planned for two review authors to independently extract data and to assess the methodological quality of identified trials using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions.

Main results

No studies were identified that met the inclusion criteria.

Authors' conclusions

There is no randomised controlled trial evidence for the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE, and therefore we can not draw any conclusions. Well-conducted research is required before informed practice decisions can be made.

Résumé scientifique

Traitement anticoagulant pour l'embolie pulmonaire sous-segmentaire

Contexte

L'embolie pulmonaire aiguë (EP) est une cause fréquente de décès, représentant 50 000 à 200 000 décès par an. Elle est la troisième cause la plus fréquente de mortalité parmi les maladies cardio-vasculaires, après la maladie coronarienne et l'accident vasculaire cérébral (AVC).

L'introduction de l'angiographie tomographique pulmonaire (CTPA) à détecteurs multiples assistée par ordinateur a permis une meilleure évaluation de l'EP concernant la visualisation des artères pulmonaires périphériques, augmentant son taux de diagnostic. Plus de cas d'EP périphériques, tels que l'EP sous-segmentaire isolée (EPSS) et l'EP accidentelle, ont donc été identifiés. Ces deux pathologies sont généralement observées chez les patients avec peu ou pas de symptômes classiques, tels que la douleur hémoptysique et pleurétique, une respiration aiguë, ou un collapsus des voies respiratoires. Cependant, chez les patients présentant une réserve cardio-pulmonaire (C / P) réduite, les symptômes classiques de l'EP peuvent être observés lors d'EPSS isolées. L'EPSS accidentelle est occasionnellement détectée chez les patients asymptomatiques, généralement par l'imagerie diagnostique réalisée pour d'autres raisons (par exemple la TDM de routine pour la stadification du cancer chez les patients oncologiques).

Traditionnellement, toutes les EP sont anticoagulées de manière similaire, indépendamment de l'emplacement, du nombre et de la taille du thrombus. Il a été suggéré que de nombreux patients atteints d'EPSS peuvent être traités sans bénéfice, augmentant les effets indésirables par une possible utilisation non nécessaire d'anticoagulants.

Les patients souffrant d'EPSS isolée ou accidentelle pourraient avoir une présentation clinique plus bénigne par rapport à ceux atteints d'une EP proximale. Toutefois, la signification clinique et le pronostic chez ces patients doivent être étudiés pour évaluer si un traitement anticoagulant est nécessaire.

Objectifs

Évaluer l'efficacité et l'innocuité du traitement anticoagulant par rapport à l'absence d'intervention chez les patients atteints de d'embolie pulmonaire sous-segmentaire (EPSS) isolée ou accidentelle.

Stratégie de recherche documentaire

Le registre des essais du groupe Cochrane sur les maladies vasculaires périphériques a effectué des recherches dans le registre spécialisé (dernière recherche en octobre 2013) et CENTRAL (2013, numéro 9). MEDLINE, EMBASE, LILACS et les bases de données d'essais cliniques ont également été consultées (octobre 2013).

Critères de sélection

Essais contrôlés randomisés portant sur un traitement anticoagulant par rapport à l'absence d'intervention chez les patients atteints d'EPSS ou d'EPSS accidentelle.

Recueil et analyse des données

Deux auteurs de la revue ont examiné toutes les références bibliographiques pour s'assurer de la fiabilité de sélection. Deux auteurs de la revue devaient extraire les données et évaluer la qualité méthodologique des essais identifiés en utilisant les critères recommandés dans le guide d'examen systématique des interventions Cochrane

Résultats principaux

Aucune étude qui répondait aux critères d'inclusion n'a été identifiée.

Conclusions des auteurs

Il n'existe pas de preuves issues d'essais contrôlés randomisés concernant l'efficacité et l'innocuité du traitement anticoagulant par rapport à l'absence d'intervention chez les patients atteints d'embolie pulmonaire sous-segmentaire (EPSS) isolée ou accidentelle, nous ne pouvons donc pas apporter de conclusions. Des recherches supplémentaires bien menées sont nécessaires avant de prendre des décisions éclairées.

Resumo

Tratamento anticoagulante para embolia pulmonar subsegmentar

Introdução

Embolia pulmonar (EP) aguda é causa comum de morte, responsável por 50.000 a 200.000 mortes por ano. Após a doença coronariana arterial e acidente cerebral, é a terceira causa mais comum entre doenças cardiovasculares.

Com advento da angiotomografia pulmonar multidetectora foi possível realizar melhor avaliação da EP em relação à visualização das artérias pulmonares periféricas e com isso aumentar a taxa de diagnóstico. Em decorrência mais casos de EPs periféricas como EP subsegmentar (EPS) isolada ou incidental puderam ser identificadas. Estas duas condições são geralmente encontradas em pacientes com pouca ou nenhuma sintomatologia clássica de EP como hemoptise, dor pleural, dispnéia aguda ou colapso circulatório. Entretanto, em pacientes com reserva cárdio-pulmonar reduzida os sintomas clássicos de EP podem ser encontrados em EPS isolada. EPS incidental pode ser encontrada casualmente em pacientes assintomáticos, geralmente por métodos de imagem realizados por outros motivos (tomografia de rotina para estadiamento de pacientes oncológicos).

Tradicionalmente, todos os casos de EP são anticoagulados de maneira similar independentemente de localização, número e tamanho do trombo. Tem sido sugerido na literatura que em alguns pacientes com EPS o tratamento pode não ser benéfico, aumentando eventos adversos por possível uso desnecessário de anticoagulantes.

Pacientes com EPS isolada ou incidental podem ter a apresentação clínica mais benigna comparada àqueles com EPs proximais. Entretanto, o significado clínico e prognóstico destes pacientes devem ser estudados para avaliar se a terapia anticoagulante é necessária.

Objetivos

Avaliar a efetividade e segurança de terapia anticoagulante versus nenhuma intervenção em pacientes com EPS isolada ou incidental.

Métodos de busca

The Cochrane Peripheral Vascular Diseases Group pesquisou em Specialised Register (última busca em Outubro de 2013) e na CENTRAL (2013, fascículo 9). Os autores pesquisaram também no MEDLINE, EMBASE, LILACS e na base de dados de ensaios clínicos (Outubro de 2013).

Critério de seleção

Ensaios clínicos controlados e randomizados de terapia anticoagulante versus nenhuma intervenção em pacientes com EPS isolada ou incidental.

Coleta dos dados e análises

Dois autores examinaram todas as citações para seleção assegurada Dois autores examinaram todas as citações para seleção assegurada dos ensaios clínicos, extraíram os dados independentemente e avaliaram a qualidade metodológica dos ensaios clínicos identificados utilizando os critérios recomendados pelo the Cochrane Hadbook for Systematic Review of Interventions..

Principais resultados

Nenhum estudo foi identificado que preencheu os critérios de inclusão

Conclusão dos autores

Não há ainda evidências provindas de ensaios clínicos randomizados sobre a efetividade e segurança da terapia anticoagulante versus nenhuma intervenção em pacientes com EPS isolada ou incidental e portanto, não pudemos apresentar nenhuma conclusão. Pesquisas bem conduzidas são necessárias para responder esta questão.

Plain language summary

Anticoagulant treatment for subsegmental pulmonary embolism

Acute pulmonary embolism (PE) is a common cause of death, accounting for 50,000 to 200,000 deaths annually. It is the third most common cause of mortality among the cardiovascular diseases, after coronary artery disease and stroke.

The advent of multi-detector computed tomographic pulmonary angiography (CTPA) has allowed better assessment of PE regarding visualisation of the peripheral pulmonary arteries, increasing its rate of diagnosis. More cases of peripheral PEs, such as isolated subsegmental PE (SSPE) and incidental PE, have thereby been identified. These two conditions are usually found in patients with few or no classic symptoms such as coughing (including coughing up blood), chest or upper back pain, acute shortness of breath, or general or specific failure of the circulation that is either cardiac or peripheral in nature. However, in patients with an impaired cardiac and pulmonary condition the classic PE symptoms can be found with isolated SSPEs. Incidental SSPE is found casually in asymptomatic patients, usually by diagnostic imaging performed for other reasons (for example routine computed tomography (CT) for cancer staging in oncologic patients).

Patients with isolated SSPE or incidental PE may have a more benign clinical presentation compared with those with proximal PEs. However, the clinical significance and prognosis in these patients has to be studied to evaluate whether anticoagulation therapy is required.

No studies met the inclusion criteria of the review. There is no randomised controlled trial evidence for the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE and, therefore, we can not draw any conclusions. Well-conducted research is required before informed practice decisions can be made.

Résumé simplifié

Traitement anticoagulant pour l'embolie pulmonaire sous-segmentaire

L'embolie pulmonaire aiguë (EP) est une cause fréquente de décès, représentant 50 000 à 200 000 décès par an. Elle est la troisième cause la plus fréquente de mortalité parmi les maladies cardio-vasculaires, après la maladie coronarienne et l'accident vasculaire cérébral (AVC).

L'introduction de l'angiographie tomographique pulmonaire (CTPA) à détecteurs multiples assistée par ordinateur a permis une meilleure évaluation de l'EP concernant la visualisation des artères pulmonaires périphériques, augmentant son taux de diagnostic. Plus de cas d'EP périphériques, tels que l'EP sous-segmentaire isolée (EPSS) et l'EP accidentelle, ont donc été identifiés. Ces deux pathologies sont généralement observées chez les patients avec peu ou pas de symptômes classiques, tels que la toux (y compris les crachats de sang), une douleur dans la poitrine ou en haut du dos, une respiration aiguë, ou un collapsus général ou spécifique de la circulation qui est de nature soit cardiaque, soit périphérique. Cependant, chez les patients souffrant d'un disfonctionnement cardiaque, les symptômes classiques de l'EP peuvent être observés lors d'EPSS isolées. L'EPSS accidentelle est occasionnellement détectée chez les patients asymptomatiques, généralement par l'imagerie diagnostique réalisée pour d'autres raisons (par exemple la tomodensitométrie (TDM) de routine pour la stadification du cancer chez les patients oncologiques).

Les patients souffrant d'EPSS isolée ou accidentelle pourraient avoir une présentation clinique plus bénigne par rapport à ceux atteints d'une EP proximale. Toutefois, la signification clinique et le pronostic chez ces patients doivent être étudiés pour évaluer si un traitement anticoagulant est nécessaire.

Aucune étude ne remplissait les critères d'inclusion de la revue. Il n'existe pas de preuves issues d'essais contrôlés randomisés concernant l'efficacité et l'innocuité du traitement anticoagulant par rapport à l'absence d'intervention chez les patients atteints d'embolie pulmonaire sous-segmentaire (EPSS) isolée ou accidentelle, nous ne pouvons donc pas apporter de conclusions. Des recherches supplémentaires bien menées sont nécessaires avant de prendre des décisions éclairées.

Notes de traduction

Traduit par: French Cochrane Centre 6th August, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Resumo para leigos

Tratamento anticoagulante para embolia pulmonar subsegmentar

Embolia pulmonar (EP) aguda é causa comum de morte, responsável por 50.000 a 200.000 mortes por ano. Após a doença coronariana arterial e derrame cerebral, é a terceira causa mais comum entre doenças cardiovasculares.

Com advento da angiotomografia pulmonar multidetectora foi possível realizar melhor avaliação da EP em relação à visualização das artérias pulmonares periféricas e com isso aumentar a taxa de diagnóstico. Em decorrência mais casos de EPs periféricas como EP subsegmentar (EPS) isolada ou incidental puderam ser identificadas. Estas duas condições são geralmente encontradas em pacientes com pouca ou nenhuma sintomatologia clássica de EP como tosse com escarro sanguinolento, dor no peito ou falta de ar aguda. Entretanto, em pacientes com condição do coração e pulmão prejudicada, os sintomas clássicos de EP podem ser encontrados em EPS isolada. EPS incidental pode ser encontrada casualmente em pacientes sem sintomas, geralmente por métodos de imagem realizados por outros motivos (tomografia de rotina para estadiamento de pacientes com câncer).

Pacientes com EPS isolada ou incidental podem ter a apresentação clínica mais benigna comparada àqueles com EPs proximais. Entretanto, o significado clínico e prognóstico destes pacientes devem ser estudados para avaliar se a terapia anticoagulante é necessária.

Não há estudos que preencheram os critérios de inclusão da revisão. Não há ainda evidência evidências provindas de ensaios clínicos randomizados sobre a efetividade e segurança de terapia anticoagulante versus nenhuma intervenção em pacientes com EPS isolada ou incidental e portanto, não pudemos ter nenhuma conclusão. Pesquisas bem conduzidas são necessárias para responder esta questão.

Notas de tradução

Traduzido por: Hugo Hyung Bok Yoo, Unidade de Medicina Baseada em Evidências da Unesp, Brazil Contato: portuguese.ebm.unit@gmail.com

Background

Description of the condition

Acute pulmonary embolism (PE) is a common cause of death, accounting for 50,000 to 200,000 deaths annually (Torbicki 2008). As many as 95% of patients who die do so prior to diagnosis, with the majority of deaths occurring in untreated patients (Dalen 2002; Jiménez 2007).

In the early 1990s helical computed tomography (CT) was introduced for the diagnosis of PE (Remy-Jardin 1992). It could reliably detect a central PE but was limited in excluding a small PE (Mullins 2000; Rathbun 2000). Recently, the advent of multi-detector row CT (MDCT) has improved visualisation up to the levels of the segmental and subsegmental pulmonary arteries (Le Gal 2006), thereby enhancing more confident diagnosis of smaller PEs. Currently, in many institutions MDCT has replaced scintigraphy as the imaging modality of choice for the detection of PE (Schoepf 2001). Furthermore, in 2007 MDCT angiography fulfilled the conditions to replace pulmonary angiography as the reference standard for the diagnosis of an acute PE (Nazaroglu 2009).

Patients with a small PE have been found to experience less dyspnoea and proximal deep venous thrombosis (DVT) and are less frequently classified as having a high clinical probability of PE as compared with those with segmental or more proximal PE. Therefore, the diagnosis is very difficult and is sometimes incidental. Approximately half of incidental PEs can involve the lobar or more proximal pulmonary arteries, whereas the other half are more distal (Dentali 2010; O'Connell 2011).

Clinicians who are interested in small PEs, particularly those limited to the subsegmental arteries and isolated subsegmental PE (ISSPE), are beginning to question whether every small embolus that is discovered at MDCT is clinically important and requires anticoagulation (Le Gal 2006).

Description of the intervention

The clinical significance of subsegmental pulmonary embolism (SSPE), ISSPE and incidental PE is uncertain, particularly in patients with few or no symptoms of PE. Nevertheless, in most of these cases patients are anticoagulated for long periods of time after the diagnosis because even patients with a proven diagnosis of small PE are believed to have an increased risk of recurrence and mortality in the near future (Eyer 2005). However, it is not known whether these emboli in fact represent a harbinger for future thromboembolic events, and there is no consistent evidence that patients with SSPE benefit from short- and long-term anticoagulation therapy.

Anticoagulation treatment should be administered immediately in all patients with a confirmed diagnosis of PE and in patients with a high clinical suspicion of acute PE who are awaiting the outcome of diagnostic tests provided there are no absolute contraindications such as active bleeding, haemorrhagic disease, severe uncontrolled hypertension and recent surgery (Kearon 2008). Prompt anticoagulation can only be achieved with parenteral anticoagulants such as unfractionated heparin (UFH), low molecular weight heparin (LMWH), or the pentasaccharide fondaparinux as a bridge to oral vitamin K antagonists (VKA) (Ageno 2012). The majority of patients receive intravenous UFH administered as a bolus followed by a continuous infusion titrated to a target activated partial thromboplastin time of two to three times the upper limit of normal. Weight-based nomograms may achieve therapeutic levels of anticoagulation more quickly (Piazza 2006).

In some situations intravenous UFH is the preferred modality of initial anticoagulation, for 1) patients with severe renal insufficiency (creatinine clearance < 30 ml/min); 2) patients at high risk of bleeding; 3) high-risk hypotensive patients; and, as a rule, 4) extremely overweight, underweight, or older patients (≥ 80 years) (Raschke 1993). With the exception of the above circumstances, UFH has largely been replaced by LMWH given subcutaneously in weight-adjusted doses.

Long-term treatment of PE with an oral VKA, such as warfarin, remains the standard therapy of choice for the majority of patients with PE. When PE is provoked by a temporary risk factor the recommended duration of treatment is at least three months. In cases of unprovoked PE or PE provoked by a permanent risk factor (for example malignancy, thrombophilia, recurrent venous thromboembolism) the treatment should be extended (Kearon 2012).

Systematic reviews of previous trials indicate that LMWH has been shown to be as safe and effective as intravenous UFH for the initial treatment of patients with PE (Segal 2007). For acute PE treatment, the limitations of UFH include an unpredictable anticoagulant response with the need for frequent monitoring, a relatively narrow therapeutic window, and the potential for severe toxicity, especially heparin-induced thrombocytopenia (HIT) in ≤ 3% of patients (Spyropoulos 2007). The three LMWH preparations currently approved for use in the United States are enoxaparin, dalteparin and tinzaparin. Compared with UFH, LMWHs have a longer plasma half-life, a more predictable dose response relationship, and lower inter-individual variability in the anticoagulant response to fixed doses. As a result of their pharmacokinetic properties, a desirable anticoagulant effect is achieved when the LMWH is administered subcutaneously either once or twice daily, for both prophylaxis and treatment, and it usually does not require dose adjustments or laboratory monitoring (Dinwoodey 2006). However, some unsolved issues need to be addressed in specific trials before LMWHs can definitively replace UFH in the treatment of all forms of PE. The therapeutic role of LMWH in patients with massive PE who are haemodynamically unstable remains undetermined.

Fondaparinux is one of a new class of antithrombotic agents and is based on the pentasaccharide region of the heparin molecule, which is specific for antithrombin binding. Fondaparinux selectively inhibits factor Xa by binding to antithrombin (Dinwoodey 2006). In haemodynamically and clinically stable patients with acute PE, fondaparinux is as safe and effective as intravenous UFH when it is administered in a fixed dose once daily by subcutaneous injection, and it does not require laboratory monitoring. Fondaparinux, given that it is excreted via the kidneys, is contraindicated in patients with severe renal insufficiency (creatinine clearance < 30 ml/min). In contrast to heparin compounds, fondaparinux does not cause heparin-induced thrombocytopaenia (HIT) (Piazza 2006).

How the intervention might work

Anticoagulants such as UFH, LMWH and fondaparinux have no significant thrombolytic action on clot burden. These drugs act by altering the dynamic balance between inherent thrombogenic and fibrinolytic processes, so reducing blood clotting. They can, therefore, prevent PE.

The outcome of patients with acute PE, as in several diseases, depends on rapid diagnosis and appropriate treatment. For patients with diagnosed PE, anticoagulation clearly improves survival and as many as 95% of patients who die do so prior to diagnosis, with the majority of deaths occurring in untreated patients (Torbicki 2008). For patients who receive appropriate treatment, the 14- and 90-day mortality rates are nearly 10% and 20%, respectively (Dalen 1975). However, there is still controversy regarding anticoagulation in patients with SSPE who are clinically stable or without symptoms of PE, or both, and little is known about the clinical significance of SSPE.

The epidemiologic patterns of PE have changed since computed tomographic pulmonary angiography (CTPA) was introduced in 1998. Compared with the pre-CTPA era, the PE incidence has risen, mortality changed little, and case-fatality decreased. This fact has created an excess of positive tests resulting in lower thresholds for diagnosis, which could be deemed over-diagnosis. Probably in this new scenario much of the increased incidence in PE consists of cases that are clinically unimportant, that is cases that would not have been fatal even if left undiagnosed and untreated (Wiener 2011).

PE is incidentally found in 1% to 6% of all patients undergoing CTPA of the thorax for indications other than PE. At autopsy, 50% to 90% of patients show recent or old PE when the examination of the pulmonary arteries is carefully performed (Ryu 1998). Gurney (Gurney 1993) has suggested that small emboli are common and that a healthy lung acts as a filter to protect the systematic circulation, suggesting that small PE can often be asymptomatic and resolve unnoticed. It is possible that incidental SSPE can represent a more benign subset of disease.

Why it is important to do this review

Currently there is no straightforward recommendation based on systematic reviews of trials for the treatment of SSPE, and there is no consistent evidence that patients with SSPE benefit from short- and long-term anticoagulation therapy. Despite this, it appears that patients with SSPE are generally treated, mainly for ethical reasons.

Objectives

To assess the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomised controlled trials (RCTs), quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods), and controlled clinical trials (CCTs) in this systematic review. This was in anticipation of not finding many RCTs in this area.

Types of participants

Adults (> 18 years old) presenting in a stable clinical condition, as defined by the included studies, and diagnosed with asymptomatic or symptomatic isolated SSPE and incidental SSPE by one of the following: computed tomography pulmonary angiography (CTPA); multi-detector computed tomography (MDCT); pulmonary digital angiography; or pulmonary arteriograms.

We defined SSPE as small peripheral clots located beyond the fifth-order pulmonary arteries, which are now frequently detected by the new generation of CTPA or MDCT (Donato 2010). SSPE typically presents with pleuritic chest pain caused by infarction, however often it is found in patients with minor symptoms or patients who are asymptomatic.

Isolated SSPE can be unique (one subsegmental vessel involved) or multiple (two or more subsegmental vessels involved) (Le Gal 2006).

Incidental SSPE is found casually in asymptomatic patients, usually by diagnostic imaging performed for other reasons (for example routine CT for cancer staging), while symptomatic SSPE is found in patients presenting with pleuritic pain or acute dyspnoea, or both.

Asymptomatic SSPE may occur in patients with distinct risk factors including hypercoagulation state, trauma or neoplasm, and in patients with deep venous thrombosis both above and below the knee. Since modern MDCT is performed frequently in these patients, for various clinical indications, the incidental detection of SSPE on routine CTPA or MDCT is not uncommon.

We planned to exclude segmental PE since its treatment is mandatory in all cases.

Types of interventions

  1. Intervention group: anticoagulation therapy

  2. Control group: no intervention

We planned to consider anticoagulation therapy administered subcutaneously, intravenously, or orally.

Types of outcome measures

Primary outcomes
  1. Three-month thromboembolic risk (recurrence defined as a new SSPE or a new event with minimal segmental defects, or both, diagnosed by CTPA)

  2. Major bleeding defined as fatal or clinically overt bleeding resulting in a fall in haemoglobin levels by 2 g/L or more or bleeding into critical anatomical sites (retroperitoneal, intraocular, pericardial, atraumatic intra-articular, subdural haematoma, intraspinal haemorrhage) or leading to transfusion of ≥ 2 U of blood or red cells (White 2008)

Secondary outcomes
  1. Six-month thromboembolic risk (recurrence defined as a new SSPE or a new event with minimal segmental defects, or both, diagnosed by CTPA)

  2. Minor bleeding defined as bleeding requiring intervention but not qualifying as a major bleed, including bleeding precipitating treatment cessation (White 2008)

  3. All-cause mortality

  4. Dropouts and losses to follow-up (compliance with treatment)

Search methods for identification of studies

Electronic searches

The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched October 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 9), part of The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library (www.thecochranelibrary.com).

The following trial databases were searched by the TSC, using the term "subsegmental", for details of ongoing and unpublished studies:

Authors' searches

MEDLINE, EMBASE and LILACS were searched using the search strategies shown in Appendix 2, Appendix 3 and Appendix 4.

Searching other resources

We checked the reference lists of the identified studies for additional citations.

Data collection and analysis

Selection of studies

Two review authors (HHBY and RED) independently screened the trials identified by the literature search. We resolved disagreements by consulting with the third review author (THATQ) and consulted with her for quality assurance of the processes.

Data extraction and management

We planned for two review authors (HHBY and RED) to independently extract data. We planned to resolve any discrepancies by discussion. We planned to use a standard data extraction form to extract the following information: characteristics of the study (design, method of randomisation); participants; interventions; outcomes (types of outcome measures, adverse events). We then planned to check for errors before entering the data into Review Manager.

Assessment of risk of bias in included studies

For the assessment of study quality, we planned to use the risk of bias approach for Cochrane reviews (Higgins 2009). We would use the following six criteria.

  • Random sequence generation

Is the allocation sequence adequately generated, for example with random number tables, computer-generated random numbers? We planned to record this as 'low risk of bias' (the method used is either adequate or unlikely to introduce confounding), 'uncertain risk of bias' (there is insufficient information to assess whether the method used is likely to introduce confounding), or 'high risk of bias' (the method used, for example a quasi-randomised trial, is likely to introduce confounding).

  • Allocation concealment

Is allocation adequately concealed in a way that would not allow either the investigators or the participants to know or influence allocation to an intervention group before an eligible participant was entered into the study (for example using central randomisation or sequentially numbered, opaque, sealed envelopes held by a third party)? We planned to record this as 'low risk of bias' (the method used, for example central allocation, is unlikely to introduce bias in the final observed effect), 'uncertain risk of bias' (there is insufficient information to assess whether the method used is likely to introduce bias in the estimate of effect), or 'high risk of bias' (the method used, for example an open random allocation schedule, is likely to introduce bias in the final observed effect).

  • Blinding

Are the study participants and personnel blinded from knowledge of which intervention a participant received? We planned to note where there has been partial blinding (for example where it has not been possible to blind participants but where outcome assessment was carried out without knowledge of group assignment). We planned to record this as 'low risk of bias' (blinding was performed adequately, or the outcome measurement is not likely to be influenced by lack of blinding), 'uncertain risk of bias' (there is insufficient information to assess whether the type of blinding used is likely to introduce bias in the estimate of effect), or 'high risk of bias' (no blinding or incomplete blinding, and the outcome or the outcome measurement is likely to be influenced by lack of blinding).

  • Incomplete outcome data

Are incomplete outcome data adequately addressed? Incomplete outcome data essentially include attrition, exclusions, and missing data. If any withdrawals occurred, were they described and reported by treatment group with the reasons given? We planned to record whether or not there were clear explanations for withdrawals and dropouts in the treatment groups. An example of an adequate method to address incomplete outcome data is the use of an intention-to-treat analysis (ITT). This item was planned to be recorded as 'low risk of bias' (the underlying reasons for missing data are unlikely to make treatment effects depart from plausible values, or proper methods have been employed to handle missing data), 'uncertain risk of bias' (there is insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data is likely to introduce bias in the estimate of effect), or 'high risk of bias' (the crude estimate of effects, for example a complete case estimate, will clearly be biased due to the underlying reasons for missing data and the methods used to handle missing data are unsatisfactory).

  • Selective reporting

Are reports of the study free from any suggestion of selective outcome reporting? We planned to interpret this as evidence that statistically non-significant results might have been selectively withheld from publication, for example selective under-reporting of data or selective reporting of a subset of data. We planned to record this as 'low risk of bias' (the trial protocol is available and all of the trial’s pre-specified outcomes that are of interest in the review have been reported, or similar), 'uncertain risk of bias' (there is insufficient information to assess whether the magnitude and direction of the observed effect are related to selective outcome reporting), or 'high risk of bias' (not all of the trial’s pre-specified primary outcomes have been reported, or similar).

  • Other bias

As a first step, we planned to copy information relevant to making a judgment on this criterion from the original publication into an assessment table. If additional information was available from the study authors, we planned to also enter this in the table along with an indication that it was unpublished information. Two review authors (HHBY and RED) planned to independently make a judgment as to whether the risk of bias for each criterion was considered to be 'low', 'uncertain', or 'high'. We would resolve disagreements by discussion. 

We planned to consider trials which were classified as low risk of bias in sequence generation, allocation concealment, blinding, incomplete data, and selective outcome reporting as low bias-risk trials. 

Measures of treatment effect

(a) Binary outcomes

For dichotomous data, we planned to use the risk ratio (RR) as the effect measure with 95% confidence interval (CI).

(b) Continuous outcomes

For continuous data, we planned to present the results as mean differences (MD) with 95% CIs. When pooling data across studies we would estimate the MD if the outcomes were measured in the same way between trials. We planned to use the standardised mean difference (SMD) to combine trials that measured the same outcome but used different methods.

Unit of analysis issues

The unit of analysis was planned to be each patient recruited into the trials.

Dealing with missing data

An intention-to-treat analysis (ITT) is one in which all the participants in a trial are analysed according to the intervention to which they were allocated, whether they received the intervention or not. We would assume that participants who dropped out were non-responders. For each trial we planned to report whether or not the investigators stated if the analysis was performed according to the ITT principle. If participants were excluded after allocation, we would report any details provided in full.

Furthermore, we would perform the analysis on an ITT basis (Newell 1992) whenever possible. Otherwise, we planned to adopt an available-case analysis.

Assessment of heterogeneity

We planned to quantify inconsistency among the pooled estimates using the I2 statistic. This illustrates the percentage of the variability in effect estimates resulting from heterogeneity rather than sampling error (Higgins 2003; Higgins 2009). I2 = [(Q - df)/Q] x 100%, where Q is the Chi2 statistic and df its degrees of freedom. We would assess heterogeneity between the trials by visual examination of the forest plot to check for overlapping CIs, the Chi2 test for homogeneity with a 10% level of significance, and the I2 statistic. We planned to use an I2 statistic value of less than 25% to denote low heterogeneity, 50% or greater significant heterogeneity, and 75% or greater substantial heterogeneity.

Assessment of reporting biases

Apart from assessing the risk of selective outcome reporting, considered under assessment of risk of bias in included studies, we planned to assess the likelihood of potential publication bias using funnel plots provided that there were at least eight trials. When small studies in a meta-analysis tend to show larger treatment effects, we would consider other causes including selection biases, poor methodological quality, heterogeneity, artefact and chance.

Data synthesis

We planned to use the fixed-effect model to analyse the data. If significant heterogeneity (for example I2 greater than 50%) was identified, we would compute pooled estimates of the treatment effect for each outcome using a random-effects model (with two or more studies). We planned to undertake quantitative analyses of outcomes on an ITT basis.

Subgroup analysis and investigation of heterogeneity

In the case of significant clinical heterogeneity (I2 > 50%), we planned to use subgroup analysis. Subgroup analyses are secondary analyses in which the participants are divided into groups according to shared characteristics and the outcome analyses are conducted to determine if any significant treatment effect occurs according to that characteristic. If data permit, we intend to carry out the following subgroup analyses:

  1. different type of anticoagulant therapy (e.g. fractionated, non-fractionated heparin);

  2. different doses for the same anticoagulant therapy (e.g. 1 mg/kg of fractionated heparin, 2 mg/kg of fractionated heparin);

  3. different routes for the non-fractionated heparin (e.g. subcutaneous, intravenous, oral);

  4. short-term (up to 30 days) versus long-term follow-up (> 30 days);

  5. different co-morbidities (e.g. chronic obstructive pulmonary disease (COPD), cardiac insufficiency);

  6. single SSPE versus multiple SSPE.

We would perform the Chi2 test for subgroup differences set at a P value of 0.05.

Sensitivity analysis

If there were an adequate number of studies, we intended to perform a sensitivity analysis to explore causes of heterogeneity and the robustness of the results. We planned to include the following factors in the sensitivity analysis, separating studies according to:

  1. type of study design (RCTs versus CCTs);

  2. trials with low risk of bias versus those with high risk of bias;

  3. rates of withdrawal for each outcome (< 20% versus ≥ 20%).

Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies.

Results of the search

See Figure 1.

Figure 1.

Study flow diagram.

Included studies

No studies were identified that met the inclusion criteria.

Excluded studies

Three studies (Donato 2010; Eyer 2005; Stein 1995) were excluded. Donato 2010 was excluded because it was a cohort study, Eyer 2005 because it was a retrospective study and Stein 1995 because it was a case series.

Risk of bias in included studies

It was not possible to review methodological quality in the absence of studies eligible for inclusion in the review.

Effects of interventions

No published and unpublished studies were identified that assessed the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE.

Discussion

Since the 1930s and the inception of anticoagulation, the PE mortality rate has been reduced from 30% to less than 3% (Meaney 1997). Traditionally, all patients with PEs are anticoagulated in a similar manner independent of the location, number and size of the thrombus, which can range from saddle to isolated subsegmental. This can explain the unchanged PE mortality rates over recent years despite all the advances in the diagnosis and treatment of the disease. Prasad 2012 suggests that many patients with subsegmental PE (SSPE) may be treated without benefit and indeed with increasing adverse events because of possible unnecessary use of anticoagulants. However, for ethical reasons and because of uncertain outcomes, all patients diagnosed with PE are still anticoagulated, regardless of clinical presentation.

Computed tomographic pulmonary angiography (CTPA) changed the assessment of PE, improving its diagnosis and, as a consequence, increasing its incidence and the proportion of patients who receive anticoagulation therapy. Despite this, the concomitant reduction of mortality that was expected in diagnosed patients has not been observed (Carrier 2010). It is possible that the additional thrombi identified by CTPA are not massive or segmental PEs but, on the contrary, could be subsegmental or incidental PE, which usually show few or no symptoms (Wiener 2011). SSPEs have been more prevalent in patients with low or intermediate probability ventilation/perfusion scans (Stein 1995; Stein 1997) and Perrier 1996 and Perrier 1999 showed that those patients can be safely monitored and managed with serial lower extremities ultrasonography without traditional anticoagulant therapy. Some authors have considered that one of the functions of the pulmonary circulation is to prevent small clots from entering the systemic circulation by acting as a filter and believe that such distal clots may occur even in healthy people, thus causing little clinical consequences (Gurney 1993; Schoepf 2004). Therefore, in theory anticoagulation in these cases would be unnecessary.

The clinical outcomes for asymptomatic and symptomatic patients with isolated SSPE that have been missed by traditional diagnostic techniques remain an enigma. A cohort study conducted by Donato 2010 found that in patients diagnosed with SSPE who were not anticoagulated the recurrence and mortality were 0% at three months follow-up, which is fairly similar to a meta-analysis of the findings for patients with a negative CTPA for PE showing the recurrence and fatal PE to be 1.4% and 0.5%, respectively (Moores 2004). In some exceptional conditions anticoagulant treatment has been discussed as unnecessary, for: a) asymptomatic or symptomatic isolated SSPE with no deep venous thrombosis (DVT), suitable C/P reserve and self-limited risk factors; b) isolated SSPE or an indeterminate MDCT result, no DVT and anticoagulation treatment contraindicated (Eyer 2005; Goodman 2005).

It is also possible that isolated SSPE or incidental PE found by CTPA represents a more benign subset of PE, which reinforces the importance of a study on the clinical significance of peripheral and small clots and, therefore, the actual necessity of anticoagulating these patients. Not doing so would avoid the risks of this type of treatment.

Summary of main results

There is currently no evidence from randomised controlled trials to assess the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE.

Overall completeness and applicability of evidence

There is currently no evidence from randomised controlled trials.

Quality of the evidence

It was not possible to review methodological quality in the absence of studies eligible for inclusion in the review.

Potential biases in the review process

We have tried to minimise potential biases in our review process by performing extensive literature searches.

Agreements and disagreements with other studies or reviews

There are few well-conducted studies comparing the clinical outcomes among treated and untreated patients with SSPE. During the search for this review we identified three articles, but none were included in this systematic review because of the observational design. A case series by Stein 1995 demonstrated that untreated patients had mild PE, characterised by pulmonary angiograms and a ventilation/perfusion scan to involve smaller vessels and result in fewer perfusion defects, which was different from the observed PE in treated patients. In the same study, death or fatal recurrent PE occurred in one of 20 (5%) untreated patients and in nine of 376 (2.4%) of those who were treated (P = NS). A retrospective study by Eyer 2005 in which 25 of 67 (37%) patients with isolated SSPE were not treated showed that no recurrent PE or adverse effects were reported during follow-up, similar to the observed finding in the treated group (0% recurrent PE and 3% mortality from other diseases). In a cohort study Donato 2010 reviewed 10,453 consecutive CTPAs over a 74-month period and 93 patients with isolated SSPE were selected for study: 71 (76%) were treated for PE and 22 (23.6%) were observed only. After a three-month follow-up, the treated group showed two not PE-related deaths (2.8%), eight bleeding events (11.3%) and one PE recurrence (1.4%), while no deaths, no PE recurrence or bleeding events were reported in the untreated group. The authors concluded that the short-term prognosis for recurrent PE may be lower than the risk of adverse events with anticoagulation in patients at high risk of haemorrhage. Comparing the results of Donato 2010 with those of Carson 1992, it can be observed that in patients with isolated SSPE the three-month outcomes, including PE recurrence and PE-related mortality, were significantly better (1.05% recurrence, 0% mortality) than the outcomes reported in treated classic PE (8% recurrence, 1.7% mortality). Although the studies reported above are not interventional, their results reinforce the theory that isolated SSPE could represent a select group of patients with favourable prognosis even if left untreated.

A systematic review and meta-analysis by Carrier 2010 showed that CTPA has increased the rate of patients diagnosed with SSPE, with 9.4% who potentially would benefit from anticoagulant treatment. However, the expected reduction of the three-month risk of thromboembolism has not occurred, therefore suggesting that SSPE may not be clinically relevant.

A cohort study conducted by den Exter 2013 analysed 3728 consecutive patients with clinically suspected PE. Isolated symptomatic SSPE was found in 116 of 748 (15.5%) patients with PE confirmed and treated. During three months of follow-up, the respective non-significant cumulative risks for recurrent venous thromboembolism (VTE) were 3.6% for SSPE and 2.5% for proximal PE (hazard ratio (HR) 1.6, 95% CI 0.5 to 4.8); and for mortality were 10.7% and 6.5% (HR 1.5, 95% CI 0.8 to 2.6). In the group in which PE had been ruled out, 25 patients (0.8%) developed VTE during follow-up with a cumulative risk of 1.1%. There were 156 deaths out of 2980 (5.2%) patients with PE ruled out and their cumulative risk (5.4%) was significantly lower compared with the risk for patients with SSPE (P = 0.01). In contrast to the hypothesis that SSPE would represent a more benign subset of PE, this study showed that for patients with symptomatic SSPE, even treated, the incidence of recurrent VTE and mortality were significantly higher than for patients without PE.

A prospective observational study assessing the safety of withholding anticoagulation in patients with isolated symptomatic SSPE without DVT is currently being performed and is recruiting participants (NCT01455818).

Therefore, the clinical equipoise in this subject would be greatly clarified by well-conducted randomised controlled trials for further evaluation of the risk-benefit ratio of anticoagulant therapy in isolated subsegmental or incidental PE. These studies can be feasible and safe in selected groups of SSPE patients and this knowledge will bring clinical and economic advantages.

Authors' conclusions

Implications for practice

There is no evidence from randomised controlled trials to assess the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE, therefore we can not draw any conclusions regarding implications for practice.

Implications for research

This review highlights the need for continued research into the selection of appropriate treatment for acute PE. The low statistical power of the available non-RCT evidence argues strongly in favour of designing new randomised trials that can cover the lacunae in existing data.

This review therefore intends to encourage researchers to perform RCTs to answer the clinical question under study. We believe that these studies can be feasible and safe in carefully selected groups of SSPE patients (more specifically in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE). The results of the review highlight the importance of well-conducted clinical trials that relate also to economical advantages.

Acknowledgements

We would like to thank Marlene Stewart and Karen Welch of the Cochrane PVD Group for their help during the preparation of this review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy

#1MeSH descriptor: [Pulmonary Embolism] explode all trees870
#2MeSH descriptor: [Thromboembolism] explode all trees1534
#3PE or SSPE4823
#4VTE456
#5(pulmonar* near 4 embolis*)128
#6(pulmonar* near 4 clot*)53
#7(lung near 4 embolis*)27
#8(lung near 4 clot*)18
#9#1 or #2 or #3 or #4 or #5 or #6 or #7 or #87052
#10subsegmen* in Trials41
#11#9 and #10 in Trials (Word variations have been searched)8

Appendix 2. MEDLINE search strategy

Database: Ovid MEDLINE(R) <1946 to October Week 3 2013>

Search Strategy:

--------------------------------------------------------------------------------

1 exp Pulmonary Embolism/ (31202)

2 exp Thromboembolism/ (43230)

3 (PE or SSPE).ti,ab. (23034)

4 vte.ti,ab. (4537)

5 (pulmonary adj4 embolis$).ti,ab. (22484)

6 (pulmonary adj4 clot$).ti,ab. (209)

7 (lung adj4 embolis$).ti,ab. (808)

8 (lung adj4 clot$).ti,ab. (47)

9 or/1-8 (97191)

10 subsegmen$.ti,ab. (1463)

11 9 and 10 (295)

Appendix 3. EMBASE search strategy

Database: Embase <1980 to 2013 Week 42>

Search Strategy:

--------------------------------------------------------------------------------

1 (PE or SSPE).ti,ab. (32686)

2 vte.ti,ab. (7912)

3 (pulmonary adj4 embolis$).ti,ab. (30641)

4 (pulmonary adj4 clot$).ti,ab. (264)

5 (lung adj4 embolis$).ti,ab. (1119)

6 (lung adj4 clot$).ti,ab. (59)

7 exp lung embolism/ (57582)

8 thromboembolism/ (50756)

9 venous thromboembolism/ (17015)

10 or/1-9 (144330)

11 subsegment$.ti,ab. (1860)

12 10 and 11 (424)

Appendix 4. LILACS search strategy

Database: LILACS

Search on: subsegmental [Words]

Total of references: 5

http://bases.bireme.br/cgi-bin/wxislind.exe/iah/online/#refine

Contributions of authors

Conceiving the review: Hugo Hyung Bok Yoo (HHBY)
Co-ordinating the review: Regina El Dib (RED)
Undertaking manual searches: HHBY
Screening search results: HHBY and RED
Organizing retrieval of papers: HHBY
Screening retrieved papers against inclusion criteria: HHBY and RED
Appraising quality of papers: HHBY and RED
Abstracting data from papers: HHBY and RED
Writing to authors of papers for additional information: HHBY
Obtaining additional data about papers: HHBY
Obtaining and screening data on unpublished studies: HHBY
Data management for the review: HHBY and RED
Entering data into Review Manager (RevMan 5): HHBY and RED
RevMan statistical data analysis: RED
Other statistical analysis not using RevMan: RED
Double entry of data: (data entered by person one: HHBY; data entered by person two: RED)
Interpretation of data: HHBY, Thais HAT Queluz (THATQ) and RED
Statistical inferences: HHBY, THATQ and RED
Writing the review: HHBY, THATQ and RED
Guarantor for the review (one author): HHBY
Person responsible for reading and checking review before submission: HHBY, THATQ and RED

Declarations of interest

None known

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Chief Scientist Office, Scottish Government Health Directorates, The Scottish Government, UK.

    The PVD Group editorial base is supported by the Chief Scientist Office.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Donato 2010Cohort study
Eyer 2005Retrospective study
Stein 1995Case series

Ancillary